Ravon Faustine, Berns Emilie, Lambert Isaline, Rens Céline, Adnet Pierre-Yves, Kiass Mehdi, Megalizzi Véronique, Delporte Cédric, Baulard Alain, Mathys Vanessa, Boarbi Samira, Wauthoz Nathalie, Fontaine Véronique
Unit of Microbiology, Bioorganic and Macromolecular Chemistry, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium.
Unit of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium.
Pharmaceutics. 2025 May 27;17(6):705. doi: 10.3390/pharmaceutics17060705.
In vitro, vancomycin (VAN) and tetrahydrolipstatin (THL) together have been shown to synergistically inhibit (Mtb), the world's most infectious killer. The poor oral bioavailability of VAN and THL and predominant tropism of Mtb infection to the lungs and alveolar macrophages make pulmonary administration highly attractive. This study aimed to develop and assess the efficacy of dry powders for inhalation of VAN microparticles embedded with THL. : The dry powders produced by spray-drying, with or without hydrogenated castor oil (HCO), were characterized for their physicochemical properties among others by HPLC-DAD. The fast-screening impactor was used to determine powder aerodynamic properties, and VAN and THL releases were established from the paddle over disk method. Biological activities were assessed in a new -infected macrophage model and in Mtb-infected mice. : The addition of 25% HCO enables co-deposition (fine particle dose) at the desired weight ratio and co-releasing of VAN and THL in aqueous media. Microparticles with 0% to 50% HCO drastically reduced cytoplasmic survival (99.9% to 62.5%, respectively), with higher efficacy at low HCO concentration. Consequently, VAN/THL with or without 25% HCO was evaluated in Mtb-infected mice. Although no decrease in Mtb lung burden was observed after two weeks of administration, the endotracheal administration of VAN 500 mg/kg and THL 50 mg/kg with 25% HCO administrated three times during five days concomitantly with daily oral rifampicin (10 mg/kg) demonstrated 2-fold bacterial burden reduction compared to the group treated with RIF alone. : HCO was crucial for obtaining a fine particle dose at the synergistic weight ratio (VAN/THL 10:1) and for releasing both drugs in aqueous media. With oral administration of the first-line rifampicin, the dry powder VAN/THL/25% HCO was able to exert a potential anti-tubercular effect in vivo in Mtb-infected mice after five days.
在体外实验中，已证明万古霉素（VAN）和四氢脂抑素（THL）联合使用可协同抑制结核分枝杆菌（Mtb），这是全球最具传染性的致命病菌。VAN和THL口服生物利用度差，且Mtb感染主要趋向于肺部和肺泡巨噬细胞，这使得肺部给药极具吸引力。本研究旨在开发并评估载有THL的VAN吸入干粉的疗效。通过喷雾干燥制备的含或不含氢化蓖麻油（HCO）的干粉，采用高效液相色谱 - 二极管阵列检测法（HPLC - DAD）等方法对其理化性质进行表征。使用快速筛分撞击器测定粉末的空气动力学性质，并采用桨碟法确定VAN和THL的释放情况。在新感染的巨噬细胞模型和Mtb感染的小鼠中评估生物活性。添加25%的HCO可实现所需重量比的共沉积（细颗粒剂量）以及VAN和THL在水性介质中的共释放。含0%至50% HCO的微粒显著降低了细胞质内存活率（分别为99.9%至62.5%），在低HCO浓度下效果更佳。因此，对含或不含25% HCO的VAN/THL在Mtb感染的小鼠中进行了评估。尽管给药两周后未观察到Mtb肺部负荷降低，但在五天内每天口服利福平（10 mg/kg）的同时，气管内给予500 mg/kg的VAN和50 mg/kg的THL以及25%的HCO三次，与单独使用利福平治疗的组相比，细菌负荷降低了2倍。HCO对于在协同重量比（VAN/THL 10:1）下获得细颗粒剂量以及在水性介质中释放两种药物至关重要。在口服一线利福平的情况下，干粉VAN/THL/25% HCO在五天后能够在Mtb感染的小鼠体内发挥潜在的抗结核作用。
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