Development of microencapsulated PI301 targeting lung GABAergic signaling

这项拟议的研究将确定一种一流的新化学物质的可制造性和非临床安全性 用于治疗哮喘的实体。这种名为PI301的药物调节伽马氨基丁酸A型受体(GABAAR) 并代表了一种全新的哮喘药物靶向和设计方法。这药是 被开发为控制哮喘症状的口服药物。几种动物的药效学研究 哮喘模型表现出明显的收缩的气道平滑肌(ASM)在炎症和 非炎性肺和人肺外植体中。PI301治疗还可减轻Th2-High和Th2-High的肺部炎症 Th2低水平的小鼠哮喘模型。这一创新的意义是一种单一的化合物，它减轻了两个 哮喘、支气管痉挛和肺部炎症的显著症状，避免使用皮质类固醇 和吸入性支气管扩张剂，并改进了目前哮喘综合疗法的范例 控制力。这项研究的长期目标是FDA批准PI301，一种治疗哮喘的一流口服药物。这个 目的采用微胶囊化技术优化PI301的口服药代动力学。一系列 将开发微囊化药物制剂，并以体外释放为基础的最佳处方 将通过大鼠口服剂量进一步评估，以评估改善的药代动力学。精选的制剂 将在ICH Q1A(R2)之后进行稳定性测试。微囊化PI301的大鼠给药研究 确定药物安全性和最大耐受量，并为未来支持IND的GLP研究的设计提供信息。 我们的假设是，优化的配方(微囊化的PI301)将持续更长的治疗时间 PI301的血液浓度，并降低由于高峰值浓度而产生的安全隐患的可能性 反复给药。其基本原理是使用FDA可接受的药物微胶囊方法(缓释 和肠溶包衣)，其可以提高口服生物利用度并提供易于 在非临床啮齿动物和非啮齿动物物种中口服，并在胶囊中进一步配制，首次用于 人体研究。我们的假设将在三个具体目标内得到验证：(1)开发一种微囊化形式 (2)在临床前的大鼠毒性研究中证明PI301是安全的；以及(3)证明PI301是安全的 遗传毒物分析。这项研究的意义在于开发一种安全有效的药物 控制哮喘症状，避免对当前治疗方法的抵抗，并提高依从性。先进的技术 进入临床试验的PI301将建立外围GABAAR作为引人注目的新药靶点，并使 开发其他GABAAR配体用于治疗其他免疫性炎症性疾病。创新 这项研究的成果是一种新药，可以减少由过敏原或传染性引起的哮喘肺部炎症 来源和跨哮喘疾病的内型。PI301可以口服，实现高组织选择性 肺脏和有限的脑部暴露。这项研究将扩展旁分泌GABA能的横切知识 可用于治疗其他肺部疾病的肺部系统。

The proposed research will establish the manufacturability and non-clinical safety of a first-in-class new chemical entity for asthma treatment. The drug, PI301, modulates gamma amino butyric acid type A receptors (GABAAR) in the lung and represents a fundamentally novel approach to asthma drug targeting and design. The drug is being developed as an oral medication for asthma symptom control. Pharmacodynamic studies in several animal asthma models have shown significant relaxation of constricted airway smooth muscle (ASM) in inflamed and non-inflamed lung and in human lung explants. PI301 treatment also reduced lung inflammation in Th2-high and Th2-low mouse asthma models. The significance of this innovation is a single compound that alleviates two hallmark symptoms of asthma, bronchospasm and lung inflammation, which avoids the use of corticosteroids and inhaled bronchodilators and improves upon the current paradigm of combination therapies for asthma control. The long-term goal of this research is FDA approval of PI301, a first-in-class oral drug for asthma. The objective is to optimize the oral pharmacokinetics of PI301 using microencapsulation strategies. A series of microencapsulated drug preparations will be developed, and the best formulation based on in vitro dissolution will be evaluated further by oral dosing in rats to assess improved pharmacokinetics. The chosen preparation will undergo stability testing following ICH Q1A(R2). Rat dosing studies with microencapsulated PI301 will establish drug safety and the maximum tolerated dose and inform the design of future IND-enabling GLP studies. Our hypothesis is that an optimized formulation (microencapsulated PI301) will sustain a prolonged therapeutic PI301 blood concentration and reduce the possibility of safety liabilities due to high peak concentrations with repeated dosing. The rationale is to use FDA-acceptable drug microencapsulation methods (sustained release and enteric coating), which can increase oral bioavailability and provide a drug form that can be readily administrated orally in non-clinical rodent and non-rodent species and formulated further in capsules for first in human studies. Our hypothesis will be tested within three Specific Aims: (1) Develop a microencapsulated form of PI301; (2) Demonstrate PI301 safety in pre-clinical rat toxicity studies; and, (3) Demonstrate a safe PI301 genetic toxicology profile. The significance of this research is development of a safe and effective drug that controls asthma symptoms, avoids resistance to current therapies, and improves compliance. Advancement of PI301 into clinical trials will establish peripheral GABAARs as compelling new drug targets and enable development of other GABAAR ligands as treatments for other immune-inflammatory diseases. The innovation of this research is a novel drug that can reduce asthmatic lung inflammation arising from allergen or infectious origins and across asthma disease endotypes. PI301 can be administered orally, achieving high tissue selectivity for lung and limited brain exposure. This research will expand crosscutting knowledge of a paracrine GABAergic system in the lung that can be exploited therapeutically for other lung disorders.