Double-Layer dissolving microneedles for delivery of mesenchymal stem cell Secretome: Formulation, Characterisation and skin irritation study.

Regenerative therapy based on stem cells have been developed, focusing on either stem cell delivery or secretome delivery. Most marketed cellular and gene therapy products are available as injectable dosage forms, leading to several limitations requiring alternative routes, such as the intradermal route. Microneedles, capable of penetratingthe stratum corneumbarrier, offer a potential alternative for intradermal delivery. This present study aimed to develop double-layer dissolving microneedles (DMN) for the delivery of freeze-dried mesenchymal stem cell secretome. DMNs were fabricated using a two-step casting method and composed of two polymer combinations: poly(vinyl pyrrolidone) (PVP) with poly(vinyl alcohol) (PVA) or PVP with sodium hyaluronate (SH). The manufactured DMNs underwent assessments for morphology, mechanical strength, in skin dissolution, protein content, in vitro permeation, in vivo skin irritation, and physical stability. Based on evaluations of morphology and mechanical strength, two formulas (F5 and F12) met acceptance criteria. Evaluation of protein content revealed that F12 (PVP-SH combination) had a higher protein content than F5 (PVP-PVA combination), 99.02 ±â€¯3.24 µg and 78.36 ±â€¯3.75 µg respectively. In vitro permeation studies showed that F5 delivered secretome protein by 100.84 ±â€¯0.88 %, while F12 delivered 99.63 ±â€¯9.21 % in 24 h. After four days of observation onSprague-Dawleyrat's skin, no signs of irritation, such as oedema and redness, was observed after applying both formulations. The safety of using PVP-PVA and PVP-SH combinations as excipients for DMN secretome delivery has been confirmed, promising significant advancements in biotherapeutic development in the future.

Dissolving microneedle patches for delivery of amniotic mesenchymal stem cell metabolite products for skin regeneration in UV-aging induced mice.

Microneedles offer a promising solution to enhancing dermal delivery of amniotic mesenchymal stem cell metabolite product (AMSC-MP), which contains hydrophilic protein components with high molecular weight, for the purposes of skin rejuvenation and improving human health. This study aimed to evaluate the physicochemical characteristics and in vivo efficacy of AMSC-MP-loaded microneedle patches for effectively regenerating skin tissues in UV-aging induced mice. Dissolving microneedle patches, composed of polyvinyl alcohol with an MW of 9-10 kDa and polyvinylpyrrolidone with an MW of 56 kDa, were fabricated using the double-casting method at three AMSC-MP concentrations: i.e., 30% (MN30), 25% (MN25), and 20% (MN20). The microneedles patches were then evaluated for morphological, mechanical resistance, and insertion properties. An ex vivo release study was also conducted using the Franz cell method, and in vivo efficacy and irritation were then determined through collagen density scores, fibroblast cell counts, and skin irritation studies of UV-aging induced mice. The AMSC-MP microneedles displayed a pyramidal shape with 500 µm sharp tips. Mechanical testing revealed that MN30 achieved its deepest insertion into Parafilm® M (447.44 ± 37.21 µm), while MN25 achieved its deepest insertion into full-thickness porcine skin (717.92 ± 25.40 µm). The study revealed a controlled EGF release for up to 24 hours, with MN20 exhibiting the highest deposition (55.94 ± 12.34%). These findings demonstrate the successful penetration of microneedles through the stratum corneum and viable epidermis. Collagen density scores and fibroblast cell counts were significantly higher in all microneedle formulations than the control, with MN30 having the highest values. Inflammatory cell counts indicated minimal presence suggesting non-irritation in the in vivo study. Dissolving microneedle patches exhibited favorable characteristics and efficiently delivered AMSC-MP with minimal potential for irritation, providing potential technology for delivering biological anti-aging agents for the purposes of fostering skin regeneration.

Dissolving microarray patches for transdermal delivery of risperidone for schizophrenia management.

