CN-114984182-B - Preparation method of polymyxin B sulfate dry powder

Abstract

The invention discloses a preparation method of polymyxin B sulfate dry powder, which belongs to the technical field of medicine preparation, and the preparation method of the polymyxin B sulfate dry powder comprises the steps of adsorbing and filtering polymyxin B sulfate fermentation liquor by using a ZIF-8@polyurea/polyethersulfone composite membrane, eluting a filter cake by using a sulfuric acid aqueous solution, and carrying out post-treatment on an eluent to obtain the polymyxin B sulfate dry powder.

Inventors

• Yue Zhengya
• LI YONGMIN
• LIU SHAOJIE
• LIU YUJIAO
• HAN SHUAI

Assignees

• 山东鲁西药业有限公司

Dates

Publication Date

20260508

Application Date

20220530

Claims (1)

1. 1. A preparation method of polymyxin B sulfate dry powder is characterized in that polymyxin B sulfate fermentation liquor is adsorbed and filtered by a ZIF-8@polyurea/polyethersulfone composite membrane, and a filter cake is eluted by sulfuric acid aqueous solution; the ZIF-8@polyurea/polyethersulfone composite membrane is prepared by the following steps: Dissolving 7.4g of polymethylene polyphenyl polyisocyanate and 0.5g of triethylene tetramine in 35mL of acetonitrile, adding 2-2.5g of ZIF-8 nanocrystals, heating to 35-40 ℃, immersing a polyethersulfone porous membrane in the solution, carrying out heat preservation reaction for 10min, taking out, airing at room temperature, and repeating for 3-4 times to obtain a ZIF-8@polyurea/polyethersulfone composite membrane, wherein the polyethersulfone porous membrane is a polyethersulfone membrane substrate with the pore diameter of 1.0 mu m; The ZIF-8 nanocrystals were prepared by the following method: 2.5g of 2-methylimidazole is dissolved in 30mL of methanol, 1.6g of zinc nitrate hexahydrate is dissolved in 30mL of ethanol, the two solutions are mixed and placed into a variable frequency microwave synthesizer, the power of the variable frequency microwave synthesizer is 0-1000W, the variable frequency microwave synthesizer is stirred and reacts for 10min at 40 ℃, the temperature is cooled to room temperature, the obtained solution is centrifuged, washed with ethanol for 3 times, and dried to constant weight at 80 ℃ to obtain ZIF-8 nanocrystals; the concentration of the sulfuric acid aqueous solution is 0.5mol/L; The eluent is post-treated, and the steps are as follows: And (3) regulating the pH value of the eluent to 5.5-6.5 by adopting a sodium hydroxide solution with the mass fraction of 10%, concentrating until solid is separated out to obtain a polymyxin B sulfate saturated solution, dropwise adding ethanol into the saturated solution at room temperature, filtering when the separated crystals are not increased, washing a filter cake with ethanol for 3 times, heating to 40 ℃, and vacuum drying for 6 hours to obtain the polymyxin B sulfate dry powder.

Description

Preparation method of polymyxin B sulfate dry powder Technical Field The invention relates to a preparation method of polymyxin B sulfate dry powder, belonging to the technical field of medicine preparation. Background Polymyxin B is a generic term for a family of basic polypeptide antibiotics. The sulfate salt of polymyxin B is also known as polymyxin B. Polymyxin B, although having a strong bactericidal effect on gram-negative bacteria, has been stopped in clinical use in the eighth nineties of the 20 th century due to its strong toxicity and neuromuscular blocking effect. However, in recent years, more and more serious diseases are caused by multi-antibody drug-resistant gram-negative bacterial strains in clinic, so that clinical application of polymyxin B is re-emphasized, and clinical researches are also more and more. The production of polymyxin B sulfate is usually carried out by fermentation, and the production bacteria are straight-bar-shaped polymyxa. The polymyxin B sulfate fermentation broth contains impurities such as saccharides, inorganic salts, pigments, proteins, microbial cells and the like which remain in the culture medium, so that the subsequent application effect is greatly influenced, and therefore, the polymyxin B fermentation broth needs to be separated and purified to ensure the quality of the product. The extraction and purification methods of polymyxin B sulfate are more, and at present, the main extraction and purification methods include a precipitation method, a membrane filtration method, an adsorption method, an extraction method, an ion exchange method and the like. The precipitation method and the extraction method use organic solvents, which not only have high cost, but also cause certain harm to operators and environment, and the adsorption method has the defects of large consumption of adsorption materials, high cost, overlong production time of the ion exchange method, lower adsorption yield and the like. The Metal Organic-Frameworks (MOFs) material has the characteristics of large specific surface area, high porosity, adjustable pore diameter and the like. In MOFs materials, ZIF-8 has the advantages of mild synthesis conditions, good physical and chemical stability and the like, so that the ZIF-8 has important application prospects in the technical fields of adsorption separation, wastewater treatment and the like. Diisocyanate is a compound containing two high-activity isocyanate groups (-N=C=O) in the molecule, and can react with polyamine to generate polyurea containing-NHCONH-functional groups, and the polyurea has micropore, mesopore and macropore structures and has the advantages of good water resistance, ageing resistance, wear resistance and the like. Disclosure of Invention The invention aims to make up the defects of the prior art, and provides a preparation method of polymyxin B sulfate dry powder, in particular relates to a preparation method of polymyxin B sulfate dry powder, which is characterized in that polymyxin B sulfate fermentation liquor is adsorbed and filtered by a ZIF-8@polyurea/polyethersulfone composite membrane, a filter cake is eluted by sulfuric acid aqueous solution, and eluent is subjected to post-treatment, so that the polymyxin B sulfate dry powder is prepared. The technical scheme of the invention is as follows: a preparation method of polymyxin B sulfate dry powder comprises the steps of adsorbing and filtering polymyxin B sulfate fermentation liquor by using a ZIF-8@polyurea/polyether sulfone composite membrane, eluting a filter cake by using a sulfuric acid aqueous solution, and carrying out post-treatment on the eluent to obtain polymyxin B sulfate dry powder; (1) The ZIF-8 is a metal organic framework crystal prepared by the reaction of 2-methylimidazole and zinc nitrate; the polyurea is a porous reticular polymer generated by the crosslinking reaction of polymethylene polyphenyl polyisocyanate and triethylene tetramine; The ZIF-8@polyurea/polyethersulfone composite membrane is a porous composite material with MOF nanocrystals embedded on the surface and the polyurea loaded on a polyethersulfone substrate; the aqueous sulfuric acid solution is preferably 0.5mol/L. (2) The ZIF-8 nanocrystals were prepared as follows: 2.5g of 2-methylimidazole is dissolved in 30mL of methanol, 1.6g of zinc nitrate hexahydrate is dissolved in 30mL of ethanol, the two solutions are mixed and placed into a variable frequency microwave synthesizer to react for 10min at 40 ℃, the mixture is cooled to room temperature, the obtained solution is centrifuged, washed 3 times with ethanol and dried to constant weight at 80 ℃ to obtain ZIF-8 nanocrystals; the power of the variable frequency microwave synthesizer is 0-1000W. (3) The ZIF-8@polyurea/polyethersulfone composite membrane is prepared by the following steps: Dissolving 7.4g of polymethylene polyphenyl polyisocyanate and 0.5g of triethylene tetramine in 35mL of acetonitrile, adding 2-2.5g of ZIF-8 nano