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.     

Optimizing Iontophoretic Drug Delivery: Identification and Distribution of the Charge-Carrying Species

Purpose. To identify and quantify, in vitro and in vivo (in humans), the charge-carrying species during transdermal iontophoresis of lidocaine hydrochloride as a function of the concentration of drug relative to that of sodium chloride in the anodal solution. Methods. In vitro experiments in standard diffusion cells quantified lidocaine delivery and the outward migration of chloride across the skin. Electrotransport of Na⁺ was inferred by difference, allowing transport numbers of the three main charge-carrying species to be deduced. In vivo, outward electrotransport of Cl^– was measured and compared to the corresponding in vitro results. Results. The transport number of lidocaine increased linearly with increasing mole fraction and reached 0.15-0.20 at X_L = 1.0. In the absence of Na⁺, most of the charge was carried by Cl^– (>80%) despite the skin retaining its net negative charge and cation permselectivity. In vivo data correlated very well with in vitro results. Conclusions. The mole faction of drug (relative to competing ions of like polarity) is the crucial determinant of the extent to which it can carry charge across the skin during iontophoresis. The outward electromigration of Cl^–, in the sense opposite to drug delivery, may offer a useful means by which to optimize iontophoretic efficiency in the absence of competing cations in the anode formulation.     

In-vitro and in-vivo transdermal iontophoretic delivery of tramadol, a centrally acting analgesic

Objectives The feasibility of transdermal delivery of tramadol, a centrally acting analgesic, by anodal iontophoresis using Ag/AgCl electrodes was investigated in vitro and in vivo. Methods To examine the effect of species variation and current strength on skin permeability of tramadol, in‐vitro skin permeation studies were performed using porcine ear skin, guinea‐pig abdominal skin and hairless mouse abdominal skin as the membrane. In an in‐vivo pharmacokinetic study, an iontophoretic patch system was applied to the abdominal skin of conscious guinea pigs with a constant current supply (250 µA/cm²) for 6 h. An intravenous injection group to determine the pharmacokinetic parameters for estimation of the transdermal absorption rate in guinea pigs was also included. Key findings The in‐vitro steady‐state skin permeation flux of tramadol current‐dependently increased without significant differences among the three different skin types. In the in‐vivo pharmacokinetic study, plasma concentrations of tramadol steadily increased and reached steady state (336 ng/ml) 3 h after initiation of current supply, and the in‐vivo steady‐state transdermal absorption rate was 499 µg/cm² per h as calculated by a constrained numeric deconvolution method. Conclusions The present study reveals that anodal iontophoresis provides current‐controlled transdermal delivery of tramadol without significant interspecies differences, and enables the delivery of therapeutic amounts of tramadol.     

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

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

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.     

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.     

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.     

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.     

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.     

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.     

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

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

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.     

In vivo iontophoretic administration of ropinirole hydrochloride

This work explores the possibility of achieving therapeutic levels of the anti-Parkinsonian drug, ropinirole hydrochloride (RHCl), by transdermal iontophoretic delivery. An in vivo study was performed in hairless rats during which RH(+) was delivered at one current intensity (0.58 mA identical with 0.12 mA/cm(2)) and at three different drug concentrations (25, 125, and 250 mM). In vivo RH(+) flux and transport number were deduced from the steady-state plasma concentration values. Plasma concentration profiles and RH(+) transport numbers were independent of the drug donor concentration. The average iontophoretic input rate was about 3 micromol/h. Postiontophoresis transepidermal water loss (TEWL) was monitored and biopsies were histologically examined to identify any effects of iontophoresis on the skin. TEWL was elevated only at the anodal sites. TEWL recovery was faster for the "no-drug" control anodal sites, which suggests a combined effect of the drug and current on the skin. In conclusion, (1). the in vivo iontophoretic transport of RH(+) is independent of the drug donor concentration, and (2). iontophoresis can deliver therapeutic amounts of RH(+).     

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.     

