Mucus-Penetrating Antibiotics for Lung Infections Associated with Cystic Fibrosis

粘液穿透性抗生素治疗囊性纤维化相关肺部感染

基本信息

批准号：
8057564
负责人：
Hongming Chen
金额：
$ 18.04万
依托单位：
KALA PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-15 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8057564
关键词：
Acute Address Adhesions Adverse effects Animals Anti-Bacterial Agents Antibiotic Therapy Antibiotics Asthma Bacterial Infections Breathing Bronchoalveolar Lavage Canis familiaris Ceftazidime Characteristics Chemicals Chronic Chronic Obstructive Airway Disease Clinical Clinical Trials Coughing Cystic Fibrosis Development Diffuse Diffusion Dosage Forms Dose Drug Carriers Drug Delivery Systems Drug Formulations Drug Kinetics Effectiveness Engineering Ensure Excipients Fiber Frequencies Glycolates Goals Head High Pressure Liquid Chromatography Hour Human Infection Intercellular Fluid Investigational New Drug Application Kinetics Lactams Lead Legal patent Licensing Liposomes Lung Lung diseases Marketing Measures Methods Minimum Inhibitory Concentration measurement Modality Monitor Monobactams Morbidity - disease rate Mucociliary Clearance Mucous body substance Particle Size Pharmaceutical Preparations Pharmacologic Substance Phase Piperacillin Plasma Polyethylene Glycols Polymers Powder dose form Preparation Process Production Quality Control Rattus Research Institute Resistance Respiratory Tract Infections Respiratory physiology Saline Site Small Business Innovation Research Grant Sprague-Dawley Rats Sputum Structure of parenchyma of lung Surface System Technology Testing Therapeutic Thick Time Tissues Toxic effect Work absorption bactericide base clinical efficacy cystic fibrosis patients good laboratory practice improved male meetings mortality nanoparticle particle pre-clinical preclinical efficacy preclinical safety reconstitution respiratory safety study safety testing tandem mass spectrometry

项目摘要

DESCRIPTION (provided by applicant): Chronic endobronchial bacterial infections represent the primary cause of morbidity (declining lung function) and mortality in cystic fibrosis (CF). Inhaled antibiotics have become an increasingly attractive therapeutic modality compared to IV antibiotics, as inhaled drug is delivered directly to the site of infection while minimizing systemic exposure/toxicity. Nevertheless, short half-lives (typical t1/2 ~0.8 hr) in infected sputum limit antibiotic efficacy and necessitate multiple daily dosing. This shortcoming is especially critical for ¿-lactam antibiotics, whose maximum efficacy relies on maintaining drug concentration above the minimum inhibitory concentration (MIC); the only approved inhaled ¿-lactam (Cayston(r)) fails to sustain drug levels in CF sputum above MIC90 for even half the duration between dosing (3x daily). Previous attempts to achieve sustained local delivery of antibiotics were mostly based on polymeric or liposomal particles that do not possess Kala's proprietary mucus-resistant coatings (conventional particles, or "CP"). However, CP are extensively trapped at the very surface of the viscoelastic sputum lining the airways of CF patients, and are thus readily eliminated by mucociliary and cough-driven sputum clearance (thus precluding extended drug release). To overcome the sputum barrier, Hanes (co-founder of Kala) and coworkers pioneered the mucus-penetrating particle (MPP) technology, exclusively licensed to Kala. MPP rapidly penetrate into deep mucus layers and, thus, can persist longer and provide unprecedented drug-release durations at mucosal surfaces. A variety of MPP systems, including MPP composed entirely of excipients regarded by FDA as GRAS (Generally Recognized As Safe), have been engineered to penetrate purulent sputum expectorated from CF patients. In Phase I, we will build upon this work to formulate MPP for inhalation that slowly releases -lactam antibiotics. We expect that MPP will enhance bactericidal effectiveness against endobronchial bacterial infections by maintaining ¿-lactam antibiotics above MIC90 in sputum for extended durations compared to free drug. In Specific Aim 1, we will formulate MPP that contain two common IV ¿-lactams for CF lung infections. We will measure particle size, mobility in sputum, drug loading, drug release kinetics and storage stability. We will advance the MPP with the most suitable drug delivery characteristics to animal studies. In Specific Aim 2, we will administer ¿-lactam- loaded MPP to the lungs of healthy rats, and confirm if drug levels in lung mucus are maintained above MIC90 for at least 24 hrs. Successful completion of these studies will lead to a Phase II proposal to develop ¿-lactam MPP into a suitable pharmaceutical dosage form for extensive preclinical efficacy and safety testing in preparation for clinical trials. The overall goal is to develop a shelf-stable, sustained-release ¿-lactam formulation that is efficacious with convenient 1W-daily dosing (by maintaining sputum drug levels above MIC90 for at least 24 hrs). By offering improved pharmacokinetics in the lung, we expect ¿-lactam MPP will also improve therapies against bacterial infections in other pulmonary diseases, such as severe asthma and COPD. PUBLIC HEALTH RELEVANCE: Chronic endobronchial bacterial infections represent the primary cause of morbidity and mortality in cystic fibrosis. The only marketed ¿-lactam antibiotic for inhalation (Cayston(r)) provides drug levels in the lung needed for maximally-effective bactericidal activity for only ~10-12 hours per day despite frequent administration (3 times daily). Kala Pharmaceuticals seeks to prove that our proprietary delivery systems can provide local delivery of ¿-lactam antibiotics to the lungs that will markedly enhance current antibacterial therapy by providing a once-daily product that maintains drug concentration for 24h/day.

