Fungal infections affect millions of people globally and are often unreceptive to conventional topical or oral preparations because of low drug bioavailability at the infection site, lack of sustained therapeutic effect, and the development of drug resistance. Amphotericin B (AmB) is one of the most potent antifungal agents. It is increasingly important since fungal co-infections associated with COVID-19 are frequently reported. AmB is only administered via injections (IV) and restricted to life-threatening infections due to its nephrotoxicity and administration-related side effects. In this work, we introduce, for the first time, dissolving microneedle patches (DMP) loaded with micronised particles of AmB to achieve localised and long-acting intradermal delivery of AmB for treatment of cutaneous fungal infections. AmB was pulverised with poly (vinyl alcohol) and poly (vinyl pyrrolidone) to form micronised particles-loaded gels, which were then cast into DMP moulds to form the tips. The mean particle size of AmB in AmB DMP tips after pulverisation was 1.67 ± 0.01 μm. This is an easy way to fabricate and load microparticles into DMP, as few steps are required, and no organic solvents are needed. AmB had no covalent chemical interaction with the excipients, but the crystallinity of AmB was reduced in the tips. AmB was completely released from the tips within 4 days in vitro. AmB DMP presented inhibition of Candida albicans (CA) and the killing rate of AmB DMP against CA biofilm inside porcine skin reached 100% within 24 h. AmB DMP were able to pierce excised neonatal porcine skin at an insertion depth of 301.34 ± 46.86 μm. Ex vivo dermatokinetic and drug deposition studies showed that AmB was mainly deposited in the dermis. An in vivo dermatokinetic study revealed that the area under curve (AUC_0-inf) values of AmB DMP and IV (Fungizone® bolus injection 1 mg/kg) groups were 8823.0 d∙μg/g and 33.4 d∙μg/g, respectively (264-fold higher). AmB remained at high levels (219.07 ± 102.81 μg/g or more) in the skin until 7 days after the application of AmB DMP. Pharmacokinetic and biodistribution studies showed that AmB concentration in plasma, kidney, liver, and spleen in the AmB DMP group was significantly lower than that in the IV group. Accordingly, this system addressed the systemic side effects of intravenous injection of AmB and localised the drug inside the skin for a week. This work establishes a novel, easy and effective method for long-acting and localised intradermal drug delivery.

真菌感染影响全球数百万人，并且由于感染部位的药物生物利用度低、缺乏持续的治疗效果以及耐药性的发展，通常对传统的外用或口服制剂无法接受。两性霉素 B (AmB) 是最有效的抗真菌剂之一。由于与 COVID-19 相关的真菌合并感染经常被报道，因此它变得越来越重要。AmB 只能通过注射 (IV) 并且由于其肾毒性和与给药相关的副作用而仅限于危及生命的感染。在这项工作中，我们首次引入了溶解微针贴片 (DMP)，其中装有微粉化的 AmB 颗粒，以实现 AmB 的局部和长效皮内递送，用于治疗皮肤真菌感染。AmB 与聚（乙烯醇）和聚（乙烯基吡咯烷酮）一起粉碎以形成微粉化颗粒负载凝胶，然后将其浇铸到 DMP 模具中以形成尖端。粉碎后 AmB DMP 尖端中 AmB 的平均粒径为 1.67 ± 0.01 μm。这是一种制造微粒并将其加载到 DMP 中的简单方法，因为需要的步骤很少，并且不需要有机溶剂。AmB 与赋形剂没有共价化学相互作用，但尖端中 AmB 的结晶度降低。AmB在4天内从提示中完全释放体外。AmB DMP表现出对白色念珠菌（CA）的抑制作用，AmB DMP对猪皮肤内CA生物膜的杀伤率在24小时内达到100%。AmB DMP 能够以 301.34 ± 46.86 μm 的插入深度刺穿切除的新生猪皮肤。离体皮肤动力学和药物沉积研究表明 AmB 主要沉积在真皮中。一项体内皮肤动力学研究表明，曲线下面积 (AUC _0-inf) AmB DMP 和 IV (Fungizone® bolus injection 1 mg/kg) 组的值分别为 8823.0 d∙μg/g 和 33.4 d∙μg/g（高 264 倍）。AmB 在皮肤中保持高水平（219.07 ± 102.81 μg/g 或更多），直到应用 AmB DMP 后 7 天。药代动力学和生物分布研究表明，AmB DMP 组血浆、肾脏、肝脏和脾脏中的 AmB 浓度显着低于 IV 组。因此，该系统解决了静脉注射 AmB 的全身副作用，并将药物定位在皮肤内一周。这项工作建立了一种新颖、简单且有效的长效局部皮内给药方法。