草乌甲素可溶性微针的制备、质量评价及体外透皮性能研究

目的 为克服草乌甲素现有给药方式的不足,开展草乌甲素可溶性微针的制备工艺、质量评价及体外透皮性能研究.方法 采用分层浇筑法制备草乌甲素可溶性微针,通过正交法优选最佳处方及制备工艺,并对微针进行质量评价,如微针表观、机械强度、载药量、透皮释放等.结果 草乌甲素可溶性微针的最佳处方及制备工艺为:以35％乙醇溶液作为溶剂,0...     

Coupled Diffusion-Binding-Deformation Modelling for Phase-Transition Microneedles-Based Drug Delivery

Phase-transition microneedles (PTMNs)-based transdermal drug delivery (TDD) is gaining popularity due to its non-invasiveness and ability to deliver a wide range of drugs. PTMNs absorb interstitial skin fluid (ISF) and transport drugs from microneedle (MNs) domain to the skin without polymer dissolution. To establish PTMNs for practical use, one needs to understand and optimise the key parameters governing drug transport mechanisms to achieve controlled drug delivery. In addressing this point, we have developed a coupled diffusion-binding-deformation model to understand the effect of physicochemical parameters (e.g., swelling capacity, drug binding) of MN and skin mechanical properties on overall drug transport behaviour. The contact mechanics at the MN and skin interface is introduced to account for the resistive force exerted by the deformed skin to MN swelling. The model is validated with the reported data of in vitro insulin delivery using polyvinyl alcohol (PVA) MN. The drug binding parameters are estimated from the fitting of the cumulative release of insulin within 6 hours of MN insertion. To predict the in vivo data of insulin delivery using the PVA MN, one-compartment model of drug pharmacokinetics is incorporated. It is shown in the paper that the model is able to predict the final insulin concentration in blood and in good agreement with the reported experimental data. The proposed model is concluded to be a tool for the predictive design and development of PTMNs-based TDD systems.     

Development of cyclosporin A-loaded hyaluronic microsphere with enhanced oral bioavailability

To develop a hyaluronic microsphere with the improved oral bioavailability of poorly water-soluble cyclosporin A (CsA), the microspheres were prepared with varying ratios of sodium hyaluronate (HA)/sodium lauryl sulfate (SLS)/CsA using a spray-drying technique. The effects of HA and SLS on the dissolution and solubility of CsA in microspheres were investigated. The CsA-microsphere prepared with HA/SLS/CsA at the ratio of 4/2/1 gave the highest solubility and dissolution rate of CsA among those formulae tested. As solubility and dissolution rate of CsA were increased about 17- and 2-fold compared to CsA powder, respectively, this CsA-microsphere was selected as an optimal formula for oral delivery in rats. The CsA-microsphere and Sandimmun neoral sol gave significantly higher blood levels compared with CsA powder alone. Moreover, the AUC, T(max) and C(max) values of CsA in CsA-microsphere were not significantly different from those in Sandimmun neoral sol in rats, indicating that CsA-microsphere was bioequivalent to the commercial product in rats. Our results demonstrated that the CsA-microsphere prepared with HA and SLS, with improved bioavailability of CsA, might have been useful to deliver a poorly water-soluble CsA.     

Enhanced delivery of topically-applied formulations following skin pre-treatment with a hand-applied, plastic microneedle array

The purpose of this work is to characterize microchannels created by polymeric microneedles, applied by hand, and to demonstrate enhanced delivery of topically applied formulations of lidocaine hydrochloride and methylprednisolone sodium succinate (MPSS). 3M's Microstructured Transdermal System (MTS) arrays were applied to domestic swine to demonstrate reliability of penetration, depth of penetration and durability of the structures to repeat application and high force. Tissue levels of lidocaine and MPSS following topical application with and without microneedle pretreatment were determined by HPLC-MS analysis following digestion of biopsies. Almost all microneedles penetrate the stratum corneum upon hand force application. The depth of penetration varies from <100μm to nearly 150μm depending on the application force and the firmness of the underlying tissue. The arrays show excellent durability to repeated in-vivo application, with less than 5% of the structures evidencing even minimal tip bending after 16 applications. Under extreme force against a rigid surface, the microneedles bend but do not break. A lidocaine hydrochloride formulation applied topically in-vivo showed ~340% increase in local tissue levels when the MTS arrays were used to twice pre-treat the skin prior to applying the drug. Local delivery of a topically applied formulation of MPSS was over one order of magnitude higher when the application site was twice pre-treated with the MTS array. 3M's MTS array (marketed as 3M(TM) Microchannel Skin System) provides repeatable and robust penetration of the stratum corneum and epidermis and enhances delivery of some formulations such as lidocaine hydrochloride.     

