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.     

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.     

Microneedles: an emerging transdermal drug delivery system

Objectives One of the thrust areas in drug delivery research is transdermal drug delivery systems (TDDS) due to their characteristic advantages over oral and parenteral drug delivery systems. Researchers have focused their attention on the use of microneedles to overcome the barrier of the stratum corneum. Microneedles deliver the drug into the epidermis without disruption of nerve endings. Recent advances in the development of microneedles are discussed in this review for the benefit of young scientists and to promote research in the area. Key findings Microneedles are fabricated using a microelectromechanical system employing silicon, metals, polymers or polysaccharides. Solid coated microneedles can be used to pierce the superficial skin layer followed by delivery of the drug. Advances in microneedle research led to development of dissolvable/degradable and hollow microneedles to deliver drugs at a higher dose and to engineer drug release. Iontophoresis, sonophoresis and electrophoresis can be used to modify drug delivery when used in concern with hollow microneedles. Microneedles can be used to deliver macromolecules such as insulin, growth hormones, immunobiologicals, proteins and peptides. Microneedles containing ‘cosmeceuticals’ are currently available to treat acne, pigmentation, scars and wrinkles, as well as for skin tone improvement. Summary Literature survey and patents filled revealed that microneedle‐based drug delivery system can be explored as a potential tool for the delivery of a variety of macromolecules that are not effectively delivered by conventional transdermal techniques.     

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。     

Evidence for lymphatic transport of insulin by topically applied biphasic vesicles

The cutaneous delivery pathway through the lymphatics of a novel transdermal lipid-based delivery system (biphasic vesicles), which was previously shown to deliver sustained physiological levels of basal insulin in a pain-free manner across the skin, was evaluated in a diabetic rat model. Transdermal patches (one per rat) containing insulin in biphasic vesicles (1-10 mg recombinant human insulin dose) were applied to the shaved abdominal skin of streptozotocin-induced diabetic rats for 73 h. Blood glucose was monitored approximately every 2-10 h using a Lifescan glucose meter. Inguinal lymph node insulin levels were analysed by ELISA. Insulin in the lymph nodes increased in a dose- and time-dependent manner. Maximal transdermal insulin concentrations in the lymph nodes were observed with both 140 IU (5 mg: 43.0 +/- 18.0 microIU mg(-1) (mean +/- s.e.m., n = 4)) and 280 IU (10 mg: 48.0 +/- 19.6 microIU mg(-1) (mean +/- s.e.m., n = 4)) doses of recombinant insulin at t = 73 h. The level of insulin in the lymph nodes after subcutaneous injection of 1 mg insulin at the peak blood glucose response was 35.8 microIU mg(-1) (n = 2), before falling to 0.35 microIU mg(-1) by t = 48 h (n = 2). The lymphatics is involved in the transdermal insulin delivery by biphasic vesicles. This is the first report on the lymphatic transport of a protein after non-invasive topical application on the skin.     

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.     

Enhanced transdermal delivery of low molecular weight heparin by barrier perturbation

The purpose of this work was to investigate the in vitro transdermal delivery of low molecular weight heparin (LMWH). Hairless rat skin was mounted on Franz diffusion cells and treated with various enhancement strategies. Passive flux was essentially zero and remained low even after iontophoresis (0.065 U cm(-2) h(-1)) or application of ultrasound (0.058 U cm(-2) h(-1)). A significant increase in flux across tape stripped skin (4.0 U cm(-2) h(-1)) suggests the interaction of stratum corneum (SC) with LMWH which was confirmed using Differential Scanning Calorimetry and Fourier Transform-Infrared spectrophotometry. Maltose microneedles were then employed as a means to locally disrupt and bypass the SC. Transepidermal water loss (TEWL) and transcutaneous electrical resistance (TER) were measured to confirm the barrier disruption. Microneedles breached the SC resulting in increased TEWL, decreased TER and enhanced LMWH permeability (0.175 U cm(-2) h(-1)). Microneedles when used in conjunction with iontophoresis had a synergistic effect on LMWH delivery resulting in enhancement of flux by 14.7-fold as compared to iontophoresis used alone. Confocal laser scanning microscopy substantiated the evidence about LMWH interaction with SC. In conclusion, LMWH was shown to interact with SC and therefore tape stripping or microneedles dramatically increased its delivery due to disruption of the SC skin barrier.     

