The Influence of Iontophoresis on Acyclovir Transport and Accumulation in Rabbit Ear Skin

Purpose The aim of this work was to explore the effect of iontophoresis on acyclovir (ACV) accumulation and permeation. In particular, the objectives were to check the efficacy of the transport mechanisms, electromigration and electroosmosis, on drug accumulation.Methods Permeation experiments were performed in vitro, using rabbit ear skin as barrier, from donor solutions at pH 3.0, 5.8, and 7.4. At the end of the experiments, drug accumulation in epidermis and dermis was measured. Anodal and cathodal iontophoresis were applied at pH 3.0, whereas only anodal iontophoresis was used at pH 5.8 (current densities 0.06–0.50 mA/cm²) and 7.4.Results Cathodal iontophoresis was more efficient than anodal iontophoresis on ACV permeation across the skin at pH 3.0. At pH 5.8, ACV flux and accumulation increased with current density during anodal iontophoresis. At pH 7.4, anodal iontophoresis produced a remarkable increase of flux and a modest increase of accumulation. Overall, anodal flux increased as the pH of the donor solution was increased as a result of the increase of the skin net negative charge.Conclusions From the results obtained in the present work, it can be concluded that iontophoresis application increases ACV flux and, to a limited extent, accumulation in the skin.     

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.     

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

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

Effect of pH and penetration enhancers on electroosmotic flow and flux through skin

We have investigated the effect of pH and four penetration enhancers on the electroosmotic volume flow (EVF) and flux through skin to get more detailed understanding of this phenomenon and its effect on flux. The results were evaluated in relation EVF and the permeability change by current induced skin damage. At pH 7.4, we have confirmed that the direction of convective solvent flow is from anode to cathode. At pH 4.0, no permselectivity was observed and it seems that this pH is close to the isoelectric point of skin. At pH 3.0, the permselectivity of skin is reversed. From the difference in flux between just before (47 μg/cm² h) and after (32 μg/cm² h) cathodal current-off, the magnitude of EVF is estimated to be smaller than 1.5 μl/cm² h, if we consider the recovery of skin to a lower permeability after current-off. At pH 7.4, Oleic acid (OA) and propylene glycol monolaurate (PGML) increased the passive flux markedly. Synergistic effect in flux between OA and current was observed for both anodal and cathodal current. The use of isopropyl myristate (IPM) in combination with anodal current resulted in reduced flux when compared to the flux of anodal current alone. Cathodal flux of OA or PGML treated skin increased continuously until the current was off. However, to the contrary of our expectation, flux decreased after current-off. We think this is mainly due to the recovery of damaged skin (flux decreasing effect), though the disappearance of EVF may slightly increase the flux. For IPM and propylene glycol, the combination of enhancer with cathodal current inhibited the flux, similar to that observed for anodal delivery. Overall, these results provide further information on the role of electroosmosis and the effect of penetration enhancers in combination with current on flux through skin.     

电渗作用对甲硝唑经皮渗透的影响

在Ａｇ／ＡｇＣｌ电极的双室扩散池中测定不同电场对模型药物甲硝唑（１）通过离体大鼠皮肤渗透速率的影响。结果表明，１生理盐水饱和液阳极导入时的透皮速率是被动扩散的２．３倍，阴极导入时药物的透皮速率是其被动扩散的４５％，说明电渗作用明显促进了分子型药物１的经皮渗透；与药物渗透方向相反的电渗流则明显阻碍其经皮渗透     

