A. Jadoul

Effects of iontophoresis and electroporation on the stratum corneum. Review of the biophysical studies.

This review focuses on the effects induced by iontophoresis and electroporation on the stratum corneum of the skin. Hence, the aims were: (1) to contribute to the understanding of the mechanisms of drug transport by these methods; (2) to evaluate the safety issues associated with current application. Complementary biophysical methods were used to provide a complete picture of the stratum corneum. Even though the mechanism of drug transport is believed to be different, i.e., electrophoresis for iontophoresis and creation of new aqueous pathways for electroporation, the effects on the stratum corneum detected minutes after current application are very similar. For both methods, the major findings were: (1) a disorganisation of the lipid bilayers of the stratum corneum; (2) an increase in skin hydration; (3) a larger decrease in skin resistance induced by electroporation as compared to iontophoresis. These changes were partly reversible and depended on the amount of electrical charges transferred. The mechanisms of stratum corneum perturbations are discussed. These perturbations could explain partly the increase in drug transport. If iontophoresis is considered as a safe method of drug delivery, the data augurs for the safety of electroporation.

Mechanisms of a phosphorothioate oligonucleotide delivery by skin electroporation.

Skin electroporation has great potential for topical delivery of oligonucleotides. Controled therapeutic levels of an intact phosphorothioate oligonucleotide (PS) can be reached in the viable tissue of the skin. The aim of this work was to investigate the transport mechanisms of a PS in hairless rat skin by electroporation, and hence to allow optimization of oligonucleotides (ONs) topical delivery. The pulsing condition used was five exponentially-decaying pulses of 100 V and 500 ms pulse time. The main mechanism of PS transport in the skin viable tissues during pulsing was electrophoresis. The electroosmosis contribution was negligible. Electrophoresis created within minutes a reservoir of PS in the skin viable tissues, which persisted within a therapeutic range of hours. A strong PS/stratum corneum interaction occurred.

In vivo noninvasive evaluation of hairless rat skin after high-voltage pulse exposure

Short high-voltage pulses have recently been shown to dramatically increase and expedite transdermal drug transport via a mechanism hypothesized to involve electroporation. This study addresses tolerance issues of the method in vivo in hairless rat. Chromametry, transepidermal water loss (TEWL), laser Doppler flowmetry (LDF) and corneometry were jointly used for noninvasive sensing of skin biophysical parameters. Slight increases in skin redness, TEWL and LDF values followed the application of electric pulses. The changes in skin capacitance were nonsignificant. The magnitude of the alterations depended on the electrical features of the pulses. When compared to iontophoresis, high-voltage pulses did not induce stronger alterations of skin functions. This report provides the first in vivo demonstration of the safety of the high-voltage pulses proposed for transdermal delivery.

Modifications induced on stratum corneum structure after in vitro iontophoresis: ATR-FTIR and X-ray scattering studies

The aim of the present work was to investigate stratum corneum (s.c.) structure after prolonged in vitro iontophoresis by two physical techniques: ATR-FTIR and X-ray scattering. ATR-FTIR studies showed that iontophoresis induced an important and reversible increase in the hydration of the outer layers of s.c. but no increase in lipid fluidity could be detected. SAXS (small angle X-ray scattering) of s.c. showed that iontophoresis induced a disorganisation of the lipid layers stacking reversible within a few days. No modification of the intralamellar crystalline packing of lipids nor of keratin were observed by WAXS (wide angle X-ray scattering). From our ATR-FTIR and X-ray scattering observations, it can be assumed that the enhancement in transdermal permeation which characterizes iontophoresis is related to the lipid layer stacking disorganisation.

Transdermal Permeation of Alniditan by Iontophoresis: In Vitro Optimization and Human Pharmacokinetic Data

AbstractPurpose. The aim of this paper was to assess the feasibility of electrically enhanced transdermal delivery of alniditan, a novel 5 HT1D agonist for the treatment of migraine. Methods. An in vitro study was first performed to optimize the different parameters affecting iontophoresis efficiency. The mechanism of alniditan permeation by iontophoresis was investigated. Finally, a phase I clinical trial was performed to assess systemic delivery of alniditan by iontophoresis. Results. i) In vitro: The optimal conditions were found with a buffer like ethanolamine at a pH of 9.5, with Ag/AgCl electrodes and a direct current application. Alniditan permeation was enhanced when increasing the current density, the duration of current application and the drug concentration. Iontophoresis slightly increased drug quantities in stratum corneum compared to passive diffusion but it strongly increased alniditan quantities in viable skin, ii) The objective to deliver in vivo 0.5 mg of alniditan within less than 1 h was reached but an erythema was detected at the anode. Conclusions. This study demonstrates the feasibility of iontophoretic delivery system for antimigraine compounds.

