Pretreatment with a Water-Based Surfactant Formulation Affects Transdermal Iontophoretic Delivery of R-Apomorphine in Vitro

Purpose. To further increase the transdermal transport rate of R-apomorphine, a nonocclusive pretreatment with an aqueous surfactant formulation in combination with iontophoresis was explored in vitro. Methods. The human stratum corneum was pretreated nonocclusively with formulations composed of laureth-3 oxyethylene ether (C₁₂EO₃), laureth-7 oxyethylene ether (C₁₂EO₇), and cholesterol sulfate (CSO₄) prior to iontophoresis. The effect on the flux of the following parameters was examined: the composition, the charge, and the applied amount of surfactant formulations. Results. The iontophoretic flux of R-apomorphine was appreciably increased by pretreatment with surfactant formulations. A formulation containing C₁₂EO₃/C₁₂EO₇/CSO₄ at a molar ratio of 70:30:5 was very stable and increased the iontophoretic flux of R-apomorphine from 92.2 ± 13.9 nmol/cm²*h to 181.5 ± 22.6 nmol/cm²*h. When further increasing the negative charge of this formulation the iontophoretic transport rate was slightly inhibited. A dose of 40 L/cm² of the formulation with a total surfactant concentration of 5% (w/w) was sufficient for a maximum enhancing effect. Conclusions. The results obviously show that nonocclusive pretreatment with the surfactant formulation enhances the iontophoretic transport of R-apomorphine, and is a promising approach to achieve therapeutic concentrations of R-apomorphine.     

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 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.     

Mechanisms Involved in lontophoretic Transport of Angiotensin

Purpose. The feasibility of using iontophoresis to enhance the permeation rate of a model peptide was investigated in vitro using hairless mouse skin. Methods. Angiotensin 2 (AT 2) was employed as a permeant probe, using optimum iontophoresis conditions. A number of physicochemical parameters (donor ionic strength; valence of competitive ions; pH of donor solution) were studied with the aim of exploring the mechanisms involved in the iontophoretic transport through the skin: electrokinetic transport or convective transport. For this purpose, the magnitude of the convective solvent flow was also evaluated by the permeation of (³H) H₂O. The interest of pulsed currents for peptide delivery was also investigated and the effect of current density and frequency was studied. Results. AT 2 transport was found to be enhanced 20-fold in comparison to passive permeation and was found to be proportional to the current density with direct currents as with pulsed currents. Conclusions. Although the flux enhancement of ions during iontophoresis is due principally to the electrical potential gradient, secondary effects such as convective solvent flow contribute also to flux enhancement of peptide delivery. This effect is dependent of physicochemical conditions of formulation.     

Iontophoresis of a Model Peptide Across Human Skin in Vitro: Effects of Iontophoresis Protocol,pH, and Ionic Strength on Peptide Flux and Skin Impedance

