CN102532303A - Synthesis and application of exenatide joined with polyethylene glycol - Google Patents
Synthesis and application of exenatide joined with polyethylene glycol Download PDFInfo
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- CN102532303A CN102532303A CN2011104355061A CN201110435506A CN102532303A CN 102532303 A CN102532303 A CN 102532303A CN 2011104355061 A CN2011104355061 A CN 2011104355061A CN 201110435506 A CN201110435506 A CN 201110435506A CN 102532303 A CN102532303 A CN 102532303A
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- puted together
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Abstract
The invention relates to exenatide joined with polyethylene glycol. The structural general formula of exenatide is (I), mPEG represents residue of methoxy polyethylene glycol, the selected value of n is 0-3, R represents an exenatide molecule from which an amino is removed, the amino is of lysine residue or of N-end histidine residue in the exenatide molecule, and the molecular weight of the exenatide joined with polyethylene glycol is 9,800-110,000. The invention further relates to a preparation method of the compound and application of the compound in preparing medicines for curing type 2 diabetes mellitus. The exenatide joined with polyethylene glycol has the advantages of being long in half-life period and good in stability and hypoglycemic effect.
Description
Technical field
The present invention relates to a kind of medicine, particularly, relate to the synthetic of Exenatide that a kind of polyoxyethylene glycol puts together and use.
Background technology
Along with the raising of China's living standards of the people, diabetic population increased fast, according to statistics in 2010; China's onset diabetes rate has reached 9.7%, and absolute number is near 100,000,000, and the recall rate of considering China's mellitus less than 40% still; The actual diseased crowd of China is very huge, and in the mellitus afflicted of China, the diabetes B patient has surpassed 90%; Quantity has surpassed India becomes the first in the world, and quantity is also in growth.
At present, several types of common drugs of treatment diabetes B all might cause the untoward reaction, particularly N'-Dimethylguanylguanidine of health, and the danger that causes patient's lactic acidosis is arranged; Sulphur clothes class, a-glucose battalion's enzyme inhibitors class and the alkane two ketone medicines that expose to the sun can bring out weight in patients to be increased; In addition, the diabetes B patient uses the phenomenon that can occur drug failure behind the OHA after the thing treatment, and peripheral tissues reduces the susceptibility of Regular Insulin.
Exenatide (Exendin-4) is to contain 39 amino acid whose polypeptide, with people's hyperglycemic-glycogenolytic factor (Glucagon) 48% homology is arranged, and with people's GLP-1 53% homology is arranged; Can simulate glucose dependency insulin secretion; Strengthen other anti-high-blood-sugar function, increase the biosynthesizing secretion of Regular Insulin, but can not cause severe hypoglycemia; And have and reduce appetite, the absorption that reduces food, fat-reducing, neurocyte had function such as provide protection, be described as " clever antidiabetic drug ".Though the controlling blood sugar effect is obvious, Exenatide is shorter in the intravital transformation period of people, so need injection in a day to keep drug effect twice, long lasting Exenatide obviously will bring the facility of life to sufferer, meets a large amount of diabetes B patients' demand.
Along with developing rapidly of macromolecular drug in recent years, the stability of polypeptide and pharmaceutical grade protein is one of focus of paying close attention to of medical research personnel always.Have multiple mode can be used to increase macromolecular drug stability in vivo, comprise different route of administration (oral, intranasal administration; Transdermal absorption), different carriers (BSA, liposome; Microballoon); Different macromolecular material (polysaccharide), different pharmaceutical release tech (prodrug, slow release method) or the like.Polyoxyethylene glycol (polyethylene glycol wherein; PEG) puting together is the mode of an increase macromolecular drug stability relatively more commonly used; This method the earliest by Davis and Abuchowski etc. in the seventies in 20th century research and development, activatory electric PEG of parent or PEG verivate can with the terminal amino group on polypeptide or the protein, the sulfydryl of Methionin ε-amido and halfcystine reacts; Can on polypeptide or protein molecule, connect a plurality of polyethylene glycol long chain after the reaction; Put together later macromolecular drug, can reduce immunogenicity effectively, improve stability and solvability.
