Effects of ionization and penetration enhancers on the transdermal delivery of 5-fluorouracil through excised human stratum corneum

The purpose of this study was to determine the effects of ionization and penetration enhancers on the transdermal delivery of 5-fluorouracil (5-FU) through excised human stratum corneum. The in vitro transport of 5-FU was determined at three physiologically relevant pH values of 5.0, 7.4 and 8.0, and in the presence of suitable penetration enhancers, namely Azone((R)) (AZ), lauryl alcohol (LA), and isopropyl myristate (IPM). The results showed that passive permeation of 5-FU is dependent upon the pH of the donor solution, although did not fully conform to the pH-partition hypothesis. A further analysis of data suggested an inverse relationship (i.e., negative correlation) between steady-state flux and aqueous solubility of 5-FU at these pH values (correlation coefficient = -0.4205), although correlation was not statistically significant (p = 0.7237). In the absence of a penetration enhancer, the in vitro permeability of 5-FU was quite low (0.82 +/- 0.06 x 10(4) cm/h). This delivery rate was enhanced by approximately by 3, 4 and 24-fold, respectively, when IPM, LA, and AZ were incorporated into the donor solution. All these enhancements were statistically significant (p < 0.05) compared to control, and occurred regardless of the polarity (solubility parameters) of these enhancers. Out of three examined enhancers, AZ appears to be a suitable enhancer for enhancing transport of 5-FU, which merits in vivo investigation in a suitable animal model. Possible mechanisms of enhancement by these penetration enhancers are also discussed. (c) 2005 Elsevier B.V. All rights reserved.