Constant Current Iontophoresis Research Articles

Remote-controllable dosage management through a wearable iontophoretic patch utilizing a cell phone.

With regard to medical treatment through operations, remote control is possible, however, the area of remote-controllable drug treatment is yet to be established. In this study, a prototyped remote-controllable dosage management system that allows patients and caregivers to administer therapeutic drugs via an internet line without touching the dosage device or formulation was developed. This system consists of a transmitter (System A) located away from the patient, and a dosage device (System B) equipped with a receiver (B1), dosage management unit (B2), and a drug treatment unit (B3) that can be installed on the patient. Additionally, Bluetooth® is adopted to communicate from System A to System B. In the present study, System A was incorporated into a cell phone, and System B was a constant-current iontophoresis (IP) device, which was applied on excised pig skin. Sodium salt of betamethasone phosphate (BP-Na+) was selected as a model drug, and the in vitro skin permeation of BP- was evaluated. As a result, by transmitting the administration information incorporated in System A through B1 to B2, the optimal current was passed between the IP electrodes in B3, and the skin permeation of BP- was obtained by remote control. That is, the skin permeation of BP- was obtained by the current flowing from the IP device. The permeation amount decreased when the voltage load was stopped. These results suggested that remote control from System A enables dosing management of bioactive substances from dosage devices applied on the skin, intracutaneously, or subcutaneously without being near the patient. Although various trials are still required to complete the remote-controlled system, the patient does not have to go to the hospital except to take injections. Such drug administrations would lead to decreased medical expenses and increased quality of life for patients.

Iontophoresis as an Effective Drug Delivery System in Dentistry: A Review.

Iontophoresis is a non-invasive method to improve drug delivery by the application of an electric field. The iontophoresis process causes deeper penetration of ions using electric current. The drug delivered through iontophoresis was found to be around 10 to 2,000 times more than conventional forms of delivery. The better results were shown by alternating current (AC) than conventional constant current (DC) iontophoresis. The preparation used in iontophoresis should be soluble in water, of a small voltage, and prone to ionization. More mobility is seen with smaller particles. Iontophoresis could increase the diffusion of drugs into dentin, enamel, and other oral tissues. The chief drugs delivered or studied by iontophoresis in dentistry are non-steroidal anti-inflammatory drugs, local anesthetics, anti-bacterial drugs, and fluorides. To enhance the ability of drug transfer nanomaterials were introduced. Under the impact of iontophoresis, remineralizing nanomaterial can be injected at larger concentrations in the deeper layer of incipient caries. Due to the size of nanocomplexes, it is possible that they will diffuse into the body of the subsurface lesion and enter the porosities to improve remineralization utilizing the iontophoresis approach. The concept of the application of an electric current for drug delivery was introduced several years ago in clinical practice, research, and literature. This review focuses on iontophoresis application in dentistry, its mode of action, and how the technique can be utilized in a beneficial way.

Topical iontophoresis of buflomedil hydrochloride increases drug bioavailability in the mucosa: A targeted approach to treat oral submucous fibrosis.

The aim was to investigate the effect of constant current iontophoresis on the delivery and biodistribution of buflomedil hydrochloride (BUF) in the buccal mucosa. Quantification was by UHPLC-MS/MS; in addition to total delivery, the amounts present in the epithelia and the lamina propria (the target tissue) were also determined. Two-compartment vertical diffusion cells were used to investigate the effect of current density (0.5, 1 and 2 mA/cm2), application time (5, 10 and 20 min) and concentration (5, 10 and 20 mM) on iontophoretic delivery of BUF from aqueous solutions. In contrast to passive delivery, iontophoresis for 10 min at 1 mA/cm2 resulted in statistically equivalent transport from a 20 mM solution and a 2% HEC hydrogel (with equivalent BUF loading; 20 µmol). BUF delivery from the hydrogel using diffusion cells and a new coplanar "side-by-side" set-up was statistically equivalent (304.2 ± 28.9 and 278.2 ± 40.3 µg/cm2) - passive delivery was also similar. Iontophoresis (10 min at 1 mA/cm2) using a thin film (20 µmol BUF) was superior to the passive control (323.3 ± 5.9 and 24.8 ± 5.9 µg/cm2). Concentrations in the LP were ~700-fold > IC50 to block collagen production, potentially providing a new therapeutic strategy for oral submucous fibrosis.

