ABSTRACT
It has been known for a long time that sweat glands play a role in transport during iontophoresis. An early study showed that pore patterns developed on the skin following iontophoretic transfer of basic and acidic dyes and metallic ions (Abramson and Gorin, 1940). For example, thorough rubbing and washing of the skin following the iontophoretic delivery of methylene blue revealed a remarkable pattern of channels traversed by the dye. The blue dots observed on the skin were found to be the sites of the pores of the skin which are the orifices of the coils of sweat glands, suggesting that the dye enters the skin via these pores. The pore patterns persisted for several weeks in many cases. Similarly, fluorescein dye has been shown to penetrate excised human skin upon applying a current density of 0.16 mA/cm2 and appeared on the dermal surface as spots at pore sites (Burnette and Ongpipattanakul, 1988). A comprehensive review of the pathways of iontophoretic current flow through mammalian skin has been published (Cullander, 1992). The macropores and other conductive pathways in skin have been studied by scanning electrochemical microscopy during iontophoresis, and by theoretical considerations. The current maximum was found near the exit of a hair follicle and the micropore radius determined was 9.2-14.1 µm. The macropore was considered to be a long cylindrical tube which was closed at one end. As the current was applied, the charging of the capacitance of one or two layers of macropore walls was the driving force for electroactivation. The free energy of the system was reduced, which pulled water into the tube to open it gradually. The opening time was 30 min for a 4-mm long macropore (Kuzmin et al., 1996; Melikov and Ershler, 1996). During iontophoresis, the greatest concentration of ionized species is expected to move into some regions of the skin where there is damage, or along the sweat glands and hair follicles, as the diffusional resistance of the skin to permeation is lowest in these regions. Thus, a pore pathway is generally assumed for iontophoretic delivery. Iontophoresis of pilocarpine is used to induce sweating in the diagnosis of cystic fibrosis (Section 4.2.6), suggesting that some drug probably travels down the eccrine duct. In a study with desglycinamide arginine vasopressin (DGAVP) as a model peptide, its transport across human stratum corneum and snake skin was compared to assess the role of appendages such as hair follicles and sweat and sebaceous glands, which are present in human skin but absent in shed snake skin. While the initial resistance of both human and snake skin were in the same order of magnitude (about 25 kW-cm2), the steady-state iontophoretic DGAVP flux across human stratum corneum was about 140 times larger than through shed snake skin. Also, the average lag time across human stratum corneum was 0.7 h, while that across shed snake skin was 2.5 h. Azone pretreatment of the skin led to a large increase in transport across snake skin but not human skin. This suggests that the intercellular lipid pathway contributes very little to the iontophoretic flux across human skin but is very important for snake skin (Hinsberg et al., 1995). Using special electrodes, it has been suggested that the dominant pathway for flow of electric current through skin is through the sweat ducts. This study used a very thin (0.15 mm diameter) wire which was fine enough to distinguish between most pores and a very thin (0.1 µm) metal film electrode. The film electrode was placed on the skin and was permanently marked by the pathways of current flow so that dots developed after some seconds at places with sweat duct units (Grimnes, 1984). The ‘aqueous pathway’ for iontophoretic delivery has been reinforced by a study which observed the transport kinetics of an anion (salicylate), a cation (phenylethylamine), a polar neutral compound of low molecular weight (mannitol) and a polar neutral compound of high molecular weight (inulin). Using both intact and stripped
dermatomed excised human skin, iontophoresis enhanced the delivery of all compounds relative to passive transport and the skin was shown to be both ion and size selective (Singh et al., 1995).
