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Acne is a chronic inflammatory disease of pilosebaceous unit, which can be aggravated by hyperkeratosis of the pilosebaceous unit, excessive secretion of sebum and the proliferation of Propionibacterium acnes (P. acnes). Traditional drug treatment methods commonly exhibit drawbacks, including bacterial resistance and poor transdermal permeability, resulting in suboptimal efficacy and recurrent infections. Herein, we designed a dual drug-loaded microneedles patch to deliver ALA and silver nanoparticles for acne treatment. The comprehensive treatment of acne is achieved by utilizing the safe and efficient advantages of 5-aminolevulinic acid (ALA) photodynamic therapy (PDT), coupled with the superior antibacterial properties of silver nanoparticles. To enhance drug permeability, dissolving microneedles (DMNs) are employed for targeted and efficient drug delivery. In vitro and in vivo experiments demonstrated that DMNs loaded with both AgNPs and ALA-PDT (ALA/AgNPs@DMNs) have significant antibacterial activity, along with superior drug loading capacity and penetration. The application of ALA/AgNPs@DMNs in treating acne-affected rats alleviates excessive epidermal keratinization, effectively inhibits bacterial growth, and significantly improves acne symptoms. This suggests that the "dissolving microneedle" formulation holds promise for the treatment and management of acne., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Atopic dermatitis (AD) commonly manifests in skin areas subjected to flexion, particularly joints. This underscores the importance of dissolving microneedles (DMNs) used in AD treatment having strong skin adhesion to prevent drug delivery interruption due to patch detachment during patient activity. Moreover, matrine (MAT), a prominent active ingredient derived from the natural plant Sophora flavescens, is known for its significant efficacy in treating skin inflammation, itching, and allergic diseases. Herein, we presented MAT-loaded DMNs (MAT-DMNs) specifically tailored for joint skin application in AD treatment. MAT-DMNs can rapidly dissolve and hydrate after application, demonstrating adhesive properties on ex vivo pig skin, rat abdominal skin, and finger joint skin, thereby ensuring sustained and uninterrupted drug delivery to the skin. In vitro evaluations revealed that MAT-DMNs exhibited 24-hour first-order release profiles with cumulative penetration rates of 78.70 ± 4.24 % and 77.14 ± 6.65 % for the low-dose and high-dose groups, respectively. Furthermore, these DMNs showed excellent skin compatibility and therapeutic efficacy in AD mice models. Specifically, the skin lesion score in MAT-DMNs group was significantly lower (2.67 ± 0.40) compared to the model group (11.60 ± 1.62) and the blank DMNs group (10.80 ± 1.67). MAT-DMNs effectively alleviated AD symptoms such as itching and inflammation by reducing epidermal thickening, decreasing mast cell infiltration, and lowering the expression of Th2 cytokines (IL-4 and IL-10) and pro-inflammatory factors (IL-1β, IL-6, and TNF-α) compared to the blank DMNs group (p < 0.01). These findings suggest that MAT-DMNs hold promise for clinical AD treatment, particularly for skin diseases commonly affecting joint areas., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ropivacaine hydrochloride (RPL) is a local anesthetic agent that has been widely used for the treatment of pain during or after surgery. However, this drug is only available in parenteral dosage form and may contribute to the infiltration of RPL into the plasma, causing some undesirable side effects. Intradermal delivery of RPL using dissolving microneedles may become a promising strategy to deliver such drugs into the skin. This research aimed to develop RPL-loaded dissolving microneedles (DMN-RPLs) as a proof of the concept of intradermal delivery of a local anesthetic. The DMN-RPLs were fabricated using either centrifugation or air-pressurized chamber methods. Several polymers, such as poly(vinyl pyrrolidone) (PVP), poly(vinyl alcohol) (PVA), and sodium hyaluronate (SH), were utilized for manufacturing the DMN-RPLs. The prepared DMN-RPLs were assessed for their thermal properties, chemical bonds, mechanical strength, insertion ability, skin-dissolution study, and drug content. Furthermore, in-skin deposition and dermatokinetic studies were also performed. The results showed that F9 (30 % w/w PVP-4 % w/w SH) and F10 (30 % w/w PVP-5 % w/w PVA) containing 5 % w/w of RPL were the most promising formulations, as shown by their needle height reduction (<10 %) and insertion depth (∼400 μm). Both formulations were also able to deliver more than 60 % of the RPL contained in the DMNs into