Iontophoresis Enhances the Transport of Acyclovir Through Nude Mouse Skin by Electrorepulsion and Electroosmosis

Purpose. Iontophoresis was employed for enhancing the transdermal delivery of acyclovir through nude mouse skin in vitro, with the aim of understanding the mechanisms responsible for drug transport, in order to properly set the conditions of therapeutical application. Methods. Experiments were done in horizontal diffusion cells, using as donor a saturated solution of acyclovir at two different pH values (3.0 and 7.4). Different electrical conditions (current density and polarity) were employed. Results. At pH 3.0, acyclovir anodal transport was due to electrorepulsion, since acyclovir was 20% in the protonated form. In acyclovir anodal iontophoresis at pH 7.4 the main mechanism involved was electroosmosis, since the drug was substantially unionized and the negative charge of the skin at this pH caused the electroosmotic flow to be from anode to cathode. In the case of cathodal iontophoresis at pH 3.0, acyclovir transport was enhanced approx. seven times, due to the presence of an electroosmotic contribution caused by the reversal of the charge of the skin. At pH 7.4 during cathodal iontophoresis acyclovir transport was not enhanced because the electroosmotic flow was in the opposite direction, compared to drug electric transport, i.e. anode to cathode. The increased skin permeability caused by current application was demonstrated to be less important than electrorepulsion and electroosmosis. Conclusions. Anodal iontophoresis shows potential applicability for enhancing acyclovir transport to the skin, considering that both electric transport and electroosmosis can be used by appropriately setting the pH of the donor.     

Human Calcitonin Delivery in Rats by Iontophoresis

Abstract— In-vitro iontophoresis (0·33 mA cm⁻²) of calcitonin (50 μg mL⁻¹, pH 4) was performed with the hairless rat skin model. Direct current was as potent as pulse current (2·5 kHz on/off 1/1) iontophoresis in promoting transdermal permeation of calcitonin. Increase in duration of current application from 20 min to 1 h did not increase calcitonin flux. Results suggest that calcitonin can be blocked in the skin pores through which it travels or can accumulate in the skin and be progressively released from the depot. Invivo experiments showed that transdermal iontophoretic administration of calcitonin induced a hypocalcaemic effect in rats.     

Ionized Prodrugs of Dehydroepiandrosterone for Transdermal lontophoretic Delivery

Purpose. The aim of this work was to synthesize ionized dehydroepiandrosterone (DHEA) prodrugs with higher water solubility, useful for iontophoretic transdermal application. Methods. The synthesized derivatives were characterized and tested for sensitivity to chemical and enzymatic hydrolysis. Solid state and solution stability was also determined. Transdermal iontophoretic anodal transport in vitro was studied using excised rabbit skin. Results. Two DHEA ionized prodrugs were synthesized: PRO1, a primary amine derivative, and PRO2, a quaternary ammonium salt. The two derivatives possess higher water solubility and lower octanol/saline partition coefficients than DHEA. Prodrugs were sensitive to enzymatic hydrolysis; in particular the primary amine was hydrolyzed faster than the quaternary salt by esterase from porcine liver in vitro. Transdermal flux of the two prodrugs was slightly higher than the parent drug. In the case of passive diffusion, only DHEA was found in the receptor compartment, indicating the complete breakdown of the prodrug in the skin. Current application gave higher drug flux and a significant amount of prodrug was found in the receptor. Conclusions. The use of ionized prodrugs of DHEA can increase the flux attainable during transdermal anodal iontophoresis by up to 7 times, but they are useful for passive transport as well.     

Transdermal iontophoretic delivery of salmon calcitonin

Electrically enhanced transdermal delivery of salmon calcitonin could be useful for chronic treatment of postmenopausal osteoporosis and other clinical indications as a superior alternative to parenteral delivery. Calcitonin (50 microg/ml) formulation was prepared in citrate buffer (pH 4.0). Epidermis separated from human cadaver skin was used. Most iontophoresis studies were done at a current density of 0.5 m A cm2. Silver/silver-chloride electrodes were used and calcitonin was found to be best delivered under the anode. The relationship between calcitonin flux and current density during iontophoresis was linear. Passive flux was zero. Flux increased with increasing concentration up to 250 microg/ml but then it levels off. Thus, transdermal delivery of salmon calcitonin may be accomplished to achieve therapeutic levels.     

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.     

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.     

