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Background/Objectives: Indomethacin (IDM) is commonly used to treat chronic inflammatory diseases such as rheumatoid arthritis and osteoarthritis. However, long-term oral IDM treatment can harm the gastrointestinal tract. This study presents a design for encapsulating IDM within mixed micelles (MMs)-loaded dissolving microneedles (DMNs) to improve and sustain transdermal drug delivery. Methods: Indomethacin-loaded mixed micelles (IDM-MMs) were prepared from Soluplus® and Poloxamer F127 by means of a thin-film hydration method. The MMs-loaded DMNs were fabricated using a two-step molding method and evaluated for storage stability, insertion ability, in vitro release, in vitro transdermal penetration, and in vivo PK/PD studies. Results: The obtained MMs were stable at 4 °C and 30 °C for 60 days. The in vitro IDM transdermal penetration was remarkably improved by the MMs-loaded DMNs compared to a commercial patch. A pharmacokinetic study demonstrated that the MMs-loaded DMNs had a relative bioavailability of 4.1 in comparison with the commercial patch. Furthermore, the MMs-loaded DMNs showed a significantly shorter lag time than the commercial patch, as well as a more stable plasma concentration than the DMNs without MMs. The therapeutic efficacy of the IDM DMNs was examined in Complete Freund's Adjuvant-induced arthritis mice. The IDM DMN treatment effectively reduced arthritis severity, resulting in decreased paw swelling, arthritis index, spleen hyperplasia, and serum IL-1β and TNF-α levels. Conclusions: Our findings demonstrated that the novel MMs-loaded DMNs were an effective strategy for sustained IDM release, providing an alternate route of anti-inflammatory drug delivery. [ABSTRACT FROM AUTHOR]

Several drugs can be used for treating inflammatory skin pathologies like dermatitis and psoriasis. However, for the management of chronic and long-term cases, topical administration is preferred over oral delivery since it prevents certain issues due to systemic side effects from occurring. Cyclosporin A (CsA) has been used for this purpose; however, its high molecular weight (1202 Da) restricts the diffusion through the skin structure. Here, we developed a nano-in-micro device combining lipid vesicles (LVs) and dissolving microneedle array patches (DMAPs) for targeted skin delivery. CsA-LVs allowed the effective incorporation of CsA in the hydrophilic DMAP matrix despite the hydrophobicity of the drug. Polymeric matrix composed of poly (vinyl alcohol) (5% w/v), poly (vinyl pyrrolidine) (15% w/v) and CsA-LV dispersion (10% v/v) led to the formation of CsA-LVs@DMAPs with adequate mechanical properties to penetrate the stratum corneum barrier. The safety and biocompatibility were ensured in an in vitro viability test using HaCaT keratinocytes and L929 fibroblast cell lines. Ex vivo permeability studies in a Franz-diffusion cell setup showed effective drug retention in the skin structure. Finally, CsA-LVs@DMAPs were challenged in an in vivo murine model of delayed-type hypersensitivity to corroborate their potential to ameliorate skin inflammatory conditions. Different findings like photon emission reduction in bioluminescence study, normalisation of histological damage and decrease of inflammatory cytokines point out the effectivity of CsA-LVs@DMAPs to treat these conditions. Overall, our study demonstrates that CsA-LVs@DMAPs can downregulate the skin inflammatory environment which paves the way for their clinical translation and their use as an alternative to corticosteroid-based therapies. [ABSTRACT FROM AUTHOR]

Osteoporosis is a metabolic bone disorder with impaired bone microstructure and increased bone fractures, seriously affecting the quality of life of patients. Among various bisphosphonates prescribed for managing osteoporosis, minodronic acid (MA) is the most potent inhibitor of bone context resorption. However, oral MA tablet is the only commercialized dosage form that has extremely low bioavailability, severe adverse reactions, and poor patient compliance. To tackle these issues, we developed MA-loaded dissolving microneedles (MA-MNs) with significantly improved bioavailability for osteoporosis therapy. We investigated the influence of drug loading on the physicochemical properties, transdermal permeation behavior, and pharmacokinetics of MA-MNs. The drug loading of MA-MNs exerted almost no effect on their morphology, mechanical property, and skin insertion ability, but it compromised the transdermal permeability and bioavailability of MA-MNs. Compared with oral MA, MA-MNs with the lowest drug loading (224.9 μg/patch) showed a 9-fold and 25.8-fold increase in peak concentration and bioavailability, respectively. This may be ascribed to the reason that the increased drug loading can generate higher burst release, higher drug residual rate, and drug supersaturation effect in skin tissues, eventually limiting drug absorption into the systemic circulation. Moreover, MA-MNs prolonged the half-life of MA and provided more steady plasma drug concentrations than intravenously injected MA, which helps to reduce dosing frequency and side effects. Therefore, dissolving MNs with optimized drug loading provides a promising alternative for bisphosphonate drug delivery. [ABSTRACT FROM AUTHOR]

Inflammatory diseases of the skin have a considerable high prevalence worldwide and negatively impact the patients' quality of life. First-line standard therapies for these conditions inherently entail important side effects when used long-term, particularly complicating the management of chronic cases. Therefore, there is a need to develop novel therapeutic strategies to offer reliable alternative treatments. Abnormally high reactive oxygen species (ROS) levels are characteristic of this kind of illnesses, and therefore a reasonable therapeutic goal. Cyanocobalamin, also known as Vitamin B 12 , possesses notable antioxidant and ROS-scavenging properties which could make it a possible therapeutic alternative. However, its considerable molecular weight restricts passive diffusion through the skin and forces the use of an advanced transdermal delivery system. Here, we present several prototypes of Cyanocobalamin-loaded Dissolving Microarray Patches (B 12 @DMAPs) with adequate mechanical properties to effectively penetrate the stratum corneum barrier, allowing drug deposition into the skin structure. Ex vivo penetration and permeability studies noted an effective drug presence within the dermal skin layers; in vitro compatibility studies in representative cell skin cell lines such as L929 fibroblasts and HaCaT keratinocytes ensured their safe use. The in vivo efficacy of the selected prototype was tested in a delayed-type hypersensitivity murine model that mimics an inflammatory skin process. Several findings such as a reduction of MPO-related photon emission in a bioluminescence study, protection against histological damage, and decrease of inflammatory cytokines levels point out the effectivity of B 12 @DMAPs to downregulate the skin inflammatory environment. Overall, B 12 @DMAPs offer a cost-effective translational alternative for improving patients' skin healthcare. [Display omitted] • Mechanical properties of PVP/PVA DMAPs are optimal to overcome the stratum corneum ex vivo. • B 12 @DMAPs success to create a drug permeation through the skin ex vivo. • B 12 @DMAPs components do not cause toxic effects in vitro in skin cell lines. • The inflammation triggered in vivo by oxazolone exposition is diminished by B 12 @DMAPs. • No histopathological damage is observed once B 12 @DMAPs are applied. • Myeloperoxidase activity and pro-inflammatory cytokine levels are normalised by B 12 @DMAPs. [ABSTRACT FROM AUTHOR]