Drug delivery into the skin by degradable particles

Recently, it was demonstrated that particles could be utilized as carrier systems for drugs into the hair follicles. In the present study, a two-component drug delivery system is presented consisting of degradable particles loaded with fluorescein isothiocyanate and a separate protease formulation for degradation. The particles were applied alone, 30 min previous to the protease application and simultaneously with the protease onto porcine skin. Subsequently, biopsies were removed, and the penetration depths of the particles were analyzed using laser scanning microscopy.The obtained results demonstrate that the particles alone achieved a penetration depth of around 900 μm. Similar results were obtained for the successive application of particles and protease, whereas a release of the fluorescent dye was only observed in the upper 250 μm corresponding to the penetration depth of the protease. In the case of the simultaneous application, the particles were partly dissolved before application, leading to a reduced particle size and diminished penetration depth.The results revealed that degradable particles are a promising tool for drug delivery into the skin.     

Review of patents on microneedle applicators

Transdermal drug delivery offers certain advantages over conventional oral or parenteral administration. However, transdermal delivery is not available to many promising therapeutic agents, especially high molecular weight hydrophilic compounds. This is due to the excellent barrier property of the superficial skin layer, the stratum corneum (SC). Only drugs with very specific physicochemical properties (molecular weight < 500 Da, adequate lipophilicity, and low melting point) can be successfully administered transdermally. Of the several active approaches used to enhance the transport of drugs through the SC, the use of microneedles (MNs) has recently been shown to be very promising and has attracted considerable attention by researchers from both industry and academia. MNs, when used to puncture skin, will by-pass the SC and create transient aqueous transport pathways of micron dimensions and enhance the transdermal permeability. However, for effective performance of these MNs in drug delivery applications, irrespective of the type, material, height and density, it is imperative that they penetrate into the skin with the greatest possible accuracy and reproducibility. Due to the inherent elasticity and irregular surface topography of the skin, it remains a major challenge to the reproducibility of MN penetration. Therefore, in order to achieve uniform and reproducible MN penetration into skin, an external source of assistance could be very useful. Accordingly, this review deals with various innovative applicator designs developed by industry and research centres in the context of effective application of MN arrays for transdermal drug delivery, as disclosed in the recent patent literature.     

Incidence of low bioavailability of leuprolide acetate after percutaneous administration to rats by dissolving microneedles

Two-layered dissolving microneedles of which acral portion contained leuprolide acetate (LA) as solid dispersion were prepared with sodium chondroitin sulfate as the base and the systemic absorption efficiency of LA was studied in rats after administration to their abdominal skin. A patch contained 100 dissolving microneedles of which length and basement diameter were 469.8±4.7 μm and 284.5±9.8 μm, where LA content was 14.3±1.6 μg. In vitro dissolution experiment showed that LA was released from dissolving microneedle patch within 3 min. LA was stable in the patch, % recoveries for 3 months were 102.2±1.9-95.3±1.9%. One and half-patch of LA dissolving microneedles were administered to the rat skin and plasma LA concentrations were measured by LC-MS/MS. Plasma LA concentrations increased immediately after administration, and reached to the maximum level at 15 min, where C(max) were 6.0±0.7 and 16.4±0.9 μg/ml, respectively. The AUC were 5.8±0.8 and 14.5±0.4 μg h/ml and BA were 33.8±4.3% and 31.7±0.8%. When LA solution was subcutaneously (s.c.) injected to rats, 50 μg/kg, the BA was 32.0±2.1%. Relative BA of LA from dissolving microneedles against s.c. solution was 105.6±13.5%. The degradation rate of LA in the rat skin tissue homogenate was very fast where the half-life was 16.3±5.7 min. The degradation of LA in the skin tissue was the cause of the low BA of LA after percutaneous administration to rats.     

