A STABLE PGE1 PRODRUG FOR TARGETING THERAPY

Lipo-PGE1 is a passively targetable prostaglandin E1 (PGE1) preparation, in which PGE1 is incorporated into lipid microspheres (LM); it has been widely used in Japan since 1988 for the treatment of various vascular diseases. Passive targeting results from the accumulation of LM in the vascular lesions following intravenous administration. However, this preparation has two major disadvantages. One is the chemical instability of PGE1 in the LM and the other is the rapid leakage of PGE1 from the LM in the blood, leading to a decrease in the targeting of this drug. We accordingly synthesized several PGE1 prodrugs and evaluated them to develop a better LM preparation. Among the PGE1 prodrugs tested, DELTA-8-9-O-butyryl prostaglandin F1 butyl ester (AS013) was readily hydrolyzed to PGE1 in human serum. AS013 was stable as an LM preparation and 80% of this ester was recovered unchanged even after storage as LM-AS013 for 4 weeks at 40-degrees-C. In contrast, PGE1 showed a recovery of only 5% from the LM under the same conditions. Moreover, AS013 was more effectively retained in the LM after incubation with human blood or serum when compared with PGE1. These results suggested that LM-AS013 would be a far superior LM preparation than lipo-PGE1 for clinical use.