Polymer Microneedles for Controlled-Release Drug Delivery

Purpose As an alternative to hypodermic injection or implantation of controlled-release systems, this study designed and evaluated biodegradable polymer microneedles that encapsulate drug for controlled release in skin and are suitable for self-administration by patients. Methods Arrays of microneedles were fabricated out of poly-lactide-co-glycolide using a mold-based technique to encapsulate model drugs—calcein and bovine serum albumin (BSA)—either as a single encapsulation within the needle matrix or as a double encapsulation, by first encapsulating the drug within carboxymethylcellulose or poly-l-lactide microparticles and then encapsulating drug-loaded microparticles within needles. Results By measuring failure force over a range of conditions, poly-lactide-co-glycolide microneedles were shown to exhibit sufficient mechanical strength to insert into human skin. Microneedles were also shown to encapsulate drug at mass fractions up to 10% and to release encapsulated compounds within human cadaver skin. In vitro release of calcein and BSA from three different encapsulation formulations was measured over time and was shown to be controlled by the encapsulation method to achieve release kinetics ranging from hours to months. Release was modeled using the Higuchi equation with good agreement (r² ≥ 0.90). After microneedle fabrication at elevated temperature, up to 90% of encapsulated BSA remained in its native state, as determined by measuring effects on primary, secondary, and tertiary protein structure. Conclusions Biodegradable polymer microneedles can encapsulate drug to provide controlled-release delivery in skin for hours to months.     

可溶性聚合物微针用于药物经皮递送的研究进展

目的： 了解国内外对于可溶性聚合物微针这一新型药物递送系统的研究进展，并对其优势及存在的问题进行分析，对发展前景进行展望。方法： 通过文献调研，总结可溶性聚合物微针的材料及功能，分析可溶性微针所解决的临床用药问题，以及各微针基质材料所具有的优势与面临的挑战。结果： 本文以临床不同的用药需求为视角进行分类，介绍了聚合物材料在可溶性微针递药系统中的应用，并对其优势及面临的挑战进行总结，对发展前景进行展望。结论： 目前对于可溶性聚合物微针的研究已取得了令人瞩目的进展。然而，为实现临床转化，可溶性聚合物微针递药系统的载药能力、安全性等方面仍然需要进一步的研究。     

吲哚美辛包合物可溶性微针的制备及体内外特性研究

目的 制备载有吲哚美辛包合物的可溶性微针,考察其体外透皮性能并进行药动学特性研究。方法 采用溶液搅拌-冷冻干燥法制备吲哚美辛/羟丙基-β-环糊精包合物,正交试验筛选最佳制备处方。通过两步法将包合物负载于可溶性微针,用Parafilm模拟皮肤测试微针穿刺能力,以改良Franz扩散池进行体外经皮释放实验。建立HPLC测定大鼠血浆中吲哚美辛的方法,评价微针用于大鼠给药的药动学特征。结果 最佳处方制备的包合物包埋率为56.84%,载药量为11.90%;微针对第3层Parafilm的刺穿率为92%;IDM-HP-β-CD微针的初始体外经皮渗透速率和单位面积渗透量显著高于IDM-HP-b-CD溶液以及IDM饱和溶液;药动学结果显示微针与市售贴片相比能快速达到较高血药浓度,减少时滞。结论 包合物可溶性微针提高了药物溶解度和载药量,快速释放并显著提高药物的生物利用度,为吲哚美辛的临床应用开发了新的途径。     

Characterization of Solid Maltose Microneedles and their Use for Transdermal Delivery

Purpose To characterize solid maltose microneedles and assess their ability to increase transdermal drug delivery. Materials and Methods Microneedles and microchannels were characterized using methylene blue staining and scanning electron microscopy. Diffusion pattern of calcein was observed using confocal scanning laser microscopy. Transepidermal water loss (TEWL) measurements were made to study the skin barrier recovery after treatment. Uniformity in calcein uptake by the pores was characterized and percutaneous penetration of nicardipine hydrochloride (NH) was studied in vitro and in vivo across hairless rat skin. Results Microneedles were measured to be 508.46 ± 9.32 μm long with a radius of curvature of 3 μm at the tip. They penetrated the skin while creating microchannels measuring about 55.42 ± 8.66 μm in diameter. Microchannels were visualized by methylene blue staining. Pretreatment with microneedles resulted in the migration of calcein into the microchannels. TEWL increased after pretreatment and uptake of calcein by the pores was uniform as measured by the pore permeability index values. NH in vitro transport across skin increased significantly after pretreatment (flux 7.05 μg/cm²/h) as compared to the untreated skin (flux 1.72 μg/cm²/h) and the enhanced delivery was also demonstrated in vivo in hairless rats. Conclusion Maltose microneedles were characterized and shown to create microchannels in the skin, which were also characterized and shown to improve the transdermal delivery of NH.     

