Akina, Inc., 3495 Kent Avenue, Suite A200, West Lafayette, IN 47906, USA.
Akina, Inc., 3495 Kent Avenue, Suite A200, West Lafayette, IN 47906, USA; Biomedical Engineering and Pharmaceutics, Purdue University, 206 S. Martin Jischke Drive, West Lafayette, IN 47907, USA.
J Control Release. 2019 Apr 28;300:174-184. doi: 10.1016/j.jconrel.2019.03.002. Epub 2019 Mar 8.
Poly (lactide-co-glycolide) (PLGA) has been used for making injectable, long-acting depot formulations for the last three decades. An in depth understanding of PLGA polymers is critical for development of depot formulations as their properties control drug release kinetics. To date, about 20 PLGA-based formulations have been approved by the U.S. Food and Drug Administration (FDA) through new drug applications, and none of them have generic counterparts on the market yet. The lack of generic PLGA products is partly due to difficulties in reverse engineering. A generic injectable PLGA product is required to establish qualitative and quantitative (Q1/Q2) sameness of PLGA to that of a reference listed drug (RLD) to obtain an approval from the FDA. Conventional characterizations of PLGA used in a formulation rely on measuring the molecular weight by gel permeation chromatography (GPC) based on polystyrene molecular weight standards, and determining the lactide:glycolide (L: G) ratio by H NMR and the end-group by C NMR. These approaches, however, may not be suitable or sufficient, if a formulation has more than one type of PLGA, especially when they have similar molecular weights, but different L:G ratios. Accordingly, there is a need to develop new assay methods for separating PLGAs possessing different L:G ratios when used in a drug product and characterizing individual PLGAs. The current work identifies a series of semi-solvents which exhibit varying degrees of PLGA solubility depending on the L:G ratio of the polymer. A good solvent dissolves PLGAs with all L:G ratios ranging from 50:50 to 100:0. A semi-solvent dissolves PLGAs with only certain L:G ratios. Almost all semi-solvents identified in this study increase their PLGA solubility as the L:G ratio increases, i.e., the lactide content increases. This lacto-selectivity, favoring higher L:G ratios, has been applied for separating individual PLGAs in a given depot formulation, leading to analysis of each type of PLGA. This semi-solvent method allows a simple, practical bench-top separation of PLGAs of varying L:G ratios. This method enables isolation and identification of individual PLGAs from a complex mixture that is critical for the quality control of PLGA formulations, as well as reverse engineering for generic products to establish the Q1/Q2 sameness.
聚（丙交酯-乙交酯）（PLGA）已被用于制造可注射的长效储库制剂，至今已有三十年。深入了解 PLGA 聚合物对于开发储库制剂至关重要，因为它们的性质控制着药物释放动力学。迄今为止，约有 20 种基于 PLGA 的制剂已通过新药申请获得美国食品和药物管理局（FDA）批准，而目前市场上尚无它们的仿制药。缺乏通用的 PLGA 产品部分是由于逆向工程的困难。需要一种通用的可注射 PLGA 产品来建立与参考上市药物（RLD）的 PLGA 的定性和定量（Q1/Q2）相同性，以获得 FDA 的批准。制剂中使用的 PLGA 的常规特性依赖于基于聚苯乙烯分子量标准的凝胶渗透色谱（GPC）测量分子量，并通过 H NMR 确定丙交酯：乙交酯（L：G）比和 C NMR 端基。然而，如果制剂中有超过一种类型的 PLGA，特别是当它们具有相似的分子量但不同的 L：G 比时，这些方法可能不适用或不足够。因此，当在药物产品中使用时，需要开发用于分离具有不同 L：G 比的 PLGA 并对各个 PLGA 进行特性分析的新分析方法。目前的工作确定了一系列半溶剂，这些溶剂根据聚合物的 L：G 比表现出不同程度的 PLGA 溶解度。良溶剂可溶解所有 L：G 比从 50:50 到 100:0 的 PLGA。半溶剂可溶解仅某些 L：G 比的 PLGA。本研究中鉴定的几乎所有半溶剂都随着 L：G 比的增加而增加 PLGA 的溶解度，即丙交酯含量增加。这种对较高 L：G 比的乳选择性已被应用于分离给定储库制剂中的各个 PLGA，从而分析每种类型的 PLGA。这种半溶剂方法可用于简单、实用的台式分离不同 L：G 比的 PLGA。该方法可从复杂混合物中分离和鉴定各个 PLGA，这对于 PLGA 制剂的质量控制以及仿制药的逆向工程以建立 Q1/Q2 相同性至关重要。
