Improving Inhaled Drug Delivery with Self-dispersing Liquids

利用自分散液体改善吸入药物输送

• 批准号: 8777009
• 负责人: Timothy E Corcoran
• 金额: $ 46.89万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-15 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8777009
• 关键词: Adult; Aerosols; American; Animal Model; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Attention; Bacterial Infections; Breathing; Bronchiectasis; Cells; Chemical Surfactants; Chemicals; Chronic; Chronic Obstructive Airway Disease; Clinical Research; Cystic Fibrosis; Deposition; Discipline of Nuclear Medicine; Disease; Distal; Dose; Drug Delivery Systems; Drug Formulations; Drug Transport; Drug resistance; Elements; Environmental air flow; Equipment; FDA approved; Film; Functional Imaging; Generations; Goals; Hour; Image; Imaging Techniques; In Vitro; Infant; Infection; Inflammation; Investigation; Knowledge; Lipids; Liquid substance; Lung; Lung diseases; Measures; Mechanics; Modeling; Morbidity - disease rate; Mus; Obstruction; Obstructive Lung Diseases; Partial Liquid Ventilation; Pattern; Penetration; Perflubron; Performance; Pharmaceutical Preparations; Phase; Premature Infant; Property; Pseudomonas Infections; Pulmonary Cystic Fibrosis; Replacement Therapy; Resolution; Saline; Site; Soaps; Solutions; Source; Surface; Surface Tension; Techniques; Testing; Therapeutic; Tobramycin; Viscosity; Water; airway obstruction; airway surface liquid; base; chemokine; cystic fibrosis patients; cytokine; drug distribution; drug efficacy; improved; in vivo; lens; lung volume; mortality; novel; prevent; respiratory; surfactant; theories

DESCRIPTION (provided by applicant): Inhaled aerosol medications offer an opportunity to directly treat sites of disease within the lung. Current delivery techniques rely mostly on aerodynamic mechanisms to disperse and distribute these medications inside the lung after inhalation. The elements of obstruction common to lung diseases such as cystic fibrosis, bronchiectasis, or chronic obstructive pulmonary disease (COPD) can decrease ventilation in portions of the lung, preventing aerosol drugs from reaching these zones. The unusual aerodynamics associated with obstructive disease can also cause very non-uniform deposition patterns, further limiting penetration of active drug. Poor distribution of these medications ultimately limits their efficacy. For example, the inhaled antibiotics used to treat bacterial infections associated with cystic fibrosis lung disease often provide successful suppression of infection but rarely provide eradication. Drug resistance has also been associated with these therapies likely due to the consistent delivery of sub-therapeutic doses at sites of infection. Our goal here is to develop novel self-dispersing platforms for inhaled antibiotics that will provide improved drug distribution and improved performance in the treatment of bacterial infections associated with cystic fibrosis (CF) lung disease. We hypothesize that adding certain surfactants (amphiphilic molecules that adsorb to and spread over liquid surfaces) or low surface tension fluids to inhaled medications will promote the formation of self-dispersing medicated films in the lung. These films will spread medications throughout the airways improving dose uniformity and increasing the dose of medication delivered to regions of reduced ventilation. While surfactant replacement therapies for premature infants have been extensively studied, the use of surfactants as aerosol carriers to enhance drug transport in the lung, including the adult lung, has received much less attention. These studies will evolve a new generation of highly effective aerosol antibiotic medications which will allow for the eradication of infections in the lung and decrease the potential for antibiotic resistance. Airways-based bacterial infections are a major source of morbidity and mortality in CF. Reaching more sites of infection with therapeutic doses of drug would improve the efficacy of inhaled antibiotic therapies, providing immediate benefit to the 30,000 Americans afflicted with cystic fibrosis lung disease. Knowledge gained from these studies could also be applied to the other inhaled medications and ultimately benefit the nearly 35 million Americans suffering from obstructive lung diseases.

描述（由申请人提供）：吸入气雾剂药物提供了直接治疗肺部疾病部位的机会。目前的递送技术主要依赖于空气动力学机制来在吸入后将这些药物分散和分布在肺内。肺部疾病常见的阻塞因素，如囊性纤维化、支气管扩张或慢性阻塞性肺疾病（COPD），可以减少肺部分的通气，阻止气雾剂药物到达这些区域。与阻塞性疾病相关的不寻常的空气动力学也可能导致非常不均匀的沉积模式，进一步限制活性药物的渗透。这些药物的分配不当最终限制了它们的疗效。例如，用于治疗与囊性纤维化肺病相关的细菌感染的吸入抗生素通常可以成功抑制感染，但很少能根除。耐药性也与这些治疗相关，可能是由于在感染部位持续给予亚治疗剂量。我们的目标是开发用于吸入抗生素的新型自分散平台，以改善药物分布并改善与囊性纤维化（CF）肺病相关的细菌感染的治疗性能。我们假设，在吸入药物中加入某些表面活性剂（吸附并扩散到液体表面的两亲分子）或低表面张力液体将促进肺中自分散药物膜的形成。这些薄膜将药物扩散到整个气道，改善剂量均匀性，并增加输送到通气减少区域的药物剂量。虽然对早产儿的表面活性剂替代疗法进行了广泛的研究，但使用表面活性剂作为气溶胶载体来增强肺（包括成人肺）中的药物转运却很少受到关注。这些研究将开发出新一代高效的气雾剂抗生素药物，从而消除肺部感染并降低抗生素耐药性的可能性。基于气道的细菌感染是CF发病率和死亡率的主要来源。用治疗剂量的药物到达更多的感染部位将提高吸入式抗生素治疗的疗效，为3万名患有囊性纤维化肺病的美国人提供直接益处。从这些研究中获得的知识也可以应用于其他吸入性药物，并最终使近3500万患有阻塞性肺病的美国人受益。