POLYORGANOPHOSPHAZENE MICROSPHERES FOR DRUG-RELEASE - POLYMER SYNTHESIS, MICROSPHERE PREPARATION, IN-VITRO AND IN-VIVO NAPROXEN RELEASE

Microsphere preparation for naproxen slow release was investigated usi ng two newly prepared biodegradable polyorganophosphazenes, derivatize d at the phosphorus atoms with phenylalanine ethyl ester and imidazole at molar ratios of 71/29 and 80/20. The polymers were prepared by sub stitution of the chloride atoms of polydichlorophosphazene with a phen ylalanine ethyl ester-imidazole mixture followed, after 7 or 48 h reac tion, by the addition of excess imidazole. Three methods of microspher e preparation have been considered: spray-drying, emulsion/solvent eva poration and emulsion/solvent evaporation-extraction. Microparticles o btained by spray-drying were found to possess a narrow distribution si ze with a mean diameter of 2-5 mu m. Their internal structure consiste d of a porous or empty core depending upon the solvent used for the pr eparation. Furthermore the microspheres prepared with this technique r apidly released the entrapped naproxen independently of the used polym er, the drug loading or the preparation process. On the other hand mic rospheres prepared by solvent evaporation or solvent evaporation-extra ction showed a distribution size ranging between 10 and 100 mu m. By t he appropriate choice of pH and solvent composition of the external ph ase, naproxen could be entrapped, in these microspheres, with a yield higher of 80%. The polymer composition dictates the in vitro release r ate of naproxen from the particles, which was faster when the microsph eres were prepared with the polymer at higher imidazole content. In vi vo experiments, carried out by subcutaneous implantation in rats of mi crospheres prepared by solvent evaporation, demonstrated that a consta nt level of naproxen in plasma could be maintained up to 400 h at a su itable concentration for antinflammatory activity. (C) 1998 Elsevier S cience B.V.