A NEW ENHANCER-COENHANCER SYSTEM TO INCREASE SKIN PERMEATION OF MORPHINE HYDROCHLORIDE INVITRO

The effect of several chemical enhancers on the skin permeation of morphine hydrochloride (MPH) was investigated using the in vitro diffusion cell technique and excised hairless rat skin. Enhancers used were: laurocapram (Azone(R)), isopropyl myristate, Sefsol(R)-318, 1-menthol and ethanol. l-Menthol emulsified in water (5%) showed a rapid and strong enhancement of penetration, as did Azone and Sefsol-318 aqueous emulsions, although not to be the same extent. The effects of ethanol and isopropylmyristate were moderate. In experiments, the use of a combination of 1-menthol with ethanol showed greater penetration enhancement. The cumulative amount of MPH permeated through skin over 10 h with this combination system (2467 mug/cm2) was far higher than the sum of those with 40% ethanol alone (73 mug/cm2) and 5% l-menthol alone (533 mug/cm2). The intact skin permeation rate of MPH when the combination system was used was much faster than that of stripped skin when it was not used. The enhancing effect of ethanol on stripped skin was greater than those of water or 1-menthol emulsion. The experiment results on solvent (water and ethanol) and l-menthol permeation suggested that the high penetration enhancement was due to both the action of l-menthol against the stratum corneum barrier and the effect of ethanol against the viable skin layer beneath it. Ethanol and water as a second solvent may co-transport MPH across the skin when used with l-menthol. We therefore devised an enhancer-coenhancer system for this combination.