Skin electroporation for transdermal and topical delivery
Introduction
Transdermal drug delivery offers several advantages over conventional routes [1], [2]. It avoids the first-pass metabolism and the gastrointestinal tract. Transdermal delivery has the potential for sustained and controlled drug release. Moreover, it is a non-invasive mode of drug delivery with no trauma or risk of infection. Patient compliance may be improved by this user-friendly method.
In spite of the advantages of the transdermal delivery, only a small percentage of drugs can be delivered transdermally due to the barrier properties of the skin: only small potent lipophilic drugs can be delivered at therapeutic rates by passive diffusion [3]. Moreover, transport of most drugs across the skin is very slow and lag-times to reach steady state fluxes are in hours. Achievement of a therapeutically effective drug level, is therefore, difficult without enhancing skin permeation. A number of approaches have been developed to enhance and control transport across the skin, and expand the range of drugs delivered. These involve chemical and physical methods, based on two strategies: increasing skin permeability and/or providing a driving force acting on the drug [4], [5].
Electroporation or electropermeabilization is the transitory structural perturbation of lipid bilayer membranes due to the application of high voltage pulses. This phenomenon occurs in different kinds of lipid bilayer membranes: artificial (liposomes), cellular (bacteria, yeast, plant, mammalian cell) or in a more complex structure (stratum corneum). Hence, electroporation has been used for different applications. Electrical exposures typically involve electric field pulses that generate transmembrane potentials of 0.5–1.0 V and last for 10 μs to 10 ms. Reversible electrical breakdown and high molecular transport are observed, resulting from structural rearrangements of the cell membrane [6]. It has been hypothesized that these rearrangements consist of temporary aqueous pathways, with the electric field inducing pore formation and providing a local driving force for molecular transport. The first use of electroporation was to introduce some DNA materials into cells in vitro. Due to its application as a method of DNA transfection, electroporation has been applied in tissues (e.g. for gene therapy) and shown to reversibly permeabilize them. One interesting application of tissue electroporation is electrochemotherapy, which consists of applying high voltage pulses to permeabilize tumor cells to an impermeable cytotoxic drug [7]. Electrochemotherapy has been shown to be more efficient than the chemotherapy alone in eliminating local tumors, e.g. in the skin [8].
About 10 years ago, the use of electroporation for transdermal delivery was suggested (Fig. 1) [9]. Although the technique is normally used on the unilamellar phospholipid bilayers of cell membranes, it has been demonstrated that electroporation of skin is feasible, even though the stratum corneum contains multilamellar, intracellular lipid bilayers with few phospholipids [9], [10], [11], [12]. Hence, electroporation has taken its place among the physical techniques of transdermal drug delivery, like ultrasound and iontophoresis.
The concept of skin electroporation and the supporting preliminary data have motivated a number of subsequent studies, mainly in vitro but also a few in vivo in animals and in humans. The combination of electroporation with other enhancement methods open new perspectives [5], [13], [14].
In this paper, studies on transdermal and topical drug delivery using electroporation are reviewed with emphasis on potential clinical applications. Efficacy of transport by skin electroporation alone or in combination with other methods and safety issues are discussed.
Section snippets
Electroporation of the skin
Because the stratum corneum is the main barrier to transdermal transport, the disruption of the stratum corneum can dramatically influence overall skin permeability and it has been suggested that electroporation of its intercellular lipid bilayers might enhance percutaneous drug delivery. The biological composition and structure of the stratum corneum, the outermost layer of the skin, make it particularly attractive for electroporation. The stratum corneum contains approximately 100 bilayer
Parameters controlling drug delivery by electroporation
Electrical parameters of the pulses, physicochemical properties of the drug and formulation of the drug reservoir can affect and allow control of transdermal drug delivery by electroporation. These parameters are summarized in Table 1.
Potential clinical applications of skin electroporation
The dramatic and reversible increase in skin permeability caused by electroporation indicates that drugs might be delivered transdermally at significantly enhanced rates. Especially for macromolecules, such as proteins and gene-based drugs, electroporation-mediated transdermal drug delivery could be a promising route of administration. Electroporation can also be used for topical delivery.
Extensive work on molecular transport by skin electroporation has been performed in vitro. Essential
Combinations of enhancing methods
In addition to electroporation, various physical and chemical methods have been used for enhancing transdermal drug transport by different mechanisms: (i) increasing skin permeability (chemical enhancers, ultrasound and electroporation) and/or (ii) providing a driving force (ultrasound, iontophoresis and electroporation) [14]. While all these enhancers have been shown to increase drug transport, their combinations have been hypothesized to be more effective compared to each of them alone and to
Safety issues associated with skin electroporation
A major aspect in the clinical acceptability of transdermal drug delivery by electroporation is its effect on the skin and underlying tissues. Different methods have been used to assess the skin tolerance to electric pulses. Visual examination, non-invasive bioengineering methods, measurement of skin electrical properties, histological and ultrastructural studies as well as clinical studies have been performed (Table 5). Overall alterations of the skin following high voltage pulses are mild and
Conclusions
Electroporation is an efficient method for enhancing transdermal drug delivery in vitro and in vivo, and expands the range of compounds delivered transdermally. It could be a promising alternative as a non-invasive delivery of macromolecules (up to at least 40 kDa) and, fast and/or pulsatile transdermal delivery. Combined with other enhancing methods, electroporation can provide modulated and adequate delivery according to the treatment. Pulse protocol and electrode design need to be optimized
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