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PEGylation modified amifostine as well as preparation method and use of PEGylation modified amifostine

A technology for pegylated amifostine and polyethylene glycol, which is applied in pharmaceutical formulations, medical preparations with inactive ingredients, and medical preparations containing active ingredients, etc., can solve the problem of short action time, large side effects, and metabolic wait for the question

Active Publication Date: 2015-06-10
THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Based on this, in order to overcome the defects of fast metabolism, poor stability, short action time and large side effects of existing amifostine intravenous injection, one of the purposes of the present invention is to provide a long-acting protection time, high stability and low side effects. PEGylated Amifostine Intravenous Formulation

Method used

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  • PEGylation modified amifostine as well as preparation method and use of PEGylation modified amifostine
  • PEGylation modified amifostine as well as preparation method and use of PEGylation modified amifostine
  • PEGylation modified amifostine as well as preparation method and use of PEGylation modified amifostine

Examples

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Embodiment 1

[0057] This example is used for the synthesis of linear monofunctional polyethylene glycol (0.5kDa) amifostine

[0058] Linear monofunctional polyethylene glycol acetate succinimidyl ester (0.5kDa) (100mg, ≈200μmol) and amifostine trihydrate (43mg, ≈200μmol) were placed in a 50ml round bottom flask, and 10ml pH=6.0 phosphoric acid was added Salt buffer, react at 0℃ for 48h. After the reaction, the mixed solution was dialyzed in three-distilled water (pH 7-8) through a dialysis bag with a molecular weight cut-off of 300 Da. The dialysis process was carried out in a chromatography cabinet at 4°C. The three-distilled water was changed every 4 hours. Amifostine linked to ethylene glycol derivatives is eliminated during this process. The product after dialysis was freeze-dried at low temperature for 36 hours to obtain a powdered dry bulk drug with a yield of about 40%.

Embodiment 2

[0060] This example is used for the synthesis and purification of four-arm multifunctional polyethylene glycol (40kDa) amifostine.

[0061] Four-arm polyethylene glycol acetate-N-succinimidyl ester (40kDa) (200mg, ≈5μmol) and amifostine trihydrate (43mg, ≈200μmol) are placed in a 10ml reaction flask and 2ml pH=10 phosphate buffer Liquid, react at 60°C for 0.5h. After the synthesis reaction is completed, the reacted mixed solution is freeze-dried at a low temperature for 36 hours to obtain a powdery dry product. Re-dissolve PEGylated amifostine with a molecular weight of about 40kDa in 40ml of dichloromethane. After shaking to dissolve, centrifuge at 12000rpm for 10min, take the supernatant and repeat the centrifugation step 4 times, then add it to 360ml of anhydrous ether Carry out recrystallization, centrifuge at 10,000 rpm for 10 minutes, wash the precipitated product with anhydrous ether three times, and place it in a vacuum drying oven at room temperature for drying to obtai...

Embodiment 3

[0063] This example is used for the synthesis of four-arm multifunctional polyethylene glycol (5kDa) amifostine.

[0064] Four-arm polyethylene glycol acetate-N-succinimidyl ester (5kDa) (500mg, ≈95μmol) and amifostine trihydrate (125mg, 480μmol) were placed in a 50ml round bottom flask, and 10ml pH=7.4 phosphate was added Buffer, react at room temperature for 2h. After the reaction, the mixed solution was dialyzed in three-distilled water (pH 7-8) through a dialysis bag with a molecular weight cut-off of 1kDa. The dialysis process was carried out in a chromatography cabinet at 4°C. The three-distilled water was changed every 4 hours, and the Amifostine linked to ethylene glycol derivatives is eliminated during this process. The product after dialysis was freeze-dried at low temperature for 36 hours to obtain a powdery dry bulk drug. Compared with Examples 1 and 2, the structure of the amifostine linked to the polyethylene glycol derivative is stable and the product purity is h...

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Abstract

The invention provides a PEGylation modified amifostine as well as a preparation method and use of the PEGylation modified amifostine. The polymer is of a structure formed by connecting the micromolecular medicine amifostine with polyethylene glycol (PEG) by use of a covalent bond, wherein the amino on the amifostine is in covalent linkage with the long chain of a PEG derivative by use of an amido bond. The invention also provides a preparation method of the PEGylation modified amifostine. The PEGylation modified amifostine also has an enhanced oxidation effect at the cellular level.

Description

Technical field [0001] The present invention belongs to the field of pharmaceutical preparations. Specifically, the present invention relates to a pegylated amifostine and a preparation method thereof. The present invention also relates to the use of the pegylated amifostine in the preparation of drugs for the treatment of anti-oxidative damage. use. Background technique [0002] Amifostine (Formula I) is a small molecule prodrug. In cancer treatment, after amifostine enters the body, the thiophosphate structure at one end can be dephosphorylated by alkaline phosphatase in normal tissues to generate active metabolites with free sulfhydryl groups, which can be eliminated by radiotherapy. And the oxidative free radical (ROS) component caused by chemotherapy can effectively resist the oxidative damage of ROS to tissues. The distribution and pH of alkaline phosphatase in tumor tissues are lower than those in normal tissues, resulting in lower alkaline phosphatase activity than norm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/00A61K31/661A61K47/48A61P39/06
Inventor 聂广军杨霄季天骄赵晓政赵瑞芳赵潇
Owner THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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