Electrically enhanced transdermal delivery of domperidone

The aim of this study was to investigate whether transdermal delivery of domperidone can be enhanced to therapeutic levels by iontophoresis and/or electroporation. In vitro studies were performed with a solution of domperidone pH 3.5 in 9.5% (v/v) ethanol. Iontophoresis (2 h at 0.4 mA/cm(2)) increased the transdermal permeation by a factor 15 as compared to passive diffusion. Application of 5 long (tau = 700 ms) high-voltage (250 V) pulses increased the domperidone permeation by a factor of up to 70. Application of one pulse (250 V-700 ms) prior to iontophoresis provided similar penetration enhancement to 5 pulses (250 V-700 ms). No significant enhancement was provided by application of one short pulse (1000 V-4 ms) prior to iontophoresis, probably due to a different mechanism of permeabilization and/or recovery kinetics to the initial permeability state. The domperidone permeation flux by skin electroporation (1.5 mu g/cm(2) h) is in the range of the fluxes measured with chemical penetration enhancers but the lag time was reduced. However, due to the low hydrosolubility of domperidone, electrically enhanced flux remains too low for therapeutic application

Quantification and Localization of Fentanyl and Trh Delivered By Iontophoresis in the Skin

Autoradiography and the technique of stripping/slicing were used in order to investigate the pathways and to quantify drug penetration into skin after iontophoresis of two model compounds: fentanyl, a lipophilic molecule and TRH, a hydrophilic molecule. Iontophoresis was performed for 1, 4 and 6 h at a mean current density of 0.33 mA/cm(2) and was compared to passive diffusion. The quantification studies showed that iontophoresis increases the drug concentration in the part of the skin limiting molecule permeation: viable skin for fentanyl and stratum corneum for TRH. Even though, besides accumulation, autoradiography allows one to localize the route of passage, observations tend to confirm that transepidermal penetration can take place and that an important route of penetration is the transappendageal pathway.

Transdermal alniditan delivery by skin electroporation

The aim of this study was to evaluate the transdermal permeation of alniditan by electroporation and to compare with iontophoretic delivery. The influence of the electrical parameters of electroporation was investigated in vitro using a factorial design study. The transdermal flux of alniditan was enhanced by two orders of magnitude by application of high voltage electrical pulses. The electrical parameters of electroporation-i.e. the voltage, the duration and the number of pulses-allowed a control of drug permeation. Both transport during and after pulsing were shown to be important for alniditan transdermal delivery by electroporation. Electroporation was found more efficient in promoting alniditan permeation than an iontophoresis transferring the same amount of charges.

Laser-doppler Evaluation of Skin Reaction in Volunteers After Histamine Iontophoresis

Iontophoresis was used for a non-invasive administration of the agonist histamine. Flares and weals areas were measured after 1%, 0.01% and 0.0001% histamine solution iontophoresis (30 s, 1.4 mA/cm(2)). There was no clear-cut correlation between area and concentration. 0.0001% histamine solution iontophoresis induced only a vanishing redness. When a typical weal developed (1% and 0.01% histamine), the blood perfusion was lower at histamine administration site between 10 and 40 min as compared to the values recorded during the same time interval in the flare area. When the flare disappeared, the level of laser Doppler flowmetry (LDF) at the weal site still remained higher than basal values. The higher the histamine concentration, the higher the LDF values at flare sites. Controls indicated that only a low and transient increase in LDF values was observed after NaCl iontophoresis (30 s, 1.4 mA/cm(2)) and that histamine application (1%, 30 s) did not modify basal blood perfusion. Therefore, we suggest to use 1% histamine iontophoresis (30 s, 1.4 mA/cm(2)) to induce skin reaction to the agonist and to characterize the increase in skin blood perfusion using a laser Doppler velocimeter.

Comparison of Iontophoresis and Electroporation: Mechanisms and Tolerance

Drug delivery across skin offers a non invasive, user-friendly alternative to conventional route of administration. However, the skin’s outer layer, the stratum corneum is an extremely effective barrier which prevents transports of most drugs at therapeutic rate. Chemical and physical approaches have been investigated to increase and extend transdermal transport.