用于药物传输的MEMS平面金属微针

介绍了传统给药方式的局限性、微针应用于新的药物传输方式——透皮给药的优点以及微针的特点,并提出了一种基于微机电系统技术制作同平面金属微针的方法.采用该方法可制备实心微针和空心微针.这两种金属微针均采用电镀技术制作,既降低了成本又提高了微针的强度.微针为楔形,边缘比较光滑,针尖有较锋利的尖端,改善了刺入皮肤的效果;针体长度400μm,厚度50μm,其中空心微针中的微流道宽度为50μm.此类微针便于改变尺寸以满足不同的需要.用该微针进行了刺入鼠皮的实验,验证了该微针刺入皮肤的有效性.     

基于交联透明质酸的微针制备及性能

新型水凝胶微针具有安全包裹多相药物、药物持续、可控释放等优点,在微针透皮给药领域极具应用潜力.文中重点研究了交联透明质酸微针贴片的优化工艺,并对微针贴片进行了性能评价.在碱性条件下使用1,4-丁二醇二缩水甘油醚(BDDE)为交联剂对透明质酸进行交联,利用微浇注法制备交联透明质酸微针(cHA-MN),并优化其工艺.对所制备的微针贴片进行了外观形貌、力学性能、体外刺入性能及溶胀性能表征,验证其能否满足使用要求.实验结果表明,使用最优工艺制备的交联透明质酸微针贴片力学性能优良,可以顺利刺破皮肤,并实现溶胀功能.使用制备的微针搭载2.5％的右旋布洛芬药物,体外透皮扩散结果表明,微针在0～6 h释放出约38％药物,随后以一定速度缓慢释放至42 h,累计释放率约90％.     

用于构建可溶性微针的基质材料及其复合材料

可溶性微针作为新型透皮给药制剂,打破了传统皮肤给药制剂不能用于大分子药物经皮给药的局限,且具有无痛、无创、无出血、卫生、生物相容性好、便于患者自主使用等诸多优点。近年来可溶性微针的研究已成为备受关注的热点。基质材料的选择直接影响微针的制备及皮肤刺入、药物释放等性能。介绍了可溶性微针的研究现状,对基质材料进行了分类与介绍,并综述了基质材料的复合使用及效果。同时介绍了韧性材料和脆性材料的特性及其复合后的协同效果,进而对该领域存在的问题和研究方向进行了讨论和展望。     

微针协同光学疗法用于疾病治疗研究进展

微针作为一种新兴的透皮给药技术,可绕过肝脏首过效应及皮下注射带来的疼痛问题进行微创无痛的局部给药。但使用微针递送的药物大都属于被动给药,药物释放速率受限。光学疗法在癌症及皮肤病治疗等领域展现出独特的优势,但为了实现优异的治疗效果往往需要较高的光敏剂剂量和激光辐照强度,这不可避免地会带来毒性和皮肤损伤。近年来,微针已与多种策略(pH响应、电响应、光学疗法等)联合用于多种疾病治疗。微针与光动力、光热等光学疗法协同应用可以优势互补,在一定程度上降低所使用光敏剂和光热剂的剂量或激光辐照的强度,减少毒性和治疗过程中对皮肤造成的损伤。此外,微针与光响应材料结合可以精确有效地递送药物,增强疗效。综述了近年来微针协同光动力、光热疗法在癌症治疗、伤口管理、医学美容等领域的研究进展,以期为之后更多的研究提供一些参考。     

针尖载药可溶性聚合物微针的制备及释药性能

可溶性聚合物微针是一种新型经皮给药系统,受到医药领域的广泛关注.皮肤弹性会导致微针刺入不完全造成药物浪费.为了解决这一问题,文中通过优化微针溶液配方和制备工艺,采用分步浇注法制备了针尖载药可溶性聚合物微针,提高了给药效率,并通过构建不同组成结构的聚合物微针实现了释药性能的调控.研究中选择具有生物相容性的聚合物材料,以磺酰罗丹明B为模型药物.结果 表明,药物主要集中在微针针尖,占针体高度60％左右.所制备的针尖载药可溶性聚合物微针具有高力学强度和刺入皮肤能力,载药量稳定.体外释药结果表明,通过选择不同的聚合物材料,载药针尖可以实现快速溶解或缓慢溶胀,从而实现药物的快速释放或缓慢释放.文中提出的可溶性聚合物微针实现了针尖载药和释药性能调控,在经皮给药方面具有潜在的应用前景.     