This study deals with effects of electrical (current density, frequency and duty cycle) and chemical (buffer pH and ionic strength) conditions on the flux of the octapeptide, 9-desglycinamide, 8-arginine-vasopressin (DGAVP), through dermatomed human skin. A pulsed constant current was applied during iontophoresis. The anode faced the anatomical surface of the skin samples inside the diffusion cells. The resistive and capacitative components of the equivalent electrical circuit of human skin could be calculated by fitting the voltage response to a bi-exponential equation. The skin resistance prior to iontophoresis varied between 20 and 60 k .cm². During iontophoresis a decrease of skin resistance and an increase of the series capacitances was observed, which were most pronounced during the first hour of iontophoresis; thereafter both quantities gradually levelled off to an apparent steady state value. The reduction of the resistance during iontophoresis increased non-linearly with increasing current density between 0.013–0.64 mA.cm^–2. The steady state resistance and capacitances did not vary significantly with frequency and duty cycle of the current pulse. There was no pH dependence of skin resistance at steady state. Between pH 4 and 10, the steady state peptide flux had a bell-shaped pH-dependence with a maximum of 0.17 nmol.cm^–2.h^–1 at pH 7.4, which is close to the I.E.P. of the peptide. Lowering the ionic strength from 0.15 to 0.015 M NaCl increased the steady state flux at pH 5 and pH 8 by a factor 5 to 0.28 ± 0.21 and 0.48 ± 0.37 nmol.cm^–2.h^–1, respectively. Together these observations suggested that DGAVP is transported predominately by volume flow. At pH 6, at which 65% of the peptide carried a net single positive charge, the steady state flux increased with increasing current density (0.013–0.64 mA.cm^–2) from 0.11 ± 0.03 to 0.19 ± 0.04 nmol.cm^–2.h^–1. Skin permeability during passive diffusion preceding iontophoresis at pH 6.0 was 2.9 ± 0.6 * 10^–7 cm.h^–7. In accordance with theoretical predictions based on the Nernst-Planck equation, to which a volume flow term was added, the flux was proportional to the mean voltage across the skin between 0.013 and 0.32 mA.cm^–2.h^–1. Variation of frequency or duty cycle did not result in significantly different peptide transport rates. From these studies it is concluded that DGAVP can be transported iontophoretically through human skin. The pH- and ionic strength-dependence of the iontophoretic peptide flux suggests that transport of DGAVP mainly occurs by volume flow. Furthermore, the flux of DGAVP appears to be controlled by the applied voltage rather than by the current density, as predicted by the Nernst-Planck equation.     

lontophoretic Delivery of Apomorphine I: In Vitro Optimization and Validation

Purpose. To investigate the feasibility of transdermal iontophoretic delivery of apomorphine in patients with Parkinson's disease, transdermal transport rates were optimized and validated across human stratum corneum and freshly dermatomed human skin in vitro. Methods. In all experiments R-apomorphine hydrochloride was applied in the anodal compartment. The effect on the flux of the following parameters was studied, using a flow through transport cell: current density, pH, concentration, ionic strength, osmolarity, buffer strength, temperature and skin type. Results. Transdermal transport of apomorphine was directly controlled by the presence or absence of current. Passive delivery was minimal and no depot effect was observed. A linear relationship was found between current density and steady-state flux. At room temperature the lag time was 30 to 40 minutes. A maximal steady-state flux was obtained when the donor concentration approached maximum solubility. By increasing the temperature of the acceptor chamber to 37°C, the steady-state flux was increased by a factor of 2.3 and the lag time decreased to ± 3 minutes. No effect of osmolarity and buffer strength, and only a small effect of ionic strength and pH on the transport rate were observed. The flux through dermatomed human skin was decreased compared to stratum corneum. This effect was shown not to be caused by skin metabolism. Conclusions. The results obtained in vitroindicate that the iontophoretic delivery of apomorphine can be controlled and manipulated accurately by the applied current. The in vitro flux furthermore depends on the donor composition, temperature and skin type. Under optimized conditions, transport rates resulting in therapeutically effective plasma concentrations are feasible, assuming a one to one in vitro/in vivo correlation.     

Transdermal Iontophoresis of Rotigotine Across Human Stratum Corneum in Vitro: Influence of pH and NaCl Concentration

