The Effect of Vehicle Additives on the Transdermal Delivery of Nitroglycerin

Pharmaceutical Research -     

Dose Proportionality of Transdermal Nitroglycerin

The FDA Cooperative Efficacy Study of transdermal nitroglycerin utilized a combination of marketed products over a wide dose range. Unfortunately, plasma nitroglycerin concentrations were not determined. The current study was conducted to assess plasma nitrate concentrations after transdermal doses of 15, 30, 60, and 105 mg/24 hr employing the FDA Cooperative Study design. Plasma concentrations of nitroglycerin, 1,3-glyceryl dinitrate, and 1,2-glyceryl dinitrate were determined during the 24 hr of application and for 1 hr after transdermal system removal. Dose proportionality was assessed after normalizing the data by theoretical dose. For nitroglycerin, dose-normalized AUC_{(0_)} and C _max were higher for the 105 mg/24 hr dose than for the other doses. For the metabolites, 1,3-glyceryl dinitrate and 1,2-glyceryl dinitrate, there were no differences in dose-normalized AUC_{(0_)} and dose-normalized C _max between the dose levels. No differences were seen in T _max between the dose levels for all three species. Based on the dinitrate metabolites, dose proportionality was seen over the 15 to 105 mg/24 hr dose range. Nitroglycerin, however, was found to be linear only between 15 and 60 mg/24 hr.     

Novel Pharmacokinetic Modelling of Transdermal Nitroglycerin

Purpose. To construct a pharmacokinetic (PK) model and to determine population PK parameters of nitroglycerin (GTN), 1,2-dinitroglycerin (1,2-GDN), and 1,3-dinitroglycerin (1,3-GDN). Methods. Data were obtained in thirty healthy volunteers following a single dose of a GTN reservoir transdermal patch. Blood samples were obtained just before and at 0.5, 1, 2, 3, 4, 6, 8, 12, 14, and 24 hours after the patch application and 1 hour after its removal. GTN, 1,2-GDN, and 1,3-GDN concentrations were determined using HPLC and simultaneously best fitted using a first-pass mixed-order release one-compartment PK model. Individual estimates (ADAPT-II) were used as priors for a population PK analysis (IT2S). Fitted parameters included the percentage (A) of the nitroglycerin dose reaching the systemic circulation that was released from the patch by a first-order process (K₁); two absorption (ka₁ and ka₂), two metabolite formation (k_fl and k_f2) and one metabolite elimination (k(m)) rate constants; and three volumes of distribution Vc/F, V₂/F and V₃/F. Results. Nitroglycerin mean population parameter estimates and inter-individual variability (CV%) were: A 35% (65), K₁, 0.06 h^–1(91), ka₁ 5 h^–1(46), ka₂ 0.47 h^–1 (39), k_f1 11 h^–1(42), k_f2 0.6 h^–1(34), k(m) 1.4 h^–1(29), V_c/F 6 L(31), V₂ /F 73 L(34), and V₃ /F 23 L(29). The average elimination half-lives for GTN and the two metabolites were 5 and 32 minutes, respectively. Conclusions. The proposed PK model fitted observed concentrations of GTN, 1,2-GDN and 1,3-GDN very well. This model should be useful to predict drug and metabolite concentrations and to assess bioequivalence of two transdermal formulations.     

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.     

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。     

硝酸甘油透皮给药系统体外释药速率测试方法的研究

随着透皮吸收研究的兴起,先后已有东茛菪碱、硝酸甘油、硝酸异山梨醇、可乐定和雌二醇等透皮给药系统进入市场。各生产单位对这些产品都有一定的质量控制项目,主要有药物含量、粘附力及药物释放速率,其中药物的释放速率是一个较重要的质量控制项目。虽然现在上市的透皮给药系统     

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.     

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。     

Transdermal Insulin Delivery Using Microdermabrasion

Purpose  

Transdermal insulin delivery is an attractive needle-free alternative to subcutaneous injection conventionally used to treat diabetes. However, skin’s barrier properties prevent insulin permeation at useful levels.     

