Bolli Reinhard, Woodtli Karin, Bärtschi Michelle, Höfferer Liane, Lerch Peter
CSL Behring AG, Wankdorfstrasse 10, CH-3000 Bern 22, Switzerland.
Biologicals. 2010 Jan;38(1):150-7. doi: 10.1016/j.biologicals.2009.09.002.
Liquid intravenous immunoglobulin (IVIG) products offer improved convenience in preparation but often lack sufficient stability to allow room temperature storage. Furthermore, clinical tolerability may be affected due to formation of idiotype/anti-idiotype IgG dimers and/or aggregates. Here we report on the development of a 10% IVIG formulation with optimized stability achieved by the use of l-proline. The stability of concentrated liquid IVIG was strongly pH dependent. Aggregate formation, yellowish discoloration of the solution and loss of anti-hepatitis B surface antigen (HBs) antibody activity was minimal at intermediate pH (pH 4.8-5.3). Fragmentation of IgG was highest at low pH (pH 4.1). Idiotype/anti-idiotype IgG dimer formation was highest at neutral pH and was reduced with decreasing pH. The presence of L-proline further improved stability by inhibiting protein aggregation, reducing loss of anti-HBs antibody activity and decreasing coloring, particularly compared with glycine formulations. The IgG dimer content was up to 30% lower in solutions containing L-proline compared with those containing glycine or other stabilizers. In conclusion, a weakly acidic pH of approximately 5 and L-proline as stabilizer are optimal conditions for long-term stability of a liquid IVIG. L-proline, an amphiphilic, naturally occurring amino acid, is superior to glycine in restricting IgG dimer formation.
静脉注射用液体免疫球蛋白(IVIG)产品在制剂方面提供了更高的便利性,但通常缺乏足够的稳定性以允许在室温下储存。此外,由于独特型/抗独特型IgG二聚体和/或聚集体的形成,临床耐受性可能会受到影响。在此,我们报告了一种10% IVIG制剂的研发情况,该制剂通过使用L-脯氨酸实现了优化的稳定性。浓缩液体IVIG的稳定性强烈依赖于pH值。在中等pH值(pH 4.8 - 5.3)下,聚集体形成、溶液发黄以及抗乙型肝炎表面抗原(HBs)抗体活性的丧失最小。IgG的片段化在低pH值(pH 4.1)时最高。独特型/抗独特型IgG二聚体的形成在中性pH值时最高,并随着pH值的降低而减少。L-脯氨酸的存在通过抑制蛋白质聚集、减少抗HBs抗体活性的丧失以及减少着色进一步提高了稳定性,特别是与甘氨酸制剂相比。与含有甘氨酸或其他稳定剂的溶液相比,含有L-脯氨酸的溶液中IgG二聚体含量低达30%。总之,约5的弱酸性pH值和L-脯氨酸作为稳定剂是液体IVIG长期稳定性的最佳条件。L-脯氨酸是一种两亲性的天然氨基酸,在限制IgG二聚体形成方面优于甘氨酸。