Cathodal Iontophoresis Research Articles

The Microvascular Response to Transdermal Iontophoresis of Insulin is Mediated by Nitric Oxide

Insulin has direct effects on blood flow in various tissues, most likely due to endothelial NO production. We investigated whether insulin delivered to the skin by iontophoresis increases microvascular perfusion and whether this effect is partly or completely mediated by the release of NO. In healthy subjects, regular insulin and monomeric insulin were delivered to the skin by cathodal iontophoresis. The skin was pretreated either with L-NAME or control solution (PBS) using anodal iontophoresis. Microvascular responses were measured using laser Doppler flowmetry. A dose-dependent increase in perfusion was observed during iontophoresis of regular and monomeric insulin. The maximum perfusion was significantly elevated compared with control after PBS (regular insulin 53.6 (12.7-95.6) PU vs. 4.2 (3.4-4.8) PU, p = 0.002; monomeric insulin 32.6 (8.9-92.6) PU vs. 5.9 (3.4-56.0) PU, p = 0.03). The microvascular response to insulin was abolished after L-NAME (regular insulin: 25.6 (11.6-54.4) PU vs. control: 4.7 (2.9-11.5) PU, p = 0.15; monomeric insulin 10.9 (5.4-56.8) PU vs. control: 4.7 (2.9-11.5) PU, p = 0.22). The main finding is that iontophoresis of insulin induces a dose-dependent vasodilation in the skin, which could be suppressed after pretreatment with a NO synthase inhibitor. This suggests that vasodilation in the skin after iontophoresis of insulin is mediated by the NO pathway.

In vitro trans-scleral iontophoresis of methylprednisolone hemisuccinate with short application time and high drug concentration

Trans-scleral iontophoresis, i.e. the application of small electric current to enhance drug transport across sclera is an option for non-invasive delivery of corticosteroids to the posterior segment of the eye. In this paper, in vitro trans-scleral iontophoresis of methylprednisolone hemisuccinate was investigated using concentrated drug solutions and short application times to mimic the iontophoretic conditions of in vivo studies. The drug at the donor concentration of 45 mg/ml was delivered through isolated porcine sclera under passive and iontophoretic conditions (cathodal, 2.4 mA) for 2-15 min. In a second set of experiments, the drug was delivered for 5 min at current intensities of 0.9-7.2 mA. After donor removal, drug release was followed up to 24 h. The exposure of concentrated solutions to sclera for 2-15 min under passive conditions caused a notable accumulation of drug up to 0.8 mg/cm², the release of which was successively followed for 24 h. In cathodal iontophoresis, the amount of accumulated drug increased proportionally to the charge between 0.3 and 1.44 Coulomb. When the charge was increased to 2.16 Coulomb by increasing the application time or current intensity, no further enhancement was recorded. This behaviour can be ascribed to substantial drug adsorption on the scleral tissue, as demonstrated through streaming potential studies, with the consequent increase of the electroosmotic flow that opposes drug transport. The set up suggested here could help in defining the optimal conditions for in vivo studies with animal models and reducing the number of in vivo experiments.

Electrically induced transport of macromolecules through oral buccal mucosa

ObjectiveTo investigate the feasibility of iontophoretic delivery of large molecules across buccal mucosa, and to establish its potential for enhanced drug delivery. MethodsQualitative (6h) and quantitative (8 and 36h) assessment of porcine buccal mucosa, using a diffusion cell in vitro model, was carried out by fluorescent microscopy and UV/Vis spectroscopy respectively, with four fluorescently-labeled model species (3 and 10kDa dextrans, 12kDa parvalbumin and 66kDa bovine serum albumin, BSA). Passive and iontophoresis parameters were obtained. The experimental iontophoresis data were compared with theoretical predictions. ResultsThe two dextrans and parvalbumin showed enhanced permeation through buccal mucosa after anodal iontophoresis (1–6h). Passive diffusion and cathodal iontophoresis resulted in minimal permeation. BSA could not be measured by either mode. Iontophoretic delivery profiles compared to passive delivery, had reduced time lags (30–50 versus ~270min) and increased flux (~37 times faster). Time lag factor/enhancement ratio (TLF/ER) data confirmed that iontophoresis significantly enhanced permeation. The diffusion coefficients (D, passive) for dextrans were significantly higher than for parvalbumin, with the converse obtained for solubility (C0); permeability coefficients (P) were similar for all three species. Potential differences (V) for the two higher kDa species were significantly higher than for the lowest kDa species. Experimental and theoretical data were in reasonable agreement. SignificanceThe experimental and theoretical data, confirming enhanced delivery of the model species via iontophoresis, gave a suitable basis for its potential application in the mouth, in a clinical setting and opens pathways to further research for delivering precious drugs topically and systemically.