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。     

微针技术在经皮给药中的应用

微针是经皮给药的物理促渗方法之一,有着很好的市场前景。本文介绍微针的透皮促渗机制、促进药物经皮渗透的因素、复合技术以及微针在大分子经皮促渗中的应用。     

Microinfusion Using Hollow Microneedles

Purpose The aim of the study is to determine the effect of experimental parameters on microinfusion through hollow microneedles into skin to optimize drug delivery protocols and identify rate-limiting barriers to flow. Methods Glass microneedles were inserted to a depth of 720–1080 μm into human cadaver skin to microinfuse sulforhodamine solution at constant pressure. Flow rate was determined as a function of experimental parameters, such as microneedle insertion and retraction distance, infusion pressure, microneedle tip geometry, presence of hyaluronidase, and time. Results Single microneedles inserted into skin without retraction were able to infuse sulforhodamine solution into the skin at flow rates of 15–96 μl/h. Partial retraction of microneedles increased flow rate up to 11.6-fold. Infusion flow rate was also increased by greater insertion depth, larger infusion pressure, use of a beveled microneedle tip, and the presence of hyaluronidase such that flow rates ranging from 21 to 1130 μl/h were achieved. These effects can be explained by removing or overcoming the large flow resistance imposed by dense dermal tissue, compressed during microneedle insertion, which blocks flow from the needle tip. Conclusions By partially retracting microneedles after insertion and other methods to overcome flow resistance of dense dermal tissue, protocols can be designed for hollow microneedles to microinfuse fluid at therapeutically relevant rates.     

可溶微针在经皮药物递送领域的研究进展

可溶微针是一种极具潜力的新型透皮给药技术,它具有药物递送可控性、可调节性以及自我给药的便捷性等特点,在生物医学领域具有广阔的应用前景。综述微针技术的研究进展,包括微针分类、常用材料和制备方法,重点介绍了可溶微针在小分子、多肽、蛋白和核酸等药物递送领域的研究进展,系统讨论了可溶微针在生物医学领域的发展前景,以期为更精准智能的可溶微针经皮递药系统的研发提供参考。     

微针经皮给药应用的新进展

微针有助于改善患者的用药依从性,提高药物的生物利用度.近年来,微针在疫苗接种、蛋白质和多肽给药、DNA给药、皮肤美容、眼科用药、局部麻醉、微量取样等领域均有应用.微针在胰岛素给药和局部麻醉中的研究已进入临床试验阶段,在皮肤美容、疫苗接种和蛋白质给药方面已有上市产品.     

生物大分子药物的经皮给药

对多肽、蛋白质等生物大分子的经皮给药研究的最新进展进行综述     

可溶性微针的研究进展

微针是一种新型经皮给药技术,具有无痛高效递送药物、良好的患者依从性以及便于自主给药等优势。较其他类型的微针而言,可溶性微针具有制备成本低、载药量大、应用范围广、无尖锐废弃物残留、易于控制药物释放等优点。综述可溶性微针的基质和制备方法、质量评价及其在药物递送、免疫接种等多个领域的应用,探讨可溶性微针发展中存在的问题并展望其未来的研究方向,为进一步开发、应用可溶性微针提供参考。     

Rapidly Dissolving Microneedle Patches for Transdermal Iron Replenishment Therapy

The prevalence of iron deficiency anemia (IDA) is predominant in women and children especially in developing countries. The disorder affects cognitive functions and physical activity. Although oral iron supplementation and parenteral therapy remains the preferred choice of treatment, gastric side effects and risk of iron overload decreases adherence to therapy. Transdermal route is an established approach, which circumvents the side effects associated with conventional therapy. In this project, an attempt was made to investigate the use of rapidly dissolving microneedles loaded with ferric pyrophosphate (FPP) as a potential therapeutic approach for management of IDA. Microneedle array patches were made using the micromolding technique and tested in vitro using rat skin to check the duration required for dissolution/disappearance of needles. The ability of FPP-loaded microneedles to replenish iron was investigated in anemic rats. Rats were fed iron-deficient diet for 5 weeks to induce IDA following which microneedle treatment was initiated. Recovery of rats from anemic state was monitored by measuring hematological and biochemical parameters. Results from in vivo study displayed significant improvements in hemoglobin and serum iron levels after 2-week treatment with FPP-loaded microneedles. The study effectively demonstrated the potential of microneedle-mediated iron replenishment for treatment of IDA.     

