Liposomal formulations of glucagon-like peptide-1: improved bioavailability and anti-diabetic effect.
Glucagon-like peptide-1 (GLP-1), an incretin hormone, is recognized to be potent drug candidate for treatment of diabetes, however its clinical application has been highly limited, because of rapid enzymatic degradation by dipeptidyl-peptidase IV. To protect GLP-1 from enzymatic degradation and improve pharmacological effects, liposomal formulations of GLP-1 were prepared using three types of lyophilized empty liposomes such as anionic, neutral and cationic liposomes. Electron microscopic and dynamic light scattering experiments indicated the uniform size distribution of GLP-1-loaded liposomes with mean diameter of 130-210 nm, and inclusion of GLP-1 did not affect the dispersibility and morphology of each liposome. Of all liposomal formulations tested, anionic liposomal formulation exhibited the highest encapsulation efficiency of GLP-1 (ca. 80%). In intraperitoneal glucose tolerance testing in rats, marked improvement of hypoglycemic effects were observed in anionic liposomal formulation of GLP-1 (100 nmol/kg) with 1.7-fold higher increase of insulin secretion, as compared to GLP-1 solution. In pharmacokinetic studies, intravenous administration of anionic liposomal formulation of GLP-1 (100 nmol/kg) resulted in 3.6-fold higher elevation of serum GLP-1 level as compared to GLP-1 injection. Upon these findings, anionic liposomal formulation of GLP-1 would provide the improved pharmacokinetics and insulinotropic action, possibly leading to efficacious anti-diabetic medication.
Hanato
Junko
J
Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Kuriyama
Kazuki
K
Mizumoto
Takahiro
T
Debari
Kazuhiro
K
Hatanaka
Junya
J
Onoue
Satomi
S
Yamada
Shizuo
S
D000818:Animals; D001682:Biological Availability; D001786:Blood Glucose / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical; D004339:Drug Compounding; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D005951:Glucose Tolerance Test; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D007328:Insulin / Q000097:blood*; D008027:Light; D008081:Liposomes; D008297:Male; D046529:Microscopy, Electron, Transmission; D010316:Particle Size; D051381:Rats; D017208:Rats, Wistar; D012542:Scattering, Radiation; D013499:Surface Properties; D013678:Technology, Pharmaceutical / Q000379:methods
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D008081:Liposomes; D052216:Glucagon-Like Peptide 1