Comparison of the effects of Mg(OH)(2) and sucrose on the stability of bovine serum albumin encapsulated in injectable poly(D,L-lactide-co-glycolide)implants

Incomplete release and poor stability of encapsulated proteins are common h urdles to overcome when developing poly(lactide-co-glycolide) (PLGA) con tr olled-re lease systems. Antacid excipients such as Mg(OH)(2), which increas e both microclimate pH and polymer water uptake, have been shown to prevent acid-induced instability of proteins encapsulated in PLGA. The purpose of this study was to delineate the effects of microclimate pH and polymer wate r content on the stability of encapsulated bovine serum albumin (BSA) by co mparing the effects of Mg(OH)(2) With those of another excipient, sucrose, which increases polymer water content without significantly affecting acid- base chemistry of the polymer. These two excipients, when encapsulated in P LGA at appropriate levels (3% Mg(OH)(2) vs. 10% sucrose), were found to cau se identical water sorption kinetics, thus allowing the effect of the two m icroclimate parameters to be determined. In contrast to their similar effec ts on polymer water sorption, Mg(OH)(2) afforded a much greater stabilizati on effect on encapsulated BSA than did sucrose, with less than 7% aggregate s for 3% Mg(OH)(2) compared to 51% for 10% sucrose and 81% without either e xcipient after 4 Weeks of incubation at 37 degreesC. When the protein stabi lization rationale of neutralizing the acidic microenvironment by adding Mg (OH)(2) was applied to the delivery of an important therapeutic protein, ti ssue plasminogen activator (t-PA), t-PA stability was also improved and the active protein was completely recovered during a one month period of in vi tro release. These data demonstrated that although increased water uptake i nduced by antacid excipients may improve the stability of the encapsulated proteins, the homogeneous acid neutralization effect is unique to antacid e xcipients such as Mg(OH)(2), which is necessary to maintain the stability o f proteins in acidic PLGA specimens. (C) 2001 Elsevier Science Ltd. All rig hts reserved.