Effect of formulation composition on stability and aerosol performance of respirable high load monoclonal antibody powders.
制剂组成对可吸入高载药量单克隆抗体粉末稳定性及气溶胶性能的影响
📄 英文摘要 English Abstract
Inhalation-based delivery can efficiently transport monoclonal antibodies (mAbs) to the lungs for respiratory and other diseases. While several attempts have been made to develop inhaled formulations of mAbs in the nebulized or dry powder form, these formulations typically rely on high quantities of sugar stabilizers. While sugars can stabilize the mAbs during processing and storage, they are characterized by high hygroscopicity, which could hamper product's physical stability in certain drug product configurations and requires aggressive moisture protection during storage and use. The addition of stabilizing excipients like sugars may also lead to a higher powder burden for high-dose therapies. Additionally, sugars may react adversely with certain mAbs via reactions such as the Maillard reaction. This study aimed at delivering mAbs in lipid-based formulations and abrogate potential storage issues that limit typical sugar-based formulations by reducing hygroscopicity and cohesivity while maintaining high doses of the mAb. The broader goal was to evaluate if the dry powder formulation approach could enable a patient-friendly system that allows a minimal number of inhalations to achieve therapeutic efficacy by increasing the payload of IgG, reducing excipients, in each actuation. Anti-streptavidin IgG1 antibody was used as a model biologic and a series of formulations were prepared using one representative lipid, amino acid, and surfactant in different compositions. A "mixture design of experiments" was utilized to identify stability and dose constraints using these excipients when processed via spray drying. Three formulations containing high IgG content (50 %, 73 %, and 79 % w/w) were chosen for further characterization and assessment of storage stability. The prepared IgG powders exhibited excellent aerosol performance, with over 80 % fine particle fraction and more than 85 % emitted fraction. The powders also had reduced moisture sorption relative to control powders. Additionally, size exclusion chromatography showed that the powders remained stable for at least one month under accelerated conditions (e.g., 40°C with 75 % relative humidity). These findings suggest lipid-based mAb formulations can provide enhanced physical stability to the protein, while exhibiting superior aerosol performance and hence may offer promise for dry powder inhaled therapies.
📄 中文摘要 Chinese Abstract
📋 英文结构化总结 English Structured Summary
摘要整理
Header:
Background: Inhalation-based delivery can efficiently transport monoclonal antibodies (mAbs) to the lungs for respiratory and other diseases. While several attempts have been made to develop inhaled formulations of mAbs in the nebulized or dry powder form, these formulations typically rely on high quantities of sugar stabilizers. While sugars can stabilize the mAbs during processing and storage, they are characterized by high hygroscopicity, which could hamper product's physical stability in certain drug product configurations and requires aggressive moisture protection during storage and use. The addition of stabilizing excipients like sugars may also lead to a higher powder burden for high-dose therapies. Additionally, sugars may react adversely with certain mAbs via reactions such as the Maillard reaction. This study aimed at delivering mAbs in lipid-based formulations and abrogate potential storage issues that limit typical sugar-based formulations by reducing hygroscopicity and cohesivity while maintaining high doses of the mAb. The broader goal was to evaluate if the dry powder formulation approach could enable a patient-friendly system that allows a minimal number of inhalations to achieve therapeutic efficacy by increasing the payload of IgG, reducing excipients, in each actuation.
Header:
Methods: Anti-streptavidin IgG1 antibody was used as a model biologic and a series of formulations were prepared using one representative lipid, amino acid, and surfactant in different compositions. A "mixture design of experiments" was utilized to identify stability and dose constraints using these excipients when processed via spray drying. Three formulations containing high IgG content (50 %, 73 %, and 79 % w/w) were chosen for further characterization and assessment of storage stability.
Header:
Results: The prepared IgG powders exhibited excellent aerosol performance, with over 80 % fine particle fraction and more than 85 % emitted fraction. The powders also had reduced moisture sorption relative to control powders. Additionally, size exclusion chromatography showed that the powders remained stable for at least one month under accelerated conditions (e.g., 40°C with 75 % relative humidity).
Header:
Data Summary: Three formulations containing high IgG content (50 %, 73 %, and 79 % w/w) were chosen for further characterization and assessment of storage stability. The prepared IgG powders exhibited over 80 % fine particle fraction and more than 85 % emitted fraction. The powders remained stable for at least one month under accelerated conditions (e.g., 40°C with 75 % relative humidity).
Header:
Conclusions: These findings suggest lipid-based mAb formulations can provide enhanced physical stability to the protein, while exhibiting superior aerosol performance and hence may offer promise for dry powder inhaled therapies.
Header:
Practical Significance: The broader goal was to evaluate if the dry powder formulation approach could enable a patient-friendly system that allows a minimal number of inhalations to achieve therapeutic efficacy by increasing the payload of IgG, reducing excipients, in each actuation.
📋 中文结构化总结 Chinese Structured Summary
背景:
吸入给药可将单克隆抗体（mAbs）高效递送至肺部，用于治疗呼吸系统疾病及其他疾病。尽管目前已有多项尝试开发雾化或干粉形式的吸入用mAb制剂，但这些制剂通常依赖大量糖类稳定剂。糖类虽能在加工和储存过程中稳定mAb，但其高吸湿性可能影响某些剂型配置下的物理稳定性，并需要在储存和使用过程中采取严格的防潮措施。此外，添加糖类等稳定辅料可能导致高剂量治疗时粉末负荷增加。糖类还可能通过美拉德反应等途径与某些mAb发生不良反应。本研究旨在开发基于脂质的mAb制剂，通过降低吸湿性和黏聚性来克服糖基制剂常见的储存限制问题，同时维持高剂量的mAb。更广泛的目标是评估干粉制剂方法能否实现一种患者友好的系统，通过提高每次给药中IgG的载药量并减少辅料用量，以最少的吸入次数达到治疗效果。
方法:
以抗链霉亲和素IgG1抗体为模型生物药，使用一种代表性脂质、氨基酸和表面活性剂按不同配比制备了一系列制剂。采用"混合物实验设计"方法，通过喷雾干燥工艺确定这些辅料在稳定性和剂量方面的限制。选取三种高IgG含量（50%、73%和79% w/w）的制剂进行进一步表征和储存稳定性评估。
结果:
所制备的IgG粉末表现出优异的气溶胶性能，细粒子分数超过80%，呼出分数超过85%。与对照粉末相比，这些粉末的吸湿性显著降低。此外，尺寸排阻色谱分析显示，粉末在加速条件（如40°C、75%相对湿度）下至少一个月内保持稳定。
数据摘要:
选取三种高IgG含量（50%、73%和79% w/w）的制剂进行进一步表征和储存稳定性评估。所制备的IgG粉末细粒子分数超过80%，呼出分数超过85%。粉末在加速条件（如40°C、75%相对湿度）下至少一个月内保持稳定。
结论:
这些结果表明，基于脂质的mAb制剂可为蛋白质提供增强的物理稳定性，同时表现出优异的气溶胶性能，因此有望成为干粉吸入治疗的有前景方案。
实际意义:
更广泛的目标是评估干粉制剂方法能否实现一种患者友好的系统，通过提高每次给药中IgG的载药量并减少辅料用量，以最少的吸入次数达到治疗效果。