Summary of the invention
The technical problem that the present invention will solve is to overcome existing defective; The Exenatide that provides a kind of polyoxyethylene glycol to put together; The Exenatide that polyoxyethylene glycol proposed by the invention is puted together has long half time, good stability, advantage that hypoglycemic effect is good; Simultaneously, the present invention proposes its preparation method and application.
For solving above technical problem, technical scheme of the present invention is following:
The Exenatide that a kind of polyoxyethylene glycol is puted together, represent by general structure (I):
（Ⅰ）
In the formula, mPEG representes the residue of methoxy poly (ethylene glycol);
The n value is 0-3;
R representes to remove the Exenatide molecule of an amino, and wherein, said amino is the amino of lysine residue in the Exenatide molecule or the amino of N-terminal histidine residues;
The molecular weight of the Exenatide that said polyoxyethylene glycol is puted together is 9800-110000.
Preferably, the n value is 1.
Preferably, the molecular weight of the Exenatide puted together of polyoxyethylene glycol is 9800-15000.
The preparation method of the Exenatide that the polyoxyethylene glycol that the present invention proposes is puted together comprises following reaction:
Particularly, reaction process may further comprise the steps:
(1) Exenatide (III) is dissolved with the Tris-HCl damping fluid, regulating its pH is 6.5-8.5;
(2) add activatory compound (II), wherein, Exenatide (III) is 1:0.1-100 with the mol ratio of compound (II), and the reaction times is 20-240 minute, and the temperature of reaction is 0-37 ℃;
(3) reaction finishes, and adds and surpasses the glycocoll termination reaction of reactant molar weight more than 100 times, makes the Exenatide (I) that polyoxyethylene glycol is puted together.
Particularly, the separation and purification and the analysis of the Exenatide (I) that polyoxyethylene glycol is puted together described in the step (3) may further comprise the steps:
(1) separation and purification of the Exenatide (I) puted together of polyoxyethylene glycol:
End reaction liquid is filtered, carry out purifying with reversed phase high efficiency liquid phase (HPLC) chromatogram, chromatographic condition is following:
Chromatographic column: 10um, 20 x 250mm
Moving phase: A:0.1% trifluoroacetic acid (TFA)
B: acetonitrile
The 35%B isocratic elution
Flow velocity: 20ml/min
Detect wavelength: 210nm
With above-mentioned condition operation, carry out separation and purification through peak value;
(2) analysis of the Exenatide (I) puted together of polyoxyethylene glycol:
The title product that the separation and purification of last step is later is analyzed with performance liquid chromatography, and chromatographic condition is following:
Chromatographic column: 5um, 4.6 x 250mm
The trifluoroacetic acid of moving phase: A:0.1%
B: acetonitrile
10 minutes inside gradient wash-outs of 30%-40%B wash with 95%B then
Flow velocity: 1ml/min
Detect wavelength: 210nm
Column temperature: 35 ℃
With above-mentioned condition operation, analyze through peak value.
Particularly, compound (II) is a kind of in propionic acid methoxy poly (ethylene glycol) succinimide ester 1000, propionic acid methoxy poly (ethylene glycol) succinimide ester 2000, propionic acid methoxy poly (ethylene glycol) succinimide ester 5000, propionic acid methoxy poly (ethylene glycol) succinimide ester 10000, propionic acid methoxy poly (ethylene glycol) succinimide ester 20000, propionic acid methoxy poly (ethylene glycol) succinimide ester 30000, butyric acid methoxy poly (ethylene glycol) succinimide ester 1000, butyric acid methoxy poly (ethylene glycol) succinimide ester 2000, butyric acid methoxy poly (ethylene glycol) succinimide ester 5000, butyric acid methoxy poly (ethylene glycol) succinimide ester 10000, butyric acid methoxy poly (ethylene glycol) succinimide ester 20000 or the butyric acid methoxy poly (ethylene glycol) succinimide ester 30000.
