Pilot study of topical delivery of methotrexate by electroporation

Background: The topical administration of methotrexate (MTX) for the treatment of psoriasis and neoplastic diseases is restricted by the poor diffusion of MTX across the stratum corneum. Objectives: We applied electroporation to increase the transdermal transport of MTX. Methods: Electrodes were placed either side-by-side on the surface of excised full thickness pig skin, or on a piece of skin clamped between compartments of a vertical diffusion chamber. Sixty rectangular electric pulses at 120 V, 1 ms and 1 Hz were applied across the skin. MTX was left on the skin surface for an additional 10 min to take advantage of diffusion through electropores. Cumulative drug transport was measured by radioactive tracing, using [ ³H]-methotrexate, from punch biopsy samples taken from under the cathode. The integrity of the radioisotope was verified by high-performance liquid chromatography. Results: Using side-by-side electrodes, treatment with the pulses alone resulted in a 2.5-fold increase; adding anionic lipid enhancers to the pulses resulted in a 4.4-fold enhancement compared with passive diffusion. Concurrent iontophoresis for the 11-min time period made a nonsignificant contribution. To reduce tissue resistance we used 40 °C hyperthermia in a vertical diffusion chamber; transport was increased 11-fold to 53 μg cm^-2 (flux = 290 μg cm^-2 h^-1). MTX penetration profiles indicated that more than half of the MTX was confined to the epidermis and papillary dermis. The tissue concentration in this superficial reactive unit was 1.7 mmol L^-1. Conclusions: Electroporation of MTX with an anion lipid enhancer under a mild hyperthermic environment provided a significant transdermal delivery within a short application time. The method may be an effective means of drug delivery for treating psoriasis or other MTX-sensitive disorders and avoids the potential systemic toxicity.