Comprehensive evaluation of formulation effects on metered dose inhaler performan

处方对定量吸入器性能影响的综合评价

• 批准号: 8997745
• 负责人: Guenther Hochhaus
• 金额: $ 24.37万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8997745
• 关键词: Comprehensive; evaluation; formulation; effects; metered

Summary Metered dose inhalers represent a large proportion of inhaled products used in the treatment and prevention of asthma and chronic obstructive lung disease. These products were developed in the middle of the last century and have changed little in the intervening period. One significant change was the replacement of ozone depleting chlorofluorocarbon (CFC) propellants with more environmentally friendly hydrofluoroalkanes as both the suspending medium and the means by which drug is generated as an aerosol. The role of co-solvent and surfactants in the performance and the quality of the product is significant. The pharmaceutical industry performed the Herculean task of reformulating all of their inhaled products into the new propellants quickly and efficiently to accommodate the impending international phase out and elimination of CFCs. Despite the success of their endeavors there remains a need for a systematic evaluation of excipient effects on the efficacy of metered dose inhaler products. It is proposed that controlling key manufacturing variables and measuring a range of quality and performance attributes will highlight factors contributing to accuracy and reproducibility of the delivered dose and aerodynamic particle size distribution. These outcomes are relevant to efficacy, and important for development of predictive models. The specific aims of the proposal are: Selection of drug and preparation in a range of primary sizes suitable for delivery as a respirable aerosol; evaluation of the effects of (a) different amounts of co-solvent (ethanol) and surfactant (oleic acid) will be evaluated. A multivariate statistical design will be employed to optimize the manufacture and maintain efficiency without losing study power. A range of concentrations of the additives will be employed to explore process design space within and outside the Q2 acceptance limits of 5% and (b) other surfactants will be studied based on the experience gained with oleic acid and principles of physical chemistry; construction and utilization of mathematical models to describe the influence of formulation and device variables on performance of the metered dose inhalers. The important variables in pMDI product manufacture that may impact on performance include: drug substance and its intrinsic physico-chemical properties; particle size and distribution of milled particles for suspension formulations; composition of the formulation with respect to: Propellant; Co-solvent; Surfactant; formulation, device (canister, valve and actuator) interactions. Important quality and performance variables include: delivered dose and uniformity; aerodynamic particle size distribution; plume geometry and spray pattern and; potentially dissolution (for poorly soluble or delayed dissolution materials) The intent by regulatory agencies to design quality into products based on sound scientific and engineering principles requires that the manufacturing variables and the testing protocols and procedures are suitable to achieve the desired monitoring and control of the product. It is the intent of this project to develop a framework from which to develop criteria for product performance based on control of input process and product variables.

总结 定量吸入器在治疗和预防哮喘的吸入产品中占很大比例 和慢性阻塞性肺病。这些产品是在上个世纪中期开发的， 在此期间变化不大。一个重要的变化是取代臭氧消耗 含氯氟烃（CFC）推进剂与更环保的氢氟烷烃作为悬浮剂， 介质和药物作为气雾剂产生的手段。共溶剂和表面活性剂在聚合反应中的作用 产品的性能和质量至关重要。制药业完成了艰巨的任务， 将他们所有的吸入产品快速有效地重新配制成新的推进剂， 即将在国际上逐步淘汰和消除氟氯化碳。尽管他们的努力取得了成功， 用于系统评价赋形剂对定量吸入器产品功效的影响。 建议控制关键制造变量并测量一系列质量和性能 属性将突出显示有助于输送剂量和空气动力学的准确性和再现性的因素 颗粒大小分布。这些结果与疗效相关，对预测模型的开发很重要。 该提案的具体目标是：选择适用于以下情况的一系列初级尺寸的药物和制剂： 作为可吸入气雾剂递送;评价（a）不同量的共溶剂（乙醇）和表面活性剂的作用 （油酸）将被评价。将采用多变量统计设计来优化生产， 保持效率而不失去学习动力。将采用一系列浓度的添加剂来探索 在Q2验收限度5%以内和以外的工艺设计空间和（B）其他表面活性剂将根据 在油酸和物理化学原理方面取得的经验; 描述制剂和器械变量对定量给药性能影响的数学模型 吸入器 pMDI产品生产中可能影响性能的重要变量包括：原料药和 其固有的物理化学性质;悬浮液制剂研磨颗粒的粒度和分布; 制剂的组成：推进剂;助溶剂;表面活性剂;制剂、装置（罐、阀 和致动器）相互作用。重要的质量和性能变量包括：输送剂量和均匀性; 空气动力学粒度分布;羽流几何形状和喷雾模式;潜在溶解（对于难溶性 或延迟溶解材料） 监管机构基于合理的科学和工程设计将质量纳入产品的意图 原则要求制造变量和测试方案和程序适用于实现 对产品进行所需的监测和控制。本项目的目的是开发一个框架， 根据对输入过程和产品变量的控制，制定产品性能标准。