Transdermal delivery of relatively high molecular weight drugs using novel self-dissolving microneedle arrays fabricated from hyaluronic acid and their characteristics and safety after application to the skin

The purpose of this study was to develop novel dissolving microneedle arrays fabricated from hyaluronic acid (HA) as a material and to improve the transdermal permeability of relatively high molecular weight drugs. In this study, fluorescein isothiocyanate-labeled dextran with an average molecular weight of 4 kDa (FD4) was used as a model drug with a relatively high molecular weight. The microneedle arrays significantly increased transepidermal water loss (TEWL) and reduced transcutaneous electrical resistance (TER), indicating that they could puncture the skin and create drug permeation pathways successfully. Both TEWL and TER almost recovered to baseline levels in the microneedle array group, and relatively small pathways created by the microneedles rapidly recovered as compared with those created by a tape stripping treatment. These findings confirmed that the microneedle arrays were quite safe. Furthermore, we found that the transdermal permeability of FD4 using the microneedle arrays was much higher than that of the FD4 solution. Furthermore, we found that the microneedle arrays were much more effective for increasing the amount of FD4 accumulated in the skin.These findings indicated that using novel microneedle arrays fabricated from HA is a very useful and effective strategy to improve the transdermal delivery of drugs, especially relatively high molecular weight drugs without seriously damaging the skin.     

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.     

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.     

Hyaluronan-decorated liposomes as drug delivery systems for cutaneous administration

The work aimed to evaluate the feasibility to design hyaluronic acid (HA) decorated flexible liposomes to enhance the skin penetration of nifedipine. Egg phosphatidylcholine (e-PC) based transfersomes (Tween 80) and transethosomes (ethanol) were prepared. HA was reacted with 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (HA-DPPE) and two molar ratios (0.5 and 3%) of conjugate with respect to e-PC were tested. The presence of HA significantly increased the packing order of the bilayer (as verified by differential scanning calorimetry), reducing both the encapsulation efficiency and the flexibility of the decorated liposomes in a dose-dependent manner. In fact, at the highest HA content the constant of deformability (K, N/mm) increased and the carriers remained on the skin surface after topical application. The stiffening effect of HA was counterbalanced by the addition of ethanol as fluidizing agent that allowed to maintain the highest HA concentration, meanwhile reducing the K value of the vesicles. HA-transethosomes allowed a suitable nifedipine permeation (J?～?30?ng/cm²/h) and significantly improved the drug penetration, favouring the formation of a drug depot in the epidermis. These data suggest the potentialities of HA-transethosomes as drug delivery systems intended for the treatment of cutaneous pathologies and underline the importance of studying the effect of surface functionalization on carrier deformability to rationalize the design of such systems.     

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。     

Hydrogel-Forming Microneedle Arrays Can Be Effectively Inserted in Skin by Self-Application: A Pilot Study Centred on Pharmacist Intervention and a Patient Information Leaflet

Purpose

To investigate, for the first time, the influence of pharmacist intervention and the use of a patient information leaflet on self-application of hydrogel-forming microneedle arrays by human volunteers without the aid of an applicator device.

Methods

A patient information leaflet was drafted and pharmacist counselling strategy devised. Twenty human volunteers applied 11?×?11 arrays of 400 μm hydrogel-forming microneedle arrays to their own skin following the instructions provided. Skin barrier function disruption was assessed using transepidermal water loss measurements and optical coherence tomography and results compared to those obtained when more experienced researchers applied the microneedles to the volunteers or themselves.

