Transdermal Drug Delivery Applications Research Articles

Cationic Moieties in Polystyrene Gels Swollen with d-Limonene Improved Transdermal Delivery System.

d-limonene, a terpene and natural compound, has been found to be an excellent penetration enhancer for transdermal drug delivery (TDD). It hence has been incorporated within various transdermal formulations. Herein, we report the application of polystyrene gel swollen with d-limonene and its derivatives for TDD. Poly(styrene-co-divinylbenzene) (PS gel), poly(styrene-co-divinylbenzene-co-4-vinylpyridine) (PS-4VP) gel and poly(styrene-co-divinylbenzene-co-(vinylbenzyl) trimethylammonium chloride) (PS-VBAC gel) were employed as chemical gels to improve the stability of the TDD substrates. The drug permeation properties from the PS gels swollen in limonene were examined, regarding the effect of its network density as well as their rheological properties. The lowest density of the network showed the highest steady flux of the permeation at 43.7 ± 0.3 μg/cm2. FT-IR spectra were confirmed for PS-4VP and PS-VBAC, bearing cationic moieties and they could control the release of ibuprofen by the electrostatic interaction at the interface of organogel and skin. The steady state flux of skin permeation got low values from 55.2 ± 0.8 to 11.6 ± 2.0 μg/cm2, when the cationic moieties were increased. Moreover, the chemical network of PS gel swollen in limonene showed high mechanical stability illustrated by elastic modulus (G’) of about 98 kPa for 10% cross-linked PS gel. The developed PS gels swollen in limonene show highly promising results, suggesting their possible application in TDD.

Design rules for a tunable merged-tip microneedle

This publication proposes the use of an elasto-capillarity-driven self-assembly for fabricating a microscale merged-tip structure out of a variety of biocompatible UV-curable polymers for use as a microneedle platform. In addition, the novel merged-tip microstructure constitutes a new class of microneedles, which incorporates the convergence of biocompatible polymer micropillars, leading to the formation of a sharp tip and an open cavity capable of both liquid trapping and volume control. When combined with biocompatible photopolymer micropillar arrays fabricated with photolithography, elasto-capillarity-driven self-assembly provides a means for producing a complex microneedle-like structure without the use of micromolding or micromachining. This publication also explores and defines the design rules by which several fabrication aspects, such as micropillar dimensions, shapes, pattern array configurations, and materials, can be manipulated to produce a customizable microneedle array with controllable cavity volumes, fracture points, and merge profiles. In addition, the incorporation of a modular through-hole micropore membrane base was also investigated as a method for constitutive payload delivery and fluid-sampling functionalities. The flexibility and fabrication simplicity of the merged-tip microneedle platform holds promise in transdermal drug delivery applications.

Fabrication and characterization of gold-coated solid silicon microneedles with improved biocompatibility

In this paper, we discussed biocompatibility improvement and mechanical strength of the solid silicon (Si) microneedles for transdermal drug delivery systems. The pyramidal shape and sharp tip of microneedles are fabricated using an optimized Tetramethylammonium Hydroxide (TMAH) etching factors. The mechanical strength and biocompatibility of the microneedle array are enhanced after coating gold (Au) layer through metal sputtering technique. The needles thus fabricated are suitable for sustained transdermal drug delivery applications with a height of 250 μm and a base width of 52.8 μm, the aspect ratio of 4.73, and tip angle and diameter of 24.5° and 45 μm. The Vickers hardness value of 3800 Hv is obtained for the fabricated Au-coated solid Si microneedles. The attained Vickers hardness value is substantially higher than the skin resistive force. It shows that the capability of drug delivery by piercing these microneedles into the skin becomes readily feasible.

Novel structure of microneedle arrays for the transdermal drug delivery applications

Novel structure of microneedle arrays for the transdermal drug delivery applications

Evaluation of Amphiphilic Star/Linear-Dendritic Polymer Reverse Micelles for Transdermal Drug Delivery: Directing Carrier Properties by Tailoring Core versus Peripheral Branching.

