title: Extending residence time and stability of peptides by protected graft copolymer (PGC) excipient: GLP-1 example.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  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.
  
  
  CONCLUSIONS
  PGC can be an ideal in vivo stabilizing excipient for biologically labile peptides.
authors.affiliation: PharmaIN Corporation, 720 Broadway Suite 511, Seattle, Washington 98122, USA. gcastillo@pharmain.com
authors.forename: Gerardo M
authors.initials: GM
authors.lastname: Castillo
authors.forename: Sandra
authors.initials: S
authors.lastname: Reichstetter
authors.forename: Elijah M
authors.initials: EM
authors.lastname: Bolotin
mesh_terms: D000818:Animals; D003692:Delayed-Action Preparations; D003920:Diabetes Mellitus / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005079:Excipients / Q000737:chemistry*; D000077270:Exenatide; D005227:Fatty Acids / Q000737:chemistry; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry*; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D054795:Incretins / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry; D050417:Insulin-Secreting Cells / Q000187:drug effects; D010455:Peptides / Q000008:administration & dosage; D011092:Polyethylene Glycols / Q000737:chemistry; D011107:Polylysine / Q000737:chemistry; D055550:Protein Stability; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D014688:Venoms / Q000008:administration & dosage
chemical_list: D003692:Delayed-Action Preparations; D018819:Dipeptidyl Peptidase 4; D005079:Excipients; D000077270:Exenatide; D005227:Fatty Acids; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D054795:Incretins; D010455:Peptides; D011092:Polyethylene Glycols; D011107:Polylysine; D014688:Venoms; C517652:hemoglobin A1c protein, human; C028210:monomethoxypolyethylene glycol