Transdermal Delivery of Heparin Using Pulsed Current Iontophoresis

Purpose In clinical practice heparin has to be administered by injection with obvious disadvantages; thus, transdermal delivery by electrically assisted methods have been studied. In this study we evaluated the efficacy of a Food and Drug Administration-approved pulsed current iontophoresis system in delivering heparin through living rat skin. Methods Fluorescent and radioactive heparin as well as a commercial heparin preparation were delivered through rat skin via a pulsed current iontophoresis system. Results Pulsed current iontophoresis allowed fluorescent heparin to cross the stratum corneum localizing in epidermis and dermis. Unfractionated, high-, and low molecular weight fraction pools, obtained by fractionating [³⁵S]-unfractionated heparin on a molecular weight sieve, were then separately tested. Pulsed current iontophoresis elicited the transdermal delivery of low molecular weight heparin, but not that of high molecular weight heparin. Finally, pulsed current iontophoresis of an unfractionated pharmaceutical heparin preparation significantly decreased plasmatic factor Xa activity. Conclusions We hypothesize that this technique could be used to administer low molecular weight heparin in a cost-efficient and safe manner without the need for syringes and needles.     

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。     

Transdermal Delivery of Sumatriptan Succinate Using Iontophoresis and Dissolving Microneedles

This study focuses on the in vitro transdermal transport of sumatriptan succinate using combined iontophoresis and dissolving polymeric microneedle arrays. Permeation experiments were performed to evaluate the effects of formulation parameters on drug release from polyvinylpyrrolidone systems under mild electrical current (≤500 μA/cm²). The preparations consisted of hydrophilic, positively charged molecules encapsulated in a water-soluble and biocompatible polymeric material. Current densities of 100, 300, and 500 μA/cm² were applied during a 6-h period using silver/silver chloride electrodes. The circular array consisted of 600 needles and occupied a 0.785 cm² area. Tests, carried out with Franz diffusion cells and skin of Göttingen minipigs, showed that small decreases in the polymer concentration led to negligible lag times and marked increases in the cumulative amount of drug permeated in 6 h (Q_6h) and in the flux (J_ss). At 500 μA/cm², Q_6h and J_ss nearly doubled for a microneedle loaded with 5% (w/w) sumatriptan and 20% (w/w) PVP (lag time = 0 min; Q_6h = 2888 μg/cm²; J_ss = 490 μg/cm²/h) relative to a system loaded with 5% (w/w) drug and 30% (w/w) PVP (lag time = 36 min; Q_6h = 1437 μg/cm²; J_ss = 266 μg/cm²/h).     

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.     

Electrically-Assisted Transdermal Drug Delivery

Electrically-assisted transdermal delivery (EATDD) is the facilitated transport of compounds across the skin using an electromotive force. It has been extensively explored as a potential means for delivering peptides and other hydrophilic, acid-labile or orally unstable products of biotechnology. The predominant mechanism for delivery is iontophoresis, although electroosmosis and electroporation have also been investigated. The focus of this review is to put these different mechanisms in perspective and relate them to the drug and skin model system being investigated.     

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.     

Iontophoretic Transdermal Delivery of Haloperidol

The in vitro iontophoretic transdermal delivery of haloperidol (HP) across pig skin was investigated. Anodal iontophoresis considerably increased HP skin penetration and accumulation as compared to the passive controls.

The effect of NaCl and HP concentrations on the vehicle were also studied. As expected, HP iontophoretic transport decreased with NaCl content. On the other hand, HP concentration did not modify its electrotransport in the range of concentrations between 0.4 and 0.9 mg/mL, except at 24 hours. The influence of the current density (0.20–0.50 mA/cm²) was also investigated. The iontophoretic transport of HP tends to increase with current density. On the whole, this work shows that iontophoresis may be used to improve the topical application of HP for the treatment of chronic psychosis.     