Schizophrenia is a psychiatric disorder that results from abnormal levels of neurotransmitters in the brain. Risperidone (RIS) is a common drug prescribed for the treatment of schizophrenia. RIS is a hydrophobic drug that is typically administered orally or intramuscularly. Transdermal drug delivery (TDD) could potentially improve the delivery of RIS. This study focused on the development of RIS nanocrystals (NCs), for the first time, which were incorporated into dissolving microneedle array patches (DMAPs) to facilitate the drug delivery of RIS. RIS NCs were formulated via wet-media milling technique using poly(vinylalcohol) (PVA) as a stabiliser. NCs with particle size of 300 nm were produced and showed an enhanced release profile up to 80 % over 28 days. Ex vivo results showed that 1.16 ± 0.04 mg of RIS was delivered to both the receiver compartment and full-thickness skin from NCs loaded DMAPs compared to 0.75 ± 0.07 mg from bulk RIS DMAPs. In an in vivo study conducted using female Sprague Dawley rats, both RIS and its active metabolite 9-hydroxyrisperidone (9-OH-RIS) were detected in plasma samples for 5 days. In comparison with the oral group, DMAPs improved the overall pharmacokinetic profile in plasma with a âˆ¼ 15 folds higher area under the curve (AUC) value. This work has represented the novel delivery of the antipsychotic drug, RIS, through microneedles. It also offers substantial evidence to support the broader application of MAPs for the transdermal delivery of poorly water-soluble drugs.

A five-day treatment course of zanamivir for the flu with a single, self-administered, painless microneedle array patch: Revolutionizing delivery of poorly membrane-permeable therapeutics.

Seasonal influenza virus infections cause a substantial number of deaths each year. While zanamivir (ZAN) is efficacious against oseltamivir-resistant influenza strains, the efficacy of the drug is limited by its route of administration, oral inhalation. Herein, we present the development of a hydrogel-forming microneedle array (MA) in combination with ZAN reservoirs for treating seasonal influenza. The MA was fabricated from Gantrez® S-97 crosslinked with PEG 10,000. Various reservoir formulations included ZAN hydrate, ZAN hydrochloric acid (HCl), CarraDres™, gelatin, trehalose, and/or alginate. In vitro permeation studies with a lyophilized reservoir consisting of ZAN HCl, gelatin, and trehalose resulted in rapid and high delivery of up to 33 mg of ZAN across the skin with delivery efficiency of up to ≈75% by 24 h. Pharmacokinetics studies in rats and pigs demonstrated that a single administration of a MA in combination with a CarraDres™ ZAN HCl reservoir offered a simple and minimally invasive delivery of ZAN into the systemic circulation. In pigs, efficacious plasma and lung steady-state levels of ∼120 ng/mL were reached within 2 h and sustained between 50 and 250 ng/mL over 5 days. MA-enabled delivery of ZAN could enable a larger number of patients to be reached during an influenza outbreak.

Nestorone nanosuspension-loaded dissolving microneedles array patch: A promising novel approach for "on-demand" hormonal female-controlled peritcoital contraception.

"On demand" hormonal female-controlled pericoital contraception is one strategy which could be used to minimize the impact of unintended pregnancy. Nestorone (NES) is a potent contraceptive, with relatively few side effects in comparison with other contraceptives. NES presents an attractive option for "on demand" pericoital contraceptive. Unfortunately, the drug is inactive if taken orally, but it has high progestational activity and antiovulatory potency if administered parenterally. Current drug delivery systems, such as a transdermal hydrogel are not so satisfactory. Dissolving microneedles array (DMNs) are an attractive alternative, minimally-invasive, delivery system. In this study, we report, for the first time, development of tip-loaded NES-nanosuspension (NES-NS)-loaded bilayer DMNs to deliver NES intradermally for subsequent release. NES-NS was prepared and optimised, freeze-dried and then used to fabricate DMNs using a blend of two biocompatible polymers, namely poly(vinyl alcohol) and poly(vinyl pyrrolidone). Both NES-NS and the NES-NS-loaded DMNs were fully characterised and the performance of the DMNs was evaluated in vivo using Sprague Dawley rats. Results showed that the finalised NES-NS had particle size and PDI values of 666.06 ± 1.86 nm and 0.183 ± 0.01, respectively. The NES-NS-DMNs had relatively high tips-localised drug loading (approximately 2.26 ± 1.98 mg/array) and exhibited satisfactory mechanical and insertion properties. In Sprague Dawley rats, DMNs delivered NES into the skin, with the drug then appearing in blood and rapidly reaching its maximum concentration (Cmax of 32.68 ± 14.06 ng/mL) within 1 h post-DMNs application. Plasma levels above 3.4 ng/mL were maintained for 2 days. This suggests that DMNs are a promising drug delivery system that could be used to deliver NES as an "On demand" hormonal female-controlled pericoital contraceptive.