Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba, 274-8510, Japan.
Int J Pharm. 2010 Apr 15;389(1-2):107-13. doi: 10.1016/j.ijpharm.2010.01.027. Epub 2010 Jan 25.
Physical properties and protein-stabilizing effects of sugar alcohols in frozen aqueous solutions and freeze-dried solids were studied. Various frozen sugar alcohol solutions showed a glass transition of the maximally freeze-concentrated phase at temperatures (T(g)'s) that depended largely on the solute molecular weights. Some oligosaccharide-derived sugar alcohols (e.g., maltitol, lactitol, maltotriitol) formed glass-state amorphous cake-structure freeze-dried solids. Microscopic observation of frozen maltitol and lactitol solutions under vacuum (FDM) indicated onset of physical collapse at temperatures (T(c)) several degrees higher than their T(g)'s. Freeze-drying of pentitols (e.g., xylitol) and hexitols (e.g., sorbitol, mannitol) resulted in collapsed or crystallized solids. The glass-forming sugar alcohols prevented activity loss of a model protein (LDH: lactate dehydrogenase) during freeze-drying and subsequent storage at 50 degrees C. They also protected bovine serum albumin (BSA) from lyophilization-induced secondary structure perturbation. The glass-forming sugar alcohols showed lower susceptibility to Maillard reaction with co-lyophilized L-lysine compared to reducing and non-reducing disaccharides during storage at elevated temperature. Application of the oligosaccharide-derived sugar alcohols as alternative stabilizers in lyophilized protein formulations was discussed.
研究了糖醇在冷冻水溶液和冷冻干燥固体中的物理性质和蛋白质稳定作用。各种冷冻糖醇溶液在很大程度上取决于溶质分子量的温度（T(g)）下表现出最大冷冻浓缩相的玻璃化转变。一些低聚糖衍生的糖醇（如麦芽糖醇、乳糖醇、麦芽三糖醇）形成玻璃态无定形蛋糕结构的冷冻干燥固体。在真空中观察冷冻麦芽糖醇和乳糖醇溶液的微观结构（FDM）表明，在比其 T(g)高几度的温度下开始发生物理塌陷。戊糖醇（如木糖醇）和己糖醇（如山梨糖醇、甘露醇）的冷冻干燥导致塌陷或结晶固体。形成玻璃的糖醇可防止模型蛋白（LDH：乳酸脱氢酶）在冷冻干燥和随后在 50°C 下储存过程中的活性损失。它们还保护牛血清白蛋白（BSA）免受冻干诱导的二级结构扰动。与在高温下储存时与共冻干的 L-赖氨酸相比，形成玻璃的糖醇在与还原和非还原二糖发生美拉德反应时的敏感性较低。讨论了将低聚糖衍生的糖醇用作冷冻干燥蛋白配方中的替代稳定剂的应用。
