Kelley Ryan A, Ghaffari Alireza, Wang Yan, Choi Stephanie, Taylor Jonathan R, Hartman Rachel R, Kompella Uday B
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Food and Drug Administration, White Oak Campus, Silver Spring, Maryland.
J Ocul Pharmacol Ther. 2020 Jun;36(5):290-297. doi: 10.1089/jop.2019.0074. Epub 2020 Apr 24.
Reliable drug therapy with injectable intravitreal implants requires implants of consistent quality. The purpose of this study was to prepare dexamethasone-poly(d,l-lactide-co-glycolide) (PLGA) biodegradable implants and assess implant quality within and between batches for different polymer compositions. Implants containing 20% w/w dexamethasone with 3 theoretical rates of release (fast, intermediate, and slow) were manufactured with decreasing proportion of acid-terminated PLGA (50:50) and increasing proportion of ester-terminated PLGA (50:50) in a batch process using hot-melt extrusion. The implants were manufactured without and with in-process modification of extrusion/conveyor speed in the late phase of each batch. Implant samples collected at early, middle, and late phases of each batch were analyzed for diameter, drug loading, mechanical properties (strength and toughness), and drug release. With a fixed process, unlike a modified process with an increase in extrusion speed and reduction of conveyor speed in the late phase, all implant formulations tended to decrease in diameter and mechanical properties in the late phase. Drug release profiles for the intermediate and slow release compositions were similar with or without process modification, unlike the fast release composition. Addition of ester-terminated PLGA resulted in a slower drug release. When all formulations are grouped together, the implant diameter exhibited a moderate correlation with mechanical properties, but no correlation was observed with drug release. Within a hot-melt extrusion batch process, the dexamethasone-PLGA implant diameter and hence toughness and strength tend to decline in the latter phase. In-process adjustment of extrusion and conveyor speeds can improve batch consistency and, potentially, implant integrity or performance during or after injection. Process changes did not affect drug release for 2 of the 3 implant compositions.
使用可注射玻璃体内植入物进行可靠的药物治疗需要质量一致的植入物。本研究的目的是制备地塞米松-聚（d，l-丙交酯-共-乙交酯）（PLGA）可生物降解植入物，并评估不同聚合物组成批次内和批次间的植入物质量。采用热熔挤出的批量工艺，制备了含20%w/w地塞米松且具有3种理论释放速率（快、中、慢）的植入物，其中酸封端PLGA（50:50）的比例逐渐降低，酯封端PLGA（50:50）的比例逐渐增加。在每一批次的后期，植入物的制造过程有或没有对挤出/输送速度进行过程中调整。对每一批次的早期、中期和后期收集的植入物样品进行直径、载药量、机械性能（强度和韧性）和药物释放分析。在固定工艺下，与后期提高挤出速度并降低输送速度的改进工艺不同，所有植入物制剂在后期直径和机械性能都趋于下降。无论有无工艺改进，中速和慢速释放组合物的药物释放曲线相似，而快速释放组合物则不同。添加酯封端的PLGA导致药物释放较慢。当所有制剂归为一组时，植入物直径与机械性能呈中度相关，但与药物释放无相关性。在热熔挤出批量工艺中，地塞米松-PLGA植入物直径以及韧性和强度在后期往往会下降。在过程中调整挤出和输送速度可以提高批次一致性，并可能改善注射期间或之后植入物的完整性或性能。工艺变化对3种植入物组合物中的2种的药物释放没有影响。
