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NEW DRUG DELIVERY SYSTEMS: VALIDATION OF IN VITRO MODELS.
Daddona, P.
ALZA Corporation, Palo Alto, CA.
ATLA, 24, Special Issue, 111, (1996).
Keywords: Drug delivery, Drug delivery systems, Electro-transport assisted transdermal drug delivery, EpiDerm, Percutaneous absorption, Percutaneous penetration, Pre-validation, Prevalidation, Transdermal, Transdermal drug delivery, Transdermal transport, Validation
Summary: The development of new drug delivery systems requires optimization of the device, drug formulation and assessment for the performance at the biological interface. Electro-transport systems (E-TRANSsm) 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-TRANSsm assisted peptide (<5kDa) in vitro transderrmal 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 electro-transport 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 electro-transport assisted transdermal drug delivery.
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EpiDerm Data Sheet
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Percutaneous Absorption (EpiDerm Application)
Transdermal Drug Delivery (EpiDerm Application)
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