the epidermis, dermis, and receiver compartment. This study, for the first time, has provided a proof concept to deliver RPL as a local anesthetic using DMNs and the intradermal route, aiming to minimize pain and discomfort during administration and improve the patient's experience., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Microneedles have garnered considerable attention over the years as a versatile pharmaceutical platform that could be leveraged to deliver drugs into and across the skin. In the current work, poly (N-isopropylacrylamide) (PNIPAm) is synthesized and characterized as a novel material for the development of a physiologically responsive microneedle-based drug delivery system. Typically, this polymer transitions reversibly between a swell state at lower temperatures and a more hydrophobic state at higher temperatures, enabling precise drug release. This study demonstrates that dissolving microneedles patches made from PNIPAm, incorporating BIS-PNIPAm, a crosslinked polymer variant, exhibit enhanced mechanical properties, evident from a smaller height reduction in microneedle (∼10 %). Although microneedles using PNIPAm alone were achievable, it displayed poor mechanical strength, requiring the inclusion of additional polymeric excipients like PVA to enhance mechanical properties. In addition, the incorporation of a thermoresponsive polymer did not have a significant (p > 0.05) impact on the insertion properties of the needles as all formulations inserted to a similar depth of 500 µm into ex vivo skin. Furthering this, the needles were loaded with a model payload, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate (DID) and the deposition of the cargo was monitored via multiphoton microscopy that showed that a deposit is formed at a depth of ≈200 µm. Also, it was revealed that crosslinked-PNIPAm (Bis-PNIPAm) formulations exhibited notable skin accumulationof the dye only after 4 h, independent of the excipient matrix used. This phenomenon was absent in non-crosslinked PNIPAm formulations, indicating a deposit formation in Bis-PNIPAm microneedle formulation. Collectively, this proof-of-concept study has advanced our understanding on the possibility to use PNIPAm for dissolving microneedle fabrication which could be harnessed for the deposition of nanoparticles into the dermis, for extended drug release within the skin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Currently, one of the main problems encountered in wound healing therapy is related to inefficient drug delivery. However, dissolving microneedles (DMNs) can be administered percutaneously to effectively deliver a drug to a deep wound area. Simvastatin (SIM) can promote wound healing, albeit its insolubility in water limits its application. Here, we designed a DMNs (SIM-NC@DMNs) drug delivery system loaded with SIM nanocrystals (SIM-NC) and evaluated its efficacy in wound healing. Based on our observations, the dissolution performance of insoluble SIM is significantly improved after the preparation of SIM-NC. For example, the saturation solubility of SIM-NC in deionized water and PBS increased by 150.57 times and 320.14 times, respectively. After the SIM-NC@DMNs are deeply inserted into the wound, the needle portion, which is composed of hyaluronic acid (HA), dissolves rapidly, and the SIM-NC loaded on the needle portion is efficiently released into the deep wound area for optimal therapeutic efficacy. The combination of NC and DMNs makes this system further effective for wound healing. Our cumulative work suggests that the newly developed SIM-NC@DMNs possess great potential in accelerating wound healing. By day 12 after treatment, the residual wound area in the Control group was 21.34 %, while the residual wound area in the SIM-NC@DMNs group was only 2.36 %. This result as well as provides certain evidence of its efficacy for wound healing therapy. The SIM-NC@DMNs drug delivery system may become an efficient treatment modality that promotes wound healing, with a promising potential in the field of wound healing research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Methicillin-resistant Staphylococcus aureus (MRSA) is a prevailing bacterial pathogen linked to superficial skin and soft tissue infections (SSTIs). Rifampicin (RIF), a potent antibiotic against systemic and localised staphylococcal infections, faces limitations due to its low solubility. This constraint hampers its therapeutic potential for MRSA-induced SSTIs. To address this, an advanced liposomal system was designed for efficient dermal RIF delivery. Rifampicin-loaded liposomes (LipoRIF) were embedded within polymeric dissolving microneedles (DMNs) to enable targeted intradermal drug delivery. A