Wang Xiaoyi, Wang Ruifeng, Roy Mckenzie, Kwok Owen, Burgess Diane J
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA; State Key Laboratory of Biochemical Engineering, Key Laboratory of Biopharmaceutical Preparation and Delivery (CAS), Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China(1).
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
Int J Pharm. 2025 Feb 10;670:125080. doi: 10.1016/j.ijpharm.2024.125080. Epub 2024 Dec 26.
Poly(DL-lactide-co-glycolide) (PLGA) and N-methyl-2-pyrrolidone (NMP)-based in situ forming implants are liquid formulations that solidify through phase separation following injection into the body. Drug is dissolved or suspended in the final formulation liquid prior to injection. Depending on the polymers used, the depots formed can deliver drug over different periods of time. Accordingly, it is important to understand the impact of PLGA properties on implant drug release. However, currently available publications only investigate such impacts based on a single drug, which is insufficient to determine the potential interplay between drug and PLGA properties affecting drug release, or to draw any solid conclusions concerning the general impact of PLGA on drug release. The current work explores in situ forming implants with different active pharmaceutical ingredients (APIs) to determine whether any interplay between the APIs and the polymer attributes might affect drug release. In particular, the drug state (solution or suspension form) may impact polymer interaction and drug release. Naproxen and meloxicam were chosen as model drugs and were loaded into in situ forming implants. The final implants of naproxen and meloxicam were solutions and suspensions, respectively. The impact of PLGA properties (slight changes in molecular weight (MW), slight/major changes in lactic/glycolic acid (L/G) ratio, as well as changes in polymer blockiness in end-cap (acid vs ester)) on drug release was investigated. The slight changes in PLGA MW (18-31 KDa), L/G ratio (75/15-85/15) and blockiness had similar impacts on the release of naproxen and meloxicam from the formulations. These impacts were consistent with a previous report on risperidone implants. However, the impact of end-cap and significant change in the L/G ratio (from 75/15-85/15 to 50/50) was determined to be drug dependent. For meloxicam and for risperidone (previous report), the ester end-cap (compared to the acid end-cap) and much higher L/G ratio (75/15-85/15 versus 50/50) resulted in significantly longer overall drug release durations. In contrast, the naproxen implants had shorter release durations when prepared with the ester end-caped polymer (compared to acid end-cap), and when prepared with significantly higher L/G ratio polymers (75/15-85/15 versus 50/50). In addition, using the same PLGA polymer, implants loading different APIs demonstrated different release durations. This work highlights the complexity of PLGA attributes in determining the performance of implant drug formulations and the critical role of the interplay with the API properties. This study provides valuable knowledge for the future development of in situ forming implant drug products.
聚（DL-丙交酯-共-乙交酯）（PLGA）和基于N-甲基-2-吡咯烷酮（NMP）的原位成型植入剂是液体制剂，注入体内后通过相分离固化。药物在注射前溶解或悬浮于最终制剂液体中。根据所使用的聚合物不同，形成的贮库可在不同时间段释放药物。因此，了解PLGA性质对植入剂药物释放的影响很重要。然而，目前已发表的文献仅基于单一药物研究此类影响，这不足以确定药物与影响药物释放的PLGA性质之间的潜在相互作用，也无法就PLGA对药物释放的总体影响得出任何确凿结论。当前的研究探索了含有不同活性药物成分（API）的原位成型植入剂，以确定API与聚合物属性之间是否存在任何相互作用可能影响药物释放。特别是，药物状态（溶液或悬浮液形式）可能会影响聚合物相互作用和药物释放。选择萘普生和美洛昔康作为模型药物，并将其载入原位成型植入剂中。萘普生和美洛昔康的最终植入剂分别为溶液和悬浮液。研究了PLGA性质（分子量（MW）的轻微变化、乳酸/乙醇酸（L/G）比例的轻微/重大变化以及封端（酸与酯）中聚合物嵌段性的变化）对药物释放的影响。PLGA分子量（18 - 31 kDa）、L/G比例（75/15 - 85/15）和嵌段性的轻微变化对制剂中萘普生和美洛昔康的释放具有相似的影响。这些影响与先前关于利培酮植入剂的报告一致。然而，封端和L/G比例的显著变化（从75/15 - 85/15变为50/50）的影响被确定为取决于药物。对于美洛昔康和利培酮（先前报告），酯封端（与酸封端相比）和更高的L/G比例（75/15 - 85/15对50/50）导致总体药物释放持续时间显著更长。相比之下，用酯封端聚合物制备的萘普生植入剂（与酸封端相比）以及用显著更高L/G比例聚合物制备的萘普生植入剂（75/15 - 85/15对50/50）的释放持续时间较短。此外，使用相同的PLGA聚合物，载入不同API的植入剂表现出不同的释放持续时间。这项工作突出了PLGA属性在确定植入剂药物制剂性能方面的复杂性以及与API属性相互作用的关键作用。本研究为原位成型植入剂药物产品的未来开发提供了有价值的知识。
