Extending Residence Time and Stability of Peptides by Protected Graft Copolymer (PGC) Excipient: GLP-1 Example

• DOI: 10.1007/s11095-011-0542-2
• Publication Date: 2011-08-09T12:10:44Z
• Authors: Gerardo M. Castillo; Sandra Reichstetter; Elijah M. Bolotin
• Keywords: Glycated Hemoglobin; 0301 basic medicine; Dose-Response Relationship, Drug; Protein Stability; Dipeptidyl Peptidase 4; Fatty Acids; Incretins; Polyethylene Glycols; Rats; Rats, Zucker; 3. Good health; Excipients; Rats, Sprague-Dawley; 03 medical and health sciences; Glucagon-Like Peptide 1; Delayed-Action Preparations; Insulin-Secreting Cells; Diabetes Mellitus; Animals; Exenatide; Humans; Polylysine; Peptides

To determine whether a Protected Graft Copolymer (PGC) containing fatty acid can be used as a stabilizing excipient for GLP-1 and whether PGC/GLP-1 given once a week can be an effective treatment for diabetes.To create a PGC excipient, polylysine was grafted with methoxypolyethyleneglycol and fatty acid at the epsilon amino groups. We performed evaluation of the binding of excipient to GLP-1, the DPP IV sensitivity of GLP-1 formulated with PGC as the excipient, the in vitro bio-activity of excipient-formulated GLP-1, the in vivo pharmacokinetics of excipient-formulated GLP-1, and the efficacy of the excipient-formulated GLP-1 in diabetic rats.We showed reproducible synthesis of PGC excipient, high affinity binding of PGC to GLP-1, slowed protease degradation of excipient-formulated GLP-1, and that excipient-formulated GLP-1 induced calcium influx in INS cells. Excipient-formulated GLP-1 stays in the blood for at least 4 days. When excipient-formulated GLP-1 was given subcutaneously once a week to diabetic ZDF rats, a significant reduction of HbA1c compared to control was observed. The reduction is similar to diabetic ZDF rats given exendin twice a day.PGC can be an ideal in vivo stabilizing excipient for biologically labile peptides.