Mucus-Penetrating Antibiotics for Lung Infections Associated with Cystic Fibrosis

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，吸入型抗生素已成为一种越来越有吸引力的治疗方式，因为吸入型药物直接输送到感染部位，同时将全身暴露/毒性降至最低。然而，感染痰的半衰期很短(典型的T1/2~0.8小时)，限制了抗生素的疗效，需要每天多次给药。这一缺点对内酰胺类抗生素尤其严重，其最大疗效依赖于保持药物浓度高于最低抑制浓度(MIC)；唯一获得批准的吸入内酰胺类药物(Cayston(R))无法在两次给药之间(每天3次)的一半时间内将CF痰中的药物水平维持在MIC90以上。以前实现抗生素持续局部给药的尝试大多是基于聚合物或脂质体颗粒，这些颗粒不具有Kala公司专有的粘液抵抗涂层(常规颗粒，或“CP”)。然而，CP广泛地滞留在CF患者呼吸道衬里的粘弹性痰的非常表面，因此很容易被粘液纤毛和咳嗽驱动的痰清除(从而阻止药物的延长释放)。为了克服痰屏障，Hanes(Kala的联合创始人)和他的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认为是GRAS(公认为安全)的赋形剂组成的MPP，已经被设计成能够穿透CF患者的化脓性痰。在第一阶段，我们将在这项工作的基础上制定吸入性MPP，缓慢释放内酰胺类抗生素。我们预计，与免费药物相比，MPP将在更长的时间内将痰中的内酰胺类抗生素保持在MIC90以上，从而增强对支气管内细菌感染的杀菌效果。在特定的目标1中，我们将研制含有两种常见的IV-内酰胺类药物的MPP，用于治疗CF肺部感染。我们将测量颗粒大小、痰中流动性、载药量、药物释放动力学和储存稳定性。我们将把具有最合适给药特性的MPP推进到动物研究中。在具体目标2中，我们将内酰胺类药物MPP注入健康大鼠的肺部，并确认肺粘液中的药物浓度是否保持在MIC90以上至少24小时。这些研究的成功完成将导致第二阶段的提案，将内酰胺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、缓释的内酰胺制剂，该制剂有效，每天1W剂量(通过将痰药水平保持在MIC90以上至少24小时)。通过改善肺部的药代动力学，我们预计内酰胺MPP还将改善对其他肺部疾病的细菌感染的治疗，如严重哮喘和慢性阻塞性肺病。 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。唯一上市的吸入用β-内酰胺类抗生素(Cayston(R))在肺部提供最有效杀菌活动所需的药物水平，每天只需~10-12小时，尽管频繁给药(每天3次)。Kala制药公司试图证明，我们的专有递送系统可以向肺部提供局部递送-内酰胺类抗生素，通过提供每天一次的产品，使药物浓度保持24小时/天，从而显著增强当前的抗菌治疗。

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.