In order to overcome the high barrier function in the stratum corneum for delivering these macromolecular drugs through the skin, several penetration-enhancing physical means have already been evaluated in addition to chemical enhancers to promote their skin permeation, such as iontophoresis (Chien and Banga 1989), electroporation (Prausnitz et al. 1993), phonophoresis (sonophoresis) (Mitragotri et al. 1995), and microneedles (McAllister et al. 2003), as aforementioned. These physical means usually show higher penetration-enhancing ability than chemical penetration enhancers, like low molecular alcohols and aliphatic esters (Bhatia and Singh 1999). Iontophoresis has been shown to increase the skin permeation of many molecules (Wu et al. 2007). Leduc had shown nearly 100 years ago that this technique could be used to deliver drugs across mammalian skin in vivo, but this did not gain scientific prominence until 20 years ago (Chien and Banga 1989). Iontophoretic flux is obtained not only due to electrorepulsion but also electroosmotic solvent flow, which is generated from anode to cathode by anodal iontophoresis. Thus, iontophoresis can be used to enhance transdermal delivery of ionic drugs as well as nonionic compounds. In the present chapter, iontophoresis-induced electroosmotic flow, electroosmosis, was combined with microneedle drug delivery as a “push force.” The question now is whether the electrical properties of the skin, which are the origin of electroosmotic flow (Pikal 2001), are affected by microneedle pretreatment. Physical abrasion of the stratum corneum and the application of a depilatory cream on the skin surface can facilitate the iontophoretic delivery of insulin (Kari 1986; Kanikkannan et al. 1999). However, removal of the stratum corneum by tape stripping decreased or even abolished the skin electroosmotic flow (Abla et al. 2005). Hirsch et al. also reported that iontophoresis applied on stripped skin did not result in a higher drug delivery than iontophoresis alone (Hirsch et al. 2005). The question whether iontophoresis in conjunction with physical impairment of the skin barrier can further enhance the transdermal delivery of high molecular weight compounds must therefore be related to the electrical properties of the skin, i.e., electroosmotic flow, after the pretreatment. On the other hand, another physical means, electroporation technology, widely used for introducing deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) into cells, biological tissues, and bacteria (Zimmermann et al. 1973; Neumann and Rosenheck 1972), is also an attractive skin penetration-enhancing method (Prausnitz et al. 1993, 1995). Electroporation involves the creation of tiny and transient aqueous pathways (pores) in the transcellular lipid region in the stratum corneum barrier by applying a high-voltage pulse for a very short period (millisecond order) (Chen et al. 1999). Electroporation application with a high-voltage electric pulse for a short period results in the enhanced permeation of high molecular weight compounds (molecular weight of several hundreds to kilodaltons) through the skin (Wong et al. 2006; Tokumoto et al. 2006). For both microneedles and electroporation, in spite of their different mechanisms, enhancement of the skin permeability of drugs is a result of the creation of new permeation pathways in the stratum corneum; however, the pathways do not persist, so that the skin barrier function is recovered immediately after the pathways close up. Transepidermal water loss (TEWL), an index of skin permeability for drugs (Zhou et al. 2010), increases after the application of microneedles or electroporation and then decreases with time, which explains the recovery of the skin barrier function. In this chapter, the new combination of microneedles and electroporation, the so-called in-skin electroporation (IN-SKIN EP), was developed to combine the advantages of microneedles and electroporation.

To date, iontophoresis and electroporation have shown great success in increasing skin permeation of many low molecular weight molecules. The transport of large molecules, however, remains a challenge (Abla et al. 2006). Since the microelectronics industry could fabricate uniform arrays of micron-scale needles, microneedle systems gained high interest as transdermal drug delivery systems. However, only few studies have reported on the combination of iontophoresis or electroporation with microneedles. Therefore, in the present chapter, the enhancement of skin permeation of high molecular weight compounds by a combination of microneedles and iontophoresis or electroporation is discussed (Wu et al. 2007).