Transdermal Delivery of Hyaluronan Tetrasaccharide by Constant Current Iontophoresis

Ascorbic Acid 2-Glucoside (AA2G), l-ascorbic acid derivatives, is provided whitening, anti-oxidation effect and more stable in physicochemical properties. AA2G used in the cosmetic industrial area, however, it hydrophilic character caused lower ability across stratum corneum to the skin, the whitening effect was limited. A microemulsions is the best choice in the study due to the scale up easily in the cosmetic industrial. We aim to optimized microemulsion formulation which easily preparation and stabilized in the cosmetic industrial and enhance the penetration ability into skin simultaneous remain lightening effect. AA2G microemulsion was prepared archive approximately 150 nm. The results showed that the AA2G microemulsion has powerful permeation ability and high skin deposition when compared with the AA2G aqueous control solution and the commercial emulsion product (p<0.05). In human study demonstrated that AA2G microemulsion group could archived lightening (c*) and colorful (e*) by colormery evaluation. The results support that AA2G microemulsion as a potential carrier application in the cosmetic industrial.

Transdermal Delivery of Hyaluronan Tetrasaccharide by Constant Current Iontophoresis

It is well known that scars, wrinkles, and intra articular diseases such as rheumatoid arthritis can be healed by injecting hyaluronan (HA) into the skin and joints. However, based on its varying molecular size, skin penetration of HA may be limited. In this study, we aimed to investigate the effect of transdermal enhancements such as electroporation (EP) and iontophoresis (IP) on the in vitro skin permeability of HA tetrasaccharide (HA4) to deliver HA4 into skin effectively. The effects of EP and IP on the skin permeation of HA4 were studied in in vitro skin permeation experiments. Cumulative amounts of HA4 through full-thickness skin after 6 h were 0.3 μg/cm2 for passive diffusion, 2.3 μg/cm2 after application of EP (100 V, 10 ms, 50 times), 2310.7 μg/cm2 after application of IP (cathodal IP, 0.1 mA/cm2), and 797.9 μg/cm2 after application of IP (cathodal IP, 0.05 mA/cm2), respectively. The skin permeability of the IP (cathodal IP, 0.1 mA/cm2) treatment was about 7700 and 1000-fold increased than that of passive diffusion and the EP treatment. The cumulative amount of HA4 through stripped skin after 6 h was 1384.3 μg/cm2 for passive diffusion. The skin permeability of the cathodal IP (full-thickness skin, 0.05 mA/cm2) treatment was about 1.7-fold increased than that of passive diffusion (stripped skin). We showed that cathodal IP is useful for delivering HA4 into skin effectively.

Comparative Evaluation Of Ion Exchange Resins And Fibers In Iontophoretic Transdermal Delivery Of Sumatriptan Succinate

Iontophoresis is a convenient and suitable technique for delivering charged sumatriptan succinate (SS) across the skin. The objective of study was to examine the applicability of ion exchange resins and fibers as drug carrier to enhance the efficiency of transdermal iontophoresis. The complexes of drug with cationic resins Indion 204 and Indion 224 (DRC-1, DRC-2) as well as with fibers Smopex 102 and Smopex 101 (DFC-1, DFC-2) were formed by batch method. These complexes were characterized by DSC and PXRD and compared for drug loading, drug release and permeation across rat skin. Effects of constant and pulsed current iontophoresis on drug permeation were also evaluated. The iontophoresis study was conducted using silver–silver chloride electrodes across rat skin. The results suggested that fibers due to their open structure showed more drug loading and release compared to resins. The transdermal flux as well as amount of drug permeated from drug-fiber complexes was higher as compared to that of drug-resin complexes and drug solution. DFC-2 assisted with pulsed iontophoresis at 50 % duty cycle significantly increased the skin permeation of SS and reduced the fluctuation in drug permeation with constant drug delivery compared with the passive controls. Copyright © 2016 VBRI Press.