Current Status and Future Prospects of Transdermal Drug Delivery

Pharmaceutical Research -     

Transdermal Delivery of Fentanyl by Electroporation I. Influence of Electrical Factors

Purpose. Electroporation, a method of reversibly permeabilizing lipid bilayers by the application of an electric pulse, has been shown to induce increased transdermal passage of molecules. The aim of the present report was to study in vitro with hairless rat skin the potential of electroporation for transdermal delivery of fentanyl. Results. The application of electric pulses can strongly promote transdermal delivery of fentanyl compared to passive diffusion through untreated skin. We also point out that the choice of the waveform of the electric pulses is important: at the same applied energy, a few exponentially-decaying (ED) pulses increased fentanyl permeation more than a few square-wave pulses and to the same extent as the repeated application of higher voltage-shorter duration ED pulses. A factorial design showed that the voltage, duration, and number of ED pulses allowed control of the quantity of drug transported through the skin. Conclusions. Skin electroporation could be a good way to improve the transdermal diffusion of fentanyl.     

LHRH离子电渗透皮给药系统的研究I.LHRH的离子电渗透皮吸收

研究了影响ＬＨＲＨ体子电渗透过裸鼠皮肤的因素。发现２５００ＨＺ（占空比３：１）的方波电流体外透皮效果最好，且透皮速率随着电流密度的增加而增加。ＬＨＲＨ在皮肤中会滞留，外加电场撤去后，ＬＨＲＨ仍持续透过。采用交变电渗技术可以达到脉冲电渗效果。因而可模拟ＬＨＲＨ体内分泌的模式     

Topical Iontophoresis of Valaciclovir Hydrochloride Improves Cutaneous Aciclovir Delivery

Purpose To investigate the topical iontophoresis of valaciclovir (VCV) as a means to improve cutaneous aciclovir (ACV) delivery.Methods ACV and VCV electrotransport experiments were conducted using excised porcine skin in vitro.Results While the charged nature of the prodrug, VCV, enabled it to be more efficiently iontophoresed into the skin than the parent molecule, ACV, only the latter was detectable in the receptor chamber, suggesting that VCV was enzymatically cleaved into the active metabolite during skin transit. Iontophoresis of VCV was significantly more efficient than that of ACV; the cumulative permeation of ACV after 1, 2 and 3 h of VCV iontophoresis at 0.5 mA cm⁻² and using an aqueous 2 mM (∼0.06%) formulation was 20 ± 10, 104 ± 47 and 194 ± 82 μg cm⁻², respectively (cf. non-quantifiable levels, 0.1 and 1.0 ± 0.7 μg cm⁻² after ACV iontophoresis).Conclusions These delivery rates provide ample room to reduce either current density or the duration of current application. Preliminary in vitro data serve to emphasize the potential of VCV iontophoresis to improve the topical therapy of cutaneous herpes simplex infections and merit further investigation to demonstrate clinical efficacy.     

Transdermal lontophoretic Delivery of Luteinizing Hormone Releasing Hormone (LHRH): Effect of Repeated Administration

The transdermal iontophoretic delivery of the reproductive peptide hormone, luteinizing hormone releasing hormone (LHRH) is investigated in the isolated perfused porcine skin flap model (IPPSF). LHRH is delivered twice in a single flap experiment in efforts to identify factors inherent to iontophoretic delivery that might effect the drug flux of a subsequent iontophoretic episode. Initial iontophoretic delivery of LHRH is quite reproducible; however, subsequent iontophoretic episodes result in widely divergent fluxes thought to be caused by iontophoretic influences on the skin. Iontophoretic application of a drug on a previous active site, enhances the flux during the second application. A mass balance study is performed to explain these findings. By iontophoretically delivering I¹²⁵ labelled LHRH in the isolated perfused porcine skin flap model, the entire iontophoretic dose is identified and quantified. A drug depot is identified in the skin underlying the electrode which is approximately two times as large as the entire mass of drug delivered systemically.     

