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 Jun 28;304:75-89. doi: 10.1016/j.jconrel.2019.04.039. Epub 2019 May 2.
Poly(lactide-co-glycolide) (PLGA) has been used in many injectable, long-acting depot formulations. Despite frequent use of PLGA, however, its characterization has been limited to measuring its molecular weight, lactide:glycolide (L:G) ratio, and end-group. These conventional methods are not adequate for characterization of unique PLGA polymers, such as branched PLGA. Glucose-initiated PLGA (Glu-PLGA) has been used in Sandostatin® LAR Depot (octreotide acetate for injectable suspension) approved by the U.S. Food and Drug Administration (FDA) in 1998. Glu-PLGA is a branched (also known as star-shaped) polymer and determining its properties has been challenging. It is necessary to develop methods that can determine and characterize the branching parameters of Glu-PLGA. Such characterization is important not only for the quality control of formulations, but also for developing generic parenteral formulations that are required to have the same excipients in the same amount (qualitative/quantitative (Q1/Q2) sameness) as their Reference Listed Drug (RLD). In this study, an analytical technique was developed and validated using a series of branched-PLGA standards, and it was used to determine the branching parameters of Glu-PLGA extracted from Sandostatin LAR, as well as Glu-PLGAs obtained from three different manufacturers. The analytical technique was based on gel-permeation-chromatography with quadruple detection systems (GPC-4D). GPC-4D enabled characterization of Glu-PLGA in its concentration, absolute molecular weight, hydrodynamic radius and intrinsic viscosity. The plot of the branch units per molecule as a function of molar mass provides a unique profile of each branched PLGA. The Mark-Houwink plots were also used to distinguish different Glu-PLGAs. These ensemble identification methods indicate that the branch units of Glu-PLGAs extracted from Sandostatin LAR range from 2 (i.e., linear) at the lower end of the molecular weight to <4 for the majority (94%) of Glu-PLGA.
聚（丙交酯-乙交酯）（PLGA）已被广泛应用于许多可注射长效储库制剂中。然而，尽管 PLGA 的应用非常频繁，但其特性的描述仅限于测量其分子量、丙交酯：乙交酯（L:G）的比例和端基。这些传统方法对于独特的 PLGA 聚合物（如支化 PLGA）的特性描述是不够的。葡萄糖引发的 PLGA（Glu-PLGA）已被用于 1998 年美国食品和药物管理局（FDA）批准的注射用混悬剂 Sandostatin®LAR Depot（醋酸奥曲肽）。Glu-PLGA 是一种支化（也称为星形）聚合物，其性质的测定具有挑战性。因此，有必要开发能够确定和表征 Glu-PLGA 支化参数的方法。这种特性描述不仅对于制剂的质量控制很重要，而且对于开发需要具有相同赋形剂且用量相同（定性/定量（Q1/Q2）相同）的通用注射制剂也很重要。在这项研究中，开发并验证了一种分析技术，该技术使用一系列支化-PLGA 标准品进行，用于确定从 Sandostatin LAR 中提取的 Glu-PLGA 的支化参数，以及从三个不同制造商获得的 Glu-PLGAs 的支化参数。该分析技术基于凝胶渗透色谱法与四重检测系统（GPC-4D）。GPC-4D 能够对 Glu-PLGA 的浓度、绝对分子量、流体力学半径和特性粘度进行特性描述。以分子摩尔质量为函数的支化单元数的图为每个支化 PLGA 提供了独特的图谱。Mark-Houwink 图也可用于区分不同的 Glu-PLGAs。这些整体鉴定方法表明，从 Sandostatin LAR 中提取的 Glu-PLGA 的支化单元数从分子量较低端的 2（即线性）到 Glu-PLGA 的大部分（94%）<4。
