Mutual Hairless Rat Skin Permeation-Enhancing Effect of Ethanol/Water system and Oleic Acid

Abstract

The mutual hairless rat skin permeation-enhancing effect of ethanol (EtOH)/water systems and oleic acid (OA) was investigated with model lipophilic (estradiol, progesterone, levonorgestrel) and hydrophilic drugs (zalcitabine, didanosine, zidovudine). The aqueous solubility and hairless rat skin permeation rate of each drug, saturated in various compositions of EtOH/water system (with and without OA), was determined at 37°C. The hairless rat skin permeation rates of ethanol from EtOH/water systems (with and without OA) were also measured to investigate the skin permeation-enhancing mechanism of EtOH/water systems and OA. Both saturated solubility and steady-state permeation rates of each drug in EtOH/water systems increased exponentially as the volume fraction of ethanol increased, reached the maximum value, and then decreased with further increases in the ethanol volume fraction. Moreover, the hairless rat skin permeation rate of each drug had a good linear relationship with that of ethanol up to 70% (v/v) of ethanol in the EtOH/water system. The addition of OA in the EtOH/water system (70:30 and 60:40 for lipophilic and hydrophilic drugs, respectively) further enhanced the skin permeation rate of both ethanol and drugs. However, >2.0% (v/v) OA was required to achieve the plateau level in the skin permeation rate of lipophilic drugs, whereas only 0.3% (v/v) OA was required for hydrophilic drugs. The skin permeation rate of ethanol also increased with the addition of OA in the EtOH/water systems (70:30 and 60:40), reached the plateau level with <1.0% (v/v) OA, and did not significantly change with higher OA concentration. These results suggest that the addition of OA in the EtOH/water system is a useful method to enhance the hairless rat skin permeation rate of both hydrophilic and lipophilic drugs, with more enhancement for hydrophilic drugs.