The electrostability and electrically assisted delivery of an organophosphate pretreatment (physostigmine) across human skin in vitro

Physostigmine is a tertiary carbamate that is utilised as a pretreatment ag ainst organophosphate intoxication. Oral delivery of physostigmine is not p ractical due to high first pass metabolism and short Elimination half life. Transdermal administration of physostigmine may circumvent such problems. The aim of this study was to assess the electrostability of physostigmine a nd the feasibility of electrically assisted transdermal drug delivery of ph ysostigmine through isolated human skin in vitro. Buffered solutions of phy sostigmine (free base, salicylate and sulphate) were electrostable under co nditions of iontophoresis and electroporation as measured by HPLC, although instability of the chloridised silver electrodes was observed. Physostigmi ne sulphate was chosen for further study as it appeared to prevent degradat ion of thr electrodes. Under conditions of iontophoresis (0.8 mA cm(-2), ap plied for 5- or 2.5-min durations for a maximum period of 45 min over 8 h), the total quantity of physostigmine sulphate that penetrated was 6.5+/-2.3 % and 3.9+/-1.7% (pH 5.0 and pH 5.5) of the total applied dose (2 mg). Phys ostigmine did not penetrate the skin when electroporated at a frequency of 0.1 Hz or 10 Hz (100 V, I ms pulse width, duration 1 s, repetition 5-10 s), but significant amounts were delivered at a frequency of 100 Hz, being 11. 3 +/- 2.9% and 5.8 +/- 2.5% of the applied dose (pH 5.0 and pH 5.5, respect ively). These data indicate that iontophoretic and electroporative drug del ivery of physostigmine sulphate was buffer-dependent. an effect tentatively attributed to a combination of co-ion competition, mono/di-cation ratio an d applied charge effects. Crown copyright (C) 2000 Published by Elsevier Sc ience B.V. All rights reserved.