The effects of terpene enhancers on the percutaneous permeation of drugs with different lipophilicities

Four model drugs were selected based on their lipophilicity denoted as log P (nicardipine hydrochloride log P -0.99 +/- 0.1, hydrocortisone log P 1.43 +/- 0.47, carbamazepine log P 2.67 +/- 0.38, and tamoxifen log P 7.87 +/- 0.75). The enhancing activities of four terpene enhancers (fenchone log P 2 .13 +/- 0.30, thymol log P 3.28 +/- 0.20, D-limonene log P 4.58 +/- 0.23, a nd nerolidol log P 5.36 +/- 0.38) were tested in vitro across full thicknes s hairless mouse skin with each of the evaluated drugs formulated in hydrox ypropyl cellulose gel formulations. The relationships between lipophilicity (log P) of the terpene enhancers and model drugs and efficacy (represented by the enhancement ratio of flux ERflux) of the drugs when coadministered with the enhancers were examined using lineal regression. Terpene enhancers had significant effect on the percutaneous permeation of the model drugs. Nerolidol (highest lipophilicity) provided the highest increase in the flux of the evaluated model drugs. The flux of nicardipine hydrochloride increa sed by approximately 135-fold, hydrocortisone by 33-fold, carbamazepine 8-f old, and tamoxifen 2-fold. The lowest increase in the flux was observed wit h fenchone. Linear relationships were generated between the ERflux of nicar dipine hydrochloride. hydrocortisone, carbamazepine, and tamoxifen and the log P of the terpene enhancers [r = 0.951, (P = 0.049), r = 0.977, (P = 0.0 23), r = 0.942, (P = 0.057), and r = 0.874, (P = 0.126), respectively]. Fur thermore, the four terpene enhancers produced linear relationships, indicat ing that they were more effective at enhancing the penetration of hydrophil ic drugs rather than lipophilic drugs r = -0.824 (P = 0.176) for fenchone, r = -0.891 (P = 0.109) for thymol, r = -0.846 (P = 0.154) for limonene, and r = -0.769 (P = 0.232) for nerolidol. (C) 2001 Published by Elsevier Scien ce B.V.