Sustained release subcutaneous delivery of BMS-686117, a GLP-1 receptor peptide agonist, via a zinc adduct.
BMS-686117 is an 11-mer GLP-1 receptor agonist with a short intrinsic pharmacokinetic half-life (t(1/2)) of approximately 2h. In order to develop an extended release formulation for once-daily (QD) subcutaneous administration, a non-covalently bonded Zn/BMS-686117 adduct with very low aqueous solubility was prepared through mixing zinc acetate and BMS-686117 solutions, followed by filtration or spray drying. At pH 6.8, free BMS-686117 concentration decreased continuously with the increase of Zn:BMS-686117 ratio. Furthermore, free BMS-686117 concentration increases in the presence of ethylenediaminetetraacetic acid (EDTA), indicating the reversibility of the zinc-peptide association. As solids, the glass transition temperature of Zn/BMS-686117 adduct increases with the increase of Zn:BMS-686117 ratio. A Zn/BMS-686117 adduct suspension, with a molar ratio of zinc:BMS-686117 of 3:1, was dosed subcutaneously to dogs along with two other solution formulations. The Zn/BMS-686117 adduct showed a prolonged BMS-686117 terminal t(1/2) of 8.5h, a mean residence time (MRT) of 16h, and a C(max) value 6-8 times lower than the solution formulations. Additionally, the Zn/BMS-686117 was encapsulated into poly(lactide-co-glycolide) (PLGA) microspheres. The Zn/BMS-686117 microspheres showed an almost zero-order release profile in vitro for at least 18 days, with minimal initial burst, indicating the potential of using this approach for long-term sustained release.
Qian
Feng
F
Biopharmaceutics R&D, Bristol-Myers Squibb Company, New Brunswick, NJ 08903, USA. feng.qian1@bms.com
Ni
Nina
N
Burton
Lori S
LS
Wang
Yue Fen
YF
Desikan
Sridhar
S
Hussain
Munir
M
Smith
Ronald L
RL
D000818:Animals; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004285:Dogs; D000067757:Glucagon-Like Peptide-1 Receptor; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D007279:Injections, Subcutaneous; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D008863:Microspheres; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics*; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D018027:Receptors, Glucagon / Q000819:agonists*; D012995:Solubility; D013997:Time Factors; D044366:Transition Temperature; D019345:Zinc Acetate / Q000737:chemistry*
C539626:BMS 686117; D003692:Delayed-Action Preparations; D000067757:Glucagon-Like Peptide-1 Receptor; D009842:Oligopeptides; D018027:Receptors, Glucagon; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D019345:Zinc Acetate