Skin Insertion Research Articles

Highly stable and fast-dissolving ascorbic acid-loaded microneedles.

Ascorbic acid has many benefits to the skin. Numerous attempts to promote its topical delivery show great challenges since its chemical instability and poor skin impermeability. Microneedle delivery is a simple, safe, painless and effective means to deliver therapeutic or nourishing molecules into the skin. The purpose of this study was twofold: (a) to develop a new formulation of ascorbic acid-loaded microneedles to enhance ascorbic acid stability by investigating an optimal amount of polyethyleneimine as an additive to the dextran-based microneedle formulation and (b) to assess microneedle properties in terms of dissolving rate, skin penetration ability, biocompatibility and antimicrobial activity. The microneedles formulated with ascorbic acid and varied polyethyleneimine concentrations were fabricated and subsequently tested for ascorbic acid stability using 2,2-diphenyl-1-picrylhydrazyl assay. The dissolution rate and skin penetration depth were investigated in porcine skin and the reconstructed human full-thickness skin model respectively. The skin irritation tests were done according to the Organisation for Economic Co-operation and Development Test Guideline No. 439. An antimicrobial disc susceptibility test was performed against Escherichia coli, Staphylococcus aureus and Staphylococcus epidermidis. Among varied amounts of 0%, 1.5%, 3.0% and 4.5% (w/v), the 3.0% polyethyleneimine showed the most desirable characteristics, including well-preserved shape integrity after demoulding, significantly improved stability of ascorbic acid (p < 0.001) from 33% to 96% antioxidant activity after 8 weeks of storage at 40°C, increased dissolving rate (p < 0.001) by being completely dissolved within 2 min after the skin insertion, passing skin penetration and biocompatibility tests as well as having a broad spectrum of antimicrobial property. With a safety profile and enhanced properties, the new formulation of ascorbic acid-loaded microneedles shows outstanding potential as commercially available cosmetics and healthcare products.

Response Surface Methodology for Optimization of Hydrogel-Forming Microneedles as Rapid and Efficient Transdermal Microsampling Tools

Microneedles (MNs) have shown a great potential for the microsampling of dermal interstitial fluid (ISF) in a minimally invasive manner for point-of-care testing (POCT). The swelling properties of hydrogel-forming microneedles (MNs) allow for passive extraction of ISF. Surface response approaches, including Box-Behnken design (BBD), central composite design (CCD), and optimal discrete design, were employed for the optimization of hydrogel film by studying the effects of independent variables (i.e., the amount of hyaluronic acid, GantrezTM S-97, and pectin) on the swelling property. The optimal discrete model was selected to predict the appropriate variables, due to the good fit of the experimental data and the model validity. The analysis of variance (ANOVA) of the model demonstrated p-value < 0.0001, R2 = 0.9923, adjusted R2 = 0.9894, and predicted R2 = 0.9831. Finally, the predicted film formulation containing 2.75% w/w hyaluronic acid, 1.321% w/w GantrezTM S-97, and 1.246% w/w pectin was used for further fabrication of MNs (525.4 ± 3.8 µm height and 157.4 ± 2.0 µm base width), which possessed 1508.2 ± 66.2% swelling, with 124.6 ± 7.4 µL of collection volume, and could withstand thumb pressure. Moreover, almost 50% of MNs achieved a skin insertion depth of approx. 400 µm, with 71.8 ± 3.2% to 78.3 ± 2.6% recoveries. The developed MNs show a promising prospect in microsample collection, which would be beneficial for POCT.

Micro-pillar tunnel stamp for enhanced transdermal delivery of topical drug formulations.

