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Preparation method of high-purity daptomycin lactone hydrolysate

A daptomycin and hydrolyzate technology, applied in the direction of peptides, etc., can solve the problems of daptomycin resistance, disrupting translocation, affecting product quality, etc.

Inactive Publication Date: 2017-06-20
PEKING UNIV FOUNDER GRP CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The mechanism of action of daptomycin is different from that of other antibiotics. It disrupts the transport of amino acids by the cell membrane, thereby hindering the biosynthesis of peptidoglycan on the bacterial cell wall and changing the properties of the plasma membrane of the cell. In addition, it can also destroy the cell membrane of the bacteria, making Its contents leak out to achieve the purpose of killing bacteria, so it may be difficult for bacteria to develop resistance to daptomycin
[0004] Although daptomycin has been industrialized in the United States, daptomycin products often contain impurities such as dehydrated daptomycin, isomeric daptomycin, and daptomycin lactone hydrolyzate, which seriously affect product quality. , it is very necessary to be able to separate and purify the impurities in daptomycin and conduct research
[0005] Existing daptomycin extraction methods, such as the impurity of daptomycin described in European Patent No. 1586580A2, do not specifically involve the separation method of impurity daptomycin

Method used

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  • Preparation method of high-purity daptomycin lactone hydrolysate

Examples

Experimental program
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Effect test

Embodiment 1

[0026] After filtering the daptomycin fermentation broth, the filtrate is chromatographed on FPDA13 resin, and the column is washed with 0.03N sodium chloride, 0.06N sodium acetate, acetic acid to adjust the pH 6.5-7.0 solution 2BV, 0.3N sodium chloride, 0.06N acetic acid Sodium and acetic acid adjust the pH 6.5-7.0 solution to elute, collect the chromatographic solution of daptomycin lactone hydrolysate with chromatographic purity greater than 10%, adjust the pH to 2.5, and store at a constant temperature of 20°C for 24 hours to obtain a chromatographic purity of 20% Daptomycin lactone hydrolysate solution.

[0027] The daptomycin lactone hydrolysate solution was separated and purified by preparative chromatography (mobile phase: methanol:0.01% trifluoroacetic acid=25:75), and followed by high-performance liquid phase detection (detection conditions are the same as the European patent "PROCESS FOR THE PURIFICATION OFDAPTOMYCIN" (EP 1 586 580 A2) discloses the same method), colle...

Embodiment 2

[0030] After filtering the daptomycin fermentation broth, the filtrate is chromatographed on FPDA13 resin, 0.03N sodium chloride, 0.06N sodium acetate, acetic acid to adjust pH 6.5-7.0 solution 2BV to wash the column, 0.3N sodium chloride, 0.06N sodium acetate , Acetic acid adjusts the pH 6.5-7.0 solution to elute, collect the chromatographic solution of daptomycin lactone hydrolysate with chromatographic purity greater than 10%, adjust pH 3, store at 20°C for 24h, obtain daptomyces with 25% chromatographic purity Hydrolysate solution of prime lactone.

[0031] The daptomycin lactone hydrolysate solution was separated and purified by preparative chromatography (mobile phase: methanol:0.01% trifluoroacetic acid=25:75), and followed by high-performance liquid phase detection (detection conditions are the same as the European patent "PROCESS FOR THE PURIFICATION OFDAPTOMYCIN" (EP 1 586 580 A2) discloses the same method), collect chromatographic purity> 90% daptomycin lactone hydroly...

Embodiment 3

[0034] After filtering the daptomycin fermentation broth, the filtrate is chromatographed on FPDA13 resin, 0.03N sodium chloride, 0.06N sodium acetate, acetic acid to adjust pH 6.5-7.0 solution 2BV to wash the column, 0.3N sodium chloride, 0.06N sodium acetate , Acetic acid adjusts the pH 6.5-7.0 solution to elute, collect the chromatographic solution of daptomycin lactone hydrolysate with chromatographic purity greater than 10%, adjust the pH 4, store at 20°C for 24 hours, obtain daptomyces with chromatographic purity 37% Hydrolysate solution of prime lactone.

[0035] The daptomycin lactone hydrolysate solution was separated and purified by preparative chromatography (mobile phase: methanol:0.01% trifluoroacetic acid=25:75), and followed by high-performance liquid phase detection (detection conditions are the same as the European patent "PROCESS FOR THE PURIFICATION OFDAPTOMYCIN" (EP 1 586 580 A2) discloses the same method), collect chromatographic purity> 90% daptomycin lacton...

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Abstract

The invention discloses a preparation method of high-purity daptomycin lactone hydrolysate; according to the method, a daptomycin resin chromatography liquid has the pH adjusted and is converted into a liquid containing a relatively-high-purity daptomycin lactone hydrolysate, then by preparative chromatography, the high-purity daptomycin lactone hydrolysate with the chromatographic purity of more than 96% is obtained. The method is simple and easy to operate and low in cost.

Description

Technical field [0001] The present invention relates to the field of pharmaceutical preparation, in particular to a preparation method of lactone hydrolyzed daptomycin, and specifically relates to a method for preparing high-purity lactone hydrolyzed daptomycin by adopting a daptomycin resin chromatography solution for certain condition conversion and a preparation chromatography method Mycin. Background technique [0002] With the development of antibiotics and the abuse of antibiotics, the resistance of pathogens to antibiotics is the most severe challenge facing society today. In addition to controlling the abuse of antibiotics, finding an effective antibiotic against drug-resistant bacteria has become the best way to solve this problem. Vancomycin was once considered the last line of defense against gram-positive bacteria, but now More and more bacteria resistant to this drug have been found clinically in the world. [0003] Daptomycin is a cyclic lipopeptide antibiotic origi...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K1/16
Inventor 赵燕张洪兰谢云
Owner PEKING UNIV FOUNDER GRP CO LTD
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