Control of micro- and nano-sphere size distributions: Implications in drug delivery

Biodegradable polymeric micro- and nano-spheres are capable of providing long term drug release, from hours to greater than a year, while protecting the encapsulated therapeutic thereby avoiding problems of patient compliance, drug overdose, and improper administration. However, micro- and nano-spheres have found limited clinical applications due to problems maintaining drug activity while controlling drug release. We have chosen to apply improved particle fabrication techniques to enhance control of drug release.; Our lab has developed two platform technologies for improving particle uniformity. Using a coaxial nozzle, we can spray a polymer-containing jet using an annular non-solvent stream to control jet diameter coupled with acoustic excitation to produce uniform microspheres in which ≥95% of the spheres were within 1.0–1.5 μm of the average for diameters ranging from 2.5-μm to >400-μm. Further, we have adapted an electrohydrodynamic method called flow-limited field-injection electrostatic spraying (FFESS) as an improved technique for the controlled deposition of polymeric material. FFESS allows us to produce precisely controlled charged polymer sprays resulting in the production of uniform nanoparticles, smooth or porous surfaces, and nonwoven or melded strings.; We fabricated various diameter poly(DL-lactide-co-glycolide) microspheres using our acoustic excitation technique to study in vitro drug release kinetics. Drug release depended strongly on microsphere diameter with small, 10- and 20-μm particles exhibiting diffusion-controlled release profiles while larger particles resulted in sigmoidal release profiles. The initial rate of release decreased and the duration increased with increasing microsphere size. Release kinetics from mixtures of uniform microspheres provided a means to attain zero-order drug release. We further investigated the impact of microsphere size on polymer degradation rate, drug distribution within the microsphere, and polymer erosion using microspheres fabricated from poly( DL-lactide-co-glycolide) and poly(sebacic anhydride).; Finally, as an extension of our acoustic excitation technique, we developed a method for fabricating uniform microcapsules exhibiting controlled shell thickness. The addition of a second concentric nozzle to our system allowed us to spray a dual polymer jet. Considering the interfacial tensions and spreading coefficients of the polymer components and non-solvent phase for the resulting emulsion, we were able to identify working parameters providing complete encapsulation of one polymer in another.