Development of synergistic clofazimine-amikacin inhalable powders for the treatment of pulmonary Mycobacterium abscessus infections

氯法齐明-阿米卡星协同吸入粉剂治疗肺部脓肿分枝杆菌感染的研制

• 批准号: 10256328
• 负责人: Zachary N Warnken
• 金额: $ 25.64万
• 依托单位: VIA THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256328
• 关键词: Abscess; Aerosols; Amikacin; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacillus; Chronic; Clinical; Communities; Complex; Cystic Fibrosis; Deposition; Development; Devices; Disease Progression; Dose; Drug Exposure; Drug Kinetics; Drug resistance; Engineering; Environment; Evaluation; Excipients; Exhibits; Formulation; Generations; Goals; Granuloma; Hydrophobicity; In Vitro; Infection; Inhalation; Inhalation Therapy; Intellectual Property; Left; Liposomes; Lung; Lung diseases; Lung infections; Microbial Biofilms; Modality; Modeling; Monitor; Mus; Mycobacterium Infections; Mycobacterium abscessus; Mycobacterium avium Complex; Mycobacterium tuberculosis; Outcome; Pathology; Penetration; Performance; Pharmaceutical Preparations; Pharmacotherapy; Population; Powder dose form; Prevalence; Property; Regimen; Research; Resistance; Risk; Route; Site; Spleen; Surface; Techniques; Therapeutic; Tissues; Translations; Treatment Protocols; Treatment outcome; Tuberculosis; Virulence; Water; alternative treatment; antimicrobial; base; clinically translatable; drug distribution; drug efficacy; drug inhalation; drug repurposing; efficacious treatment; extracellular; improved; improved outcome; in vitro Model; in vitro activity; in vivo; in vivo Model; in vivo evaluation; innovation; macrophage; mortality; mouse model; mycobacterial; non-tuberculosis mycobacteria; novel; off-patent; particle; pathogen; pre-clinical; pulmonary function; side effect; success; systemic toxicity; therapy outcome; treatment guidelines; uptake; virtual

PROJECT SUMMARY Mycobacterium abscessus (Mab) lung infections are extremely resistant to drug therapy and are growing in prevalence, particularly in the cystic fibrosis community where they are associated with decreased lung function and a high mortality rate. Current treatment guidelines recommend a two-year regimen of a combination of four antibiotics that are associated with numerous systemic toxicities that require regular monitoring, and treatments are successful in only 30% of cases. The noted virulence of Mab and recalcitrance to antibiotic therapy may be related to its ability to persist both extracellularly in biofilms and abscesses and intracellularly in macrophages. Delivery of antibiotics by the inhalation route is promising alternative for the treatment of Mab, as it would enable high drug concentrations at both sites of infection while minimizing systemic drug exposure. However, two promising inhaled antibiotics, clofazimine (CFZ) and liposomal amikacin (AMK), have resulted in little to no efficacy when utilized in vivo to treat chronic Mab lung infections, despite notable in vitro activity against Mab and in vivo activity against other mycobacterial species. Based upon the premise that inhaled monotherapy is ineffective, we have developed a patentable inhaled co- formulation of CFZ and AMK which will enable simultaneous delivery of these antibiotics to the site of Mab lung infection, thereby enabling the transition of the noted in vitro synergistic activity of the antibiotics to an in vivo environment. The proposed research seeks to optimize the mechanism of formulation engineering and composition CFZ-AMK powder through the in vitro and in vivo evaluation of composite spray dried CFZ-AMK particles and physically blended CFZ and AMK micronized powders prepared at varying mass ratios. The relationship between powder composition and properties will be determined through evaluation of powder aerosol performance using commercially available devices, modeling of in vitro dissolution rate, assessing extracellular and intracellular antimicrobial activity and determining in vivo pharmacokinetic parameters and efficacy in a chronic Mab infection model. The significance of this study is that it utilizes existing, already- proven-safe drugs and repurposes them in a patentable manner for simultaneous lung delivery and at-site synergistic activity, which will improve therapeutic outcomes in this extremely difficult to treat infection. The expected outcome is that inhaled CFZ-AMK fixed dose combination powders will successfully treat multiple facets of Mab lung disease, which will de-risk the transition from the pre-clinical to clinical stages.

项目摘要 结核分枝杆菌（Mab）肺部感染对药物治疗具有极强的耐药性， 患病率，特别是在囊性纤维化社区，他们与减少肺 功能和高死亡率。目前的治疗指南推荐一个为期两年的方案， 四种抗生素的组合与许多全身毒性相关，需要定期 监测和治疗仅在30%的病例中成功。单克隆抗体的毒力显著， 抗生素治疗可能与其在细胞外生物膜和细胞膜中持续存在的能力有关， 在巨噬细胞内。通过吸入途径递送抗生素是治疗慢性阻塞性肺疾病的有希望的替代方案。 单抗治疗，因为它可以在两个感染部位实现高药物浓度，同时最大限度地减少 全身性药物暴露。然而，两种有前途的吸入抗生素，氯法齐明（CFZ）和脂质体 阿米卡星（AMK）在体内用于治疗慢性Mab肺部感染时几乎没有功效， 尽管对Mab的体外活性和对其它分枝杆菌物种的体内活性显著。基于 在吸入单一疗法无效的前提下，我们开发了一种可申请专利的吸入联合疗法， CFZ和AMK的制剂，其能够将这些抗生素同时递送至Mab肺部位 感染，从而能够将抗生素的体外协同活性转变为体内协同活性。 环境拟议的研究旨在优化配方工程的机制， 通过对复合喷雾干燥的CFZ-AMK的体外和体内评价， 颗粒和以不同质量比制备的物理共混的CFZ和AMK微粉化粉末。的 粉末成分与性能之间的关系将通过对粉末的评价来确定。 使用市售装置的气雾剂性能，体外溶出速率建模，评估 细胞外和细胞内的抗微生物活性和测定体内药代动力学参数， 在慢性Mab感染模型中的有效性。这项研究的意义在于它利用了现有的，已经- 证明安全的药物，并以可专利的方式将其重新用于同时肺部输送和现场 协同活性，这将改善这种极难治疗的感染的治疗效果。的 预期的结果是，吸入CFZ-AMK固定剂量组合粉末将成功地治疗多个 这将降低从临床前阶段过渡到临床阶段的风险。