PURPOSE: The aim of this study was to characterize the influence of pH and NaCl concentration on the transdermal iontophoretic transport of the dopamine receptor agonist rotigotine across human stratum corneum (HSC). METHODS: Rotigotine transport was studied in vitro in side by side diffusion cells according to the following protocol: 6 h of passive diffusion, 9 h of iontophoresis, and 5 h of passive diffusion. A current density of 0.5 mA cm(-2) was used. The influence of donor phase pH (4, 5, and 6) and different concentrations of NaCl (0.07 and 0.14 M) on rotigotine iontophoretic flux were examined. The acceptor phase was phosphate-buffered saline (PBS) at pH 7.4 except in one series of experiments aimed to study the effects of rotigotine solubility on its iontophoretic transport. In this study, PBS at pH 6.2 was used. In separate studies. 14C-mannitol was used as a marker to determine the role of electro-osmosis during iontophoresis. RESULTS: The estimated iontophoretic steady-state flux (Flux(ss)) of rotigotine was influenced by the pH of the donor solution. At a drug donor concentration of 0.5 mg ml(-1), the iontophoretic flux was 30.0 +/- 4.2 nmol cm(-2) h(-1) at pH 6 vs. 22.7 +/- 5.5 nmol cm(-2) h(-1) at pH 5. However, when the donor concentration was increased to 1.4 mg ml(-1), no significant difference in iontophoretic rotigotine transport was observed between pH 5 and 6. Increase of NaCl concentration from 0.07 M to 0.14 M resulted in a decrease of the rotigotine Flux(ss) from 22.7 +/- 5.5 nmol cm(-2) h(-1) to 14.1 +/- 4.9 nmol cm(-2) h(-1). The contribution of electro-osmosis was estimated less than 17%. Probably due to the lipophilic character of the drug, impeding the partitioning of rotigotine from HSC to the acceptor compartment, steady-state transport was not achieved during 9 h of iontophoresis. CONCLUSIONS: Both pH and NaCl concentration of the donor phase are crucial on the iontophoretic transport of rotigotine. Electro-repulsion is the main mechanism of the iontophoretic transport of rotigotine.     

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.     

Ion-exchange and iontophoresis-controlled delivery of apomorphine

The objective of this study was to test a drug delivery system that combines iontophoresis and cation-exchange fibers as drug matrices for the controlled transdermal delivery of antiparkinsonian drug apomorphine. Positively charged apomorphine was bound to the ion-exchange groups of the cation-exchange fibers until it was released by mobile counter-ions in the external solution. The release of the drug was controlled by modifying either the fiber type or the ionic composition of the external solution. Due to high affinity of apomorphine toward the ion-exchanger, a clear reduction in the in vitro transdermal fluxes from the fibers was observed compared to the respective fluxes from apomorphine solutions. Changes in the ionic composition of the donor formulations affected both the release and iontophoretic flux of the drug. Upon the application of higher co-ion concentrations or co-ions of higher valence in the donor formulation, the release from the fibers was enhanced, but the iontophoretic steady-state flux was decreased. Overall, the present study has demonstrated a promising approach using ion-exchange fibers for controlling the release and iontophoretic transdermal delivery of apomorphine.     

Electrically Modulated Transdermal Delivery of Fentanyl

Purpose. Test to determine if iontophoresis and electroporation, alone or in combination, can be used for rapid and modulated delivery of fentanyl. Methods. Fentanyl citrate (5 mg/ml) dissolved in pH 4.0 citrate buffer was delivered in vitro across human epidermis. For iontophoresis, a current of 0.5 mA/cm² was applied for 5 h, using silver/silver chloride electrodes. Electroporation protocol consisted of applying 15 exponential pulses of 500V (applied voltage) and 200 msec duration at the rate of 1 pulse per minute at time zero and, in some cases, repeating at 1.5 and 2.5 h. Results. There was no measurable permeation of fentanyl through human epidermis under passive conditions. A significant flux (about 80 g/cm²-hr) was achieved using iontophoresis and decreased once the current was turned off. A 4-fold higher flux and shorter lag time was observed with electroporation as compared to iontophoresis. The flux was found to recover quickly (within 1 h) following pulsing. Modulation of transdermal delivery of fentanyl was demonstrated by both iontophoresis and electroporation. Conclusions. Electrically assisted transdermal delivery of fentanyl significantly increased transport compared to passive delivery. Also, rapid and modulated delivery was shown to be feasible by programming the electrical parameters.     

