Résorption transcutanée de médicaments par iontophorèse

La voie transdermique d’administration de médicaments est une alternative intéressante à la voie injectable. Elle s’adresse principalement à des médicaments actifs à faible dose, de demi-vie biologique brève et dont la biodisponibilité orale est faible ou inconstante. Les variations d’absorption, les effets de premier passage hépatique et le profil en « dents de scie » de la concentration plasmatique sont supprimés. Pour les médicaments qui ont un indice thérapeutique étroit, l’avantage est majeur. Pourtant, les perspectives offertes par l’administration transdermique sont très limitées : en raison de la nature du tissu cutané, seuls les composés hydrophobes sont capables de le traverser par diffusion. Par contre, le transport de substances hydrophiles ou ioniques conduit rarement à des taux plasmatiques suffisants. Il est pourtant important de trouver une méthode efficace pour promouvoir le passage transdermique de ces substances : la majorité des principes actifs utilisés en thérapeutique sont des acides ou des bases faibles ionisés au pH physiologique (Lee et Kim, 1987). Les systèmes classiques d’administration transdermique ne permettent que certaines cinétiques de libération : libération d’ordre zéro ou d’ordre un pendant une période prolongée sans aucune possibilité de modulation. Les cinétiques sont entièrement déterminées par la composition du dispositif. De plus, le temps de latence nécessaire avant d’obtenir une pénétration constante est souvent élevée (Yoshida et Roberts, 1992). L’iontophorèse est une technique qui induit le transport de molécules ionisées dans un tissu par l’application d’un champ électrique à travers une solution d’électrolytes contenant la substance à délivrer. Les ions sont donc transférés à travers le membrane cutanée par une force électromotrice (Banga et Chien, 1988a). L’avantage principal de l’iontophorèse sur l’administration transdermique classique est d’étendre son champ d’application à de nombreuses molécules hydrophiles, ionisées ou non. De plus, la taille du principe actif devient un facteur beaucoup moins limitant (Siddiqui et al, 1987). D’autre part, la maîtrice du champ électrique appliqué (intensité du courant et durée d’application) et de la composition de la phase médicamenteuse permet de moduler le profil de libération. Enfin, l’utilisation de promoteurs d’absorption, souvent irritants, pourrait désormais devenir inutile parce que l’efficacité du système iontophorétique est nettement plus élevée que celle d’une administration transdermique par simple diffusionThèse de doctorat en sciences pharmaceutiques -- UCL, 199

In vivo iontophoresis of fentanyl and sufentanil in rats: pharmacokinetics and acute antinociceptive effects.

Iontophoresis is a process which enhances skin permeation of ionized species by using an electrical field as driving force. The aim of the present study was to investigate whether transdermal iontophoresis of fentanyl or sufentanil could induce therapeutic plasma levels and antinociceptive effect. Fentanyl and sufentanil were introduced in an acidic buffer (acetate buffer 0.01 M at pH 5) at 40 micrograms/mL. A platinum electrode was clamped in an hydrophilic foam soaked with the drug solution and linked to the anode. A cathodic foam reservoir was filled with saline solution. The device was applied on the abdominal skin of hairless rats and direct current (0.17 mA/cm2) was applied for 1 h. Opioid plasma concentrations were monitored. In the experimental conditions used, iontophoresis strongly increased transdermal permeation of the drugs as compared to diffusion. A 1.5 h Tmax was observed. The maximal plasma levels after 1.5 h were 29.3 +/- 14 ng/mL for fentanyl and 29.1 +/- 14 ng/mL for sufentanil. The plasma level of the narcotics decreased slowly after iontophoresis was terminated. Iontophoretic transdermal permeation of fentanyl and sufentanil in rats induced analgesic effects as measured by the tail-flick test. These effects lasted for about 4 h. Thus, transdermal iontophoresis with a miniaturized device is effective for the controlled and pulsatile or sustained delivery of synthetic opiates for pain management in humans. As compared to classical patches, it could reduce the lag time before reaching steady state and allow variable drug release rate

Transdermal Ionotophoretic Delivery of Sufentanil

Iontophoresis promotes the penetration of charged and uncharged molecules through the skin using an electrical current application. In vitro assays were performed to investigate the influence of several electrical and physicochemical parameters on the transdermal permeation of sufentanil. Continuous current application strongly enhanced sufentanil flux through hairless rat skin as compared to passive diffusion. Direct current was more potent than pulse current to promote sufentanil transdermal permeation. An enhancement in current density applied induced an increase in the flux of the drug. When current application was terminated before the end of the experiment, the flux decreased but remained higher than diffusion flux. The pH of the medium affected diffusion and iontophoretic fluxes: in contrast with diffusion, acidic pH was more efficient for iontophoresis. An enhancement of drug concentration enhanced the iontophoretic flux. Application of direct or pulse current induced similar changes in skin permeability to water

Factors affecting iontophoretic mobility of metoprolol.

