盐酸丁卡因离子导入凝胶的研究

目的研究电流强度对盐酸丁卡因离子导入凝胶的渗透速率的影响。方法以盐酸丁卡因为模型药物,采用离子导入作为促透方法,分别测定不同电流强度下的盐酸丁卡因离子导入凝胶在离子导入后接受室溶液的吸收度,计算它们的稳态透皮速率。结果电流强度为0.05,0.1,0.15,0.2和0.25mA时,稳态透皮速率分别为10.18,22.94,34.62,41.60和51.35μg/cm2×h。结论在一定的电流强度下,漏槽条件下,盐酸丁卡因离子导入凝胶渗透速率与电流强度有较好的线性关系。     

乙醇对双氯芬酸钠经皮离子导入的影响

探讨了不同浓度乙醇对双氯芬酸钠（１）离子导入透过离体大鼠腹部皮肤的影响。乙醇对１波动扩散几乎不产生影响。但乙醇浓度为２０％～８０％的１饱和溶液，离子导入时的透皮速率均比药物饱和水溶液离子导入的透皮速率有不同程度的增加，浓度为６０％时药物的透皮速率最大，达到２９７±３４．７μｇ／ｈ／ｃｍ２，为波动扩散的１４．６倍，为饱和水溶液离子导入的透皮速率的３倍。     

乙醇对萘普生经皮离子导入的影响

探讨了不同浓度乙醇对萘普生离子导入透过离体大鼠腹部皮肤的影响，乙醇对萘普生被动扩散具有一定的促渗作用，乙醇浓度为３０％到８０％的萘普生饱和溶液，离子导入时的透皮速率均比药物饱和水溶液离子导入的透皮速率有不同程度的增加，其中乙醇浓度为７０％时药物的透皮速率最大，达到１８５±２３．７ｕｇ／ｈ·ｃｍ２，为被动扩散的６．４倍，药物饱和水溶液离子导入透皮速率的３倍。     

吡罗昔康离子导入的实验研究

探讨了离子导入和月桂氮酮预处理对吡罗昔康通过离体大鼠皮肤的影响，选用Ｖａｌｉａ－Ｃｈｉｅｎ扩散池和改良的Ｆｒａｎｚ扩散池，得到吡罗昔康饱和液及其膜剂的透皮速率分别为４．８±０．１７和１．０±０．０４μｇ／ｈ·ｃｍ－２，采用电流强度为０．８ｍＡ的离子导入，药物的透皮速率分别增加１１倍和８倍．另外，月桂氮酮预处理合用离子导入能产生协同作用，其透皮速率为单用月桂氮酮与单用电场透皮速率之和的４倍。     

电致孔-离子导入技术对胰岛素经皮给药促渗作用的研究

目的:以胰岛素为模型药物,大鼠的离体皮肤为皮肤模型,采用电致孔-离子导入联合物理促渗新技术,进行体外经皮导入生物大分子药物的研究。方法:以胰岛素为实验药物,采用经皮被动扩散方法,分别考察人体、家兔、小鼠、大鼠离体皮肤的透皮速率,从而进行皮肤模型的筛选;在预实验的基础上,选择pH值分别为4.0、6.0、7.4的三种渗透介质,采用离子导入法,考察渗透介质对胰岛素经皮渗透量的影响,从而确定渗透介质最适pH;应用电致孔-离子导入并用、电致孔、离子导入技术,在生理pH7.4、阴极转运条件下,对胰岛素的经皮渗透量进行考察,并与胰岛素的被动扩散经皮给药进行比较。结果:胰岛素对人体、家兔、小鼠、大鼠皮肤的透皮速率分别为0.78±0.03×10-1u/cm2·h、2.25±0.18×10-1u/cm2·h、2.02±0.19×10-1u/cm2·h、1.12±0.14×10-1u/cm2·h;在pH值分别为4.0、6.0、7.4的三种渗透介质中,胰岛素的经皮渗透速率分别为18.28±1.06×10-1u/cm2·h、9.42±0.29×10-1u/cm2·h、8.66±0.40×10-1u/cm2·h;采用电致孔-离子导入并用、离子导入、电致孔技术对胰岛素经皮促渗时,胰岛素的渗透速率分别达到19.63±6.37×10-1u/cm2·h、8.66±0.40×10-1u/cm2·h、1.83±0.07×10-1u/cm2·h。结论:电致孔-离子导入并用技术能够显著地促进生物大分子体外经皮给药的渗透速率。     

