Costello Mark A, Liu Joseph, Chen Beibei, Wang Yan, Qin Bin, Xu Xiaoming, Li Qi, 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.
Eur J Pharm Biopharm. 2023 Jun;187:46-56. doi: 10.1016/j.ejpb.2023.04.003. Epub 2023 Apr 8.
Ozurdex is an FDA-approved sustained-release, biodegradable implant formulated to deliver the corticosteroid dexamethasone to the posterior segment of the eye for up to 6 months. Hot-melt extrusion is used to prepare the 0.46 mm × 6 mm, rod-shaped implant by embedding the drug in a matrix of poly(lactic-co-glycolic acid) (PLGA) in a 60:40 drug:polymer ratio by weight. In our previous work, the Ozurdex implant was carefully studied and reverse engineered to produce a compositionally and structurally equivalent implant for further analysis. In this work, the reverse-engineered implant was thoroughly characterized throughout the in vitro dissolution process to elucidate the mechanisms of controlled drug release. The implant exhibited a triphasic release profile in 37 °C normal saline with a small burst release (1-2 %), a one-week lag phase with limited release (less than 10 %), and a final phase where the remainder of the dose was released over 3-4 weeks. The limited intermolecular interaction between dexamethasone and PLGA rendered the breakdown of the polymer the dominating mechanism of controlled release. A close relationship between drug release and total implant mass loss was observed. Unique chemical and structural differences were seen between the core of the implant and the implant surface driven by diffusional limitations, autocatalytic hydrolysis, and osmotic effects.
Ozurdex是一种经美国食品药品监督管理局（FDA）批准的缓释、可生物降解植入物，其配方旨在将皮质类固醇地塞米松输送到眼后段，作用长达6个月。通过将药物以60:40（重量比）的药物:聚合物比例嵌入聚乳酸-乙醇酸共聚物（PLGA）基质中，采用热熔挤出法制备0.46毫米×6毫米的棒状植入物。在我们之前的工作中，对Ozurdex植入物进行了仔细研究并进行逆向工程，以生产出成分和结构等效的植入物用于进一步分析。在这项工作中，对逆向工程植入物在整个体外溶解过程中进行了全面表征，以阐明药物控释机制。该植入物在37℃生理盐水中呈现三相释放曲线，有一个小的突释（1 - 2%），一个为期一周的有限释放滞后阶段（小于10%），以及最后一个阶段，在此阶段剩余剂量在3 - 4周内释放。地塞米松与PLGA之间有限的分子间相互作用使得聚合物的分解成为控释的主导机制。观察到药物释放与植入物总质量损失之间存在密切关系。由于扩散限制、自催化水解和渗透效应，在植入物核心与植入物表面之间观察到独特的化学和结构差异。