Effect of iontophoresis on the in vitro trans-scleral transport of three single stranded oligonucleotides

Oligonucleotides represent a subject of clinical interest due to their potential ability to treat several diseases, including those affecting the posterior segment of the eye. Unfortunately, therapeutic oligonucleotides are currently administered by means of highly invasive approaches, such as intravitreal injections. The aim of the present work was to study in vitro, across isolated bovine sclera, the effect of iontophoresis on the transport of three single stranded oligonucleotides (ssDNA), 12-, 24- and 36-mer, selected as reference compounds in view of a non-invasive drug delivery to the back of the eye.All the three sequences were able to cross bovine sclera in vitro without iontophoresis. When anodal iontophoresis was applied, no change in flux was observed, while in the presence of cathodal iontophoresis the permeability coefficients increased four-fold compared to passive conditions. This behavior can be ascribed to the electrorepulsive mechanism, due to the negative charge of the nucleic acid backbone. It was also observed that the molecular weights of the three sequences did not affect trans-scleral transport, neither in passive, nor in current assisted permeation. Furthermore, increasing the current intensity from 1.75mA to 3mA, no effect on the trans-scleral transport of the 24-mer was noticed.Although preliminary, the results demonstrate that cathodal iontophoresis enhances trans-scleral transport of single stranded oligonucleotides and suggest its use as a novel non-invasive approach for the treatment of diseases affecting the posterior segment of the eye.

Transdermal Iontophoretic Delivery of Propofol: A General Anaesthetic in the Form of its Phosphate Salt

The main objective of this study was to investigate the feasibility of delivery of propofol phosphate (PP), a prodrug of propofol, via transdermal route using iontophoresis in combination with chemical permeation enhancers (CPEs). PP, a prodrug, was synthesized and its structure was characterized. In vitro passive and iontophoretic drug transport studies were carried out using Franz diffusion cell across freshly excised hairless rat skin at different concentrations of PP in combination with CPE. Among all the CPEs screened, 0.1% sodium dodecyl sulfate (SDS) increased the passive transdermal flux to 13.43 ± 0.73 μg/(cm(2) h) from 8.52 ± 0.82 μg/(cm(2) h) (control). Cathodal iontophoresis in combination with 0.1% SDS synergistically enhanced the flux [249.24 ± 6.12 μg/(cm(2) h)] of PP. The Pharmacokinetic studies were performed in rat model to assess the feasibility of transdermal delivery of PP. The amount of propofol present in plasma samples in control group (passive) was below the detectable levels at all the time points during the study. The plasma concentration-time profile of iontophoresis group of rats was fit to a noncompartmental model and the pharmacokinetic parameters were calculated. These studies suggest the plausibility of achieving therapeutically relevant levels of propofol when delivered via transdermal route by combining iontophoresis with CPE.

Iontophoretic Transdermal Delivery of Glycyrrhizin: Effects of pH, Drug Concentration, Co-ions, Current Intensity, and Chemical Enhancers

