Frenvik Janne Olsen, Dyrstad Knut, Kristensen Solveig, Ryan Olav B
a Bayer AS , Lysaker, Oslo , Norway.
b KD Metrix , Spireaveien , Oslo , Norway.
Drug Dev Ind Pharm. 2017 Sep;43(9):1440-1449. doi: 10.1080/03639045.2017.1318906. Epub 2017 Apr 27.
Tumor targeting pharmaceuticals will play a crucial role in future pharma pipelines. The targeted thorium conjugate (TTC) therapeutic platform could provide real benefit to patients, whereby targeting moieties like monoclonal antibodies are radiolabelled with the alpha-emitting radionuclide thorium-227 (Th, t = 18.7 days). A potential problem could be the accumulation of the long-lived daughter nuclide radium-223 (Ra, t = 11.4 days) in the drug product during manufacturing and distribution. Therefore, the level of Ra must be standardized before administration to the patient. The focus in this study has been the removal of Ra, as the other progenies will have a very limited stay in the formulation. In this study, the purification of TTCs labeled with decayed Th has been explored. Columns packed with a strong cation exchange resin have been used to sequester Ra. The separation of TTC from Ra has been evaluated as influenced by both formulation and process parameters with a design of experiments (DOE) study; including citrate or acetate buffer, pH, buffer concentration, presence or absence of pABA + EDTA, resin amount and sodium chloride concentration. The aim was to achieve a separation with high sorption of Ra and accompanying low TTC sorption. The results were analyzed by multivariate analysis. Four regression models of TTC and Ra sorption from citrate and acetate buffered formulations were developed. The predictive accuracy of sorption in the four statistical models was given by standard deviations and confidence intervals. The TTC sorption in citrate and acetate buffered formulations was affected by the identical variables and the variation in TTC sorption was comparable for the two models. However, the DOE variables had a significantly stronger impact on the Ra sorption in citrate buffered formulations than the Ra sorption in acetate buffer. An optimal separation with a TTC sorption below 25% and Ra sorption above 90% can be achieved in both citrate and acetate buffered formulations. Stability studies of radiochemical purity (RCP) indicated that the measured Th values may be partly due to free Th and not TTC, but the results indicate that TTC stability may be controlled by optimizing formulation parameters. Hence, the sorption data and the regression models presented must be reviewed and further explored with regard to what is known about the stability of the TTC in the different buffered formulations.
肿瘤靶向药物在未来的制药产品线中将发挥关键作用。靶向钍偶联物（TTC）治疗平台可为患者带来切实益处，即通过用发射α粒子的放射性核素钍 - 227（Th，半衰期t = 18.7天）对单克隆抗体等靶向部分进行放射性标记。一个潜在问题可能是在生产和分发过程中，长寿命子核素镭 - 223（Ra，半衰期t = 11.4天）在药品中积累。因此，在给患者用药前必须对镭的含量进行标准化。本研究的重点是去除镭，因为其他子代在制剂中的停留时间非常有限。在本研究中，探索了对已衰变钍标记的TTC进行纯化。已使用填充有强阳离子交换树脂的柱子来螯合镭。通过实验设计（DOE）研究评估了制剂和工艺参数对TTC与镭分离的影响；包括柠檬酸盐或醋酸盐缓冲液、pH值、缓冲液浓度、对氨基苯甲酸（pABA）+乙二胺四乙酸（EDTA）的有无、树脂量和氯化钠浓度。目的是实现镭的高吸附和伴随的低TTC吸附的分离。通过多变量分析对结果进行了分析。建立了柠檬酸盐和醋酸盐缓冲制剂中TTC和镭吸附的四个回归模型。四个统计模型中吸附的预测准确性由标准差和置信区间给出。柠檬酸盐和醋酸盐缓冲制剂中TTC的吸附受相同变量影响，且两个模型中TTC吸附的变化相当。然而，DOE变量对柠檬酸盐缓冲制剂中镭吸附的影响比对醋酸盐缓冲制剂中镭吸附的影响显著更强。在柠檬酸盐和醋酸盐缓冲制剂中均可实现TTC吸附低于25%且镭吸附高于90%的最佳分离。放射化学纯度（RCP）的稳定性研究表明，测得的钍值可能部分归因于游离钍而非TTC，但结果表明可通过优化制剂参数来控制TTC的稳定性。因此，必须根据不同缓冲制剂中TTC稳定性的已知情况，对所呈现的吸附数据和回归模型进行审查并进一步探索。
