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: 8235605
• 负责人: Timothy E Corcoran
• 金额: $ 36.87万
• 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 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235605
• 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; Disorder by Site; 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. PUBLIC HEALTH RELEVANCE: Inhaled aerosol antibiotics are often used to treat pulmonary infections associated with cystic fibrosis (CF) lung disease; however, the airway obstructions associated with CF can make it difficult to reach all sites of infection with the aerosol. We propose to create special self-dispersing inhaled antibiotics that will spread medication throughout the lungs, like soap spreads over water, bringing more medication to sites of infection and improving the efficacy of these drugs. These medications could provide immediate benefit to the 30,000 CF patients in the U.S. and may ultimately be of benefit to the 35 million other Americans suffering from obstructive lung diseases.

描述(由申请人提供)：吸入雾化药物提供了直接治疗肺部疾病部位的机会。目前的给药技术主要依靠空气动力学机制来分散和分配这些药物在吸入后在肺内。肺病常见的阻塞因素，如囊性纤维化、支气管扩张症或慢性阻塞性肺疾病(COPD)，可减少肺部分的通气量，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。这些药物分配不善，最终限制了它们的疗效。例如，用于治疗与囊性纤维性肺病相关的细菌感染的吸入抗生素通常能有效抑制感染，但很少能根除感染。耐药性也与这些疗法有关，可能是因为在感染部位持续提供亚治疗剂量。我们的目标是开发用于吸入抗生素的新型自分散平台，以改善药物分布和改善与囊性纤维化(CF)肺部疾病相关的细菌感染的治疗效果。我们假设，在吸入的药物中加入某些表面活性剂(吸附在液体表面并在液体表面扩散的两亲性分子)或低表面张力液体将促进肺内自分散药物膜的形成。这些薄膜将在呼吸道中传播药物，改善剂量的一致性，并增加向通风减少区域输送的药物剂量。虽然早产儿的表面活性物质替代疗法已经得到了广泛的研究，但使用表面活性物质作为气雾剂载体来促进药物在肺内的转运，包括成人肺，受到的关注要少得多。这些研究将演变出新一代高效气雾剂抗生素药物，这种药物将能够根除肺部感染，并降低抗生素耐药性的可能性。以呼吸道为基础的细菌感染是慢性阻塞性肺疾病发病率和死亡率的主要来源。用治疗性剂量的药物到达更多的感染部位将提高吸入抗生素疗法的疗效，为3万名患有囊性纤维性肺病的美国人带来直接好处。从这些研究中获得的知识也可以应用于其他吸入性药物，最终使近3500万患有阻塞性肺病的美国人受益。 公共卫生相关性：吸入型气雾剂抗生素通常用于治疗与囊性纤维化(CF)肺部疾病相关的肺部感染；然而，与囊性纤维性肺疾病相关的呼吸道阻塞可能使气雾剂难以到达所有感染部位。我们建议创造特殊的自我分散的吸入型抗生素，将药物传播到整个肺部，就像肥皂在水中传播一样，将更多的药物带到感染部位，并提高这些药物的疗效。这些药物可以立即为美国30,000,000名CF患者带来好处，并可能最终造福于其他3,500万患有阻塞性肺病的美国人。