Iontophoretic drug transport

Over the last 20 years, the mechanisms of iontophoretic drug transport have been elucidated. In the process, several models have been developed which (a) describe drug transport across the skin under the influence of an electric field, (b) permit drug candidates to be selected rationally, and (c) optimize iontophoretic conditions and formulations. In the first part of this chapter, the main contributions of these models to the field are summarized, and... 

To date, Monteiro-Riviere and co-workers [60] have published the only studies using electron microscopy to examine the mechanism of iontophoretic transport. They applied mercuric chloride (7.4%) in vivo in pigs for 1 hr (current density 200 p,A/cm ) and subsequently exposed the biopsies to ammonium sulfide vapor to precipitate and localize the mercury, similar to earlier passive transport studies [28]. The micrographs revealed that mercuric chloride traverses intracellularly through the first few layers and intercellularly through the remainder of the stratum comeum. The authors concluded that the intercellular pathway is the predominant route for passive and iontophoretic drug delivery systems. However, it is difficult to eliminate follicular transport as a possible pathway, since only small areas can be examined at a time ( 1 mm ) and the low density of hair follicles (11/cm ) makes it difficult to study them with the electron microscope. 

In addition to solute structure, a number of factors affecting iontophoretic transport need to be gained for the development of useful optimal iontophoretic drug delivery systems. These include the behavior of solute ions in solution during iontophoresis, mechanisms of solute ion transport through the skin, the effect of different power sources, the choice of electrodes, the composition of vehicles, and the influence of other ions present in the process of drug delivery. 

Henry White was born in Chapel Hill. North Carolina in 1956. He received a B.S. in Chemistry from the University of North Carolina in 1978 and a Ph.D. in Chemistry from the University of Texas at Austin in 1982. He held a postdoctoral appointment at the Massachusetts Institute of Technology from 1983 to 1984 and was on the faculty of the Department of Chemical Engineering and Materials Science at the University of Minnesota from 1984 to 1993. He is currently a Professor of Chemistry at the University of Utah. His research interests include magnetic-field-induced transport, oxide films and corrosion, iontophoretic transdermal drug delivery, and electrochemical phenomena at electrodes of nanometer dimensions. 

The development of the first transdermal patches in the 1980s generated considerable interest in this route of drug administration. Soon afterwards, iontophoresis was rediscovered and its potential to contribute to the new field of transdermal drug delivery was examined. This work provided the basic principles for modern iontophoretic devices [13,18-21]. Furthermore, and importantly, they demonstrated the existence of a (primarily) electroosmotic, convective solvent flux during transdermal iontophoresis [10,11,22-24], and it was shown that the permselective properties of the skin (a) could be exploited to enhance the transport of neutral, polar species and (b) have a clear impact on ionic transport. Subsequent research has better characterized skin permselectivity and the factors which determine the magnitude of electroosmosis [25-27],... 

The previous model [57] has been further developed for the iontophoretic delivery of a monovalent drug. The first case considered (the single-ion situation) is exemplified by the anodal iontophoresis of a monovalent, cationic drug (m+), which is the only available charge carrier at the skin surface. The cathodal (subdermal) electrolyte is assumed to be normal saline. Under these circumstances, the transport number of the drug is given by... 

A significant modification of the model is the addition of an additional term to include the convective contribution to the total iontophoretic transport. This is achieved by adding a linear term (v xQ [58], where v is the average velocity of the solvent and C is the concentration of the drug. Because the skin has a net negative charge, this term is positive for cations and negative for anions. From the constant field approximation, the EF is predicted to be... 

FIGURE 14.4 Linear dependence of ropinirole hydrochloride iontophoretic flux (mean SD, n > 5) upon the intensity of current applied. The transport number of the drug is estimated from the slope of the line. (Data from Luzardo-Alvarez, A., Delgado-Charro, M.B., and Blanco-Mendez, J., Pharm. Res., 18 (12), 1714, 2001.)... 

Masada, T., et al. 1989. Examination of iontophoretic transport of ionic drugs across skin Baseline studies with the four-electrode system. Int J Pharm 49 57. 

Roberts, M.S., et al. 1997. Solute structure as a determinant of iontophoretic transport. In Mechanisms of transdermal drug delivery, eds. R.H.G. Potts and R.H. Guy. New York Marcel Dekker, chap. 9. 

Ruddy, S.B., and B.W. Hadzija. 1992. Iontophoretic permeability of polyethylene glycols through hairless rat skin Application of hydrodynamic theory for hindered transport through liquid-filled pores. Drug Des Discov 8 207. 

Brouneus, F., et al. 2001. Diffusive transport properties of some local anesthetics applicable for iontophoretic formulation of the drugs. Int J Pharm 218 57. 

Figure 9 (A) lontophoretic flux of various cations across excised pig skin versus molecular weight. The donor concentration was 1.0 M of drug as chloride salt. (Data from Ref. 108.) Key. ( ) monovalent ions, (O) divalent ions. (B) Normalized cathodal iontophoretic flux of anionic solutes across hairless mice versus molecular weight. (Data from Ref. 109.) (C) Cathodal iontophoretic permeability coefficient of alkanoic acid across nude rat skin versus molecular weight. (From Ref. 64.) (D) Comparison of transport number and molecular weight in human epidermis.

Fig. 5 Effect of molecular size on the relative importance of electrorepulsion (ER) and electroosmosis (EO) to the overall iontophoretic transport of cations and anions. Small, highly mobile cations are principally moved across the skin by ER. But, as molecular size increases, the fraction of charge carried by a cationic drug decreases, and the principal mechanism of transport becomes EO. For anions, on the other hand, EO is a negative contribution to the total flux and, once the molecular size reaches a critical value (me, completely cancels out the ER contribution to electrotransport (resulting in no net flux).

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