Passive and Iontophoretic Transdermal Penetration of Chlorpromazine

The in vitro iontophoretic transdermal delivery of chlorpromazine (CPZ) across pig skin was investigated. Anodal iontophoresis considerably increased CPZ skin penetration and accumulation compared with the passive controls.

The effect of CPZ concentration in the donor solution was studied (1.4–8.2 mM). A higher penetration was observed with an increase of the concentration. In addition, the effect of NaCl concentration was also studied (154–200 mM). As expected, CPZ iontophoretic transport decreased with NaCl content. Finally, the influence of the current density (0.20–0.50 mA/cm²) was investigated. The iontophoretic transport of CPZ tends to increase with current density, although this effect was not statistically significant between 0.35 and 0.5 mA/cm². On the whole, this work shows that iontophoresis may be used to improve the transdermal delivery of CPZ for the treatment of chronic psychosis.     

Role of Appendages in Skin Resistance and lontophoretic Peptide Flux: Human Versus Snake Skin

Purpose. 1. The assessment of the role of hair follicles and sweat glands in skin resistance and percutaneous iontophoretic flux of 9-desglycinamide, 8-arginine vasopressin (DGAVP) by comparing two skin species: human stratum corneum which contained hair follicles, sweat and sebaceous glands, and shed snake skin which lacked all appendages. 2. The effect of l-dodecylazacycloheptan-2-one (dodecyl-Azone, a lipid perturbing agent) on the iontophoretic DGAVP flux. Methods. Iontophoresis in vitro was performed in a transport cell (0.79 cm² area available for percutaneous transport) by 8-hours application of a pulsed constant current of 100 Hz, 50% duty cycle and 0.26 mA.cm^–2 current density delivered by a pair of Ag/AgCl electrodes, of which the anode was facing the anatomical surface of the skin samples. Results. The initial resistances of human stratum corneum and shed snake skin samples were of the same order of magnitude (20–24 k.cm²) and both skin species showed a comparable resistance-decrease profile during 8-hours iontophoresis, indicating that the resistances were mainly determined by the stratum corneum and not greatly influenced by the appendageal structures. The initial resistances of the skin samples pretreated with dodecyl-azone were less than 50% of the values of untreated samples. Because dodecyl-azone is known to perturb the ordering of the intercellular lipids, the effect of azone on the resistance confirms that the resistance mainly resides within the intercellular lipids of the stratum corneum. No correlation was found between the iontophoretic DGAVP-flux and the conductance of human skin. For shed snake skin, however, a good correlation was found, indicating that the iontophoretic permeability of human skin in vitro for a peptide such as DGAVP is, unlike shed snake skin, not related to its overall permeability to ions. While the initial resistances of both human and snake skin were in the same order of magnitude and showed the same declining profile during iontophoresis, the steady state iontophoretic DGAVP flux across human stratum corneum was approximately 140 times larger than through shed snake skin. These findings suggest that small ions follow pathways common to both skin types, presumably the intercellular route, while the peptide on the other hand is transported differently: across snake skin presumably along intercellular pathways only, but across human stratum corneum along additional pathways (most likely of appendageal origin) as well. This interpretation is supported by the observations made of the effects of dodecyl-azone on DGAVP-iontophoresis. Pretreatment with dodecyl-azone did not significantly change steady state fluxes and lag times of DGAVP-iontophoresis across human stratum corneum, but resulted in a significant 3-fold lag time decrease and a 3-fold flux increase of DGAVP-iontophoresis across snake skin. Conclusions. The results of these in vitro studies emphasize the importance of the appendageal pathway for iontophoretic peptide transport across human stratum corneum.     

