Controlled delivery of therapeutic agents from polymer-based, in situ, gel-forming systems

The purpose of this study was to develop injectable controlled release systems of aspirin and protein/peptide therapeutics while conserving their stability and activity. A poly(lactide-glycolide) (PLGA) based, injectable, phase-sensitive system was chosen for controlled delivery of aspirin. The effect of drug/polymer interaction on the in vitro release of aspirin and polymer degradation was investigated. Aspirin-loaded polymeric formulations showed good injectability and controlled the release of aspirin for 7 days while conserving its chemical stability. The PLGA in aspirin-loaded formulations exhibited a significantly (p<0.05) faster degradation compared to the blank formulation. These findings suggest that aspirin causes a faster degradation of PLGA. Thus, this polymeric delivery system might be suitable for short-term continuous delivery of aspirin.;Eleven batches of monomethoxy poly(ethylene glycol)-poly(lactide-glycolide)-monomethoxy poly(ethylene glycol) (mPEG-PLGA-mPEG) copolymers were synthesized and characterized. Four of the eleven synthesized copolymers showed suitable thermosensitive sol-gel transition property for in vivo use. These copolymer-based, drug-delivery systems prolonged the in vitro release of model proteins (lysozyme, bovine serum albumin, and insulin) over ∼10 to ∼30 days, depending on copolymer structure and type of proteins, while conserving their stability. Furthermore, these formulations showed excellent biocompatibility and biodegradability as tested by MTT assay and in vivo histological evaluation. Based on the above findings, the copolymer mPEG-PLGA-mPEG (EG12-L35G12-EG12) based delivery system was chosen to develop controlled-release system for salmon calcitonin (sCT). The polymeric formulations of sCT showed good injectability and controlled the in vitro release of sCT for ∼20 to ∼40 days following a zero-order release kinetic while conserving structure and chemical stability of sCT. In vivo studies showed that the delivery systems controlled the release of sCT in rats while conserving its biological activity and significantly (p<0.05) prevented methyl prednisolone acetate induced osteoporosis in rats. In conclusion, biocompatible and biodegradable mPEG-PLGA-mPEG based thermosensitive, in situ, gel-forming drug delivery systems were suitable for controlled delivery of proteins/peptides in conformationally-stable, chemically-stable and biologically-active forms for a longer duration after single injection.