Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA; Office of Research Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Int J Pharm. 2020 Aug 30;586:119495. doi: 10.1016/j.ijpharm.2020.119495. Epub 2020 Jun 14.
Drug particle size distribution (PSD) and dispersion viscosity are two critical quality attributes that govern the performance of topical ophthalmic suspensions, such as suspension physical stability, ocular retention, and drug release characteristics.. An in-depth knowledge of the effects of formulation and manufacturing process on these critical quality attributes may facilitate the product and process development, quality control, as well as support regulatory policy and approval. The current study has investigated the effect of formulation and process parameters on the quality attributes of brinzolamide ophthalmic suspensions. In the first step, three milling techniques (probe sonication, microfluidization, and media milling with a planetary centrifugal mixer) were evaluated for manufacturing of brinzolamide suspension. Out of the three techniques, the planetary centrifugal media milling yielded the narrowest PSD and thus was considered the most viable lab-scale technique for this purpose. In the next step, various process parameters of media milling were evaluated using a central-composite experimental design. The independent variables included bead size, agitating intensity, and process time while the PSD of drug particles (D) was the response variable. The effect of shear rate and shear time of the homogenization process and the concentration of carbomer on the rheological properties of the suspension were studied using a Box-Behnken design. Additionally, effects of sodium chloride and mannitol concentration on the rheological properties of the suspension was also investigated. Sodium chloride was found to exert a pronounced effect on rheology of the suspension. Despite variations in the carbomer concentration, a suspension of comparable rheology could be prepared by controlling the process parameters namely the shear rate and process time.
药物颗粒大小分布（PSD）和分散黏度是控制眼部混悬剂性能的两个关键质量属性，例如混悬剂的物理稳定性、眼部滞留和药物释放特性。深入了解配方和制造工艺对这些关键质量属性的影响，可以促进产品和工艺开发、质量控制，以及支持监管政策和批准。本研究考察了配方和工艺参数对布林佐胺眼部混悬剂质量属性的影响。在第一步中，评估了三种制粒技术（探针超声、微流化和行星离心搅拌式介质研磨）制造布林佐胺混悬剂的效果。在这三种技术中，行星离心介质研磨得到的 PSD 最窄，因此被认为是最可行的实验室规模技术。在下一步中，使用中心组合实验设计评估了介质研磨的各种工艺参数。独立变量包括珠粒大小、搅拌强度和工艺时间，而药物颗粒的 PSD（D）是响应变量。使用 Box-Behnken 设计研究了匀化过程中的剪切速率和剪切时间以及卡波姆浓度对混悬剂流变性的影响。此外，还研究了氯化钠和甘露醇浓度对混悬剂流变性的影响。氯化钠对混悬剂的流变性有显著影响。尽管卡波姆浓度有所变化，但通过控制剪切速率和工艺时间等工艺参数，可以制备出具有类似流变性的混悬剂。
