A bioresorbable, polylactide reservoir for diffusional and osmotically controlled drug delivery.
The purpose of this study was to design and characterize a zero-order bioresorbable reservoir delivery system (BRDS) for diffusional or osmotically controlled delivery of model drugs including macromolecules. The BRDS was manufactured by casting hollow cylindrical poly (lactic acid) (PLA): polyethylene glycol (PEG) membranes (10 x 1.6 mm) on a stainless steel mold. Physical properties of the PLA:PEG membranes were characterized by solid-state thermal analysis. After filling with drug (5 fluorouracil [5FU] or fluorescein isothiocyanate [FITC]-dextran:mannitol, 5:95 wt/wt mixture) and sealing with viscous PLA solution, cumulative in vitro dissolution studies were performed and drug release monitored by ultraviolet (UV) or florescence spectroscopy. Statistical analysis was performed using Minitab (Version 12). Differential scanning calorimetry thermograms of PLA:PEG membranes dried at 25 degrees C lacked the crystallization exotherms, dual endothermal melting peaks, and endothermal glass transition observed in PLA membranes dried at -25 degrees C. In vitro release studies demonstrated zero-order release of 5FU for up to 6 weeks from BRDS manufactured with 50% wt/wt PEG (drying temperature, 25 degrees C). The release of FITC dextrans of molecular weights 4400, 42 000, 148 000, and 464 000 followed zero-order kinetics that were independent of the dextran molecular weight. When monitored under different concentrations of urea in the dissolution medium, the release rate of FITC dextran 42 000 showed a linear correlation with the calculated osmotic gradient(DeltaPi). This study concludes that PEG inclusion at 25 degrees C enables manufacture of uniform, cylindrical PLA membranes of controlled permeability. The absence of molecular weight effects and a linear dependence of FITC-dextran release rate on DeltaPi confirm that the BRDS can be modified to release model macromolecules by an osmotically controlled mechanism.
Jonnalagadda
S
S
Department of Pharmaceutical Sciences, College of Pharmacy, 986025 Nebraska Medical Center, Omaha, NE 68198-6025, USA.
Robinson
D H
DH
D002152:Calorimetry, Differential Scanning; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics; D004058:Diffusion; D004337:Drug Carriers / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D005472:Fluorouracil / Q000493:pharmacokinetics; D006358:Hot Temperature; D057927:Hydrophobic and Hydrophilic Interactions; D019344:Lactic Acid / Q000493:pharmacokinetics; D008567:Membranes, Artificial; D008956:Models, Chemical; D009997:Osmotic Pressure; D011091:Polyesters / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000493:pharmacokinetics; D011108:Polymers / Q000493:pharmacokinetics
D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008567:Membranes, Artificial; D011091:Polyesters; D011108:Polymers; D019344:Lactic Acid; D011092:Polyethylene Glycols; C033616:poly(lactide); D005472:Fluorouracil