离子导入经皮给药系统

综述了离子导入技术的基本组成、促渗机制、影响因素及应用前景。离子导入技术可有效提高药物的经皮渗透性，该技术扩大了经皮给药系统的研究范围，其对多肽和蛋白质等大分子药物的透皮促渗作用日益受到关注。     

LHRH离子电渗透皮给药系统的研究Ⅱ．离子电渗仪的研制和LHRH的大鼠药动学研究

设计了便携式离子电渗装置，采用石墨材料作电极，可以输出恒定的和不同频率、不同波形的脉冲直流电流，电渗时间和停药时间可以预先设置。研制了LHRH的PVA水凝胶贴片，进行了大鼠在体恒定和脉冲离子电渗透皮给药，结果表明离子电渗技术可以促进凝胶贴片中LHRH的透皮转运，持续实验的24h内，血清中可以维持平稳的LHRH水平，从而诱导大鼠体内分泌的LH水平有较明显的提高。通过电场的反转和中断可以模拟体内周期性的LHRH分泌。     

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.     

青霉素钠离子导入经皮吸收的研究

采用Valia-Chien扩散池法,以离体SD大鼠皮肤为渗透屏障,比较青霉素钠经离子导入与被动扩散的透皮速率,并以HPLC法测定皮肤和接收液中青霉素钠的含量.结果表明,离子导入和被动扩散的透皮速率分别为241.02和31.91μg·cm-2·h-1.提示离子导入能促进青霉素钠的经皮吸收(P＜0.05),且导入量随着导入时间的延长而增加.以皮内注射为对照,考察了青霉素钠经离子导入在SD大鼠在体皮肤中的滞留情况.结果表明,离子导入组皮肤中的青霉素钠含量[(72.52±22.06)μg/g]与皮内注射组[(54.04±12.31)μg/g]相比无显著性差异(P＞0.05).     

盐酸奥丹西酮离子导入的研究

本文研究了奥丹西酮在不同电流密度下经小鼠全皮的渗透动力学,当电流密度从0．05mA.cm^-2升高到0．3mA.cm^-2时,药物的稳态流量从30．29ug.cm^-2.h^-1增加到160．70ug.cm^-2.h^-1,研究中药物稳态流量和应用电流之间不严格呈线性关系,铂在供药池中作阳极时,可导致药物溶液变色,而应用银电极代替铂电极,则可以避免此问题的出现,应用铂电极时,供药池和接受池中均发现有pH变化,文章对以上问题以及解决的方法进行了讨论。     

盐酸奥丹西酮离子导入的研究(英)

本文研究了奥丹西酮在不同电流密度下经小鼠全皮的渗透动力学。当电流密度从0.05mA．cm-2升高到0.3mA．cm-2时，药物的稳态流量从30．29μg．cm-2.h-1增加到160.70μg．cm-2.h-1。研究中药物稳态流量和应用电流之间不严格呈线性关系。铂在供药池中作阳极时，可导致药物溶液变色；而应用银电极代替铂电极，则可以避免此问题的出现。应用铂电极时，供药池和接受池中均发现有pH变化。文章对以上问题以及解决的方法进行了讨论。     

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     

电渗作用对替硝唑经皮离子导入的影响

考察了电扬下电渗作用对分子型药物替硝唑经皮渗透的影响。实验结果表明,替硝唑从饱和水溶液经正极导入时,透皮速率比其被动扩散增加12.8倍,负极导入也产生一定的促进作用。替硝唑的透皮速率随电流强度而增加。另外,NaCl的加入使用电场下替硝唑的透皮速率明显下降,而在NaCl浓度为0.05mol/L时药物在电场下的透皮率相对较大。     

Optimization of Iontophoretic Parameters for the Transdermal Delivery of Methotrexate

The aim of this work was to study the in vitro factors affecting transdermal iontophoretic delivery of methotrexate across hairless rat skin. Initial screening studies evaluated the effect of ionic strength and donor concentration. A response surface model using factorial design shows an increase in the cumulative amount of methotrexate delivered (Y₁) with an increase in current density (X₁) and time of application (X₂). However, 10 min iontophoresis and 0.05 mA/cm² current density did not show an increase in delivery with an increase in current density or time of application, respectively. The factorial design was able to identify the optimal parameters that would have been difficult to predict with a conventional one at a time-experimental approach.     

