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论文类型：期刊论文

发表时间：2018-11-07

发表刊物：INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH

收录刊物：SCIE、Scopus

卷号：57

期号：44

页面范围：14915-14925

ISSN号：0888-5885

关键字：Amino acids; Purification; Reaction kinetics, Cation exchange chromatography; Cysteine residues; Industrial scale; Minimum generations; Optimized reaction conditions; Reaction kinetic models; Reaction process; Type 2 diabetes mellitus, Byproducts

摘要：PEG-loxenatide is a new once-weekly GLP-1 receptor agonist candidate for the treatment of type 2 diabetes mellitus. Site-specific thiol-PEGylation of loxenatide with Y-shaped mPEG(2)-MAL of 40 kDa was first optimized using a reaction kinetic model based approach on a laboratory scale. The optimized reaction conditions were further scaled up to a pilot scale, and PEG-loxenatide achieved a high yield and purity. This result demonstrated an efficient and convenient scale-up PEGylation reaction process, which achieved the maximum utilization of the raw materials and the minimum generation of byproducts. Furthermore, PEG-loxenatide was efficiently purified using cation exchange chromatography on a pilot scale. The purified PEG-loxenatide was further desalted, concentrated, and lyophilized to improve its stability. PEGylation site analysis revealed that a single PEG molecule was conjugated to the unique cysteine residue at the C-terminus of loxenatide. This study will provide useful information for the preparation of PEG-loxenatide on an industrial scale.