长春新碱透皮给药系统筛选及其透皮机理研究

分别制备了含不同表面活性剂的载长春新碱传递体(VCR-T)和载长春新碱壳聚糖纳米粒(VCR-CS-NPs),通过体外透皮试验,比较了不同透皮给药系统的透皮效果,并用DSC扫描探索了透皮效果差异的原因.所制备的VCR-T包封率从50%至80%不等,粒径90nm左右;VCR-CS-NPs的包封率为50%,粒径200nm左右;透射电镜下观察VCR-T和VCR-CS-NPs均外形圆整光滑,不粘连.体外透皮结果显示含Brij78的VCR-T为最佳的VCR透皮给药系统,DSC扫描认为这与载体与Brij78的相互作用有关;VCR-CS-NPs不能很好地透过皮肤,这可能与其粒径较大有关.     

新型透皮给药系统

自从80年代初期美国ALZA公司将抗晕车药物东莨菪碱作为贴剂推向市场以来，TTS(transdermal therapeutic systems)透皮给药系统已经走过了20个年头。随着其优势不断为人们认识．随着新型技术特别是透皮促进技术不断发展，越来越多的药物选挥了透皮给药模式。     

管状Silicalite—1分子筛膜的乙醇／水渗透汽化分离性能

采用原位水热合成的方法在管状α－ Ａｌ２ Ｏ３ 基膜上合成了 Ｓｉｌｉｃａｌｉｔｅ － １ 分子筛膜． Ｘ Ｒ Ｄ、 Ｓ Ｅ Ｍ、 Ｅ Ｄ Ｘ 和气体渗透等表征方法表明该膜没有裂缺．研究了原料液中乙醇浓度和渗透温度对乙醇／ 水渗透汽化分离的影响．研究发现,当温度为３０ ℃、原料液乙醇的摩尔分数为１ ．２ ％ 时,乙醇／水的分离系数为６０ ,透量为３ ．１ ｍｏｌ／（ ｍ ２·ｈ） ;温度升高,分离系数稍有下降,透量大大提高;当温度为６０ ℃、原料液乙醇浓度不变,乙醇／ 水的分离系数为４６ ,透量为１３ ．３ ｍｏｌ／（ ｍ ２·ｈ） ．原料液中乙醇浓度增加,乙醇／ 水的分离系数有一最大值;透量则随原料液中乙醇浓度的增加而降低．吸附－ 扩散机理很好地解释了实验结果．     

一种用于药物释控系统的微针阵列及其制作方法的研究

 通过皮肤输送药物最大的障碍是皮肤最外层的角质层．传统的静脉注射用针只有刺透皮肤深入到深层组织内部,才能有效地输送药物,这容易引起感染和疼痛,给患者造成很大的不适．介绍了一种采用硅微加工技术制作的微针,它长度适中,既能穿透皮肤的角质层,又刺激不到深层组织的神经,实现无痛注射的目的．其加工工艺是采用硅的HNA(硝酸+氢氟酸+乙酸)腐蚀系统,是一种硅的各项同性的湿法腐蚀方法．     

驻极体与氮酮促进利多卡因透皮吸收的比较研究

将多孔聚四氟乙烯（PTFE）、聚乙烯（PE）、聚丙烯（PP）制成正极性多孔PTFE／PE／PP驻极体。用改进的Franz扩散池和高效液相色谱仪比较研究多孔PTFE/PE／PP驻极体和不同浓度氮酮对利多卡因的透皮吸收效应．结果显示：（1）lkV多孔PTFE／PE／PP驻极体作用利多卡因24h，其累积渗透量比对照组增加4．57倍；（2）正极性多孔PTFE/PE／PP对利多卡因的增渗效应与其表面电位呈正相关．（3）正极性多孔PTFE／PE／PP驻极体与1％氮酮和5％氮酮联用能显著增加利多卡因的经皮渗透量．     

Microneedle assisted iontophoretic transdermal delivery of prochlorperazine edisylate

This paper investigates the microneedle (MN) mediated in vitro transdermal iontophoretic delivery of prochlorperazine edisylate (PE) across dermatomed human skin. The Dermaroller? induced microchannels were visualized using methylene blue staining and scanning electron microscopy. In vitro skin permeation studies were performed using vertical static Franz diffusion cells. Iontophoretic protocols involved application of direct current at a density of 0.4 mA/cm(2) using Ag as an anode and Ag/AgCl as a cathode. The effect of PE concentration (20, 50 and 100 mg/mL), number of passes of microneedles (0, 5, 10 and 20) on both iontophoretic and passive delivery of PE was studied. The Dermarollertm was found to successfully breach the skin barrier and a linear relationship (r(2) = 0.99) was observed between the number of passes of the Dermaroller? and the number of microchannels created. Passive transdermal flux of PE (0.060 ± 0.003 μg/cm(2)/h) at 50 mg/mL donor PE concentration) was low and increased (4.15 ± 0.57 μg/cm(2)/h) with the application of direct current. Application of iontophoresis in conjunction with microneedle pre-treatment resulted in enhanced flux (4.90 ± 0.39 μg/cm(2)/h at 50 mg/mL donor PE concentration) of PE. The projected transdermal PE flux indicates that a 9 cm(2) patch could deliver PE in a sufficient amount to maintain therapeutic levels of the drug. In conclusion, microneedles when used in conjunction with iontophoresis significantly enhanced the transdermal delivery of PE and it may be feasible to develop an iontophoretic transdermal patch that could be integrated with MN.     

