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

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

Polyisobutylcyanoacrylate Nanoparticles As Sustained-release System for Calcitonin

The potential of nanoparticles of polyisobutylcyanoacrylate as sustained release for peptide was assessed using calcitonin as a model drug. Calcitonin-loaded nanoparticles were obtained following the addition of the peptide before or after polymerization of isobutylcyanoacrylate (CT-NP and CT/NP, respectively). For both formulations, the percentage of binding of calcitonin to the nanoparticles was more than 95% and the particles had an average size of 150 nm. In vitro studies indicate that the release of calcitonin from CT/NP in saline solution containing esterases resulted from the bioerosion of the polymer. However the peptide was not released from CT-NP in this medium. SDS-PAGE electrophoresis and HPLC also showed that calcitonin is tightly bound to the nanoparticles in the CT-NP formulation, very likely by a covalent binding. After intravenous injection in rats, free calcitonin, CT/NP and CT-NP had the same hypocalcemic activity (at the same dose). Following a subcutaneous injection in rats, the two encapsulated forms of calcitonin showed a more important and more prolonged hypocalcemic effect than free calcitonin. 1 h after injection, calcitonin level was lower after CT-NP injection than CT/NP or free calcitonin injection. However, calcitonin level was sustained for more than 24 h after CT-NP injection