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

Purpose To demonstrate the transdermal iontophoretic delivery of a small (12.4 kDa) protein across intact skin. Materials and Methods 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). Results The data confirmed the transdermal iontophoretic delivery of intact Cyt c. Electromigration was the principal transport mechanism, accounting for ∼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 μg.cm⁻².h⁻¹, respectively) were statistically equivalent. Formulation in PBS (pH 8.2) confirmed the impact of competing charge carriers; inclusion of ∼170 mM Na⁺ resulted in a 3.9-fold decrease in total flux. Conclusions Significant amounts (∼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 selegiline hydrochloride,in vitro

Transdermal iontophoretic delivery of selegiline hydrochloride (SH) across dermatomed human skin was studied. Electrochemical stability and various factors affecting the skin permeation were investigated. SH was stable under the influence of an electrical field. The permeation of SH was very low by passive delivery (2.29?±?0.05 μg/cm²/h) as compared to iontophoresis at 0.5 mA/cm² (65.10?±?5.04 μg/cm²/h). An increase in drug concentration from 1 to 20?mg/mL increased the iontophoretic flux by 13-fold. Optimal pH and salt (NaCl) concentration for iontophoretic delivery of SH were found to be pH 5 and 100?mM, respectively. Overall, with 20?mg/mL SH and a current density of 0.4 mA/cm², a maximum flux of 305.5?μg/cm²/h was obtained. Based on reported pharmacokinetic parameters, input target delivery rate to achieve effective plasma concentration of SH (2.2?ng/mL) was calculated. With a surface area of 40?cm², iontophoretic delivery can provide six to seven times higher levels of SH than the target delivery rate, which enables lowering of the dose and/or patch surface area. Further in vivo studies will be required to prove the efficacy of ionophoresis for enhanced delivery of SH.     

Iontophoretic Transdermal Delivery of Haloperidol

The in vitro iontophoretic transdermal delivery of haloperidol (HP) across pig skin was investigated. Anodal iontophoresis considerably increased HP skin penetration and accumulation as compared to the passive controls.

The effect of NaCl and HP concentrations on the vehicle were also studied. As expected, HP iontophoretic transport decreased with NaCl content. On the other hand, HP concentration did not modify its electrotransport in the range of concentrations between 0.4 and 0.9 mg/mL, except at 24 hours. The influence of the current density (0.20–0.50 mA/cm²) was also investigated. The iontophoretic transport of HP tends to increase with current density. On the whole, this work shows that iontophoresis may be used to improve the topical application of HP for the treatment of chronic psychosis.     

Transdermal iontophoretic delivery of [3H]GHRP in rats

In this study, we demonstrate transdermal iontophoretic delivery of radiolabeled growth hormone-releasing peptide ([³H]GHRP, [³H]SK&F 110 679) from an iontophoretic patch delivery device in rats. [³H]SK&F 110 679 was adsorbed on a hydrophilic microporous membrane, which was positioned on a support in the device and sealed in place. A silver/silver chloride electrode system was used for iontophoresis and a potential of 4.5 V (rectangular pulse, 40 kHz, 30% duty cycle) was applied using an Advance depolarizing pulse iontophoresis system (ADIS-4030). Current-dependent appearance of [³H]SK&F 110 679 equivalents in blood, bile and urine did not depend on membrane loading between 1.8 and 8 mg adsorbed on the membrane. Blood levels of [³H]SK&F 110 679 equivalents persisted for at least 2 h after the current was turned off, indicative of depot formation in the skin. Fractions of bile and urine were analyzed by reversed-phase high-performance liquid chromatography (HPLC). The radiochemical profiles were dominated by a single species, coeluting with intact [³H]SK&F 110 679. A flux of at least 0.8–1.2 ug/h per cm² was achieved, indicating that, with appropriate optimization of the patch device, therapeutic levels of SK&F 110 679 in man may be attainable by transdermal iontophoresis.     

Transdermal Iontophoretic Delivery of Vapreotide Acetate AcrossPorcine Skin <Emphasis Type="BoldItalic">in Vitro</Emphasis>

Purpose The purpose of this study was to evaluate the feasibility of delivering vapreotide, a somatostatin analogue, by transdermal iontophoresis.Methods 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.Results 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 μg/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 μg 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.Conclusion 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.     

