Iontophoresis-based transdermal delivery systems

Transdermal iontophoresis is the administration of ionic therapeutic agents through the skin by the application of a low-level electric current. This article presents an overview of transdermal iontophoretic delivery of drugs, including peptides and oligonucleotides. Recent advances in the area of iontophoretic delivery, including devices, hydrogel formulations, safety, clinical relevance and future prospects, are discussed. Electroporation, another method of electrically assisted drug delivery, is also briefly reviewed. Transdermal iontophoresis appears to be a promising technique for the delivery of a variety of compounds in a controlled and preprogrammed manner. Transdermal iontophoresis would be particularly useful in the delivery of hydrophilic drugs produced by biotechnology (peptides and oligonucleotides). However, because of the complex physicochemical properties of peptides, many factors must be carefully considered for the proper design of an iontophoretic drug delivery system for peptides. Iontophoresis has been successfully used in the delivery of small peptides, such as leuprolide and calcitonin analogues, in humans. However, it appears that transdermal iontophoresis may not be a suitable method for the systemic delivery of larger peptides (>7,000D). The combined use of iontophoresis and electroporation may be more effective in the delivery of peptides, proteins, genes and oligonucleotides. The long-term safety of iontophoresis, patient compliance with the technique and the commercial success of this technology are yet to be demonstrated. Iontophoretic delivery of drugs would be beneficial in the treatment of certain skin disorders such as skin cancer, psoriasis, dermatitis, venous ulcers, keloid and hypertrophic scars. Investigations on reverse iontophoresis may yield interesting results that would be useful in the noninvasive measurement of clinically important molecules in the body.     

基于STC12C5S60S2单片机经皮给药系统的设计

背景：经皮给药技术为蛋白质多肽类药物的导入提供了一种方便有效的方式。 目的：研制一种基于微控制器的经皮给药系统,实现药物经皮无创导入的同时维持药物的活性,提高药物的生物利用度。 方法：经皮给药系统以微控制器为核心,采用电致孔导入技术,电离导入技术和超声波导入技术从不同角度克服皮肤屏障,促进药物经皮吸收,在软硬件上合理的设计实现3种机制的协同作用,提高药物导入的效率。 结果与结论：试制出经皮给药系统样机,该系统操作简便,以无创的方式经皮给药可以提高患者的依从性,通过各治疗参数的调节,可用于多种药物的经皮导入,为实现个体化治疗提供可能。     

脉冲电场诱致皮肤电穿孔的荧光显微观察

从组织形态学角度观察脉冲电场和直流电场作用后皮肤结构的变化,以阐明这两种技术的差别.将人皮和蛇皮置于Valia-Chien双室扩散池,用电穿孔脉冲电场(脉幅380V,脉率4ppm,脉宽5.5ms,脉冲数100个,电容量22μF)和离子导入直流电流(0.5mA/cm2)作用于这些皮肤,用荧光显微镜观察被动扩散(对照)、离子导入和电穿孔三组皮肤的结构变化,荧光素为FITC.结果表明,对于人皮被动扩散见有少量15～30μm边缘粗糙的高亮荧光斑点;离子导入见高亮荧光斑点边缘变得光滑,尺度不变;电穿孔的高亮荧光斑点扩大至80～90μm,边缘光滑.对于蛇皮被动扩散和离子导入都未观察到高亮荧光斑点,但在电穿孔观察到25～30μm的高亮荧光斑点.提示脉冲电场可以诱致皮肤电穿孔,产生药物经皮渗透的新途径.     

经皮给药系统的研究进展

经皮给药系统作为一种非侵入式药物递送系统,与传统的注射、口服等给药方式相比具有许多优势,非常适用于需要频繁治疗或长期治疗的疾病.根据近年来经皮给药系统的研究进展,对经皮给药机制、影响药物经皮渗透的因素、促进药物经皮吸收的方法进行归纳和评述,并对经皮给药系统的未来发展趋势进行展望.     

