Faculty of Pharmacy, Universitas Indonesia, Depok 16424, Indonesia.
Department of Pharmacy, School of Life Sciences, Indonesia International Institute of Life Sciences, Jakarta 13210, Indonesia.
Eur J Pharm Biopharm. 2024 Nov;204:114495. doi: 10.1016/j.ejpb.2024.114495. Epub 2024 Sep 12.
Regenerative therapy based on stem cells have been developed, focusing on either stem cell 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 ± 3.24 μg and 78.36 ± 3.75 μg respectively. In vitro permeation studies showed that F5 delivered secretome protein by 100.84 ± 0.88%, while F12 delivered 99.63 ± 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.
基于干细胞的再生疗法已经得到了发展，主要集中在干细胞或分泌组的递送上。大多数市售的细胞和基因治疗产品都以可注射剂型提供，这导致了一些限制，需要替代途径，如皮内途径。能够穿透角质层屏障的微针为皮内递送提供了一种潜在的替代方法。本研究旨在开发用于递送冻干间充质干细胞分泌组的双层溶解微针（DMN）。DMN 采用两步浇铸法制造，由两种聚合物组合组成：聚乙烯吡咯烷酮（PVP）与聚乙烯醇（PVA）或 PVP 与透明质酸钠（SH）。制造的 DMN 进行了形态学、机械强度、皮肤溶解、蛋白质含量、体外渗透、体内皮肤刺激和物理稳定性评估。基于形态学和机械强度的评估，两种配方（F5 和 F12）符合验收标准。蛋白质含量评估显示，F12（PVP-SH 组合）的蛋白质含量高于 F5（PVP-PVA 组合），分别为 99.02±3.24μg 和 78.36±3.75μg。体外渗透研究表明，F5 在 24 小时内递送 100.84±0.88%的分泌组蛋白，而 F12 递送 99.63±9.21%。在 Sprague-Dawley 大鼠皮肤观察四天后，两种配方应用后均未观察到刺激迹象，如水肿和发红。使用 PVP-PVA 和 PVP-SH 组合作为 DMN 分泌组递送赋形剂的安全性已得到证实，有望在未来推动生物治疗的发展。
