A new approach to the in vivo and in vitro investigation of drug release from locoregionally delivered microspheres

The purpose of this work was to determine the in vivo release profile of doxorubicin (Dox) delivered locoregionally by dextran-based microspheres (MS) and to develop an in vitro method for predicting in vivo drug release from MS- in vitro-in vivo correlation (IVIVC). For the determination of in vivo Dox release, drug-loaded MS were placed into hollow fibers (HF) and implanted subcutaneously into C3H mice. Samples were retrieved at various times following implantation, MS removed from HF, and the amount of Dox remaining determined via ultraviolet/visible (UV/Vis) spectrophotometry. Various in vitro systems were designed and investigated for their ability to link in vivo and in vitro release profiles, including an open system (e.g. a column) with continuous flow of release medium at different flow rates and closed systems (e.g. a cuvette) using different release media and conditions. About 34% of loaded Dox was released from MS in vivo at 48 h. Only an incremental release was observed over the ensuing 72 h. The release kinetics of Dox from MS using three of the investigated in vitro systems, column system and HF immersed in a buffer solution or growth medium gave release profiles that were highly correlated with the in vivo release profile (r(2)>0.9). The relationships, both linear and non-linear, suggest that Level A IVIVC models can be developed for Dox release from locoregionally delivered MS using specially designed release systems. (C) 2004 Elsevier B.V. All rights reserved.