The purpose of the present study was to explore the passive and electrically assisted transdermal transport of diphenhydramine hydrochloride (DPH) by iontophoresis. For better bioavailability, better patient compliance, and enhanced delivery of DPH, an iontophoretic drug delivery system of a thermosensitive DPH gel was formulated using Lutrol F-127. The study was conducted using silver-silver chloride electrodes across hairless pig skin. The effects of pH, polymer concentration, electrode design, and pulse rate on the DPH permeation were investigated. The relationship between temperature, viscosity, and conductance of DPH was correlated using conductometry. Iontophoretic transport of DPH was found to increase with a decrease in the pH of the medium and an increase in the surface area of the electrode. Viscosity measurements and flux calculations indicated the suitability of the Lutrol gel for transdermal iontophoretic delivery of DPH. Anodal pulsed iontophoresis with disc electrode significantly increased the DPH skin permeation as compared with the passive controls.
Pig skin; thermosensitive gel; conductance; viscosity; Permeation; pulsed current
The objective of the study was to investigate in vitro transdermal delivery of venlafaxine hydrochloride across the pigskin by passive diffusion and iontophoresis. For passive diffusion, experiments were carried out in Franz diffusion cell whereas for iontophoretic permeation, the diffusion cell was modified to contain both the donor and return electrode on the same side of skin. Anodal iontophoresis was carried out using a current density of 0.5 mA/cm2. Donor concentrations used were 585.5 mg/ml (saturated solution) and 100 mg/ml. Experiments initially performed to determine the transport efficiency of venlafaxine ions showed promising results. Iontophoresis increased the permeation rate at both concentration levels over their passive counterparts (P < 0.01), but surprisingly higher steady-state flux was obtained from lower donor drug load (P < 0.01). The favorable pH of the unsaturated solutions is suggested to be the cause for this effect. Mild synergistic effect was observed when iontophoresis was carried out incorporating peppermint oil in the donor but the same was not found in passive diffusion. Highest steady-state flux obtained in the experiment was 3.279 μmol/cm2/h when peppermint oil (0.1%) was included in the donor. As the maintenance requirement of venlafaxine hydrochloride is approximately 9.956 μmol/h, the results suggested that the drug is a promising candidate for iontophoretic delivery.
iontophoresis; menthol; peppermint oil; transdermal; venlafaxine hydrochloride
The objective of the present study was to investigate the iontophoretic transport behavior across multiple membranes of different barrier properties. Spectra/Por® (SP) and Ionac membranes were the synthetic membranes and sclera was the biomembrane in this model study. The barrier properties of SP membranes were determined individually in passive and iontophoresis transport experiments with tetraethylammonium ion (TEA), chloride ion (Cl), and mannitol as the model permeants. Passive and iontophoretic transport experiments were then conducted with an assembly of SP membranes. The contribution of electroosmosis to iontophoresis was assessed using the mannitol data. Model analysis was performed to study the contribution of diffusion and electromigration to electrotransport across the multiple membrane system. The effects of membrane barrier thickness upon ion-exchange membrane-enhanced iontophoresis were examined with Ionac, SP, and sclera. The present study shows that iontophoretic transport of TEA across the membrane system was related to the thicknesses and permeability coefficients of the membranes and the electromobilities of the permeant across the individual membranes in the assembly. Model analysis suggests significant contribution of diffusion within the membranes across the membrane system, and this mechanism is relatively independent of the current density applied across the system in iontophoresis dominant transport.
iontophoresis; membrane; transport; transference number; electrophoresis; diffusion; mathematical model; drug delivery
The presence of endogenous competing counterions is a main reason for the generally low efficiency of transdermal iontophoretic drug delivery. The objective of the present study was to test the hypothesis that the incorporation of an ion-exchange membrane (Ionac) in an iontophoresis system to hinder transdermal transport of these counterions can enhance iontophoretic delivery. The properties of Ionac were characterized in passive and iontophoretic transport experiments. Iontophoretic transport across human epidermal membrane (HEM) and across HEM in series with Ionac was then studied. To assess the effect of HEM electrical resistance upon Ionac-assisted iontophoresis, HEM resistance was reduced in the iontophoresis experiments with alternating current (AC). Salicylate (SA) was the negatively charged permeant first tested in this study. Mannitol was the model permeant to examine the effects of electroosmosis. At the completion of the SA study, experiments were performed with acyclovir (ACV), an antiviral drug with limited water solubility. When Ionac was used to enhance SA transdermal fluxes, higher SA .uxes were observed with HEM of lower resistances in Ionac-assisted iontophoresis. Up to a four-fold flux enhancement was achieved when the electrical resistance of HEM was reduced using an AC iontophoresis method. For ACV, two-fold flux enhancement was observed in Ionac-assisted iontophoresis compared with the conventional iontophoresis baseline. In all experiments, the contribution of electroosmosis to drug transport was less than 10%. The present study has demonstrated the potential of a new approach using a positively charged ion-exchange membrane to enhance transdermal iontophoretic transport of negatively charged drugs.
