| The purpose of this study was to design and characterize a biodegradable, reservoir delivery system (BRDS) for the zero-order delivery of drugs including macromolecules. The use of polylactic acid (PLA) in controlled drug delivery has been limited because it is brittle and impermeable. This research describes the addition of a permeability-enhancing agent, polyethylene glycol (PEG), into PLA-based formulations to overcome these limitations. Initial studies in films and microcapsules demonstrated that addition of PEG lowered the glass transition temperature, intrinsic crystallinity, and enhanced permeability of PLA while decreasing residual solvent in these formulations.; A two-step procedure was used to prepare the BRDS to avoid exposing drug to manufacturing stresses. Hollow, cylindrical membranes of PLA or PLA:PEG were cast, and after drying, filled with drug and excipients. A three factor, two level, factorial design was used to investigate the effect of the addition of PEG, drying temperature, and film thickness on the properties of the BRDS. The incorporation of PEG and drying at 25°C were necessary to prepare PLA membranes with improved thermal properties. The release of the model drug, 5FU, was diffusion-controlled at a constant rate for up to 6 weeks. By adding an osmotic excipient, it was demonstrated that drug release from the BRDS was osmotically controlled. Specifically, with the inclusion of mannitol, the BRDS released model macromolecular drugs, FITC dextrans, at a constant rate independent of molecular weight in the range of 4,400 to 464,000 g/mole.; In vitro studies indicated the degradation half-life of the BRDS ranged between 35 to 55 weeks depending on the concentration of PEG and the thickness of the membrane. The ability of the BRDS to enhance drug stability and control the delivery of macromolecules in their active form was demonstrated using insulin in the streptozotocin-induced diabetic rat model. Relative to the diabetic control group, the group treated with the BRDS demonstrated a 93% decrease in the blood glucose concentration and a 20% increase in body weight. |
