A kind of preparation method of hydroxyethyl starch-doxorubicin bond drug

A technology of hydroxyethyl starch and doxorubicin, which is applied in pharmaceutical formulations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., can solve the problem of low drug loading and lack of intelligence in the release of doxorubicin and other issues to achieve enhanced drug effects, good biocompatibility, and easy modification

Inactive Publication Date: 2016-10-12
NORTHEAST NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above-mentioned doxorubicin-bonded drugs have problems such as too stable chemical bonds, low drug loading, and lack of intelligence in the release of doxorubicin.

Method used

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  • A kind of preparation method of hydroxyethyl starch-doxorubicin bond drug
  • A kind of preparation method of hydroxyethyl starch-doxorubicin bond drug
  • A kind of preparation method of hydroxyethyl starch-doxorubicin bond drug

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Put 0.4g of hydroxyethyl starch and 0.1ml of triethylamine in a dry reaction bottle, add 10ml of anhydrous dimethyl sulfoxide to dissolve, and dissolve 0.07g of p-nitrophenyl chloroformate in 5ml of anhydrous Dimethyl sulfoxide was added dropwise to the reaction flask at 25°C under stirring with a stirrer. After the dropwise addition, the reaction was continued for 24 hours. After the reaction was completed, the mixed solution was put into a dialysis bag for dialysis and freeze-dried to obtain formic acid. Hydroxyethyl starch modified with p-nitrophenyl ester. Carry out nuclear magnetic resonance analysis, infrared analysis to the hydroxyethyl starch modified by formic acid p-nitrophenyl ester obtained, by nuclear magnetic resonance analysis and infrared analysis, the hydroxyethyl starch modified by formic acid p-nitrophenyl ester prepared by the embodiment of the present invention has Formula (III) structure.

[0029] The obtained hydroxyethyl starch modified with p-n...

Embodiment 2

[0032] Put 0.4g of hydroxyethyl starch and 0.13ml of triethylamine in a dry reaction bottle, add 10ml of anhydrous dimethyl sulfoxide to dissolve, and dissolve 0.09g of p-nitrophenyl chloroformate in 5ml of anhydrous Dimethyl sulfoxide was added dropwise to the reaction flask at 25°C under stirring with a stirrer. After the dropwise addition, the reaction was continued for 24 hours. After the reaction was completed, the mixed solution was put into a dialysis bag for dialysis and freeze-dried to obtain formic acid. Hydroxyethyl starch modified with p-nitrophenyl ester. Carry out nuclear magnetic resonance analysis, infrared analysis to the hydroxyethyl starch modified by formic acid p-nitrophenyl ester obtained, by nuclear magnetic resonance analysis and infrared analysis, the hydroxyethyl starch modified by formic acid p-nitrophenyl ester prepared by the embodiment of the present invention has Formula (III) structure.

[0033] Put the obtained hydroxyethyl starch modified by ...

Embodiment 3

[0036] Put 0.4g of hydroxyethyl starch and 0.15ml of triethylamine in a dry reaction flask, add 10ml of anhydrous dimethyl sulfoxide to dissolve, and dissolve 0.12g of p-nitrophenyl chloroformate in 5ml of anhydrous Dimethyl sulfoxide was added dropwise to the reaction bottle under the condition of 25°C and stirred by a stirrer. After the dropwise addition, the reaction was continued for 24 hours. Nitrophenyl ester modified hydroxyethyl starch. Carry out nuclear magnetic resonance analysis, infrared analysis to the hydroxyethyl starch modified by formic acid p-nitrophenyl ester obtained, by nuclear magnetic resonance analysis and infrared analysis, the hydroxyethyl starch modified by formic acid p-nitrophenyl ester prepared by the embodiment of the present invention has Formula (I) structure.

[0037] Put the obtained hydroxyethyl starch modified by p-nitrophenyl formate and 0.07ml of hydrazine hydrate into a reaction flask, add 10ml of anhydrous dimethyl sulfoxide to dissolv...

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Abstract

The invention provides a preparation method of a hydroxyethyl starch-amycin conjugate medicine (a structure formula is shown as a formula I). The preparation method comprises the following steps: (1) reacting hydroxyethyl starch, 4-nitrophenyl chloroformate and triethylamine in an organic solvent to obtain 4-nitrophenyl formate-modified hydroxyethyl starch (HES-NPC); (2) reacting the HES-NPC with water and hydrazine in an organic solvent to obtain hydrazine bond-modified hydroxyethyl starch (HES-NHNH2); and (3) reacting the HES-NHNH2, doxorubicin hydrochloride and triethylamine in an organic solvent to obtain the hydroxyethyl starch-amycin conjugate medicine shown as the formula I. The hydroxyethyl starch-amycin conjugate medicine provided by the invention has good biocompatibility, the introduced hydrazone bond has good pH responsiveness, and amycin that is bonded on the high molecular medicine via a hydrazone bond can be rapidly released under pH condition in tumor tissues or tumor cells, so as to enhance the medicine efficacy.

Description

technical field [0001] The invention relates to the technical field of polymer drug preparation, in particular to a method for preparing a hydroxyethyl starch-doxorubicin bonded drug. Background technique [0002] Doxorubicin, also known as daunorubicin, daunorubicin, doxorubicin or ADR, is a broad-spectrum anti-tumor drug of anthracycline antibiotics. It is a non-specific drug for the cell cycle and has the strongest effect on the S phase. It also has effects on M, G1, and G2 phases, and its mechanism of action is to embed DNA molecules, destroy nucleic acid structures, and thereby inhibit the synthesis of biological macromolecules. Doxorubicin is mainly used in the treatment of acute leukemia, malignant lymphoma, liver cancer, lung cancer, gastric cancer, esophageal cancer, cervical cancer, bladder cancer, testicular cancer, thyroid cancer, soft tissue tumors, osteosarcoma and neuroblastoma, etc. At present, doxorubicin is the main way of clinical administration is intrav...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/704A61K47/48A61P35/00A61P35/02
Inventor 陈莉姚雪梅栗迪
Owner NORTHEAST NORMAL UNIVERSITY
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