Iontophoretic Delivery of 5-Aminolevulinic Acid (ALA): Effect of pH

Purpose. To examine the iontophoretic delivery of ALA as a function of pH and to determine the principal mechanisms responsible for its electrotransport. Methods. Anodal iontophoretic transport of ALA was measured as a function of its concentration and pH of the donor solution. Experiments were performed in vitro using skin excised from porcine ears as the membrane. To deduce mechanism, the concomitant transport of the electroosmotic marker, mannitol, was also assessed. Results. ALA iontophoresis at pH 7.4 is a linear function of concentration over the range 1-100 mM. The mechanism was deduced to be electroosmosis. By reducing the pH from 7.4 to 4.0, the dominant mechanism of ALA transport was shifted from electroosmosis to electrorepulsion as the skin's net negative charge was progressively neutralized. However, the total delivery of the compound was not altered by lowering the pH suggesting that the increased electrorepulsive contribution was essentially balanced by the concomitantly reduced electroosmosis. Conclusions. Significant ALA delivery at pH 7.4 can be achieved by increasing the drug concentration in the anodal formulation to 100 mM. Lowering the pH does not result in increased ALA transport. Alternative strategies are therefore required to maximize and optimize ALA delivery by iontophoresis.     

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.     

lontophoretic Delivery of a Telomeric Oligonucleotide

Purpose. To evaluate the feasibility of iontophoretically enhanced transdermal delivery of a phosphorothioate oligonucleotide across hairless mouse skin. Methods. The phosphorothioate sequence, 5-d(TTAGGG)-3 (TAG-6) which mimics the repeat sequence of the telomere was used as a model compound. Iontophoresis was performed on hairless mouse skin using an in vitro flow-through diffusion system. Both 5-FITC and uniformly ³⁵S labeled oligonucleotide were used to monitor transdermal flux. Results. Cathodal delivery of TAG-6 resulted in substantial oligonucleotide flux. The molecular label did not alter transport properties. No flux was measured with either anodal or passive delivery. The oligonucleotide was not degraded as it crossed the skin. Molecular transport was donor condition dependent, with pH and salt concentration both having significant effects. Pre-treating the skin with ethanol reduced iontophoretic transport. Conclusions. These data demonstrate that iontophoresis can enhance transdermal flux of an intact phosphorothioate oligonucleotide and that this penetration is donor condition dependent. Furthermore, iontophoretically enhanced transdermal delivery is a feasible apprach to the administration of phosphorothioate oligonucleotides.     

Controlled delivery of ropinirole hydrochloride through skin using modulated iontophoresis and microneedles

Abstract

The objective of this study was to investigate the effect of modulated current application using iontophoresis- and microneedle-mediated delivery on transdermal permeation of ropinirole hydrochloride. AdminPatch® microneedles and microchannels formed by them were characterized by scanning electron microscopy, dye staining and confocal microscopy. In vitro permeation studies were carried out using Franz diffusion cells, and skin extraction was used to quantify drug in underlying skin. Effect of microneedle pore density and ions in donor formulation was studied. Active enhancement techniques, continuous iontophoresis (74.13?±?2.20?µg/cm²) and microneedles (66.97?±?10.39?µg/cm²), significantly increased the permeation of drug with respect to passive delivery (8.25?±?2.41?µg/cm²). Modulated iontophoresis could control the amount of drug delivered at a given time point with the highest flux being 5.12?±?1.70?µg/cm²/h (5–7?h) and 5.99?±?0.81?µg/cm²/h (20–22?h). Combination of modulated iontophoresis and microneedles (46.50?±?6.46?µg/cm²) showed significantly higher delivery of ropinirole hydrochloride compared to modulated iontophoresis alone (84.91?±?9.21?µg/cm²). Modulated iontophoresis can help in maintaining precise control over ropinirole hydrochloride delivery for dose titration in Parkinson’s disease therapy and deliver therapeutic amounts over a suitable patch area and time.     

