Purdue University, Biomedical Engineering and Pharmaceutics, 206 S. Martin Jischke Drive, West Lafayette, IN 47907, USA; Akina, Inc., 3495 Kent Avenue, Suite A200, West Lafayette, IN 47906, USA.
Purdue University, Biomedical Engineering and Pharmaceutics, 206 S. Martin Jischke Drive, West Lafayette, IN 47907, USA.
J Control Release. 2021 Jan 10;329:1150-1161. doi: 10.1016/j.jconrel.2020.10.044. Epub 2020 Oct 24.
Injectable long-acting formulations, specifically poly(lactide-co-glycolide) (PLGA) based systems, have been used to deliver drugs systemically for up to 6 months. Despite the benefits of using this type of long-acting formulations, the development of clinical products and the generic versions of existing formulations has been slow. Only about two dozen formulations have been approved by the U.S. Food and Drug Administration during the last 30 years. Furthermore, less than a dozen small molecules have been incorporated and approved for clinical use in PLGA-based formulations. The limited number of clinically used products is mainly due to the incomplete understanding of PLGA polymers and the various variables involved in the composition and manufacturing process. Numerous process parameters affect the formulation properties, and their intricate interactions have been difficult to decipher. Thus, it is necessary to identify all the factors affecting the final formulation properties and determine the main contributors to enable control of each factor independently. The composition of the formulation and the manufacturing processes determine the essential property of each formulation, i.e., in vivo drug release kinetics leading to their respective pharmacokinetic profiles. Since the pharmacokinetic profiles can be correlated with in vitro release kinetics, proper in vitro characterization is critical for both batch-to-batch quality control and scale-up production. In addition to in vitro release kinetics, other in vitro characterization is essential for ensuring that the desired formulation is produced, resulting in an expected pharmacokinetic profile. This article reviews the effects of a selected number of parameters in the formulation composition, manufacturing process, and characterization of microparticle systems. In particular, the emphasis is focused on the characterization of surface morphology of PLGA microparticles, as it is a manifestation of the formulation composition and the manufacturing process. Also, the implication of the surface morphology on the drug release kinetics is examined. The information described here can also be applied to in situ forming implants and solid implants.
可注射长效制剂，特别是基于聚（乳酸-共-乙醇酸）（PLGA）的系统，已被用于将药物全身递送到长达 6 个月。尽管使用这种长效制剂有很多好处，但临床产品和现有制剂的仿制药的开发一直很缓慢。在过去的 30 年中，美国食品和药物管理局仅批准了大约二十几种制剂。此外，只有不到十几个小分子被纳入并批准用于基于 PLGA 的制剂的临床使用。临床使用的产品数量有限主要是由于对 PLGA 聚合物的不完全了解以及组成和制造过程中涉及的各种变量。许多工艺参数会影响制剂的特性，并且它们之间复杂的相互作用难以解析。因此，有必要确定影响最终制剂特性的所有因素，并确定主要贡献因素，以能够独立控制每个因素。制剂的组成和制造工艺决定了每个制剂的基本特性，即体内药物释放动力学导致各自的药代动力学特征。由于药代动力学特征可以与体外释放动力学相关联，因此适当的体外表征对于批间质量控制和放大生产都至关重要。除了体外释放动力学之外，其他体外表征对于确保生产所需的制剂并产生预期的药代动力学特征也很重要。本文综述了制剂组成、制造工艺和微球系统特性的选定参数的影响。特别是，重点是 PLGA 微球表面形态的表征，因为它是制剂组成和制造工艺的表现。还检查了表面形态对药物释放动力学的影响。这里描述的信息也可以应用于原位形成植入物和固体植入物。