Iontophoresis; Transdermal; Ion-exchange membrane; Salicylate; Acyclovir; Transport enhancement
The mechanisms of transscleral iontophoresis have been investigated previously with small molecules in rabbit sclera. The objective of the present study was to examine transscleral iontophoretic transport of charged macromolecules across excised human sclera. Passive and 2-mA iontophoretic transport experiments were conducted in side-by-side diffusion cells with human sclera. The effects of iontophoresis upon transscleral transport of model permeants bovine serum albumin (BSA) and polystyrene sulfonic acid (PSS) as well as a model drug bevacizumab (BEV) were determined. Passive and iontophoretic transport experiments of tetraethylammonium (TEA) and salicylic acid (SA) and passive transport experiments of the macromolecules served as the controls. The results of iontophoresis enhanced transport of TEA and SA across human sclera were consistent with those in a previous rabbit sclera study. For the iontophoretic transport of macromolecules BSA and BEV, higher iontophoretic fluxes were observed in anodal iontophoresis as compared to passive and cathodal iontophoresis. This suggests the importance of electroosmosis. For the polyelectrolyte PSS, higher iontophoretic flux was observed in cathodal iontophoresis compared to anodal iontophoresis. Both electroosmosis and electrophoresis affected iontophoretic fluxes of the macromolecules; the relative contributions of electroosmosis and electrophoresis were a function of molecular size and charge of the macromolecules.
Electrophoresis; Electroosmosis; Charged macromolecules; Human sclera
Transport across the human nail under hydration can be modeled as hindered transport across aqueous pore pathways. As such, nail permselectivity to charged species can be manipulated by changing the ionic strength of the system in transungual delivery to treat nail diseases. The present study investigated the effects of ionic strength upon transungual passive and iontophoretic transport.
Transungual passive and anodal iontophoretic transport experiments of tetraethylammonium ion (TEA) were conducted under symmetric conditions in which the donor and receiver had the same ionic strength in vitro. Experiments under asymmetric conditions were performed to mimic the in vivo conditions. Prior to the transport studies, TEA uptake studies were performed to assess the partitioning of TEA into the nail.
Permselectivity towards TEA was inversely related to ionic strength in both passive and iontophoretic transport. The permeability and transference number of TEA were higher at lower ionic strengths under the symmetric conditions due to increased partitioning of TEA into the nail. Transference numbers were smaller under the asymmetric conditions compared with their symmetric counterparts.
The results demonstrate significant ionic strength effects upon the partitioning and transport of a cationic permeant in transungual transport, which may be instrumental in the development of transungual delivery systems.
charge-charge interactions; human nail; ionic strength; iontophoresis; partition coefficient
The present study investigated the effects of pH on nail permeability and the transport of ions such as sodium (Na) and chloride (Cl) ions endogenous to nail and hydronium and hydroxide ions present at low and high pH, which might compete with drug transport across hydrated nail plate during iontophoresis. Nail hydration and passive transport of water across the nail at pH 1–13 were assessed. Subsequently, passive and iontophoretic transport experiments were conducted using 22Na and 36Cl ions under various pH conditions. Nail hydration was independent of pH under moderate pH conditions and increased significantly under extreme pH conditions (pH>11). Likewise, nail permeability for water was pH independent at pH 1–10 and an order of magnitude higher at pH 13. The results of passive and iontophoretic transport of Na and Cl ions are consistent with the permselective property of nail. Interestingly, extremely acidic conditions (e.g., pH 1) altered nail permselectivity with the effect lasting several days at the higher pH conditions. Hydronium and hydroxide ion competition in iontophoretic transport was generally negligible at pH 3–11 was significant at the extreme pH conditions studied.