透皮给药研究的新进展

透皮给药安全可控，是无创给药的新途径，有着广阔的市场前景。现有的透皮药物限于小分子和低浓度，角质层屏障使大多数药物难以通过或难以达到有效浓度和有效速率。透皮给药的关键在于促进药物渗透，使药物透皮吸收进毛细血管。促渗手段有：使用化学促渗剂；对药物进行化学修饰制成前体药物；使用物理方法；将药物载入载体。这些方法的原理大致分为三种：改变角质层结构；外力驱动药物；将药物进行修饰或包裹。简要地介绍了增强药物透皮的物理方法和载体方法研究的新进展。     

透皮给药研究的新进展

透皮给药安全可控,是无创给药的新途径,有着广阔的市场前景。现有的透皮药物限于小分子和低浓度,角质层屏障使大多数药物难以通过或难以达到有效浓度和有效速率。透皮给药的关键在于促进药物渗透,使药物透皮吸收进毛细血管。促渗手段有:使用化学促渗剂;对药物进行化学修饰制成前体药物;使用物理方法;将药物载入载体。这些方法的原理大致分为三种:改变角质层结构;外力驱动药物;将药物进行修饰或包裹。简要地介绍了增强药物透皮的物理方法和载体方法研究的新进展。     

复方骨肽不同给药方法促进骨折愈合的实验研究

目的比较局部应用复方骨肽超声经皮导入与静脉使用复方骨肽对于骨折愈合的影响。方法制备60只成年健康新西兰兔双侧桡骨骨折模型,分为超声电导局部给药组、静脉给药组、对照组3组。术后在4个时间点﹙按第2、4、6、8周﹚通过X片,光镜下观察及骨组织形态计量学分析评价骨折愈合情况。结果 X片半定量、光镜下组织学观察以及骨组织形态计量学分析表明通过超声组和静脉组骨折愈合较对照组明显提前,有统计学意义﹙<0.05﹚。超声组结果稍优于静脉组,但无统计学意义﹙>0.05﹚。结论复方骨肽超声经皮导入与静脉使用对于骨折愈合全过程有相似的促进作用。     

MRI in ocular drug delivery

Conventional pharmacokinetic methods for studying ocular drug delivery are invasive and cannot be conveniently applied to humans. The advancement of MRI technology has provided new opportunities in ocular drug-delivery research. MRI provides a means to non-invasively and continuously monitor ocular drug-delivery systems with a contrast agent or compound labeled with a contrast agent. It is a useful technique in pharmacokinetic studies, evaluation of drug-delivery methods, and drug-delivery device testing. Although the current status of the technology presents some major challenges to pharmaceutical research using MRI, it has a lot of potential. In the past decade, MRI has been used to examine ocular drug delivery via the subconjunctival route, intravitreal injection, intrascleral injection to the suprachoroidal space, episcleral and intravitreal implants, periocular injections, and ocular iontophoresis. In this review, the advantages and limitations of MRI in the study of ocular drug delivery are discussed. Different MR contrast agents and MRI techniques for ocular drug-delivery research are compared. Ocular drug-delivery studies using MRI are reviewed.     

