The in vitro release study is a critical test to assess the safety, efficacy, and quality of nanoparticle-based drug delivery systems, but there is no compendial or regulatory standard. The variety of testing methods makes direct comparison among different systems difficult. We herein proposed a novel sample and separate (SS) method by combining the United States Pharmacopeia (USP) apparatus II (paddle) with well-validated centrifugal ultrafiltration (CU) technique that efficiently separated the free drug from nanoparticles. Polymeric drug nanoparticles were prepared by using a four-stream multi-inlet vortex mixer with d-α-tocopheryl polyethylene glycol 1000 succinate as a stabilizer. Itraconazole, cholecalciferol, and flurbiprofen were selected to produce three different nanoparticles with particle size <100 nm. By comparing with the dialysis membrane (DM) method and the SS methods using syringe filters, this novel SS + CU technique was considered the most appropriate in terms of the accuracy and repeatability to provide the in vitro release kinetics of nanoparticles. Interestingly, the DM method appeared to misestimate the release kinetics of nanoparticles through separate mechanisms. This work offers a superior analytical technique for studying in vitro drug release from polymeric nanoparticles, which could benefit the future development of in vitro-in vivo correlation of polymeric nanoparticles.

中文翻译：

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聚合物药物纳米颗粒的体外释放研究：新方法的开发和验证。

体外释放研究是评估基于纳米颗粒的药物递送系统的安全性、有效性和质量的关键测试，但没有药典或监管标准。测试方法的多样性使得不同系统之间的直接比较变得困难。我们在此提出了一种新颖的样品分离 (SS) 方法，将美国药典 (USP) 装置 II（桨）与经过充分验证的离心超滤 (CU) 技术相结合，可有效地将游离药物与纳米颗粒分离。以d-α-生育酚聚乙二醇1000琥珀酸酯为稳定剂，采用四流多入口涡旋混合器制备聚合物药物纳米粒。选择伊曲康唑、胆钙化醇和氟比洛芬来生产三种不同的粒径<100 nm的纳米颗粒。通过与透析膜 (DM) 方法和使用注射器过滤器的 SS 方法进行比较，这种新型 SS + CU 技术被认为在准确性和可重复性方面最适合提供纳米颗粒的体外释放动力学。有趣的是，DM 方法似乎通过不同的机制错误地估计了纳米粒子的释放动力学。这项工作为研究聚合物纳米颗粒的体外药物释放提供了一种卓越的分析技术，这可能有利于聚合物纳米颗粒体外-体内相关性的未来发展。