| Summary: | The skin is an amazingly resilient and relatively impermeable barrier that provides protective,
perceptive and communication functions to the body (Ramachandran & Fleisher, 2000). The
stratum corneum is widely accepted as the barrier of the skin - limiting the transport of
molecules into and across the skin. One of the bottlenecks in the successful development of
transdermal drug delivery devices is the fact that the skin (more accurately, the stratum corneum
- SC) tends to control the rate of drug transport. This makes it very difficult to influence or
regulate the transdermal drug absorption kinetics from outside, Le. by means of the vehicle. A
possible, and even elegant, solution may be the use of so-called "penetration enhancers",
thereby suppressing the dominant role of the stratum corneum penetration barrier (Bodde et al.,
1990).
For this study 5-fluorouracil (5-FU), a polar hydrophilic drug, was chosen as model drug to study
its penetration through the stratum corneum. Terpenes used as possible penetration enhancers
for 5-FU were menthol, isomenthol, menthone, l3-myrcene, limonene and 1,8-cineole. In
previous studies, terpenes with low skin irritancy and low systemic toxicity, were found to be
effective penetration enhancers for a number of hydrophilic and lipophillic drugs (Cornwell &
Barry, 1994; Cornwell et a/., 1996; Godwin & Michniak, 1999).
The objective of this study was to determine the different flux rates of 5-FU in the absence of
any pre-treatment of the stratum corneum and also through ethanol and selected terpene
pre-treated SC. The effect of each terpene on the penetration of 5-FU was determined. The
penetration of the selected terpenes themselves through the human stratum corneum was also
determined in vitro permeation studies were performed using vertical Franz diffusion cells with human skin
(stratum corneum). A saturated aqueous solution of 5-fluorouracil in the absence and presence
of pre-treatment of the SC was used as the donor phase. Pre-treatment was performed by
applying a 5 % terpene solution or absolute ethanol to the SC half an hour before the saturated
III
solution was applied in the donor compartment. A 50/50 ethanol/water solution was used as the
receptor phase. All the experiments were conducted over a 24 h period. The 37°C
temperature was held constant by means of a water bath. For the analysis of 5-FU flux rates,
samples from the receptor compartment were obtained and were analysed by means of high-pressure
liquid chromatography (HPLC). In order to determine the cumulative percentage of
terpenes penetrated through human stratum corneum, the samples were analysed by gas
chromatography (GC).
In this study, only menthol and isomenthol (both oxygen-containing terpenes) showed a
statistically significant increase on the flux of 5-FU, with flux values of 1.13 +- 0.38 and
1.45 +- 0.68 ug/cm2/h, respectively, compared to untreated skin with a flux value of 0.54 +- 0.23
ug/cm2/h for 5-FU. It was also proved that ethanol itself had an enhancing effect on 5-FU and
showed synergistic effects on the enhancement activities of all the terpenes. It was found that
all the terpenes (applied as a 5 % solution in ethanol) penetrated through the stratum corneum
in the absence of 5-fluorouracil. 5-Fluorouracil had either an increasing or decreasing effect on
the penetration of the terpenes.
From these findings, it could be concluded that oxygen-containing terpenes had the best
penetration enhancing effect on 5-FU and that menthol and isomenthol were the most effective
penetration enhancers, although the extend of penetration enhancement is not large enough for
clinical application. All the terpenes have the ability to penetrate through human stratum
corneum, and 5-FU either had an increasing or decreasing effect on their penetration. === Thesis (M.Sc.)--North-West University, Potchefstroom Campus, 2004.
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