TRANSDERMAL PATCH DELIVERY OF ACETYLCHOLINESTERASE INHIBITORS

Transdermal delivery of cholinesterase inhibitors (ChEI) for treatment of dementia would have advantages associated with continuous and enha nced compliance, but feasibility depends on achieving desired levels o f central nervous system enzyme inhibition. We developed a patch techn ique for assessing delivery of ChEI in rats and examined two organopho sphate compounds, metrifonate and DDVP and a carbamate, heptylphysosti gmine, for production of peripheral and central nervous system ChE inh ibition at target levels. With DDVP, a log-dose/percent brain A ChE in hibition was obtained over a range of 10-65% inhibition within a 10-fo ld concentration of inhibitor in the patch. Brain cholinesterase was i nhibited up to seven days after a 24-h patch application. Long-term in hibition was greater than that attained after intramuscular injection, but without the rapid initial inhibition peak seen with the latter ro ute. In contrast to DDVP, sustained high levels of brain enzyme inhibi tion could not be produced by transdermal delivery of metrifonate or h eptylphysostigmine. Apparently DDVP has features, i.e., liquid state i n pure form and high inhibitor potency, which make it particularly sui table for patch administration.