Transdermal Drug Delivery Applications Research Articles

Development of a facile, versatile and scalable fabrication approach of solid, coated, and dissolving microneedle devices for transdermal drug delivery applications

Nowadays, microneedles as novel transdermal delivery systems are interested in scientists for biomedical applications. This work aims to present a Cascade Microneedle Molding Technique (CMMT) for the reusable fabrication of polydimethylsiloxane (PDMS) molds to produce microneedle devices. To produce a positive master mold from epoxy resin, a negative PDMS mold was first fabricated. PDMS can be molded, and microneedles can be fabricated using this epoxy mold in a scalable and cost-effective manner. These molds were used to manufacture solid, coated, and dissolving microneedles, which were characterized comprehensively. Microneedle morphology and geometry were evaluated using Scanning Electron Microscopy (SEM). The mechanical integrity and ability to insert the microneedle device into the skin were assessed using compression strength analysis and force-displacement measurements. Drug penetration through animal skin was evaluated for Rhodamine B (RhB) loaded microneedles. The depth of needle insertion was also visualized using histological analysis while the spatial distribution of released cargo was determined by using confocal microscopy. Taken together, CMMT offers a simple, rapid, cost-effective, and scalable method for mass-producing microneedles with remarkable properties compared to direct 3D printing or laser ablation.

Direct 3D printing of triple-responsive nanocomposite hydrogel microneedles for controllable drug delivery

Hydrogel microneedle patches have emerged as promising platforms for painless, minimally invasive, safe, and portable transdermal drug administration. However, the conventional mold-based fabrication processes and inherent single-functionality of such microneedles present significant hurdles to broader implementation. Herein, we have developed a novel approach utilizing a precursor solution of robust nanocomposite hydrogels to formulate photo-printable inks suitable for the direct 3D printing of high-precision, triple-responsive hydrogel microneedle patches through digital light processing (DLP) technology. The ink formulation comprises four functionally diverse monomers including 2-(dimethylamino)ethyl methacrylate, N-isopropylacrylamide, acrylic acid, and acrylamide, which were crosslinked by aluminum hydroxide nanoparticles (AH NPs) acting as both reinforcing agents and crosslinking centers. This results in the formation of a nanocomposite hydrogel characterized by exceptional mechanical strength, an essential attribute for the 3D printing of hydrogel microneeedle patches. Furthermore, this innovative 3D printing strategy facilitates facile customization of microneedle geometry and patch dimensions. As a proof-of-concept, we employed the fabricated hydrogel microneedles for transdermal delivery of bovine serum albumin (BSA). Importantly, these hydrogel microneedles displayed no cytotoxic effects and exhibited triple sensitivity to pH, temperature and glucose levels, thereby enabling more precise on-demand drug delivery. This study provides a universal method for the rapid fabrication of hydrogel microneedles with smart responsiveness for transdermal drug delivery applications.

Innovative freeze-drying technique in the fabrication of dissolving microneedle patch: Enhancing transdermal drug delivery efficiency.

