空心微针透皮给药技术的研究进展

空心微针类似于微米级的注射针,具有注射给药和透皮给药的双重特点.作为一种新型的透皮给药技术,空心微针近年来在疫苗和胰岛素等生物大分子药物的递送方面显示出极大的潜力.笔者根据近年来国内外相关的研究报道,对空心微针的促透机制、常用制备材料及工艺和在透皮给药中的应用等进行归纳总结,以期为空心微针技术的研究和发展提供参考借鉴.     

纳米制剂在透皮药物递送系统中的应用研究进展

透皮药物递送系统作为一种非侵入式给药途径，与传统给药方式相比具有顺应性高、无首过效应等优势。纳米技术的应用使得透皮药物递送系统的药物选择范围进一步扩大，并提高了药物的治疗效果，形成了一种极具价值、令人期待的新型给药方式。目前常用于透皮药物递送系统的纳米制剂包括纳米乳、脂质纳米囊泡、脂质纳米粒、聚合物纳米粒、纳米晶体、溶致液晶纳米粒等。介绍了皮肤屏障和透皮递送的常用促渗方法，综述了各类应用于透皮药物递送系统的纳米制剂及其与物理促渗方法联合应用的研究进展，以期为纳米制剂在透皮递送方面的深入研究提供参考。     

多肽透皮给药研究进展

针对近年来多种多肽类药物的透皮给药系统进行综述。通过查阅国内外多种相关期刊文献。将多肽类药物透皮给药方法分为化学促渗剂、多种物理促渗技术,以及透皮肽、微针技术并对其进行论述。反向离子导入技术应用前景广阔,微针给药系统研究逐步深入,出现了胰岛素智能化微针给药系统,透皮肽的研究发展迅速,相信未来多种蛋白质及多肽的透皮给药方式将应用于临床,极大地促进医疗事业的发展。     

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。本文介绍了该技术的装置组成、促渗机制以及影响因素,然后分析了近年来离子电渗技术在医药科学领域的应用方向,得出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。     

胰岛素透皮吸收研究进展

经皮给药是理想的胰岛素给药方式。但由于皮肤屏障原因,胰岛素通透皮肤能力极差。该文综述了增加胰岛素透皮吸收的研究进展,包括应用渗透促进药、离子导入、超声技术、微针阵列、电致孔、载体等方法。     

物理方法促进胰岛素经皮吸收的实验研究进展

目的胰岛素经皮吸收制剂是一种理想的胰岛素给药方式,但由于皮肤角质层的阻力、胰岛素分子在皮肤中的累积等因素限制了胰岛素的经皮给药。方法本文介绍了微针、电致孔、超声导入、离子导入等物理方法促进胰岛素经皮吸收实验研究进展。结果研究安全、有效、经济、方便的胰岛素透皮吸收物理促渗技术。结论随着对上述新技术、新方法实验研究的深入,物理促渗技术必将为胰岛素透皮吸收制剂的发展开辟更广阔的前景     