离子导入和促渗剂对布洛劳经皮渗透的影响

探讨了离于导人和促渗剂月桂氮酮、丙二醇、Ｎ－甲基－２－毗咯烷酮预处理对布洛芬饱和溶液通过大鼠皮肤渗透速率的影响。布洛芬饱和液的透皮速率为２３．０７±０．４５ｕｇ／ｈ·ｃｍ２，采用电流强度为０．２５ｍＡ的离子导入，药物的透皮速率增加１．５倍。采用月桂氮酮、丙二醇、Ｎ－甲基－２－毗咯烷酮预处理后药物的透皮速率分别增加８倍、３．５倍和１倍。月桂氮酮预处理合用离于导人和丙二醇预处理合用离子导人能产生协同作用，药物的透皮速率均比单用促渗剂和离于导人之和高。Ｎ－甲基－２－毗咯烷酮预处理合用离子导人无此作用。     

布洛芬离子导入凝胶剂在家兔体内的药动学

目的:通过研究布洛芬凝胶剂的药动学,为布洛芬离子电导入经皮给药系统的临床应用提供理论依据.方法:采用反相高效液相色谱法测定布洛芬凝胶剂透皮给药后不同时间家兔血药浓度,计算药动学参数.结果:布洛芬离子导入凝胶剂的吸收速度、峰浓度及血药浓度时间曲线下面积虽低于离子导入溶液剂,但AUC及C max 分别为透皮给药对照组的 2.6 倍和 4.5 倍,且吸收速度快.结论:布洛芬凝胶剂经离子导入有良好的吸收性.     

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。     

盐酸普鲁卡因经皮离子导入的研究

目的:考察盐酸普鲁卡因的离子导入与电流强度、药物浓度的关系。方法:测定不同的电流强度、不同的药物浓度的离子导入增渗倍数(ER) 。结果:固定药物浓度,电流强度为0 .1 ,0 .2 和0 .3m A 时的ER 值分别为68 ,99和127 。固定电流强度为0 .2m A,药物浓度为0 .0151 ,0 .0304 和0 .0605g/100ml 时的ER 值分别为95 ,99 和98 。结论:离子导入可以显著提高药物渗透速率,增渗倍数(ER) 随着电流强度的增加而增加,但与药物浓度无关     

在脉冲电流作用下胰岛素经皮吸收对糖尿病大鼠血糖的影响

实验结果表明,在一定范围内糖尿病大鼠血糖下降的幅度与脉冲电流强度、频率及治疗时间成正比,但当脉冲电流强度超过0.8mA/cm2,频率超过3000Hz时,糖尿病大鼠血糖下降的幅度不再继续增加,即应用较小的电流强度及脉冲频率就能有效地促进胰岛素透皮吸收。同时脉冲电流的占空比为1:l时,糖尿病大鼠血糖下降的幅度最大。为使糖尿病大鼠血糖下降的幅度基本相当,皮下注射与经皮吸收方式给药所用胰岛素的剂量约为1:16。     

Iontophoretic enhancement of timolol across human dermatomed skin in vitro

The objective of this study was to assess the in vitro the iontophoretic delivery of Timolol across human dermatomed skin in order to determine whether therapeutic doses of this drug can be delivered. Anodal iontophoresis of Timolol was performed by manipulating the donor vehicle and the current density. It was observed that by reducing simultaneously the competitive ions (NaCl) from 8 to 4 g/l and the pH from 7.4 to 4.7, the iontophoretic flux was significantly increased by a factor of 1.5 (669+/-81 microg/cm h). In order to simulate the situation in a transdermal patch, the iontophoretic delivery of Timolol was also studied after adding an artificial porous membrane placed between the Timolol formulation and the human dermatomed skin. No significant difference was observed in the steady state flux across the skin when an artificial membrane was added. Furthermore, a linear relationship was found between current density and steady state flux. These results indicate that the iontophoretic delivery of Timolol can be accurately controlled by the applied current. Assuming a one to one in vitro/in vivo correlation the Timolol transport in vitro results in therapeutic plasma concentrations in humans with very low current densities limiting possible skin irritation.     