pH; human nail plate; transungual transport; iontophoresis
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.
iontophoresis; terpene; buspirone hydrochloride; gel; transdermal
Transungual delivery of antifungal drugs is hindered by the low permeability of human nail plates, and as such, repeated dosing over a long period of time is necessary for effective treatment. The objectives of this study were to explore the possibilities of (a) enhancing the delivery of ciclopirox (CIC) across human nail plates and (b) sustaining CIC delivery from the larger resultant drug depot in the nail plates with constant voltage iontophoresis. In vitro passive and 9 V cathodal iontophoretic transport experiments of CIC across human nails were performed. Transungual CIC delivery with Penlac® was the control. The amounts of CIC released from and deposited in the nails were determined in drug release and extraction experiments, respectively. Iontophoresis increased the flux of CIC permeated across the nail approximately 10 times compared to passive delivery from the same formulation or from Penlac®. A significant amount of CIC was loaded into and released from the nails; the CIC concentrations were estimated to be above the minimum inhibitory concentrations of CIC for dermatophytic molds. The apparent transport lag time decreased in iontophoretic transport. The results demonstrate that iontophoresis was able to deliver an effective amount of CIC into and across the nails, and this suggests the feasibility of a constant voltage battery-powered transungual iontophoretic device.
iontophoresis; ciclopirox; human nail plate; constant voltage; transungual delivery
The delivery of drugs into systemic circulation via skin has generated much attention during the last decade. Transdermal therapeutic systems propound controlled release of active ingredients through the skin and into the systemic circulation in a predictive manner. Drugs administered through these systems escape first-pass metabolism and maintain a steady state scenario similar to a continuous intravenous infusion for up to several days. However, the excellent impervious nature of the skin offers the greatest challenge for successful delivery of drug molecules by utilizing the concepts of iontophoresis. The present review deals with the principles and the recent innovations in the field of iontophoretic drug delivery system together with factors affecting the system. This delivery system utilizes electric current as a driving force for permeation of ionic and non-ionic medications. The rationale behind using this technique is to reversibly alter the barrier properties of skin, which could possibly improve the penetration of drugs such as proteins, peptides and other macromolecules to increase the systemic delivery of high molecular weight compounds with controlled input kinetics and minimum inter-subject variability. Although iontophoresis seems to be an ideal candidate to overcome the limitations associated with the delivery of ionic drugs, further extrapolation of this technique is imperative for translational utility and mass human application.
Drug delivery; Translational research; Transdermal therapeutic system; Iontophoresis
Transungual iontophoretic transport of model neutral permeants mannitol (MA), urea (UR), and positively charged permeant tetraethylammonium ion (TEA) across fully hydrated human nail plates at pH 7.4 were investigated in vitro. Four protocols were involved in the transport experiments with each protocol divided into stages including passive and iontophoresis transport of 0.1 and 0.3 mA. Water and permeant uptake experiments of nail clippings were also conducted to characterize the hydration and binding effects of the permeants to the nails. Iontophoresis enhanced the transport of MA and UR from anode to cathode, but this effect (electroosmosis) was marginal. The transport of TEA was significantly enhanced by anodal iontophoresis and the experimental enhancement factors were consistent with the Nernst–Planck theory predictions. Hindered transport was also observed and believed to be critical in transungual delivery. The barrier of the nail plates was stable over the time course of the study, and no significant electric field-induced alteration of the barrier was observed. The present results with hydrated nail plates are consistent with electrophoresis-dominant (the direct field effect) transungual iontophoretic transport of small ionic permeants with small contribution from electroosmosis.
transungual; iontophoresis; human nail plate; electroosmosis; electrophoresis
As a continuing effort to understand the mechanisms of alternating current (AC) transdermal iontophoresis and the iontophoretic transport pathways in the stratum corneum (SC), the objectives of the present study were to determine the interplay of AC frequency, AC voltage, and iontophoretic transport of ionic and neutral permeants across human epidermal membrane (HEM) and use AC as a means to characterize the transport pathways.
Materials and Methods
Constant AC voltage iontophoresis experiments were conducted with HEM in 0.10 M tetraethyl ammonium pivalate (TEAP). AC frequencies ranging from 0.0001 to 25 Hz and AC applied voltages of 0.5 and 2.5 V were investigated. Tetraethyl ammonium (TEA) and arabinose (ARA) were the ionic and neutral model permeants, respectively. In data analysis, the logarithm of the permeability coefficients of HEM for the model permeants was plotted against the logarithm of the HEM electrical resistance for each AC condition.