A Unique Iontophoretic Patch for Optimal Transdermal Delivery of Sumatriptan

Purpose Migraines affect approximately 10% of the adult population worldwide. The purpose of this study was to assess the pharmacokinetic and safety profile of a novel iontophoretic sumatriptan delivery system, NP101, which uses an electrical current to propel sumatriptan across intact skin and into underlying tissue. Four unique prototype iontophoretic sumatriptan patch conditions were compared to a 6 mg subcutaneous injection and an oral 50 mg tablet of sumatriptan succinate. Materials and Methods This was a randomized, single-center, single-dose, six-period Phase I study. Results Patches were well tolerated with fewer adverse events than the subcutaneous injection. Adverse events that were more prevalent for NP101 than other formulations included localized sensations and reactions at the patch site. A linear relationship was observed between total applied current and sumatriptan delivery. Patches delivering 6 and 12 mA per h yielded favorable sumatriptan systemic profiles, delivering drug at a rate that maintained plasma levels above the target level (≥10 ng/ml) for greater than 7 h. Conclusions This study met the initial objective to define the dose–current relationship in humans as well as delimiting specific current and current density targets for a well tolerated patch design that can deliver therapeutic drug levels for longer periods than currently possible.     

Enhancement of Transdermal Iontophoretic Delivery of a Liposomal Formulation of Colchicine by Electroporation

Iontophoresis of colchicine solution through electroporated skin showed maximum enhancement as compared to iontophoresis and electroporation alone. Encapsulation of colchicine in positively charged liposomes further augmented the delivery,with the amount of drug in the receptor after 24 h being 1348 342 mug/cm2 when iontophoresis was performed through electroporated skin as compared to 666 38mug/cm2 when it was performed through nonelectroporated skin and 41 18mug/cm2 when only electroporation was performed. The impedance of the skin was observed to drop sharply due to electroporation, with a postpulse recovery of about 30% over 24h. Also the total amount transported was compared to the total charge delivered in the case of each of the protocols. Hence this serves as initial evidence for potential of charged liposomes for the enhanced transdermal delivery of nonionized or neutral drugs using a combination of electroporation and iontophoresis.     

Enhancement of Transdermal Iontophoretic Delivery of a Liposomal Formulation of Colchicine by Electroporation

Iontophoresis of colchicine solution through electroporated skin showed maximum enhancement as compared to iontophoresis and electroporation alone. Encapsulation of colchicine in positively charged liposomes further augmented the delivery,with the amount of drug in the receptor after 24 h being 1348 342 mug/cm2 when iontophoresis was performed through electroporated skin as compared to 666 38mug/cm2 when it was performed through nonelectroporated skin and 41 18mug/cm2 when only electroporation was performed. The impedance of the skin was observed to drop sharply due to electroporation, with a postpulse recovery of about 30% over 24h. Also the total amount transported was compared to the total charge delivered in the case of each of the protocols. Hence this serves as initial evidence for potential of charged liposomes for the enhanced transdermal delivery of nonionized or neutral drugs using a combination of electroporation and iontophoresis.     

Effect of Lipophilicity on Microneedle-Mediated Iontophoretic Transdermal Delivery Across Human Skin In Vitro

The effect of lipophilicity of drug on the microneedle (MN)-mediated iontophoretic delivery across dermatomed human skin was studied. Beta blockers with similar pK_a but varied log P values were selected as model drugs in this study. Iontophoresis (ITP) or MNs, when used independently, increased the transdermal flux of beta blockers as compared with passive delivery (PD). ITP across the MN-treated skin (MN + ITP) increased the permeation rate of all beta blockers as compared with PD (p < 0.001). The enhancement ratios (ER) for hydrophilic molecules (atenolol and sotalol) were 71- and 78-fold higher for ITP + MN as compared with PD. However, for lipophilic molecule such as propranolol, there was 10-fold increase in the ER as compared with PD. These observations were further substantiated by the skin retention data; an inverse relationship between the skin retention and the hydrophilicity of the drug was observed. The results in the present study point out that the lipophilicity of the molecule plays a significant role on the electrically assisted transdermal delivery of drugs across the microporated skin. Using the combination of ITP + MN, hydrophilic drugs (atenolol and sotalol) were delivered at a much higher rate as compared with lipophilic molecules (propranolol and acebutolol).     