Modulation of electroosmosis and flux through skin: effect of propylene glycol

The effect of propylene glycol (PG) on transdermal flux under current was investigated using conventional in vitro iontophoresis methodology. The results were evaluated to explain how PG affects the electroosmotic volume flow (EVF) and electromigrational flux through skin. As a marker molecule for the direction and magnitude of EVF, a non-charged neutral molecule, acetaminophen (AAP), was used. At pH 7.4, the direction of EVF was from anode to cathode. During anodal and cathodal current application, PG decreased AAP flux and this decrease was proportional to the concentration of PG, indicating that the presence of PG in the medium decreased the EVF. This decrease is likely due to the decrease in dielectric constant of the medium and the increases in medium viscosity by the addition of PG. The increase in AAP solubility and the viscosity of the medium by PG may also contribute to the decrease in diffusional flux. The magnitude of EVF was estimated to be about 4.2 μl/cm² h. The effect of PG on the flux of a positively charged drug, donepezil hydrochloride (DH), was further investigated using pH 4.6 phosphate buffer solution. The permselectivity of skin in this solution was also investigated and revealed that the isoelectric point of hairless mouse skin is higher than pH 4.6. Anodal delivery showed much higher flux than cathodal and passive flux, indicating that electromigration is playing the major role for DH flux. As the concentration of PG increased, anodal flux of DH decreased. The main reason for this decrease in electromigration is likely due to the increase in medium viscosity. These results and discussions clearly suggest that the incorporation of frequently used organic cosolvents and penetration enhancers into the iontophoretic formulation should be carefully chosen with a thorough investigation for their effect on flux. Overall, these results provided further mechanistic insights into the role of electroosmosis and electromigration in flux across skin, and how they can be modulated by organic cosolvent, PG.     

Mechanistic study of electroosmotic transport across hydrated nail plates: effects of pH and ionic strength

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.     

Drug Reservoir Composition and Transport of Salmon Calcitonin in Transdermal Iontophoresis

Purpose. The aim of the work was to study iontophoretic transdermal administration of salmon calcitonin (sCt) in rabbits, with particular attention to drug reservoir composition. A dry sCt disc, to be dissolved on the application site, was used for preparing the reservoir for transdermal iontophoresis. As a reference drug reservoir, a pad wetted with drug solution was used. Methods. Experiments were done in rabbits depositing 100 IU of salmon calcitonin on skin and applying anodal iontophoresis. Serum calcium concentration was measured during iontophoresis, passive diffusion and after i.v. administration. Parameters such as pH value and reservoir type were examined. Results. Transdermal iontophoresis of sCt elicited a decrease in the serum calcium level, whereas, in the absence of electric current, no significant fall was measured. Using the reservoir prepared from drug solution, anodal iontophoresis at pH 4.2 was more effective than at pH 7.4, probably due to higher sCt net positive charge. Using the reservoir prepared from dry disc, similar kinetics and extent of drug effect were observed at both pH values. The reservoir prepared from solid drug deposit concentrated sCt next to the skin. Conclusions. Anodal iontophoresis for transdermal calcitonin administration shows therapeutical applicability. The type of reservoir is an important parameter affecting sCt transdermal iontophoresis.     

Electrorepulsion Versus Electroosmosis: Effect of pH on the lontophoretic Flux of 5-Fluorouracil

Purpose. To delineate the contributions of electrorepulsion and electroosmosis to the iontophoretic flux of 5-FU across porcine skin in vitro. Also, the isoelectric point (pI) of the skin model was determined. Methods. The electrotransport of 5-FU, anode-to-cathode ('anodal') and cathode-to-anode ('cathodal') was determined as a function of the pH of the electrolyte bathing the skin. Results. At pH 8.5, the drug (pK_a 8) is negatively charged and 'cathodal', viz. electrorepulsive, transport is much greater than that in the opposite direction. At pH 7.4, where 25% of 5-FU is charged, electrorepulsive and electroosmotic ('anodal') fluxes are balanced. Decreasing the pH to 6, and then 5, reduces the percentage of ionized 5-FU such that 'anodal' electroosmosis dominates across the negatively-charged membrane. But, at pH 4, 'anodal' and 'cathodal' fluxes are again equal suggesting neutralization of the skin (i.e., pI 4). This is confirmed at pH 3, where 'cathodal' electroosmosis dominates across the now net-positively charged barrier. Conclusions. Electrotransport is sensitive, mechanistically, to the properties of the permeant and of the skin; interactions of, for example, the drug or constituents of a formulation, that alter the barrier's net charge, can affect iontophoretic delivery. The pI of porcine ear skin is 4.     