Enhanced Bioavailability of Calcitonin Formulated with Alkylglycosides Following Nasal and Ocular Administration in Rats

Purpose. The purpose of this study was to characterize the effects of alkylglycosides on the bioavailability of calcitonin following nasal and ocular administration. Methods. A salmon calcitonin specific radioimmunoassay kit was used to measure calcitonin levels in anesthetized rats at various times after nasal or ocular administration of calcitonin formulated with saline or with octylmaltoside, a medium chain length alkylglycoside or tetradecylmaltoside, a long chain alkylglycoside. The extent of calcitonin absorption was determined directly from the plasma calcitonin level-time curve and the bioavailability of calcitonin was determined from the area under the plasma calcium level-time curve. The calcium level was determined using a colorimetric method. Results. When the nasal formulation contained calcitonin plus saline or 0.125% octylmaltoside, little or no calcitonin was absorbed. However, plasma calcitonin levels were increased and plasma calcium levels were decreased when the nasal formulation contained calcitonin plus 0.125% or 0.25% tetradecylmaltoside. Maximal calcitonin levels were observed 7.5-10 min after nasal administration of the formulation. Ocular administration of calcitonin formulated with tetradecylmaltoside also resulted in calcitonin absorption, but less calcitonin absorption was found after ocular administration than after nasal administration. Conclusion. The experimental data indicate that tetradecylmaltoside, but not octylmaltoside, can be effectively used to enhance the bioavailability of nasally and ocularly administered calcitonin.     

脉冲电流对胰岛素经皮渗透的促进作用

实验结果表明,脉冲电流能有效地提高胰岛素的透皮扩散速率,并随着释放池中胰岛素浓度的递增,透皮扩散速率呈线性增加。同时,胰岛素在pH值偏离等电点的酸性溶液(pH3.6)中透皮速率最高,为324.2±33.4μU/(cm²·h),而在pH值高于等电点的溶液(pH7.4)中其透皮速率降至143.7±27.3μU/(cm²·h),在pH值接近等电点(pH5.3)时,胰岛素的透皮速率最低,为78.4±21.9μU/(cm²·h)。     

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.     

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.     

Enhancing effect of switching iontophoresis on transdermal absorption of glibenclamide

Glibenclamide(GLI) is widely used as an oral hypoglycemic drug in the treatment of non-insulin dependent diabetes mellitus (NIDDM). We investigated The enhancing effect of switching iontophoresis on the transdermal absorption and reduction of skin irritation to develop a transdermal dosage form of GLI. The 0.1% of Gli suspensions in 0.2 M tris-HCl buffer of pH 7.4, 8.0 and 8.5 were prepared as donor solutions. We examined drug permeation through the excised rat abdominal skin, drug absorption in rats and reduction of skin irritation after application of switching iontophoresis for 1 h using DC 10 V. The solubility of GLI in 0.2 M tris-HCl buffer increased with a rise in pH. In the permeation study, GLI was permeated continuously and the cumulative amount of permeated GLI increased using an alkaline donor solution. In the drug absorption study, the application group of pH 8.5 gave higher plasma concentration levels than those of pH 7.4 and 8.0 groups. The skin irritation evoked by the application of iontophoresis was pathologically studied. A total irritation score (TIS) was estimated as a judging standard for the skin damage. The TIS value increased dependently with a rise in pH. However, it was considered that the skin irritations were not serious and small matters. The results demonstrate the possibility of iontophoretic transdermal administration of GLI and the effect of drug solubility in the donor solution on the absorption of GLI.     

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.     

Transdermal iontophoretic delivery of [3H]-betamethasone sodium phosphate to the hind knee joints of rabbits: visualization of drug permeation routes and distributions

We used semimicro autoradiographs (ARGs) to investigate how tritium-labeled betamethasone sodium phosphate (beta-Na-phos) permeates the skin and is delivered to deeper tissues when it was transdermally administered to the hind knee joints of rabbits with and without iontophoresis. In passive transdermal administration, ARGs revealed the presence of beta-Na-phos only in the epidermis immediately beneath the site of drug administration. In active administration using iontophoresis, on the other hand, the plasma concentrations of beta-Na-phos after 30- and 120-min iontophoretic administrations were 0.090 and 12 μg eq./mL, respectively. Furthermore, ARGs indicated that beta-Na-phos was non-uniformly distributed from the skin to tissues surrounding the joint capsule (pericapsular tissues). The procedure suggested that beta-Na-phos reached pericapsular tissues via the perimysium. These results indicated the marked effect of iontophoresis to enhance the skin permeation of beta-Na-phos and that at least 30-min iontophoretic administration allowed its delivery to pericapsular tissues.     

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.     

