Coating Formulations for Microneedles

Purpose To develop a rational basis for designing coating solution formulations for uniform and thick coatings on microneedles and to identify coating strategies to form composite coatings, deliver liquid formulations, and control the mass deposited on microneedles. Materials and Methods Microneedles were fabricated using laser-cutting and then dip-coated using different aqueous, organic solvent-based or molten liquid formulations. The mass of riboflavin (vitamin B₂) coated onto microneedles was determined as a function of coating and microneedle parameters. Coated microneedles were also inserted into porcine cadaver skin to assess delivery efficacy. Results Sharp-tipped microneedles, including pocketed microneedles, were fabricated. Excipients that reduced coating solution surface tension improved coating uniformity, while excipients that increased solution viscosity improved coating thickness. Evaluation of more than 20 different coating formulations using FDA approved excipients showed that hydrophilic and hydrophobic molecules could be uniformly coated onto microneedles. Model proteins were also uniformly coated on microneedles using the formulations identified in the study. Pocketed microneedles were selectively filled with solid or liquid formulations to deliver difficult-to-coat substances, and composite drug layers were formed for different release profiles. The mass of riboflavin coated onto microneedles increased with its concentration in the coating solution and the number of coating dips and microneedles in the array. Coatings rapidly dissolved in the skin without wiping off on the skin surface. Conclusions Microneedles and coating formulations can be designed to have a range of different properties to address different drug delivery scenarios.     

Fabrication of Dissolving Polymer Microneedles for Controlled Drug Encapsulation and Delivery: Bubble and Pedestal Microneedle Designs

Dissolving microneedle patches offer promise as a simple, minimally invasive method of drug and vaccine delivery to the skin that avoids the need for hypodermic needles. However, it can be difficult to control the amount and localization of drug within microneedles. In this study, we developed novel microneedle designs to improve control of drug encapsulation and delivery using dissolving microneedles by (i) localizing drug in the microneedle tip, (ii) increasing the amount of drug loaded in microneedles while minimizing wastage, and (iii) inserting microneedles more fully into the skin. Localization of our model drug, sulforhodamine B in the microneedle tip by either casting a highly concentrated polymer solution as the needle matrix or incorporating an air bubble at the base of the microneedle achieved approximately 80% delivery within 10 min compared to 20% delivery achieved by the microneedles encapsulating nonlocalized drug. As another approach, a pedestal was introduced to elevate each microneedle for more complete insertion into the skin and to increase its drug loading capacity by threefold from 0.018 to 0.053 μL per needle. Altogether, these novel microneedle designs provide a new set of tools to fabricate dissolving polymer microneedles with improved control over drug encapsulation, loading, and delivery.     

In vivo assessment of safety of microneedle arrays in human skin

Microneedle arrays are promising devices for the delivery of drugs and vaccines into or the skin. However, little is known about the safety of the microneedles. In this study we obtained insight in the ability of microneedles to disrupt the skin barrier, which was evaluated by transepidermal water loss (TEWL). We also determined the safety in terms of skin irritation (skin redness and blood flow) and pain sensation. We applied microneedle arrays varying in length and shape on the ventral forearms of 18 human volunteers. An effect of needle length was observed, as TEWL and redness values after treatment with solid microneedle arrays of 400mum were significantly increased compared to 200mum. The blood flow showed a similar trend. Needle design also had an effect. Assembled microneedle arrays induced higher TEWL values than the solid microneedle arrays, while resulting in less skin irritation. However, for all microneedles the irritation was minimal and lasted less than 2h. In conclusion, the microneedle arrays used in this study are able to overcome the barrier function of the skin in human volunteers, are painless and cause only minimal irritation. This opens the opportunity for dermal and transdermal delivery of drugs and vaccines.     

Design, Optimization and Characterisation of Polymeric Microneedle Arrays Prepared by a Novel Laser-Based Micromoulding Technique

Purpose

Design and evaluation of a novel laser-based method for micromoulding of microneedle arrays from polymeric materials under ambient conditions. The aim of this study was to optimise polymeric composition and assess the performance of microneedle devices that possess different geometries.