Dissolving microneedles (DMNs), despite their minimally invasive drug administration, face challenges in skin insertion and drug-loading capacity, which lead to less effective drug delivery. The micro-pillar tunnel stamp (MPTS) was designed to enhance the transdermal delivery efficacy of externally provided topical formulations via the creation of microchannels. The tunnel and canal of the MPTS enable the simultaneous application of DMNs and topical drugs. The application of micro-pillar-polycaprolactone (MP-PCL), which is a DMN made of a slowly dissolving polymer, exhibited a drug permeation rate 1.3-fold and 2.6-fold higher than that of micro-pillar-hyaluronic acid (MP-HA), a DMN made of a rapidly dissolving polymer, and the topical group, respectively. The base diameter of MP-PCL was set to 700 μm for maximized delivery efficacy, achieving 2.8-fold higher L-ascorbic acid accumulation than that of the topical group. In vivo analysis showed that, compared to topical administration, MPTS-delivered lidocaine had 5-fold greater permeation and the MPTS-delivered group showed 1.25-fold higher skin residual amount, confirming enhanced delivery. Thus, the optimized MPTS system can be presented as an attractive alternative to overcome the limitations of the existing MN systems such as incomplete insertion and limited drug-loading capacity, enhancing the delivery of topical formulations in the transdermal market. STATEMENT OF SIGNIFICANCE: We developed a micro-pillar tunnel stamp (MPTS) to enhance the delivery of externally provided topical formulations. The functional tunnel and canal of the MPTS enabled the simultaneous application of a dissolving microneedle (DMN) array insertion and administration of external topical drugs. Upon insertion, the DMNs created skin microchannels that allowed the externally administered drug to diffuse. DMNs were fabricated using polycaprolactone (PCL), a slowly dissolving polymer, to maintain their structure inside the skin and prolong the opening duration of the microchannels. This system achieved significantly improved delivery of topically administered external drugs via integration with slowly dissolving DMNs, while offering the possibility of its development as a universal delivery system for various topical pharmaceuticals.

The eradication of biofilm for therapy of bacterial infected chronic wound based on pH-responsive micelle of antimicrobial peptide derived biodegradable microneedle patch

Chronic wound caused by bacterial biofilm infection is difficult to heal and has been regard as a medical challenge. Herein, a biodegradable drug-loaded microneedle (MN) patch is designed for biofilm eradication and chronic wound repair. The microneedle system is loaded with micelle (DPP@AC) formed by the self-assembly of pH-responsive tri-block polymer (DMA-PEI-PLGA, DPP) and Ce6-coupled antimicrobial peptide (AMP-Ce6, AC), the micelle is about 68 nm in size and can release the DMA group and present positive charge in an acidic environment, thereby significantly improving the specific targeting ability of the antimicrobial peptide to bacteria. In vitro experiment shows that the MIC90 value of DPP@AC against S. aureus under laser irradiation is less than 5 μM and can inhibit 90% of biofilm formation. In vivo experiment shows that the MNs are basically degraded after 10 min of skin insertion, and the MN patch loaded with DPP@AC is applied to the wound of S. aureus biofilm-infected diabetic mice and irradiated with laser, showing excellent antibacterial peptide and photodynamic synergistic antimicrobial effect, which completely heals the wound within 15 d and achieved synergistic biofilm eradication and subsequent cascade activation of wound healing. Both in vitro and in vivo experiments confirm the biosafety of the microneedle system. This microneedle-assisted antimicrobial therapy provides a highly effective strategy for the treatment of chronic wound with biofilm-associated infection.

Latch Applicator for Efficient Delivery of Dissolving Microneedles Based on Rapid Release of Elastic Strain Energy by Thumb Force (Adv. Funct. Mater. 11/2023)

Latch Applicator In article number 2210805, Hyungil Jung and co-workers develop a novel applicator that enables efficient skin insertion of dissolving microneedle patches with optimized force and velocity. It is cost-competitive with simple components and easy to use with the thumb-force operation. Using a model antigen, they show that the microneedle and applicator system can produce significantly higher antibodies than intramuscular injection.

Hybrid microneedle arrays for antibiotic and near-IR photothermal synergistic antimicrobial effect against Methicillin-Resistant Staphylococcus aureus

The rise of antibiotic-resistant skin and soft tissue infections (SSTIs) necessitates the development of novel treatments to improve the efficiency and delivery of antibiotics. The incorporation of photothermal agents such as plasmonic nanoparticles (NPs) improves the antibacterial efficiency of antibiotics through synergism with elevated temperatures. Hybrid microneedle (MN) arrays are promising local delivery platforms that enable co-therapy with therapeutic and photothermal agents. However, to-date, the majority of hybrid MNs have focused on the potential treatment of skin cancers, while suffering from the shortcoming of the intradermal release of photothermal agents. Here, we developed hybrid, two-layered MN arrays consisting of an outer water-soluble layer loaded with vancomycin (VAN) and an inner water-insoluble near-IR photothermal core. The photothermal core consists of flame-made plasmonic Au/SiO2 nanoaggregates and polymethylmethacrylate (PMMA). We analyzed the effect of the outer layer polymer, polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP), on MN morphology and performance. Hybrid MNs produced with 30 wt% PVA contain a highly drug-loaded outer shell allowing for the incorporation of VAN concentrations up to 100 mg g−1 and temperature increases up to 60 °C under near-IR irradiation while showing sufficient mechanical strength for skin insertion. Furthermore, we studied the combinatorial effect of VAN and heat on the growth inhibition of methicillin-resistant Staphylococcus aureus (MRSA) showing synergistic inhibition between VAN and heat above 55 °C for 10 min. Finally, we show that treatment with hybrid MN arrays can inhibit the growth of MRSA due to the synergistic interaction of heat with VAN reducing the bacterial survival by up to 80%. This proof-of-concept study demonstrates the potential of hybrid, two-layered MN arrays as a novel treatment option for MRSA-associated skin infections.