Transdermal iontophoresis of flufenamic acid loaded PLGA nanoparticles

The objective of this study was to test in vitro a drug delivery system that combines nanoencapsulation and iontophoresis for the transdermal delivery of lipophilic model drug using poly(lactic-co-glycolic acid) (PLGA) as the carrier polymer. Negatively charged fluorescent nanoparticles loaded with negatively charged flufenamic acid were prepared. The colloidal properties of the particles were stable under iontophoretic current (constant, pulsed and alternating) profiles and in contact with skin barrier. The release of the drug from the particles was not affected by iontophoresis and remained always limited (≈50%), leading to significantly lower transdermal fluxes across human epidermis and full thickness porcine skin compared to respective free drug formulation. From nanoparticles, pulsed current profile resulted in comparable or higher fluxes compared to constant current profile although fluorescence imaging was not able to confirm deeper distribution of nanoparticles in skin. Based on our results, there is no clear advantage with respect to drug permeation from nanoencapsulating flufenamic acid into PLGA nanoparticles compared to free drug formulation, either in passive or iontophoretic delivery regimens. However, pulsed current iontophoresis could be an effective alternative instead of traditional constant current iontophoresis to enhance transdermal permeation of drugs from nanoencapsulated formulations.

Transport Behavior of Hairless Mouse Skin During Constant Current DC Iontophoresis, Part 2: Iontophoresis of Nonionic Molecules with Cotransport of Polystyrene Sulfonate Oligomers

The purpose of this study was to characterize changes that occur in the iontophoretic transport of nonionic probe permeants in hairless mouse skin epidermal membrane from the anode to cathode when polystyrene sulfonate (PSS) oligomers are cotransported from the cathode to anode. The experiments were conducted with trace levels of the nonionic probe permeants: urea, mannitol, and raffinose. In order to systematically assess changes that occur as a result of having PSS in the cathodal chamber, the steady-state transport parameters of the membrane and the experimental permeability coefficients of the probe permeants were determined and compared with results obtained from earlier baseline experiments where both the cathodal and anodal chamber media were phosphate buffered saline. In addition, the physicochemical properties of the PSS solutions were determined including the solution viscosity and conductance as well as the mobilities of individual PSS oligomers. The effective pore radii of the transport pathways were calculated using a theoretical expression based on simultaneous diffusion and electroosmosis. Compared with the baseline results, the calculated radii were found to have increased up to around twofold and the iontophoretic fluxes of the probe permeants increased by as much sixfold.

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.

Synergistic effects of iontophoresis and jet injector pretreatment on the in-vitro skin permeation of diclofenac and angiotensin II.

A non-needle syringe (jet injector) was utilized to increase skin permeation of drugs by iontophoresis. Briefly, physiological saline was initially flushed by the injector to make a pore in the stratum corneum of excised hairless rat skin, and the iontophoretic skin permeation of two model compounds, sodium diclofenac and angiotensin II, was followed using a 2-chamber diffusion cell. Constant voltage and constant current iontophoresis treatments were evaluated. Pretreatment using the jet injector alone resulted in about 13- and 22-fold increases in the steady-state flux of diclofenac and angiotensin II, respectively, through the skin, compared with non-treated controls. Jet injector pretreatment with constant voltage iontophoresis further enhanced skin permeation of diclofenac and angiotensin II, and the enhancement was also greater than that by constant voltage iontophoresis alone. Thus, a synergistic effect was observed. The ratio of enhancement was greater compared with the control. Jet injector pretreatment with constant current iontophoresis, however, did not always yield higher skin permeation of the drugs than injector pretreatment alone, although the lag time was shortened. The difference in the enhancement between the constant voltage- and constant current iontophoresis can be explained by the electric current through the excised skin. Constant current iontophoresis after a short period of constant voltage iontophoresis with multiple jet injector pretreatments may be the best way to increase drug permeability while preventing severe skin damage.