The reverse micelle self-assembly of lipophile-functionalized poly(ethylene glycol) (PEG) dendrimer hybrids is probed for applications in carrier-mediated transdermal drug delivery. Under investigation are topologically diverse amphiphiles featuring controlled branching motifs at either the polymer core (one-, two-, and four-arm PEG) and the polar/nonpolar interface (peripheral dendritic generations 0-2). Thus, a systematic investigation of the effect of branching location (core vs peripheral) on carrier properties is described. Dye-encapsulation experiments verify these materials are capable of forming well-defined aggregates and solubilizing polar compounds. Further quantification of reverse micelle critical micelle concentration and dye loading capacity for the branched amphiphile library was obtained through spectroscopy characterization. Both core and peripheral branching are shown to significantly influence dynamic encapsulation behavior, with evidence of location-based contributions extending beyond multiplicity of branching alone. Finally, the in vitro transdermal diffusion of the reverse micelle carriers was investigated through Franz diffusion cell experiments using physiologically relevant juvenile porcine dermis. The permeation results, combined with previously reported aggregate size trends, show the complex relationship between polymer branching and transdermal transport, with the lowest core- and highest peripherally-branched amphiphilic analogs exhibiting optimal transdermal permeation characteristics for this set of branched carriers.

Novel Bletilla striata polysaccharide microneedles: Fabrication, characterization, and in vitro transcutaneous drug delivery

Dissolving microneedles (MNs) have been widely studied for their applications in effective transdermal drug delivery due to their ability to dissolve within the skin. This study details the first reported successful preparation of novel dissolving MNs using Bletilla striata polysaccharide (BSP), a natural glucomannan material, and investigates the potential for using such MNs as a transdermal drug delivery vector. The prepared dissolving Bletilla striata polysaccharide microneedles (BMNs) had excellent moldability and were easily detached from the mold. Texture analysis and histological examination confirmed BMNs were strong enough to insert into the skin. The skin appeared slight irritation after removal of BMNs, but recovered within 24 h. Confocal laser scanning microscopy (CLSM) studies indicated that rhodamine B (RB) loaded in BMNs (as a model drug) could be gradually released, along with the dissolution of BSP in vivo, and then diffused from the insertion site to the periphery. Furthermore, we found that the RB-loaded BMNs could provide sustained drug release via the in vitro Franz cell experiment. These findings demonstrate that novel dissolving BMNs can be easily-manufactured, loaded with drug, and inserted into the skin for drug delivery.

Design and analysis of MEMS based piezoelectric micro pump integrated with micro needle

This paper presents the design and simulation of piezoelectric micro pump integrated with micro needle. The proposed micro pump adopted rectangular piezoelectric vibrator supplied with an external alternating current voltage. It has four primary components: electrodes, piezoelectric plate, PDMS (polydimethylsiloxane) membrane and channel with inlet and outlet bottom up and whole setup is constructed on a glass base. The simulations are carried out by subjecting the developed model to voltage changes, material changes which shows the satisfactory results. The micro pump possesses a flow rate of 4.1 ml/min at an input voltage 10 V with frequency 300 Hz while it is integrated with Micro Needle is having 4.67 ml/min. High pumping rates at low applied voltages making the proposed model significantly important for Transdermal controlled drug delivery applications.

Finite element analysis of hollow out-of-plane HfO2 microneedles for transdermal drug delivery applications.

Transdermal drug delivery (TDD) based on microneedles is an excellent approach due to its advantages of both traditional transdermal patch and hypodermic syringes. In this paper, the fabrication method of hollow out-of-layer hafnium oxide (HfO2) microneedles mainly based on deep reactive ion etching of silicon and atomic layer deposition of HfO2is described, and the finite element analysis of the microneedles based on ANSYS software is alsopresented. The fabrication process is simplified by using a single mask. The finite element analysis of a single microneedle shows that the flexibility of the microneedles can be easily adjusted for various applications. The finite element analysis of a 3×3 HfO2 microneedle array applied on the skin well explains the "bed of nail" effect, i.e., the skin is not liable to be pierced when the density of microneedles in array increases. The presented research work here provides useful information for design optimization of HfO2 microneedles used for TDD applications.

Polymer based microneedle patch fabricated using microinjection moulding

This paper presents the development of a polymer based microneedle patch for transdermal drug delivery application using plastic microinjection moulding. Design and analysis of the microneedle cavities and mould insert used in the injection moulding process were carried out using Computer-Aided Engineering (CAE) software. A mould insert with low surface roughness was fabricated using Micro Electrical Discharge Machining (μ-EDM). The injection moulding parameters including clamping force, temperature, injection pressure and velocity were characterized in order to obtain the optimum reproducibility. Solid truncated cone microneedles, made of biocompatible polymethyl methacrylate (PMMA), with a round tip radius of 50 μm and 500 μm in height have been realized by microinjection moulding process demonstrating the potential of a low cost, high production efficiency, and suitable for mass production. In addition, a mould insert of cylindrical microneedles fabricated using X-ray LIGA has been proposed.

In-silico design of nanoparticles for transdermal drug delivery application.

