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。     

经扩散法载门冬胰岛素的相转化微针的制备与性能研究

基于聚乙烯醇(PVA)的相转化微针可利用溶胀形成的孔隙载药,在生物大分子药物递送上具有潜力。然而,经传统预混法制备的载药微针中的药物在微针根部和中心也有分布,造成药物在释放过程中的扩散距离较长,且难以穿透水凝胶网状基质,限制了药物的生物利用度。因此,该研究采用扩散法载药,并优化了PVA溶液与辅料(羧甲纤维素钠和葡聚糖)溶液的质量比,以提高载药量、释药率和表皮渗透性。结果显示,当PVA溶液与辅料溶液的质量比为3∶1、固形物含量为17.8%时,微针的溶胀性能较高且机械性能强,可有效递送药物至真皮层。以门冬胰岛素为模型药物时,相比传统预混法(透皮率不到25%),扩散法载药微针的透皮率可达31.0%～34.6%,体外释放率最高达93%。该研究中以扩散法制备的载药微针可提高亲水性大分子药物的释放率和生物利用度,为透皮给药系统的研发提供新策略。     

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.     

复合基质水凝胶微针的制备及性能研究

该研究以聚乙烯醇(PVA)和甲基乙烯基醚/马来酸共聚物(PVM/MA)或甲基乙烯基醚/马来酸酐共聚物(PMVE/MAH)作为复合基质材料，采用热交联法制备水凝胶微针，考察热交联温度、时间以及复合材料种类对水凝胶微针形态、溶胀率的影响，筛选并优化热交联工艺条件。PVM/MA和PVA(1∶1)在80℃/2 h、95℃/0.5 h和110℃/0.5 h以及PMVE/MAH和PVA(1∶1)在80℃/2 h、95℃/1 h和110℃/0.5 h条件下制备的水凝胶微针均显示出良好的溶胀率(>200%)、凝胶组分百分比(>80%)、疗效和安全性。对制备的水凝胶微针进行XRD和DSC分析，结果显示，与物理混合物相比，以PMVE/MAH和PVA(1∶1)制备的水凝胶微针的XRD图谱中2θ为19.45°处PVA衍射峰的消失，玻璃化转变温度(Tg)从约150℃降至约58℃，说明聚合物发生了酯化反应，成功交联。该研究为PVA和PVM/MA或PMVE/MAH复合基质水凝胶微针的透皮给药应用提供了参考。     

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。     

经皮载药微针的现代研究进展

本研究以“微针”和“microneedles”为关键词,检索2017—2022年中国知网(CNKI)和PubMed数据库中的相关文献,从微针载体的结构研究、制备方法、药效学研究及临床应用研究四方面进行综述。在两大数据库中共检索得到有效文献1 040篇。其中,微针结构的研究包含固体微针、涂层微针、可溶性微针、水凝胶微针及中空微针;微针的制备方法包括微模塑法、拉延光刻法及3D打印法;微针载体的药效学研究涵盖对皮肤类、代谢类、免疫类及眼部疾病的治疗;微针的临床应用研究包括疫苗、射频疗法及生物诊断研究等。结合药物制剂新技术,开发新的经皮微针给药系统是微针未来研究的主要方向,本研究为进一步开发微针透皮给药制剂提供参考,以期为微针相关研究提供参考和借鉴。     

透明质酸钠可溶微针的制备及性能特征

目的 探讨透明质酸钠(SH)微针的制备方法并考察其性能特征.方法 利用聚二甲基硅氧烷微针模具制备SH微针,采用离心注模和恒温干燥的方式,根据微针针尖的填充完整性、成型性及基底平整度筛选适宜分子量的SH,并优选最佳制备工艺.采用封口膜穿刺试验测试微针的机械性能,选取制备的空白SH微针进行小鼠体内溶解实验,测试体内溶解度....     

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。     

一种pH敏感水凝胶的性质及用于胰岛素口服给药的研究

目的研究pH敏感水凝胶的性质及其用于胰岛素口服给药的降血糖作用。方法制备了聚(甲基丙烯酸 泊洛沙姆 )共聚物水凝胶 ;在不同pH值的介质中研究凝胶溶胀、药物扩散和药物释放性质 ;含胰岛素的凝胶经口服给予糖尿病大鼠。结果水凝胶具有 pH敏感的性质 ;糖尿病大鼠口服给予含胰岛素的聚合物后有明显的剂量依赖的降血糖作用。结论这种水凝胶有望用作药物传递的载体。     

