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Multi-arm fork type functional polyethylene glycol preparation method and its application in medicine

A polyethylene glycol, functionalized technology, used in drug combinations, anti-tumor drugs, pharmaceutical formulations, etc., can solve the problems of difficult control and difficulty of the quality of the conjugates

Inactive Publication Date: 2002-11-27
PEGBIO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The second is that for proteins with multiple reaction sites, it is generally difficult to control the reaction site well, which makes it difficult to control the quality of the conjugate

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] mPEG with different arm length 3 CO 2 PhNO 2 preparation of

[0018] Lysine (439 mg, 3 mmol) was dissolved in 20 mL of water with a pH value of 8.0-8.3, and mPEG was added in portions over 3 hours 2 CO 2 PhNO 2 (two-arm mPEG p-nitrophenol ester, molecular weight 10,000, one arm is 7,000, the other arm is 3,000, 10 g, 1 mmol), while maintaining the pH of the system at 8.3 with 0.2N NaOH. After stirring at room temperature overnight, the reactant was cooled to 0°C, and the pH value of the system was adjusted to 3 with 2N hydrochloric acid. First use ether to extract impurities from water, and then use chloroform to continuously extract three times. After the extract is concentrated, add anhydrous ether dropwise to obtain a white precipitate. After the obtained precipitate is recrystallized twice by ethanol, mPEG is obtained. 2 Mono-substituted lysine (mPEG 2 -mono-Lysine). The product was characterized by amine titration, GPC and MALDI, and its purity reached 99%....

Embodiment 2

[0021] Embodiment 2 different arm length mPEG 3 CO 2 Preparation of Su

[0022] The mPEG in the above-mentioned embodiment 1 3 CO 2 H (9g, 0.6mmol) was dissolved in anhydrous dichloromethane (20mL), and after cooling to 0°C, N-hydroxysuccinimide (0.138g, 1.2mmol) and DCC (0.48g, 1.2 mmol), stirred overnight at room temperature, filtered, and the filtrate was concentrated and precipitated with anhydrous ether, and then recrystallized from ethyl acetate to obtain pure product mPEG 3 CO 2 Su, the content of active ester in the product is measured by ultraviolet spectroscopic method, is 98%.

Embodiment 3

[0023] Embodiment 3 different arm length mPEG 4 CO 2 PhNO 2 preparation of

[0024] To dissolve the product mPEG described in Implementation 1 2 - Mono-Lysine (molecular weight 10,000, 9 g, 0.9 mmol) in anhydrous dichloromethane (20 mL) was added with triethylamine (TEA) until the pH value reached 8. mPEG 2 -CO 2 PhNO 2 (Molecular weight 10,000, one arm is 6,000, the other arm is 4,000, 10.5g, 1.05mmol) was added to the reaction solution in batches within 3 hours, while maintaining the pH of the system at about 8 with TEA. After reflux for 72 hours, the reactant was cooled to room temperature, concentrated, filtered, precipitated with ether, and then recrystallized with a small amount of ethanol. excess mPEG 2 -CO 2 PhNO 2 It was hydrolyzed after being stirred overnight in a pH9-10 buffer solution, the solution was cooled to 0°C, and the pH value of the system was adjusted to 3 with 2N hydrochloric acid. The p-nitrophenol in the solution was then extracted by diethy...

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PUM

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Abstract

A multi-arm tree fork type polyethanediol with active terminal group is disclosed, and can be used to modify the low-molecular medicines, and protein or polypeptide medicines for improving their solubility, stability and immunogenicity, resulting in elongated half life period and raised curative effect.

Description

technical field [0001] The present invention relates to macromolecule synthesis, more specifically a method for preparing multi-arm tree-branch type functionalized polyethylene glycol by reacting single-chain polyethylene glycol with small molecule compounds. Background technique [0002] At present, there are many kinds of antineoplastic drugs, which can be generally divided into two categories according to their molecular weight: one class has a lower molecular weight, usually below 1000, most of which are commonly used chemically synthesized drugs and some natural drugs, such as Nitrogen mustard, cisplatin, 5-fluorouracil, paclitaxel, etc. all belong to this category; the other category has a larger molecular weight, and most protein and polypeptide drugs produced by genetic engineering belong to the second category. However, both small molecule drugs and macromolecular drugs have disadvantages such as high toxicity, poor solubility, and short half-life. For protein and ...

Claims

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Application Information

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IPC IPC(8): A61K47/34A61K31/196A61K31/337A61K31/513A61K31/519A61K31/704A61K33/24A61K38/00A61K38/21A61K38/27A61K38/44A61K47/48A61P35/00C08G65/329C08G65/331
CPCA61K47/60A61P35/00C08G65/329C08L2203/02
Inventor 黄骏廉黄兆华张海涛
Owner PEGBIO
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