MECHANISM OF SKIN PENETRATION-ENHANCING EFFECT BY LAUROCAPRAM

In order to clarify the mechanism of action of laurocapram (Azone) on the skin permeation of drugs, the following experiments were done. First, the effect of Azone on the skin components was compared with that of other penetration enhancers. Azone markedly fluidized liposomal lipids (as a model lipid system) compared with other enhancers. Ethanol extracted large amounts of the stratum corneum lipids, whereas Azone did not. These results suggest that the effect of Azone on the lipids in the stratum corneum is not the same as that of ethanol. In addition, ethanol increased the amount of free sulfhydryl (SH) group of keratin in the stratum corneum, whereas Azone did not directly affect the stratum corneum protein. Azone increased water content in the stratum corneum, as measured by skin conductance. This effect might be a reason for the action of Azone. For further understanding, the enhancing effects of Azone on the skin permeation of several model compounds (alcohols, sugars, and inorganic ions) were compared with the effects of pretreatment with distilled water, which was thought to increase water-holding capacity, and pretreatment with ethanol, which was thought to affect the lipids and protein in the skin barrier (i.e., stratum corneum). Pretreatment with water or ethanol enhanced skin permeation of hydrophilic compounds, whereas they decreased that of octanol, a hydrophobic compound. The tendency of Azone to increase or decrease the skin permeation rate of most compounds was similar to that of pretreatment with water or ethanol. However, the effect of Azone on the skin permeation of inorganic ions was relatively low, whereas that of pretreatment with water or ethanol was high. We then hypothesized three permeation routes in the skin: a lipid-rich route, where hydrophobic compounds can permeate; a water-rich route, where relatively hydrophilic compounds can permeate; and a pore (shunt) route, where even inorganic ions can permeate. Azone may act on the lipid-rich route because it fluidizes the stratum corneum lipids, but also on the water-rich route because it enriches the water content. In general, increase in the pore (shunt) route would be expected when lipid has been extracted by enhancers or solvents such as ethanol. Therefore, the effect of Azone on the enlargement in the pore (shunt) route may be negligible. The reason why Azone affects the skin permeation of a relatively broad spectrum of drugs may be that it affects at least two permeation routes in the skin barrier.