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The use of iontophoresis can be traced back to ancient Greece. Iontophoresis was first reported in the literature in 1748, but initial experiments using iontophoresis did not occur until the early 1900’s (Roberts, 1999). Iontophoresis refers to the administration of an electrical current to the skin to aid the absorption of molecules. Increased absorption is achieved through altering the structure of the lipid bilayers, hair follicles and sweat glands to facilitate movement of charged and polar species (Curdy, et al.,

2001). It has been used for years to aid in transdermal administration of low molecular- weight drugs.

The structure of the human skin prevents the transdermal delivery of drugs of differing molecular weight and charge into the human body. The outermost layer of the skin is the stratum corneum, which is comprised of dead keratinocytes (skin cells filled with keratin fibres), sweat glands and hair follicles surrounded by impermeable lipid bilayers. The composition of the stratum corneum limits water loss from the body, is an impermeable barrier to molecules entering the body and provides resistance to the passage of an electrical current (Mitragotri et al., 1995; Curdy et al., 2001). The

properties of the stratum corneum affect the movement of water and ions. Water displays diffusion characteristics independent of the thickness of the stratum corneum, while ion mobility (created and directed by the application of an alternating electric current) is affected by its depth and the structure (Kalia et al., 1998). Increasing the

magnitude of the electrical current may sufficiently disrupt the stratum corneum so that passage of ions through the skin is uniform.

When a drug is dissolved in water, it separates into anions and cations (ions that have negative or positive charge, respectively). When an electrical current is passed through the solution the ions move towards the electrode with the opposing charge (Roberts, 1999). Iontophoresis alters the nature of the stratum corneum so that the molecules are ‘pushed’ or repelled through the skin when the electrical current is applied, often using an electrode that contains a ‘patch’ containing the drug to be administered.

The advantages of iontophoresis compared to traditional drug administration include the elimination of first-pass metabolism of the drug, either in the gastrointestinal system or by the liver, before it has reached its site of action. Other advantages include reduced frequency of drug dosing and increased compliance, and it also introduces the possibility of sustained drug administration over a lengthy time period without the use of needles or intravenous drips that can invoke anxiety (Curdy, et al., 2001). Other

benefits are a more controlled site of action of the drug, more rapid termination of administration, maintenance of the histological and barrier properties of the skin once the iontophoresis is complete, and reduction of the use of needles and the associated risk of infection (Mitragotri, et al., 1995; Roberts, 1999).

Measurements of trans-epidermal water loss by infrared spectroscopy, impedance spectroscopy and laser Doppler flowimetry have shown that there are no lasting changes to variables of skin hydration, lipid structure or ionic concentration, and that the mild oedema and/or erythema occasionally experienced is only transient (Curdy, et al.,

2001). Drugs that can be administered in this fashion include topical non-steroidal anti- inflammatories, corticosteroids, local anaesthetics and antibiotics (Roberts, 1999).

The disadvantages that accompany iontophoresis are considered to be solvable with further research, which will aim to reduce skin irritation, tingling and burning, and improve transferral rates of non-polar drugs (Roberts, 1999).

An example of the use of iontophoresis in clinical practice is the transdermal administration of anaesthesia such as lidocaine by dermatologists. The advantages of

using the iontophoretic technique with local anaesthetics include minimal absorption into the blood, an 80 to 100% reduction in pain in performing several dermatological techniques, a lack of bolus distortion of the area (seen with injectable lidocaine) and a reduction in anxiety in patients of all ages with needle phobias (Greenbaum, 2001).

Low-frequency ultrasound (sonophoresis) has been used to increase the rate of transdermal delivery. Ultrasound waves have frequencies beyond the range of human ears, at 800 to 1000 kHz, and cause the air pockets within the keratinocytes to increase in size and oscillations (Roberts, 1999). This phenomenon disrupts the lipid bilayer, increasing the permeability of the skin and making transportation of high molecular weight proteins such as insulin, γ-interferon and erythropoietin possible (Mitragotri, et al., 1995). Ultrasound also increases blood circulation at the area of administration,

which increases diffusion of the drug through the layers of the skin and into the capillaries for clearance (Roberts, 1999).

The area of skin, the concentration of the drug and the frequency, pulse length and intensity of the ultrasound application all influence the efficacy of drug administration (Mitragotri, et al., 1995). Therefore, specific techniques need to be determined for each

individual drug. As ultrasound can penetrate deeper into tissue (up to 5cm below the skin), it can be used to treat non-superficial inflammation, however care needs to be taken to avoid periosteal burns and tissue necrosis (Roberts, 1999). The beneficial use of ultrasound to alter the permeability characteristics of the skin is now widely applied in both iontophoresis and reverse iontophoresis (Kost, et al., 2000).