Clausi Amber L, Merkley Scott A, Carpenter John F, Randolph Theodore W
Department of Chemical and Biological Engineering, ECCH 111, Campus Box 424, University of Colorado, Boulder, Colorado 80309, USA.
J Pharm Sci. 2008 Jun;97(6):2049-61. doi: 10.1002/jps.21143.
Aluminum-salt adjuvants are widely used to increase immunogenicity of recombinant protein vaccines. However, when vaccines formulated with these adjuvants are frozen or lyophilized, losses of efficacy are often reported. This loss of potency is usually attributed to the aggregation of adjuvant particles during processing. In this study, we examine the aggregation behavior of Alhydrogel, a commercial aluminum hydroxide adjuvant, during freeze-thawing and freeze-drying. By cooling Alhydrogel formulations at faster rates or by the addition of sufficient amounts of a glass forming excipient such as trehalose, aggregation of Alhydrogel, can be prevented or minimized. We propose that freeze-concentration of buffer salts induces modifications in adjuvant surface chemistry and crystallinity, which in turn favor aggregation. These modifications, and the resulting aggregation of Alhydrogel particles can be minimized through choice of buffer ions, or kinetically inhibited by rapidly forming a glassy state during freezing.
铝盐佐剂被广泛用于增强重组蛋白疫苗的免疫原性。然而，当用这些佐剂配制的疫苗被冷冻或冻干时，经常会出现效力损失的情况。这种效力损失通常归因于加工过程中佐剂颗粒的聚集。在本研究中，我们研究了市售氢氧化铝佐剂Alhydrogel在冻融和冻干过程中的聚集行为。通过以更快的速率冷却Alhydrogel制剂或添加足够量的玻璃形成赋形剂（如海藻糖），可以防止或最小化Alhydrogel的聚集。我们认为缓冲盐的冷冻浓缩会引起佐剂表面化学和结晶度的改变，进而有利于聚集。通过选择缓冲离子可以最小化这些改变以及由此导致的Alhydrogel颗粒聚集，或者在冷冻过程中通过快速形成玻璃态来动力学抑制聚集。
