Combination of Hydroxypropyl-Beta-Cyclodextrin and Trehalose for Improved Stability of Spray-Dried Monoclonal Antibodies
羟丙基-β-环糊精与海藻糖联用提高喷雾干燥单克隆抗体稳定性
📄 英文摘要 English Abstract
Developing a stabilized spray-dried formulation for proteins is one key approach to extending the stability of a dehydrated drug product and providing a broad range of different drug delivery applications. Trehalose has been extensively studied as an excipient to preserve the protein stability in spray-dried formulations. However, the hygroscopic nature of amorphous trehalose makes it prone to recrystallization upon exposure to high temperature and humidity conditions, which can be detrimental to protein stability in the solid state. Herein, we report a formulation approach with the use of 2-hydroxypropyl-β-cyclodextrin (HPβCD) in combination with trehalose to enhance the physical stability of spray-dried solids by inhibiting or delaying the recrystallization of trehalose. Specifically, the effect of HPβCD and trehalose as an excipient alone or the combination of both excipients in stabilizing a model therapeutic monoclonal antibody (mAb1) in a spray-dried formulation has been evaluated at 25 °C/60% relative humidity (RH) and 40 °C/75% RH over 4 weeks. In the solid state, HPβCD can inhibit trehalose recrystallization of spray-dried solids exposed to stress conditions of higher temperatures and humidity. The recrystallization tendency of trehalose was found to be dependent on the protein-to-excipient mass ratios. At a 1:1 protein-to-excipient mass ratio, trehalose is insufficient to ensure adequate protein stability after stress under high humidity, which leads to a significant change in conformational stability and the highest degree of subvisible particle formation for mAb1, primarily due to trehalose recrystallization and high-temperature stresses, while the combination of HPβCD and trehalose has resulted in improved protein stability with a reduction in aggregation propensity. These results show that a combination of HPβCD and trehalose is a viable approach in mitigating trehalose recrystallization and maintaining protein stability of mAbs in spray-dried formulations.
📄 中文摘要 Chinese Abstract
📋 英文结构化总结 English Structured Summary
摘要整理
Header:
Background
Background:
Developing a stabilized spray-dried formulation for proteins is one key approach to extending the stability of a dehydrated drug product and providing a broad range of different drug delivery applications. Trehalose has been extensively studied as an excipient to preserve the protein stability in spray-dried formulations. However, the hygroscopic nature of amorphous trehalose makes it prone to recrystallization upon exposure to high temperature and humidity conditions, which can be detrimental to protein stability in the solid state.
Header:
Methods
Methods:
Herein, we report a formulation approach with the use of 2-hydroxypropyl-β-cyclodextrin (HPβCD) in combination with trehalose to enhance the physical stability of spray-dried solids by inhibiting or delaying the recrystallization of trehalose. Specifically, the effect of HPβCD and trehalose as an excipient alone or the combination of both excipients in stabilizing a model therapeutic monoclonal antibody (mAb1) in a spray-dried formulation has been evaluated at 25 °C/60% relative humidity (RH) and 40 °C/75% RH over 4 weeks.
Header:
Results
Results:
In the solid state, HPβCD can inhibit trehalose recrystallization of spray-dried solids exposed to stress conditions of higher temperatures and humidity. The recrystallization tendency of trehalose was found to be dependent on the protein-to-excipient mass ratios. At a 1:1 protein-to-excipient mass ratio, trehalose is insufficient to ensure adequate protein stability after stress under high humidity, which leads to a significant change in conformational stability and the highest degree of subvisible particle formation for mAb1, primarily due to trehalose recrystallization and high-temperature stresses, while the combination of HPβCD and trehalose has resulted in improved protein stability with a reduction in aggregation propensity.
Header:
Data Summary
Data Summary:
At a 1:1 protein-to-excipient mass ratio, trehalose alone led to a significant change in conformational stability and the highest degree of subvisible particle formation for mAb1. The combination of HPβCD and trehalose resulted in improved protein stability with a reduction in aggregation propensity. The recrystallization tendency of trehalose was dependent on the protein-to-excipient mass ratios, and HPβCD inhibited trehalose recrystallization under stress conditions at 25 °C/60% RH and 40 °C/75% RH over 4 weeks.
Header:
Conclusions
Conclusions:
These results show that a combination of HPβCD and trehalose is a viable approach in mitigating trehalose recrystallization and maintaining protein stability of mAbs in spray-dried formulations.
Header:
Practical Significance
Practical Significance:
Developing a stabilized spray-dried formulation for proteins is one key approach to extending the stability of a dehydrated drug product and providing a broad range of different drug delivery applications.
📋 中文结构化总结 Chinese Structured Summary
背景:
开发稳定的蛋白质喷雾干燥制剂是延长脱水药品稳定性并提供多种不同药物递送应用的关键途径之一。海藻糖已被广泛研究用作喷雾干燥制剂中保持蛋白质稳定性的辅料。然而，无定形海藻糖的吸湿性使其在高温高湿条件下容易发生重结晶，这可能对固态蛋白质的稳定性产生不利影响。
方法:
本文报道了一种采用2-羟丙基-β-环糊精（HPβCD）与海藻糖联合使用的制剂策略，通过抑制或延缓海藻糖的重结晶来提高喷雾干燥固体的物理稳定性。具体而言，在25°C/60%相对湿度（RH）和40°C/75% RH条件下评估了HPβCD和海藻糖单独作为辅料或两者组合作为辅料对喷雾干燥制剂中模型治疗性单克隆抗体（mAb1）的稳定效果，评估周期为4周。
结果:
在固态条件下，HPβCD能够抑制喷雾干燥固体在高温高湿胁迫条件下海藻糖的重结晶。海藻糖的重结晶倾向取决于蛋白质与辅料的质量比。在1:1的蛋白质-辅料质量比下，海藻糖不足以确保高湿度胁迫后蛋白质的充分稳定性，导致mAb1的构象稳定性发生显著变化并形成最高程度的亚可见颗粒，这主要是由于海藻糖重结晶和高温胁迫所致；而HPβCD与海藻糖的联合使用则改善了蛋白质稳定性，降低了聚集倾向。
数据总结:
在1:1的蛋白质-辅料质量比下，单独使用海藻糖导致mAb1的构象稳定性发生显著变化并形成最高程度的亚可见颗粒。HPβCD与海藻糖的联合使用改善了蛋白质稳定性，降低了聚集倾向。海藻糖的重结晶倾向取决于蛋白质与辅料的质量比，HPβCD在25°C/60% RH和40°C/75% RH条件下4周内抑制了海藻糖的重结晶。
结论:
这些结果表明，HPβCD与海藻糖联合使用是一种减轻海藻糖重结晶并保持喷雾干燥制剂中单克隆抗体蛋白质稳定性的可行策略。
实际意义:
开发稳定的蛋白质喷雾干燥制剂是延长脱水药品稳定性并提供多种不同药物递送应用的关键途径之一。