For the non-invasive treatment of rheumatoid arthritis (RA), a chondroitin sulfate C (CSC)-based dissolving microneedles (cMN) was prepared to deliver human adipose stem cell-derived extracellular vesicles (hASC-EV) into inflamed joints. Owing to their anti-inflammatory function, the hASC-EV-bearing cMN (EV@cMN) significantly suppressed activated fibroblast-like synoviocytes (aFLS) and M1 macrophages (M1), which are responsible for the progression of RA. In addition, EV@cMN facilitated the chondrogenic differentiation of bone marrow-derived stem cells. In mice with collagen-induced arthritis, EV@cMN efficiently delivered both hASC-EV and CSC to inflamed joints. Interestingly, pro-inflammatory cytokines in the inflamed joints were remarkably downregulated by the synergistic effect of CSC and hASC-EV. Consequently, as judged from the overall clinical score and joint swelling, EV@cMN showed an outstanding therapeutic effect, even comparable to the wild-type mice, without significant adverse effects. Overall, EV@cMN might have therapeutic potential for RA by efficiently delivering CSC and hASC-EV into the inflamed joints in a non-invasive manner. [Display omitted] • Macrophages and synoviocytes contribute significantly to the progression of rheumatoid arthritis. • Stem cell-derived extracellular vesicle (hASC-EV) inhibits M1 polarization of macrophages. • We discovered that chondroitin sulfate (CSC) reduces the invasiveness of synoviocytes. • Co-delivery of hASC-EV and CSC via microneedle effectively inhibits the progression of RA. [ABSTRACT FROM AUTHOR]

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 0.61 N/Needle, and skin penetration rate was 97%, with a penetration depth of 215 μm. The tips of the FD-MNP dissolved completely within approximately 60 s after skin penetration, which is much faster than conventional MNP (180 s). 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. [ABSTRACT FROM AUTHOR]

Introduction. Dissolving polymeric microneedles are attractive drug delivery system especially for vaccine delivery. Still there are a lot of obstacles in developing scalable manufacturing process of them.Aim. To develop a scalable manufacturing process for producing polymeric dissolving microneedles, which can enable keeping protein activity during manufacturing process.Materials and methods. Microneedles were produced from aqua solution of 20 % w.v. pullulan and 3 % w.v. polyvinyl alcohol by casting in hollow negative polyethylene terephthalate mold. Human serum albumin was chosen as a model protein for this investigation.Results and discussion. There were chosen the mode of mold filling and microneedle drying process, which can guarantee keeping of protein activity during manufacturing process.Conclusion. The designed technology can be easily scaled up and used for producing vaccine drug delivery systems, because it doesn’t contain any restraining processes.

Abstract Dissolving microneedles (DMNs) represent an innovative advancement in drug delivery and skincare technologies, offering significant advantages compared to traditional needles. This paper presents an overview of the historical evolution of microneedles and the rise of dissolving types, exploring their definition, concept, and diverse clinical applications such as vaccinations, drug delivery, and skincare treatments. Design and manufacturing considerations cover the materials employed, fabrication techniques, and methods for characterizing DMNs, focusing on aspects like mechanical strength, dissolution rate, and delivery efficiency. The mechanism of action section examines skin penetration mechanics, the process of microneedle dissolution, controlled release of active compounds, and considerations of biocompatibility and safety. Recent developments in DMNs encompass technological advancements, improved delivery systems, and updates on clinical trials and studies. Challenges and opportunities in scaling up production, overcoming market adoption barriers, and future research directions are discussed, aiming to address unmet medical needs and expand applications. In summary, DMNs have the potential to transform drug delivery and skincare treatments, with ongoing advancements aimed at tackling current challenges and unlocking new opportunities for enhanced healthcare outcomes. Graphical Abstract

Transdermal drug delivery using dissolving microneedles (DMNs) is promising due to increased patient compliance and safety. This article presents a comprehensive simulation and experimental analysis of DMNs with varying tip and base diameters and polymers. The objective of the simulation study is to identify the optimal tip and base diameter of DMNs, as well as the most suitable polymer, for achieving maximum penetration depth. The simulation results showed that the compound consisting of polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP) in a ratio of 2:1, with a tip radius of 17.5 μm and a base radius of 150 μm, achieved the deepest penetration among the different types of polymers investigated (including PVA, hyaluronic acid (HA), and PVA/PVP in ratios of 1:1 and 1:2). In addition, mechanical and skin penetration experiments were performed on PVA/PVP 2:1 DMNs with varying concentrations of 4, 7, 10, and 15% w/w to determine the optimal polymer concentration. The results of this study indicated that the optimal composition, considering the viscosity of the polymer solution and the simplicity of filling the silicone negative molds, is a PVA/PVP 2:1 with a concentration of 7% w/w. [ABSTRACT FROM AUTHOR]

Skin and soft-tissue infections require significant consideration because of their prolonged treatment duration and propensity to rapidly progress, resulting in severe complications. The primary challenge in their treatment stems from the involvement of drug-resistant microorganisms that can form impermeable biofilms, as well as the possibility of infection extending deep into tissues, thereby complicating drug delivery. Dissolving microneedle patches are an innovative transdermal drug-delivery system that effectively enhances drug penetration through the stratum corneum barrier, thereby increasing drug concentration at the site of infection. They offer highly efficient, safe, and patient-friendly alternatives to conventional topical formulations. This comprehensive review focuses on recent advances and emerging trends in dissolving-microneedle technology for antimicrobial skin-infection therapy. Conventional antibiotic microneedles are compared with those based on emerging antimicrobial agents, such as quorum-sensing inhibitors, antimicrobial peptides, and antimicrobial-matrix materials. The review also highlights the potential of innovative microneedles incorporating chemodynamic, nanoenzyme antimicrobial, photodynamic, and photothermal antibacterial therapies. This review explores the advantages of various antimicrobial therapies and emphasizes the potential of their combined application to improve the efficacy of microneedles. Finally, this review analyzes the druggability of different antimicrobial microneedles and discusses possible future developments. [ABSTRACT FROM AUTHOR]

