Controlled release of ionic compounds from poly ( l-lactide) microspheres produced by precipitation with a compressed antisolvent

Abstract

Poly ( l-lactide) microspheres containing low molecular weight pharmaceutical agents were prepared using the precipitation with a compressed antisolvent (PCA) process with supercritical carbon dioxide as the antisolvent. Gentamycin, naloxone, and naltrexone were solubilized in methylene chloride using hydrophobic ion pairing (HIP) to stoichiometrically replace polar counter ions with an anionic detergent, aerosol OT (AOT, sodium bis-2-ethylhexyl sulfosuccinate). Through HIP complexation, solubilities in excess of 1 mg/ml were attainable in methylene chloride, allowing levels of direct incorporation that are not possible with other PCA approaches. The drug/polymer particles were spherical in shape and between 0.2 and 1.0 μm in diameter, as determined by scanning electron microscopy. Drug incorporation efficiencies were determined and in vitro release profiles measured. At 37°C, the release of the ion-paired drugs into phosphate-buffered saline displays minimal burst effects and exhibits release kinetics that are approximately linear with the square root of time, indicating matrix diffusion control of drug release. For gentamycin, linear release from the poly ( l-lactide) microspheres was observed for more than 7 weeks, even at a drug loading of near 25% (w/w). Naltrexone exhibits similar release characteristics, although more drug was found on the surface of the microspheres. Conversely, rifampin, which was not ion-paired, was poorly encapsulated.