Preparation Strategies of the Anti-Mycobacterial Drug Bedaquiline for Intrapulmonary Routes of Administration.
Preparation Strategies of the Anti-Mycobacterial Drug Bedaquiline for Intrapulmonary Routes of Administration.
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抗菌药物的制备策略，用于肺内给药途径。
DOI：
10.3390/ph16050729
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发表时间：
2023-05-11
期刊：
影响因子：
--
通讯作者：
Hickey AJ
中科院分区：
文献类型：
--
作者：
Maloney SE;Stewart IE;Podell BK;Gary HE;Mecham JB;Berube BJ;Baldwin SL;Coler RN;Hickey AJ
根据世界卫生组织的估计，结核分枝杆菌感染了世界四分之一的人口，并在2021年导致160万人死亡。耐多药和广泛耐药结核分枝杆菌菌株流行率的上升，加上治疗这些菌株的疗法不足，促使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类抗细菌药物，有效靶向分枝杆菌ATP合成酶，但口服给药时可能导致全身并发症。有针对性地将贝达喹啉输送到肺部是利用该药物对结核分枝杆菌的灭菌益处同时减轻脱靶副作用的另一种策略。本文提出了两种肺给药方式，包括干粉吸入和液体滴注。尽管贝达喹啉的水溶性很差，但喷雾干燥主要在水条件下进行（≥80%），以避免闭环惰性系统。与l -亮氨酸辅料一起喷雾干燥的贝达喹啉气雾剂优于单独喷雾干燥的贝达喹啉，显示出优越的细颗粒分数指标（<5µm以下放射剂量的~89%），适合吸入治疗。此外，使用2-羟丙基-β-环糊精赋形剂可以使贝达喹啉在水溶液中分子分散，用于液体滴注。两种给药方式均成功地给予哈特利豚鼠进行药代动力学分析，并被动物良好耐受。肺内液体输送贝达喹啉导致充分的血清吸收和适当的血药浓度峰值。与粉末制剂相比，液体制剂在全身吸收方面优于粉末制剂。结核分枝杆菌进入人体的主要途径是沉积在气道表面的气溶胶液滴。因此，我们认为进一步的研究应该集中在针对结核分枝杆菌进入部位和原发感染部位的吸入或肺内治疗上。
Mycobacterium tuberculosis (M.tb) 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 M.tb 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 M.tb 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 M.tb 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 M.tb.
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影响因子：
5.4
作者：
Fox, Gregory J;Menzies, Dick
通讯作者：
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影响因子：
3.3
作者：
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