Ferroptosis-mediated multimodal therapy has emerged as a promising strategy for tumor elimination, with lipid peroxide (LPO) playing a pivotal role. However, the therapeutic efficiency is limited due to insufficient intracellular levels of free fatty acids (FFA), which severely hinder the production of LPO. To address this limitation, we proposed a lipophagy strategy aimed at degrading lipid droplets (LDs) to release FFA, serving as the essential "fuel" for LPO production. In this study, the lipophagy inducer epigallocatechin gallate (EGCG) was self-assembled with reactive oxygen species (ROS)-producer phenethyl isothiocyanate (PEITC) mediated by Fe2+ to form EFP nanocapsules, which were further integrated into microneedle patches to form a "all-in-one" EFP@MNs. The metal-polyphenol network structure of EFP endow it with photothermal therapy capacity. Upon insertion into tumors, the released EFP nanocapsules were demonstrated to induce lipophagy through metabolic disturbance, thereby promoting LPO production and facilitating ferroptosis. When combined with photothermal therapy, this approach significantly remolded the tumor immune microenvironment by driving tumor-associated macrophages toward M1 phenotype and enhancing dendritic cell maturation. Encouragingly, in conjunction with αPD-L1 treatment, the proposed EFP@MNs exhibited remarkable efficacy in tumor ablation. Our study presents a versatile framework for utilizing microneedle patches to power ferroptosis-mediated multimodal therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Dissolving microneedles are extensively applied in drug delivery systems to enhance penetration into the skin. In this study, dissolving microneedles fabricated from polyvinylpyrrolidone K90 (PVP-K90) and hydroxypropylmethyl cellulose (HPMC) E50 in different ratios were characterized. The selected formulations incorporated Oryza sativa L. extract complex and its characteristics, transfollicular penetration, and safety were observed. The microneedles, fabricated from PVP K90: HPMC E50 in a ratio of 25:5 (P25H5) and 20:10 (P20H10), revealed excellent morphological structure, proper mechanical strength, and excellent skin insertion. P25H5 microneedles exhibited faster dissolution than P20H10 microneedles. Microneedles containing Oryza sativa L. extract complex showed excellent morphological structure via scanning electron microscopy but decreased mechanical strength. P25H5-O, which exhibited an effective ability to enter skin, was selected for further investigation. This microneedle formulation had a high percentage of drug-loading content, enhanced skin penetration via the transfollicular route, and was safe for keratinocytes. As a result, the dissolving microneedle containing Oryza sativa L. extract complex can be used to enhance transfollicular delivery through the skin with safety. [ABSTRACT FROM AUTHOR]

Dissolving microneedles (DMNs) represent an innovative advancement in drug delivery and skincare technologies, offering significant advantages compared to traditional needles. This paper presents an overview of the historical evolution of microneedles and the rise of dissolving types, exploring their definition, concept, and diverse clinical applications such as vaccinations, drug delivery, and skincare treatments. Design and manufacturing considerations cover the materials employed, fabrication techniques, and methods for characterizing DMNs, focusing on aspects like mechanical strength, dissolution rate, and delivery efficiency. The mechanism of action section examines skin penetration mechanics, the process of microneedle dissolution, controlled release of active compounds, and considerations of biocompatibility and safety. Recent developments in DMNs encompass technological advancements, improved delivery systems, and updates on clinical trials and studies. Challenges and opportunities in scaling up production, overcoming market adoption barriers, and future research directions are discussed, aiming to address unmet medical needs and expand applications. In summary, DMNs have the potential to transform drug delivery and skincare treatments, with ongoing advancements aimed at tackling current challenges and unlocking new opportunities for enhanced healthcare outcomes. [ABSTRACT FROM AUTHOR]

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Objective: The objective of the present study was to enhance the bioavailability of cannabidiol (CBD) using 3D Digital Light Processing (DLP)-printed microneedle (MN) transdermal drug delivery system. Methods: CBD MN patch was fabricated and optimized using 3D DLP printing using CBD (8% w/v), Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) (0.49% w/v), distilled water (20% w/v), and poly (ethylene glycol) dimethacrylate 550 (PEGDAMA 550) (up to 100% w/v). CBD MNs were characterized for their morphology, mechanical strength, in vitro release study, ex vivo permeation study, and in vivo pharmacokinetic (PK) profile. Key findings: Microscopic images showed that sharp CBD MNs with a height of ~800 μm, base diameter of ~250 μm, and tip with a radius of curvature (RoC) of ~15 μm were successfully printed using optimized printing parameters. Mechanical strength studies showed no significant deformation in the morphology of CBD MNs even after applying 0.5N/needle force. Ex vivo permeation study showed significant (P <.0001) permeation of CBD in the receiving media as compared to CBD patch (control). In vivo PK study showed significantly (P <.05) enhanced bioavailability in the case of CBD MN patch as compared to CBD subcutaneous inj. (control). Conclusion: Overall, systemic absorption of CBD was significantly enhanced using 3D-printed MN drug delivery system. Graphical Abstract [ABSTRACT FROM AUTHOR]

Fluconazole (FLZ) has been widely used in the treatment of infection caused by Candida albicans, including the treatment of vulvovaginal candidiasis (VVC). However, when delivered orally, FLZ faces numerous limitations due to its poor solubility and undergoes the symptoms of first-pass metabolism. In this study, we developed the combinatorial approach of nanocrystals (NCs) and dissolving microneedles (DMNs) for effective local vaginal delivery of FLZ. The formulation containing 1.0% w/v PVA as stabilizer with 12 h of milling time process was found to be an optimal combination to fabricate FLZ as NCs (FLZ-NCs) with optimum size particle and PDI value (less than 0.25). Furthermore, the in vitro release study also showed a superior percentage of FLZ release up to 89.51 ± 7.52%. In combination with the DMNs, the FLZ recovery was 96.45 ± 2.38% with the insertion percentage in average of 76.14 ± 2.28% and height decreased percentage was only 7.53 ± 0.56%. Moreover, the ex vivo investigation and anti-candidiasis activity of DMNs-FLZ-NCs in vaginal model showed better results compared to other conventional preparations, such as film patch and hydrogel containing FLZ. [ABSTRACT FROM AUTHOR]

