Martin-Luther-University Halle-Wittenberg, Institute of Pharmacy, Faculty of Biosciences, Wolfgang-Langenbeck-Strasse 4, 06120 Halle (Saale), Germany.
Boehringer Ingelheim Pharma GmbH & Co. KG, Innovation Unit, PDB, Birkendorfer Straße 65, 88397 Biberach an der Riss, Germany.
Int J Pharm. 2020 Dec 15;591:119934. doi: 10.1016/j.ijpharm.2020.119934. Epub 2020 Oct 13.
Two of the most widely used surfactants to stabilize biologicals against e.g. interfacial stress are polysorbate20 (PS20) and polysorbate 80 (PS80). In recent years, polysorbate degradation in biopharmaceutical formulations has been observed. Polysorbate (PS) is mainly composed of sorbitan and isosorbide fatty acid (FA) esters, varying in their FA composition. Especially hydrolysis, which can be induced chemically as well as enzymatically, leads to the release of FAs from PS. These FAs are poorly soluble in aqueous buffer systems due to their hydrophobic nature and therefore prone to precipitation and particle formation. Since the emergence of particles in liquid formulations has to be avoided, it is important to prevent their formation. This study evaluates the solubility limits of selected FAs, which are likely to be released during the degradation of PS20 and PS80 in the presence of defined PS concentrations. Our results show that the solubility is highly dependent on the pH, the temperature, the used PS concentration and the aliphatic chain of respective FAs. Solubility of FAs, such as palmitic and oleic acid under the conditions determined in this study, are in the range of 3-130 µg·ml (12-460 µM). Furthermore, the results allow making an estimation to which extent PS may degrade before particle formation in the drug product may be expected.
两种最广泛使用的表面活性剂，例如聚山梨酯 20（PS20）和聚山梨酯 80（PS80），用于稳定生物制剂以抵抗界面压力。近年来，在生物制药制剂中观察到聚山梨酯的降解。聚山梨酯（PS）主要由山梨糖醇和异山梨醇脂肪酸（FA）酯组成，其 FA 组成不同。特别是水解，它可以化学诱导也可以酶促诱导，导致 PS 从 PS 中释放 FA。由于这些 FA 的疏水性，它们在水性缓冲体系中溶解度较差，因此容易沉淀和形成颗粒。由于必须避免液体制剂中出现颗粒，因此防止其形成很重要。本研究评估了在存在特定 PS 浓度的情况下，PS20 和 PS80 降解时可能释放的选定 FA 的溶解度极限。我们的结果表明，溶解度高度依赖于 pH 值、温度、所用 PS 浓度和相应 FA 的脂肪链。在本研究中确定的条件下，诸如棕榈酸和油酸等 FA 的溶解度在 3-130μg·ml（12-460μM）范围内。此外，这些结果可以估计在药物产品中可能出现颗粒形成之前 PS 可能降解到何种程度。