robust Design of Experiment (DoE) methodology guided the systematic preparation and optimisation of LipoRIF formulations. The optimal LipoRIF formulation integrated within polymeric DMNs. These LipoRIF-DMNs exhibited favourable mechanical properties and effective skin insertion characteristics. Notably, in vitro assays on skin deposition unveiled a transformative result - the DMN platform significantly enhanced LipoRIF deposition within the skin, surpassing LipoRIF dispersion alone. Moreover, LipoRIF-DMNs displayed minimal cytotoxicity toward cells. Encouragingly, rigorous in vitro antimicrobial evaluations demonstrated LipoRIF-DMNs' capacity to inhibit MRSA growth compared to the control group. LipoRIF-DMNs propose a potentially enhanced, minimally invasive approach to effectively manage SSTIs and superficial skin ailments stemming from MRSA infections., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Osteoporosis is a fatal bone-wearing malady and a substantial reason behind the impermanence of human life and economic burden. Risedronate Sodium along with Ursolic acid has been studied to ameliorate osteoporosis. To bypass problems associated with bioavailability, we have developed a microneedle transdermal patch loaded with optimized formulation nanotransfersomes. It was optimized using three factor, three-level Central composite design with independent variables namely, the concentration of phospholipid, surfactant, and sonication time on dependent variables (vesicle size, entrapment efficiency and Polydispersity index). Vesicles of size 271.9 ± 8.45 nm with PDI 0.184 ± 0.01, having entrapment efficiency of 86.12 ± 5.20% and 85.65 ± 4.88% for RIS and UA respectively were observed. In vitro release study showed the sustained release pattern with 78.16 ± 1.12% and 75.72 ± 1.01% release of RIS and UA respectively. Dissolving MN patch prepared from gelatin was found to have good strength and folding endurance with uniform drug content (98.68 ± 0.004%). Ex vivo permeation study revealed that up to 80% of the drug can be permeated within 24 h. CLSM analysis was also performed to show penetration of RU-NTRs. From the results obtained, we can conclude that dissolving MN patch loaded with RU-NTRs has great potential than its conventional counterpart., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Delivery of cancer cell membranes (CM) is a new approach for the activation of the immune system and the induction of immunotherapy of cancer. Local delivery of melanoma CM into skin can induce efficient immune stimulation of antigen presenting cells (APCs), such as dendritic cells. In the current study, fast dissolving microneedles (MNs) were developed for the delivery of melanoma B16F10 CM. Two polymers were tested for the fabrication of MNs: poly(methyl vinyl ether-co-maleic acid) (PMVE-MA) and hyaluronic acid (HA). The incorporation of CM in MNs was achieved through coating of the MNs using a multi-step layering procedure or the micromolding technique. The CM loading and its stabilization were improved by adding sugars (sucrose and trehalose) and a surfactant (Poloxamer 188), respectively. In an ex vivo experiment, both PMVE-MA and HA showed fast dissolutions (<30 s) after insertion into porcine skin. However, HA-MN showed better mechanical properties, namely improved resistance to fracture when submitted to a compression force. Overall, a B16F10 melanoma CM-dissolving MN system was efficiently developed as a promising device suggesting further studies in immunotherapy and melanoma applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The objective of the present study was to fabricate microneedles for delivering lipophilic active ingredients (APIs) using digital light processing (DLP) printing technology and quality by design (QbD) supplemented by artificial intelligence (AI) algorithms. In the present study, dissolvable microneedle (MN) patches using ibuprofen (IBU) as a model drug were successfully fabricated with DLP printing technology at ∼ 750 μm height, ∼250 μm base diameter, and tip with radius of curvature (RoC) of ∼ 15 μm. MN patches were comprised of IBU, photoinitiator, Lithium phenyl (2,4,6-trimethylbenzoyl) phosphinate (LAP), polyethylene glycol dimethacrylate (PEGDAMA)550 and distilled water and were developed using the QbD optimization approach. Optimization of print fidelity and needle morphology were achieved using AI implementing a semi-supervised machine learning approach. Mechanical strength tests demonstrated that IBU MNs formed pores both on Parafilm M® and human cadaver skin. IBU-MNs consisting of 0.23 %w/v and 0.49 %w/v LAP with 10 %w/v water showed ∼ 2 mg/cm 2 sustained drug permeation at 72 h in skin permeation experiments with flux