Fabrication of PLG microspheres with precisely controlled and monodisperse size distributions

The size distribution of biodegradable polymer microspheres critically impacts the allowable routes of administration, biodistribution, and release rate of encapsulated compounds. We have developed a method for producing microspheres of precisely controlled and/or monodisperse size distributions. Our apparatus comprises spraying a polymer-containing solution through a nozzle with (i) acoustic excitation to produce uniform droplets, and (ii) an annular, non-solvent carrier stream allowing further control of the droplet size. We used this apparatus to fabricate poly(D,L-lactide-co-glycolide) (PLG) spheres. The acoustic excitation method, by itself, produced uniform microspheres as small as 30 μm in diameter in which ≥95% of the spheres were within 1.0-1.5 μm of the average. The carrier stream method alone allowed production of spheres as small as ∼1-2 μm in diameter from a 100-μm diameter nozzle, but generated broader size distributions. By combining the two devices, we fabricated very uniform spheres with average diameters from ∼5 to >500 μm. Furthermore, by discretely or continuously varying the experimental parameters, we fabricated microsphere populations with predefined size distributions. Finally, we demonstrate encapsulation and in vitro release of a model drug compound, rhodamine B. In summary, our apparatus provides unprecedented control of microsphere size and may allow development of advanced controlled-release delivery systems.