物理技术促进药物经皮吸收的研究进展

目的:为加强经皮给药制剂的开发与应用提供参考。方法:以"微针""驻极体""离子导入""经皮给药系统""促渗""Microneedle""Electret""Inotophoresis""Transdermal drug delivery system"等为关键词,组合查询2001年1月-2017年2月在PubMed、ScienceDirect、中国知网、万方、维普等数据库中的相关文献,对促进药物经皮吸收的物理技术的研究进行综述。结果与结论:共检索到相关文献584篇,其中有效文献65篇。常用的单一物理技术促渗方法有微针、驻极体、离子、超声、电致孔、激光、磁场导入、热穿孔。其中,微针经皮给药适用于大分子药物(如皮肤渗透率较低的多肽、蛋白质和疫苗等);微针的针体长度、形状以及硬度、针壁厚度、载药量、滞留时间和体内降解问题是今后重点的研究对象。驻极体对离子型药物和非离子型药物都有良好的透皮促渗作用,但对离子型药物效果更佳;国内对于驻极体促渗的实验研究少,目前其临床应用无相关报道。离子导入、电致孔促渗在中药中的运用较热门,适用于电离性能较好的小分子药物(如胰岛素),但依赖带电装置及能量的特点导致推广受限。离子导入适用于慢性疾病如癌症和糖尿病的治疗;今后研究重点在于明确导入体内发挥作用的主要成分及其作用机制。超声导入主要适用于水溶性好的药物(如多肽和蛋白质);加强系统的安全性研究以及空化作用的机制研究、改善装置设计缺陷是今后研究的重点。利用激光破坏表皮的屏障作用促进药物经皮吸收,在医药领域应用前景良好。目前磁场导入与热穿孔技术促渗的国内外相关文献报道较少,今后的重点是加强这两者的机制、优化装置性能研究以及解决安全性问题。两种或多种物理技术的联用尽管能大大提高药物经皮透过率,但制作的复杂性和高成本是亟需突破的难题。     

经皮给药系统促渗方法研究的新进展

促渗方法的发展对于经皮给药的研究意义重大。笔者从化学促渗技术，包括化学促渗剂、前体药物、传递体、含醇脂质体、非离子表面活性剂脂质体和微乳；以及物理促渗技术，包括离子导入、电致孔、超声波促渗、微针、照相波、热致孔和磁场导入等诸多方面综述了近年来经皮给药促渗方法研究的新进展。     

以纳米颗粒为载体转染基因的发展概况

目的综述以纳米颗粒作为基因载体进行基因治疗的发展概况。方法依据国内外刊物公开发表的文献,对有关以纳米颗粒作为基因递送载体进行基因治疗的研究进行分类、归纳与整理。结果纳米颗粒转运系统能够保护被转运的基因,有较高的转染效率,具有良好的靶向性,并且提高了药物的生物利用度,显示出一定的缓控释作用。结论纳米颗粒作为基因递送载体具有广阔的发展前景。     

微针透皮给药系统应用研究进展

微针透皮给药系统是近年来透皮给药系统研究的热点。微针透皮给药系统具有注射给药和透皮给药的双重优势,具有快速、方便、无痛等众多优点,研究表明可以显著提高药物透皮速率和吸收量,特别是在蛋白质、多肽、DNA和RNA等大分子物质的透皮制剂研究领域表现出良好的效果和应用前景,本文对微针透皮给药系统应用研究的最新进展进行了综述。随着微针加工技术、载药技术和应用研究的不断深入,微针透皮技术在临床领域将会有更广泛的应用。     

Modulated iontophoretic delivery of small and large molecules through microchannels

The objective of this work was to modulate transdermal drug delivery by iontophoresis though skin microchannels created by microneedles. Calcein and human growth hormone were used as a model small and large molecule, respectively. In vitro permeation studies were performed on porcine ear skin under three different settings: (a) modulated iontophoresis alone, (b) pretreatment with microneedles and (c) combination of microneedles pretreatment and modulated iontophoresis. For modulated iontophoresis, 0.5 mA/cm(2) current was applied for 1h each at 2nd and 6th hour of the study. Methylene blue staining, calcein imaging and pore permeability index suggested maltose microneedles created uniform microchannels in skin. Application of iontophoresis provided two peaks in flux of 1.04 μg/(cm(2)h) at 4th hour and 2.09 μg/(cm(2)h) at 8th hour of study for calcein. These peaks in flux were significant higher when skin was pretreated with microneedles (p<0.05). Similarly, for human growth hormone, modulation in transdermal flux was achieved with combination of microneedles and iontophoresis. This combination also provided significant increase in cumulative amount of calcein and human growth hormone delivered as compared to microneedles or iontophoresis alone (p<0.05). Therefore, iontophoresis can be used to modulate drug delivery across skin microchannels created by microneedles.     

Transdermal iontophoresis: combination strategies to improve transdermal iontophoretic drug delivery.