丹酚酸B-丹参酮ⅡA-甘草次酸微乳凝胶微针透皮给药的评价

目的 优化丹酚酸B （SalB）-丹参酮Ⅱ_A（TSNⅡ_A）-甘草次酸（GA）（STG）微乳凝胶的处方工艺,并考察微针给药对其促透和抗炎药效的影响。方法 以微乳凝胶的综合评分为响应值,选取卡波姆用量、微乳用量、pH值作为考察因素,通过Box-Behnken响应面法筛选最佳处方工艺。采用透皮扩散试验仪考察STG微乳凝胶、STG微乳凝胶+微针（长度分别为500、750、1 000μm）给药的体外经皮渗透特性,高效液相色谱（HPLC）测定TSNⅡ_A、Sal B和GA的含量。采用10%蛋清诱导小鼠足肿胀考察STG微乳凝胶（每次l g,每天2次,给药3 d）、STG微乳凝胶+微针（长度分别为500、750、1000μm）背部给药的抗炎作用,同时考察给药7d对小鼠皮脂腺斑组织的作用。结果 STG微乳凝胶的最佳制备工艺中卡波姆用量为1.00%、微乳用量为0.10 g、pH值为6,制备的STG微乳凝胶中含TSNⅡ_A、SalB、GA分别为0.18、1.05、1.53 mg·g^-1。与TSNⅡ_A比较,SalB和GA的透皮吸收较好;STG微乳凝胶经过与不同长度微针配合使用后的累积透皮量：STG微乳凝胶+1 000μm微针组>STG微乳凝胶+700μm微针组>STG微乳凝胶+500μm微针组>STG微乳凝胶组;3种药物在皮肤中的滞留量相对较高。与空白凝胶组比较,STG微乳凝胶组小鼠足肿胀度有所减轻,但无显著性差异;与STG微乳凝胶组比较,STG微乳凝胶+微针组小鼠足肿胀程度均明显减轻,以1 000μm微针组作用最显著（P<0.05、0.01）。小鼠皮脂腺斑组织HE染色结果表明,与空白凝胶组比较,各组小鼠皮脂腺数目减少且体积变小,以微针长度1 000μm组效果最显著。结论 STG微乳凝胶+微针给药具有良好的透皮特性和缓释效果,发挥抗炎及控制皮脂腺分泌作用,微针长度与透皮率的增加呈正相关。     

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.     

Novel lyophilized hydrogel patches for convenient and effective administration of microneedle-mediated insulin delivery

A lyophilized hydrogel patch system was developed for microneedle-mediated insulin delivery. The matrix of Cross-linked poly(acrylamide-co-acrylic acid) were synthesized by precipitation polymerization. Recombinant human Insulin was loaded into the lyophilized polymer matrix, which can be rehydrated by water. After the hydrated patch was applied to the abdominal skin of diabetic rats after microneedle pretreatment, pharmacodynamics and pharmacokinetics evaluation was performed. The blood samples were collected to monitor blood glucose and serum insulin levels for 12h. Blood glucose was lowered in proportion to the concentration of insulin loaded in lyophilized hydrogel patches (R(2)=0.99), with a longer duration of action compared to subcutaneous injection. Stability study confirmed more than 90% of insulin activity was retained in lyophilized hydrogel after 6 months of storage at 4°C. In conclusion, hydrogel patches were demonstrated to be appropriate drug reservoir for sustained release of insulin with microneedle mediated transdermal delivery.     

Pharmaceutical development of biologics: fundamentals, challenges and recent advances

The 46th Arden Conference, held in West Point, NY, USA, March 2011, focused on development of protein therapeutics, comprising preformulation, formulation, manufacturing, advanced delivery systems, protein characterization/analysis, and regulatory landscape. The sessions of preformulation and formulation development consisted of nine lectures discussing protein stability implications and characterization during purification, freeze-drying and manufacturing. The session on advanced drug delivery encompassed two new sustained-release microsphere formulations (protein microencapsulation by annealing of premade porous PLGA microspheres and aqueous-aqueous emulsion for preformulating proteins to solvent-resistant particles), two transdermal insulins (patching after thermal ablation of skin and phase-transition hydrogel microneedle patch), and a responsible hydrogel system for intra-ear delivery. The sessions on analytical technologies and regulatory landscape both focused on challenges for biosimilars.     

Determination of parameters for successful spray coating of silicon microneedle arrays

Coated microneedle patches have demonstrated potential for effective, minimally invasive, drug and vaccine delivery. To facilitate cost-effective, industrial-scale production of coated microneedle patches, a continuous coating method which utilises conventional pharmaceutical processes is an attractive prospect. Here, the potential of spray-coating silicon microneedle patches using a conventional film-coating process was evaluated and the key process parameters which impact on coating coalescence and weight were identified by employing a fractional factorial design to coat flat silicon patches. Processing parameters analysed included concentration of coating material, liquid input rate, duration of spraying, atomisation air pressure, gun-to-surface distance and air cap setting. Two film-coating materials were investigated; hydroxypropylmethylcellulose (HPMC) and carboxymethylcellulose (CMC). HPMC readily formed a film-coat on silicon when suitable spray coating parameter settings were determined. CMC films required the inclusion of a surfactant (1%, w/w Tween 80) to facilitate coalescence of the sprayed droplets on the silicon surface. Spray coating parameters identified by experimental design, successfully coated 280μm silicon microneedle arrays, producing an intact film-coat, which follows the contours of the microneedle array without occlusion of the microneedle shape. This study demonstrates a novel method of coating microneedle arrays with biocompatible polymers using a conventional film-coating process. It is the first study to indicate the thickness and roughness of coatings applied to microneedle arrays. The study also highlights the importance of identifying suitable processing parameters when film coating substrates of micron dimensions. The ability of a fractional factorial design to identify these critical parameters is also demonstrated. The polymer coatings applied in this study can potentially be drug loaded for intradermal drug and vaccine delivery.     

