Preformed porous microspheres for controlled and pulsed release of macromolecules

Abstract

The release of dextran (mol. wt. 10,200), selected as a macromolecular model drug, from preformed porous poly( l-lactic)acid microspheres was studied. For all preparations an initial fast release (burst) was observed. At moderate loading levels (> 2.5 wt%), essentially all the dextran was released during the burst phase. However, at lower loading levels (< 1 wt%), the burst was reduced and the remaining portion was uniformly released for up to several months. By exposing the spheres to low ultrasonic energy (∼0.3 W/cm 2) dextran release could be reversibly increased by nearly three orders of magnitude. Studies in rats also showed that drug release was sustained from s.c. implanted porous microspheres. Preliminary mechanistic studies suggest that the release of drugs from porous microspheres can be described by three phases: 1. Fluid penetration into the porous microspheres. 2. Dissolution of the drug within the fluid-filled pores. 3. Diffusion of the drug out of the porous microspheres. Penetration of fluid into the microspheres appears to be the rate-limiting step. Since porous microspheres can be loaded by a simple and mild procedure they may be particularly useful for controlled release of labile macromolecular drugs.