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.     

Future of the transdermal drug delivery market – have we barely touched the surface?

ABSTRACT

Introduction: Transdermal drug delivery is the movement of drugs across the skin for absorption into the systemic circulation. Transfer of the drug can occur via passive or active means; passive transdermal products do not disrupt the stratum corneum to facilitate delivery whereas active technologies do. Due to the very specific physicochemical properties necessary for successful passive transdermal drug delivery, this sector of the pharmaceutical industry is relatively small. There are many well-documented benefits of this delivery route however, and as a result there is great interest in increasing the number of therapeutic substances that can be delivered transdermally.

Areas Covered: This review discusses the various transdermal products that are currently/have been marketed, and the paths that led to their success, or lack of. Both passive and active transdermal technologies are considered with the advantages and limitations of each highlighted. In addition to marketed products, technologies that are in the investigative stages by various pharmaceutical companies are reviewed.

Expert Opinion: Passive transdermal drug delivery has made limited progress in recent years, however with the ongoing intense research into active technologies, there is great potential for growth within the transdermal delivery market. A number of active technologies have already been translated into marketed products, with other platforms including microneedles, rapidly progressing towards commercialisation.     

Pectin/Ethylcellulose Film Coating Formulations for Colonic Drug Delivery

Purpose. The purpose of the study was to investigate the potential of pectin, ethylcellulose combinations as a practical film coating for colonic delivery. Methods. Combinations of pectin and ethylcellulose, in the form of an aqueous dispersion, were used as coating formulations. Paracetamol cores were used as the substrate. The coatings were assessed by a flow through dissolution system simulating in vivo conditions by changes in pH and residence time. Pectinolytic enzymes were used to simulate the bacterial flora of the colon. Results. Drug release was controlled by the ratio of ethylcellulose to pectin in the film coat. Increasing the proportion of ethylcellulose and increasing the coat weight reduced drug release in pHl and pH7.4 media. The addition of pectinolytic enzymes to pH6 media increased the release of drug. Conclusions. Combinations of ethylcellulose and pectin can provide protection to a drug in the upper g.i. tract while allowing enzymatic breakdown and drug release in the colon.     

Dissolving Microneedles Loaded With Etonogestrel Microcrystal Particles for Intradermal Sustained Delivery

The study design is that lipophilic drug was encapsulated within dissolving microneedles (DMNs) for sustained-release delivery over 1 week. Etonogestrel (ENG), the progestogen used in hormonal contraceptives, was loaded in 2-layered DMNs in the form of microcrystal particles (MPs). In vitro release study indicated that ENG in the MP form could sustain drug release compared to noncrystal form. Hydroxypropyl methylcellulose and polyvinyl alcohol were used to prepare the fast dissolving needle tips and flexible back layer, respectively. The mechanical strength of microneedles was not affected even with the drug-loading efficiency of 50.0% in needle tips. The penetration depth of DMNs in skin, observed using a confocal laser scanning microscope, was approximately 280 μm. The tips of DMNs could be dissolved in rat skin within 1 h with a drug delivery efficiency of 63.8 ± 2.0%. The pharmacokinetic study of DMN treatment in rats showed that the plasma levels of ENG were a dose-dependent profile and were much steadier than intradermal (ID) injections. There was no statistical difference between bioavailability of ENG treated with DMNs or ID injections (p >0.05). Therefore, the novel DMNs loaded with drug MP provided a potential minimally invasive route for ID sustained delivery of lipophilic drug.     

