Daddona, P. New Drug Delivery Systems: Validation of In Vitro Models. ATLA 1996. 24: 111.

The development of new drug delivery systems requires optimization of the device, drug formulation and assessment for the performance at the biological interface. Electrotransport systems (E-TRANS^SM) for the transdermal delivery of small hydrophilic drugs and peptides are being developed by ALZA as well as in vitro models to predict in vivo drug flux. Using cultured human skin, as well as heat stripped human or hairless guinea-pig skin, electrically assisted small (<1000MW) cationic or anionic in vitro drug flux was shown to be independent of skin site or type. Compounds larger than 1000MW required natural skin appendages (hair follicles and/or sweat glands) as drug flux pathways since these larger compounds did not flux through cultured human skin. E-TRANS^SM assisted peptide (<5kDa) in vitro transdermal transport was dependent on a number of formulation and structural parameters. Neural net models have been developed for both small conventional drugs and small peptides that predict in vitro flux with a median error of some 20-40%. Both of these neural net models for in vitro flux predicted: a) a dependence of flux on donor pH which agrees with the known perm-selectivity of skin; b) that skin flux was proportional to free solution drug mobility; c) that the larger the molecular weight the lower the flux; and d) that flux is logarithmically dependent on drug concentration. Advancement of electrotransport drug delivery technology has been accelerated by the use of appropriate in vitro cell based models that mimic human skin in vivo. While these models have limitations, they do provide a means for rapid screening of drug candidates, formulations and electrical conditions for electrotransport assisted transdermal drug delivery.