Stability of exenatide in poly(D,L-lactide-co-glycolide) solutions: a simplified investigation on the peptide degradation by the polymer

Abstract

A solution model can be used to elucidate drug stability issues in a complex system. The aim of this study was to investigate the interaction between poly(D,L-lactide-co-glycolide) (PLGA) and exenatide in organic solvent-acetate buffer saline (ABS) solutions. The effect of solvent composition on exenatide stability was investigated first. In the selected 90:10 dimethyl sulfoxide (DMSO):ABS solution, exenatide stability was examined as a function of PLGA comonomer ratios, molecular weight (Mw) and concentrations. The specific rotation analysis and second derivative UV absorbance spectroscopy were used to monitor the variation of exenatide higher order structure. The effect of ABS pH on the interaction was also investigated. Exenatide degradation products were characterized by HPLC-MS/MS. It was found that exenatide was relatively stable in glacial acetic acid (HAc)-ABS solutions, whereas DMSO content had a strong influence on the conformation state and stability of exenatide. PLGA 50:50 promoted exenatide degradation more than PLGA 75:25 and poly(D,L-lactide) (PLA). Lower Mw and higher concentration of PLGA were beneficial for exenatide degradation. Exenatide was more stable in 90:10 DMSO:ABS (pH 3.0) solution than in 90:10 DMSO:ABS (pH 4.5 and 3.0) solutions during the incubation. HPLC-MS/MS analysis of exenatide demonstrated that acylation was the main degradation route of the peptide.

Keywords: 100DL2A; 5050DLG1A; 5050DLG2A; 5050DLG2E; 5050DLG3A; 7525DLG2A; ABS; Acylation; DMSO; Exenatide; HAc; Mw; PLA (0.15–0.25dl/g) with free carboxyl end groups; PLGA; PLGA (50:50, 0.15–0.25dl/g) with ester end groups; PLGA (50:50, 0.15–0.25dl/g) with free carboxyl end groups; PLGA (50:50, 0.25–0.35dl/g) with free carboxyl end groups; PLGA (75:25, 0.15–0.25dl/g) with free carboxyl end groups; PLGA (comonomer ratio 50:50, inherent viscosity 0.05–0.15dl/g in chloroform at 30°C) with free carboxyl end groups; Poly(d,l-lactide-co-glycolide) (PLGA); Solution model; Stability; acetate buffer saline (pH 4.5, unless otherwise noted); dimethyl sulfoxide; glacial acetic acid; molecular weight; poly(D,L-lactide-co-glycolide).