CN102250219A - Method for preparing colistine sulfate B - Google Patents
Method for preparing colistine sulfate B Download PDFInfo
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- CN102250219A CN102250219A CN2011101928377A CN201110192837A CN102250219A CN 102250219 A CN102250219 A CN 102250219A CN 2011101928377 A CN2011101928377 A CN 2011101928377A CN 201110192837 A CN201110192837 A CN 201110192837A CN 102250219 A CN102250219 A CN 102250219A
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Abstract
The invention discloses a method for preparing colistine sulfate B. The colistine sulfate B is prepared by the following steps of: pretreating fermentation liquor, concentrating under reduced pressure, heating, separating a precipitate, performing spray drying, and extracting the colistine sulfate B from fermentation liquor. The method has the advantages of high specificity, short procedure, small equipment investment, low cost, a little wastewater, light reduction, and high yield of 75-80 percent.
Description
Technical field
The invention belongs to bioengineering field, relate to the preparation of polypeptide antibiotics, specifically is the preparation method of a kind of colistine sulfate B.
Background technology
Colistin is produced by bacillus polymyxa, the antibiotic general name of being made up of multiple amino acids and lipid acid of the alkaline cyclic polypeptide class of gang.Up to the present research found in a plurality of components such as colistin A, B, C, D, E, M wherein have only colistin B(polymyxin B to be called for short polymyxin), colistin E(polymyxin E is called for short Colistin) have lower toxicity and a good antibiotic vigor.Therefore relative more to colistin B with colistin E research, and existing at present corresponding product uses clinically.Use their vitriol or mesylate clinically always.
Colistin B is the microbiotic of anti-gram negative bacillus, the tool germicidal action, most of gram negative bacilluses there is stronger anti-microbial effect, effect to Pseudomonas aeruginosa is more remarkable, and intestinal bacteria, Salmonellas, dysentery bacterium, hemophilus influenza, bordetella pertussis, gas bacillus and pneumobacillus etc. are also had good effect.Be mainly used in urinary system infection, meningitis, septicemia, burn infection and mucocutaneous infections etc. that responsive microbial infection and Pseudomonas aeruginosa cause clinically.
Preparation colistine sulfate B mainly is an ion exchange method at present, and this method separating step is long, yield is low, cost is high, and brings a large amount of waste water, serious environment pollution.
Summary of the invention
At the problems referred to above of prior art, the invention provides a kind of yield of colistine sulfate B and preparation method of quality of improving.
The objective of the invention is to be achieved by the following technical programs:
The preparation method of a kind of colistine sulfate B is characterized in that, it in turn includes the following steps:
(1) pre-treatment of fermented liquid: the fermented liquid that will contain colistin B is 2.0 ~ 3.5 with acid accent pH, adds the flocculating aids after-filtration of 2 ~ 5%wt while stirring, obtains first-time filtrate;
(2) concentrating under reduced pressure: with first-time filtrate-0.095 ~-concentrate under the 0.098Mpa, temperature is 50 ~ 90 ℃, obtains the concentrated solution that liquid content is 20000 ~ 30000ug/ml after concentrating;
(3) heating: it is 80 ~ 100 ℃ that concentrated solution is heated to temperature while stirring, and insulation 10 ~ 30min is cooled to room temperature then, obtains turbid solution;
(4) suction filtration: get 0.5 ~ 1g flocculating aids by every 100ml turbid solution, flocculating aids is added in the pure water, carry out suction filtration after the stirring and form cake layer, add step (3) gained turbid solution to cake layer again and carry out suction filtration, obtain secondary filtrate;
(5) precipitate and separate: is 10.0 ~ 12.0 with secondary filtrate with adjusting PH with base, stir 0.5 ~ 4 h, static 2 ~ 4 h under 0 ~ 10 ℃ of condition, secondary filtrate suction filtration with post precipitation, obtain filter cake, with pure water washing leaching cake 2 ~ 3 times, add while stirring in the filter cake after washing dilute sulphuric acid to pH be 3.0 ~ 7.0, obtain acidizing fluid;
(6) spraying drying: will obtain colistine sulfate B after the acidizing fluid spraying drying, inlet temperature is 140 ~ 200 ℃ during spraying drying, and air outlet temperature is 70 ~ 120 ℃.
Shortcoming at prior art exists the invention provides a kind of novel process for preparing colistine sulfate B.Its characteristics are that it has not only improved yield and the quality of colistine sulfate B, and environmental protection more, the production of colistine sulfate B is had the meaning of Sustainable development.The present invention adopts the thalline remove by filter earlier in the fermented liquid, reconcentration filtrate, adds the foreign protein in the heat extraction concentrated solution, precipitate and separate then, and last spraying drying obtains colistine sulfate B.Have that specificity is strong, operation is short, facility investment is few, yield is high, cost is low, and whole process do not adopt solvent, reduce advantages such as environmental pollution.
Specifically, the present invention removes thalline earlier, carries out separation and purification again.Because colistin B is a kind of polypeptides matter, the character of foreign protein in the fermentating liquid filtrate and colistin B has similar part, in the precipitate and separate process, can be precipitated out simultaneously, influence quality product, therefore, the present invention adopts heating to make the filtering then method of foreign protein sex change remove foreigh protein removing, the colistine sulfate B purity height of preparation, good product quality.The purpose of concentrated filtrate is to improve the concentration of filtrate, the content of foreign protein and colistin B can improve simultaneously, can make like this that to add the heat extraction foreign protein more thorough, the yield in the time of also improving colistin B precipitate and separate simultaneously has vital role to whole technology.Precipitate and separate is under certain conditions colistin B to be precipitated out with certain form, and impurity is dissolved in the solute, obtains solid after the filtration, again solid is dissolved with sulfuric acid acidation, obtain highly purified colistine sulfate B solution, play effect of separating purification, specificity is strong, good product quality.