As expected, linear correlations between the logarithms of permeability coefficients and the logarithms of resistances of HEM were observed, and the permeability data were first normalized and then compared at the same HEM electrical resistance using these correlations. Transport enhancement of the ionic permeant was significantly larger than that of the neutral permeant during AC iontophoresis. The fluxes of the ionic permeant during AC iontophoresis of 2.5 V in the frequency range from 5 to 1,000 Hz were relatively constant and were approximately 4 times over those of passive transport. When the AC frequency decreased from 5 to 0.001 Hz at 2.5 V, flux enhancement increased to around 50 times over passive transport.
While the AC frequency for achieving the full effect of iontophoretic enhancement at low AC frequency was lower than anticipated, the frequency for approaching passive diffusion transport at high frequency was higher than expected from the HEM morphology. These observations are consistent with a transport model of multiple barriers in series and the previous hypothesis that the iontophoresis pathways across HEM under AC behave like a series of reservoirs interconnected by short pore pathways.
AC; human skin; iontophoresis; transdermal; transport
Transungual transport is hindered by the inherent small effective pore size of the nail even when it is fully hydrated. The objectives of this study were to determine the effects of chemical enhancers thioglycolic acid (TGA), glycolic acid (GA), and urea (UR) on transungual transport and iontophoresis efficiency. In vitro passive and iontophoretic transport experiments of model permeants mannitol (MA), UR, and tetraethylammonium (TEA) ion across the fully hydrated, enhancer-treated and untreated human nail plates were performed in phosphate-buffered saline. The transport experiments consisted of several stages, alternating between passive and anodal iontophoretic transport at 0.1 mA. Nail water uptake experiments were conducted to determine the water content of the enhancer-treated nails. The effects of the enhancers on transungual electroosmosis were also evaluated. Nails treated with GA and UR did not show any transport enhancement. Treatment with TGA at 0.5 M enhanced passive and iontophoretic transungual transport of MA, UR, and TEA. Increasing the TGA concentration to 1.8 M did not further increase TEA iontophoresis efficiency. The effect of TGA on the nail plates was irreversible. The present study shows the possibility of using a chemical enhancer to reduce transport hindrance in the nail plate and thus enhance passive and iontophoretic transungual transport.
Transungual iontophoresis; Human nail plate; Chemical enhancer; Thioglycolic acid; Glycolic acid; Urea
The flux enhancing mechanisms of transscleral iontophoresis are not well understood. The objective of the present study was to investigate the ocular barrier and barrier alterations in transscleral iontophoretic delivery with magnetic resonance imaging (MRI). Experiments involving constant current transscleral iontophoresis of 2 mA (current density 10 mA/cm2) and subconjunctival injection were conducted with rabbits in vivo and postmortem and with excised sclera in side-by-side diffusion cells in vitro. The postmortem and in vitro experiments were expected to be helpful in clarifying the importance of vascular clearance and other transport barriers in transscleral iontophoresis. Manganese ion (Mn2+) and manganese ethylenediaminetetraacetic acid complex (MnEDTA2−) were the model permeants. The results show that pretreatment of the eye with an electric field by iontophoresis enhanced subconjunctival delivery of the permeants to the anterior segment of the eye in vivo. This suggests that electric field-induced barrier alterations can be an important absorption enhancing mechanism of ocular iontophoresis. Penetration enhancement was magnified in the postmortem experiments with larger amounts of the permeants delivered into the eye and to the back of the eye. The different results observed in the in vivo and postmortem studies can be attributed to ocular clearance in ocular delivery.