Iontophoretic Delivery of Apomorphine In Vitro: Physicochemic Considerations

Purpose. To examine the mechanisms of transdermal iontophoretic delivery of apomorphine. Methods. Anodal iontophoresis of R-apomorphine across human stratum corneum was determined in vitro. The effects on the flux of the following parameters were studied: stability of drug, pH of donor solution, concentration of NaCl, and type of Na⁺ co-ions. Results. Ascorbic acid was effective to prevent apomorphine degradation. The iontophoretic transport of apomorphine was strongly influenced by the pH of the donor formulation. Increasing the pH from 3 to 6 resulted in an increase in the iontophoretic apomorphine flux from 27.9 ± 4.4 nmol/cm²*h to 78.2 ± 6.9 nmol/cm²*h. Upon decreasing NaCl concentration from 8 to 2 g/L, the iontophoretic flux was not significantly changed. Replacing NaCl in the donor formulation by tetraethylammonium chloride or tetrabutylammonium chloride resulted in 1.3 fold greater steady-state flux. Conclusions. For optimized apomorphine iontophoretic delivery, a constant pH of the donor formulation is of great importance. The results suggest that although flux enhancement during iontophoresis is largely due to the electrical potential gradient, secondary effects, such as convective flow and electroosmosis may also contribute.     

Delivery and stability of LHRH and Nafarelin in human skin: the effect of constant/pulsed iontophoresis.

Poor absorption and stability of peptides are the major obstacles concerning the development of therapeutically relevant iontophoretic devices for the transdermal delivery of peptides. The present study examined the impact of constant and pulsed (direct/alternating) current profiles on the transport and stability of two decapeptides LHRH and Nafarelin. The stability of these peptides was studied in a physiological buffer solution, with electrical current, and when the peptide solution was exposed to the stratum corneum or to the epidermal/dermal side of human skin. Pulsed direct current profile was shown to be the most efficient in transporting both LHRH and Nafarelin across the human epidermis. Furthermore, the percentage of intact LHRH in the receiver phase was slightly higher when a pulsed current profile was used. Both the peptides were stable in a physiological buffer and under the influence of current, but LHRH was degraded especially in contact with the dermal side of the skin. Altogether five hydrolytic degradation products of LHRH were observed, and they were identified by LC-ESI/MS and LC-ESI/MS/MS. No degradation products of Nafarelin were observed. It is concluded that the pulsed direct current profile may provide at least a partial solution for the transdermal delivery of peptides in terms of improved transport efficacy and peptide stability.     

A novel method to enhance the efficiency of drug transdermal iontophoresis delivery by using complexes of drug and ion-exchange fibers

The main reason for generally low efficiency of the transdermal iontophoretic drug delivery is that the fraction of the total current contributed by the drug ions is very small. The objective of this study was to find a method to increase the fraction of the total current contributed by the drug ions so as to enhance the drug's iontophoretic delivery. Iontophoretic transport of diclofenac solution and diclofenac assisted by ion exchange materials, including ion-exchange resin, ion-exchange membrane and ion-exchange fiber, across the rat skin were investigated. Both in vitro and in vivo iontophoretic transport experiments showed the amount of diclofenac permeated across rat skin from the diclofenac-fibers was highest among those from the diclofenac simple solutions and ion exchange materials complexes. The results of this study suggested that there is an enhancement of drug across rat skin by ion-exchange fibers in ion-exchange fibers assisted iontophoresis. The present study has demonstrated the potential of a new approach using ion-exchange fibers to enhance transdermal iontophoretic transport of an ionizable drug.     

Iontophoretic transdermal delivery of buspirone hydrochloride in hairless mouse skin

The transdermal delivery of buspirone hydrochloride across hairless mouse skin and the combined effect of iontophoresis and terpene enhancers were evaluated in vitro using Franz diffusion cells. Iontophoretic delivery was optimized by evaluating the effect of drug concentration, current density, and pH of the vehicle solution. Increasing the current density from 0.05 to 0.1 mA/cm² resulted in doubling of the iontophoretic flux of buspirone hydrochloride, while increasing drug concentration from 1% to 2% had no effect on flux. Using phosphate buffer to adjust the pH of the drug solution decreased the buspirone hydrochloride iontophoretic flux relative to water solutions. Incorporating buspirone hydrochloride into ethanol:water (50:50 vol/vol) based gel formulations using carboxymethylcellulose and hydroxypropylmethylcellulose had no effect on iontophoretic delivery. Incorporation of three terpene enhancers (menthol, cineole, and terpineol) into the gel and when combined with iontophoresis it was possible to deliver 10 mg/cm²/day of buspirone hydrochloride.     