Minoxidil (MIN) is used topically to treat alopecia. However, its low absorption limits its use, warranting a new strategy to enhance its delivery into skin layers. The objective of this study was to evaluate the dermal delivery of MIN by utilizing dissolved microneedles (MNs) loaded with MIN nanosuspension (MIN-NS) for hair regrowth. MIN-NS was prepared by the solvent-antisolvent precipitation technique. The particle size of MIN-NS was 226.7 ± 9.3 nm with a polydispersity index of 0.29 ± 0.17 and a zeta potential of −29.97 ± 1.23 mV. An optimized formulation of MIN-NS was selected, freeze-dried, and loaded into MNs fabricated with sodium carboxymethyl cellulose (Na CMC) polymeric solutions (MIN-NS-loaded MNs). MNs were evaluated for morphology, dissolution rate, skin insertion, drug content, mechanical properties, ex vivo permeation, in vivo, and stability studies. MNs, prepared with 14% Na CMC, were able to withstand a compression force of 32 N for 30 s, penetrate Parafilm M® sheet at a depth of 374–504 µm, and dissolve completely in the skin within 30 min with MIN %recovery of 95.1 ± 6.5%. The release of MIN from MIN-NS-loaded MNs was controlled for 24 h. MIN-NS-loaded MNs were able to maintain their mechanical properties and chemical stability for 4 weeks, when kept at different storage conditions. The in vivo study of the freeze-dried MIN-NS and MIN-NS-loaded MNs proved hair regrowth on rat skin after 11 and 7 days, respectively. These results showed that MIN-NS-loaded MNs could potentially improve the dermal delivery of MIN through the skin to treat alopecia. [ABSTRACT FROM AUTHOR]

Immunogenic cell death (ICD) is associated with the release of damage-associated molecular patterns, including ATP, to promote an effective immune cycle against tumors. However, tumors have evolved an effective strategy for degrading extracellular immunostimulatory ATP via the ATP-adenosine axis, allowing the sequential action of the ectonucleotidases CD39 to degrade accumulated immunostimulatory ATP into pleiotropic immunosuppressive adenosine. Here, an ingenious dissolving microneedle patch (DMNs) is designed for the intralesional delivery of CD39 inhibitor (sodium polyoxotungstate, POM-1) and ICD inducer (IR780) co-encapsulated solid lipid nanoparticles (P/I SLNs) for antitumor therapy. Upon insertion into the tumor site, IR780 induces ICD modalities with the release of damage-associated molecular patterns from endogenous tissues, which activates the antitumor immune cycle. Simultaneously, POM-1 promotes the liberation of immunostimulatory ATP and lowers the level of immunosuppressive extracellular adenosine, which supported immune control of tumors via recruiting CD39-expressing immune cells. In vivo antitumor studies prove that this platform can effectively eliminate mice melanoma (tumor growth inhibitory rate of 96.5%) and colorectal adenocarcinoma (tumor growth inhibitory rate of 93.5%). Our results shed light on the immunological aspects of combinatorial phototherapy and ATP-adenosine regulation, which will broaden the scope of synergistic antitumor immunotherapy. [Display omitted] • CD39 blockade was utilized to strengthen the effect of photoimmunotherapy by regulating the ATP-adenosine axis. • An ingenious dissolving microneedle patch was designed for the intralesional delivery of CD39 blockade and immunogenic cell death inducer co-encapsulated solid lipid nanoparticles. • This system aroused a robust immune response against B16 and MC38 tumors via suppressing the CD39 expression on the surface of relevant immune cells and subsequently inducing DCs maturation, boosting antigen-specific lymphocytes infiltration, and reversing macrophages polarization. [ABSTRACT FROM AUTHOR]

Microneedles (MNs) offer a promising solution for increasing the effectiveness of transdermal drug delivery and diagnostics. However, challenges such as large‐scale manufacturing, partial MN penetration, and uncontrolled drug delivery limit the effectiveness of the technology. To overcome these challenges, current research examines the effects of skin strain and vibration on MN insertion and drug delivery. A novel multifeatured impact applicator are developed for improving skin insertion that features a combination of skin stretching, eccentric rotating mass (ERM), and linear resonant actuator (LRA) micro‐vibration capabilities. In addition, a scalable replication method for dissolving microneedle patches (DMNPs) are developed using two‐photon polymerization (TPP) and soft embossing processes. The DMNPs are used to evaluate the diffusion and concentration of a model drug, fluorescein sodium salt (FSS), when applied using ERM and LRA micro‐vibration at different frequencies. Additionally, a new computer simulation method is presented to model the MN insertion into the multilayered hyperelastic skin model, incorporating skin strain and vibrational effects. The results indicate that applying skin strain and vibration decreases the force required for MN insertion and enhances the dissolution and diffusion depth of the drug in the skin, which can enhance the drug permeability and effectiveness of MN devices. [ABSTRACT FROM AUTHOR]

Three-dimensional (3D) printing can be used to fabricate custom microneedle (MN) patches instead of the conventional method. In this work, 3D-printed MN patches were utilized to fabricate a MN mold, and the mold was used to prepare dissolving MNs for topical lidocaine HCl (L) delivery through the skin. Topical creams usually take 1–2 h to induce an anesthetic effect, so the delivery of lidocaine HCl from dissolving MNs can allow for a therapeutic effect to be reached faster than with a topical cream. The dissolving-MN-patch-incorporated lidocaine HCl was constructed from hydroxypropyl methylcellulose (HPMC; H) and polyvinyl pyrrolidone (PVP K90; P) using centrifugation. Additionally, the morphology, mechanical property, skin insertion, dissolving behavior, drug-loading content, drug release of MNs and the chemical interactions among the compositions were also examined. H51P2-L, H501P2-L, and H901P2-L showed an acceptable needle appearance without bent tips or a broken structure, and they had a low % height change (<10%), including a high blue-dot percentage on the skin (>80%). These three formulations exhibited a drug-loading content approaching 100%. Importantly, the composition-dependent dissolving abilities of MNs were revealed. Containing the lowest amount of HPMC in its formulation, H901P2-L showed the fastest dissolving ability, which was related to the high amount of lidocaine HCl released through the skin. Moreover, the results of an FTIR analysis showed no chemical interactions among the two polymers and lidocaine HCl. As a result, HPMC/PVP K90 dissolving microneedles can be used to deliver lidocaine HCl through the skin, resulting in a faster onset of anesthetic action. [ABSTRACT FROM AUTHOR]

