ALTEX :: Alternatives to Animal Experiments

2001, VOLUME 1

The Use of Reconstructed Skin Equivalents in Permeation Studies with Pharmaceutical Dosage Forms

Nadia Zghoul, Heike Wagner, Claus-Michael Lehr and Ulrich Schäfer

Dept. of Biopharmaceutics and Pharmaceutical Technology, Saarland University, D-Saarbrücken

INTRODUCTION

Over the past years the skin has become an increasingly important route of drug administration for local, but also for systemic treatment. Transdermal drug delivery is an attractive alternative to the oral route for drugs with high first-pass effects and adverse side-effects. Up to now, mostly animal skin has been used to determine the most suitable formulation during the development of the drug formulation. Nowadays, reconstructed skin equivalents are commercially available. Therefore we tested the suitability of Epiderm® (MatTek Corp., USA-Ashland, MA 01721) for use in permeation experiments as an alternative test system.

METHODS

The lipophilic model drug flufenamic acid was applied in two pharmaceutical formulations i) dissolved in wool alcohols ointment (0.1125% ,0.225%, 0.45% and 0.9%) and ii) dissolved in Soerensen phosphate buffer solution pH 7.4 (0.1125%) to different batches of Epiderm® mounted on Franz diffusion cells. The receptor fluid was sampled at predetermined time intervals and analyzed for drug content by RP-HPLC. To check the barrier function of the reconstructed skin equivalents, diffusion experiments with cell free inserts were carried out as control experiments. For the 0.9% ointment, additional experiments were performed with separated human Stratum corneum.

RESULTS

In comparison to cell free inserts a barrier function of EpidermŽ could clearly be detected. The flux of flufenamic acid was 45 times higher when using the 0.1125% solution as donor compared with the 0.1125% ointment. For the 0.1125% ointment, no differences in permeation could be detected for two batches of Epiderm®. Further, there was a linear correlation between the concentration of the drug in the ointment and the flux values obtained. Additionally, for the 0.9% ointment a 10 fold higher flux could be detected for the Epiderm® model in comparison to separated human Stratum corneum.

CONCLUSIONS

Our results suggest that reconstructed human skin equivalents have barrier properties with respect to drug transport and therefore may become useful tools in the optimisation of drug preparations for dermal drug delivery. Hopefully, the use of these models will considerably reduce experiments with animal skin in this field of research. Future experiments will show whether these experiments can also be used as a surrogate for clinical in vivo studies in humans.

The ZEBET (BgVV, D-Berlin) is being thanked for financial support.