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。     

在脉冲电流作用下胰岛素经皮吸收对糖尿病大鼠血糖的影响

实验结果表明,在一定范围内糖尿病大鼠血糖下降的幅度与脉冲电流强度、频率及治疗时间成正比,但当脉冲电流强度超过0.8mA/cm2,频率超过3000Hz时,糖尿病大鼠血糖下降的幅度不再继续增加,即应用较小的电流强度及脉冲频率就能有效地促进胰岛素透皮吸收。同时脉冲电流的占空比为1:l时,糖尿病大鼠血糖下降的幅度最大。为使糖尿病大鼠血糖下降的幅度基本相当,皮下注射与经皮吸收方式给药所用胰岛素的剂量约为1:16。     

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.     

Feasibility of microneedles for percutaneous absorption of insulin.

Insulin loaded microneedles were prepared using dextrin as the base for the percutaneous administration of insulin. Under room temperature, insulin solution was added to high concentration of dextrin solution, glue, and microneedles were prepared by forming thread with polypropylene tips. The mean weight of the microneedles was 0.59+/-0.01 (S.E.) mg. The mean length and basal diameter were 3.24+/-0.16 and 0.55+/-0.03 mm, respectively. Five microneedles were percutaneously administered to mice at the insulin dose levels of 0.5, 1.0 and 2.5IU/kg. After administration, blood samples were collected for 5 h and plasma glucose levels were measured. Lowest plasma glucose level appeared at 1 h after the administration of microneedles and dose-dependent hypoglycemic effect of insulin was clearly observed in those dose range. By comparing the mean area above the plasma glucose level versus time curve (AAC) between microneedle preparation and i.v. solution, the pharmacological availabilities were calculated to be 97.7% (0.5IU/kg), 93.3% (1.0IU/kg) and 91.3% (2.5IU/kg), respectively. When highly loaded insulin loaded microneedle was administered to mice with one microneedle, there was not a significant difference on the plasma glucose level versus time curves between 5 and 1 microneedle experiments. In vitro release study showed that almost all of the formulated insulin was released within 1 h. The T50% was estimated to be 15.4+/-1.1 min. Stability of insulin in the microneedle preparations showed that the remaining insulin after 1 month of the storage were 98.2% (-80 degrees C), 98.9% (20 degrees C) and 99.0% (40 degrees C). Evans blue (EB) loaded microneedles were also prepared and histological study was performed with HWY-Slc hairless rats. The diffusion of EB from the microneedle to the environmental skin reached to the maximum at 3 h after administration. The scab was formed at 24 h after administration. The wound formed by the administration of microneedle was cured at 72 h after administration. Those results suggest the usefulness of a self-dissolving microneedle for the percutaneous delivery of peptide/protein drugs like insulin.     

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.     

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.     

Synergistic effect of iontophoresis and soluble microneedles for transdermal delivery of methotrexate

The aim of this study was to investigate the transdermal iontophoretic delivery of methotrexate, alone or in combination with microneedles, in-vitro and in-vivo using intracutaneous microdialysis in the hairless rat. The average depth of the microdialysis probe in the skin was found to be 0.54 mm. Methotrexate was stable in the presence of an applied electric field as determined by cyclic voltammetry. A current density of 0.4 mA cm(-2) applied for 60 min was used in combination with maltose microneedles to enhance delivery of methotrexate across the skin. Delivery was enhanced by iontophoresis and microneedles, both in-vitro and in-vivo. A synergistic 25-fold enhancement of delivery was observed in-vivo when a combination of microneedles and ionto- phoresis was used compared with either modality alone.     