For several decades, there has been interest in using the skin as a port of entry into the body for the systemic delivery of therapeutic agents. However, the upper layer of the skin, the stratum corneum, poses a barrier to the entry of many therapeutic entities. Given a compound, passive delivery rate is often dependent on two major physicochemical properties: the partition coefficient and solubility. The use of chemical enhancers and modifications of the thermodynamic activity of the applied drug are two frequently employed strategies to improve transdermal permeation. Chemical enhancers are known to enhance drug permeation by several mechanisms which include disrupting the organized intercellular lipid structure of the stratum corneum , 'fluidizing' the stratum corneum lipids , altering cellular proteins, and in some cases, extracting intercellular lipids . However, the resulting increase in drug permeation using these techniques is rather modest especially for hydrophilic drugs. A number of other physical approaches such as iontophoresis, sonophoresis, ultrasound and the use of microneedles are now being studied to improve permeation of hydrophilic as well as lipophilic drugs. This article presents an overview of the use of iontophoresis alone and in conjunction with other approaches such as chemical enhancement, electroporation, sonophoresis, and use of microneedles and ion-exchange materials.     

促进药物经皮吸收的物理学方法研究进展

总结了近年来促进药物经皮吸收的几种物理方法，如离子导入、电致孔、超声导入、微针穿刺、热穿孔、激光技术和电极扫描系统的作用机制、影响因素以及目前的研究成果。     

New technologies to allow transdermal delivery of therapeutic proteins and small water-soluble drugs

Drugs currently on the market that can be delivered in patch form tend to be small, moderately lipophilic, potent drug molecules. The horizon of transdermal delivery can be expanded to small water-soluble drugs as well as macromolecules, such as therapeutic proteins, by several enhancement technologies that are being actively investigated. One promising technique is iontophoresis, which has been used for localized delivery of drugs, such as corticosteroids or lidocaine, for several years. Recently, a self-contained pre-filled wearable patch utilising this process has been commercialized for systemic delivery of fentanyl. A glucose-monitoring device based on electro-osmotic flow, which enables extraction of glucose from the interstitial fluid via reverse iontophoresis, is also on the market. Most of the other technologies use physical energy to permeabilize the skin. However, the current used in iontophoresis primarily acts on the drug itself. Delivery is controlled by the current and can thus be modulated if desired. The charge, size, structure, and lipophilicity of the drug all influence its transport. For peptides and proteins, the ideal candidate for iontophoretic delivery is that with a high isoelectric point and a molecular weight <10 kDa. For larger proteins, skin microporation and phonophoresis are promising techniques. Skin microporation can be achieved by thermal means or by using mechanical microneedles. This minimally invasive technique is painless and can deliver a drug of any size through the micron-sized holes created in the skin. Mechanical microneedles may be made of silicon, metal, polymer, or maltose and may be solid or hollow. Phonophoresis or sonophoresis uses sounds that have a frequency beyond 20 kHz to permeabilize the skin. Electroporation is another technology that reversibly permeabilizes the skin by the application of short, high-voltage pulses. Other technologies being evaluated include chemical enhancers, liquid spray-on products, controlled skin abrasion, radiofrequency induced microchannels, and particle mediated immunization.     

Controlled delivery of ropinirole hydrochloride through skin using modulated iontophoresis and microneedles

