POLYMERIC SUSTAINED-RELEASE FORMULATIONS OF THE BRONCHIAL DILATOR VEPHYLLINE

Sustained release formulations of the Bulgarian bronchial dilator Vephylline (7-[2-bis{2-hydroxyethyl}aminoethyl]-1,3-dimethylxanthine) were prepared using two types of poly(ethylene oxide) (PEO)-based hydrogels: biodegradable polyether-polyesters with malic acid as cross-linking agent, and amphiphilic polyureas with large hydrophobic tri- or tetraisocyanates as cross-linker. Depending on the PEO chain length and the nature of the cross-linker, gels could be loaded up to 50 wt% of Vephylline by swelling in a saturated ethanolic solution of the drug. A novel cross-linked prodrug of Vephylline in the form of microspherical particles containing up to 52 wt% of the active substance was obtained in a polycondensation process between R,S-malic acid and the dihydroxy compound Vephylline. The microsphered prodrug has a lower toxicity than Vephylline itself and is essentially non-toxic (LD(50)(i.p.)>6000 mg/kg, and LD(50)(p.os)>10 000 mg/kg). Half-change tests in the pH range 1.2-7.4 at 37 degrees C show that the pH does not affect the release of Vephylline from physically loaded formulations. For the biodegradable polyester microspheres reasonable release rates were achieved (60% over a period of 8 h and 90% in 24 h).