The Use of Iontophoresis in the Administration of Nicotine and New Non-Nicotine Drugs through the Skin for Smoking Cessation

Cigarette smoking is the primary cause of lung cancer, cardiovascular diseases, reproductive disorders and delayed wound healing all over the world; as such, the goals of smoking cessation are both to reduce health risks and to improve quality of life. The development of novel and more effective medications for smoking cessation is crucial in the treatment of nicotine dependence. Currently, first-line smoking cessation therapies include nicotine replacement products and bupropion. The partial nicotinic receptor agonist, varenicline, has recently been approved by the FDA for smoking cessation. A newer product seeking approval by the FDA is nicotine vaccine. Clonidine and nortriptyline have demonstrated some efficacy, but side effects may limit their use to second-line treatment products. Other therapeutic drugs that are under development include rimonabant, mecamylamine, monoamine oxidase inhibitors, and dopamine D3 receptor antagonists. In order to increase the range of drugs available for transdermal delivery a number of chemical and physical enhancement techniques have been developed in an attempt to compromise skin barrier function in a reversible manner without concomitant skin irritation. The controlled delivery afforded by constant current iontophoresis, which involves the application of a small electrical potential sets it apart from other technologies. The amount of compound delivered is directly proportional to the quantity of charge passed; it depends on the applied current, the duration of current application and the area of the skin surface in contact with the active electrode compartment. For these reasons, iontophoresis will provide smokers with an additional option to assist in achieving smoking cessation.

Transdermal Delivery of Cytochrome C—A 12.4 kDa Protein—Across Intact Skin by Constant–Current Iontophoresis

To demonstrate the transdermal iontophoretic delivery of a small (12.4 kDa) protein across intact skin. The iontophoretic transport of Cytochrome c (Cyt c) across porcine ear skin in vitro was investigated and quantified by HPLC. The effect of protein concentration (0.35 and 0.7 mM), current density (0.15, 0.3 or 0.5 mA.cm(-2) applied for 8 h) and competing ions was evaluated. Co-iontophoresis of acetaminophen was employed to quantify the respective contributions of electromigration (EM) and electroosmosis (EO). The data confirmed the transdermal iontophoretic delivery of intact Cyt c. Electromigration was the principal transport mechanism, accounting for approximately 90% of delivery; correlation between EM flux and electrophoretic mobility was consistent with earlier results using small molecules. Modest EO inhibition was observed at 0.5 mA.cm(-2). Cumulative permeation at 0.3 and 0.5 mA.cm(-2) was significantly greater than that at 0.15 mA.cm(-2); fluxes using 0.35 and 0.7 mM Cyt c in the absence of competing ions (J ( tot ) = 182.8 +/- 56.8 and 265.2 +/- 149.1 microg.cm(-2).h(-1), respectively) were statistically equivalent. Formulation in PBS (pH 8.2) confirmed the impact of competing charge carriers; inclusion of approximately 170 mM Na(+) resulted in a 3.9-fold decrease in total flux. Significant amounts ( approximately 0.9 mg.cm(-2) over 8 h) of Cyt c were delivered non-invasively across intact skin by transdermal electrotransport.

