Mono modified exendin with polyethylene glycol or its derivatives and uses thereof
Inventors
Lee, Kang Choon • Park, Chan Woong • Youn, Yu Seok • Chae, Su Young
Assignees
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Publication Number
US-8420598-B2
Publication Date
2013-04-16
Expiration Date
Abstract
Disclosed herein are exendin singly modified with polyethylene glycole or a derivative thereof, a method for the preparation of the same, and uses thereof. Exendin modified at lysine (27) with polyethylene glycol shows biological activity similar to that of natural exendin, but is improved in half life. In addition, the modification position and the number of PEG or its derivative are restricted so as to minimize the side effects caused by a variety of combinations of such factors. The exendin is useful in the prevention and treatment of diseases caused by the over-secretion of insulin, or diseases caused due to a decrease in plasma glucose level, the inhibition of gastric or intestinal motility, the promotion of satiety, or the inhibition of food intake, especially diabetes, obesity and irritable colon syndrome.
Core Innovation
The invention relates to an isolated exendin modified with polyethylene glycol or a polyethylene glycol derivative in which a single amino acid of the exendin is modified with polyethylene glycol or a polyethylene glycol derivative. The polyethylene glycol or polyethylene glycol derivative is a tribranched type. The modification preserves biological activity while improving half-life/retention time for extended anti-diabetic efficacy.
The technical problem addressed is to improve in vivo pharmacokinetics and thereby extend anti-diabetic efficacy of exendin, while maintaining biological activity. The described solution is a PEG-singly modified exendin, preferably exendin-4, with PEG attached at a restricted site, lysine 27, and with restricted PEG number/structure, including tri-branched PEG.
The document describes that the improved in vivo effects are associated with PEG molecular weight and branching, including long-acting effects with high MW PEG and tri-branched PEG. Reported supporting results include improved insulin secretion, GLP-1 receptor binding, glucose lowering in db/db mice, and pharmacokinetics characterized by an increased elimination half-life.
Claims Coverage
The independent claim covers an isolated exendin modified by attaching a single PEG or PEG derivative to a single amino acid of the exendin, with the PEG/PEG-derivative being a tribranched type. The dependent claims further constrain the PEG type and/or specify preparation and composition-related aspects, including PEG molecular weight range and a tribranched PEG derivative structure defined by Chemical Formula 1.
Single amino acid PEGylation of isolated exendin with tribranched PEG
An isolated exendin modified with polyethylene glycol or a polyethylene glycol derivative, wherein a single amino acid of said exendin is modified with polyethylene glycol or a polyethylene glycol derivative and wherein the polyethylene glycol or the polyethylene glycol derivative is a tribranched type.
Tri-branched PEG derivative defined by Chemical Formula 1
The PEG derivative is a tribranched polyethylene glycol derivative defined by Chemical Formula 1, with parameter ranges and a N-hydroxysuccinimide moiety as a reactive group/linker.
PEG molecular weight range for the PEG or PEG derivative
The polyethylene glycol or the polyethylene glycol derivative has a molecular weight ranging from 20 to 45 kDa.
Reducing-agent-assisted coupling with dark incubation and purification
Preparing the modified exendin by reacting PEG or a derivative with exendin in the presence of a reducing agent in a solvent, storing the reaction mixture at a predetermined temperature for a predetermined period of time in the dark, removing unreacted materials, and separating or purifying the modified exendin free of unreacted materials.
Solvent selection for the coupling step
The solvent used in the reacting step is phosphate buffer saline or an organic solvent.
PEG-to-exendin reaction molar ratio
The reaction molar ratio of PEG or its derivative to exendin is within the range of 1:1 to 4.
Overall claim coverage focuses on a PEG-singly modified isolated exendin where a single amino acid is modified with a tribranched PEG or PEG derivative, together with dependent constraints that specify the tribranched PEG derivative structure, PEG molecular weight range, and aspects of coupling preparation including reducing-agent presence, dark incubation, and purification to remove unreacted materials, as well as solvent options and PEG-to-exendin molar ratio.
Stated Advantages
Preserves biological activity while improving half-life/retention time.
Extends anti-diabetic efficacy, including long-acting effects.
Improves in vivo pharmacokinetics, including increased elimination half-life.
Documented Applications
Treatment or use in diabetes, obesity, and irritable colon, as described for pharmaceutical composition uses in the document.
In vivo evaluation context including improved insulin secretion, glucose lowering, and pharmacokinetics in db/db mice.
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