of ∼ 40 μg/cm 2 /h. Pharmacokinetic studies in rats displayed biphasic rapid first-order absorption with sustained zero-order input of Ko = 150ug/hr, AUC 0-48h  = 62812.02 ± 11128.39 ng/ml*h, Tmax = 2.66 ± 1.12 h, and Cmax = 3717.43 ± 782.25 ng/ml (using 0.23 %w/v LAP IBU MN patch). An in vitro in vivo relation (IVIVR) was conducted identifying a polynomial relationship between patch release and fraction absorbed in vivo. This study demonstrates fabrication of dissolvable DLP-printed microneedle patches for lipophilic API delivery with biphasic rapid first-order and sustained zero-order release., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The objective of this study was to investigate the feasibility of the bolus administration of PLS via skin by using dissolving microneedles of palonosetron hydrochloride (PLS-DMNs). Tip-loaded PLS-DMNs were fabricated by a casting method using sodium hyaluronate (HA) as DMNs-forming polymer. PLS-DMNs were shown to have a content of 118.5 ± 8.7 μg per piece with sufficient mechanical strength for insertion into pig skin ex vivo. In situ dissolution of PLS-DMNs was achieved within 5 min and 83.2 % of PLS was delivered. In vitro studies showed that PLS-DMNs provided much higher PLS permeation than that after passive permeation using a PLS hydrogel. Moreover, the application of 30 min-iontophoresis at the beginning of PLS-DMNs administration further enhanced PLS delivery. In vivo pharmacokinetic studies were carried out in rats. The area under the curve (AUC) and the time to reach the peak (T max ) after application of PLS-DMNs was not significantly different compared to those after subcutaneous (S.C.) injection. PLS-DMNs plus 30 min-iontophoresis enabled the pharmacokinetic profile to be even closer to that seen after S.C. administration. These results suggest that application of PLS-DMNs with short-duration iontophoresis exhibits promise as an alternative PLS delivery method that can be painlessly self-administered with rapid onset., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yong Chen reports financial support was provided by China National Natural Science Foundation (81603044), the Postgraduate Research and Practice Innovation Program Project of Jiangsu Province (SJCX21-1481) and the Science and Technology Funding of Nantong City (JC2021117). Bohui Xu reports financial support was provided by Science and Technology Funding of Nantong City (JC2021116)., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Centella asiatica, a medicinal herb used for wound healing, has a limited effect when delivered as an ointment. Centella asiatica's active component asiatic acid (AA) increases extracellular matrix development and reduces inflammation but cannot penetrate the stratum corneum to access deeper skin layers. To bypass the stratum corneum, we formulated two types of AA-loaded microneedle arrays. We fabricated, characterised and optimised a dissolving array made from chitosan and PVA and a hydrogel array made from chitosan and PVP. Both needles were strong and long enough to pierce the epidermis without breaking. Both were biocompatible with keratinocytes and fibroblasts (>75% viability at 100% concentration) and showed a sustained drug release over 48 h. The hydrogel microneedle released more AA (52.2%) than the dissolving formulation (26.4%); thus, we evaluated them in an excisional rat model. The hydrogel microneedle arrays significantly increased the rate of wound closure compared to the control. This research has shown that the chitosan-PVA hydrogel microneedles could penetrate the epidermis, effectively release AA, and increase the wound closure rate. This AA-loaded delivery system shows promise as a natural treatment for wound healing and may be applied to other bioactive compounds with similar physiochemical properties in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Osteoarthritis (OA) is a prevalent degenerative disease that has a significant impact on patients' lives. Celecoxib (CXB) is now primarily used to treat OA with oral dosing. CXB's limited water solubility, on the other hand, restricts its therapeutic application. We developed a delivery system of dissolving microneedles (DMNs) loaded with CXB-nanocrystals (CXB-NCs) for the treatment of OA. Oral administration's inefficiency and injectable administration's poor compliance might be solved using DMNs. Furthermore, carrier-free NCs may dramatically increase the dissolution of drugs with poorly water-solubility, as well as the drug load of DMNs. Antisolvent precipitation was used to make CXB-NCs. CXB-NC@DMNs were prepared by mixing CXB-NCs with hyaluronic acid (HA) that had high mechanical qualities and could permeate the skin efficiently in