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。     

In vitro and in vivo assessment of polymer microneedles for controlled transdermal drug delivery

Microneedles (MNs) system for transdermal drug delivery has the potential to improve therapeutic efficacy, proving an approach that is more convenient and acceptable than traditional medication systems. This study systematically researched dissolving polymer MNs fabricated from various common FDA-approved biocompatible materials, including gelatine, chitosan, hyaluronic acid (HA) and polyvinyl alcohol (PVA). Upon application of MN patches to the porcine cadaver skin, the MNs effectively perforated the skin and delivered drugs to subcutaneous tissue on contact with the interstitial fluid. Both the in vitro and in vivo drug release tests showed the similar trends but different release rates among the prepared MNs. Interestingly, the drug-release kinetics of PVA MNs were able to be altered by changing the molecular weight. To evaluate the feasibility using the proposed MNs for treating diabetes, an in vivo insulin absorption study in diabetic mice was performed. The results showed different insulin release properties of MNs fabricated from various kinds of polymer, leading to different decrease in blood glucose levels. We made a systematic and comprehensive study of some drug-loaded polymer MNs, and anticipated that dissolving polymer MNs have potential to improve therapeutic efficacy through controlled drug release.     

胰岛素气雾剂经正常及糖尿病大鼠肺部给药后的降血糖作用

目的：研究胰岛素气雾剂经肺部给药后的降血糖作用。方法：建立了大鼠的肺部给药模型,通过经口有入及气管内给药两种途径将溶液型胰岛素气雾剂导入大鼠肺内,采用葡萄糖氧化酶法测定给药后正常大鼠及糖尿病大鼠的血糖水平,并计算其药理生物利用度。结果：在同一种剂量下,经口吸入和气管内给药两种途径在正常及糖尿病大鼠体内均呈现显著的降血糖作用,其药理生物利用度在正常大鼠体内分别为6．0％和11．4％,在糖尿病大鼠体内分别为5．6％和8．7％,结论：胰岛素气雾剂能有效地降低正常及糖尿病大鼠血糖,为进一步开发临床治疗糖尿病的新剂型打下基础。     

Microporation and ‘Iron’tophoresis for Treating Iron Deficiency Anemia

Purpose

Iontophoretic mediated transdermal delivery of ferric pyrophosphate (FPP) in combination with microneedle pretreatment was investigated as a potential treatment for iron deficiency anemia (IDA).

Methods

In vitro transdermal delivery studies were performed using hairless rat skin and pharmacodynamic studies were performed in hairless anemic rat model. The hematological and biochemical parameters like hemoglobin, hematocrit and % serum transferrin were monitored in rats at healthy, anemic condition and post treatment. Micropores created by the microneedles were visualized in histological skin sections after staining with hemotoxylin and eosin. The recovery of micropores was investigated in vivo by measuring Transepidermal water loss (TEWL) at different time points.

Results

The passive, microneedle and iontophoresis mediated delivery did not lead to significant improvement in hematological and biochemical parameters in anemic rats, when used individually. When iontophoresis (0.15 mA/cm² for 4 hours) was combined with microneedle pretreatment (for 2 min), therapeutically adequate amount of FPP was delivered and there was significant recovery of rats from IDA.

Conclusions

Microneedle and iontophoresis mediated delivery of iron via transdermal route could be developed as a potential treatment for IDA. The transdermal controlled delivery of iron could become a potential, safe and effective alternative to parenteral iron therapy.     

Simultaneous basal-bolus delivery of fast-acting insulin and its significance in diabetes management

Insulin delivery relies on subcutaneous or intravascular injection, leading to reduced patient compliance. Transdermal delivery of insulin has been successfully demonstrated but dose accuracy and skin irritation are problematic in addition to the complex basal-bolus delivery profile required by insulin therapy. Here we present a novel intraepidermal delivery technology (delivered site at epidermis layer, <150 μm) by combining skin pretreatment with short microneedles (<150 μm in length) and iontophoresis transdermal patch (enhanced transport via electrical field) that can provide a continuous basal dose and on-demand bolus dosing for mealtime insulin needs. To our knowledge, this is the first demonstration of therapeutic equivalence between fast-acting human regular insulin and long-acting insulin with possibilities for on-demand dose adjustment. This new intraepidermal delivery technology is likely to change the therapy regimen of patients suffering from insulin-dependent diabetes mellitus and provide a way to lower cost in comparison with insulin pumps and improve patient compliance. FROM THE CLINICAL EDITOR: The authors present a novel intraepidermal insulin delivery technology by combining skin pretreatment with short microneedles and iontophoresis transdermal patch to provide a continuous basal dose and on-demand bolus dosing. This new method is has the potentials to replace insulin pumps by offering a cost effective alternative with less inconvenience and improved compliance.