Controlled Transdermal Drug Delivery by Iontophoresis and Ion-exchange Fiber

Kankkunen, T., 2002. Controlled transdermal drug delivery by iontophoresis and ionexchange fiber. Dissertationes Biocentri Viikki Universitatis Helsingiensis 17/2002, pp. 57 ISBN 952-10-0313-8 (print) ISBN 952-10-0314-6 (pdf) ISSN 1239-9469 A common aim in the development of new transdermal devices is the controlled delivery of drugs, so that the rate of drug input into the blood stream is predictable and reproducible. The transdermal therapeutic systems act as drug reservoirs and control the penetration rate of the drug into the skin and subsequent permeation into the blood circulation. Obviously, the release of the drug from the device can be controlled more exactly than the permeability of drugs in the skin. The outermost layer of the skin, stratum corneum, is usually the rate-limiting step in the permeation of drugs through the skin. Passive permeability of drugs across this layer is especially difficult to compounds which are hydrophilic, very lipophilic, of high molecular weight or charged. Iontophoresis is a process, by which the transport of ions into and through the skin is increased by the application of an external electric field across the skin. One alternative to achieve controlled transdermal drug delivery is binding the drug into an ion-exchange fiber. Ion-exchange fibers consist of a polymeric framework, into which the ionic groups (e.g. –COO, NH3) are bound. Controlled drug delivery by the ion-exchanger may be achieved by manipulating the properties of drug, ion-exchanger and/or external solution in the device. In the present study, the effects of drug properties (six model drugs), fiber properties (six anionand cation-exchange fibers), and medium properties (ionic strength, pH, volume, salt choice) on the drug binding into and drug release from the fibers were determined. Drug release from the fibers, with and without iontophoresis, and fluxes of the drugs across human stratum corneum were investigated in vitro. Drug stability in the ion-exchange fiber formulations was studied as well. Iontophoretic delivery of tacrine from a solution formulation and an ion-exchange fiber formulation was compared in vivo in healthy human volunteers. Finally, permeation of tacrine in vitro was compared to the in vivo results. The binding and release of drugs into/from the ion-exchange fibers depends on a specific combination of the drug, fiber, and the concentration and nature of the external electrolyte. The distribution equilibrium of the drug is affected by drug-fiber interactions, which are specific to the ion-exchange group and the fiber nature. In vitro permeation of tacrine across the skin was directly related to the iontophoretic current density and to the drug concentration used. As the drug has to be released from the ion-exchanger before permeating across the skin, a clear reduction in the drug fluxes from the ion-exchange fibers were observed as compared to the corresponding fluxes of the drugs from solution. Ion-exchange fiber also improved the stability of easily oxidised levodopa during storage in water. Iontophoretic current and ion-exchange fiber may be used to control tacrine permeation across the skin and to achieve clinically relevant plasma concentrations with minor irritation on the skin. The in vitro and in vivo correlation of tacrine permeation was dependent on the experimental conditions and device structure. In conclusion, cationand anion-exchange fibers were shown to be promising materials to form a drug reservoir and to control the drug release from an iontophoretic transdermal system. By optimal selection of the external conditions (ionic-strength, pH, and salt), the drug properties (charge, lipophilicity, molecular weight), and the fiber quality (ion-exchange groups, capacity), one could achieve controlled release kinetics of a drug from the ion-exchange fiber and, subsequently, controlled transdermal drug permeation.