Combined effect of ultrasound and chemical enhancers on the skin permeation of aminopyrine

The combined effect of 150 kHz ultrasound with 111 mW/cm²intensity and chemical enhancers on the skin permeation of aminopyrine (AMP) was investigated using excised hairless rat skin. Monoterpenes (l-menthol, l-calvone and D-limonene), laurocapram (Azone®), glycerol monocaprylate (Sefsol-318®), isopropyl myristate and ethanol were selected as enhancers. Combined application of ultrasound and enhancers increased the skin permeation rate (flux) of AMP compared with ultrasound or enhancers alone. Better effects were obtained by the combination with monoterpenes. The influence of detailed conditions of ultrasound and enhancer applications on the AMP flux was further investigated using l-menthol. The enhancement effect by this combination was increased with an increase in ultrasonic application duration and l-menthol concentration, suggesting that these conditions might be used to achieve the controlled drug delivery. A pretreatment experiment with ultrasound or l-menthol was carried out, and l-menthol content in the skin and the skin permeation of deuterium oxide (D₂O), used as a donor vehicle, were measured to understand the role of ultrasound in the combined effect. Application of ultrasound to the l-menthol-pretreated skin increased the AMP flux, while the effect of l-menthol on ultrasonic-pretreated skin was similar to that of l-menthol alone. The ultrasound increased the l-menthol content in the skin as well as the skin permeation of D₂0 from a vehicle with l-menthol. These results suggested that simultaneous application of ultrasound and enhancers is essential to obtain the pronounced effect. Ultrasound application also strongly assisted migration of l-menthol into skin, which increases the enhancing action on the skin permeation for a drug.