TRANSDERMAL DELIVERY OF TACRINE .1. IDENTIFICATION OF A SUITABLE DELIVERY VEHICLE

Peroral administration of tacrine, a drug approved for the treatment o f Alzheimer's disease, is associated with low bioavailability (due to first-pass effect), short elimination half-life and reversible hepatot oxicity. Transdermal administration may reduce the degree of these pro blems. In this investigation the influence of three commonly used solv ents (water, propylene glycol and ethanol), and their mixtures, on the in vitro permeation of tacrine through rat and human skin were evalua ted. Maximum flux and permeability were observed from ethanol-propylen e glycol and water-ethanol binary mixtures, respectively. The permeabi lity of tacrine through rat skin was about 2.5 times higher than that through human skin. Excellent correlation between the rat and human sk in data was observed. The flux from the ethanol-propylene glycol binar y mixture was 98 mu g/cm(2) per h through rat skin and was selected fo r in vivo transdermal administration. The observed in vivo tacrine pla sma concentrations were in good agreement with the concentration-time profile simulated using in vitro flux and tacrine clearance in rat. Pr eliminary short-term (24 h) irritation studies did not indicate any ir ritation. The results from this investigation indicate that transderma l delivery of tacrine may be feasible and that the ethanol-propylene g lycol(1:1) mixture appears to be a promising solvent system.