Preferably, the said pH of step (1) is 6.5-7.5; The said mol ratio of step (2) is 1:8-10, and the said reaction times is 20-30 minute, and said temperature of reaction is 20-25 ℃.
The application of the Exenatide that the polyoxyethylene glycol that the present invention proposes is puted together in the medicine of preparation treatment diabetes B.
The chemical general formula of above-described mPEG is CH
3O-(CH
2CH
2O) a-CH
2CH
2OH, a>=1; Said Tris-HCl is the mixing solutions of Tutofusin tris and hydrochloric acid.
Technical scheme proposed by the invention has following beneficial effect:
(1) polyoxyethylene glycol Exenatide transformation period in vivo of puting together is 20 hours; And there is not the Exenatide transformation period in vivo of puting together is 2 hours; Therefore; The Exenatide that institute of the present invention synthetic polyoxyethylene glycol is puted together is compared with the Exenatide that nothing is puted together, and being superior to greatly on the stability does not in vivo have the Exenatide molecule of puting together.
(2) because long half time, the good stability of the Exenatide puted together of polyoxyethylene glycol, therefore, its in vivo action time longer, more obvious to the diabetes B hypoglycemic effect.
(3) preparation method of the Exenatide puted together of polyoxyethylene glycol proposed by the invention is simple and effective, and single step reaction can make end product, is particularly suitable for industrialized production.
Description of drawings
Accompanying drawing is used to provide further understanding of the present invention, and constitutes the part of specification sheets, is used to explain the present invention with embodiments of the invention, is not construed as limiting the invention.In the accompanying drawings:
Fig. 1 is the HPLC color atlas of the Exenatide separation and purification that polyoxyethylene glycol is puted together among the embodiment 1;
Fig. 2 is the HPLC color atlas of the Exenatide analysis that polyoxyethylene glycol is puted together among the embodiment 1;
Fig. 3 is the HPLC color atlas that does not have the Exenatide analysis of puting together among the embodiment 1.
Embodiment
Below in conjunction with accompanying drawing the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein only is used for explanation and explains the present invention, and be not used in qualification the present invention.
One, the embodiment of the Exenatide product puted together of polyoxyethylene glycol
The Exenatide that polyoxyethylene glycol proposed by the invention is puted together, represent by general structure (I):
（Ⅰ）
In formula, mPEG representes the residue of methoxy poly (ethylene glycol); The n value is 0-3; R representes to remove the Exenatide molecule of an amino, and wherein, said amino is the amino of lysine residue in the Exenatide molecule or the amino of N-terminal histidine residues; Wherein, at the chemical general formula CH of mPEG
3O-(CH
2CH
2O) a-CH
2CH
2Among the OH, through the value of control a, the molecular weight control of the Exenatide that can polyoxyethylene glycol be puted together is at 9800-110000.
In the aminoacid sequence of Exenatide; 2 lysine residues are arranged, they on the Exenatide molecule one near N-terminal, another is near C-terminal; The amino of these 2 lysine residues can be puted together with polyoxyethylene glycol, and the amino of N-terminal also is the site that polyoxyethylene glycol is puted together simultaneously.
As optimal way of the present invention, the n value is 1, and at this moment, the molecular formula of the Exenatide that polyoxyethylene glycol is puted together is:
More preferably, through the molecular weight of mPEG, promptly through the value of control a, the molecular weight that makes the Exenatide that polyoxyethylene glycol puts together is between 9800-15000.
Two, the Exenatide synthetic embodiment that puts together of polyoxyethylene glycol
Embodiment 1
The preparation method of the Exenatide that polyoxyethylene glycol proposed by the invention is puted together comprises following reaction:
Particularly, reaction process may further comprise the steps:
(1) Exenatide (III) is dissolved with the Tris-HCl damping fluid, regulating its pH is 7.0;
(2) add activatory compound (II), wherein, Exenatide (III) is 1:8 with the mol ratio of compound (II), and the reaction times is 30 minutes, and the temperature of reaction is 25 ℃;
Wherein, compound (II) is a propionic acid methoxy poly (ethylene glycol) succinimide ester 5000 (mPEG-SPA-5000);
(3) reaction finishes, and adds the glycocoll termination reaction that surpasses 110 times of reactant molar weights, makes the Exenatide (I) that polyoxyethylene glycol is puted together.
