BIODEGRADABLE CROSS-LINKED PRODRUG OF BRONCHIAL DILATOR VEPHYLLINE .1. MECHANISM OF THE RELEASE

The release mechanism of the bronchial dilator vephylline from the bio degradable cross-linked prodrug vephylline-malate (Veph-malate) has be en studied. It was found that the active constituent vephylline was re leased due to two-step hydrolysis of the ester bonds of the network. I nitially, the only product of the hydrolytic degradation was found to be an oligomer eater fraction which displayed no biological activity i n vitro. After 12 h due to a further hydrolysis of the oligomers in so lution, the active form started to be released as vephylline monomer. It was found that blood plasma enzymes in rats did not affect the hydr olytic processes. Veph-malate cross-linked prodrug synthesized in the form of microspheres can be considered as a typical sustained release formulation releasing the active constituent in a slightly alkaline me dia (pH 7.4) for a prolonged period of time (t(90)approximate to 70 h) implying a future parentheral application.