Xia Ziyun, Liu Yayuan, Lu Ziyi, Gan Jingyao, Yu Minzhi, Olsen Karl, Wang Yan, Xu Xiaoming, Schwendeman Steve, Schwendeman Anna
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA.
BioInterfaces Institute, University of Michigan, NCRC, 2800 Plymouth Road, Ann Arbor, MI, 48109, USA.
Drug Deliv Transl Res. 2025 Mar 4. doi: 10.1007/s13346-025-01806-y.
A bupivacaine multivesicular liposomal injectable formulation, Exparel™, is a nonopioid long-acting local analgesic indicated for pain management across and/or post surgeries. For such products, preclinical data is lacking to support bioequivalence determination for potential generic products. Therefore, in the present work, in vivo studies were set up in male Sprague-Dawley rats to understand the in vivo performance of bupivacaine multivesicular liposomes (MVLs), aiming to provide information on bioequivalence establishment between comparator products. Bupivacaine MVLs show a multiphasic release profile, and their pharmacokinetics (PK) may differ with different experimental conditions including doses, administration routes, and sample dilution factors. In this work, compromised bupivacaine MVLs were either generated in lab by freeze-thawing, mechanical agitation, and high-temperature incubation, or chosen from years-old expired batches of Exparel™, for a preliminary investigation on the in vitro and in vivo association. The formulation attributes of different bupivacaine MVLs were characterized, including morphology, particle size distribution, formulation pH, free drug contents, in vitro release, and in vivo PK. In the rat study, even with an observation of inter- and intra-variability in PK, an association between product attributes and in vivo behaviors was demonstrated with bupivacaine MVLs. Overall, investigating the bupivacaine MVLs in vivo is beneficial not only to fill in gaps in preclinical data in the field of bupivacaine MVLs, but also to help pave the path for developing other MVL-related products.
一种布比卡因多泡脂质体注射剂配方Exparel™，是一种非阿片类长效局部镇痛药，适用于手术中和/或手术后的疼痛管理。对于此类产品，缺乏临床前数据来支持潜在仿制药的生物等效性判定。因此，在本研究中，在雄性Sprague-Dawley大鼠中开展了体内研究，以了解布比卡因多泡脂质体（MVL）的体内性能，旨在提供有关对照产品之间生物等效性确立的信息。布比卡因MVL呈现多相释放曲线，其药代动力学（PK）可能因不同的实验条件而有所不同，包括剂量、给药途径和样品稀释因子。在本研究中，受损的布比卡因MVL要么是在实验室通过冻融、机械搅拌和高温孵育生成的，要么是从过期多年的Exparel™批次中选取的，用于体外和体内相关性的初步研究。对不同布比卡因MVL的制剂属性进行了表征，包括形态、粒径分布、制剂pH值、游离药物含量、体外释放和体内PK。在大鼠研究中，即使观察到PK存在个体间和个体内变异性，但布比卡因MVL的产品属性与体内行为之间仍显示出相关性。总体而言，对布比卡因MVL进行体内研究不仅有助于填补布比卡因MVL领域临床前数据的空白，也有助于为开发其他与MVL相关的产品铺平道路。
