Polymer-drug conjugate and preparation method thereof

A technology of conjugates and drugs, applied in the field of TPGS-sorafenib conjugates and its preparation, can solve the problems of poor water solubility, poor solubility of sorafenib, and low oral bioavailability, and achieve improved solubility Effect

Active Publication Date: 2018-09-28
宁波市杭州湾医院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Sorafenib has poor solubility and strong hydrophobicity
In order to improve its solubility in water, it is clinically made into tosylate, but the water solubility is still poor, the oral bioavailability is low, less than 10%, and the diet has a significant impact on its absorption
In the existing reports, most of them use the method of dosage form modification, and the method of increasing the solubility and bioavailability of sorafenib through the TPGS-sorafenib conjugate has not been reported so far.

Method used

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  • Polymer-drug conjugate and preparation method thereof
  • Polymer-drug conjugate and preparation method thereof
  • Polymer-drug conjugate and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Embodiment 1: the synthesis of TPGS-Sorafenib

[0028] (1) Preparation of TPGS-SA

[0029] Weigh 0.3g (0.2mmol) of TPGS, SA 0.1g (0.8mmol, 4eq), 4-dimethylaminopyridine (DMAP) 0.03g (0.2mmol, 1eq) into the reaction flask, under nitrogen protection, add DCM 2ml , stirred at room temperature for 24 hours, after the reaction was terminated, filtered, spin-dried the solvent, added anhydrous ether, and precipitated a solid, then frozen overnight at -20°C, filtered, dissolved the solid in DMSO, and purified by dialysis for 48 hours (ethanol as a solvent), and then purified Water was used as a solvent for dialysis for 24 hours, and post-treatment was performed to obtain TPGS-SA.

[0030] (2) Preparation of intermediate TPGS-NHS

[0031] Under the protection of nitrogen, weigh 0.32g (0.2mmol) of TPGS-COOH, 0.1g (0.8mmol, 4eq) of NHS, and 0.164g (0.8mmol, 4eq) of DCC into the reaction flask, add 2ml of DCM, stir at room temperature for 24h, and react After the termination, fi...

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Abstract

The invention provides a TPGS-sorafenib conjugate and a synthesis method thereof. The conjugate drug can be self-assembled into a micelle in water, which takes sorafenib as a hydrophobic kernel and takes TPGS as a hydrophilic shell, so that the dissolvability and an anti-tumor effect of the sorafenib can be improved, and the drug resistance of the sorafenib is reduced. The TPGS-sorafenib conjugatedrug is prepared by the following steps: activating TPGS and succinic anhydride (SA) through ring-opening reaction to obtain carboxyl-modified intermediate TPGS-SA, then connecting TPGS-SA to the sorafenib through typical carbodiimide coupling reaction, and finally obtaining the TPGS-sorafenib.

Description

Technical field: [0001] The invention relates to the field of medicines, in particular to a TPGS-sorafenib conjugate and a preparation method thereof. Background technique: [0002] Polymer-drug conjugation is one of the main strategies for drug modification, by which their solubility, permeability, and stability can be increased, and at the same time, their biological activity may also be increased. Such strategies are based on a central assumption that the molecular structure of a drug can be modified to create analogs, which differ chemically from the compound but produce similar or even better biological effects. Polymer-drug conjugation can significantly alter the biodistribution of therapeutic agents, thereby improving their pharmacokinetics and pharmacodynamics, increasing their therapeutic efficacy and reducing their side effects, and avoiding the development of multidrug resistance. Drug resistance is mainly caused by the overexpression of MDR transporters such as ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K47/60A61K31/44A61P35/00
CPCA61K31/44A61K47/60A61K47/6907A61P35/00
Inventor 王凯峰陈艺丹吴式琇余波张晓敏莫丽钦陈碧龚琳燕杨斐
Owner 宁波市杭州湾医院
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