Abstract
Thermosensitive polymeric delivery system (PLA-PEG-PLA) loaded with chitosan-zinc-insulin complex was designed for continuous in vivo insulin delivery at basal level for prolonged period after a single subcutaneous injection. Chitosan-zinc-insulin complex was optimized to restrict the diffusion of insulin from the delivery system by forming large complexes and thereby reducing the initial burst release. The in vivo absorption and bioactivity of insulin released from the delivery systems were studied in streptozotocin-induced diabetic rat model. The amount of insulin released in vivo was quantified using the Enzyme Linked Immunosorbent Assay (ELISA), and its bioactivity was determined by its ability to reduce the blood glucose levels in diabetic rats. An indirect ELISA was performed to determine the immunogenic potential of insulin released from the formulations. Furthermore, the in vitro and in vivo biocompatibility of the delivery system was studied using an MTT assay, and by studying the histology of skin samples, respectively. Chitosan-zinc-insulin complex significantly (P<0.05) reduced the initial burst release of insulin from the polymeric delivery system in comparison to zinc-insulin or insulin alone. The delivery system released insulin for ~3 months in biologically active form with corresponding reduction in blood glucose levels in diabetic rats. The insulin released from the delivery systems did not provoke any immune response. The delivery systems demonstrated excellent biocompatibility both in vitro and in vivo and were non-toxic. The results indicate that the chitosan-zinc-insulin complex incorporated in the thermosensitive polymeric delivery system can be used as an alternative to the conventional daily basal insulin therapy.