Dissolving microneedles (MNs) are novel transdermal drug delivery systems that can be painlessly self-administered. This study investigated the effects of experimental conditions on the mechanical characterization of dissolving MNs for quality evaluation. Micromolding was used to fabricate polyvinyl alcohol (PVA)-based dissolving MN patches with eight different cone-shaped geometries. Axial force mechanical characterization test conditions, in terms of compression speed and the number of compression needles per test, significantly affected the needle fracture force of dissolving MNs. Characterization using selected test conditions clearly showed differences in the needle fracture force of dissolving MNs prepared under various conditions. PVA-based MNs were divided into two groups that showed buckling and unbuckling deformation, which occurred at aspect ratios (needle height/base diameter) of 2.8 and 1.8, respectively. The needle fracture force of PVA-based MNs was negatively correlated with an increase in the needle's aspect ratio. Higher residual water or higher loading of lidocaine hydrochloride significantly decreased the needle fracture force. Therefore, setting appropriate methods and parameters for characterizing the mechanical properties of dissolving MNs should contribute to the development and supply of appropriate products. [ABSTRACT FROM AUTHOR]

Conventional transnasal brain-targeted drug delivery strategies are limited by nasal cilia clearance and the nasal mucosal barrier. To address this challenge, we designed dissolving microneedles combined with nanocarriers for enhanced nose-to-brain drug delivery. To facilitate transnasal administration, a toothbrush-like microneedle patch was fabricated with hyaluronic acid-formed microneedles and tannic acid-crosslinked gelatin as the base, which completely dissolved in the nasal mucosa within seconds leaving only the base, thereby releasing the loaded cyclodextrin-based metal-organic frameworks (CD-MOFs) without affecting the nasal cilia and nasal microbial communities. As nanocarriers for high loading of huperzine A, these potassium-structured CD-MOFs, reinforced with stigmasterol and functionalized with lactoferrin, possessed improved physical stability and excellent biocompatibility, enabling efficient brain-targeted drug delivery. This delivery system substantially attenuated H 2 O 2 - and scopolamine-induced neurocyte damage. The efficacy of huperzine A on scopolamine- and D-galactose & AlCl 3 -induced memory deficits in rats was significantly improved, as evidenced by inhibiting acetylcholinesterase activity, alleviating oxidative stress damage in the brain, and improving learning function, meanwhile activating extracellular regulated protein kinases-cyclic AMP responsive element binding protein-brain derived neurotrophic factor pathway. Moreover, postsynaptic density protein PSD-95, which interacts with two important therapeutic targets Tau and β-amyloid in Alzheimer's disease, was upregulated. This fruitful treatment was further shown to significantly ameliorate Tau hyperphosphorylation and decrease β-amyloid by ways including modulating beta-site amyloid precursor protein cleaving enzyme 1 and a disintegrin and metalloproteinase 10. Collectively, such a newly developed strategy breaks the impasse for efficient drug delivery to the brain, and the potential therapeutic role of huperzine A for Alzheimer's disease is further illustrated. [Display omitted] • Lactoferrin-functionalized stigmasterol-reinforced CD-MOFs were developed for brain-targeting drug delivery. • Microneedles-mediated nose-to-brain drug delivery strategy were demonstrated. • Huperzine A improved memory deficits via regulating ERK-CREB-BDNF, PSD-95/Tau, and Aβ-BACE1-ADAM10 pathways. [ABSTRACT FROM AUTHOR]

Peng Guo,1,&ast; Chi Huang,2,&ast; Qin Yang,1 Guofeng Zhong,1 Junbo Zhang,1 Mengyu Qiu,1 Rui Zeng,3 Kaijun Gou,3 Chen Zhang,1 Yan Qu1 1State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People’s Republic of China; 2Department of Pharmacy, Jiang’an Hospital of Traditional Chinese Medicine, Yibin, 644200, People’s Republic of China; 3Institute of Tibetan Plateau, Southwest Minzu University, Chengdu, 610225, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Qu; Chen Zhang, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, People’s Republic of China, Email quyan028@126.com; chenzhang_1990@126.comAbstract: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic joint inflammation, eventually leading to severe disability and premature death. At present, the treatment of RA is mainly to reduce inflammation, swelling, and pain. Commonly used drugs are non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and disease-modifying anti-rheumatic drugs (DMARDs). These drugs lack specificity and require long-term, high-dose administration, which can cause serious adverse effects. In addition, the oral, intravenous, and intra-articular injections will reduce patient compliance, resulting in high cost and low bioavailability. Due to these limitations, microneedles (MNs) have emerged as a new strategy to efficiently localize the drugs in inflamed joints for the treatment of RA. MNs can overcome the cuticle barrier of the skin without stimulating nerves and blood vessels. Which can increase patient compliance, improve bioavailability, and avoid systemic circulation. This review summarizes and evaluates the application of MNs in RA, especially dissolving MNs (DMNs). We encourage the use of MNs to treat RA, by describing the general properties of MNs, materials, preparation technology, drug release mechanism, and advantages. Furthermore, we discussed the biological safety, development prospects, and future challenges of MNs, hoping to provide a new strategy for the treatment of RA. Keywords: rheumatoid arthritis, dissolving microneedles, transdermal delivery system, degradability, biosafety

In this study, a dosage form consisting of dissolving (D) microneedles (M) and an adhesive (A) transdermal patch (P; DMAP) was designed and pre-clinically evaluated for the treatment of rheumatoid arthritis (RA). The tip of the dissolving microneedles (DMNs) was loaded with the macromolecular drug melittin (Mel@DMNs), this to treat joint inflammation and bone damage, while the adhesive transdermal patches contained the low molecular weight drug diclofenac sodium (DS; DS@AP) for pain relief. Mel@DMNs and DS@AP were ingeniously connected through an isolation layer for compounding Mel-DS@DMAP for the simultaneous delivery of the drugs. In vitro and in vivo experiments showed that DS@AP did not affect the mechanical properties and dissolution process of Mel@DMNs while the pores formed by the microneedles promoted the skin penetration of DS. Treatment of rats suffering from RA with Mel-DS@DMAP reduced paw swelling and damage of the synovium, joint and cartilage, suggesting that the 'patch-microneedle' dosage form might be promising for the treatment and management of RA. [Display omitted] [ABSTRACT FROM AUTHOR]