The aim of the present study was to evaluate the feasibility of transdermal delivery of glycyrrhizin, an agent used in the treatment of chronic hepatitis C, by cathodal iontophoresis using Ag/AgCl electrodes in vitro. The effects of donor pH (pH 4-7), concentration of drug (0.025-0.2% (w/v)), concentration of external chloride ions (Cl(-)) (0-133 mM), current strength (0-0.5 mA/cm(2)), and permeation enhancers (urea and Tween 80) on the skin permeability of glycyrrhizin were examined in in vitro skin permeation studies using porcine ear skin as the membrane. The cumulative amount of permeated glycyrrhizin and the steady-state skin permeation flux of glycyrrhizin across porcine skin increased in a pH-dependent manner. The skin permeability of glycyrrhizin was independent of the concentration of drug and competed only with a high external Cl(-) concentration. The skin permeation flux of glycyrrhizin increased with the current (R(2)=0.8955). The combination of iontophoresis and enhancers provided an additive or synergistic effect, and a skin permeation flux of about 60 µg/h/cm(2) was achieved. The plasma concentration of glycyrrhizin in humans, extrapolated from the in vitro steady-state permeation flux across porcine skin, was within the therapeutic level. These results suggest that cathodal iontophoresis can be used as a transdermal drug delivery system for glycyrrhizin using reasonable patch sizes and acceptable levels of current intensity.

Cathodal Iontophoresis of Treprostinil Induces a Sustained Increase in Cutaneous Blood Flux in Healthy Volunteers

Prostacyclin analogues are the most effective drugs to treat sclerodermic digital ulcers, but their systemic use is limited by their frequent side effects. The authors tested whether the prostacyclin analogues treprostinil and iloprost, delivered by cutaneous iontophoresis, induce sustained vasodilatation. Twenty healthy volunteers received treprostinil by cathodal iontophoresis on the forearm. Skin blood flux was quantified using laser Doppler imaging. Treprostinil 250 µM induced an increase in cutaneous vascular conductance AUC(80) (min) (31 897 ± 24 390 %BL·min) compared with NaCl 0.9% (P < .005), treprostinil 2.5 µM (P < .005), and treprostinil 25 µM (P < .005). This was confirmed when flux was recorded for up to 10 hours. Systemic and skin tolerance of treprostinil were good. Iloprost was stopped early because of local toxicity. Treprostinil cathodal iontophoresis induces a sustained increase in cutaneous blood flow with good local tolerance. This could be investigated as a new local therapy for digital ulcers in scleroderma.

Synergistic effect of chemical penetration enhancer and iontophoresis on transappendageal transport of oligodeoxynucleotides

Gap junction protein connexin43 (Cx43) specific antisense oligodeoxynucleotides (AsODN) have been shown to improve a number of inflammatory conditions and may therefore offer a novel strategy for persistent pain management. However, for such molecules to be clinically effective, delivery challenges owing to the molecules' high molecular weight, negative charge and hydrophilicity have to be overcome. In this study, the effect of various chemical penetration enhancers and cathodal iontophoresis on transdermal delivery was evaluated. Initial skin permeation studies revealed only a slight increase in the passive flux of the model anionic drug sodium fluorescein using limonene/ethanol. Applying cathodal iontophoresis, the amount of the model drug permeated through untreated skin was tripled, while a combination of chemical and physical penetration enhancement resulted in a fourfold increase in the fluorescein amount permeated. However, even the synergistic effect of limonene/ethanol and iontophoresis was insufficient to achieve complete permeation of Cy3-labeled Cx43 AsODN across the entire skin thickness. Instead, molecules were trapped in the epidermis or permeated deeply into the hair follicles. These results suggest that the synergistic effect of chemical and physical penetration enhancement increases intradermal delivery of oligonucleotides but is insufficient to deliver such large molecules across intact skin.

Iontophoretic permeation of lisinopril at different current densities and drug concentrations.

The purpose of the present work was to assess iontophoretic permeation of Lisinopril at different current densities and concentrations for development of patient-controlled active transdermal system. In vitro iontophoretic transdermal delivery of Lisinopril across the pigskin was investigated at three different drug concentrations and three different current densities (0.25- 0.75 mA/cm2) in the donor cell of the diffusion apparatus, using cathodal iontophoresis along with the passive controls. For passive permeation, the steady state flux significantly increased with the increasing of donor drug concentration. At all concentration levels, iontophoresis considerably increased the permeation rate compared to passive controls. Iontophoretic transport of Lisinopril was to be found increase with current densities. Flux enhancement was highest at the lowest drug load and lowest at the highest drug load. The obtained results indicate that permeation rate of Lisinopril across the pigskin can be considerably enhanced, controlled or optimized by the use of Iontophoresis technique.