Effect of electroporation and iontophoresis on skin permeation of Defibrase--a purified thrombin-like enzyme from the venom of Agkistrodon halys ussuriensis Emelianov

The purpose of this study was to investigate electroporation and iontophoresis as a means for in vitro delivery of Defibrase--a thrombin-like enzyme (TLE) from Agkistrodon halys ussuriensis Emelianov snake venom--through human epidermis membrane (HEM). Electroporation was carried out using an exponential decay pulse generator (BioR-ad Genepulser, USA) for a period of 0.5 h, followed by a period of 5.5 h passive diffusion or iontophoresis. The results indicated that the combined use of electroporation and anodal iontophoresis in pH 6.4 permeation medium could effectively enhance the skin permeation of Defibrase, whose apparent permeability coefficient was 1.6 +/- 0.8 x 10(-4) cm.h-1. The delivery of Defibrase by the combined use of electroporation and anodal iontophoresis was more effective than by electroporation alone (P < 0.01) or by the combined use of electroporation and cathodal iontophoresis (P < 0.01). Moreover, when the pH of the permeation medium was raised from 6.4 to 7.4 the permeation of Defibrase caused by a combined use of electroporation and anodal iontophoresis showed a tendency to increase. These results implied that electroosmotic flow effect might be important for the iontophoretic (following electroporation) skin permeation of Defibrase.     

Contributions of Electromigration and Electroosmosis to Iontophoretic Drug Delivery

Purpose. To determine the electromigration and electroosmotic contributions to the iontophoretic delivery of lidocaine hydrochloride, in addition to the more-lipophilic quinine and propranolol hydrochlorides, in the presence and absence of background electrolyte.Methods: In vitro experiments, using excised pig ear skin and both vertical and side-by-side diffusion cells, were performed as a function of drug concentration and with and without background electrolytes in the anodal formulation. Concomitantly, the contribution of electroosmosis in each experimental configuration was monitored by following the transport of the neutral, polar marker molecule, mannitol. Results. Electromigration was the dominant mechanism of drug iontophoresis (typically representing 90% of the total flux). In the presence of background electrolyte, lidocaine delivery increased linearly with concentration as it competed more and more effectively with Na⁺ to carry the charge across the skin. However, iontophoretic delivery of quinine and propranolol increased non-linearly with concentration. Without electrolytes, on the other hand, electrotransport of the three drugs was essentially independent of concentration over the range 1-100 mM. Transport efficiency of lidocaine was 10%, whereas that of the more lipophilic compounds was significanly less, with the major charge carrier being Cl^– moving from beneath the skin into the anodal chamber. Both quinine and propranolol induced a concentration-dependent attenuation of electroosmotic flow in the normal anode-to-cathode direction. Conclusion. Dissecting apart the mechanistic contributions to iontophoretic drug delivery is key to the optimization of the formulation, and to the efficient use of the drug substance.     

Visualization and Analysis of Electroosmotic Flow in Hairless Mouse Skin

Purpose. To identify the physiological structures in hairless mouseskin responsible for the generation of electroosmotic flow duringiontophoresis. Also, to determine the effects of changing the pH of thecontacting solution on the magnitude of electroosmotic flow in thesestructures.Methods. Localized diffusive and iontophoretic fluxes of a neutralmolecule, hydroquinone (HQ), across hairless mouse skin were quantifiedusing scanning electrochemical microscopy (SECM). Theiontophoretic flux was determined as a function of the direction of theapplied current and pH of the contacting solution.Results. SECM images of HQ transport recorded during iontophoresisat moderate current densities (±0.1 mA/cm²) demonstrate that electroosmotic flow is localized to hair follicles. The direction of flow isfrom anode to cathode at pH > 3.5 and from cathode to anode atpH <3.5.Conclusions. Electroosmotic flow through hair follicles is an efficientand controllable means of transporting small, electrically neutral moleculesacross hairless mouse skin. Transport through the appendages issensitive to the pH of the solution in contact with the skin. The isoelectricpoint of hair follicles, pI, is estimated to be 3.5 from the dependenceof electroosmotic flow on the solution pH.     

