title: Preparation of glucagon-like peptide-1 loaded PLGA microspheres: characterizations, release studies and bioactivities in vitro/in vivo.
abstract: The gut hormone glucagon-like peptide-1 (GLP-1) is proposed for treatment of Type II diabetes mellitus. However, the short half life of GLP-1 in vivo is a major limitation for its application due to the frequent invasive administrations. To provide a optimal formulation to overcome this limitation, we developed a GLP-1 entrapped microspheres to achieve sustained release GLP-1 for 4-week. GLP-1 was stabilized by GLP-1-zinc complexation with zinc carbonate and encapsulated in poly(D,L-lactic-co-glycolic acid) (PLGA) with S/O/O solvent extraction to obtain GLP-1 loaded PLGA microspheres (MS). The characteristics of MS were evaluated as follows: The surface morphology was assessed by scanning electron microscopy (SEM); The drug encapsulation efficiency and GLP-1 controlled release profile was tested by HPLC; The sustained release of GLP-1 MS in vivo and pharmacological efficacy were studied in normal mice and streptozotocin (STZ)-induced diabetic mice model after subcutaneous administration of GLP-1 MS. GLP-1-zinc complexation significantly reduced initial burst release from 37.2 to 7.5%. The controlled release bioactive GLP-1 in vitro was achieved for 4-week period by zinc complexation and addition of ZnCO(3). The optimal and complete cumulative release of GLP-1 from MS was increased from 23 to 63% in 28 d by using low MW PLGA (MW 14000). The in vivo testing in normal mice and diabetic mice suggest that this zinc-stabilized technique combined with S/O/O method in the presence of water insoluble antacid additive ZnCO(3) preserve the biological activity of GLP-1. GLP-1 MS formulation achieved controlled released in vivo for 28 d and exhibit sustained long term pharmacological efficacy to decrease blood glucose level in diabetic mice. This GLP-1 MS formulation provides a practical formulation for long-term sustained delivery of GLP-1 to treat Type II diabetes.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Second Military Medical University, Shanghai, PR China.
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Yin
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu
authors.forename: He
authors.initials: H
authors.lastname: Zhang
authors.forename: Guoqing
authors.initials: G
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Zou
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
authors.forename: Yanqiang
authors.initials: Y
authors.lastname: Zhong
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D004655:Emulsions; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D019344:Lactic Acid; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D010316:Particle Size; D010592:Pharmaceutic Aids; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents; D019345:Zinc Acetate
chemical_list: D001786:Blood Glucose; D003692:Delayed-Action Preparations; D004655:Emulsions; D010592:Pharmaceutic Aids; D011108:Polymers; D012997:Solvents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D052216:Glucagon-Like Peptide 1; D019345:Zinc Acetate