Methods

A range of microneedle geometries was engineered into silicone micromoulds, and their physicochemical features were subsequently characterised.

Results

Microneedles micromoulded from 20% w/w aqueous blends of the mucoadhesive copolymer Gantrez® AN-139 were surprisingly found to possess superior physical strength than those produced from commonly used pharma polymers. Gantrez® AN-139 microneedles, 600 ??m and 900 ??m in height, penetrated neonatal porcine skin with low application forces (>0.03 N per microneedle). When theophylline was loaded into 600 ??m microneedles, 83% of the incorporated drug was delivered across neonatal porcine skin over 24 h. Optical coherence tomography (OCT) showed that drug-free 600 ??m Gantrez® AN-139 microneedles punctured the stratum corneum barrier of human skin in vivo and extended approximately 460 µm into the skin. However, the entirety of the microneedle lengths was not inserted.

Conclusion

In this study, we have shown that a novel laser engineering method can be used in micromoulding of polymeric microneedle arrays. We are currently carrying out an extensive OCT-informed study investigating the influence of microneedle array geometry on skin penetration depth, with a view to enhanced transdermal drug delivery from optimised laser-engineered Gantrez® AN-139 microneedles.     

Influence of the delivery systems using a microneedle array on the permeation of a hydrophilic molecule, calcein.

Despite the advantages of drug delivery through the skin, such as easy accessibility, convenience, prolonged therapy, avoidance of the liver first-pass metabolism and a large surface area, transdermal drug delivery is only used with a small subset of drugs because most compounds cannot cross the skin at therapeutically useful rates. Recently, a new concept was introduced known as microneedles and these could be pierced to effectively deliver drugs using micron-sized needles in a minimally invasive and painless manner. In this study, biocompatible polycarbonate (PC) microneedle arrays with various depths (200 and 500mum) and densities (45, 99 and 154ea/cm(2)) were fabricated using a micro-mechanical process. The skin permeability of a hydrophilic molecule, calcein (622.5D), was examined according to the delivery systems of microneedle, drug loading, depth of the PC microneedle, and density of the PC microneedle. The skin permeability of calcein was the highest when the calcein gel was applied to the skin with the 500mum-depth PC microneedle, simultaneously. In addition, the skin permeability of calcein was the highest when 0.1g of calcein gel was coupled to the 500mum-depth PC microneedle (154ea/cm(2)) as well as longer microneedles and larger density of microneedles. Taken together, this study suggests that a biocompatible PC microneedle might be a suitable tool for transdermal drug delivery system of hydrophilic molecules with the possible applications to macromolecules such as proteins and peptides.     

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.     

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。     

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.     

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.     

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.     

Microneedles and other physical methods for overcoming the stratum corneum barrier for cutaneous gene therapy

The outermost layer of skin, the epidermis, has developed formidable physical and immunological barrier properties that prevent infiltration of deleterious chemicals and pathogens. Consequently, transdermal delivery of medicaments is currently restricted to a limited number of low molecular weight drugs. As a corollary, there has been significant recent interest in providing strategies that disrupt or circumvent the principal physical barrier, the stratum corneum, for the efficient cutaneous delivery of macromolecular and nucleic acid based therapeutics. These strategies include: electrical methods, intradermal injection, follicular delivery, particle acceleration, laser ablation, radiofrequency ablation, microscission, and microneedles. The application of microfabricated microneedle arrays to skin creates transient pathways to enable transcutaneous delivery of drugs and macromolecules. Microneedle use is simple, pain-free, and causes no bleeding, with further advantages of convenient manufacture, distribution, and disposal. To date, microneedles have been shown to deliver drug, peptide, antigen, and DNA efficiently through skin. Robust and efficient microneedle designs and compositions can be inserted into the skin without fracture. Further progress in microneedle array design, microneedle application apparatus, and integrated formulation will confirm this methodology as a realistic clinical strategy for delivering a range of medicaments, including DNA, to and through skin.     