Modelling transdermal delivery of high molecular weight drugs from microneedle systems

In the past few years, a number of microneedle designs have been proposed for transdermal drug delivery of high molecular weight drugs. However, most of them do not increase the drug permeability in skin significantly. In other cases, designs developed based on certain criteria (e.g. strength of the microneedles) have failed to meet other criteria (e.g. drug permeability in skin, throughputs of the drugs, etc.). It is obvious therefore that in order to determine the 'optimum' design of these microneedles, the effect of different factors (e.g. length of the microneedle, surface area of the patch, etc.) along with various transport properties of drug transport behaviour using microneedles should be determined accurately. Appropriate mathematical models for drug transport from these systems into skin have the potential to resolve some of these issues. To address this, a parametric analysis for transdermal delivery of a high molecular weight drug from a microneedle is presented in this paper. The simulations have allowed us to identify the significance of various factors that influence the drug delivery while designing microneedle arrays. A scaling analysis is also done which shows the functional dependence of drug concentration on other variables of skin and microneedle arrays.     

A simple method of microneedle array fabrication for transdermal drug delivery

Abstract

The outermost layer of skin, stratum corneum, being lipophilic limits the passive transport of hydrophilic and large molecular weight drugs. Microfabrication technology has been adapted to fabricate micron scale needles, which are minimally invasive, yet able to deliver the drugs across this barrier layer. In this study, we fabricated microneedles from a biocompatible polymer, namely, poly (ethylene glycol) diacrylate. A simple lithographical approach was developed for microneedle array fabrication. Several factors including polymerization time, ultraviolet light intensity and distance from light source were studied for their effects on microneedle formation. The microneedle length and tip diameter can be controlled by varying these factors. The microneedles were shown to be able to penetrate cadaver pig skin. Model drug rhodamine B was encapsulated in the range of 50 µg to 450 µg per microneedle array. The fabricated microneedles containing rhodamine B increased the permeability by four times than the control. Altogether, we demonstrated that the microneedle arrays can be fabricated through a simple single-step process and needles were mechanically strong to penetrate skin, increasing the permeability of encapsulated drug through skin.     

Transdermal Delivery Devices: Fabrication,Mechanics and Drug Release from Silk

Microneedles are a relatively simple, minimally invasive and painless approach to deliver drugs across the skin. However, there remain limitations with this approach because of the materials most commonly utilized for such systems. Silk protein, with tunable and biocompatibility properties, is a useful biomaterial to overcome the current limitations with microneedles. Silk devices preserve drug activity, offer superior mechanical properties and biocompatibility, can be tuned for biodegradability, and can be processed under aqueous, benign conditions. In the present work, the fabrication of dense microneedle arrays from silk with different drug release kinetics is reported. The mechanical properties of the microneedle patches are tuned by post‐fabrication treatments or by loading the needles with silk microparticles, to increase capacity and mechanical strength. Drug release is further enhanced by the encapsulation of the drugs in the silk matrix and coating with a thin dissolvable drug layer. The microneedles are used on human cadaver skin and drugs are delivered successfully. The various attributes demonstrated suggest that silk‐based microneedle devices can provide significant benefit as a platform material for transdermal drug delivery.     

Advances in Antimicrobial Microneedle Patches for Combating Infections

Skin infections caused by bacteria, viruses and fungi are difficult to treat by conventional topical administration because of poor drug penetration across the stratum corneum. This results in low bioavailability of drugs to the infection site, as well as the lack of prolonged release. Emerging antimicrobial transdermal and ocular microneedle patches have become promising medical devices for the delivery of various antibacterial, antifungal, and antiviral therapeutics. In the present review, skin anatomy and its barriers along with skin infection are discussed. Potential strategies for designing antimicrobial microneedles and their targeted therapy are outlined. Finally, biosensing microneedle patches associated with personalized drug therapy and selective toxicity toward specific microbial species are discussed.     