Microneedle patch (MNP) has become a hot research topic in the field of transdermal drug delivery due to its ability to overcome the stratum corneum barrier. Among the various types of microneedles, dissolving microneedles represent one of the most promising transdermal delivery methods. However, the most used method for preparing dissolving microneedles, namely microfabrication, suffers from issues such as long drying time, susceptibility to humidity, and large batch-to-batch variability, which limit the development of dissolving microneedles. In this study, we report for the first time a method for preparing dissolving microneedles using freeze-drying technology. We screened substrates suitable for freeze-dried microneedle patch (FD-MNP) and used coating technology to enhance the mechanical strength of FD-MNP, allowing them to meet the requirements for skin penetration. We successfully prepared FD-MNP using hyaluronic acid as the substrate and insulin as the model drug. Scanning electron microscopy revealed that the microneedles had a porous structure. After coating, the mechanical strength of the microneedles was 0.61N/Needle, and skin penetration rate was 97%, with a penetration depth of 215μm. The tips of the FD-MNP dissolved completely within approximately 60s after skin penetration, which is much faster than conventional MNP (180s). In vitro transdermal experiments showed that the FD-MNP shortened the lag time for transdermal delivery of rhodamine 123 and insulin compared to conventional MNP, indicating a faster transdermal delivery rate. Pharmacological experiments showed that the FD-MNP lowered mouse blood glucose levels more effectively than conventional MNP, with a relative pharmacological availability of 96.59 ± 2.84%, higher than that of conventional MNP (84.34 ± 3.87%), P = 0.0095. After storage under 40℃ for two months, the insulin content within the FD-MNP remained high at 95.27 ± 4.46%, which was much higher than that of conventional MNP (58.73 ± 3.71%), P < 0.0001. In conclusion, freeze-drying technology is a highly valuable method for preparing dissolving microneedles with potential applications in transdermal drug delivery.

Application of Biomaterials in the Development of Hydrogel-Forming Microneedles Integrated with a Cyclodextrin Drug Reservoir for Improved Pharmacokinetic Profiles of Telmisartan.

Telmisartan (TEL) is a promising antihypertensive agent among other angiotensin receptor blockers. However, its oral application is limited by its poor water solubility. This study presents the successful utilization of biomaterial-based hydrogel-forming microneedles integrated with a direct compressed tablet reservoir (HFMN-DCT) for the transdermal delivery of telmisartan in the treatment of hypertension. The combination of PVP, PVA, and tartaric acid was used in the HFMN formulation. A range of cross-linking temperatures and times were employed to optimize the characteristics of the HFMN. The HFMN exhibited excellent swelling capacity, mechanical strength, and insertion properties. Additionally, the poorly soluble characteristic of TEL was improved by the inclusion complex formulation with β-cyclodextrin (βCD). Phase solubility analysis showed an Ap-type diagram, indicating a higher-order complex between TEL and βCD, with respect to βCD. A ratio of TEL:βCD of 1:4 mM demonstrates the highest solubility enhancement of TEL. The inclusion complex formation was confirmed by FTIR, XRD, DSC, and molecular docking studies. A significantly higher release of TEL (up to 20-fold) from the inclusion complex was observed in the in vitro release study. Subsequently, a DCT reservoir was developed using various concentrations of sodium starch glycolate. Essentially, both the HFMN and DCT reservoir exhibit hemocompatibility and did not induce any skin irritation. The optimized combination of the HFMN-DCT reservoir showed an ex vivo permeation profile of 83.275 ± 2.405%. Notably, the proposed system showed superior pharmacokinetic profiles in the in vivo investigation using male Wistar rats. Overall, this study highlights the potential of HFMN-DCT reservoir systems as a versatile platform for transdermal drug delivery applications.

Development of stretchable microneedle arrays via single-step digital light-processing printing for delivery of rhodamine B into skin tissue

This paper introduces a novel approach for loading and releasing Rhodamine B (RhB) into the skin using minimally-invasive microneedle technology developed through digital light-processing (DLP) printing. Notably, this process involves the direct 3D fabrication of rigid microneedle arrays affixed to a flexible patch, marking a pioneering application of DLP printing in this context. The stretchable and durable design of the microneedle substrate enables it to adapt to dynamic movements associated with human activities. Moreover, the microneedle features a pore on each side of the pyramid needle, effectively optimizing its drug-loading capabilities. Results indicate that the microneedle patch can withstand up to 50 % strain without failure and successfully penetrates rat skin. In vitro drug release profiles, conducted through artificial and rat skin, were observed over a 70 h period. This study establishes the potential of a simple manufacturing process for the creation of pore-designed microneedle arrays with a stretchable substrate, showcasing their viability in transdermal drug delivery applications.

3D Printing of Biodegradable Polymeric Microneedles for Transdermal Drug Delivery Applications.

