Effect and mode of action of aliphatic esters on the in vitro skin permeation of nicorandil

Abstract

The effect and mode of action of aliphatic esters such as isopropyl myristate (IPM), which were known as percutaneous absorption enhancers, on the in vitro permeation of a drug across the excised hairless rat skin were investigated. Nicorandil and propylene glycol (PG) or water were used as a model drug and solvent in a drug-donor compartment. It was found that IPM markedly enhanced nicorandil permeation across the full-thickness skin, especially when PG was used as a solvent. The skin permeation profiles e.g., flux and lag time, of nicorandil widely differed with the change of IPM content in PG. The large differences in flux and lag time were also affected by the alteration of kinds of aliphatic esters. That is, the flux increased inversely proportional to a lipophilic index of aliphatic esters derived from partition coefficient between n-hexane and water, and the lag time period was almost proportional to the lipophilic index. Fluxes of an IPM-PG treatment and PG treatment across the stratum corneum-stripped skin, however, were almost the same. The permeation-enhancing effect of aliphatic esters could not be explained only by the effects of the aliphatic esters on the solubility of nicorandil in vehicle and the release of the drug from vehicle. On the other hand, the skin permeation profiles of solvents (PG and water) were almost the same as the nicorandil permeation. Therefore, aliphatic esters such as IPM would mainly act on the stratum corneum, and would increase the diffusivity in the stratum corneum and/or partition coefficient between the stratum corneum and vehicle both of the drug and solvent.