Dissolvable microneedle patches for the delivery of cell-culture-derived influenza vaccine antigens

Microneedle patches are gaining increasing attention as an alternative approach for the delivery of vaccines. In this study, a licensed seasonal influenza vaccine from 2007 to 2008 was fabricated into dissolvable microneedles using TheraJect's microneedle technology (VaxMat). The tips of the microneedles were made of antigens mixed with trehalose and sodium carboxymethyl cellulose. The patches containing 15 μg per strain of the influenza antigen were characterized extensively to confirm the stability of the antigen following fabrication into microneedles. The presence of excipients and very low concentrations of the vaccine on the microneedle patches made it challenging to characterize using the conventional single radial immunodiffusion analysis. Novel techniques such as capture enzyme-linked immunosorbent assay and enzyme digestion followed by mass spectroscopy were used to characterize the antigens on the microneedle patches. The in vivo studies in mice upon microneedle administration show immunogenicity against monovalent H1N1 at doses 0.1 and 1 μg and trivalent vaccine at a dose of 1 μg. The initial data from the mouse studies is promising and indicates the potential use of microneedle technology for the delivery of influenza vaccine.     

新型经皮传递胰岛素透明质酸微针制剂的制备及性能考察

目的证明透明质酸微针制剂在药物经皮传递系统方面的应用前景。方法通过皮肤及微针的显微照片考察微针刺入皮肤的性能和在大鼠体内的溶解性能;用皮肤刺激性实验评价透明质酸微针的安全性;以人的离体皮肤为透皮释药模型,通过体外经皮通透实验考察微针对模型药物胰岛素经皮吸收的促进作用。结果微针能够均匀刺穿角质层,在皮肤表面产生与微针一致的阵列形状,在皮肤断面可观察到直至真皮层的通道;在大鼠体内使用1 h后,针体能够完全溶解,皮肤刺激性指数为1.7,属于轻度刺激性;体外经皮实验中,微针中的胰岛素能够以活性形式释放,与同剂量的溶液相比,微针对胰岛素的体外经皮吸收具有显著的促进作用,稳态通透速率达75.33×10-6U.cm-2.h-1。结论以透明质酸为基质制备的微针具有良好的皮肤刺入性、溶解性和轻度的刺激性,对于生物大分子类药物的经皮吸收有明显的促进作用,具有良好的开发前景。     

Touch-actuated microneedle array patch for closed-loop transdermal drug delivery

To date, only approximately 20 drugs synthesized with small molecules have been approved by the FDA for use in traditional transdermal patches (TTP) owing to the extremely low permeation rate of the skin barrier for macromolecular drugs. A novel touch-actuated microneedle array patch (TMAP) was developed for transdermal delivery of liquid macromolecular drugs. TMAP is a combination of a typical TTP and a solid microneedle array (MA). High doses of liquid drug formulations, especially heat-sensitive compounds can be easily filled and stored in the drug reservoir of TMAPs. TMAP can easily penetrate the skin and automatically retract from it to create microchannels through the stratum corneum (SC) layer using touch-actuated ‘press and release’ actions for passive permeation of liquid drugs. Comparison of subcutaneous injection, TTP, solid MA, and dissolvable MA, indicated that insulin-loaded TMAP exhibited the best hypoglycemic effect on type 1 diabetic rats. A ‘closed-loop’ permeation control was also provided for on-demand insulin delivery based on feedback of blood glucose levels (BGLs). Twenty IU-insulin-loaded TMAP maintained the type 1 diabetic rats in a normoglycemic state for approximately 11.63?h, the longest therapeutic duration among all previously reported results on microneedle-based transdermal patches. TMAP possesses excellent transdermal drug delivery capabilities.     

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.     

Microneedle delivery: clinical studies and emerging medical applications

The concept of microneedle drug delivery was described three decades ago; however, effective clinical demonstration has only occurred within the past 10-15 years. Substantial progress in microneedle design and fabrication including extensive in vitro, ex vivo, and in vivo preclinical evaluation with various drugs, vaccines and other agents has transpired over the last decade. In contrast with this large volume of preclinical data, there are relatively few published microneedle clinical studies. To date, the clinical investigative focus has included testing to reduce dermal barrier properties and enhance transdermal delivery; evaluation of enhanced vaccine antigenicity, including development of the first commercial microneedle product for intradermal influenza vaccination; evaluation of altered microneedle protein pharmacokinetics and pharmacodynamics, especially for insulin; and evaluation of the pain and other perceptions associated with microneedle usage. This review summarizes the various aspects of microneedle clinical evaluation to date and identifies areas requiring further clinical evaluation.