Iontophoresis is the use of an electric current applied to the skin to drive drugs through the epithelium. Iontophoresis enhances transdermal drug delivery by three mechanisms: (a) the ion-electric field interaction provides a directional force which drives ions through the skin; (b) flow of electric current increases the permeability of the skin; and (c) electroosmosis produces bulk motion of the solvent itself that carries ions or neutral species, with the solvent 'stream'. Electroosmosis is the movement of the solvent which occurs when an electric field is imposed near a charged surface. The membrane attracts a predominance of counterions and the movement of these ions in the field causes the solvent to flow in the same direction to maintain the osmotic balance. As both human skin and hairless mouse skin are negatively charged above about pH 4, the adjacent solvent layer contains a predominance of positive ions and electroosmotic flow occurs from anode to cathode. Thus, delivery of positively charged drugs is assisted by electroosmosis, but delivery of negatively charged drugs is retarded41. There is evidence that iontophoretic delivery facilitates the deep penetration of drugs compared to direct topical application; for example a study of penetration of lidocaine42 demonstrated a penetration depth of 10-12 mm compared to 5 mm for direct application.
The effects of electric current on the epithelium have been widely studied but are still incompletely understood43. The current does not pass uniformly through the skin, but is largely carried transappendageally via the pores, although some additional pathways open through the lipid channels44 45. A number of studies using dyes or tracers have demonstrated that drugs similarly follow these pathways46 47. In common with penetration enhancers, electrical enhancement of transdermal drug delivery is limited by similar side-effects, such as tissue damage and pain43. Studies of the interaction of penetration enhancers and electrical enhancement suggests that they operate through similar channels, since skin impedance drops substantially after several penetration enhancers are used48.
A number of factors influence the iontophoretic transport of drugs:
a) The pH of the medium. As the ionization of drugs is controlled by pH, transport is optimum in the pH range in which the drug is fully ionized49 50 although uncharged species can be carried by the electroosmotic solvent flow41.
b) The nature of the other ions in the formulation, which compete for transport of the current. These can be ions in the formulation (for example buffers controlling the pH) or endogenous ions such as sodium, potassium, chloride and bicarbonate. The fraction of the total ionic current carried by the drug ion is called the transport number, and it is always less than 1 due to competition from other ions. Consequently when formulating iontophoretic systems, it is important to use a minimum amount of buffer, and choose competing ions with low mobilities (large highly hydrated ions)51.
c) The current density. The drug flux is proportional to the current density, but the allowable density is limited by safety and patient tolerance to about 0.5 mA cm-2. The working area can be increased but there are practical limits of a few square cm52.
d) Molecular weight. Larger drugs have lower transport numbers and so are delivered less effectively. This is the major difficulty with the iontophoretic delivery of peptides, which for a time held much promise53 54. However, this is partly offset by the need to deliver only extremely small doses of these agents55. As the drug size increases, the importance of ionic transport decreases and the drugs become predominantly carried by the electro-osmotic solvent flow56.
e) Concentration of drug in the delivery system. As the drug concentration at the donor site is increased, the flux across the skin increases50 52. This is probably due to the increase in transport number of the drug as its concentration increases relative to that of the competing ions in the system, and so is only significant if the drug is relatively large and has a low transport number. If the transport number is high, then the drug is already carrying the majority of the current and so increasing its concentration will have little effect.
f) Physiological variation. A major advantage of iontophoresis is that a relatively low level of variation in delivery rate is observed. This is probably due to the fact that the applied voltage is adjusted to achieve a specific current, and this will take account of much variability between the subjects due to, for example, site, age, and colour of skin.
g) Waveform of applied current. A number of authors have studied the effect of using AC voltages instead of a steady DC voltage, which can reduce efficiency due to polarization of the skin. Despite these studies there is little agreement about the optimum conditions for delivery57 58.
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