Numerical simulation of microneedles' insertion into skin

Microneedles have recently received much attention as a novel way for transdermal drug delivery. In this paper, a numerical simulation of the insertion process of the microneedle into human skin is reported using the finite element method. A multilayer skin model consisting of the stratum corneum, dermis and underlying hypodermis has been developed. The effective stress failure criterion has been coupled with the element deletion technique to predict the complete insertion process. The numerical results show a good agreement with the reported experimental data for the deformation and failure of the skin and the insertion force. The influences of the mechanical properties of the skin and the microneedle geometry (e.g. tip area, wall angle and wall thickness) on the insertion force are discussed. The numerical results are helpful for the optimum design of the microneedles for the transdermal drug delivery system.     

Numerical simulation of microneedles' insertion into skin

Microneedles have recently received much attention as a novel way for transdermal drug delivery. In this paper, a numerical simulation of the insertion process of the microneedle into human skin is reported using the finite element method. A multilayer skin model consisting of the stratum corneum, dermis and underlying hypodermis has been developed. The effective stress failure criterion has been coupled with the element deletion technique to predict the complete insertion process. The numerical results show a good agreement with the reported experimental data for the deformation and failure of the skin and the insertion force. The influences of the mechanical properties of the skin and the microneedle geometry (e.g. tip area, wall angle and wall thickness) on the insertion force are discussed. The numerical results are helpful for the optimum design of the microneedles for the transdermal drug delivery system.     

Intradermal ballistic delivery of micro-particles into excised human skin for pharmaceutical applications

A unique form of needle-free drug and vaccine delivery is under investigation. The principle of the concept is to accelerate pharmaceuticals in particle form to a momentum sufficient to penetrate the outer layer of the human skin for a pharmacological effect. The relationship between the key particle impact parameters and particle penetration depth in excised human skin has been experimentally determined. Research devices have been used to deliver particles of a range of radii (0.89-53 microm), and density (1.08-18.2 g/cm3) at controlled and incremental impact velocities between 160 and 640 m/s. Analysis of the particle impact data reveals particle penetration depth as a function of particle density, radius and impact velocity. The experimental relationship provides a criterion for the optimal selection of particle parameters and velocity to target specific layers within the skin. Furthermore, some sources of variability in penetration depth have also been established. The experimental data have also been compared with a mechanistic Unified Penetration Model with good agreement.     

Discovery of transdermal penetration enhancers by high-throughput screening

Although transdermal drug delivery is more attractive than injection, it has not been applied to macromolecules because of low skin permeability. Here we describe particular mixtures of penetration enhancers that increase skin permeability to macromolecules (approximately 1-10 kDa) by up to approximately 100-fold without inducing skin irritation. The discovery of these mixtures was enabled by an experimental tool, in vitro skin impedance guided high-throughput (INSIGHT) screening, which is >100-fold more efficient than current tools. In vitro experiments demonstrated that the mixtures delivered macromolecular drugs, including heparin, leutinizing hormone releasing hormone (LHRH) and oligonucleotides, across the skin. In vivo experiments on hairless rats with leuprolide acetate confirmed the potency and safety of one such mixture, sodium laureth sulfate (SLA) and phenyl piperazine (PP). These studies show the feasibility of using penetration enhancers for systemic delivery of macromolecules from a transdermal patch.     

Quantifying the mechanical properties of human skin to optimise future microneedle device design

Microneedle devices are a promising minimally invasive means of delivering drugs/vaccines across or into the skin. However, there is currently a diversity of microneedle designs and application methods that have, primarily, been intuitively developed by the research community. To enable the rational design of optimised microneedle devices, a greater understanding of human skin biomechanics under small deformations is required. This study aims to develop a representative stratified model of human skin, informed by in vivo data. A multilayer finite element model incorporating the epidermis, dermis and hypodermis was established. This was correlated with a series of in-vivo indentation measurements, and the Ogden material coefficients were optimised using a material parameter extraction algorithm. The finite element simulation was subsequently used to model microneedle application to human skin before penetration and was validated by comparing these predictions with the in-vivo measurements. Our model has provided an excellent tool to predict micron-scale human skin deformation in vivo and is currently being used to inform optimised microneedle designs.     