vitro. The therapeutic effect of oral CXB-NCs was substantially better than that of the same dose of oral CXB in an in vivo pharmacodynamic trial, demonstrating that the preparation of CXB into NCs might greatly increase CXB bioavailability. Furthermore, we discovered that DMNs loaded with low-dose CXB-NCs had similar or even better efficacy than the oral CXB-NCs group. The findings suggested that CXB-NC@DMNs may be a very efficient and promising drug delivery strategy in the treatment of OA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Osteoarthritis (OA) is a chronic disease that seriously impairs people's physical function and quality of life. Triptolide (TP), as a promising anti-inflammatory drug for the treatment of OA, has limited clinical application due to its severe systemic toxicity, poor solubility and rapid elimination in the body. To extend its application prospect for OA treatment. We have developed a liposome-loaded dissolving microneedle (DMN) system, which can effectively deliver poorly water-soluble TP and improve OA symptoms. To incorporate TP into DMNs, triptolide liposome (TP-Lipo) with entrapment efficiency of 90.25% was prepared by ethanol injection. Subsequently, TP-Lipo was concentrated by ultrafiltration tube and mixed with hyaluronic acid solution to prepare DMNs, TP-Lipo-loaded DMNs (TP-Lipo@DMNs) showed sufficient mechanical and insertion properties to penetrate about 200 μm of rat skin. The drug distribution in vivo showed that TP-Lipo@DMNs had a slow-release effect compared with intra-articular injection. In vivo pharmacodynamic research showed that TP-Lipo@DMNs significantly reduced knee joint swelling and the level of inflammatory cytokines (TNF-α, IL-1β, IL-6). Micro-CT and histological evaluation showed that TP-Lipo@DMNs effectively reduced cartilage destruction and alleviated OA symptoms. These results support that TP@Lipo@DMNs may be a promising option for OA treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In recent years, transdermal preparations have emerged as one of the most promising modes of administration. In particular, dissolving microneedles have attracted extensive attention because of their painlessness, safety, high delivery efficiency and easily operation for patients. This article mainly reviews the preparation methods, the types of matrix polymer materials, the content of dissolving microneedles performance testing, and the applications of dissolving microneedles. It is expected to lay a solid knowledge foundation for the in-depth study of the dissolving microneedles., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The aim of this study was to prepare dissolving microneedles (DMNs) patches containing tranexamic acid (TA) for the treatment of melasma. Polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) were preferred as matrix materials through the compatibility experiment. In the in vitro permeation study, the transdermal amount of TA was significantly promoted through dissolving microneedles with the cumulative release was 44.43 ± 6.55%. By comparison, the release of TA solution assisted with solid microneedles (SMNs) was merely 11.31 ± 2.30% (p < 0.05). Pharmacokinetics study indicated the bioavailability of dissolving microneedles was more than 1.3 times compared with oral administration. In pharmacodynamics investigation, TA dissolving microneedles obviously reduced melanin deposition in the skin of melasma guinea pigs after 8 consecutive administrations. In particular, the combination of tranexamic acid and licorice extract (LIC) dissolving microneedles worked better than tranexamic acid alone. Accelerated stress conditions including high temperature, high humidity, as well as photostability were designed to prove that TA microneedles maintained good pharmaceutical stability. In conclusion, tranexamic acid dissolving microneedles showed reliable quality and remarkable effect. Moreover, the combination of tranexamic acid and licorice extract had a synergistic therapy in melasma., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Topical photodynamic therapy (PDT) is widely used to treat non melanoma skin cancers. It consists of topically applying on the skin lesions a cream containing a prodrug (5-aminolevulinic acid (5-ALA) or methyl aminolevulinate (MAL)) that is then metabolized to the photosensitizer protoporphyrin IX (PpIX). Light irradiation at PpIX excitation wavelength combined with oxygen then lead to a photochemical reaction inducing cell death. Nevertheless, this conventional PDT treatment is currently restricted to superficial skin lesions since the penetration depth of the prodrug is limited and hampers the production of PpIX in deep seated lesions. To overcome