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Polyethylene glycol prodrug of gambogicacid, its preparation method, formulation and use

A technology for PEGylation of gambogic acid and polyethylene glycol is applied in the field of natural medicines and polymer materials, and can solve the problems of poor water solubility, limited clinical application, and high toxicity.

Active Publication Date: 2006-10-04
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It has been reported in the literature that it has good antitumor effects, but its clinical application is limited due to its poor water solubility and high toxicity.

Method used

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  • Polyethylene glycol prodrug of gambogicacid, its preparation method, formulation and use
  • Polyethylene glycol prodrug of gambogicacid, its preparation method, formulation and use
  • Polyethylene glycol prodrug of gambogicacid, its preparation method, formulation and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Preparation of Polyethylene Glycol 4K—Gambogic Acid

[0056] Weigh gambogic acid (0.346g, 0.55mmol), dicyclohexylcarbodiimide (DCC) (1.23g, 0.6mmol), p-dimethylaminopyridine (DMAP) (0.03g, 0.25mmol), dissolve in 30ml of dichloromethane was stirred at 0°C for 2h, PEG4K (1g, 0.25mmol) was added, the temperature was raised to 25°C, and stirred overnight. After filtration, the filtrate was concentrated to dryness, recrystallized from isopropanol, purified on a Sephadex G-25 dextran gel column, and freeze-dried to obtain 1.0 g of polyethylene glycol 4K-gambogic acid as a yellow powder, with a yield of 76.1%. mp: 52-54°C. Gambogic acid content: 21.93% (theoretical: 23.9%). Solubility in water at room temperature is about: 650mg / ml

[0057] 1 HNMR (500MHz, CDCl 3 ): Around δ3.6 is the strong peak of hydrogen on PEG, and the remaining peaks are peaks of hydrogen on gambogic acid, δ1.28-1.45 (C24-H, C25-H, 12H), δ1.55-2.06 (C29- H, C34-H, C35-H, C39-H, C40-H, 30H), δ2.31-2...

Embodiment 2

[0060] Preparation of polyethylene glycol 20K-glycine-gambogic acid

[0061] 1. Preparation of polyethylene glycol 20K-glycine trifluoroacetate (PEG20K-Gly-FA):

[0062] Weigh PEG20K (40g, 2mmol), N-tert-butoxycarbonylglycine (Boc-Gly) (0.77g, 4.4mmol), p-dimethylaminopyridine (DMAP) (0.12g, 1mmol), dissolve in 100ml dichloromethane , Another weighed dicyclohexylcarbodiimide (DCC) (1.2g, 4.8mmol), dissolved in 4ml of dichloromethane, and added dropwise to the reaction solution. Stir overnight at room temperature. Centrifuge, discard the precipitate, concentrate the clear liquid to dryness, add 40ml of cold acetone, filter again to remove a small amount of insoluble matter, concentrate the filtrate to dryness again, dissolve the residue in 20ml of dichloromethane, add dropwise to 300ml of vigorously stirred ice ether, and statically After the solid was completely precipitated, it was filtered and vacuum-dried to obtain 36.4 g of a white solid. Dissolve this white solid in 60...

Embodiment 3

[0068] Preparation of polyethylene glycol 10K-lysine-gambogic acid

[0069] 1. Preparation of polyethylene glycol-lysine trifluoroacetate (PEG10K-Lys-FA):

[0070] The operation method is the same as in Example 2, and the yield is 78.7%.

[0071] 2. Preparation of polyethylene glycol 10K-lysine-gambogic acid:

[0072] Weigh PEG-Lys-FA (1.25g, 0.125mmol), gambogic acid (0.47g, 0.75mmol), DCC (0.16g, 0.8mmol), triethylamine or 2ml dissolved in 20ml dichloromethane, stir at room temperature overnight. Filtrate, concentrate the filtrate to dryness, recrystallize from isopropanol, purify on a Sephadex G-25 dextran gel column, and lyophilize to obtain a yellow powder polyethylene glycol 20K-lysine-gambogic acid (PEG-Lys-GA ) 1.2g, yield: 68.3%. Gambogic acid content: 16.46% (theoretical: 19.79%). Solubility in water at room temperature is about 440mg / ml.

[0073] 1 HNMR (500MHz, CDCl 3 ): Around δ3.6 is the strong peak of hydrogen on PEG, and the remaining peaks are peaks of...

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Abstract

This invention relates to the field of nature medicament and high molecular material, specifically relates to a kind of former medicine (1)of polietilenglicol. This invention also discloses the method for preparing the former medicine and the medicine composition that taking (1) as active constituent and their application in tumour threatment.

Description

technical field [0001] The present invention relates to the field of natural medicines and polymer materials, in particular to a class of PEGylated gambogic acid prodrugs, and also discloses its preparation method, pharmaceutical compositions with the prodrugs as active ingredients and their use in treating tumors Applications. Background technique [0002] Total gambogic acid includes gambogic acid, neogambogic acid, and allogambogic acid, which are acidic active ingredients extracted from the dry resin secreted by gambogic. It has been reported in the literature that it has a good antitumor effect, but its clinical application is limited due to its poor water solubility and high toxicity. [0003] CN01108049.3 discloses that gambogic acid compounds and different bases or ions form water-soluble complexes, which improves the effectiveness of gambogic acid compounds and reduces irritation and toxicity. LD of total sodium gambogic acid injected intravenously in mice 50 It ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K31/352A61P35/00A61K47/60
Inventor 平其能张灿叶海张鹏
Owner CHINA PHARM UNIV
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