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PEG-erythrocyte-stimulating factor and preparation method and use thereof

A technology of erythropoietin and PEGylation, which is applied in the fields of erythropoietin, chemical instruments and methods, and extracellular fluid diseases, can solve the problems of protease degradation, short plasma half-life, and low utilization rate, and improve Residence time and circulation half-life, quality control, effect of reduced clearance

Active Publication Date: 2009-06-17
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, currently available unmodified erythropoietins have short plasma half-lives, are susceptible to protease degradation, and are not readily available, limitations that prevent them from achieving maximum clinical efficacy
Therefore, the acquisition of long-acting erythropoietin has become a hotspot of research and development by major research institutions and pharmaceutical companies. For example, the long-acting erythropoietin product (aransp) of Amgen Company, which has been on the market, increases the sugar group by means of genetic engineering. The number of glycosylation sites can be improved, and the degree of glycosylation can be increased to achieve injection once every two weeks, which improves the half-life of erythropoietin in the body. Limited degree of half-life and high production costs

Method used

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  • PEG-erythrocyte-stimulating factor and preparation method and use thereof
  • PEG-erythrocyte-stimulating factor and preparation method and use thereof
  • PEG-erythrocyte-stimulating factor and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Example 1: Preparation of acetyl mercaptopropionaldehyde

[0077]

[0078] 11.2g (20mmol) of acrolein and dry 100ml of THF were added to the reaction flask, cooled to 0°C, and then slowly added dropwise a mixed solution of 1.52g (0.2mol) of thioacetic acid / 20ml of THF. After the dripping is completed, the reaction is kept for 2 hours. It was concentrated under reduced pressure at 35°C to remove excess acrolein. Then the column was quickly loaded (eluent pure n-hexane→n-hexane / ethyl acetate=50 / 1), the product spots were collected together, and concentrated under reduced pressure to dryness to obtain 0.6 g of an oily liquid.

Embodiment 2

[0079] Example 2: Preparation of mPEG-MAL-01 (20kD)

[0080]

[0081] Put 20g (1mmol) of mPEG-OH (20kD) into a 200ml single-necked flask, add 100ml of toluene, reflux and separate water for 2.5hr; then distill off the toluene, cool to room temperature, add 100ml of DCM, and then add 1.18g (4mmol) Triphosgene (triphosgene), the reaction was airtightly stirred overnight at room temperature; next day treatment: the reaction solution was washed in a fume hood into 200 ml of anhydrous ether, filtered and dried in vacuum to obtain 15 g of white solid. Put 15g of the white solid from the previous step into a 200ml single-necked flask, add 100ml of Toluene / DCM (2:1) solution, then add 0.25g of HOSu, and then add 0.3g of triethylamine, airtight and stir at room temperature for 4hr (or overnight) ); After the reaction is over, the reaction solution is filtered, and the filtrate is directly washed into 100ml of anhydrous ether, filtered, and vacuum dried to obtain 14g of white solid, which...

Embodiment 3

[0084] Example 3: Preparation of mPEG-MAL-02 (20kD)

[0085]

[0086] Dissolve 2.0 g of MAL-ONP in 50 mL DCM, add 0.05 g of triethylamine, and add 15 g of mPEG-NH 2 (20kD) was dissolved in 100ml of freshly opened DCM, and then added to the DCM solution of MAL-ONP, reacted overnight at room temperature; the next day, the DCM was concentrated under reduced pressure, and the residue was added to 200ml of anhydrous ether. The solid was precipitated by precipitation. After drying, 13 g of white solid is obtained, which is mPEG-MAL-02 (20kD).

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Abstract

The invention discloses a polyethylene glycol erythropoietin conjugate, which is prepared by forming -NH-CH2- bond connection between methoxyl polyethylene glycol groups and amino groups of erythropoietin through -CH2- groups in -CH2-X-S-Y-. The invention also discloses a method for preparing the conjugate, wherein the conjugate is prepared by generating reductive amination reaction between the erythropoietin and aldehyde substances containing protected sulfhydryl groups, forming activated erythropoietin subjected to -NH-CH2- bond connection, and further coupling the activated erythropoietin with methoxyl polyethylene glycol derivatives. The method has the advantages of single reaction site and controllable quality. The polyethylene glycol erythropoietin conjugate or a medicine composition containing the polyethylene glycol erythropoietin conjugate can be widely applied to treatment of diseases which are characterized by erythropoietin shortage or erythrocyte shortage or defect.

Description

Technical field [0001] The invention relates to a polyethylene glycol erythropoietin conjugate, which has the biological activity of increasing the hemoglobin content and the number of reticulocytes in the body. The application field of the invention relates to biochemistry, medicinal chemistry and human diseases Treatment. technical background [0002] Erythropoietin (EPO) is a glycoprotein hormone with a molecular weight of about 34kD. The erythropoietin present in plasma is composed of 165 amino acids and has a high degree of glycosylation. The glycosylation is mainly sialic acid. According to different carbohydrate content, naturally occurring erythropoietin is divided into two types, α type contains 34% carbohydrates, and β type contains 26% carbohydrates. The two types are the same in biological characteristics, antigenicity and clinical application effects. The human erythropoietin gene is located in the 22nd region of chromosome 7. In 1985, its cDNA was successfully clone...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K38/19A61P7/06A61P29/00A61P37/02A61P35/00A61P39/06A61P43/00
CPCA61K47/48215C07K14/505A61K47/60A61P7/06A61P11/00A61P13/12A61P25/00A61P29/00A61P35/00A61P37/00A61P37/02A61P39/06A61P43/00
Inventor 吕爱锋孙长安王瑞军陈克然李蕴波王亚里
Owner JIANGSU HANSOH PHARMA CO LTD
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