Mucus-Penetrating Antibiotics for Lung Infections Associated with Cystic Fibrosis

描述（由申请方提供）：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。与静脉注射抗生素相比，吸入抗生素已成为一种越来越有吸引力的治疗方式，因为吸入药物直接输送到感染部位，同时最大限度地减少全身暴露/毒性。然而，感染痰液中的短半衰期（典型t1/2 ~0.8小时）限制了抗生素的疗效，需要每日多次给药。这一缺点对于内酰胺类抗生素尤其重要，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;唯一获批的吸入型内酰胺（Cayston（r））未能将CF痰液中的药物水平维持在MIC 90以上，即使是给药之间的一半持续时间（每日3次）。以前实现抗生素持续局部递送的尝试主要基于不具有Kala专有的粘液抗性涂层的聚合物或脂质体颗粒（常规颗粒，或“CP”）。然而，CP被广泛地捕获在CF患者的气道内衬的粘弹性痰的最表面处，并且因此容易通过粘膜纤毛和咳嗽驱动的痰清除而被消除（因此排除延长的药物释放）。为了克服痰液屏障，Hanes（Kala的联合创始人）和同事开创了粘液穿透颗粒（MPP）技术，该技术独家授权给Kala。MPP迅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。各种MPP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患者吐出的脓痰。在第一阶段，我们将建立在这项工作，制定MPP吸入缓慢释放-内酰胺抗生素。我们预计，与游离药物相比，MPP将通过延长痰液中的<$-内酰胺类抗生素MIC 90以上的持续时间来增强对支气管内细菌感染的杀菌有效性。在具体目标1中，我们将配制含有两种常见IV-内酰胺的MPP，用于CF肺部感染。我们将测量颗粒大小、痰液流动性、载药量、药物释放动力学和储存稳定性。我们将推进MPP与最合适的药物输送特性的动物研究。在特定目标2中，我们将对健康大鼠的肺给予负载β-内酰胺的MPP，并确认肺粘液中的药物水平是否维持在MIC 90以上至少24小时。这些研究的成功完成将导致一个II期提案，将β-内酰胺MPP开发成一种合适的药物剂型，用于广泛的临床前疗效和安全性测试，为临床试验做准备。总体目标是开发一种货架稳定的缓释？-内酰胺制剂，该制剂在方便的每日1次给药（通过维持痰液药物水平高于MIC 90至少24小时）时有效。通过改善肺部的药代动力学，我们预计内酰胺MPP还将改善其他肺部疾病（如严重哮喘和COPD）中细菌感染的治疗。 公共卫生相关性：慢性支气管内细菌感染是囊性纤维化发病率和死亡率的主要原因。唯一上市的…尽管频繁给药（每日3次），吸入用β-内酰胺类抗生素（Cayston（r））在肺中提供的药物水平仅为每天约10-12小时的最大有效杀菌活性所需。Kala Pharmaceuticals旨在证明我们的专有输送系统可以提供局部输送的戊-内酰胺抗生素的肺部，这将显着提高目前的抗菌治疗，通过提供每日一次的产品，保持药物浓度为24小时/天。

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.