Nanoparticle delivery for transdermal HRT

Nanomedicine is an emerging technology and the first nano-engineered medical products have come to light in the last decade. Transdermal drug delivery has significant advantages compared to other routes of drug administration. Nanoparticles unique physical and chemical properties enable transport of substances directly into the skin. The objective of this paper is to review different aspects of nanoparticle delivery, generally, and discuss its current use for transdermal hormone therapy. Transdermal estrogen therapy remains the most effective treatment for bothersome menopausal symptoms, particularly in those women for whom the potential adverse effects associated with "first pass" hepatic metabolism are to be avoided. Available alternatives for transdermal estrogen delivery include patches, gels, sprays and lotions. Other non-oral therapies which likewise avoid "first pass" hepatic metabolism include: subcutaneous implants and vaginal rings. Some of the transdermal products are associated with mild adverse skin effects such as redness and irritation, but more severe and bothersome consequences include blistering and tattooing. Even the mild adverse skin effects are frequently cited as reasons for discontinuation. Micellar nanoparticle estradiol emulsion (MNPEE) is a lotion-like therapy which constitutes an alternative transdermal delivery system not requiring the permeation enhancers or temporary skin digestion, both of which increase the possibility of irritation. MNPEE's advantages include low fluctuation of plasma estradiol concentrations, infrequent skin related adverse effects, and pleasant cosmetic-like moisturizing properties. The efficacy of MNPEE for management of menopausal vasomotor symptoms has been demonstrated in a randomized placebo controlled trial, and the product is FDA approved for management of moderate to severe vasomotor symptoms. None of the observed adverse effects in the MNPEE group were statistically different from the placebo group. Studies addressing inadvertent transference of estradiol to the male partners of menopausal women using this delivery technology have demonstrated small, but real amounts of transference, which do not exceed the normal physiological male estradiol range. MNPEE is safe and effective for treatment of vasomotor symptoms and represents the commercial validation of nanoparticle technology for transdermal delivery of estrogen therapy (ET) for postmenopausal women with vasomotor symptoms.     

Recent developments of collagen-based materials for medical applications and drug delivery systems

In this review, an attempt was made to summarize some of the recent developments in the application of collagen as a biomaterial and in drug delivery systems. The main applications covered include: collagen for burn/wound cover dressings; osteogenic and bone filling materials; antithrombogenic surfaces; and immobilization of therapeutic enzymes. Recently, collagen used as a carrier for drug delivery has attracted many researchers throughout the world. The use of collagen for various drug delivery systems has also been reviewed in this article. Collagen-based drug delivery systems include: injectable microspheres based on gelatin (degraded form of collagen); implantable collagen-synthetic polymer hydrogels; interpenetrating networks of collagen; and synthetic polymers collagen membranes for ophthalmic delivery. Recent efforts to use collagen-liposomal composites for controlled drug delivery, as well as collagen as controlling membranes for transdermal delivery, were also reviewed. In this review, the main emphasis was on the work done in our laboratory.     

低频超声透皮给药的研究进展与应用

低频超声可以增强包括大分子药物在内的许多药物的透皮传输,其主要机制是超声的空化作用,大多数人认为是通过改变角质层角化细胞排列结构来提高皮肤渗透能力的.低频超声透皮给药已被人们用于离体实验和动物活体实验,到目前为止,无论是小分子透皮传输还是大分子透皮传输都有很多成功的例子.但是真正通过低频超声透皮导入药物进行治疗的临床应用报道很少,需要更进一步大量的临床试验以确定其安全性与实用价值.一旦其安全性得以证实,合适的低频超声透皮仪研制成功,低频超声快速透皮必将成为一种安全、有效、可控、经济的新型给药方式.     

Hercon technology for transdermal delivery of drugs

The Hercon controlled drug delivery technology is based on a multi-layered laminated polymeric structure, in which a layer of vinyl chloride copolymer or terpolymer containing the drug is sandwiched between two or more layers of polymeric films. The drug is released from the device at a controlled rate by a process of diffusion through the reservoir and one of the outer layers, which can function as a rate controlling membrane. This basic technology has been successfully utilized for the development and commercialization of Nitroglycerin Transdermal System (NTS, Bolar Pharmaceutical Co., Inc). In vitro and in vivo investigations of transdermal delivery of different other drugs from the Hercon polymeric devices have indicated the feasibility of using this system to meet a variety of therapeutic needs.     

