Challenges and strategies in developing microneedle patches for transdermal delivery of protein and peptide therapeutics

The birth of microneedles, an array of needles sufficiently long to penetrate epidermis but small enough to do not cause skin injury and pain feeling, has offered a highly promising solution for non-invasive delivery of protein and peptide drugs, a long-cherished desire over eighty years. However, the attempts to develop clinically feasible microneedle transdermal delivery methods encountered series of difficulties, for which a decade research efforts have yet to result in a single product. Microneedles may be incorporated into devices as skin pre-treatment tools, skin microinjectors as well as transdermal patches by their functions in drug delivery. They may also be categorized to insoluble solid microneedles, hollow microneedles, soluble/degradable solid microneedles and phase-transition microneedles by their structure and forming materials. This review article is aimed to update the progress and discuss the technical challenges raised in developing protein/peptide loaded microneedle patches.     

Microneedles for transdermal drug delivery

The success of transdermal drug delivery has been severely limited by the inability of most drugs to enter the skin at therapeutically useful rates. Recently, the use of micron-scale needles in increasing skin permeability has been proposed and shown to dramatically increase transdermal delivery, especially for macromolecules. Using the tools of the microelectronics industry, microneedles have been fabricated with a range of sizes, shapes and materials. Most drug delivery studies have emphasized solid microneedles, which have been shown to increase skin permeability to a broad range of molecules and nanoparticles in vitro. In vivo studies have demonstrated delivery of oligonucleotides, reduction of blood glucose level by insulin, and induction of immune responses from protein and DNA vaccines. For these studies, needle arrays have been used to pierce holes into skin to increase transport by diffusion or iontophoresis or as drug carriers that release drug into the skin from a microneedle surface coating. Hollow microneedles have also been developed and shown to microinject insulin to diabetic rats. To address practical applications of microneedles, the ratio of microneedle fracture force to skin insertion force (i.e. margin of safety) was found to be optimal for needles with small tip radius and large wall thickness. Microneedles inserted into the skin of human subjects were reported as painless. Together, these results suggest that microneedles represent a promising technology to deliver therapeutic compounds into the skin for a range of possible applications.     

Microneedles: a valuable physical enhancer to increase transdermal drug delivery

Transdermal drug delivery offers an attractive alternative to the conventional drug delivery methods of oral administration and injection. However, the stratum corneum acts as a barrier that limits the penetration of substances through the skin. Recently, the use of micron-scale needles in increasing skin permeability has been proposed and shown to dramatically increase transdermal delivery. Microneedles have been fabricated with a range of sizes, shapes, and materials. Most in vitro drug delivery studies have shown these needles to increase skin permeability to a broad range of drugs that differ in molecular size and weight. In vivo studies have demonstrated satisfactory release of oligonucleotides and insulin and the induction of immune responses from protein and DNA vaccines. Microneedles inserted into the skin of human subjects were reported to be painless. For all these reasons, microneedles are a promising technology to deliver drugs into the skin. This review presents the main findings concerning the use of microneedles in transdermal drug delivery. It also covers types of microneedles, their advantages and disadvantages, enhancement mechanisms, and trends in transdermal drug delivery.     

Influence of the delivery systems using a microneedle array on the permeation of a hydrophilic molecule, calcein.

Despite the advantages of drug delivery through the skin, such as easy accessibility, convenience, prolonged therapy, avoidance of the liver first-pass metabolism and a large surface area, transdermal drug delivery is only used with a small subset of drugs because most compounds cannot cross the skin at therapeutically useful rates. Recently, a new concept was introduced known as microneedles and these could be pierced to effectively deliver drugs using micron-sized needles in a minimally invasive and painless manner. In this study, biocompatible polycarbonate (PC) microneedle arrays with various depths (200 and 500mum) and densities (45, 99 and 154ea/cm(2)) were fabricated using a micro-mechanical process. The skin permeability of a hydrophilic molecule, calcein (622.5D), was examined according to the delivery systems of microneedle, drug loading, depth of the PC microneedle, and density of the PC microneedle. The skin permeability of calcein was the highest when the calcein gel was applied to the skin with the 500mum-depth PC microneedle, simultaneously. In addition, the skin permeability of calcein was the highest when 0.1g of calcein gel was coupled to the 500mum-depth PC microneedle (154ea/cm(2)) as well as longer microneedles and larger density of microneedles. Taken together, this study suggests that a biocompatible PC microneedle might be a suitable tool for transdermal drug delivery system of hydrophilic molecules with the possible applications to macromolecules such as proteins and peptides.     

