Topical delivery by iontophoresis

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Ionophorèse et électroporation : administration cutanée de médicaments et d'ADN

La peau est une cible intéressante pour l'administration de médicaments et d'ADN qui cependant reste limitée par la faible perméabilité du stratum corneum. L'ionophorèse et l'électroporation ont été largement étudiées afin d'obtenir une administration transdermique. Dans les deux cas, le passage de courant perturbe la perméabilité de la peau et même la perméabilité cellulaire dans le cas précis de l'électroporation. Ces deux techniques permettent d'élargir le spectre des substances administrables de manière transcutanée. Quelques exemples d'applications sont détaillés dans cet articl

Reverse iontophoresis of lithium: electrode formulation using a thermoreversible polymer

This work investigated the use of a thermoreversible get as a collector vehicle in reverse iontophoresis applications. A 20% (w/w) aqueous gel of Pluronic F127 was a suitable receptor medium to be used at the cathodal chamber. In vitro iontophoresis experiments investigated the simultaneous extraction of lithium (analyte of interest) and sodium (used as an internal standard) into either a control buffer or a gelled receptor. The gelification process at room temperature provided a suitable consistency and contact with the skin surface during the iontophoresis experiments. Subsequent cooling of the gelled solution to 4 degreesC allows an easy recovery of lithium and sodium for later quantification. Both the lithium extraction fluxes and the lithium to sodium ratio of extraction fluxes were linearly related to the subdermal lithium concentration. On the whole, the results show that thermoreversible polyiner solutions offer a simple and convenient way to handle samples in reverse iontophoresis Studies. (C) 2004 Elsevier B.V. All rights reserved

Improvement of the decision efficiency of the accuracy profile by means of a desirability function for analytical methods validation - Application to a diacetyl-monoxime colorimetric assay used for the determination of urea in transdermal iontophoretic extracts

Validation of analytical methods is a widely used and regulated step for each analytical method. However, the classical approaches to demonstrate the ability to quantify of a method do not necessarily fulfill this objective. For this reason an innovative methodology was recently introduced by using the tolerance interval and accuracy profile, which guarantee that a pre-defined proportion of future measurements obtained with the method will be included within the acceptance limits. Accuracy profile is an effective decision tool to assess the validity of analytical methods. The methodology to build such a profile is detailed here. However, as for any visual tool it has a part of subjectivity. It was then necessary to make the decision process objective in order to quantify the degree of adequacy of an accuracy profile and to allow a thorough comparison between such profiles. To achieve this, we developed a global desirability index based on the three most important validation criteria: the trueness, the precision and the range. The global index allows the classification of the different accuracy profiles obtained according to their respective response functions. A diacetyl-monoxime colorimetric assay for the determination of urea in transdermal iontophoretic extracts was used to illustrate these improvements

Assessment of the "skin reservoir" of urea by confocal Raman microspectroscopy and reverse iontophoresis in vivo.

PURPOSE: To demonstrate the "skin reservoir" of urea by confocal Raman microspectroscopy in vivo and to evaluate its impact on the non-invasive monitoring of the analyte by reverse iontophoresis. METHODS: Urea was extracted iontophoretically over a 2-h period across the skin of adult volunteers and patients with chronic kidney disease. Confocal Raman microspectroscopic profiles of skin were recorded before and after 30 min of current application. RESULTS: Urea extraction was higher at the beginning of current passage, but then decreased to achieve stable values after 2 h of iontophoresis. After 30 min of iontophoresis, the Raman spectra highlighted a clear depletion of urea at the surface of the skin. Lactate distribution was also modified both at the surface and deeper into the skin. CONCLUSIONS: A source of urea in the skin, unrelated to the concentration circulating in the blood, was strongly suggested by extracted urea flux observed over time and by the Raman spectroscopy. This "urea reservoir" must be removed before systemic urea levels can be non-invasively monitored by reverse iontophoresis

Non-invasive diagnosis and monitoring of chronic kidney disease by reverse iontophoresis of urea in vivo

BACKGROUND: Reverse iontophoresis uses a small current to extract molecules and ions through the skin. The aim of the study was to determine whether reverse iontophoresis of urea can be used (i) to diagnose and monitor non-invasively chronic kidney disease (CKD), and (ii) to track urea levels closely during a hemodialysis session. METHODS: A current of 0.8mA was applied for 2h in 10 healthy volunteers, in 9 patients with CKD, and in 10 patients undergoing hemodialysis. Urea fluxes extracted by reverse iontophoresis and urea concentrations in the blood were measured. RESULTS: Extracted urea fluxes discriminated healthy volunteers from patients with CKD within 90min. A non-invasive measure of blood urea concentrations can be achieved after 120min. A urea reservoir in the skin interferes with the extraction and a pre-hemodialysis "depletion" period is required. Mild and transient sensation and erythema induced by iontophoresis were significantly lower in the CKD group. Gelling the formulation of the iontophoresis reservoir gave similar results to those obtained when using a simple aqueous solution. CONCLUSIONS: Reverse iontophoresis can be used to non-invasively diagnose individuals with CKD and to monitor urea concentrations in blood

