Costello Mark A, Liu Joseph, Wang Yan, Qin Bin, Xu Xiaoming, Li Qi, Smith William C, Lynd Nathaniel A, Zhang Feng
University of Texas at Austin, College of Pharmacy, Department of Molecular Pharmaceutics and Drug Delivery, Austin, TX, USA.
U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, Office of Research and Standards, Silver Spring, MD, USA.
Int J Pharm. 2023 Nov 25;647:123515. doi: 10.1016/j.ijpharm.2023.123515. Epub 2023 Oct 14.
Over 20 long-acting injectable formulations based on poly(lactide-co-glycolide) (PLGA) have been approved by the FDA to date. PLGA is a biodegradable polymer that can extend drug release from these dosage forms for up to six months after administration. Despite the commercial success of several of these formulations, there are still a limited number of products that utilize PLGA, and there are currently no generic counterparts of these products on the market. Significant technical challenges are associated with preparation of chemically and structurally equivalent formulations that yield an equivalent drug release profile to the reference listed drug (RLD) both in vitro and in vivo. In this work, Ozurdex (dexamethasone intravitreal implant) was used as a model system to explore how the manufacturing process of PLGA-based solid implants impacts the quality and performance of the dosage form. Control of implant structural characteristics, including diameter, internal porosity, and surface roughness, was required to maintain accurate unit dose potency. Implants were prepared by a continuous hot-melt extrusion process that was thoroughly characterized to show the importance of precise feeding control to meet dimensional specifications. Five extruder die designs were evaluated using the same hot-melt extrusion process to produce five structurally-distinct implants. The structural differences did not alter the in vitro drug release profile when tested in both normal saline and phosphate-buffered saline (pH 7.4); however, implant porosity was shown to impact the mechanical strength of the implants. This work seeks to provide insight into the manufacturing process of PLGA-based solid implants to support development of future novel and generic drug products.
截至目前，已有20多种基于聚（丙交酯-共-乙交酯）（PLGA）的长效注射制剂获得了美国食品药品监督管理局（FDA）的批准。PLGA是一种可生物降解的聚合物，给药后可使这些剂型中的药物释放长达六个月。尽管其中几种制剂取得了商业成功，但使用PLGA的产品数量仍然有限，目前市场上尚无这些产品的仿制药。制备在体外和体内均能产生与参比上市药品（RLD）等效药物释放曲线的化学和结构等效制剂存在重大技术挑战。在这项工作中，Ozurdex（地塞米松玻璃体内植入剂）被用作模型系统，以探索基于PLGA的固体植入剂的制造过程如何影响剂型的质量和性能。需要控制植入物的结构特征，包括直径、内部孔隙率和表面粗糙度，以维持准确的单位剂量效力。通过连续热熔挤出工艺制备植入物，并对其进行了全面表征，以显示精确进料控制对于满足尺寸规格的重要性。使用相同的热熔挤出工艺评估了五种挤出机模具设计，以生产五种结构不同的植入物。在生理盐水和磷酸盐缓冲盐水（pH 7.4）中测试时，结构差异并未改变体外药物释放曲线；然而，植入物的孔隙率显示会影响植入物的机械强度。这项工作旨在深入了解基于PLGA的固体植入物的制造过程，以支持未来新型和仿制药产品的开发。