基于透皮离子导入技术的戒烟药物金雀花碱的可控递送研究

目的 探索烟碱乙酰胆碱受体部分激动剂金雀花碱(cytisine,CTS)经阳极离子导入透过离体猪皮。方法 采用HPLC-PDA建立并验证CTS的分析方法。研究了电流密度、药物浓度和药物基质对CTS透皮离子导入的影响。采用标志物对乙酰氨基酚解析CTS离子导入过程中电迁移和电渗的贡献。结果 CTS从水溶液中被动透皮不佳,但在离子导入条件下CTS的透皮递送量显著增加,将电流密度从0.15 mA·cm^–2增加到0.5 mA·cm^–2可使离子导入CTS的稳态流量呈线性增加(J=452.8I+31.51,r=0.998 3)。在使用0.5 mA·cm^–2电流密度的条件下,给药池药物浓度的增加(2.5,5.0,10.0 mg·mL^–1)可使累积透皮递送量显著增加。共离子导入对乙酰氨基酚证实了电迁移是CTS的主要递送机制(˃90%)。CTS的传导效率良好(6.63%~8.82%)。递送效率,即递送药物占所给予的制剂中的药物的百分数较高(在0.5 mA·cm^–2时>40%)。CTS从离子导入贮库HEC水凝胶中递送时的累积透皮递送量为(1 551.94±322.19)μg×cm^–2,与从CTS溶液中递送时的累积透皮递送量无统计学差异。结论 体外数据表明,使用较小面积的凝胶贴片通过透皮离子导入可以方便地递送治疗剂量的CTS。     

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.     

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.     

Transdermal iontophoresis of ranitidine: an opportunity in paediatric drug therapy

The objective of this study was to examine the use of transdermal iontophoresis for the delivery of ranitidine hydrochloride in children. Constant, direct current, anodal iontophoresis of ranitidine was performed in vitro across dermatomed pig skin. The effect of donor vehicle, current intensity, and drug concentration were first examined using aqueous solutions. It was found that drug delivery was higher at pH 7 (donor: 5 mM Tris) than pH 5.6 (donor: water). In the presence of low levels of competing background electrolyte, ranitidine delivery increased linearly with applied current but was independent of the donor drug concentration. The second part of the study evaluated two Pluronic^® F-127 gels as potential vehicles for ranitidine delivery. The formulations were characterised in terms of apparent viscosity, conductivity and passive permeation measurements. Iontophoretic delivery of ranitidine was only slightly affected when delivered from the gels relative to aqueous solutions. Overall the results demonstrated that therapeutic paediatric doses of ranitidine (neonates: 0.09–0.17 μmol/kg h; 1 month to 12 years: 0.36–0.71 μmol/kg h) could be easily achieved by transdermal iontophoresis with simple gel patches of practical surface area (0.2–1.5 cm²/kg).     

The influence of positive or negative charges in the passive and iontophoretic skin penetration of porphyrins used in photodynamic therapy

Meso-tetra-(N-methylpiridinium-4-yl)-porphyrin (TMPyP) and meso-tetra-(4-sulfonatophenyl)-porphyrin (TPPS₄) are photosensitizing drugs (PS) used in photodynamic therapy (PDT). Based on the fact that these compounds present similar chemical structures but opposite charges at pH levels near physiological conditions, this work aims to evaluate the in vitro and in vivo influence of these electrical charges on the iontophoretic delivery of TMPyP and TPPS₄, attempting to achieve maximum accumulation of PS in skin tissue. The iontophoretic transport of these drugs from a hydrophilic gel was investigated in vitro using porcine ear skin and vertical, flow-through diffusion cells. In vivo experiments using rats were also carried out, and the penetration of the PSs was analyzed by fluorescence microscopy to visualize the manner of how these compounds were distributed in the skin after a short period of iontophoresis application. In vitro, both passive and iontophoretic delivery of the positively charged TMPyP were much greater (20-fold and 67-fold, respectively) than those of the negatively charged TPPS₄. TPPS₄ iontophoresis in vivo increased the fluorescence of the skin only in the very superficial layers. On the other hand, iontophoresis of the positively charged drug expressively increased the rat epidermis and dermis fluorescence, indicating high amounts of this drug throughout the skin layers. Moreover, TMPyP was homogeneously distributed around and into the nuclei of the skin cells, suggesting its potential use in topical PDT.     

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.