LHRH离子电渗透皮给药系统的研究 II.离子电渗仪的研制和LHRH的大鼠药动学研究

设计了便携式离子电渗装置 ,采用石墨材料作电极 ,可以输出恒定的和不同频率、不同波形的脉冲直流电流 ,电渗时间和停药时间可以预先设置。研制了 L HRH的 PVA水凝胶贴片 ,进行了大鼠在体恒定和脉冲离子电渗透皮给药 ,结果表明离子电渗技术可以促进凝胶贴片中 L HRH的透皮转运 ,持续实验的 2 4h内 ,血清中可以维持平稳的 L HRH水平 ,从而诱导大鼠体内分泌的 L H水平有较明显的提高。通过电场的反转和中断可以模拟体内周期性的 L HRH分泌。     

Pretreatment with a Water-Based Surfactant Formulation Affects Transdermal Iontophoretic Delivery of R-Apomorphine in Vitro

Purpose. To further increase the transdermal transport rate of R-apomorphine, a nonocclusive pretreatment with an aqueous surfactant formulation in combination with iontophoresis was explored in vitro. Methods. The human stratum corneum was pretreated nonocclusively with formulations composed of laureth-3 oxyethylene ether (C₁₂EO₃), laureth-7 oxyethylene ether (C₁₂EO₇), and cholesterol sulfate (CSO₄) prior to iontophoresis. The effect on the flux of the following parameters was examined: the composition, the charge, and the applied amount of surfactant formulations. Results. The iontophoretic flux of R-apomorphine was appreciably increased by pretreatment with surfactant formulations. A formulation containing C₁₂EO₃/C₁₂EO₇/CSO₄ at a molar ratio of 70:30:5 was very stable and increased the iontophoretic flux of R-apomorphine from 92.2 ± 13.9 nmol/cm²*h to 181.5 ± 22.6 nmol/cm²*h. When further increasing the negative charge of this formulation the iontophoretic transport rate was slightly inhibited. A dose of 40 L/cm² of the formulation with a total surfactant concentration of 5% (w/w) was sufficient for a maximum enhancing effect. Conclusions. The results obviously show that nonocclusive pretreatment with the surfactant formulation enhances the iontophoretic transport of R-apomorphine, and is a promising approach to achieve therapeutic concentrations of R-apomorphine.     

Passive and Iontophoretic Transdermal Penetration of Chlorpromazine

The in vitro iontophoretic transdermal delivery of chlorpromazine (CPZ) across pig skin was investigated. Anodal iontophoresis considerably increased CPZ skin penetration and accumulation compared with the passive controls.

The effect of CPZ concentration in the donor solution was studied (1.4–8.2 mM). A higher penetration was observed with an increase of the concentration. In addition, the effect of NaCl concentration was also studied (154–200 mM). As expected, CPZ iontophoretic transport decreased with NaCl content. Finally, the influence of the current density (0.20–0.50 mA/cm²) was investigated. The iontophoretic transport of CPZ tends to increase with current density, although this effect was not statistically significant between 0.35 and 0.5 mA/cm². On the whole, this work shows that iontophoresis may be used to improve the transdermal delivery of CPZ for the treatment of chronic psychosis.     

