title: In vitro and in vivo evaluation of a once-weekly formulation of an antidiabetic peptide drug exenatide in an injectable thermogel.
abstract: An injectable thermogel composed of poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers was evaluated as the matrix of a long-acting drug delivery system of exenatide (EXT), an antidiabetic peptide. The optimal gel formulation containing 2 mg/mL EXT and three pharmaceutical excipients (1.25 wt % zinc acetate, 5 wt % PEG200, and 5 wt % sucrose) was injected subcutaneously, and its pharmacokinetics was investigated. Both in vitro and in vivo release profiles exhibited a sustained release of EXT over 1 week. After a subcutaneous injection of the EXT formulation into db/db mice, the blood glucose level was maintained in a normal range up to 7 days and meanwhile the growth of body weight was suppressed. The in vivo results were consistent with the in vitro EXT-release profile. Moreover, twice injections of the gel formulation resulted in the higher blood insulin level and lower plasma concentration of glycosylated hemoglobin compared with twice-daily injections of an EXT solution for 18 days. Histological observations manifested the protection of islet due to administration of the gel formulation. Therefore, the PLGA-PEG-PLGA thermogel provided an excellent candidate for a once-weekly delivery system of EXT, and the optimal EXT formulation not only afforded therapeutic efficacy but also improved patient compliance.
authors.affiliation: State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai, 200433, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yu
authors.forename: Kun
authors.initials: K
authors.lastname: Li
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Liu
authors.forename: Chang
authors.initials: C
authors.lastname: Chen
authors.forename: Yongchu
authors.initials: Y
authors.lastname: Bao
authors.forename: Tianyuan
authors.initials: T
authors.lastname: Ci
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Chen
authors.forename: Jiandong
authors.initials: J
authors.lastname: Ding
mesh_terms: D000818:Animals; D003692:Delayed-Action Preparations / Q000737:chemistry*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D000077270:Exenatide; D020100:Hydrogels / Q000737:chemistry*; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D010455:Peptides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry*; D011098:Polyglactin 910 / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014688:Venoms / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D003692:Delayed-Action Preparations; D020100:Hydrogels; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; C528571:poly(lactic-co-glycolic acid)-polyethylene glycol-poly(lactic-co-glycolic acid); D011098:Polyglactin 910; D011092:Polyethylene Glycols; D000077270:Exenatide
keywords: biodegradable polymers; db/db mice; exenatide; hydrogels; in vivo/in vitro correlations; peptide delivery; pharmacodynamics; pharmacokinetics; type II diabetes