Two-layered dissolving microneedles for percutaneous delivery of sumatriptan in rats

A novel transdermal delivery of sumatriptan (ST) was attempted by application of dissolving microneedle (DM) technology. Dextran DM (d-DM) and hyaluronate DM (h-DM) were prepared by adding ST solution to dextran solution or hyaluronic acid solution. One DM chip, 1.0?×?1.0?cm, contains 100 microneedle arrays in a 10?×?10 matrix. The mean lengths of DMs were 496.6?±?2.9 μm for h-DM and 494.5?±?1.3 μm for d-DM. The diameters of the array basement were 295.9?±?3.9 μm (d-DM) and 291.7?±?3.0 μm (h-DM), where ST contents were 31.6?±?4.5?μg and 24.1?±?0.9?μg. These results suggest that ST was stable in h-DM. Each DM was administered to rat abdominal skin. The maximum plasma ST concentrations, Cmax, and the areas under the plasma ST concentration versus time curves (AUC) were 44.6?±?4.9?ng/ml and 24.6?±?3.9?ng · h/ml for h-DM and 38.4?±?2.7?ng/ml and 14.1?±?1.5?ng · h/ml for d-DM. The bioavailabilities of ST from DMs were calculated as 100.7?±?18.8% for h-DM and 93.6?±?10.2% for d-DM. Good dose dependency was observed on Cmax and AUC. The stability study of ST in DM was performed for 3 months under four different conditions, ?80, 4, 23, and 50°C. At the end of incubation period, they were, respectively, 100.0?±?0.3%, 97.8?±?0.2%, 98.8?±?0.2%, and 100.7?±?0.1%. These suggest the usefulness of DM as a noninvaisive transdermal delivery system of ST to migraine therapy.     

Built-In Active Microneedle Patch with Enhanced Autonomous Drug Delivery

The use of microneedles has facilitated the painless localized delivery of drugs across the skin. However, their efficacy has been limited by slow diffusion of molecules and often requires external triggers. Herein, an autonomous and degradable, active microneedle delivery platform is introduced, employing magnesium microparticles loaded within the microneedle patch, as the built-in engine for deeper and faster intradermal payload delivery. The magnesium particles react with the interstitial fluid, leading to an explosive-like rapid production of H₂ bubbles, providing the necessary force to breach dermal barriers and enhance payload delivery. The release kinetics of active microneedles is evaluated in vitro by measuring the amount of IgG antibody (as a model drug) that passed through phantom tissue and a pigskin barrier. In vivo experiments using a B16F10 mouse melanoma model demonstrate that the active delivery of anti-CTLA-4 (a checkpoint inhibitor drug) results in greatly enhanced immune response and significantly longer survival. Moreover, spatially resolved zones of active and passive microneedles allow a combinatorial rapid burst response along with slow, sustained release, respectively. Such versatile and effective autonomous dynamic microneedle delivery technology offers considerable promise for a wide range of therapeutic applications, toward a greatly enhanced outcome, convenience, and cost.     

Controllable coating of microneedles for transdermal drug delivery

Coated microneedles have been paid much attention recently, and several coating strategies have been developed to address the problems during coating process. However, there are still some unresolved issues, such as, precise control requirements, microneedle substrate contamination and high processing temperature. The purpose of this study was to develop a simple and controllable method to make uniform coatings on microneedles at room temperature. This novel method avoids the contamination of microneedle substrate by providing both the adsorption force of thickener and micro-scale coating film produced by a newly design device. Thickeners were screened to enhance the mass of coatings. The parameters that influence the coatings were tested systematically, which made coating process controllable. Finally, three model drugs were coated onto microneedles to prove the method is applicable more broadly. In addition, insertion experiments were carried out to test the drug delivery feasibility of the coated microneedles. In conclusion, this study presents a simple and controllable method to coat microneedles with small molecular chemical drugs or large proteins for rapid skin drug delivery.     

Fabrication of microneedles using two photon polymerization for transdermal delivery of nanomaterials

Microneedle devices for transdermal delivery of nanoscale pharmacologic agents were fabricated out of organically-modified ceramic (Ormocer) materials using two photon polymerization. Out-of-plane hollow microneedle arrays with various aspect ratios were fabricated using this rapid prototyping process. Human epidermal keratinocyte (HEK) viability on Ormocer surfaces fabricated using two photon polymerization was similar to that on control surfaces. Nanoindentation studies were performed to determine hardness and Young's modulus values for Ormocer materials. Microneedies were shown to enable more rapid distribution of the PEG-amine quantum dot solution to the deep epidermis and dermis layers of porcine skin than topical administration. Our results suggest that two photon polymerization may be used to create microneedle arrays for transdermal delivery of nanoscale pharmacologic agents.