Conventional treatments for tumors were frequently accompanied by drawbacks and side effects. It might be useful to use the revolutionary microneedle technology which combines photothermal therapy with tumor immunotherapy. In this study, we created a microneedle drug delivery system with mercapto-modified gold nanorods and immune checkpoint blocker anti-PD-1 polypeptide. With good mechanical strength, the microneedle system can efficiently penetrate the skin and deliver drugs. When inserted into human skin, anti-PD-1 peptides and gold nanorods can be released, boosting the capacity of cytotoxic T lymphocytes to destroy tumor cells. Additionally, the elimination of the tumor is aided by the production of heat while being exposed to near-infrared light. This microneedle drug delivery system can enhance the immunological reaction and prolong the survival time of mice. Moreover, it has been demonstrated that the system has mild toxic and side effects on normal tissues and can effectively inhibit the growth of tumors, indicating a bright prospect for the treatment of cancers. [ABSTRACT FROM AUTHOR]

Proteins and peptides are rapidly developing pharmaceutical products and are expected to continue growing in the future. However, due to their nature, their delivery is often limited to injection, with drawbacks such as pain and needle waste. To overcome these limitations, microneedles technology is developed to deliver protein and peptide drugs through the skin. One type of microneedles, known as dissolving microneedles, has been extensively studied for delivering various proteins and peptides, including ovalbumin, insulin, bovine serum albumin, polymyxin B, vancomycin, and bevacizumab. This article discusses polymer materials used for fabricating dissolving microneedles, which are poly(vinylpyrrolidone), hyaluronic acid, poly(vinyl alcohol), carboxymethylcellulose, GantrezTM, as well as other biopolymers like pullulan and ulvan. The paper is focused solely on solvent casting micromoulding method for fabricating dissolving microneedles containing proteins and peptides, which will be divided into one-step and two-step casting micromoulding. Additionally, future considerations in the market plan for dissolving microneedles are discussed in this article. [ABSTRACT FROM AUTHOR]

Abstract Background Conventional dissolving microneedles (DMNs) face significant challenges in anti-melanoma therapy due to the lack of active thrust to achieve efficient transdermal drug delivery and intra-tumoral penetration. Methods In this study, the effervescent cannabidiol solid dispersion-doped dissolving microneedles (Ef/CBD-SD@DMNs) composed of the combined effervescent components (CaCO3 & NaHCO3) and CBD-based solid dispersion (CBD-SD) were facilely fabricated by the “one-step micro-molding” method for boosted transdermal and tumoral delivery of cannabidiol (CBD). Results Upon pressing into the skin, Ef/CBD-SD@DMNs rapidly produce CO2 bubbles through proton elimination, significantly enhancing the skin permeation and tumoral penetration of CBD. Once reaching the tumors, Ef/CBD-SD@DMNs can activate transient receptor potential vanilloid 1 (TRPV1) to increase Ca2+ influx and inhibit the downstream NFATc1-ATF3 signal to induce cell apoptosis. Additionally, Ef/CBD-SD@DMNs raise intra-tumoral pH environment to trigger the engineering of the tumor microenvironment (TME), including the M1 polarization of tumor-associated macrophages (TAMs) and increase of T cells infiltration. The introduction of Ca2+ can not only amplify the effervescent effect but also provide sufficient Ca2+ with CBD to potentiate the anti-melanoma efficacy. Such a “one stone, two birds” strategy combines the advantages of effervescent effects on transdermal delivery and TME regulation, creating favorable therapeutic conditions for CBD to obtain stronger inhibition of melanoma growth in vitro and in vivo. Conclusions This study holds promising potential in the transdermal delivery of CBD for melanoma therapy and offers a facile tool for transdermal therapies of skin tumors.

In recent years, microneedle technology has been widely used for the transdermal delivery of substances, showing improvements in drug delivery effects with the advantages of minimally invasive, painless, and convenient operation. With the development of nano- and electrochemical technology, different types of microneedles are increasingly being used in other biomedical fields. Recent research progress shows that dissolving microneedles have achieved remarkable results in the fields of dermatological treatment, disease diagnosis and monitoring, and vaccine delivery, and they have a wide range of application prospects in various biomedical fields, showing their great potential as a form of clinical treatment. This review mainly focuses on dissolving microneedles, summarizing the latest research progress in various biomedical fields, providing inspiration for the subsequent intelligent and commercial development of dissolving microneedles, and providing better solutions for clinical treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] Vulvovaginal candidiasis (VVC) is a vaginal infection caused by abnormal growth of Candida sp., especially Candida albicans , in the vaginal mucosa. A shift in vaginal microbiota is prominent in VVC. The presence of Lactobacillus plays a vital role in maintaining vaginal health. However, several studies have reported resistance of Candida sp. against azoles drugs, which is recommended as VVC treatment. The use of L. plantarum as a probiotic would be an alternative to treat VVC. In order to exert their therapeutic activity, the probiotics needed to remain viable. Multilayer double emulsion was formulated to obtain L. plantarum loaded microcapsules (MCs), thus improving its viability. Furthermore, a vaginal drug delivery system using dissolving microneedles (DMNs) for VVC treatment was developed for the first time. These DMNs showed sufficient mechanical and insertion properties, dissolved rapidly upon insertion, facilitating probiotic release. All formulations proved non-irritating, non-toxic, and safe to apply on the vaginal mucosa. Essentially, the DMNs could inhibit the growth of Candida albicans up to 3-fold than hydrogel and patch dosage forms in ex vivo infection model. Therefore, this study successfully developed the formulation of L. plantarum-loaded MCs with multilayer double emulsion and its combination in DMNs for vaginal delivery to treat VVC. [ABSTRACT FROM AUTHOR]

Polymeric hydrogels are a complex class of materials with one common feature—the ability to form three-dimensional networks capable of imbibing large amounts of water or biological fluids without being dissolved, acting as self-sustained containers for various purposes, including pharmaceutical and biomedical applications. Transdermal pharmaceutical microneedles are a pain-free drug delivery system that continues on the path to widespread adoption—regulatory guidelines are on the horizon, and investments in the field continue to grow annually. Recently, hydrogels have generated interest in the field of transdermal microneedles due to their tunable properties, allowing them to be exploited as delivery systems and extraction tools. As hydrogel microneedles are a new emerging technology, their fabrication faces various challenges that must be resolved for them to redeem themselves as a viable pharmaceutical option. This article discusses hydrogel microneedles from a material perspective, regardless of their mechanism of action. It cites the recent advances in their formulation, presents relevant fabrication and characterization methods, and discusses manufacturing and regulatory challenges facing these emerging technologies before their approval. [ABSTRACT FROM AUTHOR]

