Liquid Degradable Poly(trimethylene-carbonate-co-5-hydroxy-trimethylene carbonate): An Injectable Drug Delivery Vehicle for Acid-Sensitive Drugs.
AbstractLiquid, injectable hydrophobic polymers have advantages as degradable drug delivery vehicles; however, polymers examined for this purpose to date form acidic degradation products that may damage acid-sensitive drugs. Herein, we report on a new viscous liquid vehicle, poly(trimethylene carbonate-co-5-hydroxy-trimethylene carbonate), which degrades through intramolecular cyclization producing glycerol, carbon dioxide, and water-soluble trimethylene carbonate. Copolymer degradation durations from weeks to months were achieved with the 5-hydroxy-trimethylene carbonate (HTMC) content of the oligomer having the greatest impact on the degradation rate, with oligomers possessing a higher HTMC content degrading fastest. The degradation products were non-cytotoxic towards 3T3 fibroblasts and RAW 264.7 macrophages. These copolymers can be injected manually through standard gauge needles and, importantly, during in vitro degradation, the microenvironmental pH within the oligomers remained near neutral. Complete and sustained release of the acid-sensitive protein vascular endothelial growth factor was achieved, with the protein remaining highly bioactive throughout the release period. These copolymers represent a promising formulation for local and sustained release of acid sensitive drugs.