this problem, dissolving microneedles (MNs) included in a square flexible patch were developed. This easy-to-handle MN-patch is composed of 5-ALA mixed with hyaluronic acid (HA) and has the ability to dissolve after skin application. To evaluate the efficiency of this MN-patch in vivo, a skin lesion model has been developed on rats by applying UV-B illuminations. After 40 UV-B illuminations, histological and pharmacokinetic controls confirmed that the rats presented skin lesions. Once the rat skin lesion model has been validated, it was demonstrated that the MNs penetrated into the skin and fully dissolved in one hour on most of the rats. After one hour, the fluorescence images showed that the MN-patch produced a consequent and homogeneous level of PpIX. Overall, the dissolving MN-patch is a recent technology that has interesting features and several preclinical investigations should be led to compare its efficiency to that of the conventional treatment for PDT of non melanoma skin cancers., (Copyright © 2020. Published by Elsevier B.V.)

Autoimmune-mediated inflammatory skin diseases, such as psoriasis, alopecia areata, and vitiligo, have been reported as the 4th leading cause of nonfatal disease burden worldwide. This is mainly related to the poor quality of life experienced by these patients. Although topical and systemic steroids represent the most common treatment, the variability in success rates and side effects often lead to treatment discontinuation. Recent off-label clinical studies using oral Janus Kinase (JAK) inhibitors (e.g., ruxolitinib, tofacitinib, baraticinib) have shown promising results. However, frequent side effects, such as infections and blood clots have been reported. Therefore, the aim of this research was to enhance the intradermal delivery of tofacitinib citrate with MN arrays. Using crosslinked hydrogels containing modifying agents (urea, sorbitol and sodium chloride), hollow MN arrays were fabricated and then loaded with tofacitinib citrate. Their efficiency in intradermal delivery of tofacitinib was compared with dissolving MN arrays and a control (Aqueous cream BP), using neonatal porcine skin. Despite the fact that the hydrogel was only present on the outer surface, hollow MN arrays showed comparable resistance to compression values and insertion capabilities to dissolving MN arrays. Although hollow MN arrays containing NaCl in the formulation led to slightly higher depositions of tofacitinib in epidermis and dermis of neonatal porcine skin when compared to a control cream, dissolving MN arrays showed superiority in terms of tofacitinib deposition in the dermis. Indeed, at 24 h of the study, control cream and dissolving MN arrays delivered 143.98 ug/cm 2 and 835 ug/cm 2 of drug in the dermis, respectively, confirming the enhanced intradermal drug delivery capacity of MN arrays and their potential for treatment of autoimmune skin diseases., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Photodynamic therapy induced by protoporphyrin IX (PpIX) is widely used to treat precancerous skin lesions. The penetration depth of the prodrug 5-aminolevulinic acid (5-ALA) using topical application is currently limited, which hampers the production of PpIX in deep seated lesions. To enhance 5-ALA delivery in deep skin layers, a soluble microneedles patch (MN-patch) containing 5-ALA has been successfully developed by using a fast solvent casting molding method which could be easily up-scaled. The shape, number and height of the needles have been designed according to the medical application and the mechanical strain necessary for skin insertion. Hyaluronic acid (HA) has been chosen as the needle materials due to its biocompatibility, fast solubility and biodegradation and was mixed with 5-ALA prior to casting. HA-based MN-patch containing 5-ALA have exhibited mechanical properties enabling a good insertion into the skin without significant damages to MN. Interactions between HA and 5-ALA were evaluated by Fourier transform infrared spectroscopy (FTIR) and carbon nuclear magnetic resonance ( 13 C NMR), stability of 5-ALA in the MN-patch was monitored by proton nuclear magnetic resonance ( 1 H NMR) and exhibited a good stability over 5 months after manufacturing. Dissolution rate of the whole patch was completed in 1 hour in ex vivo rat skin without cytotoxicity. Overall, the MN-patch can be a promising technique to enhance 5-ALA penetration and produce PpIX in deeper skin lesions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In this study, polyacrylic acid-co-maleic acid (PAMA) and polyvinyl alcohol (PVA) (1:4) were used to fabricate dissolving microneedles (DMNs) and hydrogel forming microneedles (HMNs) which incorporated α-arbutin. Αlpha-arbutin