Design, analysis and fabrication of solid polymer microneedle patch using CO2 laser and polymer molding.

Microneedle-based transdermal drug delivery into the skin has gained attraction for the past few years. An affordable and effective fabrication methodology is required for the development of micron size needle. Manufacturing cost-effective microneedle patches in batch production is a challenging process. In this work, we proposed a cleanroom-free technique for fabrication of conical and pyramidal geometry of microneedle array for transdermal drug delivery. Using the COMSOL Multiphysics tool, the mechanical strength of the designed microneedle array under axial, bending, and buckling loads for the geometries during skin insertion was investigated. A CO2 laser and polymer molding technique are used to fabricate 10 × 10 designed microneedle array structure. On an acrylic sheet, a designed pattern is engraved to produce a 20mm × 20mm sharp conical and pyramidal shape master mold. We successfully created a biocompatible polydimethylsiloxane (PDMS) microneedle patch with an average height of 1200µm, base diameter of 650µm, and a tip diameter of 50µm using acrylic master mold. According to structural simulation analysis, the microneedle array will experience resultant stress that is within a safe range. The mechanical stability of the fabricated microneedle patch was investigated using hardness test and universal testing machine. The depth of penetration studies were performed in an in vitro Parafilm® M model by manual compression tests and its detailed insertion depth was reported. The developed master mold is efficient to replicate several polydimethylsiloxane microneedle patches. The proposed combined method of laser processing and molding mechanism is simple and low-cost for rapid prototyping of microneedle array.

Dissolvable Self-Locking Microneedle Patches Integrated with Immunomodulators for Cancer Immunotherapy.

Advancements in micro-resolution 3D printers have significantly facilitated the development of highly complex mass-producible drug delivery platforms. Conventionally, due to the limitations of micro-milling machineries, dissolvable microneedles (MNs) are mainly fabricated in cone-shaped geometry with limited drug delivery accuracy. Herein, to overcome the limitations of conventional MNs, a novel projection micro-stereolithography 3D printer-based self-locking MN for precise skin insertion, adhesion, and transcutaneous microdose drug delivery is presented. The geometry of self-locking MN consists of a sharp skin-penetrating tip, a wide skin interlocking body, and a narrow base with mechanical supports fabricated over a flexible hydrocolloid patch to improve the accuracy of skin penetration into irregular surfaces. Melanoma, a type of skin cancer, is selected as the model for the investigation of self-locking MNs due to its irregular and uneven surface. In vivo immunotherapy efficacy is evaluated by integrating SD-208, a novel transforming growth factor-β (TGF-β) inhibitor that suppresses the proliferation and metastasis of tumors, and anti-PD-L1 (aPD-L1 Ab), an immune checkpoint inhibitor that induces T cell-mediated tumor cell death, into self-locking MNs and comparing them with intratumoral injection. Evaluation of (aPD-L1 Ab)/SD-208 delivery effectiveness in B16F10 melanoma-bearing mice model confirms significantly improved dose efficacy of self-locking MNs compared with intratumoral injection.