Transport of Ionic Species in Skin: Contribution of Pores to the Overall Skin Conductance

Two methods are reported that allow visualization of high conductance paths in skin at current densities typically used during clinical iontophoretic drug delivery (10–200 µA/cm²). In the first method, the counter-directional iontophoretic transport of Fe(CN)₆ ^4– and Fe³⁺ across skin results in the precipitation of colloidal prussian blue, Fe₄[Fe(CN)₆]₃, at sites of high iontophoretic flux. The appearance of localized deposits of Fe₄[Fe(CN)₆]₃ is recorded by video microscopy and used to document the activation of low-resistance paths. In the second method, the ionic flux of Fe(CN)₆ ^4– through pores is directly imaged by scanning electrochemical microscopy (SECM). Both methods demonstrate that the iontophoretic flux across skin is highly localized. Activation of low-resistance pores in hairless mouse skin is shown to occur during iontophoresis. The spatial density of current carrying pores increases from 0 to 100–600 pores/cm² during the first 30–60 min of iontophoresis. At longer times, the active pore density approaches a quasi-steady-state value that is proportional to the applied current density. The total conductance of the skin is proportional to the number of pores, consistent with a model of conduction in skin that is comprised of low-resistivity pores in parallel with a high-resistivity bulk phase. The contribution of pores to the total skin conductance during iontophoresis increases from an initial value of 0–5% to a quasi-steady-state value of 50–95%.     

Reverse Iontophoresis: Development of a Noninvasive Approach for Glucose Monitoring

Solvent flow generated during iontophoresis can be used to convect neutral molecules through the skin, thereby greatly enhancing their flux. This concept was exploited to realize noninvasive glucose measurement by its iontophoretic extraction from the subcutaneous tissue. The hypothesis was tested in vitro using hairless mouse skin. The dermal surface was bathed with a glucose solution; chambers on the epidermal surface housed the current delivery electrodes. Iontophoresis (at 0.36 mA/cm²) was performed for 2 hr, at the end of which the solutions in contact with the electrodes were analyzed. The amount extracted was proportional to the glucose solution concentration bathing the dermis. Higher radioactivity levels were found at the anode than at the cathode, possibly because of glucose metabolism during its outward transport across the skin. Glucose biotransformation results in negatively charged metabolites which migrate to the anode. Two sensitive glucose sensors were developed; one was selective for glucose, the other for glucose and related compounds. Both sensors indicated the presence of glucose at the cathode but an abnormally high value was also recorded at the anode. This signal, however, was not due to glucose but rather to electroactive ascorbate withdrawn from the skin. Finally, a system has been developed with which glucose can be extracted noninvasively from the subcutaneous tissue and unambiguously measured. Whether iontophoretic glucose sampling in vivo will be equally suc-cessful remains to be answered.     

lontophoretic Delivery of a Series of Tripeptides Across the Skin in Vitro

The iontophoresis of eight tripeptides, of the general structure alanine–X–alanine, has been measured across hairless mouse skin in vitro. The peptides were blocked (a) at the carboxyl terminus using the mixed anhydride reaction with t-butylamine and (b) at the amino terminus by acetylation with ¹⁴C-acetic anhydride. The nature of the central residue (X) was varied by selecting one of five neutral amino acids, two negatively chargeable moieties (aspartic and glutamic acids), and a positively chargeable species (histidine). Constant current iontophoresis at 0.36 mA/cm², using Ag/AgCl electrodes, was performed for 24 hr in diffusion cells, which allowed both anode and cathode to be situated on the same (epidermal) side of a single piece of skin. Due to a combination of osmotic and electroosmotic forces, the anodal iontophoretic flux of neutral peptides was significantly greater than passive transport. Steady-state fluxes were not achieved, however, suggesting that time-dependent changes in the properties of the skin barrier may be occurring. Limited, further experiments confirmed that, on a 24-hr time scale, these changes were not fully reversible. The cathodal delivery of anionic permeants was well controlled at a steady and highly enhanced rate by the current flow. This behavior closely paralleled earlier work using simple negatively charged amino acids and N-acetylated amino acid derivatives. It appears that the normalized iontophoretic flux of these anionic species is independent of lipophilicity but may be inversely related to molecular weight. The positively charged peptide, Ac–Ala–His–Ala–NH(Bu^t), showed greater anodal iontophoretic enhancement when delivered from a donor solution at pH 4.0 than from a solution at pH 7.4. This was consistent with (a) the corresponding behavior of histidine alone and (b) the existence of a pK _a for these compounds at 6. Steady-state delivery was not achieved, although the levels of enhancement, especially at pH 4, were the largest observed. A preliminary investigation of tripeptide stability to either (i) electrolysis in the donor compartment or (ii) cutaneous metabolism revealed very little degradation under the conditions of the experiment. Overall, this research supports the principle of enhanced peptide delivery across the skin by iontophoresis and indicates a number of areas (e.g., mechanism and extent of current-induced changes in skin barrier function, molecular size dependence, pathways of current flow) on which further work should be focused.     

