Analysis of enhanced transdermal transport by skin electroporation (original) (raw)
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Journal of Controlled Release, 1999
High-voltage pulses have been shown to increase rates of transport across skin by several orders of magnitude on a time scale of minutes to seconds. Two main pulse protocols have been employed to promote transport: the intermittent application of short (|1 ms) high-voltage (|100 V across skin) pulses and a few applications of long (5100 ms) medium-voltage (.30 V across skin) pulses. In order to better evaluate the benefits of each protocol for transdermal drug delivery, we compared these two protocols in vitro in terms of changes in skin electrical properties and transport of sulforhodamine, a fluorescent polar molecule of 607 g / mol and a charge of 21. Whereas both protocols induced similar alterations and recovery processes of skin electrical resistance, long pulses of medium-voltage appeared to be more efficient in transporting molecules across skin. Skin resistance decreased by three (short pulses) and two (long pulses) orders of magnitude, followed by incomplete recovery in both cases. For the same total transported charge, long pulses induced faster and greater molecular transport across skin than short pulses. In addition, a greater fraction of the aqueous pathways created by the electric field was involved in molecular transport when using long pulse protocols. Transport was concentrated in localized transport regions (LTRs) for both protocols but LTRs created by long pulses were an order of magnitude larger than those formed by short pulses and the short pulses created an order of magnitude more LTRs. Overall, this study is consistent with the creation of fewer, but larger aqueous pathways by long, medium-voltage pulses in comparison to short, high-voltage pulses. (J.C. Weaver) ters . Electroporation of the stratum corneum 0168-3659 / 99 / $ -see front matter
Bioelectrochemistry and Bioenergetics, 1999
. Ž . A combined electrical HV, ''high voltage'', pulsing and chemical topical sodium thiosulfate intervention is hypothesized to create Ž . enlarged aqueous pathways that allow large quantities of macromolecules to be transported through human skin's stratum corneum SC , the dominant barrier for transdermal drug delivery and biochemical analyte extraction. This expectation is based on the known structure Ž . and composition of the SC, and previous models and experiments for local transport regions LTRs due to transdermal HV pulsing. In skin straight-through aqueous pathways that penetrate multilamellar bilayer membranes, corneocyte envelopes and corneocyte interiors within the SC. q 1999 Elsevier Science S.A. All rights reserved.
Transdermal transport pathway creation: Electroporation pulse order
Mathematical Biosciences, 2014
In this study we consider the physics underlying electroporation which is administered to skin in order to radically increase transdermal drug delivery. The method involves the application of intense electric fields to alter the structure of the impermeable outer layer, the stratum corneum. A generally held view in the field of skin electroporation is that the skin's drop in resistance (to transport) is proportional to the total power of the pulses (which may be inferred by the number of pulses administered). Contrary to this belief, experiments conducted in this study show that the application of high voltage pulses prior to the application of low voltage pulses result in lower transport than when low voltage pulses alone are applied (when less total pulse power is administered). In order to reconcile these unexpected experimental results, a computational model is used to conduct an analysis which shows that the high density distribution of very small aqueous pathways through the stratum corneum associated with high voltage pulses is detrimental to the evolution of larger pathways that are associated with low voltage pulses.
Physical modelling of transdermal drug delivery through non-invasive electroporation
HAL (Le Centre pour la Communication Scientifique Directe), 2022
We are researching a method for non-invasive, transdermal drug delivery. An alternative to needle injections for the delivery of therapeutic macromolecules through the skin. The skin's outer layer, the stratum corneum, is impermeable to big and/or lipophilic molecules. To overcome this barrier, we are based on electroporation, a biological technique where high-voltage, short-duration electric pulses temporarily permeabilize lipid bilayers. Freshly-isolated skin from hairless mice is used to test the macromolecule delivery. A generator applies a pulsed electric field on the skin while we evaluate the electroporation extent through skin impedance changes and fluorescence microscopy. Our first results show that the application of a pulsed electric field rapidly decreases skin impedance, an effect attributed to the electrical breakdown of lipid bilayers. Depending on the pulse characteristics (intensity and duration), the changes observed may be reversible or permanent.
