Polyethylene glycol modified iron ionic chelator

A technology of polyethylene glycol and polyethylene glycol monomethyl ether, which is applied in drug combinations, medical preparations of non-active ingredients, blood diseases, etc., and can solve problems such as inconvenient treatment methods, poor patient compliance, and obvious adverse reactions , to achieve excellent clinical application prospects, improved drug efficacy, and extended half-life

Active Publication Date: 2017-10-24
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But it has obvious defects: 1. Desferrioxamine in the blood will be rapidly degraded by enzymes in the body, and its half-life in the body is less than 30 minutes, resulting in poor drug efficacy, and it is necessary to increase the dosage or prolong the medication time; 2. It is toxic , can cause many adverse reactions, such as hypotension and tachycardia (see Yu Tianji, Desferrioxamine—New Toxicity of Old Drugs, Foreign Medicine: Pharmacy, 1991.P249,), especially at high doses, its Adverse reactions are particularly obvious
In order to take into account the efficacy and safety, the current usual treatment method is low-dose and long-term intravenous injection to maintain the concentration in the body to achieve a certain effect, but this treatment method is very inconvenient and the patient's compliance is poor

Method used

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  • Polyethylene glycol modified iron ionic chelator
  • Polyethylene glycol modified iron ionic chelator
  • Polyethylene glycol modified iron ionic chelator

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] 1 gram of carboxylated polyethylene glycol monomethyl ether (molecular weight 2kDa) was dissolved in 10 ml of HEPES (4-hydroxyethylpiperazineethanesulfonic acid) buffer solution, according to 1:2:2:2 (carboxylated polyethylene glycol The carboxyl molar ratio in the alcohol monomethyl ether is 1), adding deferoxamine, EDC and NHS in a molar ratio, and stirring in the dark for 24 hours, the reaction solution is purified through a silica gel column and a cation exchange column to obtain the product polyethylene glycol monomethyl ether Ether-modified deferoxamine ferric ion chelator MPEG 2k -DFO.

[0044] Infrared spectrum test: KBr tablet method, the test results are as follows figure 2 shown. The characteristic peak is assigned to: 3445cm -1 (O-H stretching vibration in polyethylene glycol monomethyl ether molecule); 3300cm -1 (N-H stretching vibration in deferoxamine molecule); 2878cm -1 (CH2 symmetric stretching vibration in polyethylene glycol monomethyl ether an...

Embodiment 2

[0047] 1 gram of carboxylated polyethylene glycol monomethyl ether (molecular weight 2kDa) was dissolved in 10 milliliters of methanol solution, placed in an ice bath, according to 1:1.2:1.2:1.2 (the carboxyl group in the carboxylated polyethylene glycol monomethyl ether Add deferoxamine, DCC and NHS respectively at a molar ratio of 1), and finally add triethylamine dropwise to adjust the pH to 7-8. After stirring in the dark for 24 hours, the reaction solution is first precipitated with ether and then rotary evaporated to obtain the crude product , and then purified through a silica gel column and a cation exchange column to obtain the deferoxamine iron ion chelating agent MPEG modified by polyethylene glycol monomethyl ether 2k -DFO-2.

Embodiment 3

[0049] 1 gram of formylated polyethylene glycol monomethyl ether (molecular weight 5kDa) is dissolved in 10 milliliters of ultrapure water, according to 1:2:2 (the aldehyde molar ratio in the formylated polyethylene glycol monomethyl ether is 1 ) were added in molar ratios of deferoxamine and sodium cyanoborohydride respectively, and after stirring for 48 hours in the dark at 10°C, the reaction solution was purified through a silica gel column to obtain the product polyethylene glycol monomethyl ether-modified deferoxamine iron ion chelate MPEG 5k -DFO.

[0050] H NMR test: Dissolve 40mg sample in 1ml D 2 O, 25 ℃ detection, the results are as follows image 3 shown.

[0051] The characteristic peaks are assigned as follows: 3.6 and 3.3ppm correspond to hydrogen in methoxy and methylene in polyethylene glycol monomethyl ether respectively; 3.4ppm corresponds to H-5, H-12 and H-19 in deferoxamine molecule ; 3.1ppm corresponds to H-1, H-8 and H-15 in deferoxamine molecule; 2....

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Abstract

The invention discloses a polyethylene glycol modified iron ionic chelator and a preparation method thereof. The iron ionic chelator is prepared from derivatives of polyethylene glycol with good biocompatibility and deferoxamine. The preparation method comprises the step of preparing the polyethylene glycol modified iron ionic chelator by covalent binding of carboxylated polyethylene glycol monomethyl ether or formylated polyethylene glycol monomethyl ether with deferoxamine. Compared with deferoxamine, the iron ionic chelator has the advantages of long action and low toxicity, and has potential application value in treatment of iron overload related diseases.

Description

technical field [0001] The invention belongs to the field of chemically modified condensation polymers, and in particular relates to deferoxamine grafted polyethylene glycol, and also relates to its application as an iron ion chelating agent. Background technique [0002] Iron ion overload is associated with many clinical diseases, such as thalassemia, stroke, Alzheimer's, Parkinson's disease and other neurodegenerative diseases. [0003] Desferrioxamine is an iron ion chelator commonly used clinically, and has therapeutic effects on diseases related to iron ion overload. But it has obvious defects: 1. Desferrioxamine in the blood will be rapidly degraded by enzymes in the body, and its half-life in the body is less than 30 minutes, resulting in poor drug efficacy, and it is necessary to increase the dosage or prolong the medication time; 2. It is toxic , can cause many adverse reactions, such as hypotension and tachycardia (see Yu Tianji, Desferrioxamine—New Toxicity of Ol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/60A61K31/16A61P7/06A61P9/10A61P25/28A61P25/16C08G65/333
CPCA61K31/16C08G65/33396C08G2650/04C08G2650/38C08G2650/50
Inventor 田猛马潞李浩游潮李蹊林森
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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