Nanoparticles are used in the medical field for various applications like cell imaging, drug delivery, gene and si-RNA delivery, to name a few. Designing nanoparticles for a given application, purely based on the trial and error experimentation, requires a lot of time and effort. In this study we show that computer simulations could help in designing nanoparticles for drug delivery thus reducing the time and cost associated with their design, development and deployment. The permeation of nanoparticles, having various surface chemistries and patterns, through the skin lipid bilayer was studied using constrained and unconstrained molecular dynamics simulations. Interestingly, the permeation mechanism of nanoparticles having the same surface chemistry but different patterns was found to be completely different. Nanoparticles (NPs) were screened based on the free energy of permeation through the skin lipid bilayer. The behavior of the screened NPs was further validated with unconstrained simulations using the skin lipid bilayer. Nanoparticles thus screened through both of the techniques were further used for the co-delivery of a model protein into the skin lipid bilayer. It was observed that the nanoparticles having a 2 : 1 homogeneous ratio of hydrophobic to hydrophilic regions were the most promising in transdermal delivery of proteins. The obtained results are in line with the results of recent permeation experiments on cell and plasma membrane. Our study could help in in-silico design of nanoparticles for delivery of actives through skin. These in-silico experiments thus could help speed up the development process by guiding formulation chemists.

Wearable Sensing Systems with Mechanically Soft Assemblies of Nanoscale Materials

Emerging classes of wearable sensing systems that measure motion, physiological, electrophysiological, and electrochemical signals emanating from the human body have driven significant advances in clinical and academic research. These wearable systems rely on important breakthroughs in micro/nano‐electronics, information technology, and materials science. Compared to conventional bulk materials, nanomaterials with zero, one, and two dimensional (0D, 1D, and 2D) architectures exhibit unusual physical properties that could dramatically improve the performance of sensors. By integrating high performance sensors with soft and stretchable electronics, research groups are enabling fully‐integrated multifunctional sensing systems in skin‐worn formats, optimized for managing specific disease models. In this progress report, recent advances in soft wearable sensing systems based on assemblies of 0D, 1D, and 2D nanomaterials, unpackaged integrated circuits, and highly elastic (moisture resistant) encapsulating layers are reviewed. These advanced bioelectronic constructs combine multimodal sensor arrays, data storage elements, wireless data transmission modules, and actuators for continuous monitoring. The soft wearable systems that embody these unusual electronic materials and soft packaging strategies are beginning to impact big data analysis, remote health monitoring, and transdermal drug delivery applications, by transitioning from primary research discoveries to commercial adoption.

Effect of Size and Surface Charge of Gold Nanoparticles on their Skin Permeability: A Molecular Dynamics Study

Molecular level understanding of permeation of nanoparticles through human skin establishes the basis for development of novel transdermal drug delivery systems and design and formulation of cosmetics. Recent experiments suggest that surface coated nano-sized gold nanoparticles (AuNPs) can penetrate the rat and human skin. However, the mechanisms by which these AuNPs penetrate are not well understood. In this study, we have carried out coarse grained molecular dynamics simulations to explore the permeation of dodecanethiol coated neutral hydrophobic AuNPs of different sizes (2–5 nm) and surface charges (cationic and anionic) through the model skin lipid membrane. The results indicate that the neutral hydrophobic AuNPs disrupted the bilayer and entered in it with in ~200 ns, while charged AuNPs were adsorbed on the bilayer headgroup. The permeation free energy calculation revealed that at the head group of the bilayer, a very small barrier existed for neutral hydrophobic AuNP while a free energy minimum was observed for charged AuNPs. The permeability was maximum for neutral 2 nm gold nanoparticle (AuNP) and minimum for 3 nm cationic AuNP. The obtained results are aligned with recent experimental findings. This study would be helpful in designing customized nanoparticles for cosmetic and transdermal drug delivery application.

Preparation of hollow out-of-plane hafnium oxide microneedle arrays for transdermal drug delivery

Due to the incapacity of many drugs to enter the skin at therapeutically useful rates, transdermal drug delivery with the advantages of controlled release, high safety and low degree of side effects is seriously hampered in efficiency and success. A microneedle approach can dramatically promote transdermal delivery, especially for macromolecules. In this paper, a fabrication process for hollow out-of-plane hafnium oxide microneedles on silicon wafer using only one mask has been developed. Photoresist is spun on a 4ź silicon (100) wafer and patterned by a mask. Deep reactive ion etching is used to form deep molds inside the wafer. A hafnium oxide film is deposited by atomic layer deposition to cover the top side of the wafer and the inside walls of the molds. Then the back side of silicon wafer is etched under the condition of 30 wt% KOH solution and a water-bath temperature of 81 °C until exposed hollow hafnium oxide microneedles are obtained. Compared to the processes that have been developed for silicon, silicon oxide, or polymer microneedles, the process presented here is simpler, and the strength and flexibility of hollow hafnium oxide microneedles can be easily adjusted by modifying the depositing time of hafnium oxide films. Hafnium oxide microneedles have potential applications in transdermal drug delivery.