Coating Formulations for Microneedles

Purpose To develop a rational basis for designing coating solution formulations for uniform and thick coatings on microneedles and to identify coating strategies to form composite coatings, deliver liquid formulations, and control the mass deposited on microneedles. Materials and Methods Microneedles were fabricated using laser-cutting and then dip-coated using different aqueous, organic solvent-based or molten liquid formulations. The mass of riboflavin (vitamin B₂) coated onto microneedles was determined as a function of coating and microneedle parameters. Coated microneedles were also inserted into porcine cadaver skin to assess delivery efficacy. Results Sharp-tipped microneedles, including pocketed microneedles, were fabricated. Excipients that reduced coating solution surface tension improved coating uniformity, while excipients that increased solution viscosity improved coating thickness. Evaluation of more than 20 different coating formulations using FDA approved excipients showed that hydrophilic and hydrophobic molecules could be uniformly coated onto microneedles. Model proteins were also uniformly coated on microneedles using the formulations identified in the study. Pocketed microneedles were selectively filled with solid or liquid formulations to deliver difficult-to-coat substances, and composite drug layers were formed for different release profiles. The mass of riboflavin coated onto microneedles increased with its concentration in the coating solution and the number of coating dips and microneedles in the array. Coatings rapidly dissolved in the skin without wiping off on the skin surface. Conclusions Microneedles and coating formulations can be designed to have a range of different properties to address different drug delivery scenarios.     

微针制备用聚合物材料研究进展

微针属于非侵入性经皮给药方式,显示出较高的生物利用度,避免了药物在胃肠道的降解和首过效应。微针材料的选择从不锈钢到硅再到陶瓷,虽各有优点,但均因生物相容性、皮内残留不降解的问题而逐渐被淘汰。聚合物因具有生物相容性、生物可降解、毒性较低、韧性良好和成本低等特点,逐渐成为微针制备的首选材料。聚合物制备微针后通过光学、机械力测试系统,皮肤模型及动物模型等表征手段来确认微针的安全有效。本文主要对微针制备中所使用的聚合物材料及微针表征的新进展进行综述,以期对微针的产业化研究提供借鉴。     

可分离微针研究进展

可分离微针属于可溶性微针的一种,应用于皮肤后其针尖与背衬可快速分离,有效减少了微针的佩戴时间以及提高了给药效率,是一种新型透皮给药系统,因此近年来成为研究热点。目前国内外已经开发出多种形式的可分离微针,体内外研究证实可分离微针具有广阔的应用前景。本文概述了当前可分离微针的特点与分类,以期对后续可分离微针的开发与应用提供参考。     

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。     

微针在经皮给药领域的研究

目的:阐述微针在经皮给药领域的研究。方法:简述并分析微针的特点、研究应用、存在的问题以及今后研究的重点。结果:作为一种新型的经皮给药技术,微针可能成为一种较为理想的经皮给药载体。结论:随着研究成果逐渐走入市场,微针将会带来良好的社会效益和经济效益。     

Macromolecular delivery into skin using a hollow microneedle

The objective of the present study was to obtain information to develop an effective delivery device regarding a sophisticated hollow microneedle array-patch system. Thus, the potential of hollow microneedles was investigated for enhancing the transdermal delivery of hydrophilic large molecular compounds, and the effect of variable parameters on drug release behavior was determined from skin. Fluorescein isothiocyanate (FITC)-dextrans (4.3 kDa), FD-4, was used as the main model compound, and it was successfully loaded into the lower epidermis as well as the superficial dermis of the skin in hairless rats by a hollow microneedle. The higher the volume of FD-4 solution injected, the faster the FD-4 release rate from skin. In addition, release rate tended to increase when FD-4 was administered dividedly by multiple injections. These release profiles of FD-4 were expressed by Fick's law of diffusion. Furthermore, a combination of the formulation strategy and hollow microneedle-assisted delivery was useful for controlling the drug release rate from skin. Release profiles from drug-loaded skin were also compared by changing the molecular weights of model compounds. The larger molecular size of compounds caused a lower release rate from skin. These results suggest the utilization of hollow microneedle to enhance transdermal delivery of large molecular compounds and provide useful information for designing an effective hollow microneedle system.     

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.     