A novel vesicular transdermal delivery of nifedipine – preparation,characterization and in vitro/in-vivo evaluation

Abstract

Nifedipine is a calcium channel blocker extensively used in the treatment of anginal and hypertension. On oral administration it undergoes extensive first pass metabolism, which outweighs its absorbance through gastrointestinal tract (GIT) and bioavailability of the drug in systemic circulation. As an alternative to oral route transdermal route of drug delivery was developed. In the present investigation, proniosomes are prepared by varying the ratio of span-40, lecithin, aqueous phase and polymer. Formulation containing span-40, lecithin, isopropyl alcohol, 0.1% glycerol (5:5:4) and HPMC (2%) showed smaller vesicle size, high entrapment efficiency. The niosomal formation after hydration and their surface morphology of optimized formulation was studied by Motic and transmission electron microscopy. FTIR and differential scanning calorimetry studies were performed to unravel and understand the solid state properties of the drug and chemical interaction with formulation excipients. The ex-vivo Franz-diffusion studies were carried out in pH 6.8 using rat skin and the results showed better permeability of niosomes with good steady state flux and enhancement ratio suggesting the potential of proniosomal carriers for improved transdermal delivery of nifedipine. Skin irritation studies for 7 days, showed that the drug when formulated as proniosomes to be non-irritant with no erythemia development compared to pure drug. From the bio-distribution studies, the vesicles prepared with hydroxy propyl methyl cellulose with span-40 was found to be ideal batch as the concentration of drug at target site was higher.     

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).     

Effects of proteolytic enzyme inhibitors as absorption enhancers on the transdermal iontophoretic delivery of calcitonin in rats.

The effects of proteolytic enzyme inhibitors, aprotinin, soybean trypsin inhibitor and camostat mesilate as absorption enhancers on the transdermal iontophoretic delivery of salmon calcitonin (SCT) have been examined in rats. The dermal absorption of SCT was evaluated with hypocalcaemic effect. Application of SCT (12.5 int. units/rat) onto abdominal skin did not produce any hypocalcaemic effect. This produced a small hypocalcaemic effect with cationic iontophoresis (drug phase, anode; reference phase, cathode; high frequency pulses of 1 V at 10 kHz, 2h). Furthermore, camostat mesilate (1 mM) and aprotinin (10(6) int. units mL-1) enhanced the hypocalcaemic effects on the application of SCT with iontophoresis. These hypocalcaemic effects were highest with the pH 4.0 preparation compared with those of the pH 5.5, pH 7.0 and pH 8.0 preparations. However, soybean trypsin inhibitor did not change the hypocalcaemic effects. This was because the soybean trypsin inhibitor is a relatively high molecular weight peptide (mol. wt 8000) and an anion at used pH, and therefore was not absorbed through rat skins with cation iontophoresis.     

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     

Passive and iontophoretic controlled delivery of salmon calcitonin through artificial membranes

The development of a transdermal delivery system for drug molecules of high molecular weight (peptides or proteins) is nowadays a great scientific and commercial challenge. For these molecules, the passive transport through the skin is generally very low and should be enhanced by the application of the electrical current (a method called iontophoresis). A very important component of a transdermal iontophoretic system is the artificial membrane, which acts as the interface between the drug reservoir and the skin. The optimum membrane should (i) provide an effective drug delivery; (ii) have low electrical resistance and (ii) have low drug adsorption. In this work, the selection of membrane(s) for a transdermal iontophoretic salmon calcitonin (sCT, MW approximately 3500) system is performed. The passive and iontophoretic transport of sCT through porous artificial membranes, the sCT adsorption to them and the electrical resistance of all porous membranes in iontophoretic experiments is studied. The sCT transport through the membranes is compared with that through human skin, and based on the above three criteria the optimum membranes are selected for the sCT transdermal system.     

Transdermal Permeation of Alniditan by Iontophoresis: In Vitro Optimization and Human Pharmacokinetic Data

Purpose. The aim of this paper was to assess the feasibility of electrically enhanced transdermal delivery of alniditan, a novel 5 HT_1D agonist for the treatment of migraine. Methods. An in vitro study was first performed to optimize the different parameters affecting iontophoresis efficiency. The mechanism of alniditan permeation by iontophoresis was investigated. Finally, a phase I clinical trial was performed to assess systemic delivery of alniditan by iontophoresis. Results. i) In vitro: The optimal conditions were found with a buffer like ethanolamine at a pH of 9.5, with Ag/AgCl electrodes and a direct current application. Alniditan permeation was enhanced when increasing the current density, the duration of current application and the drug concentration. Iontophoresis slightly increased drug quantities in stratum corneum compared to passive diffusion but it strongly increased alniditan quantities in viable skin, ii) The objective to deliver in vivo 0.5 mg of alniditan within less than 1 h was reached but an erythema was detected at the anode. Conclusions. This study demonstrates the feasibility of iontophoretic delivery system for antimigraine compounds.