Passive and iontophoretic transdermal delivery of phenobarbital: Implications in paediatric therapy

The objective of this investigation was to evaluate phenobarbital transdermal delivery for possible use in paediatric care. In vitro experiments were performed using intact pig skin and barriers from which the stratum corneum had been stripped to different extents to model the less resistant skin of premature babies. Cathodal iontophoretic delivery of phenobarbital was superior to anodal transport and optimised delivery conditions were achieved by reduction of competing co-ion presence in the drug formulation. Phenobarbital transport across intact or partially compromised skin was controlled by iontophoresis which was more efficient than passive diffusion. Across highly compromised skin, however, passive diffusion increased drastically and iontophoretic control was lost. Overall, this study demonstrates the feasibility of phenobarbital transdermal delivery for paediatric patients.     

Physicochemical considerations in the iontophoretic delivery of a small peptide: in vitro studies using arginine vasopressin as a model peptide.

Transdermal iontophoresis (TI) is a physical enhancement technique to facilitate the delivery of primarily charged molecules across the skin. TI of peptides is influenced by a complex interplay of several factors and one of the main issues in optimizing iontophoretic delivery of peptides is to improve the transport efficiency.From this perspective, this study investigates the effect of the physicochemical parameters on the TI of a peptide arginine vasopressin (AVP). The permeation of AVP showed a linear dependence on the concentration of drug in the donor medium. The iontophoretic flux of AVP was strongly influenced by the pH of the donor solution. Increasing the pH from 5.16 to 7.4 resulted in a decrease in the enhancement ratio by 4.5 times. When the ionic strength was increased by varying the amount of NaCl from 0.05 to 0.25 M the flux was found to decrease by 3.2 times. Replacing normal saline in the receptor compartment by HEPES buffer showed a resultant four times increase in drug permeation. The physiochemical parameters of the donor medium play a significant role in the efficiency of drug delivery by iontophoresis for a small peptide like AVP. Though electrorepulsion would be expected to be the main mechanism involved in the movement of charged molecules across the skin by iontophoresis, for peptides in the molecular weight range of AVP, other associated secondary effects like osmosis, electroosmosis and counter ion flow may also play a significant role in transport across the skin.     

Hydrogel-Based lontotherapeutic Delivery Devices for Transdermal Delivery of Peptide/Protein Drugs

Hydrogels were synthesized as the drug reservoir matrix for peptide-based pharmaceuticals, and the iontophoretic release and transdermal delivery of three model peptides, insulin, calcitonin, and vasopressin, from these hydrogel-based iontotherapeutic devices were investigated. The swelling behavior of polyacrylamide-type hydrogel as a function of its monomer and cross-linker concentration was studied, and a hydrogel with minimal swelling was synthesized. The release of peptides from the hydrogel matrix was found to follow a Q vs t ^1/2 relationship under passive diffusion conditions, which shifted to a Q vs t relationship under iontophoresis-facilitated transport. The release flux (dQ/dt) of peptides was observed to decline when the electric current was turned off and was resumed when the current was turned on, thus allowing for modulation of drug release by varying the application parameters of iontophoresis-facilitated transport. The permeability coefficients for these peptides across the hairless rat skin were evaluated using the hydrogel formulations prepared from polyacrylamide, p-HEMA, and carbopol. A rank order of vasopressin > calcitonin > insulin was obtained in accordance with the order of molecular size.     

