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Abstract
This work was designed to optimize the thermosensitive copolymeric depot-based system for delivering insulin at a controlled rate for a prolonged period following a single subcutaneous injection. The intrinsic ability of insulin to form hexamers in the presence of zinc and electrostatic complexes with chitosan (CS) were explored for improving stability and release characteristics of insulin through the copolymeric depot. CS–zinc–insulin complexes were prepared using CS of different chain lengths (5, 30, 50, and 200 kDa). Effect of different chain lengths of CS on the thermal stability, binding constant, and release profile of insulin was determined. Increasing chain length of CS demonstrated increasing thermal stability of insulin. However, the higher chain length of CS adversely affected the release profile of insulin. Hydrolytic degradation analysis showed rapid degradation of the copolymer in a formulation containing higher chain length of CS (200 kDa)–zinc–insulin complexes, implying the formation of bigger pores and channels in the copolymeric matrix during the initial release in this system. However, a formulation containing a smaller chain length of CS (5 kDa)–zinc–insulin complexes demonstrated slow copolymer degradation and sustained insulin release profile. Additionally, CS–zinc–insulin complexes were effective in preserving the stability of insulin during the entire duration of release and storage.
Graphical Abstract
Abbreviations: CS: chitosan; CD: circular dichroism DM: diabetes mellitus; DSC: differential scanning calorimetry; DMEM: Dulbecco’s modified Eagle’s medium; DMSO: dimethyl sulfoxide; GPC: gel permeation chromatography; HEK 293: human embryonic kidney cell line; 1H NMR: proton nuclear magnetic resonance; ΔH: transition enthalpy; ITC: isothermal calorimetry; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide; PDI: polydispersity index; PLA: poly(D,L-lactide); PEG: poly(ethylene glycol); tetrahydrofuran; PBS: phosphate buffer saline; UV: ultraviolet; Tm: Midpoint transition temperature; THF: tetrahydrofuran.
Disclosure statement
The authors declare no competing financial interest.
Scheme 1. Synthesis of triblock copolymer poly(D,L-lactide)-poly(ethylene glycol)-poly(D,L-lactide) (PLA-PEG-PLA) via ring opening polymerization of D,L-lactide with poly(ethylene glycol) catalyzed by stannous octoate. (Inset: Reaction setup). (Adapted with modifications from Oak, Mayura Arvind. Controlled Delivery of Basal Level of Insulin. North Dakota State University, 2013. pp 38.)