综述——纳米材料与药物输递：经皮给药中纳米制剂与皮肤的质构效关系

皮肤是人体最大的器官,也为药物的递送提供了重要途径。经皮给药是药物以皮肤为媒介,透过皮肤吸收的途径。因此,皮肤角质层是经皮给药的最大限速障碍。纳米经皮给药系统,具有提高透皮效率、缓释性、避免药物肝首过效应、减少副作用等优点,是通过纳米制剂与皮肤组织之间的相互作用实现的。其中,纳米制剂的结构和组分与其发挥皮肤促渗效用密切相关。对纳米制剂与皮肤质构效关系深入透彻的了解,有助于新型透皮纳米制剂的设计,并利用综合手段构建安全、高效、实用的经皮给药系统。     

Fluidity enhancement: a critical factor for performance of liposomal transdermal drug delivery system

Liposomes are well known lipid carriers for drug delivery of bioactive molecules encapsulated inside their membrane. Liposomes as skin drug delivery systems were initially promoted primarily for localized effects with minimal systemic delivery. Subsequently, a novel vesicular system, transferosomes was reported for transdermal delivery with efficiency similar to subcutaneous injection. The multiple bilayered organizations of lipids applied in these vesicles structure are somewhat similar to complex nature of stratum corneal intercellular lipids domains. The incorporation of novel agents into these lipid vesicles results in the loss of entrapped markers but it is similar to fluidization of stratum corneum lipids on treatment with a penetration enhancer. This approach generated the utility of penetration enhancers/fluidizing agents in lipids vesicular systems for skin delivery. For the transdermal and topical applications of liposomes, fluidity of bilayer lipid membrane is rate limiting which governs the permeation. This article critically reviews the relevance of using different types of vesicles as a model for skin in permeation enhancement studies. This study has also been designed to encompass all enhancement measurements and analytical tools for characterization of permeability in liposomal vesicular system.     

Synergistic Transdermal Delivery of Biomacromolecules Using Sonophoresis after Microneedle Treatment

Transdermal drug delivery systems have been studied as an attractive alternative to conventional delivery routes. However, the outermost layer of the skin, the stratum corneum, acts as a primary barrier to drug delivery. A synergistic combination of microneedles (MNs) and low-frequency ultrasound (U) was used to enhance the penetration of siRNA and ovalbumin. The specific gene knockdown caused by siRNAs through the RNA interference pathway is more stable when delivered via the transdermal route. Ovalbumin, a representative adjuvant, causes a more efficient immune response in the skin because of the numerous immune cells in the skin. The synergistic transdermal delivery resulted in approximately 7 times and 15 times greater penetration of siRNA and ovalbumin respectively than in their respective negative controls, and histological analysis showed minimal invasion. Thus, as the synergistic transdermal delivery enhanced the penetration of biomacromolecules into the skin, this technique is expected to yield a promising technology for a transdermal drug delivery system.     

In Vitro Percutaneous Permeation and Skin Accumulation of Finasteride Using Vesicular Ethosomal Carriers

In order to develop a novel transdermal drug delivery system that facilitates the skin permeation of finasteride encapsulated in novel lipid-based vesicular carriers (ethosomes)finasteride ethosomes were constructed and the morphological characteristics were studied by transmission electron microscopy. The particle size, zeta potential and the entrapment capacity of ethosome were also determined. In contrast to liposomes ethosomes were of more condensed vesicular structure and they were found to be oppositely charged. Ethosomes were found to be more efficient delivery carriers with high encapsulation capacities. In vitro percutaneous permeation experiments demonstrated that the permeation of finasteride through human cadaver skin was significantly increased when ethosomes were used. The finasteride transdermal fluxes from ethosomes containing formulation (1.34 ± 0.11 μg/cm²/h) were 7.4, 3.2 and 2.6 times higher than that of finasteride from aqueous solution, conventional liposomes and hydroethanolic solution respectively (P < 0.01).Furthermore, ethosomes produced a significant (P < 0.01) finasteride accumulation in the skin, especially in deeper layers, for instance in dermis it reached to 18.2 ± 1.8 μg/cm². In contrast, the accumulation of finasteride in the dermis was only 2.8 ± 1.3 μg/cm² with liposome formulation. The study demonstrated that ethosomes are promising vesicular carriers for enhancing percutaneous absorption of finasteride.     