Effect of Charge and Molecular Weight on Transdermal Peptide Delivery by Iontophoresis

Purpose The study was conducted to investigate the impact of charge and molecular weight (MW) on the iontophoretic delivery of a series of dipeptides. Methods Constant current iontophoresis of lysine and 10 variously charged lysine- and tyrosine-containing dipeptides was performed in vitro. Results Increasing MW was compensated by additional charge; for example, Lys (MW = 147 Da, +1) and H-Lys-Lys-OH (MW = 275 Da, +2) had equivalent steady-state fluxes of 225 ± 48 and 218 ± 40 nmol cm⁻² h⁻¹, respectively. For peptides with similar MW, e.g., H-Tyr-d-Arg-OH (MW = 337 Da, +1) and H-Tyr-d-Arg-NH₂ (MW = 336 Da, +2), the higher valence ion displayed greater flux (150 ± 26 vs. 237 ± 35 nmol cm⁻² h⁻¹). Hydrolysis of dipeptides with unblocked N-terminal residues, after passage through the stratum corneum, suggested the involvement of aminopeptidases. The iontophoretic flux of zwitterionic dipeptides was less than that of acetaminophen and dependent on pH. Conclusions For the series of dipeptides studied, flux is linearly correlated to the charge/MW ratio. Data for zwitterionic peptides indicate that they do not behave as neutral (“charge-less”) molecules, but that their iontophoretic transport is dependent on the relative extents of ionization of the constituent ionizable groups, which may also be affected by neighboring amino acids.     

A Review of: “Excipient Development for Pharmaceutical,Biotechnology, and Drug Delivery Systems”

The feasibility of delivering hydromorphone by transdermal iontophoresis to obtain therapeutically effective analgesic concentrations for the management of cancer-related pain was evaluated. Anodal iontophoresis was performed, and the effect of current strength, current duration, solution pH, presence of buffer ions, and drug concentration on the transdermal permeation of hydromorphone was investigated in vitro. Freshly excised full‐thickness hairless rat skin and side-by-side permeation cells connected to the Phoresor II^TM with Ag/AgCl electrodes was used. The flux of hydromorphone was observed to significantly increase (P < 0.05) from 72.04–280.30 μg/cm²/h with increase in current strength from 0.10–0.50 mA. A linear relationship was obtained between hydromorphone flux and current strength. Furthermore, the flux of hydromorphone was influenced by solution pH and presence of buffer ions. Also, the in vitro permeation flux of hydromorphone was observed to significantly increase (P < 0.05) with a 10-fold increase in hydromorphone hydrochloride concentration from 0.01–0.10 M. However, with further increase to 0.50 M, there was no significant difference in flux. These results show that by manipulating electronic and formulation variables, the transdermal iontophoretic delivery of hydromorphone can be controlled, and therapeutically effective concentrations of hydromorphone for the management of cancer-related pain can be obtained.     

Response Surface Method: A Novel Strategy to Optimize lontophoretic Transdermal Delivery of Thyrotropin-releasing Hormone

Purpose. To maximize the iontophoretic transdermal delivery rate of thyrotropin-releasing hormone (TRH) facilitated by periodically monophase-pulsed current across excised skin. Methods. The pH of the buffer, the ionic strength in the solution, the frequency of the periodically monophase-pulsed current and the current on/off ratio were chosen as the key variables. A response surface method was applied to optimize the transdermal delivery rate of TRH under different operational conditions. Results. The optimum operating conditions were achieved via experimentation based on the response surface method by systematically adjusting the pH of the buffer, the ionic strength in the solution, the current amplitude, frequency and the active temporal ratio of the pulsed current. The rate of permeation of TRH crossing the skin during iontophoresis varied from two to ten-fold, depending on operating conditions. Conclusions. Only a few steps, two in this work, were needed to reach the optimal. The response surface near the region of the maximal point was thoroughly described with a quadratic function. A maximal transdermal rate of permeation of TRH, 103.2 µg h^–1 cm^–2, was obtained when the donor solution was at pH = 7.0, ionic strength = 0.037, and with a periodically monophase-pulsed current iontophoresis with duty cycle = 75%. The effect of pulse frequency was not statistically significant.     

