Reversible effects of permeation enhancers on human skin

Abstract

This study outlines a systematic approach for investigating a desired characteristic of chemicals used to facilitate the permeation of drugs across the skin that is, the reversibility of the permeation enhancement effect. This implies that the vital skin barrier function is restored and not permanently impaired after the application of these enhancers. The reversible effects of two terpene enhancers, ( R)-(−)-carvone and eucarvone, on excised human skin were evaluated by in vitro permeation and extraction studies on normal (untreated) and enhancer-pretreated epidermis, respectively. For the permeation studies on normal epidermis, the donor solutions were the model drug, haloperidol (HP, 3 mg/ml), in propylene glycol (PG) with or without 5% (w/v) enhancer and for the extraction studies using epidermis pretreated with enhancer, a solution of HP (3 mg/ml) in PG was used. The solubilities of the enhancers in 0.03% lactic acid (receptor solution) and of HP in PG (donor solution) were determined to demonstrate that the sink and saturated conditions were maintained in the respective compartments of the flow-through cells throughout the in vitro experiments. ( R)-(−)-Carvone cleared out of the skin faster than eucarvone. This could be due to the 4-fold higher skin permeability of ( R)-(−)-carvone compared to that of eucarvone. The amount of HP deposited in the epidermis was much lower in the eucarvone-pretreated epidermis than that pretreated with ( R)-(−)-carvone. The permeation profile of HP across the enhancer-pretreated skin was 4-fold greater than in the vehicle alone (control), but similar to that across untreated skin with enhancer present in the donor solution, indicating that permeation across the enhancer-pretreated skin did not change. The enhancing effects of both terpenes on the skin were found to be reversible and the permeability of the skin was left intact after the passage of the drug in the vehicle with these enhancers.