ocular; iontophoresis; transscleral; drug delivery; MRI
The peroxovanadium compound VO(O2)2, 1,10 phenanthroline (bpV (phen)) is capable of lowering blood glucose levels. It is not available in oral form, but it is effective when delivered transdermally. Iontophoresis can significantly reduce the lag time of this response in vivo when compared with passive penetration. To better mimic in vivo insulin release, we explored the effects of various iontophoretic current durations on dermal penetration of bpV(phen). Iontophoretic transport was not related to total applied charge, as steady-state flux was equivalent for current durations ranging from 15 minutes to 9 hours. We hypothesized that the unexpectedly large transport after just 15 minutes of current was caused by an increase in passive penetration of bpV(phen) induced by iontophoresis. Iontophoretic pretreatment with the chelating agent 1,10 phenanthroline increased passive penetration of bpV(phen), whereas neither the nonchelating isomer 1,7 phenanthroline nor the less potent chelator EDTA were effective. The use of 1,10 phenanthroline as a penetration enhancer for other chemicals was examined with the amino acids alanine and leucine. Fifteen minutes of 1,10 phenanthroline iontophoresis enhances alanine transport 11.4-fold over passive, whereas the 1,7 phenanthroline increased transport by a factor of 4.6 and the iontophoretic control of ethanol by 1.9. Surprisingly, phenanthroline did not enhance 3H leucine penetration. The reasons for this selectivity are not clear and warrent further investigation. Overall, the data suggest that chelating agents, specifically 1,10 phenanthroline, may be used as penetration enhancers for the delivery of certain compounds.
Transdermal; Skin; Iontophoresis; Vanadium; Diabetes
The objective of this study was to investigate the effects of pH and ionic strength on electroosmotic transport in transungual iontophoresis. Transungual iontophoretic transport of model neutral permeants mannitol (MA) and urea (UR) across fully hydrated human nail plates in phosphate-buffered saline of different pH and ionic strengths were investigated in vitro. Two protocols were involved in the transport experiments with each protocol divided into stages including passive and iontophoresis transport at 0.1 and/or 0.3 mA. Nail plate electrical resistance and water uptake of nail clippings were measured at various pH and ionic strengths. In the pH study, electroosmosis enhanced the anodal transport of MA at pH 9 and cathodal transport at pH 3. The Peclet numbers of MA were more than two times higher than those of UR under these conditions. No significant electroosmosis enhancement was observed for MA and UR at pH 5. In the ionic strength study, a decrease in solution ionic strength from 0.7 to 0.04 M enhanced electroosmotic transport. Nail electrical resistance increased with decreasing the ionic strength of the equilibrating solution, but reached a plateau when the ionic strength was less than approximately 0.07 M. Solution pH and ionic strength had no significant effect on nail hydration. Under the studied pH and ionic strength conditions, the effects of electroosmosis were small compared to the direct-field effects in transungual iontophoretic transport of small to moderate size permeants.
transungual; iontophoresis; human nail plate; electroosmosis
The objective was to study the competition of chloride released from a Ag/AgCl cathode on the iontophoretic delivery of dexamethasone phosphate (Dex-Phos). Iontophoresis of Dex-Phos was performed in side-by-side diffusion cells (0.78 cm2) using pig skin. A 0.3 mA constant current was applied via Ag/AgCl electrodes. The amounts of Dex-Phos and dexamethasone (Dex) were also quantified in the stratum corneum (SC), using tape stripping, after passive and iontophoretic delivery. The profiles of Dex-Phos and Dex, as a function of position in the SC, were deduced. The iontophoretic delivery of Dex-Phos from pure water was unaffected by the accumulation of Cl− released by the donor cathode when the drug’s concentration was 4.25 mM to 17 mM. At 0.85 mM, however, Cl− competition was significant and the drug flux was significantly reduced. Formulation of the drug in the presence of Cl− resulted in a non-linear dependence of flux on the molar fraction of the drug. Tape stripping experiments confirmed the enhanced delivery of Dex-Phos by iontophoresis relative to passive diffusion, with Dex-Phos concentration greater inside the barrier post-iontophoresis than that in the donor. The latter observation could explain the robustness of Dex-Phos delivery to the presence of Cl− in the donor solution.
iontophoresis; skin; transport number; dexamethasone phosphate
Iontophoresis was used to enhance the delivery of aceclofenac (ACF) from topical gels formulated with various polymers for the purpose of relieving pain and inflammation.
Materials and Methods
Gels were formulated from hydroxypropyl methyl cellulose (HPMC), carbopol 934P, and sodium carboxymethyl cellulose (NaCMC). The formulations were evaluated for cathodal iontophoretic delivery of ACF through excised rat abdominal skin at three levels of current density of 0.5, 0.6 and 0.7 mA/cm2. The in vivo effectiveness of the drug delivered passively as well as under the influence of iontophoresis at pH 7.4 at a current density of 0.5 mA/cm2 was also investigated using male Albino rats with carrageenan induced paw edema.