Skin electroporation for transdermal and topical delivery
Advanced Drug Delivery Reviews, 2004
Electroporation is the transitory structural perturbation of lipid bilayer membranes due to the application of high voltage pulses. Its application to the skin has been shown to increase transdermal drug delivery by several orders of magnitude. Moreover, electroporation, used alone or in combination with other enhancement methods, expands the range of drugs (small to macromolecules, lipophilic or hydrophilic, charged or neutral molecules) which can be delivered transdermally. Molecular transport through transiently permeabilized skin by electroporation results mainly from enhanced diffusion and electrophoresis. The efficacy of transport depends on the electrical parameters and the physicochemical properties of drugs. The in vivo application of high voltage pulses is well tolerated but muscle contractions are usually induced. The electrode and patch design is an important issue to reduce the discomfort of the electrical treatment in humans. D
Journal of Controlled Release, 1989
Two simple models for ionic mass transport across membranes are discussed in the context of iontophoretic delivery of drugs through skin. The constant field model is mathematically the most tractable and offers some insights into the time dependence of iontophoretic transport. However, for thick membranes or for systems in which the total ion concentrations on opposite sides of the membrane differ appreciably, the electroneutrality approximation is more appropriate. Since both of these conditions are likely to be found in skin iontophoresis studies, the electroneutrality model should provide a better starting point for analyzing the details of iontophoresis experiments than does the constant field model. Equations for the diffusion potential, ion transference numbers and partition coefficients and the current-voltage characteristic of the membrane are given, enabling one to calculate ionic fluxes and active/passive flux ratios for a given applied current or voltage. As an example, the flux and transference number of a monovalent drug ion driven across a membrane in the presence of sodium chloride are calculated. Finally, known discrepancies between the predictions of the homogeneous membrane models and available experimental data are examined, and suggestions are made for modifying the theory to resolve these differences. 0168-3659/89/$03.50 0 1989 Elsevier Science Publishers B.V.
Water and solute active transport through human epidermis: Contribution of electromigration
International Journal of Heat and Mass Transfer, 2008
A triphasic, coarse-grained model of mass transport through the human epidermis is developed, consisting of free extracellular water, live cells (keratinocytes), and inert extracellular matrix. The model accounts for the superposition of active transport of Na + , K + and Cl À ions across the membrane of keratinocytes, and electromigration driven by an externally imposed electrostatic potential difference. Local cell volume is regulated by the transmembrane fluxes of water and ions according to a time-delay scheme which aims to keep the volume between certain thresholds. Numerical simulations reveal that either weak hyposmotic shocks or negative potential gradients smaller than one millivolt/micrometer across the epidermis can generate travelling waves in extracellular ion concentration. By monitoring the transmembrane (Na + ÀK + ÀATPase) pump flux, we have found that maintaining a higher transepidermal potential gradient requires faster active transport through the cells.
In vivo efficacy and safety of skin electroporation
Advanced Drug Delivery Reviews, 1999
This article reviews the studies on skin electroporation carried out in vivo in animals and emphasizes its potential therapeutic applications for transdermal and topical drug delivery. In agreement with in vitro studies, transport across skin due to high-voltage pulses in vivo was shown to increase by orders of magnitude on a timescale of minutes. Increased transdermal transport was measured by systemic blood uptake and / or pharmacological response, and demonstrated for calcein, a fluorescent tracer, fentanyl, a potent analgesic and flurbiprofen, an antiinflammatory drug. Combined electroporation with iontophoresis was shown to provide rapidly responsive transdermal transport of luteinizing hormone releasing hormone ex vivo as well. These data underline the potential of skin electroporation for improving the delivery profile of existing conventional transdermal patches, but also for replacing the injectable route.
Local transport regions (LTRs) in human stratum corneum due to long and short `high voltage' pulses
Bioelectrochemistry and Bioenergetics, 1998
Ž . Application of 'high voltage' HV pulses transdermal voltage U ) 50 V to preparations of human skin have been previously skin Ž . hypothesized to cause electroporation of multilamellar lipid barriers within the stratum corneum SC . Such pulses cause large increases Ž . in molecular transport and decrease in the skin's electrical resistance. Here we describe the local transport regions LTRs and the Ž . surrounding local dissipiation regions LDRs that dominate the skin's response to both 'long' and 'short' HV pulses. The number of LTRrLDRs depends on U , but their size depends on pulse duration, so that LDRs can merge to form large regions containing several skin LTRs. LTRs themselves are not spatially homogeneous, as they have a ringlike structure, which is interpreted as involving different transport behavior viz. aqueous pathways which are either predominantly perpendicular or parallel to the SC. Our observations are Ž . consistent with the hypothesis that localized aqueous pathway formation electroporation occurs first, followed by secondary processes involving the entry of water into the SC and also localized heating. q 1998 Elsevier Science S.A. All rights reserved.