Controlled release of tobramycin sulfate from poly(ortho esters) implantable discs for the treatment of osteomyelitis

This study was designed to investigate a new biodegradable implantable disc system based upon poly(ortho esters) (POE) which could release tobramycin sulfate (TS) over a 21-day period at a rate of 2 mg TS/day/g of implant (usual clinical requirement) for the treatment of osteomyelitis. The device was formulated in the form of discs (diameter, 1 cm) cast from methylene chloride and in vitro release was investigated in phosphate buffered saline, pH 7.4 at 37 degrees C. The POE-TS discs without any adjuvants released 20%-60% TS in 24 h and an additional 10% in subsequent 20 days with about 3% loss in polymer weight, irrespective of the drug loading (4, 8, 12% w/w) and disc thickness (148, 244, 433 mu m). In order to achieve uniform and complete TS release over 21 days, lactic acid (LA), sorbic acid (SA), oleic acid (OA) and palmitoleic acids (PA), in varying concentrations, were incorporated in the 244 mu m-discs containing 8% TS. The release of TS was near-zero order after an initial burst in the presence of lactic acid. In the presence of SA, OA and PA, the TS release was multi-phasic. The rate of polymer degradation was found to be acid concentration-dependent for all acids. The TS release from these discs could be attributed to burst effect, diffusion, and acid-catalyzed bulk erosion of POE polymer. Among these formulations, discs with 0.2% LA and 0.9% OA demonstrated release rates close to 2 mg: TS/day/g of implant with significant and simultaneous POE degradation. No physical or chemical interactions between the drug and the polymer were detected by DSC, NMR and IR.