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

• Published in: Journal of controlled release Vol. 68; no. 2; pp. 157 - 166
• Main Authors: Rowland, Caroline A, Chilcott, Robert P
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 10-08-2000; Elsevier
• Subjects: Biological and medical sciences; Cholinesterase Inhibitors - administration & dosage; Electroporation; General pharmacology; Human skin absorption; Humans; In vitro; In Vitro Techniques; Iontophoresis; Medical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Physostigmine; Physostigmine - administration & dosage; Physostigmine - pharmacokinetics; Skin Absorption; Iontophoresis; Human skin absorption; Electroporation; Physostigmine; In vitro; Antiglaucomatous agent; Human; Delivery system; Stability; Transdermal system; Pharmaceutical technology; Permeation; Epidermis; Parasympathomimetic; Absorption; Dosage form; Skin; Carbamate
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/S0168-3659(00)00242-X

Physostigmine is a tertiary carbamate that is utilised as a pretreatment against organophosphate intoxication. Oral delivery of physostigmine is not practical 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 and the feasibility of electrically assisted transdermal drug delivery of physostigmine through isolated human skin in vitro. Buffered solutions of physostigmine (free base, salicylate and sulphate) were electrostable under conditions of iontophoresis and electroporation as measured by HPLC, although instability of the chloridised silver electrodes was observed. Physostigmine sulphate was chosen for further study as it appeared to prevent degradation of the electrodes. Under conditions of iontophoresis (0.8 mA cm
−2, applied 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). Physostigmine did not penetrate the skin when electroporated at a frequency of 0.1 Hz or 10 Hz (100 V, 1 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, respectively). These data indicate that iontophoretic and electroporative drug delivery of physostigmine sulphate was buffer-dependent, an effect tentatively attributed to a combination of co-ion competition, mono/di-cation ratio and applied charge effects.