Transdermal Iontophoretic Delivery of Vapreotide Acetate AcrossPorcine Skin in Vitro

The purpose of this study was to evaluate the feasibility of delivering vapreotide, a somatostatin analogue, by transdermal iontophoresis. In vitro experiments were conducted using dermatomed porcine ear skin and heat-separated epidermis. In addition to quantifying vapreotide transport into and across the skin, the effect of peptide delivery on skin permselectivity was also measured. The influence of (1) current density, (2) pre- and post-treatment of the skin, (3) competitive ions, and (4) inclusion of albumin in the receptor on vapreotide delivery were investigated. Epidermis proved to be a better model than dermatomed skin for vapreotide transport studies. Despite the susceptibility of vapreotide to enzymatic degradation, a flux of 1.7 microg/cm2 per hour was achieved after 7 h of constant current iontophoresis (0.15 mA/cm2). Post-iontophoretic extraction revealed that, depending on the experimental conditions, 80-300 microg of peptide were bound to the skin. Vapreotide was found to interact with the skin and displayed a current-dependent inhibition of electroosmosis. However, neither the pre-treatment strategies to saturate the putative binding sites nor the post-treatment protocols to displace the bound peptide were effective. Based on the observed transport rate of vapreotide across porcine epidermis and its clinical pharmacokinetics, therapeutic concentrations should be achievable using a 15-cm2 patch.

Spreading of sudomotor axon reflexes in human skin

Acetylcholine (ACh) activates both sudomotor fibers and primary afferent nociceptors. This leads to sudomotor and vasodilator axon reflexes, which can be diminished, for example, in neuropathies. In some neuropathies, however, there is increased axon reflex sweating, a response pattern that has never been observed for vasodilator flares. To compare both types of axon reflexes and to elucidate possible differences. In healthy young male subjects, sweat response and flare reaction in response to ACh were quantified. Constant-current iontophoresis (300 mC) of ACh was performed on the lateral lower legs. The sudomotor axon reflex was visualized with iodine starch staining, and the sweat response was quantified with capacitance hygrometry (quantitative sudomotor axon reflex test [QSART]). The vasodilator flare was visualized and quantified by laser Doppler imaging. All measurements were performed during and for 10 minutes after finishing the iontophoresis. The sudomotor axon reflex area increased from 30.6 cm2 at the end of the iontophoresis to 39.2 cm2 (p < 0.001) 10 minutes later, while QSART response had already decreased. Flare size and flare intensity remained nearly constant during the observation period. Despite fast cleavage of acetylcholine by cholinesterases, sudomotor axon reflexes spread in the skin, indicating a possible peripheral amplification of sweating.

In vitro transdermal iontophoretic delivery of leuprolide under constant current application

Transdermal delivery of Leuprolide, a nonapeptide LHRH agonist, was studied using constant current iontophoresis to explore methods for improving iontophoretic efficiency and determine the feasibility of delivery of therapeutic doses of the drug. Universal buffer consisting of citrate, phosphate and borate was used to carry out in vitro permeation experiments with heat separated human epidermis at pH 4.5 and 7.2. In addition, the effect of substituting this buffer with a macromolecular electrolyte, polymaleic acid, on the drug flux and the transference number was studied. Current densities from 0.5 to 2.3 μA/cm 2 were used requiring moderate potential differences between 60 and 420 mV to be applied thus limiting irreversible epidermal membrane alterations. The rather high electrical resistance of the epidermis of the order of 200 kΩ cm 2 was related to the sub-physiological electrolyte concentration. Resistance was continuously monitored to guarantee barrier integrity of the membrane. The permeation rate increased linearly with the current density for the universal buffer and was at pH 7.2 almost double that at pH 4.5 despite the greater ionic valence of the drug at pH 4.5 compared to pH 7.2; this being because of the opposite direction of the electroosmotic flow at the two pH values. Drug transference number at both pH values was approximately 0.5%. Replacement of the universal buffer with polymaleic acid yielded higher drug permeation rates and increased its transference number at comparable pH. Transference number, however, was still approximately 1% at the highest current density, showing that concomitant ions from added electrolyte or extracted from the skin and the electrodes accounted for 99% of the total current. Further, transference number of the drug with polymaleic acid appeared to increase with current density. The fluxes obtained for both electrolyte systems with the present experimental arrangement could be extrapolated to deliver therapeutically relevant doses of the drug.