The Exenatide separation and purification that polyoxyethylene glycol proposed by the invention is puted together may further comprise the steps:
With reacting liquid filtering, with the reversed-phase HPLC purifying, chromatographic condition is following:
Chromatographic column: RP-C18,10um, 20 x 250mm
Moving phase: A:0.1% TFA
B: acetonitrile
The 35%B isocratic elution
Flow velocity: 20ml/min
Detect wavelength: 210nm
As shown in Figure 1; Move after 28 minutes, 3 main absorption peaks occurred, RT is that a plurality of residues are puted together the Exenatide molecule that connects polyoxyethylene glycol about 28min; RT is the Exenatide molecule that single residue is puted together polyoxyethylene glycol 31min's; RT is unconjugated Exenatide molecule 34min's, and unconjugated Exenatide is non-target peak, does not therefore have complete collection.
The analysis of the Exenatide that polyoxyethylene glycol proposed by the invention is puted together may further comprise the steps:
The later title product of separation and purification is analyzed with performance liquid HPLC, and condition is following:
Chromatographic column: RP-C18,5um, 4.6 x 250mm
Moving phase: A:0.1% TFA
B: acetonitrile
10 minutes inside gradient wash-outs of 30%-40%B wash with 95%B then
Flow velocity: 1ml ∕ min
Detect wavelength: 210nm
Column temperature: 35 ℃
As shown in Figures 2 and 3, the polyoxyethylene glycol Exenatide and the unconjugated Exenatide purity of puting together can reach more than 98%.
Detect through the polypeptide of SDS-PAGE after to purifying, the Exenatide that polyoxyethylene glycol is puted together is Duoed 5000 dalton than unconjugated Exenatide, shows that the single amino acids residue of polyoxyethylene glycol and peptide molecule has taken place to put together.
Embodiment 2
Different with embodiment 1 is that pH is 6.5; , Exenatide (III) is 1:10 with the mol ratio of compound (II), and the reaction times is 60 minutes, and the temperature of reaction is 30 ℃; Wherein, in the compound (II), the n value is 1, a value 120 among the mPEG.
Embodiment 3
Different with embodiment 1 is that pH is 7.5; , Exenatide (III) is 1:0.1 with the mol ratio of compound (II), and the reaction times is 240 minutes, and the temperature of reaction is 37 ℃; Wherein, compound (II) is a propionic acid methoxy poly (ethylene glycol) succinimide ester 1000.
Embodiment 4
Different with embodiment 1 is that pH is 8.0; , Exenatide (III) is 1:100 with the mol ratio of compound (II), and the reaction times is 20 minutes, and the temperature of reaction is 0 ℃; Wherein, compound (II) is a butyric acid methoxy poly (ethylene glycol) succinimide ester 1000.
Different with embodiment 1 is that pH is 8.5; , Exenatide (III) is 1:50 with the mol ratio of compound (II), and the reaction times is 120 minutes, and the temperature of reaction is 10 ℃; Wherein, compound (II) is a propionic acid methoxy poly (ethylene glycol) succinimide ester 2000.
Embodiment 6
Different with embodiment 1 is that pH is 8.0; , Exenatide (III) is 1:20 with the mol ratio of compound (II), and the reaction times is 180 minutes, and the temperature of reaction is 5 ℃; Wherein, compound (II) is a butyric acid methoxy poly (ethylene glycol) succinimide ester 10000.
Embodiment 7
Different with embodiment 1 is that pH is 7.2; , Exenatide (III) is 1:1 with the mol ratio of compound (II), and the reaction times is 200 minutes, and the temperature of reaction is 15 ℃; Wherein, compound (II) is a propionic acid methoxy poly (ethylene glycol) succinimide ester 30000.