lontophoretic Delivery Across the Skin: Electroosmosis and Its Modulation by Drug Substances

Purpose. The long-term objective of this research is to understand how the efficiency of iontophoresis depends upon the structural and physicochemical properties of the administered drug. Specifically, the ability of certain drug species to alter the permselective properties of the skin was examined. Methods. Using conventionalin vitro methodology, the inhibition of electroosmotic flow induced by the iontophoresis of five different -blockers (of varying lipophilicity) was examined. The concomitant electrotransport of the most lipophilic species (propranolol) and the convective movement of solvent in the anode-to-cathode direction were measured. In addition, the possibility that electroosmosis might be augmented by the delivery of anionic drugs was also considered. Results. Iontophoresis of lipophilic, cationic -blockers caused a concentration-dependent inhibition of conventional electroosmosis. The most hydrophilic analogs elicited no effect. As a result of this charge neutralization phenomenon, the optimal concentration for propranolol iontophoresis was significantly less than the maximum achievable in aqueous solution. Only a very modest improvement in convective solvent flow was induced by the cathodal iontophoresis of anionic compounds. Conclusions. The permselectivity of the skin can be altered by drugs which are positively charged and which possess a significant, adjacent hydrophobic surface. The latter seems able to 'anchor' the molecule in the skin and the counter charge to the membrane's negative character ensures a tight association. Both lipophilicity and a positive charge are essential—without either, the phenomenon is not observed. The conformational flexibility of the drugs studied to-date, however, prevents unambiguous conclusions about the three-dimensional nature of the putative 'binding site'.     

In vitro transscleral iontophoresis of high molecular weight neutral compounds

The aim of the work was to study in vitro, across porcine and human sclera, the effect of transscleral iontophoresis on the permeation of high molecular weight neutral dextrans, chosen as models of high molecular weight drugs.Iontophoretic (anodal and cathodal) and passive permeation experiments were performed through pig sclera using acetaminophen (MW = 151 Da) and labelled dextrans (MW between 4.4 kDa and 120 kDa) as neutral model compounds. Anodal iontophoresis of 120 kDa dextran was also performed on human sclera. Membrane charge was also determined at different pH values.Both human and pig sclera show a net negative charge at pH 7.4 and in the presence of current an electroosmotic convective solvent flow in the anode-to-cathode direction takes place. During anodal iontophoresis, the electroosmotic flow (whose entity resulted approximately 4 μl cm⁻² h⁻¹) was able to increase 2–6.5 times the transscleral flux of dextrans.Transscleral iontophoresis can be useful for enhancing the transport across the sclera of high molecular weight compounds, even though neutral. This result suggests a possible application of this technique for the non-invasive administration of new biotech drugs for the treatment of the posterior segment eye diseases.     

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.     

Effect of Sodium Dodecyl Sulfate on Iontophoresis of Hydrocortisone Across Hairless Mouse Skin

