Department of Pharmaceutical Sciences, University of Perugia, via del Liceo 1, 06123 Perugia, Italy.
Department of Medicine and Surgery, University of Perugia, piazzale Lucio Severi 1, 06132 Perugia, Italy.
J Control Release. 2023 Jan;353:1023-1036. doi: 10.1016/j.jconrel.2022.11.043. Epub 2022 Dec 21.
Inflammation is a key pathological driver in cystic fibrosis (CF). Current therapies are ineffective in treating and preventing the escalation of inflammatory events often exacerbated by superimposed infection. In this work, we propose a novel treatment based on the pulmonary administration of anakinra, a non-glycosylated recombinant form of IL-1Ra. An inhalable dry powder of anakinra was successfully developed to meet the specific needs of lung drug delivery. The new formulation was investigated in vitro for aerodynamic performances and activity and in vivo for its pharmacological profile, including the pharmacokinetics, treatment schedule, antimicrobial and anti-inflammatory activity and systemic toxicity. The protein was structurally preserved inside the formulation and retained its pharmacological activity in vitro immediately after preparation and over time when stored at ambient conditions. Anakinra when delivered to the lungs showed an improved and extended therapeutic efficacy in CF models in vivo as well as higher potency compared to systemic delivery. Peripheral side effects were significantly reduced and correlated with lower serum levels compared to systemic treatment. These findings provide proof-of-concept demonstration for anakinra repurposing in CF through the pulmonary route.
炎症是囊性纤维化 (CF) 的关键病理驱动因素。目前的治疗方法在治疗和预防炎症事件的升级方面效果不佳，这些炎症事件经常因叠加感染而加剧。在这项工作中，我们提出了一种基于肺部给予 anakinra 的新治疗方法，anakinra 是一种非糖基化的 IL-1Ra 重组形式。成功开发了一种可吸入的 anakinra 干粉剂，以满足肺部药物输送的特殊需求。该新制剂在体外进行了空气动力学性能和活性研究，在体内进行了药代动力学、治疗方案、抗菌和抗炎活性以及全身毒性研究。在制剂中，蛋白质的结构得到了保留，并且在制备后立即以及在环境条件下储存时，其体外的药理活性得以保持。当将 anakinra 递送到肺部时，与全身给药相比，它在 CF 模型中的治疗效果得到了改善和延长，并且具有更高的效力。与全身治疗相比，外周副作用显著减少，并且与血清水平降低相关。这些发现通过肺部途径为 anakinra 在 CF 中的重新利用提供了概念验证。