Applying a formulation on the skin represents a patient-acceptable and therapeutically effective way to administer drugs locally and systemically. However, the stratum corneum stands as an impermeable barrier that only allows a very limited number of drugs to be distributed in the underlying tissues, limiting the feasibility of this administration route. Microneedle arrays are minimally invasive platforms that allow the delivery of drugs within/across the skin through the temporary mechanical disruption of the stratum corneum. In this work, microneedle arrays were combined with nanosuspensions, a technology for solubility enhancement of water insoluble molecules, for the skin delivery of diclofenac. Nanosuspensions were prepared using a top-down method and loaded in the tips of 500 µm or 800 µm high microneedles. The quality of the combined platform was assessed using electron microscopy and spectroscopic and calorimetry techniques, demonstrating the ability to load high amounts of the hydrophobic drug and the compatibility between excipients. Lastly, the application of nanosuspension-loaded microneedles on the skin in vitro allowed the delivery of diclofenac within and across the stratum corneum, proving the potential of this combination to enhance skin delivery of scarcely soluble drugs. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade, especially the programmed cell death ligand 1 (PD-L1) blockade, has revolutionized the treatment of melanoma. However, PD-1/PD-L1 monotherapy leads to unsatisfactory therapeutic outcomes. The immunotherapy of melanoma could be improved by adding doxorubicin (DOX), which triggers immunogenic cell death (ICD) effect to activate anti-tumor immunity. Additionally, microneedles, especially dissolving microneedles (dMNs), can further enhance outcomes of chemo-immunotherapy due to the physical adjuvant effect of dMNs. Herein, we developed the dMNs-based programmed delivery system that incorporated pH-sensitive and melanoma-targeting liposomes to co-deliver DOX and siPD-L1, achieving enhanced chemo-immunotherapy of melanoma (si/DOX@LRGD dMNs). The incorporated si/DOX@LRGD LPs demonstrated uniform particle size, pH-sensitive drug release, high in vitro cytotoxicity and targeting ability. Besides, si/DOX@LRGD LPs effectively downregulated the expression of PD-L1, induced tumor cell apoptosis and triggered ICD effect. The si/DOX@LRGD LPs also showed deep penetration (approximately 80 μm) in 3D tumor spheroids. Moreover, si/DOX@LRGD dMNs dissolved rapidly into the skin and had sufficient mechanical strength to penetrate skin, reaching a depth of approximately 260 μm in mice skin. In mice model of melanoma tumor, si/DOX@LRGD dMNs exhibited better anti-tumor efficacy than monotherapy by dMNs and tail intravenous injection at the same dose. This was due to the higher cytotoxic CD8+ T cells and the secreted cytotoxic cytokine IFN-γ evoked by si/DOX@LRGD dMNs, thereby eliciting strong T-cell mediated immune response and resulted in enhanced anti-tumor effects. In conclusion, these findings suggested that si/DOX@LRGD dMNs provided a promising and effective strategy for enhanced chemo-immunotherapy of melanoma. After administration of si/DOX@LRGD dMNs on dorsal skin of the mouse, dMNs dissolves by skin's interstitial fluids, while the incorporated liposomes si/DOX@LRGD LPs released from dMNs. Because of the conjugation of c(RGDfk) on the surface of si/DOX@LRGD, the specific binding to αvβ3 integrin leads to receptor-mediated endocytosis. Subsequently, the acidic pH in tumor microenvironment causes collapses of liposomes and release of DOX and siPD-L1. The released DOX, induces immunogenic cell death and promotes the maturation and migration of DCs, thus increasing T cell infiltration and enhancing T cell-mediated immune responses. While, the released siPD-L1 downregulates the expression of PD-L1, hence, blocks the binding of PD-1/PD-L1 and restores anti-tumor effect of T cells. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract In this study, it was aimed to introduce a transdermal drug delivery system with dissolving microneedles (DMNs) based on gelatin (GEL) and sodium carboxymethyl cellulose (NaCMC) for lidocaine hydrochloride (LidoHCl) delivery. Different ratios of GEL and NaCMC were mixed, loaded with an active agent of LidoHCl, and treated with glutaraldehyde (GTA) as a crosslinker agent. Prepared hydrogels were cast into a silicon mold. Hereby, microneedles (MNs) with 500 µm height, 35° needle angle, 40-µm tip radius, and 960-µm tip-to-tip distance were fabricated. Samples containing LidoHCl 40%, GEL/NaCMC 5:1 (wt/wt), and polymer/GTA ratio 3.1 (wt/wt) showed the highest drug release ability (t

Microneedles have recently emerged as a promising platform for delivering therapeutic agents by disrupting the skin, resulting in improved and high drug delivery via this route. Ibuprofen is widely used topically and orally for chronic pain conditions; to avoid untoward gastric effects, topical application is preferred over the oral route. This study aimed to enhance the solubility of the poorly water-soluble ibuprofen using Soluplus (SP) as a solubilizer and to fabricate dissolving microneedle patches of the drug. The fabricated patches were compared with marketed oral and topical formulations of ibuprofen. A 432-fold increase was observed in the solubility of the drug at 8% SP. The FTIR studies revealed that the drug and polymers were compatible. MNs were of uniform morphology and released the drug in a predictable manner. The in vivo analysis on healthy human volunteers revealed a Cmax of 28.7 µg/mL ± 0.5 with a Tmax of 24 h and a MRT of 19.5 h, which was significantly higher than that observed for commercially available topical formulations. The prepared ibuprofen microneedles have higher bioavailability and MRT at a lower dose (165 µg) as compared to tablet and cream doses (200 mg). [ABSTRACT FROM AUTHOR]

