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New indication of cefoperazone sodium and sulbactam sodium drug preparation for treating infectious endocarditis

A technology of cefoperazone sodium and sulbactam sodium, which is applied in the field of new indications of cefoperazone sodium and sulbactam sodium pharmaceutical preparations for the treatment of infective endocarditis, and can solve the problems of weakening stability of finished preparations, cefoperazone sodium light, strong acid, strong alkali, oxidation, etc. And temperature instability, poor stability of cefoperazone sodium preparations and other issues, to achieve the effect of long-term storage and placement, reduce the risk of clinical sensitization, and improve the clinical treatment effect

Active Publication Date: 2019-11-01
广东金城金素制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] We have studied the stability of cefoperazone sodium and found that cefoperazone sodium is unstable to light, strong acid, strong alkali, oxidation and temperature. In addition, the impurities in the raw materials and the impurities produced in the production process remain in the finished product, which makes the finished preparation in the storage process The stability of the further weakened
However, the production process or storage method of the single preparation and the compound preparation of cefoperazone sodium have not been able to propose an effective solution at present.
Chinese patent CN 104844624A provides a preparation method of cefoperazone sodium sulbactam sodium co-crystal to improve the stability of the preparation, but this method is more complicated than the single crystal method, is not easy to implement, and cannot stably guarantee the co-crystal of cefoperazone sodium and sulbactam sodium. molar ratio in crystal
For β-lactamase inhibitors, the content of sulbactam sodium will decrease and the degradation products will increase as the oxidation time increases, under strong acid or alkaline conditions, and as the temperature increases.
[0008] Based on the consideration of cefoperazone sodium impurities on drug efficacy and safety, it is necessary to study the production process and formulation form of cefoperazone sodium preparations to solve the problems of poor stability and decreased antibacterial effect of cefoperazone sodium preparations caused by impurities

Method used

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  • New indication of cefoperazone sodium and sulbactam sodium drug preparation for treating infectious endocarditis
  • New indication of cefoperazone sodium and sulbactam sodium drug preparation for treating infectious endocarditis
  • New indication of cefoperazone sodium and sulbactam sodium drug preparation for treating infectious endocarditis

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Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0143] The synthesis of embodiment 1-1 cefoperazone sodium

[0144] Step 1), dissolve 136g (0.5mol) 7-ACA, 40g (0.55mol) MTT in 420mL dimethyl carbonate, cool down to 5°C, add AlCl 3 -BF 3 Dimethyl carbonate composite catalyst 4.6g (wherein, AlCl 3 0.67g (0.005mol), BF 3 1.7g (0.025mol)), heated to 30°C, and reacted for 3h under stirring. After the reaction, cool the reaction liquid to 10°C, add 400mL water and 2g EDTA-Na 2 , add sodium bisulfate 126g (1.5mol) in batches within 20min, stir for 1h, keep the temperature below 5°C, pH 2.0, crystallization occurs, continue to stir for 1h, filter with suction, wash with acetone, acetic acid water, and acetone respectively, and dry to obtain White solid powder compound I (7-ACT) 161.5g, yield 98.4%, HPLC content greater than 98%.

[0145] Step 2), dissolve 167.7g (0.5mol) of piperazine acid in 500mL of N,N-dimethylformamide (DMF), cool the reaction solution to -5°C, add 51.9g (0.175mol) of The toluene solution of bis(trichlor...

Embodiment 1-2

[0148] The synthesis of embodiment 1-2 cefoperazone sodium

[0149] Identical to the synthesis process of Example 1-1, the only difference is: in step 1), in step 1), AlCl 3 -BF 3 AlCl in dimethyl carbonate composite catalyst 3 and BF 3 The weight ratio is 1:8.

Embodiment 2-1

[0150] The synthesis of embodiment 2-1 sulbactam sodium

[0151] Step A), cool 275mL (3.0mol) of 25% hydrobromic acid to 0°C, add dropwise dilute sulfuric acid to adjust the pH to 2.0; weigh 120mL water and 108g 6-APA (0.5mol) to prepare a suspension, cool to 0°C, add dropwise to the hydrobromic acid solution; weigh 34.5g (0.5mol) of sodium nitrite and dissolve it in 50mL of water, add dropwise to the above system, stir continuously during the dropwise addition, and continue to stir the reaction after the dropwise addition is completed 2h, the temperature was controlled at 0-5°C during the reaction. After the reaction is completed, 14 (weight)% hydrogen peroxide (1.5 mol) is added dropwise to the above system, and the reaction is stirred for 1 hour after the dropwise addition, and the temperature is controlled at 0-5° C. during the reaction. After the reaction was completed, 15% sodium bisulfite was slowly added until the solution turned colorless, and the end point was detec...

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Abstract

The invention discloses a new indication of a cefoperazone sodium and sulbactam sodium drug preparation for treating infectious endocarditis. Cefoperazone sodium provided through a specific raw material production process is extremely low in impurity content and significant in pharmaceutical effect, the quality of a preparation product is improved advantageously, the safety and effectiveness of the preparation product are ensured, and application to the aspect of preparing a drug for treating infectious endocarditis is realized.

Description

technical field [0001] The invention relates to medicine preparation technology, in particular to a new indication of cefoperazone sodium sulbactam sodium pharmaceutical preparation for treating infective endocarditis. Background technique [0002] Cefoperazone sodium (Cefobid) is a third-generation cephalosporin antibiotic. The chemical name is 7-(((4-ethyl-2,3-dioxo-1-piperazinyl)formylamino)(4-hydroxyphenyl)acetamido)-3-((1-methyl -1H-tetrazol-5-yl)thiomethyl)-8-oxo-5-thio-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid sodium salt. Its chemical structural formula is as follows: [0003] [0004] Cefoperazone sodium has certain stability to the broad-spectrum β-lactamase produced by Gram-negative bacilli, but it is worse than some third-generation cephalosporins. In order to overcome the drug resistance caused by β-lactamase-producing bacteria, the activity of β-lactamase is inhibited, so that β-lactamase antibiotics are not damaged by hydrolysis, and β-lactamase ant...

Claims

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Application Information

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IPC IPC(8): A61K31/546A61K31/545A61P9/00A61P31/04A61P31/10
CPCA61K31/545A61K31/546A61P9/00A61P31/04A61P31/10A61K2300/00
Inventor 吴丰喆伊茂聪李秋荣应鹏黄嘉玲
Owner 广东金城金素制药有限公司
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