An Inhaled Clofazimine Formulation for the Treatment of Tuberculosis

用于治疗结核病的吸入氯法齐明制剂

• 批准号: 9622838
• 负责人: Jared Franklin Mike
• 金额: $ 16.52万
• 依托单位: LYNNTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9622838
• 关键词: Acetone; Address; Adverse effects; Aerosols; Alveolar Macrophages; Antibiotics; Benign; Cardiac; Cell Line; Cells; Clinical; Dermal; Developing Countries; Development; Dextrans; Disease; Distress; Dose; Drug Carriers; Drug Combinations; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug resistance in tuberculosis; Effectiveness; Encapsulated; Ensure; Environment; Equilibrium; Ethanol; Formulation; Future; Goals; Heart; Human body; In Vitro; Incidence; Individual; Infection; Inhalation; Insufflation; Intestines; Length; Lung; Mediating; Methods; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Nature; New Mexico; Oral; Oral Administration; Organism; Particle Size; Phagocytosis; Phagolysosome; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Polymers; Population; Powder dose form; Preparation; Regimen; Research; Resistance; Risk; Safety; Sampling; Site; Skin; Small Business Innovation Research Grant; Strategic Planning; System; Technology; Therapeutic; Time; Treatment Protocols; Tuberculosis; Universities; Work; World Health Organization; absorption; aerosolized; bactericide; cytotoxicity; dosage; drug efficacy; gastrointestinal; improved; in vivo; lipophilicity; macrophage; mortality; novel; particle; stem; systemic toxicity; treatment duration; tuberculosis drugs; tuberculosis treatment; uptake

PROJECT SUMMARY According to the World Health Organization, about one third of the world’s population is infected with Mycobacterium tuberculosis (Mtb), and as many as 10% of infected individuals will develop active tuberculosis (TB) at some point after infection. TB is a curable disease, yet it still has a high mortality rate (in 2016, 1.7 million people died from the disease). The global control of TB is complicated due to the high incidence of TB in developing countries, and the emergence of drug resistant TB. Cfz is a drug that has been recently added to WHO recommended list of drugs to treat drug resistant TB strains, effectively able to shorten treatment times. However, oral administration of Cfz poses problems such as delayed onset and deleterious side effects (gastrointestinal, dermal, cardiac). An existing goal to improve TB treatment consists of developing effective aerosolized delivery of drugs, such as Cfz, to directly target the lungs. The development of improved drug therapeutics for treatment of diseases has been listed as a priority in the strategic plan of the National Institute of Allergy and Infectious Diseases (NIAID). Microparticle encapsulation has been studied for aerosol delivery of TB drugs. Critical parameters in the development of an efficient particle delivery system are: 1) deep lung delivery, 2) particle uptake by alveolar macrophages (the primary site of invasion and replication of Mtb) 3) drug release, 4) drug dosage, and 5) safety. Balancing the mass of drug delivered against release as well as ensuring efficient dispersal and safety is critical to an effective formulation. Microparticles with precise control over particle size for deep lung delivery and size-mediated phagocytosis can be prepared using spray drying. To address the limitations in drug release and dosage, Lynntech proposes to develop polymeric acetalated dextran (Ac-Dex) encapsulating Cfz. Differential drug release can be achieved through the use of pH- responsive Ac-Dex particles, able to release Cfz within the acidic environment in phagolysosomes, quickly increasing where the bulk of Mtb infection occurs. This release mechanism can quickly enable MIC of Cfz to be reached within macrophages, simultaneously increasing effectiveness while reducing the required dosage of Cfz, thus reducing side effects. Additionally, the by-products of Ac-Dex degradation (ethanol, acetone, dextran) are relatively benign. Our specific aims are devised to provide proof-of-concept on using and tuning these Ac- Dex particles for active Cfz release within Mtb infected cells. These aims include (1) developing novel Ac-Dex particles encapsulating Cfz, (2) demonstrate that particle uptake and release enhances in vitro Cfz delivery and bactericidal effect, and (3) evaluate uptake and release in pharmacokinetic (PK) and efficacy in vivo studies. The successful completion Phase I will demonstrate feasibility of developing Ac-Dex particles for inhaled delivery of Cfz. We will then incorporate optimal samples into dry powder formulations for aerosol delivery in a future Phase II effort. This research ultimately forms a platform for delivery of a variety of TB drugs and combinations thereof for TB treatment.

项目摘要 根据世界卫生组织的说法，世界大约三分之一的人口感染了 结核分枝杆菌（MTB），多达10％的感染者会发展为活跃的结核病 （TB）感染后的某个时刻。结核病是一种可治愈的疾病，但仍具有高死亡率（2016年，1.7 百万人死于该疾病）。由于结核病的高入，结核病的全球控制变得复杂 在发展中国家以及耐药结核病的出现。 CFZ是最近添加到的药物 谁推荐了治疗抗药性结核病菌株的药物清单，有效地缩短了治疗时间。 但是，CFZ的口服给药具有延迟发作和有害副作用等问题 （胃肠道，皮肤，心脏）。改善结核病治疗的现有目标包括发展有效 诸如CFZ之类的药物的气溶性输送直接靶向肺部。改善药物的发展 用于治疗疾病的治疗方法已被列为国家研究所战略计划的优先事项 过敏和传染病（NIAID）。微粒封装已经研究了用于气溶胶输送的 结核病药物。有效粒子输送系统开发中的关键参数是：1）深肺 交付，2）肺泡巨噬细胞的颗粒吸收（MTB的入侵和复制的主要部位）3） 药物释放，4）药物剂量和5）安全性。平衡与释放和释放的药物群众的平衡 确保有效的分散和安全对于有效的公式至关重要。具有精确控制的微粒 可以使用喷雾干燥来制备颗粒尺寸以进行深肺输送和尺寸介导的吞噬作用。 为了解决药物释放和剂量的局限 核心（AC-DEX）封装CFZ。通过使用pH-可以实现差异药物释放 响应式AC-dex颗粒，可以在吞噬物体的酸性环境中释放CFZ，迅速 在大部分MTB感染发生的地方增加。这种释放机制可以快速使CFZ的MIC成为 在巨噬细胞内到达，仅提高效力，同时降低所需剂量 CFZ，从而减少副作用。另外，AC-脱核降解的副产品（乙醇，丙酮，葡萄糖） 相对良性。我们设计的具体目标是为使用和调整这些AC-提供概念概念。 在MTB感染细胞内释放活性CFZ的DEX颗粒。这些目的包括（1）开发新型的AC-DEX 封装CFZ的颗粒（2）证明颗粒的摄取和释放增强了体外CFZ的递送和 杀菌作用和（3）评估药代动力学（PK）的摄取和释放以及体内研究的有效性。 成功完成阶段I将证明为继承而开发AC-DEX颗粒的可行性 交付CFZ。然后，我们将最佳样品纳入干粉公式中，以在A中递送气溶胶 未来的第二阶段努力。这项研究最终构成了提供各种结核病药物的平台， 其组合用于结核病治疗。