The treatment of hypertrophic scars (HTSs) and keloids remains a challenge. Intralesional triamcinolone acetonide (TAC) is the mainstay treatment for these conditions. Despite its efficacy, TAC has several adverse side effects, including telangiectasias, skin atrophy, pigmentary changes, and skin necrosis. Dissolving microneedles (DMN) use the poke-and-release method to create microchannels that enhance drug delivery to the target tissue in the dermis, without causing pain and with a decreased risk of transmission of blood-borne diseases. To evaluate and compare the efficacy of a TAC-DMN versus a drug-free DMN patch for the treatment of HTSs and keloids, 20 patients (10 with HTSs and 10 with keloids) received a split-scar treatment: one half of the scar length was treated with TAC-DMNs and the other half was treated with drug-free DMN for three sessions at 14-day intervals. Efficacy was assessed by measuring the scar volume through a multispectral imaging system and using the Patient and Observer Scar Assessment Scale (POSAS). The HTSs treated with TAC-DMNs showed a significant reduction in the mean scar volume 2 weeks after the second treatment and 1 month after the third treatment (p = 0.028 and 0.020, respectively), while the HTSs treated with drug-free DMNs showed no significant reduction in the scar volume. Both sides of the keloids showed no significant reduction in mean scar volume. Using the POSAS, significant improvement in the appearance of both halves of the HTSs was observed 1 month after the treatments. A significant improvement (evaluated by POSAS) was also observed in the keloids treated with TAC-DMNs 2 weeks after the second treatment and 1 month after the third treatment. No significant improvement was observed from the patients' perspective as evaluated by POSAS in the keloids treated with drug-free DMNs. However, no significant difference was observed between the treatment and control halves. TAC-DMN is an effective treatment for HTSs. Increasing the dosage and duration of keloid scar treatment is required in future studies to determine whether it would result in a significant therapeutic outcome. This trial is registered in the Thai Clinical Trials Registry (TCTR20220318004; date of registration, March 17, 2022). [ABSTRACT FROM AUTHOR]

Guo P, Huang C, Yang Q, et al. Int J Nanomedicine. 2023;18:7759-7784. The authors have advised the correspondence section on page 7759 is incorrect. The correct correspondence address is as follows. Correspondence: Yan Qu, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, People’s Republic of China, Email quyan028@126.com The authors apologize for this error.

In this study, it was aimed to introduce a transdermal drug delivery system with dissolving microneedles (DMNs) based on gelatin (GEL) and sodium carboxymethyl cellulose (NaCMC) for lidocaine hydrochloride (LidoHCl) delivery. Different ratios of GEL and NaCMC were mixed, loaded with an active agent of LidoHCl, and treated with glutaraldehyde (GTA) as a crosslinker agent. Prepared hydrogels were cast into a silicon mold. Hereby, microneedles (MNs) with 500 µm height, 35° needle angle, 40-µm tip radius, and 960-µm tip-to-tip distance were fabricated. Samples containing LidoHCl 40%, GEL/NaCMC 5:1 (wt/wt), and polymer/GTA ratio 3.1 (wt/wt) showed the highest drug release ability (t < 10 min) with proper mechanical properties in comparison with other samples. Due to the drug release in a short time (fewer than 10 min), this drug delivery system can be used for rapid local anesthesia for pain relief as well as before minor skin surgeries. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic inflammatory skin disease caused predominantly by immune dysregulation. The global impact of AD continues to increase, making it not only a significant public health issue but also a risk factor for progression into other allergic phenotype disorders. Treatment of moderate-to-severe symptomatic AD involves general skin care, restoration of the skin barrier function, and local anti-inflammatory drug combinations, and may also require systemic therapy, which is often associated with severe adverse effects and is occasionally unsuitable for long-term use. The main objective of this study was to develop a new delivery system for AD treatment based on dissolvable microneedles containing dexamethasone incorporated in a dissolvable polyvinyl alcohol/polyvinylpyrrolidone matrix. SEM imaging of the microneedles showed well-structured arrays comprising pyramidal needles, fast drug release in vitro in Franz diffusion cells, an appropriate mechanical strength recorded with a texture analyzer, and low cytotoxicity. Significant clinical improvements, including in the dermatitis score, spleen weights, and clinical scores, were observed in an AD in vivo model using BALB/c nude mice. Taken together, our results support the hypothesis that microneedle devices loaded with dexamethasone have great potential as a treatment for AD and possibly for other skin conditions as well. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) is one of the leading causes of bronchiolitis and pneumonia in children ages five years and below. Recent outbreaks of the virus have proven that RSV remains a severe burden on healthcare services. Thus, a vaccine for RSV is a need of the hour. Research on novel vaccine delivery systems for infectious diseases such as RSV can pave the road to more vaccine candidates. Among many novel vaccine delivery systems, a combined system with polymeric nanoparticles loaded in dissolving microneedles holds a lot of potential. In this study, the virus-like particles of the RSV fusion protein (F-VLP) were encapsulated in poly (D, L-lactide-co-glycolide) (PLGA) nanoparticles (NPs). These NPs were then loaded into dissolving microneedles (MNs) composed of hyaluronic acid and trehalose. To test the in vivo immunogenicity of the nanoparticle-loaded microneedles, Swiss Webster mice were immunized with the F-VLP NPs, both with and without adjuvant monophosphoryl lipid A (MPL) NPs loaded in the MN. The mice immunized with the F-VLP NP + MPL NP MN showed high immunoglobulin (IgG and IgG2a) levels both in the serum and lung homogenates. A subsequent analysis of lung homogenates post-RSV challenge revealed high IgA, indicating the generation of a mucosal immune response upon intradermal immunization. A flowcytometry analysis showed high CD8+ and CD4+ expression in the lymph nodes and spleens of the F-VLP NP + MPL NP MN-immunized mice. Thus, our vaccine elicited a robust humoral and cellular immune response in vivo. Therefore, PLGA nanoparticles loaded in dissolving microneedles could be a suitable novel delivery system for RSV vaccines. [ABSTRACT FROM AUTHOR]

Dissolving microneedle (DMN) is an attractive alternative to parenteral and enteral drug administration owing to its painless self‐administration and safety due to non‐generation of medical waste. For reproducible and efficient DMN administration, various DMN application methods, such as weights, springs, and electromagnetic devices, have been studied. However, these applicators have complex structures that are complicated to use and high production costs. In this study, a latch applicator that consists of only simple plastic parts and operates via thumb force without any external complex device is developed. Protrusion‐shaped latches and impact distances are designed to accumulate thumb force energy through elastic deformation and to control impact velocity. The optimized latch applicator with a pressing force of 25 N and an impact velocity of 5.9 m s−1 fully inserts the drug‐loaded tip of the two‐layered DMN into the skin. In an ovalbumin immunization test, DMN with the latch applicator shows a significantly higher IgG antibody production rate than that of intramuscular injection. The latch applicator, which provides effective DMN insertion and a competitive price compared with conventional syringes, has great potential to improve delivery of drugs, including vaccines. [ABSTRACT FROM AUTHOR]