Development of Montelukast Delivery System for Childhood Asthma

儿童哮喘孟鲁司特给药系统的开发

• 批准号: 8516692
• 负责人: Je Phil Ryoo
• 金额: $ 15.44万
• 依托单位: GALAXY BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516692
• 关键词: Adolescent; Adrenal Cortex Hormones; Adverse effects; Agonist; Air; Allergens; Animals; Aspirin; Asthma; Biological Availability; Breathing; Bronchoconstriction; Caregivers; Child; Childhood; Childhood Asthma; Chronic Disease; Comparative Study; Data; Development; Dosage Forms; Dose; Drug Formulations; Drug Kinetics; Drug toxicity; Enhancers; Ensure; Excipients; Exercise; Exhibits; Film; Functional disorder; Galaxy; Gastrointestinal tract structure; Hamsters; Hour; Hyperventilation; Inflammation Mediators; Leukotriene Antagonists; Leukotriene Receptor; Liver; Lung; Masks; Mucous Membrane; Mucous body substance; Oral; Oral cavity; Oral mucous membrane structure; Oryctolagus cuniculus; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Pilot Projects; Placebos; Plasma; Play; Polymers; Population; Prevalence; Qualifying; Randomized; Rattus; Recovery; Regulation; Research Personnel; Resistance; Respiratory physiology; Role; Safety; Schools; Sodium; Steroids; Suspension substance; Suspensions; System; Tablets; Taste Perception; Technology; Toxic effect; Treatment Efficacy; absorption; animal facility; asthmatic patient; base; comparative; compliance behavior; cysteinyl leukotriene receptor; cysteinyl-leukotriene; drinking water; eosinophil; improved; innovation; irritation; juvenile animal; liquid chromatography mass spectrometry; migration; montelukast; pre-clinical; prevent; public health relevance; response; skin irritation

DESCRIPTION (provided by applicant): The cysteinyl leukotrienes are primarily endogenous mediators of inflammation and play an integral role in the pathophysiology of asthma. Activation of leukotriene receptor has numerous effects in the lungs, including increased bronchial hyper responsiveness, increased mucus secretion, increased venopermeability, and promotion of eosinophil migration into airway mucosa. Effects of the cysteinyl leukotriene can be blocked by leukotriene receptor antagonists. Leukotriene receptor antagonists inhibit bronchoconstriction and prevent many types of asthmatic responses, including allergen-induced, exercise- induced, cold-air-hyperventilation-induced, and aspirin-induced asthma (Wright et al 1998). Therefore, these antagonists represent a new class of drugs for the treatment of asthma. Montelukast is a potent and selective antagonist of the cysteinyl leukotriene receptor. It has been approved for the treatment of asthma in children 6 months and older (Skoner 2001). Studies have compared montelukast with other asthma treatments. In studies compared montelukast with inhaled corticosteroids in asthmatic patients, researchers concluded that evidence was not convincing for the use of leukotriene receptor antagonist as first-line monotherapy in mild-to-moderate asthma (Ng et al 2004), as patients on antileukotrienes are more likely to suffer an exacerbation requiring systemic steroids and to exhibit a lesser improvement in lung function. Therefore, substitution of montelukast for low-dose inhaled corticosteroid is not recommended. In a pediatric study comparing montelukast with long-acting b2-agonists (LABA), researchers concluded that addition of montelukast to low-dose steroid was more effective than the addition of LABAs (Miraglia et al 2007). More pediatric studies are needed to further compare montelukast with LABA as add-on therapy to inhaled corticosteroid in persistent asthma. In order to provide an oral dosage form of montelukast with comparable efficacy and improved tolerability profile, and as a more preferred choice by children and caregivers compared with the existing oral dosage forms, Galaxy Bio developed NAL6336 montelukast ODF that is intended for daily use. Based on the innovative and proprietary Bio-FX Oral Dissolving DDS technology, NAL6336 ODF was formulated by incorporating the drug together with Bio-FX oral cavity absorption enhancers, polymer carriers, taste-masking agents and other excipients, and display many advantages including fast onset and improved bioavailability, as well as less GI tract and liver side effects. Data from preliminary studies showed a desirable dissolution profile and satisfactory stability results, which suggest that the NAL6336 ODF may be an ideal system for oral delivery of montelukast in children. The formulation of NAL6336 has been well developed. In the proposed study, we will compare the pharmacokinetics profile of NAL6336 ODF and montelukast oral suspension in rats, and assess the irritation and safety of NAL6336 ODF by buccal oral mucosal irritation studies in rabbits and hamsters. The irritation study will be conducted in juvenile animals as differences between mature and immature systems introduce the possibility of drug toxicity, or resistance to toxicity in immature systems that are not observed in mature systems, therefore, data from juvenile animal studies can better contribute to the assessment of drug effects in the pediatric population. Upon completion of the PK and irritation studies, we will file IND to initiate the phase I clinical trial to prove safety and detrmine best dose for NAL6336 ODF.

