Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
Int J Pharm. 2022 Jun 10;621:121777. doi: 10.1016/j.ijpharm.2022.121777. Epub 2022 Apr 27.
In situ forming implants are injectable liquid formulations which form solid or semisolid depots following injection. This allows for minimally invasive administration, localized drug delivery, and extended drug release. Unfortunately, this drug delivery strategy lacks standardized in vitro dissolution methods due to the difficulties in recreating implant formation in vitro that is biomimicry and with reproducible and controllable shape and dimensions. In the present study, an innovative, adapter-based in vitro release testing method was developed to solve this problem. Two distinctively different in situ forming implants (a risperidone formulation (suspension) consisting of PLGA dissolved in N-methyl pyrrolidone (NMP), where risperidone powder was suspended to form a drug suspension, and a naproxen formulation (solution) consisting of PLGA dissolved in NMP, where naproxen was completely dissolved to form a solution), were used as model in situ-forming implants. The results revealed that the implants formed in the custom-designed adapter with a water-dissolvable polyvinyl alcohol (PVA) film were bio-mimicking and reproducible in both shape and burst release of drug according to rabbit data. For both the suspension and solution formulations, this adapter-based in vitro release testing method resulted in consistent release data. Compared with a direct injection in vitro release testing method, the release profiles generated using the adapter-based method were capable of distinguishing the different release phases (initial release within 24 h, diffusion-facilitated release, and degradation-controlled release). In addition, the adapter-based method could discriminate formulation and dissolution apparatus changes and could be utilized to develop accelerated release testing methods. This adapter-based method has the promise of wide use in release testing of in situ forming implant formulations and has the potential to be used in the development of in vivo-predictive in vitro release methods.
原位形成植入物是可注射的液体制剂，在注射后形成固体或半固体储库。这允许微创给药、局部药物递送和延长药物释放。不幸的是，由于难以在体外重现类似于生物的植入物形成，并且具有可重复和可控的形状和尺寸，这种药物递送策略缺乏标准化的体外溶解方法。在本研究中，开发了一种基于适配器的创新体外释放测试方法来解决这个问题。两种截然不同的原位形成植入物（一种包含 PLGA 溶解在 N-甲基吡咯烷酮 (NMP) 中的利培酮制剂（悬浮液），其中利培酮粉末悬浮形成药物悬浮液，以及一种包含 PLGA 溶解在 NMP 中的萘普生制剂（溶液），其中萘普生完全溶解形成溶液）被用作模型原位形成植入物。结果表明，根据兔子数据，用可水溶的聚乙烯醇 (PVA) 膜形成的定制设计适配器中形成的植入物在形状和药物突释方面具有仿生和可重现性。对于悬浮液和溶液制剂，这种基于适配器的体外释放测试方法产生了一致的释放数据。与直接注射的体外释放测试方法相比，使用适配器的方法产生的释放曲线能够区分不同的释放阶段（24 小时内的初始释放、扩散促进释放和降解控制释放）。此外，基于适配器的方法可以区分制剂和溶解设备的变化，并可用于开发加速释放测试方法。这种基于适配器的方法有望在原位形成植入物制剂的释放测试中广泛使用，并有可能用于开发体内预测性体外释放方法。
