Abstract
Injectable in situ forming depots (ISFD) that contain a peptide or a protein within a polymeric solution comprise an attractive, but challenging application system. Beyond chemical compatibility, local tolerability and acute toxicity, an important factor for an ISFD is its storage stability as a liquid. In this study, poly(D,L-lactide-co-glycolide) (PLGA) degradation in the presence of ...
Abstract
Injectable in situ forming depots (ISFD) that contain a peptide or a protein within a polymeric solution comprise an attractive, but challenging application system. Beyond chemical compatibility, local tolerability and acute toxicity, an important factor for an ISFD is its storage stability as a liquid. In this study, poly(D,L-lactide-co-glycolide) (PLGA) degradation in the presence of poly(ethyleneglycol) (PEG) as bio-compatible solvent was investigated as a function of storage temperature and water content. The PLGA molecular weight (M-w) was determined by gel permeation chromatography (GPC) and monitored by NMR during degradation. Rapid PLGA degradation of 75% at 25 degrees C storage temperature was shown to be the result of a trans-esterification using conventional PEG as solvent. A significant improvement with only 3% M-w loss was obtained by capping the PEG hydroxy- with an alkyl- endgroup to have poly(ethyleneglycol) dialkylether (PEG-DAE). The formation of PEG-PLGA block co-polymers was confirmed by NMR, only for PEG300. Reaction rate constants were used to compare PLGA degradation dissolved in conventional and alkylated PEGs. The degradation kinetics in PEG-DAE were almost completely insensitive to 1% additional water in the solution. The transesterification of the hydroxy endgroups of PEG with PLGA was the major degradation mechanism. even under hydrous conditions. The use of PEG-DAE for injectable polymeric solutions, showed PLGA stability under the chosen conditions for at least 2 months. Based on the results obtained here, PEG-DAE appears to be a promising excipient for PLGA-based, parenteral ISFD. (C) 2008 Elsevier B.V. All rights reserved.
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