Effects of Fatty Acids and Iontophoresis on the Delivery of Midodrine Hydrochloride and the Structure of Human Skin

Purpose. The purpose of this work was to investigate if fatty acids can increase the iontophoretic delivery of midodrine hydrochloride through human dermatomed skin and to observe the effects of iontophoresis and fatty acids on skin using SEM. Methods. After prehydration for 1 h, human dermatomed skin was treated with 0-0.3 M fatty acids (oleic acid, linoleic acid, decanoic acid, and lauric acid) in propylene glycol (PG) for 1 h. Then the fatty acid solution was replaced by 1% midodrine hydrochloride aqueous solution, and 0.1 mA/cm² constant current was applied. Samples were taken over 24 h and analyzed by HPLC. After the treatments outlined above, the epidermis was separated, fixed with glutaraldehyde, and dehydrated for SEM. Results. SEM studies revealed that only 1 h of treatment with fatty acids opened up the tightly compact stratum corneum cell layer, and the permeation study showed a significant increase of the permeability of skin to midodrine hydrochloride after fatty acid treatment. Conclusions. Using 5% oleic acid pretreatment, with the electrical current offset at 0.1 mA/cm², the daily delivery of midodrine hydrochloride can provide an adequate clinical application. The enhancement of passive and iontophoretic delivery by fatty acids may be occurring through the same mechanism.     

Electrically Modulated Transdermal Delivery of Fentanyl

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

Localization of a FITC-Labeled Phosphorothioate Oligodeoxynucleotide in the Skin After Topical Delivery by Iontophoresis and Electroporation

Purpose. The aim of this study was to verify the hypothesis that the application of high voltage to the skin enhances both stratum corneum and keratinocyte permeability. Therefore, the transport of FITC labelled phosphorothioate oligonucleotides (FITC-PS) administered by passive diffusion, iontophoresis or electroporation was localized. Methods. Fluorescent microscopy and laser scanning confocal microscopy were used to visualize the FITC-PS transport at the tissue and cell level respectively in hairless rat skin after electroporation (5 × (200 V 500 ms) or iontophoresis (same amount of charges transferred). Results. FITC-PS did not penetrate the viable skin by passive diffusion. Molecular transport in the skin upon electroporation or iontophoresis was localized and implied mainly hair follicles for iontophoresis. In the stratum corneum, the pathways for FITC-PS transport were more transcellular during electroporation and paracellular during iontophoresis. FITC-PS were detected in the nucleus of the keratinocytes a few minutes after pulsing. In contrast, iontophoresis did not lead to an uptake of the oligomer. Conclusions. The internalization of FITC-PS in the keratinocytes after electroporation confirms the hypothesis and suggests that electroporation, which allows both efficient topical delivery and rapid cellular uptake of the oligonucleotides, might be useful for antisense therapy of epidermal diseases.     

Transport Mechanisms in Iontophoresis. I. A Theoretical Model for the Effect of Electroosmotic Flow on Flux Enhancement in Transdermal Iontophoresis

