Polypseudorotaxane Formation of Randomly-Pegylated Insulin with Cyclodextrins: Slow Release and Resistance to Enzymatic Degradation

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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 α- and γ-CyDs, by inserting one PEG chain in the α-CyD cavity and two PEG chains in the γ-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 γ-CyD polypseudorotaxane>the α-CyD polypseudorotaxane. The pegylated insulin/γ-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.
社団法人日本薬学会の論文