Garner John, Skidmore Sarah, Overdorf Gary, Hadar Justin, Park Haesun, Park Kinam, Wang Yan, Jhon Young Kuk, Smith William C, Zhang Deyi, Zou Yuan
Akina, Inc., 3495 Kent Avenue, West Lafayette, Indiana 47906, United States.
Biomedical Engineering and Pharmaceutics, Purdue University, 206 South Martin Jischke Drive, West Lafayette, Indiana 47907, United States.
Mol Pharm. 2025 Jan 6;22(1):446-458. doi: 10.1021/acs.molpharmaceut.4c01057. Epub 2024 Nov 20.
Characterization of PLGA polymers used in FDA-approved drug products is critical for quality control and qualitative/quantitative (Q1/Q2) evaluation of potential generic formulations. Various techniques have been developed and used to characterize the molecular properties of PLGA polymers, such as molecular weight, molecular composition, and molecular structure. Commonly used techniques include gel permeation chromatography (GPC), nuclear magnetic resonance (NMR), semisolvent methods, and GPC-based intrinsic viscosity measurement. It is noted that the existing analytical methods may not be able to separate and quantify PLGA polymers when used as a mixture in a drug product (e.g., Durysta and Ozurdex). In particular, one assay method still lacking is quantitating the PLGA polymer with acid-end-cap (PLGA-A) in the mixture containing PLGA with ester-end-cap (PLGA-E), especially when the sample quantity is below the submilligram level. The total PLGA quantities available in Durysta and Ozurdex formulations are too small (<1 mg) to use existing assay methods to quantify the PLGA-A content. A new assay method was developed to quantitate PLGA-A in the mixture with PLGA-E. The acid end-cap was modified with pyrene methylamine (a UV dye) to enhance the signal and compared with the total PLGA quantity measured with the refractive index (RI) after a sample was run through a GPC. This GPC-UV/RI approach is based on measuring the total acid number (TAN) of PLGA-A and converting it to the PLGA-A quantity to compare with the total PLGA. Unlike conventional methods of measuring TAN, the GPC-UV/RI methods enables TAN measurements of submilligram PLGA quantities. Application of this method to Ozurdex-similar samples showed the expected acid:ester ratio of PLGAs. This new approach provides another powerful tool for characterizing PLGA polymers in FDA-approved drug products. This is especially significant considering that the PLGAs of commercial products are likely to have molecular properties different from those of the raw PLGAs before going through the manufacturing process.
对美国食品药品监督管理局（FDA）批准的药品中使用的聚乳酸-羟基乙酸共聚物（PLGA）聚合物进行表征，对于潜在仿制药制剂的质量控制和定性/定量（Q1/Q2）评估至关重要。已经开发并使用了各种技术来表征PLGA聚合物的分子特性，例如分子量、分子组成和分子结构。常用技术包括凝胶渗透色谱法（GPC）、核磁共振（NMR）、半溶剂法以及基于GPC的特性粘度测量。需要注意的是，当PLGA聚合物在药品中作为混合物使用时（例如，杜瑞珠和奥助得），现有的分析方法可能无法分离和定量这些聚合物。特别是，仍然缺乏一种在含有酯端基PLGA（PLGA-E）的混合物中定量酸端基PLGA（PLGA-A）的分析方法，尤其是当样品量低于亚毫克水平时。杜瑞珠和奥助得制剂中可用的PLGA总量太少（<1毫克），无法使用现有分析方法来定量PLGA-A的含量。开发了一种新的分析方法来定量PLGA-A与PLGA-E混合物中的PLGA-A。用芘甲胺（一种紫外染料）对酸端基进行修饰以增强信号，并在样品通过GPC后与用折射率（RI）测量的总PLGA量进行比较。这种GPC-UV/RI方法基于测量PLGA-A的总酸值（TAN）并将其转换为PLGA-A的量，以便与总PLGA进行比较。与传统的测量TAN的方法不同，GPC-UV/RI方法能够测量亚毫克量PLGA的TAN。将该方法应用于奥助得类似样品，显示出预期的PLGA酸/酯比。这种新方法为表征FDA批准的药品中的PLGA聚合物提供了另一种强大工具。考虑到商业产品的PLGA在经过制造过程之前可能具有与原始PLGA不同的分子特性，这一点尤为重要。