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.     

Bioceramic microneedles with flexible and self-swelling substrate

To reduce the effort required to penetrate the skin and optimize drug release profiles, bioceramic microneedle arrays with higher-aspect-ratio needles and a flexible and self-swelling substrate have been developed. Swelling of the substrate can assist in separating it from the needles and leave them in the skin as a drug depot. The preparation procedures for this bioceramic microneedle are described in the paper. Clonidine hydrochloride, the model drug, was released in a controlled manner by the microneedle device in vitro. Results showed that the microneedle array with a flexible and self-swelling substrate released the drug content faster than the array with a rigid substrate. Disintegration of the needle material and diffusion of the drug molecules are believed as the main control mechanisms of the drug release from these microneedle arrays. Ex vivo skin penetration showed that they can effectively penetrate the stratum corneum without an extra device. This work represents a progression in the improvement of bioceramic microneedles for transdermal drug delivery.     

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.     

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.     

Dissolvable Microneedle Arrays for Intradermal Delivery of Biologics: Fabrication and Application

Purpose

Design and evaluate a new micro-machining based approach for fabricating dissolvable microneedle arrays (MNAs) with diverse geometries and from different materials for dry delivery to skin microenvironments. The aims are to describe the new fabrication method, to evaluate geometric and material capability as well as reproducibility of the method, and to demonstrate the effectiveness of fabricated MNAs in delivering bioactive molecules.

Methods

Precise master molds were created using micromilling. Micromolding was used to create elastomer production molds from master molds. The dissolvable MNAs were then fabricated using the spin-casting method. Fabricated MNAs with different geometries were evaluated for reproducibility. MNAs from different materials were fabricated to show material capability. MNAs with embedded bioactive components were tested for functionality on human and mice skin.

Results

MNAs with different geometries and from carboxymethyl cellulose, polyvinyl pyrrolidone and maltodextrin were created reproducibly using our method. MNAs successfully pierce the skin, precisely deliver their bioactive cargo to skin and induce specific immunity in mice.

Conclusions

We demonstrated that the new fabrication approach enables creating dissolvable MNAs with diverse geometries and from different materials reproducibly. We also demonstrated the application of MNAs for precise and specific delivery of biomolecules to skin microenvironments in vitro and in vivo.     

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。     

Controlled transdermal delivery of model drug compounds by MEMS microneedle array

This article reports an in vitro study of microneedle-array-enhanced transdermal transport of model drug compounds dispersed in chitosan films. Each microneedle array has 400 out-of-plane, needle-shaped microstructures fabricated using micro-electro-mechanical systems (MEMS) technology to ensure adequate mechanical strength and high precision, and consistency. A nanometer coating on the microneedles ensured the biocompatibility that is important in the application of transdermal drug delivery. Model drugs selected to investigate skin permeation in vitro were calcein, a small molecule (molecular weight, 623 d) that has little skin penetration, and bovine serum albumin (BSA) (molecular weight, 66,000 d), a hydrophilic biological macromolecule. A Franz permeation cell was used to characterize the permeation rate of calcein and BSA through the rat skin. The transdermal transport behavior of BSA was investigated from solid films coated on the surface of microneedle arrays with various chitosan concentrations, film thicknesses, and BSA contents. The BSA permeation rate decreased with the increase of the chitosan concentration; the thicker the film, the slower the permeation rate. In addition, the permeation rate increased with the increase of BSA loading dose. A linear relationship existed between the permeation rate and the square root of the BSA loading dose. Results showed that the chitosan hydrophilic polymer film acts as a matrix that can regulate the BSA release rate. The controlled delivery of BSA can be achieved using the BSA-containing chitosan matrix film incorporated with the microneedle arrays. This will provide a possible way for the transdermal delivery of macromolecular therapeutic agents such as proteins and vaccines.     

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....     

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.