Microneedle (MN) technology is an optimal choice for the delivery of drugs via the transdermal route, with a minimally invasive procedure. MN applications are varied from drug delivery, cosmetics, tissue engineering, vaccine delivery, and disease diagnostics. The MN is a biomedical device that offers many advantages including but not limited to a painless experience, being time-effective, and real-time sensing. This research implements additive manufacturing (AM) technology to fabricate MN arrays for advanced therapeutic applications. Stereolithography (SLA) was used to fabricate six MN designs with three aspect ratios. The MN array included conical-shaped 100 needles (10 × 10 needle) in each array. The microneedles were characterized using optical and scanning electron microscopy to evaluate the dimensional accuracy. Further, mechanical and insertion tests were performed to analyze the mechanical strength and skin penetration capabilities of the polymeric MN. MNs with higher aspect ratios had higher deformation characteristics suitable for penetration to deeper levels beyond the stratum corneum. MNs with both 0.3 mm and 0.4 mm base diameters displayed consistent force-displacement behavior during a skin-equivalent penetration test. This research establishes guidelines for fabricating polymeric MN for high-accuracy and low-cost 3D printing.

Moisture-cured solvent free silylated poly(ether-urea) pressure-sensitive adhesives (PSAs) for use as skin adhesives for application in transdermal drug delivery (TDD)

Improving the adhesion and tack of pressure-sensitive adhesives (PSAs) in the absence of tackifier resins or fillers remains an ongoing challenge.

Transdermal drug delivery using a porous microneedle device driven by a hydrogel electroosmotic pump.

Integrating a hydrogel electroosmotic pump with a parylene C-coated porous microneedle (PMN) is developed for transdermal drug delivery applications. The hydrogel pump is fabricated by combining an anionic and a cationic hydrogel to generate enhanced electroosmosis flow (EOF) to drive the transportation of molecules via PMN.

Ionic liquid microcapsules for the topical delivery of pterostilbene: Enhanced transdermal delivery and anti-wrinkle and skin brightening effects

Pterostilbene (PTB) is a hydrophobic compound derived from plants in the Astragalus family. PTB possesses remarkable skin brightening and antioxidant properties. However, delivery methods for PTB require enhancement, and this can be achieved by formulating suitable carriers. In this study, we prepared ionic liquid microcapsules containing PTB by using a microencapsulation technique based on a matrine and cocinic acid ([Mat][Coc]) ionic liquid. The particle size of the microcapsules was 154.5 ± 3.42 nm, and the encapsulation efficiency was as high as 99.7 %. Further, the PTB-loaded ionic liquid microcapsules had good biocompatibility, enhanced skin retention (7.7-times higher than that of free PTB), and improved skin penetration without damaging the skin structure. Clinical testing with human subjects revealed that the microcapsule emulsion reduced fine lines and brightened skin tone. Therefore, PTB-loaded ionic liquid microcapsules have promise for use in cosmetic formulations and applications in transdermal drug delivery and efficacy enhancement.

Probing the mechanism of release process from metal coordination-based acrylic pressure-sensitive adhesives: Synergistic effect of coordination and hydrogen bonding for controlled drug release

Hydrogen bonding, ionic interactions, and dipole–dipole interactions have been extensively studied to control drug release from patches. However, metal coordination bonding has not been fully explored for the control of transdermal drug release. In this study, metal coordination-based acrylic pressure-sensitive adhesives (PSAs) were designed and synthesized in order to systemically elucidate the effect of metal coordination on drug release from acrylic PSAs. Ketoprofen (KET) and donepezil (DNP) were selected as model drugs. Results showed that the burst release rate of KET was controlled by N-[tris(hydroxymethyl)methyl]acrylamide (NAT) and Fe3+, while the DNP release rate had no significant changes. It was found that the PSA-drug interaction, rather than the molecular mobility of PSA, played a dominant role in the controlled release process of KET. The hydrogen bond interaction between NAT and KET controlled the release process, while the coordination bond interaction between Fe3+ and KET further slowed down the release of KET. In conclusion, it was found that the controlled release of KET was achieved by the synergistic effect of coordination bonding and hydrogen bonding, which opens up a facile but powerful avenue for the design of brand-new controlled release systems and new opportunities for their application in transdermal drug delivery.

