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（由应用提供）：慢性内与内物种细菌感染代表了囊性纤维化（CF）中发病率（肺功能下降）和死亡率的主要原因。与静脉注射抗生素相比，吸入的抗生素已成为一种越来越有吸引力的治疗方法，因为遗传药物直接递送到感染部位，同时最大程度地减少了全身暴露/毒性。然而，在感染的痰液限制抗生素效率和必要的多次每日给药中，短半衰期（典型的T1/2〜0.8小时）。这种缺点对于� -lactam抗生素特别重要，其最大效率依赖于在最低抑制浓度（MIC）以上的药物浓度中保持。唯一被批准的遗传� -lactam（Cayston（R））在MIC90上方的CF痰中无法维持药物水平，甚至在给药之间的一半持续时间（每天3倍）。以前实现抗生素局部递送的尝试主要是基于不具有Kala专有粘液耐药涂层（常规颗粒或“ CP”）的聚合物或脂质体颗粒。然而，CP被广泛捕获在CF患者气道衬里的粘弹痰的表面上，因此很容易被粘膜纤毛和COUG驱动的痰清除（排除扩展药物释放）消除。为了克服痰屏障，Hanes（Kala的联合创始人）和同事开创了粘液穿透粒子（MPP）技术，专门获得了卡拉的许可。 MPP迅速渗透到深层粘液层中，因此可以持续更长的时间，并在粘膜表面提供前所未有的药物释放持续时间。已经设计了各种MPP系统，包括完全由FDA视为GRA（通常被认为是安全的）的赋形剂组成的MPP，已设计为穿透CF患者预期的纯净痰液。在第一阶段，我们将以这项工作为基础，以制定MPP的吸入，以缓慢释放-lactam抗生素。我们预计，与免费药物相比，MIP在痰中的MIC90上以上的MIC90高于MIC90，MPP将增强对支气管细菌感染的细菌有效性。在特定的目标1中，我们将制定MPP，其中包含两个常见的IV»-lactams用于CF肺部感染。我们将测量粒度，痰液中的迁移率，药物加载，药物释放动力学和储存稳定性。我们将以最合适的药物递送特征来推进MPP。在特定的目标2中，我们将对健康大鼠的肺进行施用� -lactam -load的MPP，并确认至少24小时的MIC90以上的肺粘液中的药物水平是否保持在MIC90上方。这些研究的成功完成将导致II期提案，以开发 - lactam mpp成合适的药物剂型，以进行广泛的临床前效率和安全性测试，以准备临床试验。总体目标是开发一种固定的稳定，持续释放的`-lactam公式，该配方有效，可以通过方便的1W每日剂量（通过将痰液水平保持在MIC90高于MIC90至少24小时）。通过提供改善的肺药代动力学，我们预计-lactam mpp还将改善针对其他肺部疾病（例如严重哮喘和COPD）细菌感染的疗法。公共卫生相关性：慢性支气管细菌感染是囊性纤维化中发病率和死亡率的主要原因。唯一销售的吸入 - lactam抗生素（Cayston（R））在每天仅约10-12个小时的任务中，经常给药（每天3次），最大效率的杆菌活性所需的肺部药物水平。 Kala Pharmaceuticals试图证明我们的专有递送系统可以向肺部提供»lactam抗生素的局部递送，从而通过提供曾经每天每天的药物浓度为24H/天，可以显着增强当前的抗菌治疗。