糖类是一类流行的液体稳定剂,冷冻和冷冻干燥的蛋白质制剂。目前的工作回顾了三组糖的稳定机制:(i)二糖,特别是蔗糖和海藻糖;(ii)环糊精(CD),一类环状寡糖;和(iii)葡聚糖,一类多糖。与蔗糖相比,海藻糖在液体蛋白质制剂中表现出更明显的优先排斥效应,由于它与水分子的相互作用更强。然而,海藻糖在冷冻溶液中获得更高的相分离和结晶倾向,导致其稳定功能的丧失。在冻干制剂中,蔗糖具有较高的结晶倾向。此外,它的玻璃基质不如海藻糖均匀,从而破坏了它的冻干功能。然而,海藻糖的吸湿性可导致储存时的高吸水性。在所有的CD中,β形式被认为比α-和γ-CD具有更强的与蛋白质的相互作用。然而,稳定效应,由CD-蛋白质相互作用引起的,是个案-在一些例子中,这种相互作用可以促进蛋白质不稳定。羟丙基-β-环糊精(HPβCD)的稳定作用已得到广泛研究。由于其两亲性,它可以作为防止界面应力的表面活性剂。此外,它是冻干制剂中的双重功能赋形剂,充当无定形填充剂和冻干保护剂。最后,右旋糖酐,当与蔗糖或海藻糖结合时,可用于生产稳定的冻干蛋白制剂。通过低分子量葡聚糖实现了强的稳定作用。然而,右旋糖酐中的末端葡萄糖产生蛋白质糖基化,这在配方开发过程中需要格外小心。
Saccharides are a popular group of stabilizers in liquid, frozen and freeze dried protein formulations. The current work reviewed the stabilization mechanisms of three groups of saccharides: (i) Disaccharides, specifically sucrose and trehalose; (ii) cyclodextrins (CDs), a class of cyclic oligosaccharides; and (iii) dextrans, a class of polysaccharides. Compared to sucrose, trehalose exhibits a more pronounced preferential exclusion effect in liquid protein formulations, due to its stronger interaction with water molecules. However, trehalose obtains higher phase separation and crystallization propensity in frozen solutions, resulting in the loss of its stabilization function. In lyophilized formulations, sucrose has a higher crystallization propensity. Besides, its glass matrix is less homogeneous than that of trehalose, thus undermining its lyoprotectant function. Nevertheless, the hygroscopic nature of trehalose may result in high water absorption upon storage. Among all the CDs, the β form is believed to have stronger interactions with proteins than the α- and γ-CDs. However, the stabilization effect, brought about by CD-protein interactions, is case-by-case - in some examples, such interactions can promote protein destabilization. The stabilization effect of hydroxypropyl-β-cyclodextrin (HPβCD) has been extensively studied. Due to its amphiphilic nature, it can act as a surface-active agent in preventing interfacial stresses. Besides, it is a dual functional excipient in freeze dried formulations, acting as an amorphous bulking agent and lyoprotectant. Finally, dextrans, when combined with sucrose or trehalose, can be used to produce stable freeze dried protein formulations. A strong stabilization effect can be realized by low molecular weight dextrans. However, the terminal glucose in dextrans yields protein glycation, which warrants extra caution during formulation development.