POLYLACTIDE-POLY(ETHYLENE GLYCOL) COPOLYMERS AS DRUG-DELIVERY SYSTEMS.1. CHARACTERIZATION OF WATER DISPERSIBLE MICELLE-FORMING SYSTEMS

Copolymers of polylactide and poly(ethylene glycol) (PLA-PEG), which s elf-disperse in water to form spherical nonionic micelles, have been i nvestigated as a novel biodegradable drug delivery system. These copol ymers are defined by the molecular weight ratios of their polylactide to poly(ethylene glycol) components (1.5:2 PLA-PEG and 2:5 PLA-PEG) an d gave two peaks when purified by gel permeation chromatography (GPC). The first peak consisted of spherical micelles with a diameter of 15. 6 nm for 1.5:2 PLA-PEG, and 18.9 nm for 2:5 PLA-PEG micelles after ana lysis by dynamic light scattering (DLS) and by transmission electron m icroscopy (TEM). The second peak was a PLA-depleted species resulting from the synthesis and did not form micelles. Testosterone and sudan b lack B (SBB), which have different hydrophobicities, were used as ''mo del drugs'' to evaluate the drug loading ability of the micelles. Ultr acentrifugation sedimentation velocity studies confirmed that solubili zation of the model drugs had occurred by micellar incorporation. High er drug loading was obtained for the 1.5:2 PLA-PEG micelles (63.9% (w/ w) of SBB, 0.74% (w/w) of testosterone) than for the 2:5 PLA-PEG micel les (59.0% (w/w) of SBB, 0.34% (w/w) of testosterone). The amount of t estosterone solubilized was therefore significantly lower than SBB for both copolymers. Stability testing in the presence of salt suggested that the micelles had sterically stabilized surfaces. In vivo studies in the rat, using a radioactive marker, showed that PLA-PEG micelles d emonstrated extended circulation times in the blood during the period of study (3 h). The 1.5:2 PLA-PEG showed increased blood levels and lo wer uptake of the micelles by the liver compared to the 2:5 PLA-PEG mi celles. This is thought to be due to differences in the packing densit y of the copolymer molecules on the micelle surface.