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Extending residence time and stability of peptides by protected graft copolymer (PGC) excipient: GLP-1 example.
- Source :
-
Pharmaceutical research [Pharm Res] 2012 Jan; Vol. 29 (1), pp. 306-18. Date of Electronic Publication: 2011 Aug 04. - Publication Year :
- 2012
-
Abstract
- Purpose: 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.<br />Methods: 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.<br />Results: 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.<br />Conclusions: PGC can be an ideal in vivo stabilizing excipient for biologically labile peptides.
- Subjects :
- Animals
Delayed-Action Preparations
Dipeptidyl Peptidase 4 metabolism
Dose-Response Relationship, Drug
Exenatide
Fatty Acids chemistry
Glucagon-Like Peptide 1 blood
Glycated Hemoglobin analysis
Humans
Incretins administration & dosage
Incretins blood
Incretins chemistry
Insulin-Secreting Cells drug effects
Peptides administration & dosage
Polyethylene Glycols chemistry
Polylysine chemistry
Protein Stability
Rats
Rats, Sprague-Dawley
Rats, Zucker
Venoms administration & dosage
Diabetes Mellitus drug therapy
Excipients chemistry
Glucagon-Like Peptide 1 administration & dosage
Glucagon-Like Peptide 1 chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1573-904X
- Volume :
- 29
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Pharmaceutical research
- Publication Type :
- Academic Journal
- Accession number :
- 21830140
- Full Text :
- https://doi.org/10.1007/s11095-011-0542-2