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.