Transdermal Delivery of Sumatriptan Succinate Using Iontophoresis and Dissolving Microneedles

This study focuses on the in vitro transdermal transport of sumatriptan succinate using combined iontophoresis and dissolving polymeric microneedle arrays. Permeation experiments were performed to evaluate the effects of formulation parameters on drug release from polyvinylpyrrolidone systems under mild electrical current (≤500 μA/cm²). The preparations consisted of hydrophilic, positively charged molecules encapsulated in a water-soluble and biocompatible polymeric material. Current densities of 100, 300, and 500 μA/cm² were applied during a 6-h period using silver/silver chloride electrodes. The circular array consisted of 600 needles and occupied a 0.785 cm² area. Tests, carried out with Franz diffusion cells and skin of Göttingen minipigs, showed that small decreases in the polymer concentration led to negligible lag times and marked increases in the cumulative amount of drug permeated in 6 h (Q_6h) and in the flux (J_ss). At 500 μA/cm², Q_6h and J_ss nearly doubled for a microneedle loaded with 5% (w/w) sumatriptan and 20% (w/w) PVP (lag time = 0 min; Q_6h = 2888 μg/cm²; J_ss = 490 μg/cm²/h) relative to a system loaded with 5% (w/w) drug and 30% (w/w) PVP (lag time = 36 min; Q_6h = 1437 μg/cm²; J_ss = 266 μg/cm²/h).     

Gene Delivery to the Epidermal Cells of Human Skin Explants Using Microfabricated Microneedles and Hydrogel Formulations

Purpose Microneedles disrupt the stratum corneum barrier layer of skin creating transient pathways for the enhanced permeation of therapeutics into viable skin regions without stimulating pain receptors or causing vascular damage. The cutaneous delivery of nucleic acids has a number of therapeutic applications; most notably genetic vaccination. Unfortunately non-viral gene expression in skin is generally inefficient and transient. This study investigated the potential for improved delivery of plasmid DNA (pDNA) in skin by combining the microneedle delivery system with sustained release pDNA hydrogel formulations. Materials and Methods Microneedles were fabricated by wet etching silicon in potassium hydroxide. Hydrogels based on Carbopol polymers and thermosensitive PLGA-PEG-PLGA triblock copolymers were prepared. Freshly excised human skin was used to characterise microneedle penetration (microscopy and skin water loss), gel residence in microchannels, pDNA diffusion and reporter gene (β-galactosidase) expression. Results Following microneedle treatment, channels of approximately 150–200 μm depth increased trans-epidermal water loss in skin. pDNA hydrogels were shown to harbour and gradually release pDNA. Following microneedle-assisted delivery of pDNA hydrogels to human skin expression of the pCMVβ reporter gene was demonstrated in the viable epidermis proximal to microchannels. Conclusions pDNA hydrogels can be successfully targeted to the viable epidermis to potentially provide sustained gene expression therein.     

自溶性微针的制备及其对盐酸青藤碱凝胶透皮性能的影响

目的：优选出自溶性微针的处方工艺,并考察所制备的微针对盐酸青藤碱凝胶透皮性能的影响。方法采用浇注法制备自溶性微针,穿刺试验考察其机械性能,并采用改良Franz扩散池考察自溶性微针预处理皮肤,对盐酸青藤碱凝胶透皮性能的影响。结果采用浇注法制备自溶性微针,其最佳处方为：基质材料硫酸软骨素和聚乙烯吡咯烷酮（PVP）按照1∶1的比例混合,加入重量比60％的水;所制得的微针针形完整、机械强度良好,能够很好的穿刺铝箔和大鼠皮肤;体外透皮实验显示,自溶性微针使得盐酸青藤碱凝胶的累积渗透量增加了3．62倍。结论优选的自溶性微针的处方与制备工艺简单、可行,可显著提高盐酸青藤碱凝胶的透皮性能,为载药微针的进一步研究提供参考依据。     

Emerging strategies for the transdermal delivery of peptide and protein drugs

Transdermal delivery has been at the forefront of research addressing the development of non-invasive methods for the systemic administration of peptide and protein therapeutics generated by the biotechnology revolution. Numerous approaches have been suggested for overcoming the skin’s formidable barrier function; whereas certain strategies simply act on the drug formulation or transiently increase the skin permeability, others are designed to bypass or even remove the outermost skin layer. This article reviews the technologies currently under investigation, ranging from those in their early-stage of development, such as laser-assisted delivery to others, where feasibility has already been demonstrated, such as microneedle systems, and finally more mature techniques that have already led to commercialisation (e.g., velocity-based technologies). The principles, mechanisms involved, potential applications, limitations and safety considerations are discussed for each approach, and the most advanced devices in each field are described.