Results and Discussion:
In the ex vivo studies, though it was clear that iontophoresis significantly increased drug permeation through the excised skin from all formulations; the percentage drug permeated from HPMC gels was superior to that from carbopol 934P or NaCMC gels but increased with an increase in the current density only for the former. The steady state flux, permeability coefficient, enhancement factor were significantly greater from HPMC gels than from the gels of the ionic polymers due to the interference of competitive ions. With iontophoresis, the carrageenan induced paw edema was significantly reduced by 61.53% (P < 0.01) for HPMC gels as compared to the control although passive permeation without iontophoresis showed a 54.6% reduction (P < 0.05) at the end of 4 h.
The results of the study indicate that ACF could be administered topically by using iontophoresis from a suitably formulated gel for effective control of pain and inflammation.
Aceclofenac; drug permeation; gels; iontophoresis
Ionic selectivity of the acetylcholine-activated ionic channel of frog endplate membranes to various organic cations has been studied. The ratio of test cation permeability (PX) to sodium permeability (PNa) was estimated by two methods, one based on the measurements in test cation solutions of the amplitude of transient depolarization induced by iontophoretic application of acetylcholine, and the other on the measurements of the reversal potential for the membrane current induced by iontophoretic application of acetylcholine under voltage-clamp conditions. The endplate channel is relatively nonselective to various test cations. The permeabilities relative to Na are ammonium (1.71), formamidine (1.49), methylamine (1.39), hydrazine (1.35), and Li (0.76), as measured from the reversal potential for acetylcholine currents, and guanidine (0.74), aminoguanidine (0.20), methylguanidine (0), and choline (0) as measured from the amplitude of acetylcholine potential. Methylguanidine and aminoguanidine block the endplate channel with the apparent dissociation constants of 0.5 and 15 mM, respectively. Based on these data, the dimensions of selectivity filter of acetylcholine-activated channel appear to be slightly larger than those of the sodium channel of frog nodes and smaller than those of the epithelial membrane of gallbladder of frogs and rabbits.
Recently there has been an increased interest in using iontophoretic technique for the transdermal delivery of medications, both ionic and nonionic. This article is an overview of the history of iontophoresis and factors affecting iontophoretic drug transfer for the systemic effects and laws for development of Transdermal delivery system are discussed.
Electro repulsion; movement of ions; stratum corneum; improved systemic bioavailability
Iontophoresis uses electricity to deliver solutes into living tissue. Often, iontophoretic ejections from micropipettes into brain tissue are confined to millisecond pulses for highly localized delivery, but longer pulses are common. As hippocampal tissue has a ζ-potential of approximately –22 mV, we hypothesized that, in the presence of the electric field resulting from the iontophoretic current, electroosmotic flow in the tissue would carry solutes considerably farther than diffusion alone. A steady state solution to this mass transport problem predicts a spherically symmetrical solute concentration profile with the characteristic distance of the profile depending on the ζ-potential of the medium, the current density at the tip, the tip size and the solute electrophoretic mobility and diffusion coefficient. Of course, the ζ-potential of the tissue is defined by immobilized components of the extracellular matrix as well as cell-surface functional groups. As such, it cannot be changed at will. Therefore, the effect of the ζ-potential of the porous medium on ejections is examined using poly(acrylamide-co-acrylic acid) hydrogels with various magnitudes of ζ-potential, including that similar to hippocampal brain tissue. We demonstrated that nearly neutral fluorescent dextran (3 and 70 kD) solute penetration distance in the hydrogels and OHSCs depends on the magnitude of the applied current, solute properties, and, in the case of the hydrogels, the ζ-potential of the matrix. Steady state solute ejection profiles can be predicted semi-quantitatively.
Electroosmosis; Peclet number; Mass transport; Hippocampus; Microiontophoresis
Iontophoresis is the movement of charged molecules in solution under applied current using pulled multi-barrel glass capillaries drawn to a sharp tip. The technique is generally non-quantitative, and to address this, we have characterized the ejection of charged and neutral species using carbon-fiber electrodes attached to iontophoretic barrels. Our results show that observed ejections are due to the sum of iontophoretic and electroosmotic forces. Using the neutral, electroactive molecule 2-(4-nitrophenoxy) ethanol (NPE), which is only transported by electroosmotic flow (EOF), a positive correlation between the amount ejected and the diameter of each barrel's tip was found. In addition, using various charged and neutral electroactive compounds we found that, when each compound is paired with the EOF marker, the percentage of the ejection due to EOF remains constant. This percentage varies for each pair of compounds, and the differences in mobility are positively correlated to differences in electrophoretic mobility. Overall, the results show that capillary electrophoresis (CE) can be used to predict the percentage of ejection that will be due to EOF. With this information, quantitative iontophoresis is possible for electrochemically inactive drugs by using NPE as a marker for EOF.