Rheological insights on Carboxymethyl cellulose hydrogels

Hydrogels are copiously studied for tissue engineering, drug delivery, and bone regeneration owing to their water content, mechanical strength, and elastic behaviour. The preparation of stable and mechanically strengthened hydrogels without using toxic crosslinkers and expensive approaches is immensely challenging. In this study, we prepared Carboxymethyl cellulose based hydrogels with different polymer concentration via a less expensive physical crosslinking approach without using any toxic crosslinkers and evaluated their mechanical strength. In this hydrogel system, the carbopol concentration was fixed at 1 wt/v% and the Carboxymethyl cellulose concentration was varied between 1 and 5 wt/v%. In this hydrogel system, Carbopol serves as the crosslinker to bridge Carboxymethyl cellulose polymer through hydrogen bonds. Rheological analysis was employed in assessing the mechanical properties of the prepared hydrogel, in particular, the viscoelastic behaviour of the hydrogels. The viscoelastic nature and mechanical strength of the hydrogels increased with an increase in the Carboxymethyl cellulose polymer concentration. Further, our results suggested that gels with Carboxymethyl cellulose concentration between 3 wt/v % and 4 wt/v % with yield stresses of 58.83 Pa and 81.47 Pa, respectively, are potential candidates for use in transdermal drug delivery. The prepared hydrogels possessed high thermal stability and retained their gel network structure even at 50 °C. These findings are beneficial for biomedical applications in transdermal drug delivery and tissue engineering owing to the biocompatibility, stability, and mechanical strength of the prepared hydrogels.

Design and analysis of a reservoir-based controllable microneedle for transdermal drug delivery applications.

Microneedle has made excellent contribution in the era of biomedical sector. This paper presents a reservoir-based out-of-plane silicon carbide (SiC) microneedle which has two lumens for delivering drug. The total height of the designed microneedle is 451µm where the conical tip area is about 69.39 µm2. The additional part of this microneedle is a reservoir which is trapezium in shape having a height of 150µm. This work use COMSOL Multiphysics software for the structural analysis and Ansys Workbench software to investigate the fluid analysis. The flow analyses are performed by releasing drugs from the reservoir where different viscosity based sample drugs are included. Although reservoir-based microneedles are existing, however, there is no system to control the fluid in those microneedles. Thus, this work proposes a controllable microneedle which able to control the drug flow by using a valve. For both the case of valveless and with a valve, the drug velocities are determined. As paracetamol has highest viscosity among other drugs, it provides lowest velocities. Conversely, the flow of aspirin shows high velocity of 6.51E-2m/s without a valve and 4.26E-2m/s with a valve. To analyze the skin insertion performance, a skin model including six layers is designed. The simulation results ensure that the proposed microneedle can penetrate the human skin successfully with less stress and deformation.

Formulation optimization, in vitro and in vivo evaluation of niosomal nanocarriers for enhanced topical delivery of cetirizine