超声介导镇痛药物透皮吸收研究进展

现阶段,临床中常用的镇痛药物多采用口服或注射给药的方式,具全身不良反应多,患者依从性差等缺点,透皮给药作为一种非侵入性给药方式,相对于这些有很多显著的优势,如使用方便,患者痛苦少等。但是,如何克服皮肤的低渗透性一直是该种给药方式发展的瓶颈。近年来,使用超声能量增强镇痛药物在皮肤上的的渗透性成为新的研究热点,各项研究发现,低频超声对药物的增透效果尤为显著。本文通过检索各国文献,对超声介导镇痛药物透皮吸收的原理,临床前试验和临床试验进行综述。     

Cream Formulation Impact on Topical Administration of Engineered Colloidal Nanoparticles

In order to minimize the impact of systemic toxicity of drugs in the treatment of local acute and chronic inflammatory reactions, the achievement of reliable and efficient delivery of therapeutics in/through the skin is highly recommended. While the use of nanoparticles is now an established practice for drug intravenous targeted delivery, their transdermal penetration is still poorly understood and this important administration route remains almost unexplored. In the present study, we have synthesized magnetic (iron oxide) nanoparticles (MNP) coated with an amphiphilic polymer, developed a water-in-oil emulsion formulation for their topical administration and compared the skin penetration routes with the same nanoparticles deposited as a colloidal suspension. Transmission and scanning electron microscopies provided ultrastructural evidence that the amphiphilic nanoparticles (PMNP) cream formulation allowed the efficient penetration through all the skin layers with a controllable kinetics compared to suspension formulation. In addition to the preferential follicular pathway, also the intracellular and intercellular routes were involved. PMNP that crossed all skin layers were quantified by inductively coupled plasma mass spectrometry. The obtained data suggests that combining PMNP amphiphilic character with cream formulation improves the intradermal penetration of nanoparticles. While PMNP administration in living mice via aqueous suspension resulted in preferential nanoparticle capture by phagocytes and migration to draining lymph nodes, cream formulation favored uptake by all the analyzed dermis cell types, including hematopoietic and non-hematopoietic. Unlike aqueous suspension, cream formulation also favored the maintenance of nanoparticles in the dermal architecture avoiding their dispersion and migration to draining lymph nodes via afferent lymphatics.     

Repeated applications of a transdermal patch: analytical solution and optimal control of the delivery rate

The integral transform technique was implemented to solve a mathematical model developed for percutaneous drug absorption. The model included repeated application and removal of a patch from the skin. Fick's second law of diffusion was used to study the transport of a medicinal agent through the vehicle and subsequent penetration into the stratum corneum. Eigenmodes and eigenvalues were computed and introduced into an inversion formula to estimate the delivery rate and the amount of drug in the vehicle and the skin. A dynamic programming algorithm calculated the optimal doses necessary to achieve a desired transdermal flux. The analytical method predicted profiles that were in close agreement with published numerical solutions and provided an automated strategy to perform therapeutic drug monitoring and control.     

A Preformulation Strategy for the Selection of Penetration Enhancers for a Transungual Formulation

Onychomycosis is associated with the cutaneous fungal infection of the nail and the nail folds (skin surrounding the nail). It is therefore important to target drug delivery into the nail folds along with nail plate and the nail bed. Systematic and strategic selection of the penetration enhancers specific for the skin and the nail is discussed. Twelve penetration enhancers were screened for their ability to improve solubility, in vitro nail penetration, in vitro skin permeation, and in vitro skin penetration of the antifungal drug ciclopirox olamine. In contrast to transdermal drug delivery, the main selection criteria for skin penetration enhancer in topical drug delivery were increased drug accumulation in the epidermis and minimal permeation across the skin. Thiourea improved the solubility and nail penetration of ciclopirox olamine. It also showed enhancement in the transungual diffusion of the drug. Propylene glycol showed a 12-fold increase in solubility and 3-fold increase in epidermal accumulation of ciclopirox olamine, while minimizing the transdermal movement of the drug. Thiourea was the selected nail permeation enhancer and propylene glycol was the selected skin penetration enhancer of ciclopirox olamine. A combination of the selected enhancers was also explored for its effect on drug delivery to the nail and nail folds. The enhancer combination reduced the penetration of ciclopirox in the skin and also the permeation through the nail. The proposed preformulation strategy helps to select appropriate enhancers for optimum topical delivery and paves way towards an efficient topical formulation for passive transungual drug delivery.     