Embodiment 8
Different with embodiment 1 is that pH is 6.7; , Exenatide (III) is 1:0.5 with the mol ratio of compound (II), and the reaction times is 220 minutes, and the temperature of reaction is 22 ℃; Wherein, compound (II) is a butyric acid methoxy poly (ethylene glycol) succinimide ester 2000.
Three, the embodiment that uses of the Exenatide puted together of polyoxyethylene glycol
Embodiment 9
The Exenatide that polyoxyethylene glycol proposed by the invention is puted together; Be used to treat diabetes B, present embodiment is with the Exenatide that the polyoxyethylene glycol of embodiment 1 preparation is puted together rat to be detected, simultaneously; Exenatide and saline water so that nothing is puted together are compared, and is specific as follows:
The healthy rat that physiological status is identical is divided into three groups, fasting 24 hours, at three groups of rat abdominal cavities while injectable dextrose monohydrates (20 mmol/kg body weight), then respectively according to following processing:
Experimental group: the Exenatide (10 nmol/kg body weight) that the injection polyoxyethylene glycol is puted together;
Control group 1: injection does not have the Exenatide of puting together (with the experimental group same dose);
Control group 2: injecting normal saline (volume is identical with experimental group).
Finish in injection respectively and took a blood sample in 15,30,60,240 minutes, with the glucose content in glucose oxidase method (GOD method) the check blood, detected result is as shown in table 1:
See that from experimental result the Exenatide group rat blood sugar that nothing is puted together has reached stable hypoglycemic effect and saline water control group and compared in the time of 15 minutes; Blood sugar reduces about 15.7%; The Exenatide group rat that corresponding polyoxyethylene glycol is puted together has also been realized the blood sugar reduction in the time of 15 minutes, in the time of 60 minutes, reached the most significant hypoglycemic effect and saline water group relatively; It is about 68.4% that blood sugar has reduced, and the hypoglycemic effect can be kept above 240 minutes.
Through the insulin content in the enzyme linked immunological kit check blood of Regular Insulin, detected result is as shown in table 2:
In the detection of insulin content; Do not have the insulin content of puting together in the Exenatide group rat blood and after 15 minutes, reached peak value; And the Exenatide group rat that polyoxyethylene glycol is puted together has been realized the peak value of Regular Insulin in the blood after 30 minutes; After 30 minutes, polyoxyethylene glycol puts together that insulin concentration is not have 4.2 times that put together the group rat in the blood of Exenatide group rat.
(extract experiment mice blood by the hour through measuring; Detect wherein Exenatide content); The Exenatide that polyoxyethylene glycol is puted together is 20 hours in the intravital transformation period of rat, and to put together Exenatide be 2 hours in the intravital transformation period of rat and do not have, therefore; The long half time of the Exenatide that polyoxyethylene glycol is puted together, stable excellent, hypoglycemic effect is more obvious.
Comprehensive above result, the Exenatide that polyoxyethylene glycol is puted together has quite or surpasses the biological activity of not having the Exenatide of puting together, and is superior to not having the Exenatide of puting together greatly on stable in vivo.
What should explain at last is: the above is merely the preferred embodiments of the present invention; Be not limited to the present invention; Although the present invention has been carried out detailed explanation with reference to previous embodiment; For a person skilled in the art, it still can be made amendment to the technical scheme that aforementioned each embodiment put down in writing, and perhaps part technical characterictic wherein is equal to replacement.All within spirit of the present invention and principle, any modification of being done, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (8)
1. Exenatide that polyoxyethylene glycol is puted together, represent by general structure (I):
（Ⅰ）
In the formula, mPEG representes the residue of methoxy poly (ethylene glycol);
The n value is 0-3;
R representes to remove the Exenatide molecule of an amino, and wherein, said amino is the amino of lysine residue in the Exenatide molecule or the amino of N-terminal histidine residues;
The molecular weight of the Exenatide that said polyoxyethylene glycol is puted together is 9800-110000.
