Arkansas Laboratory, Office of Regulatory Affairs, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, United States.
Int J Pharm. 2019 Oct 5;569:118576. doi: 10.1016/j.ijpharm.2019.118576. Epub 2019 Jul 27.
Cholesterol is one of the major structural constituents in a liposomal bilayer. Cholesterol is susceptible to various reactions in the presence of oxygen, heat, light, certain metals, and radicals during manufacturing or storage, which may cause to generate cholesterol oxidation products (COPs). Herein, we report the development of a liquid chromatography-mass spectrometry based analytical method for screening and quantitating COPs present in liposomal parenteral pharmaceutical formulations (LPFs) from four different vendors. We detected and quantitated six COPs and desmosterol in LPFs, and desmosterol is an intermediate of cholesterol biosynthesis. 7α-hydroxycholesterol, 7β-hydroxycholesterol, 7-keto-cholesterol, and desmosterol were the major cholesterol-related impurities in LPFs. COPs were not detected in any of USP/NF grade cholesterol raw materials, implying that COPs were generated during liposome manufacturing and/or storage. This validated method presented here can be used to quantify cholesterol-related impurities present in liposomal pharmaceutical formulations to ensure the quality and the safety of liposomal pharmaceutical formulations.
胆固醇是脂质体双层结构的主要组成部分之一。在制造或储存过程中，胆固醇在氧气、热、光、某些金属和自由基存在的情况下容易发生各种反应，这可能导致胆固醇氧化产物（COPs）的生成。在此，我们报告了一种基于液相色谱-质谱的分析方法的开发，用于筛选和定量来自四个不同供应商的脂质体注射剂（LPF）中存在的 COPs。我们在 LPF 中检测和定量了六种 COPs 和粪甾醇，粪甾醇是胆固醇生物合成的中间产物。7α-羟胆固醇、7β-羟胆固醇、7-酮胆固醇和粪甾醇是 LPF 中主要的胆固醇相关杂质。在任何 USP/NF 级胆固醇原料药中都未检测到 COPs，这表明 COPs 是在脂质体制造和/或储存过程中产生的。这里验证的方法可用于定量脂质体药物制剂中存在的胆固醇相关杂质，以确保脂质体药物制剂的质量和安全性。
