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Effect of the simultaneous use of l-menthol and ethanol on the skin permeation of six potent cardiovascular agents: nicardipine hydrochloride, atenolol, captopril, nifedipine, vinpocetine and nilvadipine (in hydrophilic order) was investigated to evaluate the feasibility of their use in a transdermal therapeutic system (TTS). In vitro diffusion experiments were carried out using excised hairless rat and human skin, and the application area of TTS required for the minimum therapeutic effect was estimated by a simple pharmacokinetic calculation. Marked enhancing effect by the l-menthol-ethanol system was found independent of drug lipophilicity, but the mode of action was dependent on the lipophilicity of the drug. The action of the system on lipophilic drugs (nifedipine, vinpocetine and nilvadipine) was mainly due to their increase in solubility in the system, while that on hydrophilic (or water soluble) drugs (nicardipine hydrochloride, atenolol and captopril) was the result of increase in their skin permeability coefficient. This enhancing effect was adequate to assure their minimum effective concentration (MEC) in human. The area of application of a drug to maintain the MEC was calculated to be 0.15 cm2 for hydrophilic or water soluble drugs and 3.7-13 cm2 for lipophilic drugs.

Feasibility of Use of Several Cardiovascular Agents in Transdermal Therapeutic Systems with l-Menthol-Ethanol System on Hairless Rat and Human Skin.