DETERMINANTS OF RELEASE RATE OF TETANUS VACCINE FROM POLYESTER MICROSPHERES

Controlled-release formulations based on poly(lactic) (PLA) and poly(l actic/glycolic) acid (PLGA) microspheres containing tetanus vaccine we re designed. The polymers forming the microspheres were L-PLA of diffe rent molecular weights and DL-PLGA, 50:50. These microspheres were pre pared by two solvent elimination procedures, both using a double emuls ion, and were characterized for size, morphology, and toxoid release k inetics. The influence of formulation variables such as polymer type, vaccine composition, and vaccine/polymer ratio was also investigated. Both techniques yielded microspheres with similar size, morphology, an d release properties. Microsphere size was dependent on the type of po lymer and the presence of the surfactant L-alpha-phosphatidylcholine, which led to a reduction in microsphere size. On the other hand, the r elease kinetics of encapsulated protein were affected by the polymer p roperties (ratio lactic/glycolic acid and molecular weight) as well as by the vaccine composition, vaccine loading, and microsphere size. Mo reover, for some formulations, a decrease in microsphere size occurred simultaneously, with an increase in porosity leading to an augmentati on of release rate. The changes in the PLA molecular weight during in vitro release studies indicated that release profiles of tetanus toxoi d from these microspheres were only marginally influenced by polymer d egradation. A significant fraction of protein (between 15 and 35%) was initially released by diffusion through water-filled channels. In con trast, the decrease in the PLGA molecular weight over the first 10 day s of incubation suggested that erosion of the polymer matrix substanti ally affects protein release from these microspheres. Among all formul ations developed, two differing in microsphere size, polymer hydrophob icity, and release profile were selected for in vivo administration to mice. Administration of both formulations resulted in tetanus neutral izing antibody levels that were higher than those obtained after admin istration of the fluid toxoid.