Dissolving microneedle patch-assisted transdermal delivery of methotrexate improve the therapeutic efficacy of rheumatoid arthritis

Methotrexate (MTX) is a first-line treatment for rheumatoid arthritis (RA), but its clinical use is greatly limited by the adverse effects and poor patient compliance caused by traditional oral administration or injection. In recent years, some transdermal drug delivery systems have received considerable attention due to overcoming these shortcomings. In this study, we developed dissolving microneedle patch (DMNP) for transdermal delivery of MTX to treat RA safely and effectively. The morphology, mechanical strength, skin insertion, drug content, in vitro transdermal delivery, and other properties of DMNP were characterized. Meanwhile, the adjuvant-induced arthritis model of rats was established to investigate the therapeutic effect of MTX-loaded DMNP in vivo. The results showed that the microneedles had excellent morphology with neat array and complete needles, good puncture performance and mechanical strength, and rapid intradermal dissolution rate. In vitro transdermal delivery results indicated that microneedles could significantly increase drug transdermal permeation compared with the cream group. The pharmacological study showed that MTX-loaded DMNP significantly alleviated paw swelling, inhibit inflammatory response via downregulating the levels of TNF-α and IL-1β, relieved synovium destruction with less cartilage erosion, and slowed the progression of RA in AIA rats. Besides, DMNP presented better therapeutic performance than cream or intragastric administration at the same dosage of MTX. In conclusion, the MTX-loaded dissolving microneedle patch has advantages of safety, convenience, and high efficacy over conventional administrations, laying a foundation for the transdermal drug delivery system treatment of rheumatoid arthritis.

Experimental Validation of Diffraction Lithography for Fabrication of Solid Microneedles.

Microneedles are highly sought after for medicinal and cosmetic applications. However, the current manufacturing process for microneedles remains complicated, hindering its applicability to a broader variety of applications. As diffraction lithography has been recently reported as a simple method for fabricating solid microneedles, this paper presents the experimental validation of the use of ultraviolet light diffraction to control the liquid-to-solid transition of photosensitive resin to define the microneedle shape. The shapes of the resultant microneedles were investigated utilizing the primary experimental parameters including the photopattern size, ultraviolet light intensity, and the exposure time. Our fabrication results indicated that the fabricated microneedles became taller and larger in general when the experimental parameters were increased. Additionally, our investigation revealed four unique crosslinked resin morphologies during the first growth of the microneedle: microlens, first harmonic, first bell-tip, and second harmonic shapes. Additionally, by tilting the light exposure direction, a novel inclined microneedle array was fabricated for the first time. The fabricated microneedles were characterized with skin insertion and force-displacement tests. This experimental study enables the shapes and mechanical properties of the microneedles to be predicted in advance for mass production and wide practical use for biomedical or cosmetic applications.

A swellable bilateral microneedle patch with core-shell structure for rapid lactate analysis and early melanoma diagnosis

Lactate is an important biomarker in sport medicine and clinical care. Conventional methods for lactate detection mostly rely on blood withdrawing which usually causes much pain, significantly reducing patient compliance. Here, we design a bilateral core-shell microneedle (MN) patch for measuring lactate level in skin with improved compliance and accuracy. The shell layer can rapidly absorb sufficient interstitial fluid (ISF) upon skin insertion, while the core layer selectively reacts with lactate in ISF and subsequently shows two visible color changes within a short time. In rats, the colorimetric patch allows determination of lactate-level changes over time after intensive exercise, which shows excellent agreement with lactate variation in blood, indicating admirable accuracy and sensitivity of lactate sensing of the bilateral core-shell MN patch. Furthermore, the MN-based sensor can recognize the abnormally increased lactate level in melanoma mice at early stage and distinguish it from the normal lactate concentration in healthy mice without driving tumor growth, suggesting a great potential for early tumors diagnosis in clinics.

Design and Evaluation of Complex Polypeptide-Loaded Dissolving Microneedles for Improving Facial Wrinkles in Different Areas.

Wrinkles are one of the most intuitive manifestations of skin aging. Complex polypeptide-loaded dissolving microneedles (CP-DMNs) for facial wrinkles in different areas have been developed and evaluated for the first time. In optimizing formulations, we compared the differences in CP-DMNs heights on skin insertion depth and skin repair and healing. Furthermore, systemic safety experiments were carried out to provide a reference for clinical application. On this basis, an 84-day efficacy assessment based on the improvement of facial wrinkles in different areas and a comparison between CP-DMNs vs. placebo was performed on 30 healthy subjects. As a result, DMNs with a height of 300 μm presented sufficient strength to pierce the stratum corneum with minimized skin damage. In addition, CP-DMNs possessed excellent biological safety and skin compatibility for clinical application. Compared with placebo, CP-DMNs exhibited obvious improvements in wrinkles distributed in the corners of eyes, under-eyes, and nasolabial folds. Furthermore, after using CP-DMNs for 84 days, facial wrinkles in five different areas were smoothed. In short, the complex polypeptides showed apparent anti-wrinkle efficacy with the aid of DMNs technology, and CP-DMNs seemed to work better on deeper wrinkles, such as frown lines and nasolabial folds.