Transport Mechanisms in Iontophoresis. III. An Experimental Study of the Contributions of Electroosmotic Flow and Permeability Change in Transport of Low and High Molecular Weight Solutes

The objective of this research was to provide in vitro transport data designed to clarify the relative importance of permeability increase and electroosmotic flow in flux enhancement via iontophoresis, Iontophoretic fluxes were measured with both anode and cathode donor cells, and passive fluxes were measured both before iontophoresis (Passive 1) and after iontophoresis (Passive 2). Data were generated for three uncharged low molecular weight solutes (glycine, glucose, and tyrosine) and two high molecular weight anionic species (carboxy inulin and bovine serum albumin). Flux enhancement is greater for anodic delivery than for cathodic delivery, even for the negatively charged molecules, and anodic flux of glucose decreases as the concentration of NaCl increases. Both observations are consistent with a mass transfer mechanism strongly dependent on electroosmotic flow. Steady-state anodic flux at 0.32 mA/cm², expressed as equivalent donor solution flux (in µl/hr cm²), ranged from 6.1 for glycine to about 2 for the large anions. As expected, iontophoretic flux is higher at 3.2 mA/cm² than at 0.32 mA/cm², and passive flux measured after iontophoresis is about a factor of 10 greater than the corresponding flux measured before the skin was exposed to electric current. There are two mechanisms for flux enhancement relative to passive flux on fresh hairless mouse skin: (1) the effect of the voltage in increasing mass transfer over the passive diffusion level, the effect of electroosmotic flow dominating this contribution in the systems studied in this report; and (2) the effect of prior current flow in increasing the intrinsic permeability of the skin. Both effects are significant. Based on theoretical results given elsewhere, theoretical values for flux were calculated and compared with the experimental data. While agreement between theory and experiment was only qualitative in several cases, most of the data are predicted quantitatively by the theory.     

Epidermal Iontophoresis: I. Development of the Ionic Mobility-Pore Model

Purpose. An integrated ionic mobility-pore model for epidermal iontophoresis is developed from theoretical considerations using both the free volume and pore restriction forms of the model for a range of solute radii (r _j ) approaching the pore radii (r _p ) as well as approximation of the pore restriction form for r _j /r _p < 0.4. In this model, we defined the determinants for iontophoresis as solute size (defined by MV, MW or radius), solute mobility, solute shape, solute charge, the Debye layer thickness, total current applied, solute concentration, fraction ionized, presence of extraneous ions (defined by solvent conductivity), epidermal permselectivity, partitioning rates to account for interaction of unionized and ionized lipophilic solutes with the wall of the pore and electroosmosis. Methods. The ionic mobility-pore model was developed from theoretical considerations to include each of the determinants of iontophoretic transport. The model was then used to reexamine iontophoretic flux conductivity and iontophoretic flux-fraction ionized literature data on the determinants of iontophoretic flux. Results. The ionic mobility-pore model was found to be consistent with existing experimental data and determinants defining iontophoretic transport. However, the predicted effects of solute size on iontophoresis are more consistent with the pore-restriction than free volume form of the model. A reanalysis of iontophoretic flux-conductivity data confirmed the model's prediction that, in the absence of significant electroosmosis, the reciprocal of flux is linearly related to either donor or receptor solution conductivity. Significant interaction with the pore walls, as described by the model, accounted for the reported pH dependence of the iontophoretic transport for a range of ionizable solutes. Conclusions. The ionic mobility-pore iontophoretic model developed enables a range of determinants of iontophoresis to be described in a single unifying equation which recognises a range of determinants of iontophoretic flux.     

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.