Applications of Supercritical Fluids in the Controlled Release of Drugs

Abstract

Supercritical fluids have been used to form two different types of microparticles intended for controlled drug release applications: drug-loaded polymer microspheres, and small protein particles. A poly(hydroxyacid), poly(D,L-lactic acid) (DL-PLA) and a pharmaceutical (lovastatin) have been dissolved in supercritical CO 2 and coprecipitated by rapid expansion of the resulting supercritical solution (RESS) to form polymer-drug microspheres and microparticles ranging in size from 10 to 100 μm. Variations in the concentration of lovastatin in the precipitate correlated with changes in the precipitate's morphology, ranging from continuous drug-polymer networks, to microparticles, to microspheres. The formation of polymer-drug microparticles by RESS is the first step towards a feasible single-step, low-temperature process that yields solvent and surfactant-free microparticles suitable for controlled drug release. Two model proteins, catalase and insulin, have been dissolved in ethanol/water solution and fed continuously and simultaneously with supercritical CO 2 into a crystallizer to precipitate the proteins. The use of supercritical CO 2 as a gas anti-solvent (GAS) produced catalase and insulin particles ranging from 1 to 5 μm. Particle morphology ranged from microspheres, to rectangular-shaped particles, to needles. Micron-sized protein particles are needed in several controlled release formulations to accommodate the high potency and low dosage of such pharmaceuticals and to achieve a uniform dispersion of the drug in the injectable polymeric microspherical carrier. GAS crystallization is a potentially important process for comminution of proteins since conventional particle reduction methods (spray drying, lyophilization, milling, grinding) cannot produce the micron-sized protein particles needed for controlled release of highly active enzymes.