Dissolvable Carboxymethylcellulose Microneedles for Noninvasive and Rapid Administration of Diclofenac Sodium.

The aim of this study is to prepare dissolvable biopolymeric microneedle (MN) patches composed solely of sodium carboxymethylcellulose (CMC), a water-soluble cellulose derivative with good film-forming ability, by micromolding technology for the transdermal delivery of diclofenac sodium salt (DCF). The MNs with ≈456µm in height displayed adequate morphology, thermal stability up to 200 °C, and the required mechanical strength for skin insertion (>0.15 N needle-1 ). Experiments in ex vivo abdominal human skin demonstrate the insertion capability of the CMC_DCF MNs up to 401µm in depth. The dissolution of the patches in saline buffer results in a maximum cumulative release of 98% of diclofenac after 40min, and insertion in a skin simulant reveals that all MNs completely dissolve within 10min. Moreover, the MN patches are noncytotoxic toward human keratinocytes. These results suggest that the MN patches produced with CMC are promising biopolymeric systems for the rapid administration of DCF in a minimally invasive manner.

Hyaluronic acid microneedles loaded with curcumin nanodrugs and new indocyanine green inhibits human tongue squamous carcinoma cells in vitro.

To prepare the hyaluronic acid microneedle (abbreviated as microneedle) delivery system carrying curcumin nanodrugs (Cur-NDs) and photothermal trigger agent new indocyanine green (IR820), and to investigate its effect on proliferation of human tongue squamous carcinoma cells (Cal-27) in vitro. The microneedle delivery system carrying Cur-NDs and IR820 was prepared. The morphological characteristics of the microneedles were observed, and the mechanical strength test, skin insertion ability test and the photothermal test in vitro were performed. Cal-27 cells were treated with microneedles, Cur-NDs microneedles, IR820 microneedles, or Cur-NDs+IR820 microneedles in vitro, respectively. The IR820 microneedle group and Cur-NDs+IR820 microneedle group were irradiated with 808 nm near infrared light at 1 W/cm 2 for 5 min. The cell viability was tested with cell counting kit-8 method. The prepared microneedles had homogeneous needle-like morphology, good mechanical strength and skin piercing ability, among which the microneedles equipped with IR820 showed better photothermal performance. The survival rates of Cal-27 cells were 100.00% in blank control group, 99.92% in control microneedles group, 94.08% in Cur-NDs microneedles group, 0.41% in IR820 microneedles group, and 0.04% in Cur-NDs+IR820 microneedles group, respectively (all P<0.05). Compared with single drug treatment, Cur-NDs+IR820 microneedle shows better inhibitory effect on Cal-27 cell proliferation in vitro.

Transdermal delivery of colchicine using dissolvable microneedle arrays for the treatment of acute gout in a rat model

Colchicine (Col) is used to prevent and treat acute gout flare; however, its therapeutic use is strictly limited owing to severe gastrointestinal side effects after oral administration. Therefore, we developed a dissolvable Col-loaded microneedle (MN) with hyaluronic acid to deliver Col via the transdermal route. We studied the preparation, mechanical properties, skin insertion, skin irritation, drug content, and transdermal release of the Col-loaded MN. The pharmacokinetics of Col after Col-loaded MN application were compared with those of Col solution gavage over 24 h. Knee joint edema evaluation and the hindfoot mechanical threshold test were conducted to determine the pharmacodynamic profile. The dissolvable Col-loaded MN possessed sufficient mechanical strength to penetrate the skin and release the loaded drug. No skin irritation was observed for 3 days after application. We found that 3.36-fold more Col contained in MNs was delivered through the skin compared with that in gel in vitro, and moderate relative bioavailability in vivo. The Col-loaded MN significantly relieved swollen knee joints and mechanical hypernociception in an acute gout model in rats. The dissolvable Col-loaded MN array reduced inflammation and pain via topical administration when acute gout occurred. Reducing the gastrointestinal side effects of Col-loaded MNs is expected to optimize the therapeutic effects of Col and improve patient compliance.