is commonly used as a skin lightening agent. However, it has poor penetration ability due to its hydrophilic properties. The purpose of this study was to compare the permeation of α-arbutin into the skin using DMNs and HMNs. Both types of microneedles (MNs) were sharp, strong with elegant appearance and approximately 100% penetrated the neonatal porcine skin. All needles of α-arbutin loaded DMNs were completely dissolved within 45 min, whereas maximum swelling of HMNs was observed at 4 h. In vitro permeation studies showed that α-arbutin loaded DMNs and HMNs provided significantly about 4.5 and 2.8 times, respectively, greater α-arbutin permeability than gel and commercial cream (P < 0.05). In vivo study also showed high intradermal delivery of α-arbutin levels using DMNs (5.33 µg/mL) and HMNs (1.47 µg/mL) when compared to that of commercial cream 0.15 µg/mL. Moreover, the micro-holes caused by applying MNs can reseal within 1 h. MNs were also stable at 25 °C for 3 months. The results suggested that DMNs and HMNs developed have a promising platform for transdermal delivery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In this study the effect of repeated-fractional intradermal administration of diphtheria toxoid (DT) compared to a single administration in the presence or absence of adjuvants formulated in dissolving microneedles (dMNs) was investigated. Based on an adjuvant screening with a hollow microneedle (hMN) system, poly(I:C) and gibbsite, a nanoparticulate aluminum salt, were selected for further studies: they were co-encapsulated with DT in dMNs with either a full or fractional DT-adjuvant dose. Sharp dMNs were prepared regardless the composition and were capable to penetrate the skin, dissolve within 20 min and deposit the intended antigen-adjuvant dose, which remained in the skin for at least 5 h. Dermal immunization with hMN in repeated-fractional dosing (RFrD) resulted in a higher immune response than a single-full dose (SFD) administration. Vaccination by dMNs led overall to higher responses than hMN but did not show an enhanced response after RFrD compared to a SFD administration. Co-encapsulation of the adjuvant in dMNs did not increase the immune response further. Immunization by dMNs without adjuvant gave a comparable response to subcutaneously injected DT-AlPO 4 in a 15 times higher dose of DT, as well as subcutaneous injected DT-poly(I:C) in a similar DT dose. Summarizing, adjuvant-free dMNs showed to be a promising delivery tool for vaccination performed in SFD administration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Many fabrication methods for microneedle (MN) involve harsh conditions and long drying time. This study aims to fabricate a dissolving MN patch in a simple and efficient manner under mild conditions, using a combination of thermal and photo polymerisation. The MN patch was fabricated by pre-polymerisation of vinylpyrrolidone solution with heating followed by photolithography. The heating temperature and time of pre-polymer solution curing were optimized based on viscosity measurement. The MN properties including shape, size, skin penetration, dissolution, moisture absorption were determined. The fabricated MNs were sharp and consistent. The heated N-vinylpyrrolidone solution required less UV exposure time, thus reducing the total fabrication time. The percentage of MN penetration in human cadaver skin was more than 33.9%. The MN was dissolved within 1-2 min in water, or 40 min in saturated water vapor., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Nanostructured lipid carriers (NLCs) can enhance the safe transdermal delivery system of drugs. Moreover, dissolving microneedles (MNs) can enhance the permeability and controlled drug release. In this study, NLCs were formulated as a suitable vehicle for aconitine (ACO) delivery to effectively inhibit the inflammation of fibroblast-like synoviocytes isolated from a rat model of adjuvant-induced arthritis (AA-FLS). To improve drug delivery, the ACO-loaded NLCs (ACO-NLCs) were embedded in polyvinylpyrrolidone-based dissolving MNs fabricated by an ultraviolet cross-linking method. The nanoparticles maintained good physical stability in the dissolving MNs. The insertion capabilities of the ACO-NLCs-MNs were determined by observing histological sections of the skin after insertion, and scanning electron microscopy was used to observe the changes in the MNs over time. In vivo microdialysis showed that the NLCs-MNs enhanced the transdermal delivery of ACO through disrupting the barrier function of the stratum corneum (SC) and releasing the drug continuously. The ACO-NLCs-MNs showed a significant inhibitory effect on the paw swelling and inflammation in AA