Moisture effects on protein-excipient interactions in spray-dried powders. Nature of destabilizing effects of sucrose.
Moisture effects on protein-excipient interactions in spray-dried powders. Nature of destabilizing effects of sucrose.
复制标题
水分对喷雾干燥粉末中蛋白质-赋形剂相互作用的影响。
DOI：
10.1021/js9800127
复制
发表时间：
1999
影响因子：
3.8
通讯作者：
S. Prestrelski
中科院分区：
文献类型：
--
作者：
S. Tzannis;S. Prestrelski
稳定的固体蛋白制剂的制备提出了重大挑战。最终，掺入的赋形剂和药物蛋白质之间的相互作用决定了制剂的稳定性。在这项研究中，喷雾干燥后，利用水分来探测模型蛋白质、胰蛋白酶原和固态蔗糖之间的相互作用。通过研究喷雾干燥制剂的物理性质，我们试图阐明先前观察到的喷雾干燥过程中碳水化合物的稳定和不稳定作用的机制。动态和平衡吸湿研究均表明存在最佳的蛋白-糖氢键网络。在低蔗糖含量下，优先的蛋白质-蔗糖氢键相互作用占主导地位，从而导致蛋白质稳定。然而，在高碳水化合物浓度下，优先发生糖-糖相互作用，导致制剂基质内发生相分离。蔗糖分子优先掺入富糖相中减少了可与蛋白质相互作用的碳水化合物的实际量，从而减少了有效的蛋白质-蔗糖接触的数量。因此，喷雾干燥过程中蛋白质无法得到有效保护。我们假设在该蔗糖浓度范围下观察到的相分离源于喷雾干燥前其从溶液中的蛋白质中排除，进一步伴随着蔗糖分子的优先聚集。
The preparation of stable solid protein formulations presents significant challenges. Ultimately, the interactions between incorporated excipients and the pharmaceutical protein determine the formulation stability. In this study, moisture was utilized to probe the interactions between a model protein, trypsinogen, and sucrose in the solid state, following spray drying. Through investigation of the physical properties of the spray-dried formulations, we attempted to elucidate the mechanisms underlying the previously observed stabilizing and destabilizing effects of the carbohydrate during spray drying. Both dynamic and equilibrium moisture uptake studies indicated the presence of an optimal protein-sugar hydrogen bonding network. At low sucrose contents, a preferential protein-sucrose hydrogen bonding interaction was dominant, resulting in protein stabilization. However, at high carbohydrate concentrations, preferential sugar-sugar interactions prevailed, resulting in a phase separation within the formulation matrix. The preferential incorporation of the sucrose molecules in a sugar-rich phase reduced the actual amount of the carbohydrate available to interact with the protein and thereby decreased the number of effective protein-sucrose contacts. As a consequence, the protein could not be effectively protected during spray drying. We hypothesize that the observed phase separation at this sucrose concentration regime originates from its exclusion from the protein in solution before spray drying, further accompanied by preferential clustering of the sucrose molecules.
DOI：
10.1073/pnas.92.24.10969
发表时间：
1995-11-21
影响因子：
11.1
作者：
GRIEBENOW, K;KLIBANOV, AM
通讯作者：
KLIBANOV, AM