Maloney Sara E, Stewart Ian E, Podell Brendan K, Gary Hadley E, Mecham Jeffrey B, Berube Bryan J, Baldwin Susan L, Coler Rhea N, Hickey Anthony J
Technology Advancement and Commercialization, RTI International, Research Triangle Park, NC 27709, USA.
Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA.
Pharmaceuticals (Basel). 2023 May 11;16(5):729. doi: 10.3390/ph16050729.
() has infected one-quarter of the world's population and led to the deaths of 1.6 million individuals in 2021 according to estimates from the World Health Organization. The rise in prevalence of multidrug-resistant and extensively drug-resistant strains coupled with insufficient therapies to treat such strains has motivated the development of more effective treatments and/or delivery modalities. Bedaquiline, a diarylquinoline antimycobacterial agent, effectively targets mycobacterial ATP synthase but may lead to systemic complications upon oral delivery. Targeted delivery of bedaquiline to the lungs represents an alternative strategy to harness the sterilizing benefits of the drug against while mitigating off-target side effects. Two pulmonary delivery modalities were developed herein, including dry powder inhalation and liquid instillation. Despite bedaquiline's poor water solubility, spray drying was performed in predominantly aqueous conditions (≥80%) to avoid a closed-loop, inert system. Aerosols of spray-dried bedaquiline with L-leucine excipient outperformed spray-dried bedaquiline alone, demonstrating superior fine particle fraction metrics (~89% of the emitted dose below <5 µm), suitable for inhalation therapies. Furthermore, the use of a 2-hydroxypropyl-β-cyclodextrin excipient allowed a molecular dispersion of bedaquiline in an aqueous solution for liquid instillation. Both delivery modalities were successfully administered to Hartley guinea pigs for pharmacokinetic analysis and were well-tolerated by the animals. Intrapulmonary liquid delivery of bedaquiline led to adequate serum absorption and appropriate peak serum concentrations of the drug. The liquid formulation was superior in systemic uptake compared to the powder formulation. The predominant route via which bacilli enter the body is aerosol droplets that are deposited onto airway surfaces. For this reason, we believe that further studies should focus on inhalation or intrapulmonary therapies that target the site of entry and primary site of infection for .
（某病菌）已感染全球四分之一的人口，据世界卫生组织估计，2021年导致160万人死亡。耐多药和广泛耐药菌株的流行率上升，加上治疗此类菌株的疗法不足，促使人们开发更有效的治疗方法和/或给药方式。贝达喹啉是一种二芳基喹啉抗分枝杆菌药物，可有效靶向分枝杆菌ATP合酶，但口服给药可能会导致全身并发症。将贝达喹啉靶向递送至肺部是一种替代策略，既能利用该药物的杀菌益处对抗（病菌），又能减轻脱靶副作用。本文开发了两种肺部给药方式，包括干粉吸入和液体滴注。尽管贝达喹啉的水溶性较差，但喷雾干燥主要在水性条件（≥80%）下进行，以避免使用闭环惰性系统。含L-亮氨酸辅料的喷雾干燥贝达喹啉气雾剂的性能优于单独的喷雾干燥贝达喹啉，显示出优异的细颗粒分数指标（发射剂量的约89%低于<5 µm），适用于吸入疗法。此外，使用2-羟丙基-β-环糊精辅料可使贝达喹啉在水溶液中形成分子分散体用于液体滴注。两种给药方式均成功给予哈特利豚鼠进行药代动力学分析，且动物耐受性良好。贝达喹啉的肺内液体给药导致药物有足够的血清吸收和适当的血清峰值浓度。与粉末制剂相比，液体制剂的全身吸收更好。结核杆菌进入人体的主要途径是沉积在气道表面的气溶胶飞沫。因此，我们认为进一步的研究应聚焦于针对结核杆菌进入部位和主要感染部位的吸入或肺内疗法。
