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。     

改装滚轮微针促进人增生性瘢痕皮肤对醋酸曲安奈德的吸收

目的考察改装滚轮微针在人增生性瘢痕皮肤中对醋酸曲安奈德的促透作用。方法采用亚甲蓝和H-E染色法观察不同针长的微针刺入人增生性瘢痕皮肤的形态;建立高效液相色谱法测定醋酸曲安奈德含量;采用洗脱法、匀浆法分别考察给药1、12h时增生性瘢痕皮肤醋酸曲安奈德在体吸收特性;采用经皮水分流失(TEWL)测量法、激光多普勒血流量法考察其皮肤刺激性。结果所优选的针长500μm滚轮微针能有效穿透角质层,形成的微孔分布相对均匀;微针处理1、12h后,分别有27.42%、60.64%药物吸收进入皮肤。给药12h,皮内注射醋酸曲安奈德皮肤中滞留药量较给药1h下降至45.98%,而微针、直接涂布醋酸曲安奈德乳膏分别增加到2.73、4.18倍,微针组皮肤中滞留药量是直接涂布乳膏组的3.56倍(P<0.05)。皮内注射12h皮肤药量分布并不均匀,均值为(4.83±5.51)μg,微针组均值为(0.93±0.14)μg,分布相对均匀。TEWL法显示微针处理与皮内注射的皮肤刺激性差异无统计学意义,但激光多普勒血流量法显示皮内注射的皮肤刺激性是微针处理的8.40倍。结论改装滚轮微针处理后涂布醋酸曲安奈德乳膏较皮内注射醋酸曲安奈德在人增生性瘢痕中吸收均匀、皮肤刺激性较小,但其瘢痕治疗效果尚有待进一步验证。     

Design,Development, and Evaluation of a Novel Microneedle Array-based Continuous Glucose Monitor

The development of accurate, minimally invasive continuous glucose monitoring (CGM) devices has been the subject of much work by several groups, as it is believed that a less invasive and more user-friendly device will result in greater adoption of CGM by persons with insulin-dependent diabetes. This article presents the results of preliminary clinical studies in subjects with diabetes of a novel prototype microneedle-based continuous glucose monitor. In this device, an array of tiny hollow microneedles is applied into the epidermis from where glucose in interstitial fluid (ISF) is transported via passive diffusion to an amperometric glucose sensor external to the body. Comparison of 1396 paired device glucose measurements and fingerstick blood glucose readings for up to 72-hour wear in 10 diabetic subjects shows the device to be accurate and well tolerated by the subjects. Overall mean absolute relative difference (MARD) is 15% with 98.4% of paired points in the A+B region of the Clarke error grid. The prototype device has demonstrated clinically accurate glucose readings over 72 hours, the first time a microneedle-based device has achieved such performance.     

穴位放血疗法联合微针配合米诺地尔治疗进展期雄激素性秃发疗效分析

目的:探讨穴位放血疗法联合微针配合米诺地尔治疗进展期雄激素性秃发的疗效。方法:将2016年1月-2018年1月笔者科室门诊收治的85例男性进展期雄激素性秃发患者随机分成两组,联合组(放血疗法联合微针配合米诺地尔)43例和对照组(微针配合米诺地尔)42例。比较两组患者治疗3个月、6个月后的疗效、毛发密度及血清睾酮(T)、双氢睾酮(DHT)、性激素结合球蛋白(SHBG)及游离睾酮(FT)水平,比较两组患者停药后的复发情况及治疗期间出现的不良反应。结果:治疗3个月、6个月后,联合组患者总有效率均明显高于对照组,终毛密度与总毛发密度均明显高于对照组(P<0.05),毳毛密度与对照组患者相比,差异无统计学意义(P>0.05);治疗3个月、6个月后,联合组患者DHT、FT水平比对照组明显降低,SHBG水平比对照组明显升高(P<0.05);T水平与对照组相比,差异无统计学意义(P>0.05);停药12个月后,联合组患者的总复发率低于对照组患者(P<0.05),联合组患者治疗期间不良反应发生率低于对照组患者(P<0.05)。结论:穴位放血疗法联合微针配合米诺地尔治疗进展期雄激素性秃发患者疗效确切,不仅可以明显增加患者头发密度、降低复发率,还可以平衡患者的性激素,且安全性高。     

Modeling drug transport within the viable skin - a review

ABSTRACT

Introduction

In the past, mathematical modeling of the transport of transdermal drugs has been primarily focused on the stratum corneum. However, the development of pharmaceutical technologies, such as chemical enhancers, iontophoresis, and microneedles, has led to two outcomes; an increase in permeability in the stratum corneum or the ability to negate the layer entirely. As a result, these outcomes have made the transport of a solute in the viable skin far more critical when studying transdermal drug delivery.     