Iontophoresis of Endothelin Receptor Antagonists in Rats and Men

IntroductionThe treatment of scleroderma-related digital ulcers is challenging. The oral endothelin receptor antagonist (ERA) bosentan has been approved but it may induce liver toxicity. The objective of this study was to test whether ERAs bosentan and sitaxentan could be locally delivered using iontophoresis.MethodsCathodal and anodal iontophoresis of bosentan and sitaxentan were performed on anaesthetized rat hindquarters without and during endothelin-1 infusion. Skin blood flow was quantified using laser-Doppler imaging and cutaneous tolerability was assessed. Iontophoresis of sitaxentan (20 min, 20 or 100 µA) was subsequently performed on the forearm skin of healthy men (n = 5).ResultsIn rats neither bosentan nor sitaxentan increased skin blood flux compared to NaCl. When simultaneously infusing endothelin-1, cathodal iontophoresis of sitaxentan increased skin blood flux compared to NaCl (AUC0–20 were 44032.2±12277 and 14957.5±23818.8 %BL.s, respectively; P = 0.01). In humans, sitaxentan did not significantly increase skin blood flux as compared to NaCl. Iontophoresis of ERAs was well tolerated both in animals and humans.ConclusionsThis study shows that cathodal iontophoresis of sitaxentan but not bosentan partially reverses endothelin-induced skin vasoconstriction in rats, suggesting that sitaxentan diffuses into the dermis. However, sitaxentan does not influence basal skin microvascular tone in rats or in humans.

Iontophoretic transport of zinc phthalocyanine tetrasulfonic acid as a tool to improve drug topical delivery

Phthalocyanines have been used as systemic photosensitizers because of their high affinity towards tumour tissue, and the high rates of reactive oxygen species produced when they are irradiated during photodynamic therapy. However, the topical administration of these compounds is limited by their large size, poor hydrosolubility and ionic character. This study aimed to investigate the iontophoretic delivery of charged zinc phthalocyanine tetrasulfonic acid (ZnPcS4) from a hydrophilic gel to different skin layers by means of in-vitro and in-vivo studies. Six hours of passive administration was insufficient for ZnPcS4 to cross the stratum corneum (SC) and to reach the epidermis and dermis. No positive effect was reached when anodal iontophoresis was performed, showing that the drug-electrode attraction effect was higher than the electro-osmosis contribution at a pH of 5.5. Cathodal iontophoresis, however, was able to transport significant amounts of the drug to the viable epidermis. In addition, the absence of NaCl in the formulation significantly increased (by five-fold) the amount of ZnPcS4 that crossed the SC and accumulated in the epidermis and dermis. It was possible to visualize the drug accumulation in the follicle openings and in the epidermis, even after SC removal. In-vivo experiments in rat skin showed that these results were maintained in an in-vivo model, even with only 15 min of iontophoresis. In addition, confocal analysis of the treated skin showed a homogeneous distribution of ZnPcS4 in the viable epidermis after this short period of cathodal iontophoresis.

Prediction of cathodal iontophoretic transport of various anions across excised skin from different vehicles using conductivity measurements.

Solute concentration, buffer concentration, applied pH and buffer constituents affect the cathodal iontophoresis of salicylate, benzoate and butyrate across excised skin. Experiments were conducted in which the iontophoretic flux of salicylate was measured across excised human skin with variations in salicylate concentration, donor solution pH, buffer concentrations and buffer consitutents. The conductivity of these solutes and of solutions described in studies on the iontophoresis of benzoate and butyrate were then measured. The observed variations in salicylate, benzoate and butyrate fluxes across a range of conditions were found to be related to the ratio of specific conductance of the solutes in deionized distilled water to that in the buffer solution containing the solutes. The present results suggest that conductivity of solutes in vehicle solutions is one means of predicting the iontophoretic flux of solutes from different vehicle compositions.