描述（由申请方提供）：半胱氨酰白三烯主要是炎症的内源性介质，在哮喘的病理生理学中起着不可或缺的作用。白三烯受体的激活在肺中具有许多作用，包括增加支气管高反应性、增加粘液分泌、增加静脉渗透性和促进嗜酸性粒细胞迁移到气道粘膜中。半胱氨酰白三烯的作用可被白三烯受体拮抗剂阻断。白三烯受体拮抗剂抑制支气管收缩并预防多种类型的哮喘反应，包括过敏原诱导的、运动诱导的、冷空气换气过度诱导的和阿司匹林诱导的哮喘（Wright et al 1998）。因此，这些拮抗剂代表了一类新的治疗哮喘的药物。孟鲁司特是半胱氨酰白三烯受体的有效和选择性拮抗剂。它已被批准用于治疗6个月及以上儿童的哮喘（Skoner 2001）。研究将孟鲁司特与其他哮喘治疗方法进行了比较。在哮喘患者中比较孟鲁司特与吸入性糖皮质激素的研究中，研究人员得出结论，使用白三烯受体拮抗剂作为轻中度哮喘的一线单药治疗的证据并不令人信服（Ng et al 2004），因为接受抗白三烯治疗的患者更可能发生需要全身性类固醇的急性加重，并且肺功能改善较少。因此，不推荐用孟鲁司特替代低剂量吸入性皮质类固醇。在一项比较孟鲁司特与长效β 2受体激动剂（LABA）的儿科研究中，研究人员得出结论，在低剂量类固醇中添加孟鲁司特比添加LABA更有效（Miraglia et al 2007）。需要更多的儿科研究来进一步比较孟鲁司特与LABA作为吸入性糖皮质激素治疗持续性哮喘的辅助治疗。为了提供具有可比疗效和改善的耐受性特征的孟鲁司特口服剂型，并且与现有口服剂型相比，作为儿童和护理人员的更优选选择，Galaxy Bio开发了用于日常使用的NAL 6336孟鲁司特ODF。NAL 6336 ODF基于Bio-FX口腔溶解DDS技术，通过将药物与Bio-FX口腔吸收促进剂，聚合物载体，掩味剂和其他赋形剂一起配制而成，具有起效快，生物利用度高，胃肠道和肝脏副作用小等优点。初步研究的数据显示了理想的溶出曲线和令人满意的稳定性结果，这表明NAL 6336 ODF可能是用于儿童口服递送孟鲁司特的理想系统。NAL 6336的配方已经得到很好的开发。在拟议的研究中，我们将比较NAL 6336 ODF和孟鲁司特口服混悬液在大鼠中的药代动力学特征，并通过家兔和仓鼠口腔粘膜刺激研究评估NAL 6336 ODF的刺激性和安全性。刺激性研究将在幼龄动物中进行，因为成熟和不成熟系统之间的差异可能会导致药物毒性，或在成熟系统中未观察到的不成熟系统中对毒性的耐药性，因此，幼龄动物研究的数据可以更好地帮助评估儿科人群中的药物作用。在完成PK和刺激性研究后，我们将提交IND以启动I期临床试验，以证明NAL 6336 ODF的安全性并确定其最佳剂量。