Results

Volunteer self-application of the 400 μm microneedle design resulted in an approximately 30% increase in skin transepidermal water loss, which was not significantly different from that seen with self-application by the more experienced researchers or application to the volunteers. Use of optical coherence tomography showed that self-application of microneedles of the same density (400 μm, 600 μm and 900 μm) led to percentage penetration depths of approximately 75%, 70% and 60%, respectively, though the diameter of the micropores created remained quite constant at approximately 200 μm. Transepidermal water loss progressively increased with increasing height of the applied microneedles and this data, like that for penetration depth, was consistent, regardless of applicant.

Conclusion

We have shown that hydrogel-forming microneedle arrays can be successfully and reproducibly applied by human volunteers given appropriate instruction. If these outcomes were able to be extrapolated to the general patient population, then use of bespoke MN applicator devices may not be necessary, thus possibly enhancing patient compliance.     

Dissolving Microneedle Patches for Dermal Vaccination

The dermal route is an attractive route for vaccine delivery due to the easy skin accessibility and a dense network of immune cells in the skin. The development of microneedles is crucial to take advantage of the skin immunization and simultaneously to overcome problems related to vaccination by conventional needles (e.g. pain, needle-stick injuries or needle re-use). This review focuses on dissolving microneedles that after penetration into the skin dissolve releasing the encapsulated antigen. The microneedle patch fabrication techniques and their challenges are discussed as well as the microneedle characterization methods and antigen stability aspects. The immunogenicity of antigens formulated in dissolving microneedles are addressed. Finally, the early clinical development is discussed.     

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。     

Novel reverse electrodialysis-driven iontophoretic system for topical and transdermal delivery of poorly permeable therapeutic agents

Topical and transdermal drug delivery has great potential in non-invasive and non-oral administration of poorly bioavailable therapeutic agents. However, due to the barrier function of the stratum corneum, the drugs that can be clinically feasible candidates for topical and transdermal delivery have been limited to small-sized lipophilic molecules. Previously, we fabricated a novel iontophoretic system using reverse electrodialysis (RED) technology (RED system). However, no study has demonstrated its utility in topical and/or transdermal delivery of poorly permeable therapeutic agents. In this study, we report the topical delivery of fluorescein isothiocyanate (FITC)–hyaluronic acid (FITC–HA) and vitamin C and the transdermal delivery of lopinavir using our newly developed RED system in the in vitro hairless mouse skin and in vivo Sprague–Dawley rat models. The RED system significantly enhanced the efficiency of topical HA and vitamin C and transdermal lopinavir delivery. Moreover, the efficiency and safety of transdermal delivery using the RED system were comparable with those of a commercial ketoprofen patch formulation. Thus, the RED system can be a potential topical and transdermal delivery system for various poorly bioavailable pharmaceuticals including HA, vitamin C, and lopinavir.     

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。     

微针在口腔黏膜给药系统中的研究进展

口腔黏膜给药系统是近年来发展的一种新型给药系统,与传统的口服给药途径相比,可以避免胃肠道酶代谢、酸降解及肝脏首过作用,进而提高药物生物利用度,发挥局部或全身治疗和预防作用。但是口腔黏膜的物理屏障会限制药物的吸收,而微针可突破该障碍,改善药物的渗透。本文简述了口腔黏膜给药的优缺点,介绍了微针的分类及国内微针企业的发展情况,讨论了微针在口腔黏膜给药系统的研究进展,以期有更多新的口腔黏膜制剂推向市场。     

微针促渗仪经皮免疫部位对免疫应答的影响

目的 利用微针的促渗作用对小鼠进行经皮免疫,探讨不同免疫部位所引起免疫应答的特点.方法 用染色法和组织切片法考察微针促渗仪的穿刺能力和穿刺效果;采用微针促渗仪,对小鼠的后背皮肤和耳部皮肤进行处理,涂抹模型抗原卵清蛋白(OVA)和佐剂CpG ODN 1826后,采用ELISA法测定血清中的抗OVA特异性抗体.结果 微针促渗仪可成功穿刺皮肤角质层,将抗原OVA和佐剂CpG ODN 1826同时递送至皮肤表皮层.与经后背皮肤免疫比较,经耳部免疫会产生更强效的IgG、IgG 1和IgG 2a特异性抗体水平.结论 经皮免疫在耳部皮肤引起了比后背皮肤更强的免疫效果.