Iontophoretic drug delivery
Introduction
Transdermal drug delivery offers significant potential for the non-invasive administration of therapeutic agents. In addition to avoiding the hepatic first-pass effect and chemical degradation in the potentially hostile environment of the gastrointestinal tract, the skin provides a large, accessible surface area. The principal disadvantage is that the skin's homeostatic and protective functions have ensured that its outermost layer, the stratum corneum (SC), has evolved into a formidable barrier membrane [1]. In order to maintain homeostasis and regulate transepidermal water loss, the SC possesses a multilamellar lipidic structure punctuated by proteinaceous corneocytes that impose a significant tortuosity on the diffusion path across the membrane [2]. The architecture and composition of the SC have severely limited the number of molecules that can be delivered passively across the skin. The currently available transdermal drugs (clonidine, estradiol, fentanyl, nicotine, nitroglycerin, scopolamine, testosterone, oxybutynin and the combination products norelgestromin/ethinyl estradiol and estradiol/norethindrone acetate) are all potent low molecular weight molecules which are active at blood concentrations on the order of a few ng ml−1 or less [3].
In order to increase the range of drugs available for transdermal delivery a number of chemical and physical enhancement techniques have been developed in an attempt to compromise skin barrier function in a reversible manner without concomitant skin irritation. The controlled delivery afforded by constant current iontophoresis, which involves the application of a small electrical potential to maintain, as its name suggests, a constant current, sets it apart from other technologies. The amount of compound delivered is directly proportional to the quantity of charge passed; it depends on the applied current, the duration of current application and the area of the skin surface in contact with the active electrode compartment. Other advantages include an improved onset time and also a more rapid offset time—that is, once the current is switched off, there is no further transport. Moreover, the current profile can be customized to achieve the desired drug input kinetics depending on whether continuous or pulsatile delivery is required.
Section snippets
Iontophoretic electrochemistry
An iontophoretic device comprises a power source and two electrode compartments Fig. 1. The drug formulation (D+A−) containing the ionized molecule (D+) is placed in the electrode compartment bearing the same charge; for example, a positively charged drug such as lidocaine would be placed in the anodal compartment. The indifferent electrode compartment is placed at a distal site on the skin. Although there are many different types of electrode, the most well-suited to iontophoresis is the
Iontophoretic transport mechanisms
There have been a number of detailed analyses of the mechanistic aspects of iontophoresis and iontophoretic phenomena [7], [8], [9], [10], [11]. The observed iontophoretic flux of a charged species, X, at steady-state can be considered as the sum of two separate transport mechanisms—electromigration JXEM and electroosmosis JXEO, assuming that the passive permeability is negligible.
Electromigration refers to the ordered movement of the ions in the presence of the applied electric
Pain management
Iontophoresis has obvious applications in pain management—appropriate modulation of the current profile means that iontophoresis can provide relief in response to acute pain episodes, e.g. post-operative pain and also alleviate chronic pain, e.g. in cancer patients. The current controlled input kinetics allows the non-invasive administration of bolus doses as with conventional, but more invasive patient-controlled anesthesia devices; in addition, maintenance doses can be achieved using a
Diabetes and insulin delivery
Monomeric human insulin consists of an A- (21 amino acids) and a B-chain (30 amino acids), and has a molecular weight of ∼6000 Da and is negatively charged. Electromigration of the peptide would obviously be facilitated by cathodal iontophoresis; however, the increasing importance of electroosmosis in the iontophoretic transport of high molecular weight species would perhaps also suggest a role for anodal delivery. Although there are some reports of successful anodal iontophoresis, Langkjaer et
Case study: development of the Vyteris lidocaine iontophoretic delivery system
The previous sections have demonstrated that there is a considerable body of work on the iontophoretic delivery of a diverse range of molecules. However, to date, there are no pre-filled commercial iontophoretic products, equivalent to the widely-used passive transdermal patches. The situation should change during the course of 2004 as Vyteris, Inc. (Fair Lawn, NJ) brings its lidocaine product to market. In this section we describe the rationale behind the selection of lidocaine and the
Concluding remarks
The overview of iontophoretic drug delivery presented here clearly illustrates that a considerable research effort has gone into exploring the feasibility of iontophoresis as a treatment platform for a number of therapeutic areas and many different drug molecules with diverse physicochemical properties. But as yet, there are no transdermal iontophoretic patches on the market and it is reasonable to ask the proponents of this technology why this is the case. The answer comes in two parts. First,
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