聚氨酯胶黏剂的医用研究进展

聚氨酯胶黏剂因其优异的粘合性能,在医学领域越来越受到关注。寻求具有良好生物相容性、良好粘合性、可降解、无不良反应、消毒灭菌、在存在水的环境下能继续保持粘合特性的聚氨酯胶黏剂已成为医学领域的重点。该文综述了医用聚氨酯胶黏剂在创伤敷料、骨粘合剂、压疮的预防与治疗、经皮给药系统、手术薄膜及医药包装等方面应用的研究进展,并对聚氨酯胶黏剂应用于医学中的发展前景作了评述。     

Dissolving microneedles for transdermal drug administration prepared by stepwise controlled drawing of maltose

Dissolving microneedles, three-dimensional polymer structures with microscale cross-sectional dimensions, have been introduced as a means of safe transdermal drug delivery. Most dissolving microneedles have been fabricated using a traditional micro-casting method that cures biopolymers within three-dimensional mold, nevertheless, repeated molding process may cause damage to encapsulated drugs, a critical hurdle for clinical application. Here, we describe the stepwise controlled drawing technique that can directly fabricate dissolving microneedle from maltose by precise controlling the drawing time and the viscosity of the maltose. Controlled drawing shaped the particular sharp-conical microneedles of 1200 μm length with tip diameter of 60 μm, and dissolved within 20 min in-vivo after inserting to the skin. This technique surpasses the limitations of micro-casting for dissolving microneedle. Furthermore, transdermal delivery of impermeable hydrophilic molecules such as ascorbic acid-2-glucoside and niacinamide was confirmed as inhibition of cutaneous hypermelanosis. We anticipate that controlled drawing technique will be suitable to design dissolving microneedles for use in minimally invasive transcutaneous drug delivery to patients.     

Hydrogel probe for iontophoresis drug delivery to the eye

The aim of this study was to evaluate the use of a solid hydrogel loaded with a drug solution as a probe for ejecting drugs to the eye upon application of low current iontophoresis. Hydroxyethyl methacrylate (HEMA), cross-linked with ethylene glycol dimethacrylate (EGDMA), and cross-linked arabinogalactan or dextran were prepared to form solid hydrogels. The hydrogels were examined for their mechanical suitability, absorption of drug solution and in vitro release properties when applying an iontophoretic current through the drug-loaded hydrogel into a solid-agar surface. Transconjunctival and transscleral iontophoresis of gentamicin sulfate was studied in healthy rabbits using drug-loaded disposable HEMA hydrogel disc probes. Gentamicin concentrations in different eye segments were assayed using a fluorescence polarization immunoassay. Preliminary corneal toxicity was examined in rabbits using a current intensity of 2.5 and 5.1 mA/cm² for 60 and 120 s. The most appropriate hydrogel is composed of HEMA, 2% EGDMA and 75% water. Iontophoresis onto agar gel was found indicative for the evaluation of iontophoretic activity of a hydrogel. Transscleral iontophoretic treatment resulted in high concentrations of drugs in the posterior segments of the eye. Application of iontophoresis onto the rabbit eye caused a reversible swelling of the cornea which lasted a few hours after application. Low current iontophoresis using drug-loaded hydrogel has a potential clinical value in obtaining high drug concentration at posterior segments of the eye.     

Mechanical and Baicalin Delivery Properties of Adhesive Matrices for Iontophoretic Flexible Electrodes

The aim of this work was to evaluate the feasibility and efficacy of flexible adhesive electrodes (FAEs) prepared with adhesive matrices for iontophoretic delivery of baicalin, a drug used for the treatment of atopic dermatitis, viral hepatitis and HIV. Single-layer adhesive matrices (SLAMs) and double-layer adhesive matrices (DLAMs) were prepared from carbomer 940, sodium alginate and polyvinyl alcohol with appropriate mechanical and high baicalin release properties. During the direct-current (DC) iontophoresis with SLAM FAEs, electrochemical reaction caused a clear decrease of pH value at the interface IF_+,FCL and an increase of pH value at the interface IF_?,FCL. An additional pH-controlling layer in DLAMs could adjust the pH value of interfaces. Thus, deterioration of baicalin stability and the competitive delivery of hydroxyl ions produced with baicalin anions would be avoided during iontophoresis. Iontophoretic flux of baicalin from a DLAM FAE cathode increased proportionally to the time from the onset and affected by the current density and the frequency of pulsed DC. Increasing the applied current or the frequency could enhance the skin permeation flux of baicalin. Moreover, the baicalin skin permeation flux could be further improved from 0.22 μg/cm² per h in iontophoresis alone to 0.43 μg/cm² per h in the combined approach of iontophoresis and Azone^®.     