Transdermal cellular membrane penetration of proteins with gold nanoparticles: a molecular dynamics study.

Transdermal delivery, where the skin acts as the route for local or systemic distribution, presents a lot of advantages over conventional routes such as oral and intravenous and intramuscular injections. However, the delivery of large biomolecules like proteins through the skin is challenging due to their size and structural properties. A molecular level understanding of their transport across the skin barrier is desirable to design successful formulations. We have employed constrained and unconstrained coarse grained molecular dynamics simulation techniques to obtain the molecular mechanism of penetration of the horseradish peroxidase (HRP) protein into the skin, in the presence and absence of gold nanoparticles (AuNPs). Unconstrained simulations show that HRP, when considered individually, was not able to breach the skin barrier, while in the presence of AuNPs, it first binds to the AuNPs and then breaches the barrier. The constrained simulations revealed that there was a free energy barrier for HRP to permeate inside the skin lipid layer when taken alone, while in the presence of gold nanoparticles, no barrier was found. Our study opens up the field of computational modeling based design of nanoparticle carriers for a given protein's transdermal delivery.

An ex situ approach to fabricating nanosilica reinforced polyacrylamide grafted guar gum nanocomposites as an efficient biomaterial for transdermal drug delivery application

A novel biocompatible TDDS based on nano-silica reinforced polyacrylamide grafted guar-gum nanocomposite.

Solid silicon microneedles for drug delivery applications

In this work, solid silicon (Si) microneedles with a higher aspect ratio and sharper tips are fabricated. Tetramethylammonium Hydroxide (TMAH) etching factors have been optimized and used to fabricate long and tapered microneedles. The needles thus fabricated are found to be suitable for transdermal drug delivery applications. The optimized etching factors include varying the concentration of TMAH, etching time, etching rates, temperature, and window size of optical mask. It is found that by increasing the window size, the etch rates in both vertical and lateral directions increase extensively. However, on increasing the temperature beyond 90 °C, etching becomes rapid and uncontrollable. In order to obtain microneedles with high aspect ratio, sample placement in the glass boat of TMAH setup and TMAH concentration should be manipulated to attain a higher etch rate in vertical direction compared to the lateral one. Solid silicon microneedles with an average height of 158 μm, base width of 110.5 μm, aspect ratio of 1.43, tip angle of 19.4° and tip diameter of 0.40 μm are successfully fabricated. A microhardness value of 44.4 (HRC) was obtained for the fabricated Si microneedles. This is 52.2 times higher than the skin Ultimate Tensile Strength (UTS), which makes insertion of microneedles through the skin safer and easier without any breakage.

Ultrasound-mediated transdermal drug delivery of fluorescent nanoparticles and hyaluronic acid into porcine skin in vitro**Project partially supported by the National Natural Science Foundation of China (Grant Nos. 81127901, 81227004, 81473692, 81673995, 11374155, 11574156, 11274170, 11274176, 11474001, 11474161, 11474166, and 11674173), the Natural Science Foundation of Jiangsu Province, China (Grant No. BK2011812), the Fundamental Research Funds for the Central Universities, and

Transdermal drug delivery (TDD) can effectively bypass the first-pass effect. In this paper, ultrasound-facilitated TDD on fresh porcine skin was studied under various acoustic parameters, including frequency, amplitude, and exposure time. The delivery of yellow–green fluorescent nanoparticles and high molecular weight hyaluronic acid (HA) in the skin samples was observed by laser confocal microscopy and ultraviolet spectrometry, respectively. The results showed that, with the application of ultrasound exposures, the permeability of the skin to these markers (e.g., their penetration depth and concentration) could be raised above its passive diffusion permeability. Moreover, ultrasound-facilitated TDD was also tested with/without the presence of ultrasound contrast agents (UCAs). When the ultrasound was applied without UCAs, low ultrasound frequency will give a better drug delivery effect than high frequency, but the penetration depth was less likely to exceed 200 μm. However, with the help of the ultrasound-induced microbubble cavitation effect, both the penetration depth and concentration in the skin were significantly enhanced even more. The best ultrasound-facilitated TDD could be achieved with a drug penetration depth of over 600 μm, and the penetration concentrations of fluorescent nanoparticles and HA increased up to about 4–5 folds. In order to get better understanding of ultrasound-facilitated TDD, scanning electron microscopy was used to examine the surface morphology of skin samples, which showed that the skin structure changed greatly under the treatment of ultrasound and UCA. The present work suggests that, for TDD applications (e.g., nanoparticle drug carriers, transdermal patches and cosmetics), protocols and methods presented in this paper are potentially useful.

