Polypseudorotaxane formation of randomly-pegylated insulin with cyclodextrins: slow release and resistance to enzymatic degradation.
Pegylation technology has been widely used to improve therapeutic efficacies of protein drugs and a number of selective- or randomly-substituted pegylated proteins are on the market. In this study, we prepared a insulin derivative substituted randomly with poly(ethylene glycol) (PEG, MW about 2200) and its polypseudorotaxanes with cyclodextrins (CyDs). The pegylated insulin formed polypseudorotaxanes with alpha- and gamma-CyDs, by inserting one PEG chain in the alpha-CyD cavity and two PEG chains in the gamma-CyD cavity. The pegylated insulin/CyD polypseudorotaxanes were less soluble in water. The release rate of the pegylated protein from its polypseudorotaxanes decreased in the order of drug alone>the gamma-CyD polypseudorotaxane>the alpha-CyD polypseudorotaxane. The pegylated insulin/gamma-CyD polypseudorotaxane displayed a significantly higher resistance to proteolysis. The results indicated that the CyD polypseudorotaxanes could be formed with randomly-pegylated insulin and work not only as a sustained release system, but also as a stabilizing agent to enzymatic degradations of pegylated insulin.
Graduate School of Pharmaceutical Sciences, Kumamoto University, Kunamoto, Japan.
Taishi
T
Higashi
Fumitoshi
F
Hirayama
Shogo
S
Misumi
Keiichi
K
Motoyama
Hidetoshi
H
Arima
Kaneto
K
Uekama
D003505:Cyclodextrins / Q000737:chemistry*; D003692:Delayed-Action Preparations / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D004355:Drug Stability; D004789:Enzyme Activation / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D043862:Rotaxanes / Q000737:chemistry*; D013499:Surface Properties
D003505:Cyclodextrins; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D007004:Hypoglycemic Agents; D007328:Insulin; D011108:Polymers; D043862:Rotaxanes; D011092:Polyethylene Glycols