model rats. Moreover, this dual approach involving NLCs-loaded dissolving MNs formed a drug reservoir and effectively improved the ACO-induced arrhythmia. These results indicate that NLCs-containing MNs could be promising systems for the effective transdermal delivery and controlled local administration of ACO., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This study is directed towards the gentle transdermal delivery of Neurotoxin (NT) and study of the treatment of Rheumatoid Arthritis (RA) in rats by NT loaded dissolving Microneedles (DMNs-NT). The DMNs-NT fabrication involved a two-step centrifugation method. The quadrangular pyramid shape needles had great mechanical strength. The upper part of the needle contained 15.4 ± 0.5 μg of drug per patch. Blank DMNs showed favorable biocompatibility and low toxicity on the chondrocyte cells. Both NT and DMNs-NT displayed anti-inflammatory capabilities ex-vitro. The results of ex-vitro evaluation of DMNs the skin penetration depth of DMNs-NT rats was higher than 70 μm and the cumulative penetration of NT in DMNs could reach 95.8% in 4 h, whereas, the NT solution could barely penetrate the skin, thereby proving the favorable facilitation of NT transdermal delivery. The needle structure dissolved completely after 10 min in vivo and the channel on the Stratum Corneum (SC) was closed after 6 h. There was no significant adverse reaction on the skin after 15 days of administration. The pharmacodynamic study showed that DMNs-NT significantly reduced the toe swelling of RA rats and reduced the levels of TNF-α and IL-1β in serum to alleviate the injury of the ankle joints. DMNs-NT held favorable stability in 3 months. All these results established that DMNs-NT could penetrate the skin of rats in a biocompatible manner, and have a strong therapeutic effect on rat RA by transdermal delivery., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Dissolving microneedles (DMN) have been studied as a drug delivery system to enhance the transport of drug molecules across the skin with almost no pain. However, the poor dissolving ability of microneedles in the skin and low drug loading have limited their potential application. The aim of this study was to develop a novel dissolving microneedle system with improved dissolving ability for the delivery of poorly water soluble contraception drug, levonorgestrel (LNG). Chitosan and beta-sodium glycerophosphate (β-GP) were incorporated in the formulation of microneedles. It was found that 69.32±4.23% of the microneedles penetrated through the skin and dissolved within the first 2h, which was almost 2-fold higher than that of the conventional microneedles. In addition, drug loading was significantly increased by packaging LNG into the molecules of hydroxypropyl beta cyclodextrin (HP-β-CD) to form LNG-HP-β-CD inclusion compounds. The use of chitosan and β-GP together with HP-β-CD inclusion compounds was shown to enhance the bioavailability of LNG transdermally. This novel DMN system resulted in a similar pharmacokinetic profile as that following oral administration. In addition to similar C max and AUC values, drug concentrations in the blood were more consistent following the DMN in comparison to oral administration., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Dissolving microneedles (DMNs) based transdermal delivery is an attractive drug delivery approach with minimal invasion. However, it is still challenging to load poorly water-soluble drugs in DMNs for systemic delivery. The aim of the study was to develop DMNs loaded with artemether (ARM) as a model drug, to enable efficient drug penetration through skin for systemic absorption and distribution. The micro-conduits created by microneedles were imaged by confocal laser scanning microscopy (CLSM), and the insertion depth was suggested to be about 270μm. The maximum amount of ARM delivered into skin was 72.67±2.69% of the initial dose loaded on DMNs preparation. Pharmacokinetics study in rats indicated a dose-dependent profile of plasma ARM concentrations, after ARM-loaded DMNs treatment. In contrast to intramuscular injection, DMNs application resulted in lower peak plasma levels, but higher plasma ARM concentration at 8h after administration. There were no significant difference in area under the curve and bioavailability between DMNs group and intramuscular group (P>0.05). Pharmacodynamics studies performed in collagen-induced arthritis (CIA) rats showed that ARM-loaded DMNs could reverse paw edema, similar to ARM intramuscular injection. In conclusion, developed DMNs provided a potential minimally invasive route for systemic delivery of poorly water-soluble drugs., (Copyright © 2016 Elsevier B.V. All rights reserved.)