DEVELOPMENT OF IMPLANTABLE ANTITUMOR DEVICES BASED ON POLYPHOSPHAZENES .2.

Matrix devices containing the alkylating agent melphalan have been prepared in different ways and their drug release characteristics have been studied using a flow-through release system. As matrix material polyphosphazene, substituted with glycine ethyl ester, was used. Testing of devices, prepared by using methanol, the best solvent for melphalan, renders biphasic release profiles, with high initial release concentrations of melphalan. These high initial 'first-phase' releases could be eliminated by means of flow-through elution procedures. Tetrahydrofuran (THF) is the best solvent for polyphosphazene polymers, however, its use renders matrices which are too slowly releasing. In addition, the low level of release is difficult to reproduce due to difficult quantitative handling of the melphalan suspension in THF. The use of a more hydrophobic polyphosphazene, 50% substituted with glutamic acid diethyl ester and 50% with glycine ethyl ester, reduces the high initial release levels of melphalan when methanol has been used as solvent. With melphalan methyl ester free base, very low and gradual release profiles could be obtained, due to its good solubility in THF and its poor solubility in water. Devices with these release profiles showed promising therapeutic results in leukemia L1210 i.p. tumor model in mice. For both drug contents, the extension of the median survival time was statistically significant: P < 0.05 (Wilcoxon-test, two-tailed to control devices). With respect to median survival time only, in two cases slightly better to better results were observed: in one dosage group of animals receiving a higher releasing device (0.33% w/w: P < 0.01) or in another dosage group treated with repeated injections with melphalan methyl ester (33-mu-g: P < 0.01), however, for both the therapeutic range is rather narrow.