Inactivation Effects on Proteins in a Needle‐free Vaccine Injector

Needle‐free powder injectors using a supersonic gas jet to force powder particles into the skin are suitable devices for the reliable delivery of powdered vaccines into viable epidermis. The peculiarities of the injection mechanism lead to a more comfortable injection for the patient, but in return to an increase in the stress on the pharmaceutical formulation in comparison to conventional injections with needle and syringe. As a lot of the conceivable drugs for needle‐free powder injection, particularly protein vaccines, are very sensitive bio‐molecules with an extremely fragile molecular structure, their resilience to the potential molecule damaging processes during the actuation with the device and the preservation of their biological activity are the crucial factors. Therefore it was the central aim of this work to identify and investigate the reasons for the loss of biological activity. The imaginable responsible process steps were investigated separately and the amounts of activity loss related to them. The manufacture of the powder and the loading of the cassette containing the formulation are examined. Moreover, the effects of static pressure exposition, the stress occurring because of the particle transport through the injector device, inevitably accompanied by impacts and shear stress and the influence of the particle impact with the target, were the focus of this investigation. Furthermore, different formulations of protein in combination with pharmaceutical excipients well‐known for their protein stabilizing effects during the powder manufacture process were examined in regard to their potential suitability to protect protein against the stress occurring throughout the needle‐free injection.     

Investigating Transdermal Delivery of Vitamin D3

Transdermal delivery of therapeutic amounts of vitamin D₃ is proposed to overcome its variable oral bioavailability, especially for people who suffer from fat malabsorption. The main challenge for this delivery route is to overcome the barrier properties of skin, especially for very lipophilic compounds such as vitamin D₃. In this study, the effect of different penetration enhancers, such as oleic acid, dodecylamine, ethanol, oleic acid in propylene glycol, isopropyl myristate, octyldodecanol, and oleyl alcohol in propylene glycol were evaluated in vitro for their effectiveness in delivering vitamin D₃ through polyamide filter, polydimethylsiloxane membrane, and porcine skin. A diffusion cell was used to study the transdermal permeability of vitamin D₃. Ointment formulations of vitamin D₃ were prepared containing the most widely used penetration enhancers, oleic acid, and dodecylamine. The ointment containing oleic acid as chemical penetration enhancer did not improve delivery compared to control. On the other hand, the formulation containing dodecylamine as a penetration enhancer did improve the transdermal delivery of vitamin D₃. However, statistical significance and an amount high enough for nutritional supplementation purposes were reached only when the skin was pretreated with 50% ethanol. In these conditions, the ointment delivered an amount of 760-ng vitamin D₃ per cm² of skin. The research shows promise that transdermal delivery could be an effective administration route for vitamin D₃ when ethanol and dodecylamine are used as penetration enhancers.KEY WORDS: dodecylamine, ethanol, penetration enhancer, transdermal delivery, vitamin D₃     

Lecithin soybean phospholipid nano-transfersomes as potential carriers for transdermal delivery of the human growth hormone

Pharmaceutical molecules such as peptides and proteins are usually injected into the body. Numerous efforts have been made to find new noninvasive ways to administer these peptides. In this study, highly flexible vesicles (transfersomes [TFs]) were designed as a new modern transdermal drug delivery system for systemic drug administration through the skin, which had also been evaluated in vitro. In this study, two growth hormone-loaded TF formulations were prepared, using soybean lecithin and two different surfactants; F₁_sodium deoxycholate and F ₂_sodium lauryl sulfate. Thereafter, the amount of skin penetration by the two formulas was assessed using the Franz diffusion cell system. TF formulations were evaluated for size, zeta potential and in vitro skin penetration across the rat skin. Results indicated that vesicle formulations were stable for 4 weeks and their mean sizes were 241.33 ± 17 and 171 ± 12.12 nm in the F ₁ and F ₂ formulation, respectively. After application to rat skin, transport of the human growth hormone (hGH) released from the TF formulations was found to be higher than that of the hGH alone. Maximum amounts of transdermal hormone delivery were estimated to be 489.54 ± 8.301 and 248.46 ± 4.019 ng·cm−2 , for F ₁ and F ₂, respectively. The results demonstrate the capability of the TF-containing growth hormone in transdermal delivery and superiority of the F ₁ to F ₂ TFs.     

