Effect of ethanol on skin permeation of nonionized and ionized diclofenac

Abstract

The effect of ethanol on the skin permeation of diclofenac (DF) was investigated using excised hairless rat abdominal skin in vitro. The steady-state flux of DF increased with increase in the pH of DF-suspended donor solution; this phenomenon demonstrated a close correspondence with enhancement in the solubility of DF in the donor solution. In constrast, the steady-state permeability coefficient ( P) of DF was inversely proportional to the change in pH of the donor solution, suggesting that the pattern of skin permeation of DF apparently obeyed the pH-partition theory, although the contribution of the ionized form of DF cannot be taken as being negligible. In order to determine the contribution of either the nonionized or ionized form on the skin permeation of DF, the permeability coefficients for each form (nonionized and ionized molecules) were calculated using the P values and the degree of ionization of DF in the donor solution. Addition of ethanol in the donor solution led to a marked decrease in the Pvalue of nonionized DF, whereas the P value of ionized DF was not greatly affected by ethanol. A large amount of ethanol might increase the extent of permeation of DF through the lipid pathway by affecting the dense barrier structure of the skin. The flux of the ionized form of DF was particularly enhanced due to the increase in solubility as a result of the addition of ethanol, since the partition coefficient (skin/donor solution) of the ionized form was not greatly decreased compared with that of the nonionized form.