Eichenbaum G, Zhou J, De Smedt A, De Jonghe S, Looszova A, Arien T, Van Goethem F, Vervoort I, Shukla U, Lammens L
Janssen Research & Development, LLC, A Division of Janssen Pharmaceutical Companies of Johnson & Johnson, Department: Drug Safety Sciences, 1000 Route 202 South, Raritan, NJ 08869, United States.
J Pharmacol Toxicol Methods. 2013 Nov-Dec;68(3):394-406. doi: 10.1016/j.vascn.2013.08.002. Epub 2013 Aug 8.
Evaluation of infusion site tolerability is required for the development of intravenous formulations of New Molecular Entities and is of particular importance for investigational drugs that have the potential to precipitate on contact with the blood stream. Based on a comprehensive set of in vitro and in vivo studies conducted with JNJ-X, a development stage small molecule investigational drug, with a pH-dependent solubility that showed potential to cause infusion site irritation at high concentrations, we have developed a systematic approach for evaluating and selecting suitable intravenous formulations for compounds that show potential to precipitate at the infusion site.
Aqueous formulations containing a range of concentrations of JNJ-X with different excipients, and buffering agents at different pHs (3.9-7.4) were evaluated in an in vitro solubility assay, a modified hen's egg test-chorioallantoic membrane assay (HET-CAM(VT)) and in vivo in rabbit, rat, and dog intravenous infusion toxicity studies.
The data obtained with JNJ-X in the different in vitro and in vivo studies were compared and used to support the development of an in silico model and to create a systematic approach to screen and identify candidate intravenous formulations with improved tolerability.
DISCUSSION/CONCLUSION: This approach provides a framework that can be used to assess the risk for infusion site irritation and identify better tolerated formulations with a reduced need for in vivo testing.
新分子实体静脉制剂的研发需要评估输注部位的耐受性，对于有可能在接触血流时发生沉淀的研究药物而言，这一点尤为重要。基于对处于研发阶段的小分子研究药物JNJ-X开展的一系列全面的体外和体内研究，该药物具有pH依赖性溶解度，在高浓度时显示出引起输注部位刺激的可能性，我们开发了一种系统方法，用于评估和选择可能在输注部位发生沉淀的化合物的合适静脉制剂。
在体外溶解度试验、改良鸡胚绒毛尿囊膜试验（HET-CAM(VT)）以及兔、大鼠和犬的体内静脉输注毒性研究中，对含有不同浓度JNJ-X以及不同辅料和不同pH值（3.9 - 7.4）缓冲剂的水性制剂进行了评估。
比较了在不同体外和体内研究中用JNJ-X获得的数据，并用于支持计算机模拟模型的开发以及创建一种系统方法，以筛选和识别耐受性更好的候选静脉制剂。
讨论/结论：该方法提供了一个框架，可用于评估输注部位刺激的风险，并识别耐受性更好、减少体内试验需求的制剂。