Transdermal Delivery of Insulin Using Microneedles in Vivo

PURPOSE: The purpose of this study was to design and fabricate arrays of solid microneedles and insert them into the skin of diabetic hairless rats for transdermal delivery of insulin to lower blood glucose level. METHODS: Arrays containing 105 microneedles were laser-cut from stainless steel metal sheets and inserted into the skin of anesthetized hairless rats with streptozotocin-induced diabetes. During and after microneedle treatment, an insulin solution (100 or 500 U/ml) was placed in contact with the skin for 4 h. Microneedles were removed 10 s, 10 min, or 4 h after initiating transdermal insulin delivery. Blood glucose levels were measured electrochemically every 30 min. Plasma insulin concentration was determined by radioimmunoassay at the end of most experiments. RESULTS: Arrays of microneedles were fabricated and demonstrated to insert fully into hairless rat skin in vivo. Microneedles increased skin permeability to insulin, which rapidly and steadily reduced blood glucose levels to an extent similar to 0.05-0.5 U insulin injected subcutaneously. Plasma insulin concentrations were directly measured to be 0.5-7.4 ng/ml. Higher donor solution insulin concentration, shorter insertion time, and fewer repeated insertions resulted in larger drops in blood glucose level and larger plasma insulin concentrations. CONCLUSIONS: Solid metal microneedles are capable of increasing transdermal insulin delivery and lowering blood glucose levels by as much as 80% in diabetic hairless rats in vivo.     

Design, Optimization and Characterisation of Polymeric Microneedle Arrays Prepared by a Novel Laser-Based Micromoulding Technique

Purpose

Design and evaluation of a novel laser-based method for micromoulding of microneedle arrays from polymeric materials under ambient conditions. The aim of this study was to optimise polymeric composition and assess the performance of microneedle devices that possess different geometries.

Methods

A range of microneedle geometries was engineered into silicone micromoulds, and their physicochemical features were subsequently characterised.

Results

Microneedles micromoulded from 20% w/w aqueous blends of the mucoadhesive copolymer Gantrez® AN-139 were surprisingly found to possess superior physical strength than those produced from commonly used pharma polymers. Gantrez® AN-139 microneedles, 600 ??m and 900 ??m in height, penetrated neonatal porcine skin with low application forces (>0.03 N per microneedle). When theophylline was loaded into 600 ??m microneedles, 83% of the incorporated drug was delivered across neonatal porcine skin over 24 h. Optical coherence tomography (OCT) showed that drug-free 600 ??m Gantrez® AN-139 microneedles punctured the stratum corneum barrier of human skin in vivo and extended approximately 460 µm into the skin. However, the entirety of the microneedle lengths was not inserted.

Conclusion

In this study, we have shown that a novel laser engineering method can be used in micromoulding of polymeric microneedle arrays. We are currently carrying out an extensive OCT-informed study investigating the influence of microneedle array geometry on skin penetration depth, with a view to enhanced transdermal drug delivery from optimised laser-engineered Gantrez® AN-139 microneedles.     

Microneedles and transdermal applications

With the limitations of oral drug delivery and the pain and needle phobias associated with traditional injections, drug delivery research has focused on the transdermal delivery route. A formidable barrier to transdermal drug delivery is the stratum corneum, the superficial layer of the skin. In the last 10 years, microneedles were proposed as a mechanical tool to pierce through the stratum corneum, in order to create drug delivery channels without stimulating underlying pain nerves. Since then, the field of microneedles has rapidly evolved to spawn a plethora of potential transdermal applications. In this review, the authors provide an overview of the progress in microneedle research and design, and the advancements that have been made in employing this technology for transdermal applications.     

Microneedles and other physical methods for overcoming the stratum corneum barrier for cutaneous gene therapy

The outermost layer of skin, the epidermis, has developed formidable physical and immunological barrier properties that prevent infiltration of deleterious chemicals and pathogens. Consequently, transdermal delivery of medicaments is currently restricted to a limited number of low molecular weight drugs. As a corollary, there has been significant recent interest in providing strategies that disrupt or circumvent the principal physical barrier, the stratum corneum, for the efficient cutaneous delivery of macromolecular and nucleic acid based therapeutics. These strategies include: electrical methods, intradermal injection, follicular delivery, particle acceleration, laser ablation, radiofrequency ablation, microscission, and microneedles. The application of microfabricated microneedle arrays to skin creates transient pathways to enable transcutaneous delivery of drugs and macromolecules. Microneedle use is simple, pain-free, and causes no bleeding, with further advantages of convenient manufacture, distribution, and disposal. To date, microneedles have been shown to deliver drug, peptide, antigen, and DNA efficiently through skin. Robust and efficient microneedle designs and compositions can be inserted into the skin without fracture. Further progress in microneedle array design, microneedle application apparatus, and integrated formulation will confirm this methodology as a realistic clinical strategy for delivering a range of medicaments, including DNA, to and through skin.     