This study investigated the penetration of lidocaine around and through a sutured incision following the application of iontophoretic and passive patches in the CD Hairless rat.
Concentrations in localized areas (suture, dermis, subcutaneous, and vascular) were determined using microdialysis sampling followed by analysis using liquid chromatography with UV detection.
Iontophoresis significantly enhanced the dermal penetration of lidocaine. In an intact skin model, dermal concentrations were 40 times greater following iontophoretic delivery compared to passive delivery. In a sutured incision model, iontophoresis enhanced localized concentrations in the dermis, suture, and subcutaneous regions by 6, 15, and 20 fold, respectively. Iontophoretic delivery to a region containing a sutured incision was focused to the incision resulting in a greater increase in the suture concentration and in the subcutaneous region directly below the incision.
The four microdialysis probe design was successful in the determination of localized drug penetration in a sutured incision model. Iontophoresis enhanced skin penetration and allowed for site specific delivery when applied to a sutured incision.
iontophoresis; microdialysis; liquid chromatography; sutured incision; skin; transdermal drug delivery; percutaneous; lidocaine
A challenge in ocular drug delivery is to maintain the therapeutic concentration of a drug at the site of action in the eye. The objective of the present study was to investigate the feasibility of micellar carrier systems for sustained drug delivery in transscleral iontophoresis in vitro. Simple and mixed micelles prepared using sodium taurocholate (TA) alone or with egg lecithin (LE) were the carrier systems studied. Dexamethasone (DEX), a poorly water soluble corticosteroid, was the model drug. The micellar carrier systems were first characterized for their solubilization and encapsulation of the drug. Passive and 2-mA iontophoretic (both cathodal and anodal) transport experiments were conducted using these micellar carrier systems in side-by-side diffusion cells with excised human sclera in vitro. Drug release studies were performed after the transport experiments. Saturated DEX solution without the micellar carriers was used as a control. It was found that the solubilization capacity of the micellar carrier systems increased as the total lipid concentration of the systems increased. Drug release from the sclera was significantly prolonged with the micellar carrier systems as compared to the control after passive and iontophoretic delivery. Less than ~ 20% of DEX was released from the sclera in approximately 2 hours after cathodal iontophoretic delivery of the micellar carrier systems, whereas more than ~ 50% of DEX was released from the control in the same time period under the same condition. Micellar carrier systems can be a suitable transscleral drug delivery system for poorly water soluble drugs by enhancing their aqueous solubilities and providing sustained drug delivery. These micellar carrier systems can be efficiently delivered into and across the sclera by iontophoresis for drug delivery.
Human sclera; Dexamethasone; Mixed micelles; Simple micelles; Transscleral iontophoresis; Sustained release
Iontophoresis allows for localized drug ejections directly into brain regions of interest driven by the application of current. Our lab has previously adapted a method to quantitatively monitor iontophoretic ejections. Here those principles have been applied in vivo to modulate electrically evoked release of dopamine in anesthetized rats. A neutral, electroactive marker molecule that is ejected purely by electroosmotic flow (EOF) was used to monitor indirectly the ejection of electroinactive dopaminergic drugs (raclopride, quinpirole, and nomifensine). Electrode placements were marked with an iontophoretically ejected dye, pontamine sky blue. We show that EOF marker molecules, acetaminophen (AP) and 2-(4-nitrophenoxy) ethanol, have no effect on electrically evoked dopamine release in the striatum or the sensitivity of electrode. Additionally, we establish that a short, 30 second ejection of raclopride, quinpirole, or nomifensine with iontophoresis is sufficient to affect autoreceptor regulation and the re-uptake of dopamine. These effects vary in lifetime, indicating that this technique can be used to study receptor kinetics.
iontophoresis; fast-scan cyclic voltammetry; dopamine; carbon-fiber; quantitative; pre-synaptic