Cetirizine hydrochloride (CTZ), a second-generation anti-histaminic drug, has been recently explored for its effectiveness in the treatment of alopecia. Niosomes are surfactant-based nanovesicular systems that have promising applications in both topical and transdermal drug delivery. The aim of this study was to design topical CTZ niosomes for management of alopecia. Thin film hydration technique was implemented for the fabrication of CTZ niosomes. The niosomes were examined for vesicle size, surface charge, and entrapment efficiency. The optimized niosomal formulation was incorporated into a hydrogel base (HPMC) and explored for physical characteristics, ex vivo permeation, and in vivo dermato-kinetic study. The optimized CTZ-loaded niosomal formulation showed an average size of 403.4 ± 15.6 nm, zeta potential of − 12.9 ± 1.7 mV, and entrapment efficiency percentage of 52.8 ± 1.9%. Compared to plain drug solution, entrapment of CTZ within niosomes significantly prolonged in vitro drug release up to 12 h. Most importantly, ex-vivo skin deposition studies and in vivo dermato-kinetic studies verified superior skin deposition/retention of CTZ from CTZ-loaded niosomal gels, compared to plain CTZ gel. CTZ-loaded niosomal gel permitted higher drug deposition percentage (19.2 ± 1.9%) and skin retention (AUC0-10h 1124.5 ± 87.9 μg/mL.h) of CTZ, compared to 7.52 ± 0.7% and 646.2 ± 44.6 μg/mL.h for plain CTZ gel, respectively. Collectively, niosomes might represent a promising carrier for the cutaneous delivery of cetirizine for the topical management of alopecia.

Exploration of curcumin-incorporated dual anionic alginate-quince seed gum films for transdermal drug delivery

The idea of combining bioextracted polymers for wound healing applications has emerged in hopes of developing highly flexible and mechanically stable hydrogel films with controlled drug delivery, biocompatibility, and high collagen deposition. In the present research, polysaccharide films composed of Alginate and Quince Seed Gum (QSG) were fabricated by ionic crosslinking, and their potential for curcumin delivery and wound healing were examined. In this regard, microstructure, mechanical properties, thermal stability, physiochemical properties, and biocompatibility of films with three different QSG amounts (25 %, 50 %, and 75 %) were studied. Because of the optimum properties of 25 % QSG films like better transparency (Opacity = 6.1 %), higher flexibility (Elongation = 28.9 %), less water solubility (Water solubility = 66.6 %), proper absorbance (Swelling degree = >600 %), and suitable biocompatibility (Cell viability = >85 %), they were used for drug delivery examination. Curcumin administration through films with and without stearic acid modification was investigated. Stearic Acid (SA) modified samples demonstrated superior compatibility between hydrophobic drug and hydrophilic film. Stearic acid-modified film could prolong the curcumin release up to 48 h and showed increased collagen synthesis and TGF-β expression, making it an excellent candidate for transdermal drug delivery and wound healing applications.

Effect of hollow microneedle geometry structure on mechanical stability and microfluidic flow for transdermal drug delivery applications

Effect of hollow microneedle geometry structure on mechanical stability and microfluidic flow for transdermal drug delivery applications

Current Advances in Lipid Nanosystems Intended for Topical and Transdermal Drug Delivery Applications.

Skin delivery is an exciting and challenging field. It is a promising approach for effective drug delivery due to its ease of administration, ease of handling, high flexibility, controlled release, prolonged therapeutic effect, adaptability, and many other advantages. The main associated challenge, however, is low skin permeability. The skin is a healthy barrier that serves as the body's primary defence mechanism against foreign particles. New advances in skin delivery (both topical and transdermal) depend on overcoming the challenges associated with drug molecule permeation and skin irritation. These limitations can be overcome by employing new approaches such as lipid nanosystems. Due to their advantages (such as easy scaling, low cost, and remarkable stability) these systems have attracted interest from the scientific community. However, for a successful formulation, several factors including particle size, surface charge, components, etc. have to be understood and controlled. This review provided a brief overview of the structure of the skin as well as the different pathways of nanoparticle penetration. In addition, the main factors influencing the penetration of nanoparticles have been highlighted. Applications of lipid nanosystems for dermal and transdermal delivery, as well as regulatory aspects, were critically discussed.