2. the Exenatide that polyoxyethylene glycol according to claim 1 is puted together is characterized in that the n value is 1.
3. the Exenatide that polyoxyethylene glycol according to claim 1 is puted together, the molecular weight that it is characterized in that the Exenatide that polyoxyethylene glycol is puted together is 9800-15000.
4. the preparation method of the Exenatide puted together of any described polyoxyethylene glycol of claim 1-3 comprises following reaction:
Particularly, reaction process may further comprise the steps:
(1) Exenatide (III) is dissolved with the Tris-HCl damping fluid, regulating its pH is 6.5-8.5;
(2) add activatory compound (II), wherein, Exenatide (III) is 1:0.1-100 with the mol ratio of compound (II), and the reaction times is 20-240 minute, and the temperature of reaction is 0-37 ℃;
(3) reaction finishes, and adds and surpasses the glycocoll termination reaction of reactant molar weight more than 100 times, makes the Exenatide (I) that polyoxyethylene glycol is puted together.
5. the preparation method of the Exenatide that polyoxyethylene glycol according to claim 4 is puted together is characterized in that, the separation and purification and the analysis of the Exenatide (I) that polyoxyethylene glycol is puted together described in the step (3) may further comprise the steps:
(1) separation and purification of the Exenatide (I) puted together of polyoxyethylene glycol:
End reaction liquid is filtered, carry out purifying with RPLC, chromatographic condition is following:
Chromatographic column: 10um, 20 x 250mm
Moving phase: A:0.1% trifluoroacetic acid
B: acetonitrile
The 35%B isocratic elution
Flow velocity: 20ml/min
Detect wavelength: 210nm
With above-mentioned condition operation, carry out separation and purification through peak value;
(2) analysis of the Exenatide (I) puted together of polyoxyethylene glycol:
The title product that the separation and purification of last step is later is analyzed with performance liquid chromatography, and chromatographic condition is following:
Chromatographic column: 5um, 4.6 x 250mm
The trifluoroacetic acid of moving phase: A:0.1%
B: acetonitrile
10 minutes inside gradient wash-outs of 30%-40%B wash with 95%B then
Flow velocity: 1ml/min
Detect wavelength: 210nm
Column temperature: 35 ℃
With above-mentioned condition operation, analyze through peak value.
6. the preparation method of the Exenatide that polyoxyethylene glycol according to claim 4 is puted together; It is characterized in that compound (II) is a kind of in propionic acid methoxy poly (ethylene glycol) succinimide ester 1000, propionic acid methoxy poly (ethylene glycol) succinimide ester 2000, propionic acid methoxy poly (ethylene glycol) succinimide ester 5000, propionic acid methoxy poly (ethylene glycol) succinimide ester 10000, propionic acid methoxy poly (ethylene glycol) succinimide ester 20000, propionic acid methoxy poly (ethylene glycol) succinimide ester 30000, butyric acid methoxy poly (ethylene glycol) succinimide ester 1000, butyric acid methoxy poly (ethylene glycol) succinimide ester 2000, butyric acid methoxy poly (ethylene glycol) succinimide ester 5000, butyric acid methoxy poly (ethylene glycol) succinimide ester 10000, butyric acid methoxy poly (ethylene glycol) succinimide ester 20000 or the butyric acid methoxy poly (ethylene glycol) succinimide ester 30000.
7. the preparation method of the Exenatide that polyoxyethylene glycol according to claim 4 is puted together is characterized in that, the said pH of step (1) is 6.5-7.5; The said mol ratio of step (2) is 1:8-10, and the said reaction times is 20-30 minute, and said temperature of reaction is 20-25 ℃.
