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Paclitaxel polymer bonding drug and preparation method thereof

A paclitaxel and polymer technology, applied in the direction of pharmaceutical formulations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., can solve the problems of bond breaking sensitivity and unsatisfactory regioselectivity, and achieve good affinity Water and biocompatibility, efficient targeting, avoiding phagocytosis

Active Publication Date: 2014-02-26
CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the existing reports, most of the bonds between amphiphilic polymer materials and paclitaxel are in the form of ester bonds, which need to be released by esterifying enzymes in the body, and the sensitivity and regioselectivity of bond breaking are not ideal.

Method used

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  • Paclitaxel polymer bonding drug and preparation method thereof
  • Paclitaxel polymer bonding drug and preparation method thereof
  • Paclitaxel polymer bonding drug and preparation method thereof

Examples

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preparation example Construction

[0034] The preparation method of the polymer containing terminal carboxyl group is:

[0035] (A) Using polyethylene glycol monomethyl ether or polyethylene glycol as an initiator, the aliphatic cyclic ester monomer is ring-opened and polymerized under the action of a catalyst to obtain an amphiphilic polymer;

[0036] (B) reacting the amphiphilic polymer with the diacid containing disulfide bonds in the first organic solvent under the action of an organic base and a condensing agent to obtain a carboxyl-terminated polymer.

[0037] The polymer-bonded drug of paclitaxel of the present invention includes a carboxyl-terminated polymer and paclitaxel, and the paclitaxel and the carboxyl-terminated polymer are bonded together through esterification. The preparation method of the polymer containing terminal carboxyl group is:

[0038] First, using polyethylene glycol monomethyl ether or polyethylene glycol as an initiator, the aliphatic cyclic ester monomer is ring-opened and polym...

Embodiment 1

[0052] Add 10 g of polyethylene glycol monomethyl ether (MPEG) with a molecular weight of 2000 into a dry reaction bottle equipped with a water separator and a stirring device, replace the argon for 3 times, remove water by azeotropic anhydrous toluene, and remove large After removing part of the toluene, change to a decompression device to remove the remaining toluene, and dry it under vacuum at 80°C for 6 hours. After returning to room temperature, add 6 g of recrystallized lactide under the protection of an inert gas, heat the system to 100 ° C, the reactant is in a molten state, add 8 mg of stannous octoate, stir well, and react at 130 ° C for 24 hours. The product was dissolved in an appropriate amount of dichloromethane, precipitated with ether, and dried in vacuo to obtain 12.8 g of a white powder product with a yield of 80%. The NMR test result of the obtained polymer shows that the molecular weight of the polymer MPEG-PLA is 2000-1000, and the GPC test result shows a ...

Embodiment 2

[0056] (1) Add 10 g of dihydroxypolyethylene glycol (PEG) with a molecular weight of 2000 into a dry reaction flask equipped with a water separator and a stirring device, replace the argon gas 3 times, and azeotropically remove water with anhydrous toluene. After most of the toluene was removed, the remaining toluene was removed by a decompression device, and vacuum-dried at 80° C. for 6 hours. After returning to room temperature, add 6 g of recrystallized lactide under the protection of an inert gas, heat the system to 100 ° C, the reactant is in a molten state, add 8 mg of stannous octoate, stir well, and react at 130 ° C for 24 hours. The product was dissolved in an appropriate amount of dichloromethane, precipitated with ether, and dried in vacuo to obtain 12.8 g of a white powder product with a yield of 80%. The NMR test result of the obtained polymer shows that the molecular weight of the polymer PLA-PEG-PLA is 500-2000-500, and the GPC test result shows a single peak. ...

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Abstract

The invention provides a paclitaxel polymer bonding drug comprising a carboxyl end group contained polymer and paclitaxel esterified and bonded together with the carboxyl end group contained polymer. A preparation method of the carboxyl end group contained polymer comprises the steps of subjecting an aliphatic cyclic ester monomer to ring opening polymerization under the action of a catalyst by taking methoxy polyethylene glycol or polyethylene glycol as an initiator to obtain an amphiphilic polymer; subjecting the amphiphilic polymer and disulfide bond contained diacid to reaction in a first organic solvent under the action of organic alkaline and a condensing agent to obtain the carboxyl end group contained polymer. The solubility of paclitaxel in water can be increased by using the paclitaxel polymer bonding drug; the paclitaxel polymer bonding drug has reduction sensibility so as to be capable of being self-assembled to form a micelle; the paclitaxel polymer bonding drug has favorable hydrophilicity and biocompatibility, so that human reticuloendothelial system phagocytosis in blood circulation can be avoided, and the paclitaxel polymer bonding drug has sufficient time to reach a cancer position through an EPR (Enhanced Permeability and Retention) effect and further enters cells through endocytosis, thus an efficient targeting effect of the drug is achieved.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a taxol polymer bonded drug and a preparation method thereof. Background technique [0002] Paclitaxel is an anti-microtubule agent extracted from the needles and bark of Taxus brevifolia - Taxus brevifolia. Its structural formula is: [0003] [0004] Since Wani et al. first isolated and determined the structure of paclitaxel by chemical and X-ray crystallography in 1971, phase I clinical research and phase II and III clinical trials have shown that it has obvious antitumor effects on human cancer. This effect was originally discovered in advanced ovarian and breast tumors, and it has been reported in a large number of literatures to have a significant effect on small cell and non-small cell lung cancer, head and neck cancer, and metastatic melanoma. Its biological activity is related to its role in cell division. It can promote the assembly of microtubule dimers into microtubules d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K31/337A61P35/00
Inventor 孙海汤朝晖许午高战团庄秀丽陈学思
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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