Design, Development, and Testing of Polymeric Microblades: A Novel Design of Microneedles for Biomedical Applications

AbstractConventional microneedles (MNs) are designed as an array of micrometer‐sized projections that can painlessly penetrate the skin. Fabrication of MN arrays can be costly and time‐consuming; additionally, full penetration of an array of MNs with ten to thousands of projections into the skin may not be achievable. This paper reports a new design of MNs known as microblades (MBs) which consist of a singular microstructure. The single integrated design of the MBs reduces the fabrication cost and time, facilitates more effective penetration, and may pave the way for the scale‐up manufacturing of MN devices. Different designs of MBs are fabricated by two‐photon polymerization technique, followed by polydimethylsiloxane micromolding and soft embossing to create replicas. The mechanical integrity of the designs is determined by a series of compression tests. Skin insertion and drug diffusion studies are conducted using a custom‐made applicator to insert the MBs into the porcine abdominal skin to demonstrate delivery of fluorescein tracer. MBs insertion and penetration capabilities and the diffusion of a model drug into a multi‐layered human skin are demonstrated using finite element analysis and 3D diffusion models. The results demonstrate the functional capabilities of the MBs as an alternative to MN arrays.

(Digital Presentation) Fabrication and Characterization of C-MEMS Based 3-Dimensional Microelectrode Arrays for Cardiac Electrophysiological Studies

In-vitro examination of the electrical conduction characteristics and the beating of cardiomyocytes can be done using Microelectrode arrays(MEAs). The microelectrodes continuously monitor the electrical activity of the active cardiac cells on a microsecond timescale and presents a precise data based on that. Since the introduction of MEAs, many efforts have been made by scientists to evolve this technology by means of microfabrication. Previously, planar metallic electrodes were mostly used for this study but they could not penetrate the dead cells and reach the active cell layers. To overcome this, protruding 3-D microelectrodes were introduced that could puncture the dead tissues and reach the active cells for effective recording of cardiac electrical potentials.The characteristics of an electrode are defined by the characteristics of the material used to develop it. In this paper, we focus on the fabrication of cylindrical 3-dimensional Glassy Carbon microelectrode arrays (MEAs) for analyzing cell preparations from cardiac tissues. In order to improve the electrical properties of the commercially available electrodes, we have used a highly conductive material for fabrication. Glassy Carbon microelectrodes were fabricated by the pyrolysis of SU-8 microelectrodes which were developed by a standard lithographic process on Silicon wafer. The ohmic nature and high conductivity of Glassy Carbon makes it a suitable material to be implemented in electrophysiological studies. Further in our work, we have performed the theoretical and structural analysis using Comsol Multiphysics 5.2 considering different geometries of microelectrodes. The skin insertion force is calculated to be 0.012N, which is much lesser than the comprehensive force (15.38N), the maximum bending force (0.885N) and the maximum buckling force (3.28N) per cylindrical microelectrode. The maximum Von Mises stress (as shown in the figure) acting at the base where it is attached to the substrate is found out to be 6.56x106 N/m2 for each cylindrical microneedle. Among all the considered geometries, it can be concluded that the fabricated cylindrical microelectrodes penetrate successfully without breaking or bending and causing minimal damage to the cardiac tissues. The slanted tip microelectrode was also favored as it’s design makes it able to easily pierce the cardiac cell layers. However, the Maximum Von Mises stress distribution showed that the stress at the tip was much higher than the Yield strength of Glassy Carbon (4Gpa) making it evident that the tip might break while penetrating. With the theoretical and simulation analysis performed we were thus able to optimize the geometry and establish that Glassy Carbon proves to be a good material for fabrication of 3D microelectrode arrays. Figure 1

Investigation and Optimization of Hydrogel Microneedles for Transdermal Delivery of Caffeine.