Electrically-assisted delivery of an anionic protein across intact skin: Cathodal iontophoresis of biologically active ribonuclease T1

Cathodal iontophoresis of anionic macromolecules has been considered a major challenge owing to (i) the presence of a negative charge on the skin under physiological conditions and (ii) the electroosmotic solvent flow in the (opposite) anode-to-cathode direction. Moreover, electroosmosis, and not electromigration, was considered as the likely electrotransport mechanism for high molecular weight cations. However, it was recently shown that electromigration governed anodal iontophoretic transport of Cytochrome c (12.4 kDa) and Ribonuclease A (RNAse A; 13.6 kDa). Thus, the objective of this study was to investigate the feasibility of iontophoresing a negatively charged protein, the enzyme Ribonuclease T1 (RNAse T1, 11.1 kDa), from the cathode across intact skin. Cumulative permeation and skin deposition of RNAse T1 were investigated as a function of current density (0.15, 0.3 and 0.5 mA/cm 2 applied for 8 h) using porcine ear skin and quantified by an enzymatic activity assay. Although RNAse T1 permeation was dependent upon current density (22.41 ± 8.10, 76.41 ± 56.98 and 142.19 ± 62.23 μg/cm 2, respectively), no such relationship was observed with respect to skin deposition (9.78 ± 2.39, 7.76 ± 4.34 and 8.70 ± 2.94 μg/cm 2, respectively). MALDI-TOF spectra and the activity assay confirmed that RNAse T1 retained structural integrity and enzymatic function post-iontophoresis. Acetaminophen iontophoresis demonstrated the anode-to-cathode directionality of electroosmotic solvent flow confirming that RNAse T1 electrotransport was due entirely to electromigration. Interestingly, despite its lower net charge and higher molecular weight, electromigration of cationic Ribonuclease A was superior to that of RNAse T1 after iontophoresis at 0.5 mA/cm 2 for 8 h. These results provide further evidence that charge to mass ratio and hence electric mobility might not alone be sufficient to predict protein electrotransport across the skin; three dimensional structures and the spatial distribution of physicochemical properties must also be considered. The skin extraction data suggest that negatively charged molecules may have fewer potential binding sites in the skin than their cationic counterparts. This was supported by confocal laser scanning microscopy images which showed that whereas fluorescence from RNAse A was distributed throughout the epidermis and dermis, RNAse T1 appeared to be bound to the epidermis alone. In conclusion, this is the first report demonstrating successful non-invasive cathodal iontophoresis of a negatively charged functional protein (RNAse T1) across intact skin.

Cathodal iontophoresis of treprostinil and iloprost induces a sustained increase in cutaneous flux in rats

The treatment of scleroderma-related digital ulcers is still a therapeutic challenge. The most effective drugs are prostacyclin analogues. However, their usage is limited to an intravenous route of administration and by their frequent side effects. The objective of this study was to test whether treprostinil, iloprost and epoprostenol can induce sustained vasodilatation in rats when delivered locally using cutaneous iontophoresis. Treprostinil, iloprost and epoprostenol were delivered by cathodal and anodal iontophoresis onto the hindquarters of anaesthesized rats (n= 8 for each group). Skin blood flow was quantified using laser Doppler imaging and cutaneous tolerance was assessed from day 0 to day 3. Cathodal but not anodal iontophoresis of treprostinil (6.4 mM), iloprost (0.2 mM) and epoprostenol (1.4 mM) induced a significant and sustained increase in cutaneous blood flow. The effects of treprostinil and iloprost were significantly different from those of treprostinil vehicle. Only weak effects were observed when both drugs were applied locally without current. Skin resistance was unchanged in areas treated with prostacyclin analogues. Finally, skin tolerance was good, with no evidence of epidermal damage. Cathodal iontophoresis of treprostinil and iloprost increases cutaneous blood flow with a good local tolerance. The effects of cathodal iontophoresis of these drugs should be investigated in humans, as they could have potential as new local therapies for digital ulcers in patients with scleroderma.

