title: Effect of sulfobutyl ether-β-cyclodextrin on bioavailability of insulin glargine and blood glucose level after subcutaneous injection to rats.
abstract: Insulin glargine is the first long-acting basal insulin analogue used for subcutaneous administration once daily in patients with type 1 or type 2 diabetes mellitus. To obtain the further bioavailability and the sustained glucose lowering effect of insulin glargine, in the present study, we investigated the effect of sulfobutyl ether-β-cyclodextrin (SBE4-β-CyD), with the degree of substitution of sulfobutyl ether group of 3.9, on pharmaceutical properties of insulin glargine and the release of insulin glargine after subcutaneous injection to rats. SBE4-β-CyD increased the solubility and suppressed aggregation of insulin glargine in phosphate buffer at pH 9.5, probably due to the interaction of SBE4-β-CyD with aromatic amino acid residues such as tyrosine of insulin glargine. In addition, SBE4-β-CyD accelerated the dissolution rate of insulin glargine from its precipitates, compared to that of insulin glargine alone. Furthermore, we revealed that subcutaneous administration of an insulin glargine solution with SBE4-β-CyD to rats enhanced the bioavailability of insulin glargine and sustained the glucose lowering effect, possibly due to the inhibitory effects of SBE4-β-CyD on the enzymatic degradation at the injection site. These results suggest that SBE4-β-CyD can be a useful excipient for sustained release of insulin glargine.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Uehata
authors.forename: Takayuki
authors.initials: T
authors.lastname: Anno
authors.forename: Kayoko
authors.initials: K
authors.lastname: Hayashida
authors.forename: Keiichi
authors.initials: K
authors.lastname: Motoyama
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Hirayama
authors.forename: Naomi
authors.initials: N
authors.lastname: Ono
authors.forename: James D
authors.initials: JD
authors.lastname: Pipkin
authors.forename: Kaneto
authors.initials: K
authors.lastname: Uekama
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Arima
mesh_terms: D000818:Animals; D001682:Biological Availability; D001786:Blood Glucose / Q000187:drug effects*; D003692:Delayed-Action Preparations; D005079:Excipients / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007279:Injections, Subcutaneous; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D001786:Blood Glucose; D003692:Delayed-Action Preparations; D005079:Excipients; D049528:Insulin, Long-Acting; D047392:beta-Cyclodextrins; C093196:SBE4-beta-cyclodextrin; D000069036:Insulin Glargine