Mechanistic studies of flux variability of neutral and ionic permeants during constant current dc iontophoresis with human epidermal membrane

Although constant current iontophoresis is supposed to provide constant transdermal transport, significant flux variability and/or time-dependent flux drifts are observed during iontophoresis with human skin in vitro and human studies in vivo. The objectives of the present study were to determine (a) the causes of flux variability in constant current dc transdermal iontophoresis and (b) the relationships of flux variabilities among permeants of different physicochemical properties. Changes in the human epidermal membrane (HEM) effective pore size and/or electroosmosis during constant current dc iontophoresis were examined. Tetraethylammonium ion (TEA), urea, and mannitol were the model permeants. For the neutral permeants, the results in the present study showed a significant increase of fluxes with time in a given experiment and large HEM sample-to-sample variability. Although both effective pore size and pore charge density variations contributed to the time-dependent flux drifts observed in electroosmotic transport, the significant flux drifts observed were found to be primarily a result of the time-dependent increase in effective pore charge density. For the ionic permeant, the observed flux variability was smaller than that of the neutral permeants and was believed to be primarily due to effective pore size alteration in HEM during iontophoresis as suggested in a previous study. The different extents of flux variability observed between neutral and ionic permeants are consistent with the different iontophoretically enhanced transport mechanisms for the neutral and ionic permeants (i.e. electroosmosis and electrophoresis, respectively). The results of the present study also demonstrate that flux variability of two neutral permeants are inter-related, so the flux of one neutral permeant can be predicted if the permeability coefficient of the other neutral permeant is known.

In vitro and in vivo comparisons of constant resistance AC iontophoresis and DC iontophoresis

A previous in vitro constant electrical resistance alternating current (AC) iontophoresis study with human epidermal membrane (HEM) and a model neutral permeant has shown less inter- and intra-sample variability in iontophoretic transport relative to conventional constant direct current (DC) iontophoresis. The objectives of the present study were to address the following questions. (1) Can the skin electrical resistance be maintained at a constant level by AC in humans in vivo? (2) Are the in vitro data with HEM representative of those in vivo? (3) Does constant skin resistance AC iontophoresis have less inter- and intra-sample variability than conventional constant current DC iontophoresis in vivo? (4) What are the electrical and the barrier properties of skin during iontophoresis in vivo? In the present study, in vitro HEM experiments were carried out with the constant resistance AC and the conventional constant current DC methods using mannitol and glucose as the neutral model permeants. In vivo human experiments were performed using glucose as the permeant with a constant skin resistance AC only protocol and two conventional constant current DC methods (continuous constant current DC and constant current DC with its polarity alternated every 10 min with a 3:7 on:off duty cycle). Constant current DC iontophoresis was conducted with commercial constant current DC devices, and constant resistance AC iontophoresis was carried out by reducing and maintaining the skin resistance at a constant target value with AC supplied from a function generator. This study shows that (1) skin electrical resistance can be maintained at a constant level during AC iontophoresis in vivo; (2) HEM in vitro and human skin in vivo demonstrate similar electrical and barrier properties, and these properties are consistent with our previous findings; (3) there is general qualitative and semi-quantitative agreement between the HEM data in vitro and human skin data in vivo; and (4) constant skin resistance AC iontophoresis generally provides less inter- and intra-subject variability than conventional constant current DC.

Intradermal delivery of antisense oligonucleotides by the pulse depolarization iontophoretic system.