Iontophoresis-Facilitated Delivery of Prednisolone through Throat Skin to the Trachea After Topical Application of its Succinate Salt

The possibility of direct delivery of steroids through the skin to the trachea and the effect of iontophoresis on delivery efficacy were evaluated after the application of an ionic steroidal prodrug, prednisolone sodium succinate (PS-Na), to the throat skin. Fluorescein sodium salt (FL-Na) and PS-Na were applied as model compounds at a concentration of 1% in pH 7.4 phosphate-buffered saline to the throat skin of hairless rats, and constant current-cathodal iontophoresis (0.4 mA/cm(2)) was performed for 8 or 10 h. In vitro permeation experiment involving cathodal iontophoresis through excised hairless rat abdominal skin revealed 30- and 10-times higher levels of skin permeation of PS and its active drug, prednisolone (P), than those induced without iontophoresis. In vivo iontophoresis treatment of the rat's throat skin produced 2.6-, 1.6- and 12-times higher FL, PS and P concentrations, respectively, in the trachea than those observed without iontophoresis. The present results suggest the usefulness of topical application of the ionic steroidal prodrugs onto throat skin followed by iontophoresis treatment for directly delivering the steroid to the trachea.

A Study of Transdermal Delivery of Glibenclamide Using Iontophoresis

Purpose: To assess iontophoretic transdermal delivery of glibenclamide across pigskin for its transdermal development. Methods: In vitro iontophoretic transdermal delivery of glibenclamide across the pigskin was investigated at three different drug concentrations in the donor cell of the diffusion apparatus, using cathodal iontophoresis (current density 0.5 mA cm-2) along with the passive controls. Results: For passive permeation, the steady state flux significantly increased with the donor drug concentration. At all concentration levels, iontophoresis considerably increased the permeation rate compared to passive controls. Flux enhancement was highest at the lowest drug load and lowest at the highest drug load. The highest flux value obtained was 0.0603 μmol cm-2 h-1 and the target flux for glibenclamide was 0.3933 μmol h-1. Required permeation rate was achieved by iontophoresis using a much smaller application area. Conclusion: Permeation rate of drugs across the pigskin can be considerably enhanced by the use of Iontophoresis. Keywords: Glibenclamide; Iontophoresis; Pigskin; Transdermal drug delivery.

Electroosmotic transport of mannitol across human nail during constant current iontophoresis

This work aimed to elucidate the role of electroosmosis during trans-nail iontophoresis. Passive and iontophoretic experiments were performed after short hydration (10-15 min) of human nail tips. The electroosmotic fluxes of mannitol were determined during anodal and cathodal iontophoresis and at different pH values. Passive controls were also carried out. Four sets of experiments were performed: (a) three anodal delivery experiments using different nails, at pH 4.0, 5.0 and 7.4, (b) one anodal delivery experiment that kept the same nails across two pH stages, (c) one experiment, comprising an anodal delivery stage (pH 4 and 7.4) followed by a cathodal delivery stage (pH 7.4 and 4), which kept the same nails across the different polarities and pH stages, and (d) a passive experiment keeping the same nails across different pH values (4 and 7.4). The fluxes of mannitol measured were very variable and little difference between passive and electroosmotic transport was observed. Cathodal and anodal fluxes were not always significantly different. Experiments which minimised internail variability suggested that the nails were negatively charged at physiological pH, and that this negative charge was lost at pH 4. These results suggest a modest and highly variable contribution of electroosmosis to the iontophoretic transungual flux.

In vitro Passive and Iontophoretically Assisted Transport of Salbutamol sulphate through Hairless Mice Skin

Investigations were carried out to ascertain the relative importance of the described mechanism in iontophoretic transport using an ionizable drug salbutamol sulphate, which has two pKa values 9.3 (for amino group) and 10.3 (for phenolic group). Ionization of salbutamol sulphate varies with pH, hence the rate and extent of transport across the skin can be enhanced, controlled and manipulated by the application of factors like anodal and cathodal current at varied pH of donor solution and current densities. To determine these parameters, experiments were performed and data was collected at 7.4, 9.3, 10.3 and 11 pH using 4mg/ml drug concentration and 0.3mA/cm2 current density for 6 hours. After establishing the pH for optimum transport of drug, effect of current density (0.1, 0.2, 0.3 and 0.4 mA/cm2) on the transport of drug (keeping drug concentration constant) were investigated. Passive diffusion of salbutamol sulphate was maximal at pH 10.3 and 9.3, when unionized form of drug was 50%. Anodal iontophoresis at pH 7.4 was most effective (significant result, p &lt; 0.05) in transport of drug across skin as compared to cathodal iontophoresis at pH 11. The effect of current density on steady state flux by salbutamol sulphate during anodal iontophoresis at 7.4 pH showed 2.26 and 28.05µg/cm2/h at 0.0 i.e., passive diffusion and 0.4 mA/cm2, respectively. Thus, flux was enhanced nearly 12 times during anodal iontophoresis.

