title: Injectable in situ forming depot systems: PEG-DAE as novel solvent for improved PLGA storage stability.
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 biocompatible solvent was investigated as a function of storage temperature and water content. The PLGA molecular weight (Mw) 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 transesterification using conventional PEG as solvent. A significant improvement with only 3% Mw 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.
authors.affiliation: Novartis Pharma AG, Technical Research and Development, 4056 Basel, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Schoenhammer
authors.forename: H
authors.initials: H
authors.lastname: Petersen
authors.forename: F
authors.initials: F
authors.lastname: Guethlein
authors.forename: A
authors.initials: A
authors.lastname: Goepferich
mesh_terms: D020341:Absorbable Implants; D016503:Drug Delivery Systems / Q000379:methods*; D004343:Drug Implants / Q000737:chemistry*; D004355:Drug Stability; D004356:Drug Storage; D004987:Ethers / Q000737:chemistry*; D019344:Lactic Acid / Q000737:chemistry*; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012995:Solubility; D012997:Solvents / Q000737:chemistry*
chemical_list: D004343:Drug Implants; D004987:Ethers; D012997:Solvents; C518220:poly(ethylene glycol) dimethyl ether; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols