| Biodegradable poly(lactide-co-glycolide) (PLGA) microspheres are widely investigated for the controlled release of anticancer agents, antibiotics, peptides, proteins, and DNA. A major limitation of these delivery systems is a poorly defined microclimate pH (mupH) in the polymer. During the PLGA hydrolysis carboxylic acid monomers, oligomers, and/or polymer end-groups are produced. We hypothesized that the (mupH) inside PLGA microspheres becomes acidic, which results in degradation of acid-labile and stabilization of acid-stable encapsulated drugs. The purpose of this dissertation was to investigate the influence of (mupH) on the stability of encapsulated drugs in PLGA microspheres during polymer degradation.; The acid-stable, base-labile anticancer drug, 10-hydroxycamptothecin (10-HCPT), was encapsulated and exhibited remarkable stability in PLGA microspheres. An acid microclimate (pH < 4) is developed in PLGA 50/50 microspheres prepared by solvent evaporation techniques. This acidity can be neutralized by encapsulation of the base, Mg(OH)2, although without additional additives the increase in mupH is heterogeneous and localized near basic particles. 10-HCPT stability was a result of the acidic mupH and low water content in the polymer, which caused drug precipitation. A simple and reliable potentiometric method for mupH measurement, which involved coating of pH-electrodes with polymer films was developed and validated. Polymer composition, device size and porosity were critical parameters affecting mupH. The mupH kinetics was also rationalized mechanistically. The polymer mupH correlated with the extent of acid-induced aggregation of a model protein, bovine serum albumin (BSA), encapsulated in PLGA microspheres. Basic additives such as Mg(OH)2, MgCO3 , and ZnCO3 neutralized PLGA 50/50 acidity and stabilized BSA to varying extents according to their alkalinity and their ability to permeate the polymer. The rational approach to control PLGA mupH was used to stabilize and deliver the acid-labile anticancer agent, vincristine. The acid-catalyzed deformylation of vincristine was identified as a source of instability of encapsulated VCR and was successfully suppressed by the mupH neutralization with ZnCO3.; In closing, the techniques developed here for monitoring and control of PLGA mupH may be useful for the rational design of stable extended release formulations of pharmaceuticals such as proteins and DNA, which exhibit significant variations in stability as a function of pH. |