Preparation and Characterization of Rivastigmine Transdermal Patch Based on Chitosan Microparticles.

Here we report a novel approach for preparation of a 6-day transdermal drug delivery system (TDDS) as treatment for mild to moderate Alzheimer's disease. The spray drying method was used to prepare microparticles containing the anti-Alzheimer drug, Rivastigmine, in combination with the natural polymer, chitosan, for transdermal drug delivery applications. The content of the drug was determined by High Performance Liquid Chromatography (HPLC) method which was validated as per FDA guidelines. The morphology and size range of the microparticles were determined; and the effect of drug concentration in the solution injected into the spray dryer on the particles characterizations was studied. The stability of Rivastigmine at high temperature was confirmed using FTIR analysis as well as a validate HPLC assay. The obtained results show that the drug was stable at high temperatures with 7 to 42% loading in the microparticles, and the higher drug concentrations of the solution injected into the spray dryer resulted in increase of the drug loading, surface drug and microparticles distortion. The TDDS containing the microparticles was also prepared with microparticle to dry adhesive ratios of 5, 10 and 15% using acrylic adhesive. Based on adhesion properties of the patches, gained from the probe tack and the peel adhesion 180° tests, and the 15% patch by having more drug content per unit area of the patch, and still having similar adhesion properties was compared to the microparticles-free patch of 5.1% Rivastigmine salt (equivalent to the drug content of the 15% patch) from the permeation point of view by using Franz cell diffusion over 6 days. The drug permeation rate from the microparticle-free patch was slower than the 15% microparticles patch, which is the result of crystallization of Rivastigmine salt in the acrylic adhesive. The 6-day-prepared TDDS can be considered as an alternative for one-week application of 6 Exelon patches.

Hollow Microneedle for Drug Delivery Applications to Improve Patient Compliance

In recent years, microfluidic Drug Delivery System (DDS) using microneedle have been given much attention as a novel way for transdermal drug delivery. In this paper, the orthogonal array design is applied for the first time to optimize the bevel tip hollow microneedle suitable for efficient transdermal drug delivery applications. An analytical model has been presented considering the puncture force and friction forces acting on the microneedle during insertion into the soft tissue. The stiffness coefficients are derived as a function of the internal behaviour of the microneedle. Based on these outcomes, an L16 orthogonal Taguchi experiment with two factors, each having four levels, has been utilized to determine the optimal microneedle tip angle (α0) and insertion force (F) for successful penetration of microneedle into the soft tissue during drug delivery. The output responses accounted for investigation are the stiffness coefficients, forces and moments acting on the microneedle, deflection, strain and contact stress. These output response variables must be optimal to avoid failure of microneedle and their effects are studied using Analysis of Variance (ANOVA) to determine the relationship between the levels and the responses. The Taguchi experiment performed using Signal-to-Noise Ratio suggests that microneedle tip angle of 10o and insertion force of 0.25N is optimal. The microneedle tip angle is found to be the most significant control factor for the robust design of hollow microneedle to obtain successful insertion of microneedle into the soft tissue during drug delivery applications.

Studies on methylcellulose/pectin/montmorillonite nanocomposite films and their application possibilities

Films based on methylcellulose (MC) and pectin (PEC) of different ratios were prepared. MC/PEC (90:10) (MP10) gave the best results in terms of mechanical properties. Sodium montmorillonite (MMT) (1, 3 and 5wt%) was incorporated in the MP10 matrix. The resulting films were characterized by X-ray diffraction and transmission electron microscopy, and it was found that nanocomposites were intercalated in nature. Mechanical studies established that addition of 3wt% MMT gave best results in terms of mechanical properties. However, thermo-gravimetric and dynamic mechanical analysis proved that decomposition and glass transition temperature increased with increasing MMT concentration from 1 to 5wt%. It was also observed that moisture absorption and water vapor permeability studies gave best result in the case of 3wt% MMT. Optical clarity of the nanocomposite films was not much affected with loading of MMT. In vitro drug release studies showed that MC/PEC/MMT based films can be used for controlled transdermal drug delivery applications.