描述（由申请人提供）：慢性支气管内细菌感染是囊性纤维化（CF）发病（肺功能下降）和死亡的主要原因，因为吸入药物是通过吸入给药的，因此与静脉注射抗生素相比，吸入抗生素已成为越来越有吸引力的治疗方式。直接到达感染部位，同时最大限度地减少全身暴露/毒性然而，受感染痰液的半衰期短（典型的 t1/2 ~0.8 小时）限制了抗生素的功效。并且需要每日多次给药，这一缺点对于 ¿ -内酰胺类抗生素，其最大功效依赖于将药物浓度维持在最低抑菌浓度（MIC）以上，是唯一批准的吸入性抗生素；内酰胺 (Cayston(r)) 甚至在给药间隔时间的一半（每日 3 次）内也无法将 CF 痰液中的药物水平维持在 MIC90 以上，之前实现抗生素持续局部递送的尝试大多基于聚合物或脂质体颗粒，但这些颗粒并不能维持在 MIC90 以上。拥有 Kala 专有的抗粘液涂层（传统颗粒，或“CP”），但是 CP 通常被困在粘弹性痰衬的表面。因此，它很容易通过粘液纤毛和咳嗽驱动的痰液清除而消除（从而阻止药物长时间释放），Hanes（Kala 的联合创始人）和同事首创了粘液穿透颗粒（MPP）。）技术，独家授权给 Kala，可快速渗透到深层粘液层，因此可以持续更长时间，并在粘膜表面提供前所未有的药物释放持续时间。系统，包括完全由 FDA 视为 GRAS（公认安全）的赋形剂组成的 MPP，已被设计用于渗透 CF 患者预期的脓痰。在第一阶段，我们将在这项工作的基础上配制缓慢释放的吸入用 MPP。 -内酰胺类抗生素，我们预计 MPP 将通过维持 ¿ 来增强针对支气管内细菌感染的杀菌效果。 -与游离药物相比，痰液中内酰胺抗生素的持续时间高于 MIC90 在具体目标 1 中，我们将配制包含两种常见 IV 的 MPP。 -用于 CF 肺部感染的内酰胺。我们将测量粒径、痰中的流动性、药物负载、药物释放动力学和储存稳定性。在具体目标 2 中，我们将推进具有最适合的药物输送特性的 MPP。管理 ¿内酰胺负载的 MPP 进入健康大鼠的肺部，并确认肺粘液中的药物水平是否保持在 MIC90 以上至少 24 小时，这些研究的成功完成将导致制定 II 期提案。 -内酰胺 MPP 制成合适的药物剂型，用于广泛的临床前功效和安全性测试，为临床试验做准备。总体目标是开发一种货架稳定、缓释的药物。 -内酰胺制剂，每日 1W 剂量方便有效（通过将痰药物水平维持在 MIC90 以上至少 24 小时），通过改善肺部药代动力学，我们预计 ¿ -内酰胺MPP还将改善其他肺部疾病（例如严重哮喘和慢性阻塞性肺病）细菌感染的治疗。公共健康相关性：慢性支气管内细菌感染是囊性纤维化发病和死亡的主要原因。尽管频繁给药（每天 3 次），吸入用内酰胺抗生素（Cayston(r)）每天仅约 10-12 小时即可提供最大有效杀菌活性所需的肺部药物水平。交付系统可以提供 ¿ -用于肺部的内酰胺抗生素，通过提供每日一次的产品，每天 24 小时维持药物浓度，将显着增强当前的抗菌治疗。