Pharmacokinetic and local tissue disposition of [14C]sodium diclofenac following iontophoresis and systemic administration in rabbits.

The systemic pharmacokinetics and local drug distribution of sodium diclofenac in skin and underlying tissues was studied. Iontophoresis facilitated local and systemic delivery of diclofenac sodium compared with passive diffusion. The maximum plasma concentration of sodium diclofenac was achieved within 1 h of iontophoresis, and the delivery was proportional to applied current density (371 +/- 141 and 132 +/- 62 microg/L at 0.5 and 0.2 mA/cm(2), respectively). The in vivo delivery efficiency for diclofenac in rabbit was 0.15 mg/mA.h. The concentrations of sodium diclofenac in the skin, subcutaneous tissue, and muscle beneath the drug application site (cathode) were significantly greater than plasma concentrations and concentrations of drug in similar tissues at the untreated sites. The results thus suggest that the cutaneous microvasculature is not always a perfect "sink" and that transdermal iontophoresis facilitated the direct penetration of diclofenac sodium to deeper tissues. No skin irritation was observed up to 0.5 mA/cm(2) current density and 7 mg/mL sodium diclofenac concentration.     

Transdermal delivery of indomethacin by iontophoresis

The objective of this study was to construct a modified equation for the delivery of a drug by iontophoresis. Indomethacin was selected as a model since it has been widely used as a non-steroidal anti-inflammatory drug (NSAID) for external pharmaceutical preparations. The experiments were performed under a constant current in vivo using rat abdominal skin, and the plasma concentration was monitored by HPLC. Pharmacokinetic parameters were obtained from the plasma concentration profiles after intravenous injection. A theoretical value of the transdermal delivery of drug by iontophoresis was calculated from the plasma concentration and pharmacokinetic parameters. The experimental value was evidently higher than the theoretical one, suggesting the enhancement of passive diffusion with an increase of applied current. The modified equation was proposed for the delivery of a drug by iontophoresis incorporating enhanced passive diffusion.     

Iontophoretic delivery of apomorphine: from in-vitro modelling to the Parkinson patient

Apomorphine is a mixed dopamine D1/D2 receptor agonist which is potentially useful in the treatment of Parkinson's disease. The delivery of apomorphine is however complicated because it is not absorbed orally and other delivery routes with the exception of the intravenous route seem to fail. The most interesting route for controlled delivery of apomorphine is transdermal iontophoresis because this could enable the Parkinson patient to directly control the needed amount of apomorphine by increasing or decreasing the drug input in order to achieve optimal drug therapy ('on-demand') with a minimum of toxic side effects. The typical features of Parkinson's disease could be used to monitor the needed drug input and even more elegantly by means of suitable chip sensors which are able to directly measure bradykinesia, akinesia and/or tremor and to regulate in such a way the drug input. Such a chip-controlled iontophoretic system would be the first closed-loop system monitoring not pharmacokinetic data (blood levels) but more importantly externally measurable pharmacodynamic effects of Parkinson's disease. This scenario is more feasible as skin irritation and toxicity studies have proven that iontophoresis is a safe route of treatment. This review describes the basics of iontophoresis and the development of a transdermal iontophoretic delivery system on the basis of integrated pharmacokinetic/pharmacodynamic (PK/PD) investigations in patients with idiopathic Parkinson's disease. Transdermal iontophoretic transport of apomorphine was studied both in vitro with human stratum corneum using a newly developed iontophoretic continuous flow-through transport cell and in vivo in a first exploratory study in patients with Parkinson's disease. These studies showed that the delivery of apomorphine is feasible and furthermore the rate of delivery can be controlled by variation of the current densities. Additionally the pretreatment of the skin either with a mono-surfactant or a vesicular suspension of elastic liquid-state vesicles may be useful to further increase the apomorphine flux across the skin in combination with iontophoresis.     