Bulk fluid flow or volume flow in the direction of counterion flow is a probable mechanism for enhanced flux of uncharged species by iontophoresis. Both the electrical volume force effect, resulting from the interaction of the ion atmosphere and the electric field, and an induced osmotic pressure effect produce volume flow in the same direction as counterion flow through the membrane. Since each of these effects is proportional to the membrane charge and the imposed electric field, we classify both as electroosmotic flow. This research develops a detailed theoretical model which allows the effect of volume flow on flux enhancement to be evaluated. A detailed theoretical result for the electroosmotic flow coefficient also results from the analysis. The model assumes that transport occurs in three types of aqueous pores: positively charged, neutral, and negatively charged. For hairless mouse skin (HMS), pore size, charge, and number are evaluated from transference number, volume flow, and electrical resistance data. The flux enhancement ratio is J ₁/J ₁ ^D= A _ii/[l –exp( –_i)], where i = pore type, and the summation runs over the three pore types. A _i is the area fraction of pore type i effective for transport; J ₁ and J ₁ ^D are flux of species 1 with and without the electric field, respectively; and i is given by _i = F(–/RT)[ z ₁ + (–z _m ⁱ )Bar _i ² C _m ⁱ(G _i + F)]. Here F = Faraday's constant; – = voltage drop; R = gas constant; T = absolute temperature; z _m ⁱ = charge of pore i; C _m ⁱ = charge concentration in membrane pore of radius, r _i; B is a known collection of constants; a is the Stokes radius of the transported solute; G _i, is a function of membrane charge and pore radius coming from the electrical volume force effect; and F is a function of membrane charge and ion mobility arising from the induced osmotic pressure effect. For transdermal iontophoresis, F <<G, and the induced osmotic pressure effect is not significant. Negative pores dominate electroosmotic flow and usually dominate flux enhancement. The term proportional to C _m ⁱ is the contribution of electroosmotic flow and will always increase the flux enhancement ratio for anodic delivery of a positively charged ion (z ₁ > 0) or a neutral species (z ₁ = 0) in a negatively charged pore. The theoretical results are consistent with data in the literature.     

增渗剂和离子导入对尼莫地平体外经皮渗透性的影响

研究了增渗剂和离子导入技术对尼莫地平（ＮＭ）体外经皮渗透性的作用,渗透促进剂如３％和５％月桂氮卓酮及１０％油酸的２０％丙二醇溶液能增加药物的渗透性（Ｐ＜００５）,其增渗比分别为４６６、４３９及１２６４．离子导入技术能够显著增加药物的渗透性（Ｐ＜００１）,渗透比为８０３．同时表明１０％油酸和３％的月桂氮卓酮丙二醇溶液与离子导入并用,渗透比为１５、８５、８９２．     

Transdermal Reverse Iontophoresis of Valproate: A Noninvasive Method for Therapeutic Drug Monitoring

Purpose. The objectives of this work were (a) to explore the potential of transdermal reverse iontophoresis for therapeutic drug monitoring and (b) to develop an internal standard calibration procedure so as to render the technique completely noninvasive. Methods. A series of in vitro iontophoresis experiments was performed in which the subdermal concentration of sodium valproate was varied from 21 M to 1 mM. Glutamic acid was also introduced into the subdermal donor at a fixed concentration to act as an internal standard for the calibration method. Results. Both valproate and glutamate anions were recovered, as expected, at the anodal receptor chamber. The iontophoretic extraction flux of valproate was linearly correlated with the subdermal concentration. Glutamate flux was constant. It follows that the ratio of extracted fluxes (valproate/glutamate) was directly dependent upon (a) the subdermal valproate concentration and (b) the subdermal concentration ratio (valproate/glutamate), offering a means, thereby, to a completely noninvasive methodology. Conclusions. This work demonstrates the potential of reverse iontophoresis for noninvasive therapeutic monitoring. The simultaneous quantification of the analyte of interest and of an internal standard renders the withdrawal of a blood sample unnecessary.     

A New System for In Vitro Studies of Iontophoresis

This report describes a new iontophoretic diffusion cell that allows both electrodes to be applied to the same side of the same piece of skin. The cell permits a better approximation of the in vivo situation than do conventional side-by-side cells. The unique construction of the cell allows nonliquid material to be applied to the skin surface and makes it possible to investigate horizontal transport paths. Preliminary results utilizing the cell are described. Iontophoretic enhancement of morphine and clonidine delivery across full-thickness hairless mouse skin has been achieved. The importance of pH control in these experiments is apparent. Further experiments with morphine indicate that, for this drug at least, iontophoretically driven lateral transport within the skin is unimportant. Because the cell design allows significant parallels to the use of iontophoresis in vivo, we suggest that it will prove to be a useful tool in the determination of fundamental structure/transport relationships under the influence of an externally applied current.