Internal morphology of poly(D,L-lactide-co-glycolide) BCNU-loaded microspheres. Influence on drug stability

The solvent extraction/evaporation process has been used to form poly(D,L-lactide-co-glycolide) (PLAGA) BCNU-loaded microspheres designed for use as intracranial controlled-release implants. Their actual payload could reach 25% with a 20-50 microns size distribution. Scanning electron microscopy showed that such carriers had a smooth surface and a spherical geometry. Differential scanning calorimetry analyses carried out on drug-loaded microspheres established that the PLAGA Tg was markedly shifted towards the low temperatures along with the disappearance of the BCNU melting endotherm. Annealing experiments performed at room temperature did not induce any change of the loaded microsphere DSC profiles. These features indicated that the BCNU acted as a plasticizer for the coating material and formed with it a solid solution. Similarly, stability of encapsulated BCNU was assessed in different conditions of storage. It appeared that drug degradation increased with temperature increase: 5.4, 8.8, 32.4 and 51.2% of decomposition after 3 month storage at -18, 4, room temperature (RT) and 37 degrees C respectively. Since the free drug was stable at 4 degrees C and experienced only 10.6% decomposition at RT during the same storage time, the state of solid solution involving the intimate mixing of the drug and the polyester in the matrix favors a progressive decomposition of BCNU. However, keeping the microspheres 6 months at -18 degrees C or 3 months at 4 degrees C prevents a loss of drug superior to 10%.