Abstract：
These toxicity studies aimed to assess the safety and tolerability of a novel intravenous diclofenac sodium (37.5 mg/mL) formulation containing povidone K12 (80 mg/mL) as the key excipient in Wistar rats. This formulation was tested at doses of 3, 7, and 15 mg/kg/day and was administered daily for 28 days by intravenous route. Toxicokinetic estimation revealed a dose-proportional increase in plasma exposure to diclofenac. The formulation was well tolerated in males; however, mortality was observed in females (2/15) at the highest dose (15 mg/kg/day). Adverse gastrointestinal events related to NSAIDS and a few other treatment-related effects on clinical and anatomic pathology were noted at the 15 mg/kg/day dose, which normalized at the end of the 2-week recovery period. In addition, the excipient povidone K12 was present in a higher amount than the approved Inactive Ingredient Database (IID) limit in the proposed novel formulation. It was qualified through a separate 28-day repeated dose toxicity study by intravenous route in Wistar rats. Povidone K12 was found to be well tolerated and safe up to a dose of 165 mg/kg/day. No treatment-related adverse effects were observed in this study. In conclusion, repeated administration of a novel intravenous formulation containing diclofenac sodium was found to be safe up to the dose of 7 mg/kg/day in female rats and 15 mg/kg/day in male rats.
摘要：
这些毒性研究旨在评估含有聚维酮K12(80mg/mL)作为关键赋形剂的新型静脉内双氯芬酸钠(37.5mg/mL)制剂在Wistar大鼠中的安全性和耐受性。该制剂以3、7和15mg/kg/天的剂量进行测试,并通过静脉内途径每天施用28天。毒物动力学估计显示血浆暴露于双氯芬酸的剂量成比例增加。该制剂在男性中耐受性良好；然而，在最高剂量(15mg/kg/天)下观察到女性(2/15)的死亡率.在15mg/kg/天的剂量下，注意到与NSAIDS相关的不良胃肠道事件以及对临床和解剖病理学的一些其他治疗相关影响，在2周恢复期结束时恢复正常。此外,在拟议的新制剂中,赋形剂聚维酮K12的含量高于批准的非活性成分数据库(IID)限值.通过在Wistar大鼠中通过静脉内途径进行的单独的28天重复剂量毒性研究，它是合格的。发现聚维酮K12在165mg/kg/天的剂量下具有良好的耐受性和安全性。在这项研究中没有观察到治疗相关的不良反应。总之,发现在雌性大鼠和雄性大鼠中重复施用含有双氯芬酸钠的新型静脉内制剂直至7mg/kg/天和15mg/kg/天的剂量是安全的。