The intradermal delivery of an antisense oligonucleotide was examined by iontophoresis. In this experiment, the antisense sequence of [(32)P]-labeled phosphodiester oligonucleotide ([(32)P]D-oligo, 18-mer) hybridizing to mouse interleukin 10 (IL-10) mRNA was used as a model D-oligo. In in vitro iontophoretic experiments, isolated hairless mouse skin was used with a horizontal diffusion cell. The enhancing effect of pulse depolarization (PDP) iontophoresis on the [(32)P]D-oligo permeation through the skin was better, and the skin irritation was less, than those of constant direct current (CDC) iontophoresis. The apparent fluxes of [(32)P]D-oligo were enhanced with the increasing current densities and [(32)P]D-oligo concentrations in the donor solution, whereas the enhanced flux decreased with the increasing NaCl concentrations in the donor solution. An optimum electric current was observed for the intradermal delivery of [(32)P]D-oligo, and intact [(32)P]D-oligo was detected within the skin after iontophoresis for 6 h. These results suggest that PDP iontophoresis may be useful for the intradermal delivery of antisense oligonucleotides.

Change in the electrochemical properties of skin and the lipid packing in stratum corneum by ultrasonic irradiation

Effect of ultrasound on the skin permeation of benzoate anion (BA), a model compound, through excised hairless rat skin was investigated using electrochemical techniques. When the skin surface was sonicated at 150 kHz frequency and 111 mW/cm 2 intensity, skin impedance measured by alternative current with 10 Hz frequency was decreased and skin permeation rate (flux) of BA and deuterium oxide was correspondingly increased. A constant current iontophoresis with 0.1 mA/cm 2 after pretreatment of skin by the ultrasound for 60 min significantly increased the BA flux through the skin compared to that without the pretreatment. In contrast, electric potential difference across the skin during iontophoresis with the ultrasonic pretreatment was one-third lower than that without the pretreatment. Analysis of these results using the Nernst-Planck equation suggests that the ultrasound increased aqueous region in the stratum corneum (s.c.) as well as effective diffusivity of BA in the skin as a result of a structural disorder in the stratum corneum lipids. The ultrasound significantly increased leaching of sterols and ceramides, typical lipids, from the skin when 0.1% Tween 20 was used as a donor solution, and thus disordered the lipid packing of s.c. to lower the skin impedance and to increase the diffusivity in the s.c. We concluded that ultrasound acts on the s.c. lipids and increases the diffusivity of polar molecules in the skin barrier.

Reverse iontophoresis — Parameters determining electroosmotic flow: I. pH and ionic strength

It has been previously demonstrated that electroosmosis (the convective movement of solvent that occurs through a charged ‘pore’ in response to the preferential passage of counter-ions when an electric field is applied) can be used in ‘reverse iontophoresis', where the imposition of an electric current across the skin is used to extract a substance of interest (e.g., glucose) from within or beneath the tissue to the surface of the body. The goal of the research reported here was to examine parameters which determine electroosmosis, such that the convective flow of solvent across the skin during iontophoresis may be maximized, and the sensitivity and precision of the procedure optimized. Using mannitol as an appropriate marker molecule, therefore, electroosmotic flow during reverse iontophoresis has been examined as a function of the pH and ionic strength of the electrolyte solutions contained within the electrode compartments located on the skin surface. The impact of using a limited set of different current waveforms was also studied. As expected from the permselectivity of the skin, extraction to the cathode was preferred over that to the anode at pH 7.4. Cathodal extraction was enhanced by increasing the pH of the surface electrolyte conversely, electroosmosis to the anode was improved by lowering the pH (due, presumably, to neutralization of the net negative charge on the ion-conducting pathways through the skin). Reducing the electrolyte ionic strength in the electrode chambers (relative to the physiological level present beneath the tissue) enhanced both cathodal (in particular) and anodal extraction; a minimum quantity of electrolyte, however, must be present in order to sustain the necessary electrochemistry of the iontophoretic system. Finally, neither periodic interruption of current flow, nor periodic alternation of electrode polarity (strategies which have been proposed to limit the acute irritation induced by constant current iontophoresis, i.e., allowing the skin an opportunity to ‘depolarize' ) adversely affected the overall efficiency of the extraction process.