Using laser microporation to improve transdermal delivery of diclofenac: Increasing bioavailability and the range of therapeutic applications

The objective of the study was to investigate the effect of laser microporation, using P.L.E.A.S.E.® technology, on diclofenac delivery kinetics. Skin transport of diclofenac was studied from aqueous solution, propylene glycol and marketed formulations across intact and laser-porated porcine and human skins; cumulative permeation and skin deposition were quantified by HPLC. After 24 h, cumulative diclofenac permeation across skins with 150, 300, 450 and 900 shallow pores (50-80 μm) was 3.7-, 7.5-, 9.2- and 13-fold superior to that across untreated skin. It was also found to be linearly dependent on laser fluence; Permeation (μg/cm²) = 11.35 * Fluence (J/cm²) + 352.3; r² = 0.99. After 24 h, permeation was 539.6 ± 78.1, 934.5 ± 451.5, 1451.9 ± 151.3 and 1858.6 ± 308.5 μg/cm², at 22.65, 45.3, 90.6 and 135.9 J/cm², respectively. However, there was no statistically significant effect of laser fluence on skin deposition. Diclofenac delivery from marketed gel formulations was also significantly higher across laser-porated skins (e.g. for Solaraze™, cumulative permeation after 24 h across treated (900 pores/135.9 J/cm²) and untreated skin was 974.9 ± 368.8 and 8.2 ± 3.8 μg/cm², respectively. Diclofenac delivery from Solaraze™ across laser-porated porcine and human skins was also shown to be statistically equivalent. The results demonstrated that laser microporation significantly increased diclofenac transport from both simple and semi-solid formulations through porcine and human skin and that pore depth and pore number could modulate delivery kinetics. A similar improvement in topical diclofenac delivery in vivo may increase the number of potential therapeutic applications.     

Effect of Electroporation on Transdermal lontophoretic Delivery of Luteinizing Hormone Releasing Hormone (LHRH) in Vitro

Electroporation, the creation of transient, enhanced membrane permeability using short duration (microseconds to millisecond) electrical pulses, can be used to increase transdermal drug delivery. The effect of an (electroporative) electric pulse (1000 V, = 5 msec) on the iontophoretic transport of LHRH through human skin was studied in vitro. Fluxes achieved with and without a pulse under different current densities (0- 4 mA/cm²) were compared. The results indicated that the application of a single pulse prior to iontophoresis consistently yielded higher fluxes (5—10 times the corresponding iontophoretic flux). For example, at 0.5 mA/cm² fluxes were 0.27 ± 0.08 and 1.62 ± 0.05 µg/hr/cm² without and with the pulse, respectively. At each current density studied, the LHRH flux decreased after iontophoresis, approaching pre-treatment values. The results show that electroporation can significantly and reversibly increase the flux of LHRH through human skin. These results also indicate the therapeutic utility of using electroporation for enhanced transdermal transport.     

An <Emphasis Type="BoldItalic">Ex Vivo</Emphasis> Toe Model Used to Assess Applicators for the Iontophoretic Ungual Delivery of Terbinafine

Purpose  An ex vivo intact toe model was developed to assess two different applicator designs for iontophoretic delivery of terbinafine into the nail only or the nail and surrounding skin. Methods  Iontophoretic permeation studies were carried out on intact cadaver toes using nail-only and nail/skin applicators with a current dose of 10 mA*min (0.5 mA for 20 min). Results  Iontophoresis enhanced drug permeation and tissue loading with both applicators tested. Greater drug delivery was observed with the nail/skin applicator due to the additional terbinafine being delivered directly through the lower impedance skin area surrounding the nail. The concentration of drug loaded into the contact area of the nail with the nail-only and nail/skin applicator was ~13 and ~7 fold higher than their respective passive delivery levels but equivalent from each other in total drug mass delivered over the whole nail plate. In vitro release of drug from the iontophoretically loaded nails into agar suggests that a single treatment could have a prolonged effect (>50 days). Conclusions  This study demonstrates that the ex vivo toe model was useful in assessing the functionality of the different applicator designs. These results suggest that iontophoresis can significantly enhance the delivery of drugs to both the hard and soft tissues of the toe for the treatment of onychomycosis and other nail disorders.