Identification of Stability Constraints in the Particle Engineering of an Inhaled Monoclonal Antibody Dried Powder.
吸入型单克隆抗体干粉颗粒工程中的稳定性约束识别
📄 英文摘要 English Abstract
Monoclonal antibody (mAb) based therapies may provide a valuable new treatment modality for acute and chronic lung diseases, including asthma, respiratory infections, and lung cancer. Currently mAbs are delivered via systemic administration routes, but direct delivery to the lungs via the inhaled route could provide higher concentrations at the site of disease and reduced off-target effects. Though lyophilized mAbs may be reconstituted and delivered to the lungs using nebulizers, dry powder inhalers provide a more patient-friendly delivery method based upon their fast administration time and portability. However, particle engineering processes required to prepare respirable dried powders for DPI delivery involve multiple potential stressors for mAbs, which have not been fully explored. In this study, a systematic examination of various aspects of the particle engineering process (atomization, freezing, drying, and storage) was performed to further understand their impact on mAb structure and aggregation. Using anti-streptavidin IgG1 as a model mAb, atomization settings were optimized using a design of experiments approach to elucidate the relationship between feed flow rate, formulation solid content, and atomization airflow rate and protein structural changes and aggregation. The optimized atomization conditions were then applied to spray drying and spray freezing drying particle engineering processes to determine the effects of freezing and drying on IgG1 stability and aerosol performance of the powders. IgG1 was found to be particularly susceptible to degradation induced by the expansive air-ice interface generated by spray freeze drying and this process also produced powders that exhibited decreased storage stability. This study further delineates the design space for manufacturing of respirable biologic therapies and is intended to serve as a roadmap for future development work.
📄 中文摘要 Chinese Abstract
📋 英文结构化总结 English Structured Summary
摘要整理
Background:
Monoclonal antibody (mAb) based therapies may provide a valuable new treatment modality for acute and chronic lung diseases, including asthma, respiratory infections, and lung cancer. Currently mAbs are delivered via systemic administration routes, but direct delivery to the lungs via the inhaled route could provide higher concentrations at the site of disease and reduced off-target effects. Though lyophilized mAbs may be reconstituted and delivered to the lungs using nebulizers, dry powder inhalers provide a more patient-friendly delivery method based upon their fast administration time and portability. However, particle engineering processes required to prepare respirable dried powders for DPI delivery involve multiple potential stressors for mAbs, which have not been fully explored.
Methods:
In this study, a systematic examination of various aspects of the particle engineering process (atomization, freezing, drying, and storage) was performed to further understand their impact on mAb structure and aggregation. Using anti-streptavidin IgG1 as a model mAb, atomization settings were optimized using a design of experiments approach to elucidate the relationship between feed flow rate, formulation solid content, and atomization airflow rate and protein structural changes and aggregation. The optimized atomization conditions were then applied to spray drying and spray freezing drying particle engineering processes to determine the effects of freezing and drying on IgG1 stability and aerosol performance of the powders.
Results:
IgG1 was found to be particularly susceptible to degradation induced by the expansive air-ice interface generated by spray freeze drying and this process also produced powders that exhibited decreased storage stability.
Data Summary:
Atomization settings were optimized using a design of experiments approach to elucidate the relationship between feed flow rate, formulation solid content, and atomization airflow rate and protein structural changes and aggregation. IgG1 was found to be particularly susceptible to degradation induced by the expansive air-ice interface generated by spray freeze drying and this process also produced powders that exhibited decreased storage stability.
Conclusions:
This study further delineates the design space for manufacturing of respirable biologic therapies and is intended to serve as a roadmap for future development work.
Practical Significance:
Monoclonal antibody (mAb) based therapies may provide a valuable new treatment modality for acute and chronic lung diseases, including asthma, respiratory infections, and lung cancer. Direct delivery to the lungs via the inhaled route could provide higher concentrations at the site of disease and reduced off-target effects. Dry powder inhalers provide a more patient-friendly delivery method based upon their fast administration time and portability.
📋 中文结构化总结 Chinese Structured Summary
背景:
基于单克隆抗体（mAb）的治疗方法可为急性和慢性肺部疾病（包括哮喘、呼吸道感染和肺癌）提供一种有价值的新治疗方式。目前，单克隆抗体通过全身给药途径递送，但通过吸入途径直接递送至肺部可在疾病部位提供更高的浓度并减少脱靶效应。虽然冻干单克隆抗体可复溶后使用雾化器递送至肺部，但干粉吸入器因其给药时间短和便携性而提供了一种对患者更友好的递送方法。然而，制备用于干粉吸入器递送的可吸入干粉所需的颗粒工程工艺涉及多种可能对单克隆抗体产生的潜在应激因素，这些因素尚未得到充分探索。
方法:
在本研究中，对颗粒工程工艺（雾化、冷冻、干燥和储存）的各个方面进行了系统检查，以进一步了解其对单克隆抗体结构和聚集的影响。以抗链霉亲和素IgG1作为模型单克隆抗体，采用实验设计方法优化雾化设置，以阐明进料流速、配方固体含量和雾化气流速率与蛋白质结构变化和聚集之间的关系。然后将优化的雾化条件应用于喷雾干燥和喷雾冷冻干燥颗粒工程工艺，以确定冷冻和干燥对IgG1稳定性及粉末气溶胶性能的影响。
结果:
研究发现，IgG1特别容易受到喷雾冷冻干燥产生的膨胀气-冰界面诱导的降解，且该工艺生产的粉末还表现出储存稳定性下降。
数据摘要:
采用实验设计方法优化雾化设置，以阐明进料流速、配方固体含量和雾化气流速率与蛋白质结构变化和聚集之间的关系。研究发现，IgG1特别容易受到喷雾冷冻干燥产生的膨胀气-冰界面诱导的降解，且该工艺生产的粉末还表现出储存稳定性下降。
结论:
本研究进一步界定了可吸入生物治疗药物的制造设计空间，旨在为未来的开发工作提供路线图。
实际意义:
基于单克隆抗体（mAb）的治疗方法可为急性和慢性肺部疾病（包括哮喘、呼吸道感染和肺癌）提供一种有价值的新治疗方式。通过吸入途径直接递送至肺部可在疾病部位提供更高的浓度并减少脱靶效应。干粉吸入器因其给药时间短和便携性而提供了一种对患者更友好的递送方法。