Effect of menthol or O-ethylmenthol on the skin permeation of diltiazem.

Diltiazem(DZ) is widely used for the treatment of chronic anginapectoris, hypertension and arrythmia. In order to increase therapeutic efficiency, skin permeation of DZ was investigated employing 2-chamber diffusion cells in which Wistar rat abdominal skin was mounted. DZ suspended solution was used as donor solution. The receiver cell was filled with water. Ethanol(EtOH), isopropanol(IpOH), propyleneglycol(PG) were used as solvent in donor solution. The flux of DZ was increased by the addition of 30% EtOH or 30% IpOH to the donor solution. Further increase of solvent concentration from 30% to 50% led to a slight increase of the flux. To improve the skin permeation of DZ, menthol and O-ethylmenthol (MET) were selected as absorption enhancers. The flux of DZ markedly increased by the addition of these enhancers. Irrespective of kind of enhancers, the concentration of ethanol accumulated in the skin was increased by co-administration of enhancers. The concentration of menthol in the skin increased significantly with an increase of menthol in the donor phase, although the concentration of MET in the skin was very low. Therefore, the solvent dragging in the skin is an important factor to exhibit enhancement action. A little amount of MET can induce the accumulation of ethanol in the skin, however, much greater amount of menthol was required to obtain a similar efficiency. The microviscosity of the stratum corneum lipid was determined by using an electron spin resonance(ESR) spectrometer. In use of menthol, the microviscosity of stratum corneum lipid decreased gradually as an increase of menthol amount in the donor phase. On the other hand, a little amount of MET was sufficient to exhibit such decreasing efficiency. These findings suggest that menthol and MET act directly to the skin to fluidize dense barrier structure of stratum corneum under the co-existence of ethanol.