Stability and freeze-drying of cyclosporine loaded poly(D,L lactide-glycolide) carriers

The present paper describes the stability of poly (D,L-lactide-glycolide) nanoparticles (PLGA NP) and microspheres (MS), either alone or loaded with cyclosporine (CyA), stored at 8 degrees C and room temperature (RT). Freeze-drying of these formulations was evaluated as an alternative method to achieve long term stability. A significant polymer rupture was detected during PLGA MS preparation by solvent evaporation, which correlated with the stirring rates used for the formation of the primary emulsion. On the other hand, the polymer remained unchanged during NP formation. After 6 months of storage, PLGA NP of a size below 80 nm aggregated when stored at RT whereas no changes of particle size were observed for the remaining formulations and experimental conditions. Drug entrapment significantly increased by about 9.5% only during PLGA NP storage at RT. The PLGA molecular weight of NP dropped at RT being these changes related to the initial particle size and amount of CyA incorporated. The same effect was observed at 8 degrees C but only the particle size showed a significant influence. The drop of PLGA molecular weight observed during storage of MS was not dependent on the storage temperature but it was directly related to the molecular weights obtained after MS preparation. Freeze-drying studies revealed that it was not feasible to maintain the initial PLGA NP characteristics after reconstitution. On the other hand, MS lyophilized in the absence of cryoprotectants retained the drug initially entrapped; however, the presence of at least 5% cryoprotectant was essential to keep the initial particle size. Therefore, PLGA NP and MS show a significant instability when stored as suspensions. Freeze-drying offers a good alternative to stabilize polymeric MS but the preservation of the PLGA NP characteristics by freeze-drying needs for further investigations. (C) 1999 Elsevier Science B.V. All rights reserved.