Caffeine is therapeutically effective for treating apnea, cellulite formation, and pain management. It also exhibits neuroprotective and antioxidant activities in different models of Parkinson's disease and Alzheimer's disease. However, caffeine administration in a minimally invasive and sustainable manner through the transdermal route is challenging owing to its hydrophilic nature. Therefore, this study demonstrated a transdermal delivery approach for caffeine by utilizing hydrogel microneedle (MN) as a permeation enhancer. The influence of formulation parameters such as molecular weight (MW) of PMVE/MA (polymethyl vinyl ether/maleic anhydride) copolymer and sodium bicarbonate (NaHCO3) concentration on the swelling kinetics and mechanical integrity of the hydrogel MNs was investigated. In addition, the effect of different MN application methods and needle densities of hydrogel MN on the skin insertion efficiency and penetration depth was also evaluated. The swelling degree at equilibrium percentage (% Seq) recorded for hydrogels fabricated with Gantrez S-97 (MW = 1,500,000 Da) was significantly higher than formulation with Gantrez AN-139 (MW = 1,080,000 Da). Increasing the concentration of NaHCO3 also significantly increased the % Seq. Moreover, a 100% penetration was recorded for both the applicator and combination of applicator and thumb pressure compared with only 11% for thumb pressure alone. The average diameter of micropores created by the applicator method was 62.94 μm, which was significantly lower than the combination of both applicator and thumb pressure MN application (100.53 μm). Based on histological imaging, the penetration depth of hydrogel MN increased as the MN density per array decreased. The hydrogel MN with the optimized formulation and skin insertion parameters was tested for caffeine delivery in an in vitro Franz diffusion cell setup. Approximately 2.9 mg of caffeine was delivered within 24 h, and the drug release profile was best fitted to the Korsmeyer-Peppas model, displaying Super Case II kinetics. In conclusion, a combination of thumb and impact application methods and reduced needle density improved the skin penetration efficiency of hydrogel MNs. The results also show that hydrogel MNs fabricated from 3% w/w NaHCO3 and high MW of copolymer exhibit optimum physical and swelling properties for enhanced transdermal delivery.

Cyclosporine coated microneedle for transcutaneous delivery: Characterization, in vitro evaluation, and in vivo anti-psoriatic efficacy against IMQ-induced psoriasis

Cyclosporine (CsA) delivery causes liver and kidney toxicities in long-term oral use, and its injections are inconvenient for frequent administration in psoriatic patients. Therefore, we aimed to develop polyvinyl alcohol (PVA) microneedle (MNs) arrays for poke and release of cyclosporine transcutaneously for systemic effect against psoriasis-like inflammation. Microneedles were fabricated using the micro-molding-cum-solvent casting method, characterized for patch dimensions and strength. Prepared MNs evaluated for drug loading, in vitro release, skin permeation studies, and in vivo anti-psoriatic activity. MNs showed the desired mechanical strength and dimensions with 6.8 ± 0.29 mg drug coated on needles surface per patch. MNs showed slow moisture gain in humid conditions with good skin penetration strength (up to 630 μm). More than a 60% reduction in the needle length was observed within 30 min of skin insertion. MNs showed fast (87% in 60 min) drug release and efficient permeation through the skin layer 60 min post-insertion into porcine skin. The developed MNs showed a significant reduction in PASI scoring and pro-inflammatory cytokines levels and a remarkable reduction in the spleen size. It was found stable for 6 months in accelerated conditions. In conclusion, the developed MNs array could be an excellent alternative to the existing dosage forms that can deliver cyclosporine transdermally to the systemic circulation to treat psoriasis-like inflammation in long-term use.

Dual‐Mode Vasodilator M119 Delivery to Hair Follicle via Dissolving Microneedle for Advanced Alopecia Treatment

AbstractFinasteride, the most widely used oral alopecia drug, shows several side effects such as hypoactive sexual dysfunction or depression, whereas the topical drug minoxidil demonstrates unsatisfactory efficacy. Thus, there is an increasing need for new alopecia drugs and alternative delivery systems for future alopecia treatment. Researchers have developed dissolving microneedle (DMN), a transdermal drug delivery system, which can be used with minimal invasion. However, DMN has limited application for the alopecia treatment owing to its unsuccessful implantation on the hairy scalp. Here, it is suggested that TOP‐M119 (M119), a novel drug acting as a vasodilator in the scalp, and M119‐loaded DMN with a specially designed shape can be used for the alopecia treatment. This M119‐loaded DMN system is delivered using a newly designed applicator that supports patchless scalp implantation of DMN by microsized pillars designed to prevent accidental skin insertion. Enhanced hair follicle targeting drug delivery and superior alopecia treatment efficacy of specially designed shaped DMN and M119 has been demonstrated through in vitro and ex vivo studies. Moreover, M119‐loaded DMN system shows enhanced in vivo efficacy in mouse skin and through expression markers related to hair growth, such as β‐catenin, proliferating cell nuclear antigen, MECA 32, and versican.