Arkansas Laboratory, Office of Regulatory Science, Office of Regulatory Affairs, US Food and Drug Administration, Jefferson, AR 72079, USA.
Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA.
J Pharm Biomed Anal. 2022 Jan 20;208:114473. doi: 10.1016/j.jpba.2021.114473. Epub 2021 Nov 18.
Lipid composition and lipid degradation are critical to the stability of liposomal formulations which can impact the safety and efficacy of the drug. Herein we developed and validated an ultrahigh performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC-QTOF-MS) method for determining phospholipid composition and phospholipid degradation products in a verteporfin liposomal formulation (Visudyne). The high mass accuracy (<5 ppm) of the QTOF method coupled with database searching (SimLipid) and comparison with known standards accurately identified and quantified the phospholipid compositions and lipid degradation products. The analysis of Visudyne indicated that more than 50% (w/w) of the total phospholipids are composed of phosphatidylcholine (PC) 14:0-14:0 and major phosphatidylglycerol (PG) species found are PG 16:0-18:2, PG 16:0-18:1, PG 18:0-18:2, and PG 18:0-18:1. The LC-MS method developed is capable of separating structural isomers such as PG 18:1-18:1 versus PG 18:0-18:2 and the separation of PG stereoisomers, such as PG 18:1-18:1 cis and PG 18:1-18:1 trans. The major lipid degradation products in Visudyne includes lysophosphatidylcholine and a few saturated and unsaturated lysophosphatidylglycerols, and free fatty acids (FFA). Each degradation product is less than 1% of the total phospholipids (w/w). In addition, the lipid profiles of naturally sourced egg PG from six different vendors were compared with the PG composition in Visudyne. Differences in lipid composition in egg PGs from different vendors were observed and the PG composition in Visudyne is matched with the lipid profile of the some of the egg PGs from different vendors. Drug developers can utilize this method to assess raw materials and lipid-based drug product quality and regulatory scientists can monitor the quality of the drug available in the market using this validated method.
脂质组成和脂质降解对于脂质体制剂的稳定性至关重要，这会影响药物的安全性和疗效。在此，我们开发并验证了一种超高效液相色谱-四极杆飞行时间质谱联用（UPLC-QTOF-MS）方法，用于测定维替泊芬脂质体制剂（Visudyne）中的磷脂组成和磷脂降解产物。QTOF 方法具有高精度质量（<5 ppm），结合数据库搜索（SimLipid）和与已知标准的比较，可准确识别和定量磷脂组成和脂质降解产物。对 Visudyne 的分析表明，超过 50%（w/w）的总磷脂由磷脂酰胆碱（PC）14:0-14:0 和主要的磷脂酰甘油（PG）组成，发现的主要 PG 种类为 PG 16:0-18:2、PG 16:0-18:1、PG 18:0-18:2 和 PG 18:0-18:1。所开发的 LC-MS 方法能够分离结构异构体，如 PG 18:1-18:1 与 PG 18:0-18:2，以及 PG 立体异构体，如 PG 18:1-18:1 cis 和 PG 18:1-18:1 trans。Visudyne 中的主要脂质降解产物包括溶血磷脂酰胆碱和一些饱和和不饱和溶血磷脂酰甘油，以及游离脂肪酸（FFA）。每个降解产物均小于总磷脂的 1%（w/w）。此外，还比较了来自六个不同供应商的天然来源鸡蛋 PG 的脂质谱与 Visudyne 中的 PG 组成。来自不同供应商的鸡蛋 PG 的脂质组成存在差异，Visudyne 中的 PG 组成与一些来自不同供应商的鸡蛋 PG 的脂质谱相匹配。药物开发者可以利用该方法评估原料药和基于脂质的药物产品的质量，监管科学家可以使用该验证方法监测市场上可用药物的质量。