The purpose of the present work was to study the effect of sodium dodecyl sulfate (SDS), an anionic surfactant, on the iontophoretic transport of a neutral drug hydrocortisone (HC) across hairless mouse skin. The transport studies were conducted using Side-Bi-Side diffusion apparatus and drug concentration in the receptor cell was analyzed using reversed-phase HPLC. A theoretical model was described, tested, and found to agree well with experimental data (R² = 0.9766). Anodal iontophoresis significantly enhanced the transport of HC compared to cathodal iontophoresis and passive diffusion, suggesting that the transport of the neutral solute occurs via the electro-osmotic flow. The effect of SDS on the transport of HC was highly concentration-dependent and driving mode-dependent. Below the critical micelle concentration (cmc), increasing the concentration of SDS increased both the passive and the iontophoretic fluxes of HC, but the increase was most significant with anodal iontophoresis. Above the cmc, passive transport of HC continued to increase with an increase in the SDS concentration. The transport after anodal iontophoresis, however, reached a plateau and then leveled off. Further increase in SDS concentration decreased flux, suggesting that the transport of micellar-solubilized drug is retarded by anodal iontophoresis, possibly due to electrostatic attraction.     

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.     

The role of electroosmotic flow in transdermal iontophoresis

Iontophoresis enhances transdermal drug delivery by three mechanisms: (a) the ion-electric field interaction provides an additional force which drives ions through the skin; (b) flow of electric current increases permeability of skin; and (c) electroosmosis produces bulk motion of the solvent itself that carries ions or neutral species, with the solvent 'stream'. The relative importance of electroosmotic flow is the subject of this review. Experimental observations and theoretical concepts are reviewed to clarify the nature of electroosmotic flow and to define the conditions under which electroosmotic flow is an important effect in transdermal iontophoresis. Electroosmotic flow is bulk fluid flow which occurs when a voltage difference is imposed across a charged membrane. Electroosmotic flow occurs in a wide variety of membranes, is always in the same direction as flow of counterions and may either assist or hinder drug transport. Since both human skin and hairless mouse skin are negatively charged above about pH 4, counterions are positive ions and electroosmotic flow occurs from anode to cathode. Thus, anodic delivery is assisted by electroosmosis, but cathodic delivery is retarded. Water carried by ions as 'hydration water' does not contribute significantly to electroosmotic flow. Rather electroosmotic flow is caused by an electrical volume force acting on the mobile counterions. The simple 'limiting law' theory commonly given in textbooks and some research articles is a very poor approximation for transdermal systems. However, several extensions of the limiting law are compatible with each other and with the available experimental data. One of these theories, the Manning theory, has been incorporated into a theory for the effect of electroosmotic flow on iontophoresis, the latter theory being in good agreement with experiment. Both theory and experimental data indicate that electroosmotic flow increases in importance as the size of the drug ion increases. The 'ionic' or Nernst-Planck effect is the largest contributor to flux enhancement for small ions. Increased skin permeability or the skin 'damage effect', is a significant factor for both large and small ions, particularly for experiments at high current density. For monovalent ions with Stokes radii larger than about 1 nm, electroosmotic flow is the dominant flow mechanism. Because of electroosmotic flow, transdermal delivery of a large anion (or negatively charged protein) from the anode compartment can be more effective than delivery from the cathode compartment.     

Transdermal and intradermal iontophoretic delivery of dexamethasone sodium phosphate: quantification of the drug localized in skin

In this study, the effect of iontophoresis on the transdermal and intradermal delivery of dexamethasone sodium phosphate (DEX-P) was examined in vitro and in vivo in the hairless rat model by skin permeation studies, tape stripping, and skin extraction. Cathodal or anodal iontophoresis (ITP) was performed and samples were analyzed by HPLC. In vitro experiments revealed that cathodal ITP significantly enhanced the cumulative amount of DEX-P permeating through the skin when compared to passive and anodal delivery. Tape stripping and skin extraction studies performed in vivo after ITP showed enhanced deposition of the drug in the stratum corneum and underlying skin when compared to passive delivery. The DEX-P and DEX depot formed in the stratum corneum and underlying skin were retained for at least 48?h and 24?h, respectively. In conclusion, ITP demonstrated potential as a feasible enhancement technique to drive the drug into and through the skin in significant amounts as compared to passive delivery.     

Transungual iontophoretic transport of polar neutral and positively charged model permeants: effects of electrophoresis and electroosmosis

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.