Abstract

The objective of this study was to investigate the effect of modulated current application using iontophoresis- and microneedle-mediated delivery on transdermal permeation of ropinirole hydrochloride. AdminPatch® microneedles and microchannels formed by them were characterized by scanning electron microscopy, dye staining and confocal microscopy. In vitro permeation studies were carried out using Franz diffusion cells, and skin extraction was used to quantify drug in underlying skin. Effect of microneedle pore density and ions in donor formulation was studied. Active enhancement techniques, continuous iontophoresis (74.13?±?2.20?µg/cm²) and microneedles (66.97?±?10.39?µg/cm²), significantly increased the permeation of drug with respect to passive delivery (8.25?±?2.41?µg/cm²). Modulated iontophoresis could control the amount of drug delivered at a given time point with the highest flux being 5.12?±?1.70?µg/cm²/h (5–7?h) and 5.99?±?0.81?µg/cm²/h (20–22?h). Combination of modulated iontophoresis and microneedles (46.50?±?6.46?µg/cm²) showed significantly higher delivery of ropinirole hydrochloride compared to modulated iontophoresis alone (84.91?±?9.21?µg/cm²). Modulated iontophoresis can help in maintaining precise control over ropinirole hydrochloride delivery for dose titration in Parkinson’s disease therapy and deliver therapeutic amounts over a suitable patch area and time.     

Penetration and distribution of PLGA nanoparticles in the human skin treated with microneedles

This study was designed to investigate the penetration and the distribution of poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles in the human skin treated with microneedles. Fluorescent nanoparticles were prepared to indicate the transdermal transport process of the nanoparticles. Permeation study was performed on Franz-type diffusion cells in vitro. The distribution of nanoparticles was visualized by confocal laser scanning microscopy (CLSM) and quantified by high performance liquid chromatography (HPLC). CLSM images showed that nanoparticles were delivered into the microconduits created by microneedles and permeated into the epidermis and the dermis. The quantitative determination showed that (i) the permeation of nanoparticles into the skin was enhanced by microneedles, but no nanoparticle reached the receptor solution; (ii) much more nanoparticles deposited in the epidermis than those in the dermis; (iii) the permeation was in a particle size-dependent manner; and (iv) the permeation increased with the nanoparticle concentration increasing until a limit value was reached. These results suggested that microneedles could enhance the intradermal delivery of PLGA nanoparticles. The biodegradable nanoparticles would sustain drug release in the skin and supply the skin with drug over a prolonged period. This strategy would prove to be useful for topical drug administration.     

High-efficient nano-carrier gel systems for testosterone propionate skin delivery

Abstract

The purpose of the current investigation was to evaluate the skin delivery potential of the different nano-carrier gels including liposomal gel, ethosomal gel and microemulsion gel bearing testosterone propionate (TP) as a testosterone deficient therapy. The prepared nano-particles were characterized for their shape, particle size distribution and zeta potential. In vitro skin permeation and in vivo transdermal delivery of nano-carrier gels were studied with the Franz diffusion cells and confocal laser scanning microscopy (CLSM). The results showed that all of nano-particles were almost spherical with low polydispersity and nano-metric size range from 40 to 200?nm. TP ethosomal gel also provided an enhanced transdermal flux of 7.64?±?1.4?μg/cm²/h and a decreased lag time of 0.69?h across rat skin as compared with the other two formulations. The skin penetration efficiency of TP nano-carrier gels also revealed that TP ethosomal gel would enhanced penetration of rhodamine red (RR)-loaded formulation to the deeper layers of the skin (268?µm) than the liposomal gel (192?µm) and microemulsion gel (228?µm). This study demonstrated TP ethosomal gel is a promising nano-carrier for delivering TP through the skin.     

Synergistic effect of iontophoresis and soluble microneedles for transdermal delivery of methotrexate

The aim of this study was to investigate the transdermal iontophoretic delivery of methotrexate, alone or in combination with microneedles, in-vitro and in-vivo using intracutaneous microdialysis in the hairless rat. The average depth of the microdialysis probe in the skin was found to be 0.54 mm. Methotrexate was stable in the presence of an applied electric field as determined by cyclic voltammetry. A current density of 0.4 mA cm(-2) applied for 60 min was used in combination with maltose microneedles to enhance delivery of methotrexate across the skin. Delivery was enhanced by iontophoresis and microneedles, both in-vitro and in-vivo. A synergistic 25-fold enhancement of delivery was observed in-vivo when a combination of microneedles and ionto- phoresis was used compared with either modality alone.     

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。