The effect of different factors on the iontophoretic transport of metoprolol was analyzed. In vitro experiments were first performed in a diffusion cell with a cellophane membrane. Comparison of different pH, buffers, and ionic strengths in the donor compartment showed that higher iontophoretic transport was obtained with phthalate buffer (0.01 M) at pH 3. When the current density increased, the flux of metoprolol also increased. A decrease in drug concentration or an increase in viscosity slowed down the iontophoretic transport of metoprolol. The fluxes of metoprolol through hairless rat skin were strongly enhanced compared with passive diffusion. Direct current seemed to be more efficient than pulse current. When the on:off ratio of the pulse current was reduced, the flux also decreased

Transdermal Iontophoresis of Fentanyl - Delivery and Mechanistic Analysis

Studies of electrical and physicochemical factors acting on the permeation kinetics of in vitro iontophoresis of fentanyl across hairless rat skin were performed. Iontophoresis increased the transdermal permeation flux of fentanyl as compared to the diffusion. An increase in the current density applied induced an enhancement of the flux through the skin. Continuous current was more potent than pulsed current (positive square wave 2.5 kHz on/off 1:1) at promoting fentanyl transdermal permeation. At the same current density (0.33 mA/cm(2)), a decrease in the duration of iontophoresis application from 6 to 1 h reduced the cumulated quantity of drug detected in the receptor compartment but the flux remained higher than diffusion for at least 6 h. Iontophoresis and diffusion were compared when the drug was introduced into a donor solution pH 7 or 3.5. Diffusion was higher at pH 7 than at pH 3.5. Iontophoresis was more efficient at acidic pH. The enhancement of the drug concentration in the donor compartment increased the flux through the skin. The mechanism of transport of fentanyl through the skin by iontophoresis was investigated. Electro-osmosis was not involved in the differences of kinetics observed after direct and pulsed current application since both induced the same water flux across the membrane. A period of iontophoresis shorter than 1 h did not modify the skin permeability. In contrast, the drug accumulated in the skin reservoir and was slowly released when the current was cut

Human calcitonin delivery in rats by iontophoresis.

In-vitro ionotophoresis (0.33 mA cm-2) of calcitonin (50 micrograms mL-1, pH 4) was performed with the hairless rat skin model. Direct current was as potent as pulse current (2.5 kHz on/off 1/1) iontophoresis in promoting transdermal permeation of calcitonin. Increase in duration of current application from 20 min to 1 h did not increase calcitonin flux. Results suggest that calcitonin can be blocked in the skin pores through which it travels or can accumulate in the skin and be progressively released from the depot. In-vivo experiments showed that transdermal iontophoretic administration of calcitonin induced a hypocalcaemic effect in rats

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

Noninvasive investigation of human skin after in vivo iontophoresis.

The main objective of our study was to investigate skin function and structure in human volunteers after electrical current application in order to demonstrate the safety of iontophoresis in vivo. The direct current was applied for 30 min at a density of 0.1 and 0.2 mA/cm2. Iontophoresis increased cutaneous blood flow as measured by laser Doppler flowmetry (LDF). This increase was reversible within 1 h and was more pronounced at higher current density. Measurements of transepidermal water loss (TEWL) and LDF were the same at the cathode and the anode sites. Except for 5 min at 0.2 mA/cm2 density, TEWL values were not enhanced as compared to control values (no iontophoresis). Attenuated total reflectance-Fourier transform infrared spectroscopy of the stratum corneum structure showed a transient increase (30 min) in hydration after electrode application for 30 min. No alteration in lipid structure could be shown. These results augur the safety of drug delivery by iontophoresis

Essai de purification d'une activit nucl oside triphosphatase membranaire chez Saccharomyces cerevisiae

BSE B226669C / UCL - Université Catholique de LouvainSIGLEBEBelgiu