Li Jian, Tian Xin, Wang Kang, Jia Yong, Ma Fuguang
Nanjing Jiangning District Hospital of TCM, Nanjing, China.
J Drug Target. 2023 Feb;31(2):206-216. doi: 10.1080/1061186X.2022.2123492. Epub 2022 Sep 18.
Dissolving microneedles, the promising vehicles for transdermal delivery, are incapable of directly loading hydrophobic components that limit the application of transdermal drug delivery. Microemulsion holds great potential in the solubilisation of water-insoluble drugs but is limited by the high epidermal retention. In this study, we fabricated microemulsion-incorporated dissolving microneedles co-loading celecoxib and α-linolenic acid (Cel-MEs@MNs) for enhancing osteoarthritis (OA) therapy synergistic anti-inflammation and potent transdermal delivery. Cel-MEs@MNs composed of celecoxib & α-linolenic acid-coloaded microemulsion (Cel-MEs) and hyaluronic acid-based microneedles (MNs) can be completely dissolved in 90 s with a particle size of ∼30 nm. Each microneedle array with a hardness exceeding 30 N contained 57.9 ± 2.5 μg of celecoxib and 442.5 ± 24.2 μg of α-linolenic acid. The 8 h-cumulative transdermal of celecoxib from Cel-MEs@MNs was 89.2 ± 5.1 μg celecoxib/cm, which is 2.98-fold higher than that from Cel-MEs. Combinational celecoxib and α-linolenic acid with a weight ratio of 1/5 can synergistically induce M1-like macrophage to M2 repolarization, reduce M1-like macrophages-resulted chondrocytes apoptosis, and lower serum prostaglandin E-2 (PGE-2). Notably, Cel-MEs@MNs amplified such collaborated anti-inflammatory effects. More importantly, in the treatment of OA-bearing rat models, Cel-MEs@MNs with a half-dose of celecoxib and α-linolenic acid significantly shrunk the paw swelling, reduced inflammatory cytokines, and improved cartilage damage compared with the oral administration of celecoxib and α-linolenic acid, as well as transdermal administration of Cel-MEs. Such an integrational strategy of microemulsion-incorporated dissolving MNs offers the feasibility of combinational celecoxib and α-linolenic acid in transdermal permeation and boosted OA therapy.
溶蚀性微针作为一种颇具前景的透皮给药载体，无法直接负载疏水性成分，这限制了其在透皮给药中的应用。微乳在增溶水不溶性药物方面具有巨大潜力，但受限于其在表皮的高滞留性。在本研究中，我们制备了负载微乳的溶蚀性微针，同时负载塞来昔布和α-亚麻酸（Cel-MEs@MNs），以增强骨关节炎（OA）治疗中的协同抗炎和高效透皮给药效果。由塞来昔布与α-亚麻酸共负载微乳（Cel-MEs）和透明质酸基微针（MNs）组成的Cel-MEs@MNs在90秒内可完全溶解，粒径约为30纳米。每片硬度超过30 N的微针阵列含有57.9±2.5μg塞来昔布和442.5±24.2μgα-亚麻酸。Cel-MEs@MNs中塞来昔布的8小时累积透皮量为89.2±5.1μg塞来昔布/平方厘米，比Cel-MEs的高出2.98倍。重量比为1/5的塞来昔布和α-亚麻酸组合可协同诱导M1样巨噬细胞向M2极化，减少M1样巨噬细胞导致的软骨细胞凋亡，并降低血清前列腺素E-2（PGE-2）。值得注意的是，Cel-MEs@MNs放大了这种协同抗炎作用。更重要的是，在OA大鼠模型治疗中，与口服塞来昔布和α-亚麻酸以及Cel-MEs的透皮给药相比，半剂量的Cel-MEs@MNs显著减轻了 paw肿胀，减少了炎症细胞因子，并改善了软骨损伤。这种负载微乳的溶蚀性微针的整合策略为塞来昔布和α-亚麻酸在透皮渗透及增强OA治疗方面提供了可行性。