Transdermal Delivery of Metoprolol by Electroporation

Electroporation, i.e., the creation of transient pores in lipid membranes leading to increased permeability, could be used to promote transdermal drug delivery. We have evaluated metoprolol permeation through full thickness hairless rat skin in vitro following electroporation with an exponentially decaying pulse. Application of electric pulses increased metoprolol permeation as compared to diffusion through untreated skin. Raising the number of twin pulses (300 V, 3 ms; followed after 1 s by 100 V, 620 ms) from 1 to 20 increased drug transport. Single pulse (100 V, 620 ms) was as effective as twin pulse application (2200 V, 1100 V or 300 V, 3 ms; followed after 1 s by 100 V, 620 ms). In order to investigate the effect of pulse voltage on metoprolol permeation, 5 single pulses (each separated by 1 min) were applied at varying voltages from 24 to 450 V (pulse time 620 ms). A linear correlation between pulse voltage and cumulative metoprolol transported after 4 h suggested that voltage controls the quantity of drug delivered. Then, the effect of pulse time on metoprolol permeation was studied by varying pulse duration of 5 single 100 V pulses from 80 to 710 ms (each pulse also separated by 1 min). Cumulative metoprolol transported after 4 h increased linearly with the pulse time. Therefore, pulse time was also a control factor of the quantity of drug delivered but to a lesser extent than the voltage at least at 100 V. The mechanisms behind improved transdermal drug delivery by electroporation involved reversible increased skin permeability, electrophoretic movement of drug into the skin during pulse application, and drug release from the skin reservoir formed by electroporation. Thus, electroporation did occur as shown by the increased transdermal permeation, on indicator of structural skin changes and their reversibility. Electroporation has potential for enhancing transdermal drug delivery.     

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).     

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.     

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。     

Transdermal Drug Delivery Using Low-Frequency Sonophoresis

Purpose. Application of therapeutic ultrasound (frequency: 1–3 MHz and intensity: 0–2 W/cm²) enhances transdermal drug transport, although typically by a factor of less than 10. In this paper, we show that application of ultrasound at 20 KHz induces transdermal transport enhancements of up to 1000 times higher than those induced by therapeutic ultrasound. Methods. In vitro (human cadaver epidermis) as well as in vivo (hairless rat skin) permeation experiments were performed to assess the effect of low-frequency ultrasound on transdermal transport. Results. Application of low-frequency ultrasound (20 KHz, 125 mW/cm², 100 msec pulses applied every second) enhanced transdermal transport of several permeants, including estradiol, salicylic acid, corticosterone, sucrose, aldosterone, water, and butanol, across human cadaver skin by a factor in the range of 3 to 3000 and that of salicylic acid across hairless rat skin in vivo by a factor of up to 300. Low-frequency ultrasound did not induce a long-term loss of the barrier properties of the skin (in vitro) or damage to living skin of hairless rats. At a mechanistic level, it is hypothesized that application of low-frequency ultrasound enhances transdermal transport through aqueous channels in the SC generated by cavitation-induced bilayer disordering. Support for this hypothesis is provided using experimental and theoretical analyses of low-frequency sonophoresis. Conclusions. Low-frequency ultrasound enhances transdermal transport of drugs more effectively than that induced by therapeutic ultrasound.     

Testosterone Ethosomes for Enhanced Transdermal Delivery

Physiological decrease in testosterone levels in men with age causes various changes with clinical significance. Recent testosterone replacement therapy is based mainly on transdermal nonpatch delivery systems. These products have the drawback of application on extremely large areas to achieve required hormone blood levels. The objective of the present study was to design and test a testosterone nonpatch formulation using ethosomes for enhanced transdermal absorption. The ethosomal formulation was characterized by transmission electron microscopy and dynamic light scattering for structure and size distribution and by ultracentrifugation for entrapment capacity. To evaluate the feasibility of this delivery system to enhance testosterone permeation through the skin, first the systemic absorption in rats was compared with a currently used gel (AndroGel®). Further, theoretical estimation of testosterone blood concentration following ethosomal application in men was made. For this purpose, in vitro permeation experiments through human skin were performed to establish testosterone skin permeation values. In the design of these experiments, testosterone solubility in various solutions was measured and the effect of the receiver medium on the skin barrier function was assessed by confocal laser scanning microscopy. Theoretical estimation shows that testosterone human plasma concentration value in the upper part of the physiological range could be achieved by application of the ethosomal formulation on an area of 40 cm². This area is about 10 times smaller than required with current nonpatch formulations. Our work shows that the ethosomal formulation could enhance testosterone systemic absorption and also be used for designing new products that could solve the weaknesses of the current testosterone replacement therapies.     

微针经皮给药技术

微针是介于皮下注射和透皮贴剂之间的一种给药方式,利用在皮肤角质层产生的微小孔道来显著增加药物的经皮吸收。综述微针经皮给药技术的研究进展,介绍制造微针的材料和方法、微针的给药方式及其在经皮给药系统中的应用。     

Scale-up of Adhesive Transdermal Drug Delivery Systems

Pharmaceutical Research -