OPTIMIZATION OF 7-DAY RELEASE (IN-VITRO) FROM DL-PLA METHADONE MICROSPHERES

Poly(DL-lactic)acid-methadone base microspheres able to release the dr ug over 7 days have been developed using the solvent evaporation metho d and an optimization strategy. The first optimization step involved i n vitro release study of nine different formulations elaborated in agr eement with a composite rotable second order experimental design. Poly mer degradation was observed during microsphere preparation; degradati on index, defined as the number of broken bonds in relation to the ini tial number of polymer molecules, was less than 0.72 for weight averag e molecular weight (Mw) below 145000 and 0.93 for 198000 Mw. Degradati on index ranging between 1.4 and 6.54 were observed during in vitro re lease assay. Specific surface determinations show larger than expected values from the number-volume average diameters, and DSC studies show ed that methadone is dissolved to a limited extent. Once the region of interest was located, two new formulations were prepared and tested. Optimum formulation released 18.6% of drug content over the first 24 h , against a targeted value of 14.3% for a near zero order release rate over 7 days, and 68.0% after 7 days.