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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要据世界卫生组织称，世界上约三分之一的人口感染了新冠病毒结核分枝杆菌 (Mtb)，多达 10% 的感染者会发展为活动性结核病（结核病）在感染后的某个时候，结核病是一种可以治愈的疾病，但死亡率仍然很高（2016 年为 1.7）。由于结核病发病率高，全球结核病控制工作十分复杂。在发展中国家，耐药结核病的出现是最近添加的一种药物。世界卫生组织推荐的治疗耐药结核菌的药物清单，能够有效缩短治疗时间。然而，口服 Cfz 会带来起效延迟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开发有效的治疗方法。雾化给药，例如 Cfz，直接靶向肺部改进药物的开发。治疗疾病的疗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) 已研究了微粒封装用于气溶胶输送。开发有效颗粒输送系统的关键参数是：1) 肺深部。递送，2) 肺泡巨噬细胞摄取颗粒（结核分枝杆菌入侵和复制的主要部位）3) 药物释放，4) 药物剂量，以及 5) 平衡递送的药物质量与释放以及安全性。确保有效的分散和安全对于有效的微粒配方至关重要。可以使用喷雾干燥来制备用于深肺递送和尺寸介导的吞噬作用的粒径以上的颗粒。为了解决药物释放和剂量的限制，Lynntech 建议开发聚合乙缩醛葡聚糖 (Ac-Dex) 封装 Cfz 可通过使用 pH- 来实现差异药物释放。响应性 Ac-Dex 颗粒，能够在吞噬溶酶体的酸性环境中快速释放 Cfz 增加 Mtb 感染发生的地方，这种释放机制可以快速使 Cfz 的 MIC 升高。到达巨噬细胞内，同时提高有效性，同时减少所需剂量 Cfz，因此还减少了 Ac-Dex 降解的副产物（乙醇、丙酮、葡聚糖）。我们的具体目标是提供使用和调整这些Ac-的概念验证。用于在 Mtb 感染细胞内释放活性 Cfz 的 Dex 颗粒这些目标包括 (1) 开发新型 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 递送和杀菌作用，(3) 评估药代动力学 (PK) 的吸收和释放以及体内功效研究。第一阶段的成功完成将证明开发吸入用 Ac-Dex 颗粒的可行性然后，我们会将最佳样品纳入干粉配方中，以气雾剂形式输送。这项研究最终形成了一个用于提供各种结核病药物和药物的平台。其组合用于结核病治疗。