微针技术的研究进展

微针以微机电系统(m icroelectro-mechani-cal systems,MEMS)技术为基础,在近年来发展迅速。本文主要介绍微针的制备方法,插入皮肤的机制,微针给药的特点以及微针的应用,详细介绍了微针在经皮给药中的应用。由于微针给药可以避免胃肠道对药物的降解作用和肝脏的首过效应等口服给药的缺点,并可消除注射给药时引起的疼痛,随着其发展不断完善,微针给药将会有广阔的应用前景。     

Microneedles containing cross-linked hyaluronic acid particulates for control of degradation and swelling behaviour after administration into skin

Microneedles (MN) containing cross-linked hyaluronic acid (X-linked HA) particulates were prepared to control the degradation and swelling behaviour after transdermal drug delivery. The X-linked HA particulates were prepared by cross-linking HA chains and then passing the particulates through a sieve. Then, microneedles were prepared by micromolding method. The rheological properties of X-linked HA were studied. The penetration success rate, mechanical failure and dissolution rate of microneedles containing only hyaluronic acid (HA MN) and microneedles containing X-linked HA were compared. The delivery of fluorescein into the skin with X-linked HA MN was also observed using a confocal microscope. The size of the pulverised particulates in water ranged between 29 and 82?μm in diameter. The HA MN and X-linked HA MN were 270?μm in length. X-linked HA MN with fluorescein was inserted to a depth of 90% of the microneedle length successfully. There was no decrease in the penetration success rate for MN with up to 20% content of X-linked HA particulates. X-linked HA MN with up to 20% of particulate content did not change the dissolution time. Delay in degradation of HA, sustained drug release, and swelling behaviour of the skin layer can be obtained by X-linked HA MN.     

Two-photon polymerization of microneedles for transdermal drug delivery

Importance of the field: Microneedles are small-scale devices that are finding use for transdermal delivery of protein-based pharmacologic agents and nucleic acid-based pharmacologic agents; however, microneedles prepared using conventional microelectronics-based technologies have several shortcomings, which have limited translation of these devices into widespread clinical use.

Areas covered in this review: Two-photon polymerization is a laser-based rapid prototyping technique that has been used recently for direct fabrication of hollow microneedles with a wide variety of geometries. In addition, an indirect rapid prototyping method that involves two-photon polymerization and polydimethyl siloxane micromolding has been used for fabrication of solid microneedles with exceptional mechanical properties.

What the reader will gain: In this review, the use of two-photon polymerization for fabricating in-plane and out-of-plane hollow microneedle arrays is described. The use of two-photon polymerization-micromolding for fabrication of solid microneedles is also reviewed. In addition, fabrication of microneedles with antimicrobial properties is discussed; antimicrobial microneedles may reduce the risk of infection associated with the formation of channels through the stratum corneum.

Take home message: It is anticipated that the use of two-photon polymerization as well as two-photon polymerization-micromolding for fabrication of microneedles and other microstructured drug delivery devices will increase over the coming years.     

微针的特点及其在黄褐斑治疗中的应用研究分析

黄褐斑是一种后天获得性色素沉着性疾病，困扰患者的工作和生活。外用经皮给药的主要挑战是药物透过角质层屏障的阻碍。微针作为物理促渗方法和新的递药系统，能够穿透角质层形成特定的药物输送通道，促进了药物的渗透，提高了药物的生物利用度。本文主要总结了微针的特点，并以黄褐斑为切入点，分析微针近年来在黄褐斑领域的应用研究，为后续黄褐斑微针产品的开发提供一定的参考。     

不锈钢微针经皮给药的研究

目的：将不锈钢微针阵列应用于经皮给药。考察离体大鼠皮肤经不同针形微针预处理相同时间、相同针形微针预处理不同时间后，模型药物鬼臼毒素经大鼠皮肤的透皮能力。方法：微针预处理大鼠皮肤后，用改进的Franz扩散池研究鬼臼毒素对皮肤的透皮速率。高效液相色谱法测定鬼臼毒素的含量。结果：皮肤经微针预处理后进行鬼臼毒素透皮，其透皮速率比未经微针处理时有明显提高。三角形微针、梯形微针、矛形微针对鬼臼毒素的促渗能力依次增强；三者所引起的鬼臼毒素在皮肤中的滞留量有显著差异。同种针形微针预处理皮肤时间越长，鬼臼毒素的透皮速率越大；但微针预处理时间对皮肤中的药物滞留量无显著影响。结论：微针用于药物经皮给药时，微针针形、微针的预处理时间对药物的经皮渗透具有重要影响。