Transdermal iontophoresis of dexamethasone sodium phosphate in vitro and in vivo: Effect of experimental parameters and skin type on drug stability and transport kinetics

The aim of this study was to investigate the cathodal iontophoresis of dexamethasone sodium phosphate (DEX-P) in vitro and in vivo and to determine the feasibility of delivering therapeutic amounts of the drug for the treatment of chemotherapy-induced emesis. Stability studies, performed to investigate the susceptibility of the phosphate ester linkage to hydrolysis, confirmed that conversion of DEX-P to dexamethasone (DEX) upon exposure to samples of human, porcine and rat dermis for 7 h was limited (82.2 ± 0.4%, 72.5 ± 4.8% and 78.6 ± 6.0% remained intact) and did not point to any major inter-species differences. Iontophoretic transport of DEX-P across dermatomed porcine skin (0.75 mm thickness) was studied in vitro as a function of concentration (10, 20, 40 mM) and current density (0.1, 0.3, 0.5 mA cm −2) using flow-through diffusion cells. Increasing concentration of DEX-P from 10 to 40 mM resulted in a ∼4-fold increase in cumulative permeation (35.65 ± 23.20 and 137.90 ± 53.90 μg cm −2, respectively). Good linearity was also observed between DEX-P flux and the applied current density ( i d ; 0.1, 0.3, 0.5 mA cm −2; J DEX (μg cm 2 h −1) = 237.98 i d − 21.32, r 2 = 0.96). Moreover, separation of the DEX-P formulation from the cathode compartment by means of a salt bridge – hence removing competition from Cl − ions generated at the cathode – produced a 2-fold increase in steady-state iontophoretic flux (40 mM, 0.3 mA cm −2; 20.98 ± 7.96 and 41.82 ± 11.98 μg cm −2 h −1, respectively). Pharmacokinetic parameters were determined in Wistar rats (40 mM DEX-P; 0.5 mA cm −2 for 5 h with Ag/AgCl electrodes and salt bridges). Results showed that DEX-P was almost completely converted to DEX in the bloodstream, and significant DEX levels were achieved rapidly. The flux across rat skin in vivo (1.66 ± 0.20 μg cm −2 min −1), calculated from the input rate, was not statistically different from the flux obtained in vitro across dermatomed porcine skin (1.79 ± 0.49 μg cm −2 min −1). The results suggest that DEX-P delivery rates would be sufficient for the management of chemotherapy-induced emesis.

Transdermal iontophoresis of insulin. Part 1: A study on the issues associated with the use of platinum electrodes on rat skin.

We have studied the issues associated with the use of platinum electrodes for transdermal iontophoretic delivery of peptides, using insulin as a model peptide. Insulin permeation was studied using full-thickness rat skin by varying the donor solution pH as a function of electrode polarity. The stability of insulin under the iontophoretic conditions was studied using TLC, SDS-polyacrylamide gel electrophoresis and HPLC. Large pH shifts were observed during anodal iontophoresis (AI), when the donor solution pH was above the isoelectric point of insulin and in cathodal iontophoresis (CI), when the donor solution pH was below the isoelectric point of insulin. The direction and magnitude of electroosmotic flow was influenced by pH of the donor solution and the electrode polarity. On the other hand, the buffer used to maintain the pH governed the contribution of electrorepulsion to the overall transport of insulin. Electrochemical degradation of insulin was significant during AI at pH 7.4. Among the pH investigated, AI of insulin at pH 3.6 and CI at pH 8.35 were better, as the pH shift was relatively less and electrochemically more stable during iontophoresis as compared with other pH. In summary, the pH shift caused by platinum electrodes had a significant influence on the permeation and stability of insulin.