胰岛素相转化水凝胶微针透皮贴片

本研究采用化学惰性、可吸收体液溶涨从玻璃态变为水凝胶态的聚合物材料制备了可用于胰岛素透皮给药的微针贴剂,相转化水凝胶微针贴膜。胰岛素是1型和晚期2型糖尿病的必用药。针尖穿透表皮后吸收体液溶涨,使预先担栽的胰岛素在真皮层高效而精确地释放出来,同时不留下针尖物质在皮层的沉积。上述性质使得相转化水凝胶微针贴膜成为需要一生频繁用药的蛋白、多酞药物的理想剂型。     

From the Cover: Microstructured barbs on the North American porcupine quill enable easy tissue penetration and difficult removal

North American porcupines are well known for their specialized hairs, or quills that feature microscopic backward-facing deployable barbs that are used in self-defense. Herein we show that the natural quill’s geometry enables easy penetration and high tissue adhesion where the barbs specifically contribute to adhesion and unexpectedly, dramatically reduce the force required to penetrate tissue. Reduced penetration force is achieved by topography that appears to create stress concentrations along regions of the quill where the cross sectional diameter grows rapidly, facilitating cutting of the tissue. Barbs located near the first geometrical transition zone exhibit the most substantial impact on minimizing the force required for penetration. Barbs at the tip of the quill independently exhibit the greatest impact on tissue adhesion force and the cooperation between barbs in the 0–2 mm and 2–4 mm regions appears critical to enhance tissue adhesion force. The dual functions of barbs were reproduced with replica molded synthetic polyurethane quills. These findings should serve as the basis for the development of bio-inspired devices such as tissue adhesives or needles, trocars, and vascular tunnelers where minimizing the penetration force is important to prevent collateral damage.     

Pharmacokinetics and Postprandial Glycemic Excursions following Insulin Lispro Delivered by Intradermal Microneedle or Subcutaneous Infusion

Background

Intradermal (ID) delivery has been shown to accelerate insulin pharmacokinetics (PK). We compared the PK and pharmacodynamic (PD) effects of insulin lispro administered before two daily standardized solid mixed meals (breakfast and lunch), using microneedle-based ID or traditional subcutaneous (SC) delivery.

Method

The study included 22 subjects with type 1 diabetes in an eight-arm full crossover block design. One arm established each subject’s optimal meal dose. In six additional arms, the optimal, higher, and lower doses (+30%, -30%) were each given ID and SC delivery, in random order. The final arm assessed earlier timing for the ID optimal dose (-12 versus -2 min). The PK/PD data were collected for 6 h following meals. Intravenous basal regular insulin was given throughout, and premeal blood glucose (BG) adjusted to 115 mg/dl.

Results

The primary end point, postprandial time in range (70–180 mg/dl), showed no route-based differences with a high level of overall BG control for both SC and ID delivery. Secondary insulin PK end points showed more rapid ID availability versus SC across doses and meals (∆Tmax -16 min, ∆T50rising -7 min, ∆T50falling -30 min, all p < .05). Both intrasubject and intersubject variability for ID Tmax were significantly lower. Intradermal delivery showed modest, statistically significant secondary PD differences across doses and meals, generally within 90–120 min postprandially (∆12 mg/dl BG at 90 min, ∆7 mg/dl BGmax, ∆7 mg/dl mean BG 0–2 h, all p < .05).

Conclusions

This study indicates that ID insulin delivery is superior to SC delivery in speed of systemic availability and PK consistency and may improve postprandial glucose control.     

Fabrication of Polymer Microneedles Using a Two-Photon Polymerization and Micromolding Process

Background

Microneedle-mediated drug delivery is a promising method for transdermal delivery of insulin, incretin mimetics, and other protein-based pharmacologic agents for treatment of diabetes mellitus. One factor that has limited clinical application of conventional microneedle technology is the poor fracture behavior of microneedles that are created using conventional materials and methods. In this study polymer microneedles for transdermal delivery were created using a two-photon polymerization (2PP) microfabrication and subsequent polydimethylsiloxane (PDMS) micromolding process.

Methods

Solid microneedle arrays, fabricated by means of 2PP, were used to create negative molds from PDMS. Using these molds microneedle arrays were subsequently prepared by molding eShell 200, a photo-reactive acrylate-based polymer that exhibits water and perspiration resistance.

Results

The eShell 200 microneedle array demonstrated suitable compressive strength for use in transdermal drug delivery applications. Human epidermal keratinocyte viability on the eShell 200 polymer surfaces was similar to that on polystyrene control surfaces. In vitro studies demonstrated that eShell 200 microneedle arrays fabricated using the 2PP microfabrication and PDMS micromolding process technique successfully penetrated human stratum corneum and epidermis.

Conclusions

Our results suggest that a 2PP microfabrication and subsequent PDMS micromolding process may be used to create microneedle structures with appropriate structural, mechanical, and biological properties for transdermal drug delivery of insulin and other protein-based pharmacologic agents for treatment of diabetes mellitus.