click to enlarge Figure 1: Iontophoretic patch being worn by patient. (Source: NuPathe, Inc.)

Transdermal delivery is a well-accepted route of drug administration that provides an alternative to traditional methods, including oral and injection. In general, the advantages of transdermal delivery include avoidance of first-pass metabolism and other variables associated with the gastrointestinal tract, improved patient acceptance and compliance, ease of dose termination in the case of adverse events, and convenient and painless administration.¹ Passive methods (e.g. ointments, creams, passive patches) are the most familiar form of transdermal delivery; however, these methods are often limited by the barrier properties of the skin.1 To avoid this issue, several techniques to enhance the permeability of the skin have been investigated including the use of chemical enhancers and active transport such as iontophoresis.²

click to enlarge Figure 2. Schematic of iontophoretic drug delivery. (Source: NuPathe, Inc.)

Iontophoresis is a noninvasive technology based on the principle that like charges repel one another.³ A typical iontophoretic device is worn on the skin (Figure 1) and consists of two electrodes, one (the anode [+]) in a reservoir containing the positively-charged drug in solution and the other (the cathode [–]) in a negatively-charged salt solution. A power controller applies a voltage to the electrodes, which creates a mild electrical current that repulses the positively charged drug from the anode into the bloodstream where it is rapidly absorbed and distributed systemically (Figure 2). Active transdermal delivery via iontophoresis has several potential benefits over traditional passive transdermal delivery systems. Because the rate and amount of drug delivery is controlled by the electrical current,² predetermined pharmacokinetic parameters can be achieved assuring rapid and consistent therapeutic levels. Additionally, iontophoresis allows for the transdermal delivery of drugs that may not be appropriate for passive delivery such as those with a high molecular weight.¹

An example of the benefits of iontophoretic technology can be seen with Zelrix, an iontophoretic transdermal patch currently in development by NuPathe, Inc. for the delivery of sumatriptan, the most commonly prescribed treatment for acute migraine in the U.S. One problem with the current migraine therapy is pervasive treatment-limiting gastrointestinal issues, such as nausea, which often interfere with a patient’s ability to take oral medication.⁴ These concerns can be eliminated by using the iontophoretic transdermal patch system to bypass the gastrointestinal tract. Iontophoresis assures rapid delivery of sumatriptan, while still providing long-term drug plasma concentrations that are sufficiently therapeutic, but may avoid the plasma concentration-related adverse events that are common with injection and tablet formulations of sumatriptan.⁵ In a recent Phase 3 trial, Zelrix provided statistically significant improvements over placebo for rapid (within 1 hour), consistent, and sustained relief (over 24 hours) of acute migraine headache. Because of NuPathe’s iontophoretic transdermal delivery, it provided a possible means of overcoming the treatment limitations associated with other delivery methods of sumatriptan that often lead to delayed or nontreatment of migraine attacks.⁶

About the Author
Mark W. Pierce, MD, PhD, is the Chief Scientific Officer for NuPathe, a privately held specialty pharmaceutical company developing innovative products for the treatment of neurological and psychiatric diseases, in Conshohocken, Pa.

References
1. Brown MB, Martin GP, Jones SA, Akomeah FK. Dermal and transdermal drug delivery systems: current and future prospects. Drug Deliv. 2006;13(3):175-187.
2. Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol. 2008;26(11):1261-1268.
3. Priya B, Rashmi T, Bozena M. Transdermal iontophoresis. Expert Opin Drug Deliv. 2006;3(1):127-138.
4. Silberstein SD. Migraine symptoms: results of a survey of self-reported migraineurs. Headache. 1995;35(7):387-396.
5. Pierce M, Marbury T, O’Neill C, et al. Zelrix: a novel transdermal formulation of sumatriptan. Headache. 2009;49(6):817-825.
6. Goldstein J, Pugach N, Smith T, et al. Acute anti-migraine efficacy and tolerability of Zelrix, a novel iontophoretic transdermal patch of sumatriptan. 14th Congress of the International Headache Society. Philadelphia, Pa.; 2009.