Transdermal protein delivery by a coadministered peptide identified via phage display

Efficient transdermal drug delivery of large hydrophilic drugs is challenging. Here we report that the short synthetic peptide, ACSSSPSKHCG, identified by in vivo phage display, facilitated efficient transdermal protein drug delivery through intact skin. Coadministration of the peptide and insulin to the abdominal skin of diabetic rats resulted in elevated systemic levels of insulin and suppressed serum glucose levels for at least 11 h. Significant systemic bioavailability of human growth hormone was also achieved when topically coadministered with the peptide. The transdermal-enhancing activity of the peptide was sequence specific and dose dependent, did not involve direct interaction with insulin and enabled penetration of insulin into hair follicles beyond a depth of 600 microm. Time-lapse studies suggested that the peptide creates a transient opening in the skin barrier to enable macromolecular drugs to reach systemic circulation.     

The Experimental Evaluation and Molecular Dynamics Simulation of a Heat-Enhanced Transdermal Delivery System

Transdermal delivery systems are useful in cases where preferred routes such as the oral route are not available. However, low overall extent of delivery is seen due to the permeation barrier posed by the skin. Chemical penetration enhancers and invasive methods that disturb the structural barrier function of the skin can be used to improve transdermal drug delivery. However, for suitable drugs, a fast-releasing transdermal delivery system can be produced by incorporating a heating source into a transdermal patch. In this study, a molecular dynamics simulation showed that heat increased the diffusivity of the drug molecules, resulting in faster release from gels containing ketoprofen, diclofenac sodium, and lidocaine HCl. Simulations were confirmed by in vitro drug release studies through lipophilic membranes. These correlations could expand the application of heated transdermal delivery systems for use as fast-release-dosage forms.     

经皮给药载体载MD-CPT透明质酸纳米乳的细胞吞噬与体内药代动力学研究

本文在研究制备了包载10,11-亚甲二氧基喜树碱(MD-CPT)的透明质酸纳米乳(HANs)经皮给药系统的基础上,进一步研究了载MD-CPT透明质酸纳米乳的细胞吞噬,并进行了体内药代动力学分析.通过优化制备条件,得到了皮肤渗透性良好的缓释剂型.从CLSM观察到药物被细胞摄入并传递入细胞核,同时,载药纳米乳的细胞吞噬效率呈时间依赖性,不同细胞株HSF、HUVES、MCF-7、KF的细胞吞噬率略有不同.用Rhodanmine B标记HANs,通过荧光显微镜观察到载药纳米乳透过角质层到达真皮层的拟动态过程.利用HPLC检测MD-CPT血药浓度,测得经皮给药半衰期T1/2是静脉注射的3.6倍,肌肉注射的1.6倍,体内药物滞留时间显著增加;血药浓度峰谷值差异小,曲线平缓,说明经皮给药能保证血药浓度呈现可控的持续性.最终通过活体成像系统和组织切片荧光显微镜,直观地反映出经皮给药后药物在大鼠体内的分布情况和各组织器官药物含量,确定载药纳米乳主要采取胞间渗透的扩散方式,在局部给药的区域滞留时间较长,有利于对浅表性的病灶区持续给药,延长药效,而剩余的MD-CPT和解离的HANs都进入了血液循环,最终通过新陈代谢被排出体外.为无创型HANs经皮给药系统应用于浅表性肿瘤治疗提供了理论基础.     

几种辛香中药对辣椒碱巴布剂促透皮吸收作用的研究

通过对辛香中药的研究筛选辣椒碱巴布剂的透皮吸收促进剂,提高辣椒碱的透皮扩散速率。采用分别在辣椒碱巴布剂中添加薄荷醇、冰片、桉叶油3种辛香类中药的方法,以月桂氮酮为对照,进行透皮渗透试验。结果表明3种辛香类中药和月桂氮酮对药物的迁移都有一定的促进作用,其中以桉叶油最为突出,其次为冰片、薄荷、氮酮。