PDF(Pubmed)
Abstract：
Sucrose and trehalose pharmaceutical excipients are employed to stabilize protein therapeutics in a dried state. The mechanism of therapeutic protein stabilization is dependent on the sugars being present in an amorphous solid-state. Colyophilization of sugars with high glass transition polymers, polyvinylpyrrolidone (PVP), and poly(vinylpyrrolidone vinyl acetate) (PVPVA), enhances amorphous sugar stability. This study investigates the stability of colyophilized sugar-polymer systems in the frozen solution state, dried state postlyophilization, and upon exposure to elevated humidity. Binary systems of sucrose or trehalose with PVP or PVPVA were lyophilized with sugar/polymer ratios ranging from 2:8 to 8:2. Frozen sugar-PVPVA solutions exhibited a higher glass transition temperature of the maximally freeze-concentrated amorphous phase (Tg\') compared to sugar-PVP solutions, despite the glass transition temperature (Tg) of PVPVA being lower than PVP. Tg values of all colyophilized systems were in a similar temperature range irrespective of polymer type. Greater hydrogen bonding between sugars and PVP and the lower hygroscopicity of PVPVA influenced polymer antiplasticization effects and the plasticization effects of residual water. Plasticization due to water sorption was investigated in a dynamic vapor sorption humidity ramping experiment. Lyophilized sucrose systems exhibited increased amorphous stability compared to trehalose upon exposure to the humidity. Recrystallization of trehalose was observed and stabilized by polymer addition. Lower concentrations of PVP inhibited trehalose recrystallization compared to PVPVA. These stabilizing effects were attributed to the increased hydrogen bonding between trehalose and PVP compared to trehalose and PVPVA. Overall, the study demonstrated how differences in polymer hygroscopicity and hydrogen bonding with sugars influence the stability of colyophilized amorphous dispersions. These insights into excipient solid-state stability are relevant to the development of stabilized biopharmaceutical solid-state formulations.
摘要：
蔗糖和海藻糖药物赋形剂用于稳定处于干燥状态的蛋白质治疗剂。治疗性蛋白质稳定化的机制取决于以无定形固态存在的糖。与高玻璃化转变聚合物的糖的胶体化，聚乙烯吡咯烷酮(PVP),和聚（乙烯基吡咯烷酮醋酸乙烯酯）（PVPVA），增强无定形糖的稳定性。这项研究调查了冷冻溶液状态下冻干糖-聚合物系统的稳定性，冻干后干燥状态，和暴露在高湿度下。蔗糖或海藻糖与PVP或PVPVA的二元体系以2:8至8:2的糖/聚合物比率冻干。与糖-PVP溶液相比，冷冻糖-PVPVA溶液的最大冷冻浓缩无定形相（Tg\'）具有更高的玻璃化转变温度，尽管PVPVA的玻璃化转变温度(Tg)低于PVP。无论聚合物类型如何，所有冻干体系的Tg值都在相似的温度范围内。糖和PVP之间更大的氢键和PVPVA的较低的吸湿性影响聚合物的抗塑效果和残余水的塑化效果。在动态蒸汽吸附湿度上升实验中研究了由于水吸附引起的增塑。与海藻糖相比，冻干的蔗糖系统在暴露于湿气时显示出增加的无定形稳定性。观察到海藻糖的重结晶并通过加入聚合物来稳定。与PVPVA相比,较低浓度的PVP抑制海藻糖重结晶。与海藻糖和PVPVA相比,这些稳定作用归因于海藻糖和PVP之间增加的氢键。总的来说,该研究证明了聚合物吸湿性和与糖的氢键的差异如何影响冻干无定形分散体的稳定性。对赋形剂固态稳定性的这些见解与稳定的生物制药固态制剂的开发有关。