8. the application of the Exenatide puted together of any described polyoxyethylene glycol of claim 1-3 in the medicine of preparation treatment diabetes B.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102827270A (en) * | 2012-09-13 | 2012-12-19 | 无锡和邦生物科技有限公司 | Pegylated exenatide ramification and use thereof |
| CN103995062A (en) * | 2014-05-14 | 2014-08-20 | 浙江圣兆医药科技有限公司 | Method for testing exenatide and impurities thereof by using high performance liquid chromatography |
| CN104945499A (en) * | 2014-03-31 | 2015-09-30 | 博瑞生物医药技术(苏州)有限公司 | Structure-modified GLP-1 analogs and preparation method thereof |
| CN104991016A (en) * | 2015-06-25 | 2015-10-21 | 吉林大学 | Quantitative assay method of PEG-modified medicine in biological sample |
| CN107561168A (en) * | 2016-06-30 | 2018-01-09 | 山东新时代药业有限公司 | A kind of analyzing detecting method of Pegylation insulin secretion accelerating peptide analog |
| CN108676084A (en) * | 2018-05-31 | 2018-10-19 | 长春百克生物科技股份公司 | The trim of Exenatide and its application |
| US11179467B2 (en) | 2015-09-25 | 2021-11-23 | Brightgene Bio-Medical Technology Co., Ltd. | Exenatide modifier and use thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009075859A2 (en) * | 2007-12-11 | 2009-06-18 | Conjuchem Biotechnologies Inc. | Formulation of insulinotropic peptide conjugates |
| CN102234310A (en) * | 2010-04-30 | 2011-11-09 | 杭州九源基因工程有限公司 | Polyethylene glycol modified protein separating and purifying method |
-
2011
- 2011-12-22 CN CN2011104355061A patent/CN102532303A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009075859A2 (en) * | 2007-12-11 | 2009-06-18 | Conjuchem Biotechnologies Inc. | Formulation of insulinotropic peptide conjugates |
| CN102234310A (en) * | 2010-04-30 | 2011-11-09 | 杭州九源基因工程有限公司 | Polyethylene glycol modified protein separating and purifying method |
Non-Patent Citations (2)
| Title |
|---|
| JIN ZHOU ET AL.: "Preparation and PEGylation of exendin-4 peptide secreted from yeast Pichia pastoris", 《EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS》, vol. 72, 31 December 2009 (2009-12-31), pages 413 * |
| 王鹏: "聚乙二醇修饰艾塞那肽十二肽片段的研究", 《中国优秀硕士学位论文全文数据库 工程科技I辑》, no. 9, 15 September 2010 (2010-09-15), pages 016 - 128 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102827270A (en) * | 2012-09-13 | 2012-12-19 | 无锡和邦生物科技有限公司 | Pegylated exenatide ramification and use thereof |
| CN104945499A (en) * | 2014-03-31 | 2015-09-30 | 博瑞生物医药技术(苏州)有限公司 | Structure-modified GLP-1 analogs and preparation method thereof |
| CN103995062A (en) * | 2014-05-14 | 2014-08-20 | 浙江圣兆医药科技有限公司 | Method for testing exenatide and impurities thereof by using high performance liquid chromatography |
| CN103995062B (en) * | 2014-05-14 | 2015-06-17 | 浙江圣兆药物科技股份有限公司 | Method for testing exenatide and impurities thereof by using high performance liquid chromatography |
| CN104991016A (en) * | 2015-06-25 | 2015-10-21 | 吉林大学 | Quantitative assay method of PEG-modified medicine in biological sample |
| CN104991016B (en) * | 2015-06-25 | 2017-04-05 | 吉林大学 | The method for quantitatively determining of PEG chemical medicine thing in a kind of biological specimen |
| US11179467B2 (en) | 2015-09-25 | 2021-11-23 | Brightgene Bio-Medical Technology Co., Ltd. | Exenatide modifier and use thereof |
| CN107561168A (en) * | 2016-06-30 | 2018-01-09 | 山东新时代药业有限公司 | A kind of analyzing detecting method of Pegylation insulin secretion accelerating peptide analog |
| CN108676084A (en) * | 2018-05-31 | 2018-10-19 | 长春百克生物科技股份公司 | The trim of Exenatide and its application |
| CN108676084B (en) * | 2018-05-31 | 2021-12-03 | 长春百克生物科技股份公司 | Exenatide modifier and application thereof |
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