RESEARCH IN THE DEVELOPMENT OF DOSAGE FORMS OF NEW ANTITUMOR DRUGS

本项目描述了美国食品和药物管理局配方实验室的活动。 药物资源科。这些研究针对的是 解决抗肿瘤药物静脉给药中存在的问题及对策 涉及评估和提高药物的溶解度和稳定性的方法。 合成了一系列喜树碱水溶性前药。 根据溶解行为对这些化合物进行了评估， 化学稳定性，以及在小鼠和人血浆中的水解率。在……里面 体内抗肿瘤活性也与喜树碱进行了比较。 前药的溶解度大约是前药物的1000倍。 母体化合物。所有的化合物在水中都相当稳定。 介质(室温下t 1/2大于10小时)。当着大家的面 在血浆中，化合物很容易水解(t1/2=10-90分钟，37℃ 摄氏度)。人血浆中的这一速度大约是小鼠的两倍。 血浆。在大约两个剂量水平下，观察到同等的抗肿瘤活性。 比喜树碱高四倍。 六甲基三聚氰胺类似物的药学行为， 对三甲基三聚氰胺进行了评价。该化合物可配制成 在水溶液中是即兴的，但分解很快，以至于 大规模生产是不现实的。几种干燥方法 研究了从水中混溶的有机溶剂。因为这个化合物 在乙醇中比在水中更稳定，低温真空干燥 乙醇是一种稳定的干品。

This project describes the activities of the formulation laboratory of the Pharmaceutical Resources Branch. These studies are directed toward resolving problems in the intravenous delivery of antitumor agents and involve methods to evaluate and then improve drug solubility and stability. A series of water soluble prodrugs of camptothecin have been prepared. These compounds were evaluated with respect to solubility behavior, chemical stability, and rate of hydrolysis in mouse and human plasma. In vivo antitumor activity was also assessed in comparison to camptothecin. The solubilities of the prodrugs were about 1000 fold higher than the parent compound. All of the compounds are reasonably stable in aqueous media (t 1/2 greater than 10 hours at room temperature). In the presence of plasma, the compounds readily hydrolyze (t 1/2 = 10-90 minutes at 37 degrees C). The rates in human plasma were about twice as fast as in mouse plasma. Equivalent antitumor activity was noted at dose levels about two to four fold higher than camptothecin. The pharmaceutical behavior of the hexamethylmelamine analogue, trimethylmelamine was evaluated. The compound can be formulated on an extemporaneous basis in aqueous solution but decomposes so rapidly that manufacture on large scale is not practical. Several methods of drying from water miscible organic solvents were investigated. Since the compound is more stable in ethanol than in water, low temperature vacuum drying from ethanol was found to yield a stable dry product.