Modeling of Microneedle Arrays in Transdermal Drug Delivery Applications

The use of computational tools for the development of technologies in fields such as medicine and engineering has facilitated the process of designing new components and devices for these areas. In this work, two proposals focused on a hollow microneedle array (MNA) for the administration of an analgesic drug are shown and evaluated by means of a computational fluid dynamics (CFD) simulation distributed in three stages. In the first stage, the behavior of lidocaine through the MNA was evaluated as a workflow. Then, the possible entry of the drug into the organism, which was established as a porous aqueous medium, was modeled. Finally, a joint simulation was performed to understand the general behavior in the interaction between the outflow of an MNA and the body to which lidocaine is administered. The input parameters to the simulation were set at a velocity of 0.05 m∙s-1, at a pressure of 2000 Pa, the dominant behavior was defined as laminar flow, and a resistive pressure at the inlet of 400 Pa. Our results indicate that the vertical flow exhibits a better fluid distribution across the MNAs and favorable infiltration behavior, representing better delivery of the analgesic to the skin capillaries.

Biodegradable Mg Electrodes for Iontophoretic Transdermal Drug Delivery

Biodegradable metals have received limited attention for application in transdermal drug delivery, although metallic microneedles (MNs) and iontophoresis have been thoroughly researched for this purpose. Here, we present Mg as a salient candidate for an MN electrode. Its metallic properties enable the application of voltage to enhance the diffusion of charged drug molecules, while hydrogen gas generated during Mg corrosion prevents its application to electrodes. The Mg MN electrode was fabricated using a nanosecond laser, and the amount of hydrogen gas were measured with applied potential during iontophoresis. Accordingly, an appropriate potential window for iontophoresis was established based on the combined effect of enhanced drug diffusion by applied electric potential and impediment from hydrogen generation. The dye permeation tests of the Mg MN on the porcine skin demonstrated the combined effect of the Mg MN and iontophoresis. The dye migration decreased at higher voltages due to excess hydrogen generation and the corrosion of needle tips, both making the diffusion of charged dye molecules along the Mg MN surface harder. These results demonstrate optimal potential range of Mg MN electrodes for transdermal drug delivery with an electric field and bubble generation during iontophoresis.Graphical

Evaluation of design and insertion analysis of a conical shaped polymeric based microneedle for transdermal drug delivery applications

Transportation of drug through parental routes are conventionally followed through hypodermic injection methods, where hypodermic injections are administered into the human skin for drug release. However, there are some issues observed when these hypodermic needles are being used, there are instances where the needle is being inserted leaves some needle fractures in the skin. To cater to the issue scientific researchers are voraciously working on designing and developing polymeric type of microneedle structures for various medical diagnostic applications for glucose monitoring, drug delivery, and other applications. This article presents the structural design of a conicalshaped polymeric microneedle and the insertion force while being pierced into the skin. Simulations at different insertion angles on microneedle are analyzed by arriving with total needle displacements in the process of insertion. The von mises stress is also analyzed with applied force at different insertion angles resulted in incremental change in stress exerted by the microneedle. The resultant stress is below the yield stress which makes the microneedle pierce into the skin without breakage.

Synthesis of nanohybrid reinforced electrospun methylcellulose/ polyvinyl alcohol /polyethylene glycol nanofiber: study of material properties for possible biomedical applications

Over the past few epochs, emerging transdermal drug delivery systems (TDDSs) have gotten major devotion through incessant level of interest. The effort of this work is to understand the influence of nano-reinforcing agent on the morphology, property and its drug carrying capacity of the nanohybrid reinforced ketorolac tromethamine (KT) drug loaded electrospun nanofibrous web. In this study, cellulose nanocrystals (CNCs) extracted successfully from jute fibres (JF) and nanocollagen (NCG) was isolated from waste fish scales for the assembling of CNC-NCG reinforced MC/PVA/PEG electrospun nanofibrous bio-nanocomposites (BNCs) mat for transdermal drug delivery applications. The isolated nanoparticles (CNC & NCG) and the synthesized electrospun bio-nanocomposite were characterized by Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), Scanning electron microscopy (SEM), optical microscopy, Field emission scanning electron microscopy (FESEM).