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.     

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(+).     

Transdermal iontophoresis of sodium nonivamide acetate. V. Combined effect of physical enhancement methods

The effect of iontophoresis combined with treatment of other physical enhancement methods such as electroporation, low frequency ultrasound, and erbium:YAG (yttrium-aluminum-garnet) laser on the transdermal delivery of sodium nonivamide acetate (SNA) was examined in this present study. Iontophoresis increased the transdermal flux of SNA in vitro as compared to the passive diffusion without any enhancement. Furthermore, iontophoresis was always the most potent enhancement method for SNA permeation among the physical enhancement methods tested. Pulsing of high voltages (electroporation) followed by iontophoresis did not result in increased transport over iontophoresis alone. However, electroporation shortened the onset of transdermal iontophoretic delivery of SNA. Pretreatment of low frequency ultrasound (sonophoresis) alone on skin did not increase the skin permeation of SNA. The combination of iontophoresis and sonophoresis increased transdermal SNA transport more than each method by itself. The enhancement of drug transport across shunt routes and reduction of the threshold voltage in the presence of an electric field may contribute to this synergistic effect. Use of an erbium:YAG laser was a good method for enhancing transdermal absorption of SNA because it allows precise control of stratum corneum (SC) removal, and this ablation of SC could be reversible to the original normal status. The combination of laser treatment and iontophoresis also synergized the skin permeation of SNA, possibly due to a gradual drop in the electric resistance of the skin. The results in this present study point out that the choice of certain conditions with suitable physical enhancement methods can induce a synergistic effect on transdermal delivery of SNA during iontophoresis.     

Iontophoretic transdermal delivery of ketoprofen: novel method for the evaluation of plasma drug concentration in cutaneous vein

The objective of our study is to establish a novel method for the in vivo evaluation of transdermal delivery. In this study, cathodal iontophoresis of ketoprofen, a nonsteroidal anti-inflammatory drug, was performed in the thoracic area of rats at a constant direct current, and blood samples were collected from cutaneous vein passing through the thoracic part of the body. After the iontophoresis, the plasma ketoprofen concentration in cutaneous vein ipsilateral to the application site was significantly higher than that in systemic vein. On the other hand, the plasma concentration in cutaneous vein contralateral to the application site was not significantly different from that in systemic vein. A comparison of the time-course curves demonstrated that, for the duration of iontophoresis, the plasma ketoprofen concentration in cutaneous vein ipsilateral to the application site increased with the amount of ketoprofen absorbed in the skin. These results suggest that the plasma concentration in the cutaneous vein ipsilateral to the application site is related with the transfer of drug from skin to cutaneous blood circulation. Therefore, the measurement of plasma concentration in cutaneous vein close to the application site would allow us to directly quantify the local behavior of iontophoretic transdermal absorption.     

Investigation into the potential of iontophoresis facilitated delivery of ketorolac

The potential for iontophoresis facilitated transdermal transport of ketorolac was investigated using rat skin. Studies of electrical, physicochemical and device-related factors acting on the permeation kinetics of in vitro iontophoresis were performed. Iontophoresis increased the transdermal permeation flux of ketorolac as compared to the diffusion. Increase in applied current density or decrease in ionic strength of the donor solution enhanced the flux of the drug. Use of either platinum or silver/silver chloride electrodes resulted in similar enhancement of drug flux. Continuous current was more potent than pulsed current in promoting ketorolac transdermal permeation. Increasing the frequency or on:off ratio of pulse current induced an enhancement of the flux through the skin. An increase in donor drug loading dose or increasing the duration of current application resulted in enhancement of the drug flux. Pretreatment of the skin with D-limonene in ethanol or D-limonene in ethanol + ultrasound significantly enhanced the iontophoretic flux of the drug in comparison to passive flux with or without pretreatment. Trimodality treatment comprising of pretreatment with D-limonene in ethanol + ultrasound in combination followed by iontophoresis was found to be most potent for enhancing the rate of permeation of ketorolac.     

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.