Ogawa Kohei, Katsumi Hidemasa, Moroto Yasushi, Morishita Masaki, Yamamoto Akira
Formulation R&D Laboratory, CMC R&D Division, Shionogi Co., Ltd., Amagasaki-shi 660-0813, Japan.
Department of Biopharmaceutics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan.
Pharmaceutics. 2022 Mar 4;14(3):568. doi: 10.3390/pharmaceutics14030568.
To optimize the characteristics of stereocomplex polylactide-b-polyethylene glycol nanoparticles (SC-PEG NPs) in terms of pharmacokinetics (PK), we chose continuous anti-solvent precipitation with a T-junction as a preparation method and investigated the effect of using solvents containing an ion excipient (lithium bromide, LiBr) on the characteristics of SC-PEG NPs by changing the processing temperature and total flow rate (TFR). Processing temperatures above the melting temperature (T) of the PEG domain produced a sharper polydispersity and denser surface PEG densities of SC-PEG NPs than those produced by processing temperatures below the Tm of the PEG domains. Response surface analysis revealed that a higher LiBr concentration and slower TFR resulted in larger and denser hydrodynamic diameters (D) and surface PEG densities, respectively. However, a high concentration (300 mM) of LiBr resulted in a decreased drug loading content (DLC). C-tamoxifen-loaded In-SC-PEG NPs with larger D and denser surface PEG densities showed a prolonged plasma retention and low tissue distribution after intravenous injection in mice. These results indicate that the novel strategy of using solvents containing LiBr at different processing temperatures and TFR can broadly control characteristics of SC-PEG NPs, such as D, surface PEG densities, and DLC, which alter the PK profiles and tissue distributions.
为了在药代动力学（PK）方面优化立体复合聚丙交酯-b-聚乙二醇纳米颗粒（SC-PEG NPs）的特性，我们选择采用T型接头连续抗溶剂沉淀法作为制备方法，并通过改变加工温度和总流速（TFR）来研究使用含有离子赋形剂（溴化锂，LiBr）的溶剂对SC-PEG NPs特性的影响。高于PEG域熔点（T）的加工温度所产生的SC-PEG NPs的多分散性比低于PEG域熔点的加工温度所产生的更尖锐，且表面PEG密度更高。响应面分析表明，较高的LiBr浓度和较慢的TFR分别导致更大且更致密的流体动力学直径（D）和表面PEG密度。然而，高浓度（300 mM）的LiBr会导致载药量（DLC）降低。静脉注射到小鼠体内后，具有更大D和更致密表面PEG密度的载他莫昔芬的In-SC-PEG NPs显示出更长的血浆滞留时间和较低的组织分布。这些结果表明，在不同加工温度和TFR下使用含有LiBr的溶剂这一新型策略可以广泛控制SC-PEG NPs的特性，如D、表面PEG密度和DLC，而这些特性会改变PK曲线和组织分布。