Transdermal Iontophoretic Delivery of Propofol: A General Anaesthetic in the Form of its Phosphate Salt

The main objective of this study was to investigate the feasibility of delivery of propofol phosphate (PP), a prodrug of propofol, via transdermal route using iontophoresis in combination with chemical permeation enhancers (CPEs). PP, a prodrug, was synthesized and its structure was characterized. In vitro passive and iontophoretic drug transport studies were carried out using Franz diffusion cell across freshly excised hairless rat skin at different concentrations of PP in combination with CPE. Among all the CPEs screened, 0.1% sodium dodecyl sulfate (SDS) increased the passive transdermal flux to 13.43 ± 0.73 μg/(cm² h) from 8.52 ± 0.82 μg/(cm² h) (control). Cathodal iontophoresis in combination with 0.1% SDS synergistically enhanced the flux [249.24 ± 6.12μg/(cm² h)] of PP. The Pharmacokinetic studies were performed in rat model to assess the feasibility of transdermal delivery of PP. The amount of propofol present in plasma samples in control group (passive) was below the detectable levels at all the time points during the study. The plasma concentration—time profile of iontophoresis group of rats was fit to a noncompartmental model and the pharmacokinetic parameters were calculated. These studies suggest the plausibility of achieving therapeutically relevant levels of propofol when delivered via transdermal route by combining iontophoresis with CPE.     

渗透促进剂对胰岛素体外经皮离子导入渗透性的影响

本文考察了某些渗透促进剂如月桂氮Zhuo酮（AZ）、油酸（OA）、泊洛沙姆（POL）和丙二醇（PG）等对胰岛素体外经皮离子导入渗透性的影响。结果表明AZ对离子导入具有协同作用，PG能够增强这种作用，三者并用对胰岛素的经皮渗透具有特别显著的促渗效果。5％AZ／PG与离子导入并用后，较单独离子导入处理组的促渗因子为2.75。OA不能增强离子导入的作用，离子导入与某些渗透促进剂并用为胰岛素等大分子多肽类药物的透皮给药提供了新的思路和可能。     

Transdermal Macromolecular Delivery: Real-Time Visualisation of Iontophoretic and Chemically Enhanced Transport Using Two-Photon Excitation Microscopy

Purpose. To investigate the transdermal delivery of a modelmacromolecule by passive and iontophoretic means following pretreatment withC₁₂-penetration enhancers and to visualise transport across humanstratum corneum (SC) in real time. Methods. Transport studies of dextran, labelled with fluorescentCascade Blue® (D-CB; M_R = 3 kDa) across human stratum corneum,were conducted during passive and iontophoretic modes of deliveryfollowing pretreatment with either dodecyltrimethylammoniumbromide (DTAB), sodium dodecyl sulphate (SDS) or Azone®.Size-exclusion chromatography was used to assess maintenance of dextranstructural integrity throughout experimental lifetime. Two-photonexcitation microscopy was employed to visualise real-time dextran transportduring current application. Results. The positively charged C₁₂-enhancer DTAB elevated passiveD-CB steady-state flux (J_ss) and was the only enhancer to do soabove control during iontophoresis. The negatively charged SDS had theleast effect during both stages. On-line macromolecular transport wasvisualised, indicating both inter- and intra-cellular pathways across SCduring current application. No transport was visible across untreatedSC during passive transport. Conclusions. Use of a positively charged enhancer may improve J_ssof anionic macromolecular penetrants during passive and iontophoreticdelivery. On-line visualisation of iontophoresis across SC was possibleand can provide mechanistic insight into SC transport pathways.     

离子电渗给药技术研究进展

离子电渗技术作为一种非入侵性、成熟的物理促渗方式,能有效解决药物经皮肤、角膜和黏膜转运速率低下和吸收量少的难题。相比其他促透方式而言,具有给药效率高和递送剂量可控等优势。本文介绍该技术的装置组成、促渗机制以及影响因素,分析近年来离子电渗技术在医药科学领域的应用方向,该技术可广泛用于小分子乃至大分子蛋白药物的递送及医疗诊断与监测的研究领域。同时本文简述了该技术与其他促渗方式联合应用的实例,表明联合促渗技术可起到药物跨屏障递送的协同作用,大幅度提高给药效率。虽然离子电渗给药技术现阶段仍存在设备要求高、用药成本高等问题,但其较高的医疗价值与良好的市场前景将会进一步推动该技术继续发展。