Post hoc analysis of reactogenicity trends between dose 1 and dose 2 of the adjuvanted recombinant zoster vaccine in two parallel randomized trials

In two large clinical trials (ZOE-50 [NCT01165177] and ZOE-70 [NCT01165229]), two doses of the adjuvanted recombinant zoster vaccine (RZV) demonstrated >90% efficacy against herpes zoster in adults ≥50 years of age. Solicited adverse events (AEs) were collected for 7 days post-each dose in a study sub-cohort. The incidence of reported solicited AEs was higher for RZV compared to placebo recipients. Since reactogenicity may contribute to a person’s willingness to be vaccinated, knowing about expected reactogenicity might help keep high compliance with the second dose. This post hoc analysis assessed the intensity of solicited AEs post-dose 2 reported to the same event’s intensity post-dose 1. Intensity was graded from 0 to 3, grade 3 indicating the highest severity. Of the vaccinees who did not experience a specific AE post-dose 1, 72.6–91.7% did not experience the same event after dose 2. Although the frequency of grade 3 AEs post-dose 2 was the highest in participants reporting the same AEs at grade 3 post-dose 1, 65.8–89.3% of vaccinees with grade 3 specific AEs post-dose 1 reported the same AEs at lower intensity post-dose 2. These data can help inform health-care professionals about the frequency and intensity of AEs post-dose 2 with respect to post-dose 1

Targeting nanoparticles to M cells with non-peptidic ligands for oral vaccination

The presence of RGD on nanoparticles allows the targeting of β1 integrins at the apical surface of human M cells and the enhancement of an immune response after oral immunization. To check the hypothesis that non-peptidic ligands targeting intestinal M cells or APCs would be more efficient for oral immunization than RGD, novel non-peptidic and peptidic analogs (RGD peptidomimitic (RGDp), LDV derivative (LDVd) and LDV peptidomimetic (LDVp)) as well as mannose were grafted on the PEG chain of PCL–PEG and incorporated in PLGA-based nanoparticles. RGD and RGDp significantly increased the transport of nanoparticles across an in vitro model of human M cells as compared to enterocytes. RGD, LDVp, LDVd and mannose enhanced nanoparticle uptake by macrophages in vitro. The intraduodenal immunization with RGDp-, LDVd- or mannose-labeled nanoparticles elicited a higher production of IgG antibodies than the intramuscular injection of free ovalbumin or intraduodenal administration of either non-targeted or RGD-nanoparticles. Targeted formulations were also able to induce a cellular immune response. In conclusion, the in vitro transport of nanoparticles, uptake by macrophages and the immune response were positively influenced by the presence of ligands at the surface of nanoparticles. These targeted-nanoparticles could thus represent a promising delivery system for oral immunization

Monitoring of urea and potassium by reverse iontophoresis in vitro

Purpose. Reverse iontophoresis is an alternative to blood sampling for the monitoring of endogenous molecules. Here, the potential of the technique to measure urea and potassium levels non-invasively, and to track their concentrations during hemodialysis, has been examined. Materials and Methods. In vitro experiments were performed to test (a) a series of subdermal urea and potassium concentrations typical of the pathophysiologic range, and (b) a decreasing profile of urea and potassium subdermal concentrations to mimic those which are observed during hemodialysis. Results. (a) After 60-120 min of iontophoresis, linear relationships (p < 0.05) were established between both urea and potassium fluxes and their respective subdermal concentrations. The determination coefficients were above 0.9 after 1 h of current passage using sodium as an internal standard. (b) Reverse iontophoretic fluxes of urea and K+ closely paralleled the decay of the respective concentrations in the subdermal compartment, as would occur during a hemodialysis session. Conclusions. These in vitro experiments demonstrate that urea and potassium can be quantitatively and proportionately extracted by reverse iontophoresis, even when the subdermal concentrations of the analytes are varying with time. These results suggest the non-invasive monitoring of urea and potassium to diagnose renal failure and during hemodialysis is feasible, and that in vivo measurements are warranted