66KHz正向脉冲电流对皮肤刺激及其应用初步探讨

为探索提高药折离子导入量，本文研究了６６ＫＨｚ正向脉冲电流对皮肤的刺激感及其药物离子导入性能，实验证明６６ＫＨｚ正向脉冲电流无刺痛感，离子导入的性能和直流电相似。     

Hydrogel probe for iontophoresis drug delivery to the eye

The aim of this study was to evaluate the use of a solid hydrogel loaded with a drug solution as a probe for ejecting drugs to the eye upon application of low current iontophoresis. Hydroxyethyl methacrylate (HEMA), cross-linked with ethylene glycol dimethacrylate (EGDMA), and cross-linked arabinogalactan or dextran were prepared to form solid hydrogels. The hydrogels were examined for their mechanical suitability, absorption of drug solution and in vitro release properties when applying an iontophoretic current through the drug-loaded hydrogel into a solid-agar surface. Transconjunctival and transscleral iontophoresis of gentamicin sulfate was studied in healthy rabbits using drug-loaded disposable HEMA hydrogel disc probes. Gentamicin concentrations in different eye segments were assayed using a fluorescence polarization immunoassay. Preliminary corneal toxicity was examined in rabbits using a current intensity of 2.5 and 5.1 mA/cm2 for 60 and 120 s. The most appropriate hydrogel is composed of HEMA, 2% EGDMA and 75% water. lontophoresis onto agar gel was found indicative for the evaluation of iontophoretic activity of a hydrogel. Transscleral iontophoretic treatment resulted in high concentrations of drugs in the posterior segments of the eye. Application of iontophoresis onto the rabbit eye caused a reversible swelling of the cornea which lasted a few hours after application. Low current iontophoresis using drug-loaded hydrogel has a potential clinical value in obtaining high drug concentration at posterior segments of the eye.     

人造微针与生物微针研究进展

微针经皮给药技术是一种新型无痛输药技术,具有广泛的应用前景。本文首先介绍了微针技术的发展历史和现状,分析了人造微针所面临的主要问题,然后介绍了生物微针的研究概况,讨论了人造微针与生物微针存在的差距。由于受现有加工技术的限制,人造微针无法加工出像生物微针那样完美的微纳结构,在材料上也无法像生物微针那样的优化设计;此外,人造微针在刺入方式上也与生物微针有差异,不能像生物微针那样在刺入过程中可以根据各种条件实现主动控制。人造微针要真正达到生物微针那样完美,还有很多问题需要解决。     

Treatment and management strategies of onychomycosis

Onychomycosis is one of the most prevalent and severe nail fungal infections, which is affecting a wide population across the globe. It leads to variations like nail thickening, disintegration and hardening. Oral and topical drug delivery systems are the most desirable in treating onychomycosis, but the efficacy of the results is low, resulting in a relapse rate of 25–30%. Due to systemic toxicity and various other disadvantages associated with oral therapy like gastrointestinal, hepatotoxicity, topical therapy is commonly used. Topical therapy improves patient compliance and reduces the cost of treatment. However, due to poor penetration of topical therapy across the nail plate, research is focused on different chemical, mechanical and physical methods to improve drug delivery. Penetration enhancers like Thioglycolic acid, Hydroxypropyl-β-cyclodextrin (HP-β-CD), Sodium lauryl sulfate (SLS), carbocysteine, N-acetylcysteine etc. have shown results enhancing the drug penetration across the nail plate. Results with physical techniques such as iontophoresis, laser and Photodynamic therapy are quite promising, but the long-term suitability of these devices is in need to be determined. In this article, a brief analysis of the treatment procedures, factors affecting drug permeation across nail plate, chemical, mechanical and physical devices used to increase the drug delivery through nails for the onychomycosis management has been achieved.