ARN14140 is a galantamine-memantine conjugate that acts upon both cholinergic and glutamatergic pathways for better management of Alzheimer's disease. Poor oral bioavailability and pharmacokinetics meant that earlier preclinical in vivo studies employed intracerebroventricular injection to administer ARN14140 directly to the brain. The aim of the present study was to evaluate the feasibility of using constant current transdermal iontophoresis for the noninvasive systemic delivery of ARN14140 and to quantify the amounts present in the blood and the brain. Preliminary experiments in vitro were performed using porcine skin and validated with human skin. Cumulative ARN14140 permeation across the skin increased linearly with current density and concentration. Delivery efficiency (i.e., fraction of the amount applied that is delivered) reached an exceptional 76.9%. Statistically equivalent delivery was observed after iontophoresis across human and porcine skin. In vivo studies in male Wistar rats showed that iontophoretic transport of ARN14140 could be controlled using the current density (426.7 ± 42 and 1118.3 ± 73 nmol/cm2 at 0.15 and 0.5 mA/cm2 for 6 h) and demonstrated that transdermal iontophoresis was able to deliver ARN14140 noninvasively to the brain. This is the first report quantifying drug levels in the blood and the brain following transdermal iontophoresis.
Keywords: ARN14140; brain delivery; galantamine−memantine conjugate; iontophoresis; transdermal.