As preferably, the described acid of step (1) is one or more of oxalic acid, sulfuric acid, hydrochloric acid, phosphoric acid.
As preferably, described flocculating aids is one or more of perlite, diatomite, Mierocrystalline cellulose, acidic white earth, gac, asbestos.
As preferably, the described temperature of step (2) is 60 ~ 70 ℃.
As preferably, the described soaking time of step (3) is 15 ~ 20min.
As preferably, the described alkali of step (5) is one or more of sodium hydroxide, ammoniacal liquor, potassium hydroxide, yellow soda ash, sodium bicarbonate.
As preferably, step (5) is described to be 10.5 ~ 11.5 with adjusting PH with base.
As preferably, step (5) is described, and to transfer pH with dilute sulphuric acid be 6.0 ~ 7.0.
As preferably, the described inlet temperature of step (6) is 170 ~ 180 ℃.
As preferably, the described air outlet temperature of step (6) is 90 ~ 100 ℃.
Major advantage of the present invention be compare with prior art intermediate ion exchange process have that operation is short, waste water is few, pollute less, cost is low, and total recovery height can reach 75 ~ 80%.
Embodiment
The fermented liquid that contain colistin B of the B of colistin described in following examples fermented liquid for producing by the bacillus polymyxa mutant strain.At present known multiple bacterial strain can ferment and obtain above-mentioned fermented liquid, and the bacterial strain that is numbered CPCC 140301, CPCC 140855 that is numbered ATCC10401, is preserved in medicinal microbial strains center (CPCC) that for example is deposited in US mode culture collection warehousing (American type culture collection) and is ATCC all can ferment and obtain colistin B fermented liquid.
Embodiment 1
(1) pre-treatment of fermented liquid
It is 2.7 that fermented liquid is transferred pH with sulfuric acid, adds the pearlite filtering aid of 3%wt while stirring, by Plate Filtration, till not having filtrate and oozing, obtains first-time filtrate.The Plate Filtration yield is 94.5%.
(2) concentrating under reduced pressure
First-time filtrate is carried out concentrating under reduced pressure, and temperature is 75 ℃, and vacuum tightness is-0.098MPa that being concentrated into liquid content is 26300ug/ml, obtains concentrated solution.Concentrated yield is 97.5%.
(3) heating
Concentrated solution is heated to 90 ℃ while stirring, and insulation 10min is cooled to room temperature then, obtains turbid solution.
(4) suction filtration
Get the 0.9g perlite by every 100ml turbid solution, perlite is added in the pure water, carry out suction filtration after the stirring and form cake layer, add step (3) gained turbid solution to cake layer again and carry out suction filtration, obtain secondary filtrate.
(5) precipitate and separate
It is 10.6 that secondary filtrate is transferred pH with ammoniacal liquor, stirs 2.5 h, static 3.5 h under 4 ℃ of conditions, secondary filtrate suction filtration with post precipitation obtains filter cake, uses pure water washing leaching cake 2 times, to the washing after filter cake in add while stirring dilute sulphuric acid to pH be 6.2, obtain acidizing fluid.The precipitate and separate yield is 84.5%.
(6) spraying drying
Acidizing fluid is carried out drying with spray-dryer, and inlet temperature is 190 ℃, and air outlet temperature is 105 ℃, obtains colistine sulfate B.The spraying drying yield is 99%, and colistine sulfate B content is 81.6%.
Embodiment 2
(1) pre-treatment of fermented liquid
It is 3.0 that fermented liquid is transferred pH with sulfuric acid, adds the pearlite filtering aid of 4.2%wt while stirring, by Plate Filtration, till not having filtrate and oozing, obtains first-time filtrate.The Plate Filtration yield is 95%.
(2) concentrating under reduced pressure
First-time filtrate is carried out concentrating under reduced pressure, and temperature is 80 ℃, and vacuum tightness is-0.095MPa that being concentrated into liquid content is 20000ug/ml, obtains concentrated solution.Concentrated yield is 98.5%.
(3) heating
Concentrated solution is heated to 80 ℃ while stirring, and insulation 25min is cooled to room temperature then, obtains turbid solution.
(4) suction filtration
Get the 0.8g perlite by every 100ml turbid solution, perlite is added in the pure water, carry out suction filtration after the stirring and form cake layer, add step (3) gained turbid solution to cake layer again and carry out suction filtration, obtain secondary filtrate.
(5) precipitate and separate
It is 10 that secondary filtrate is transferred pH with ammoniacal liquor, stirs 3 h, static 2 h under 10 ℃ of conditions, the secondary filtrate suction filtration with post precipitation obtains filter cake, with pure water washing leaching cake 2 times, add while stirring in the filter cake after washing dilute sulphuric acid to pH be 3, obtain acidizing fluid.The precipitate and separate yield is 86%.
(6) spraying drying
Acidizing fluid is carried out drying with spray-dryer, and inlet temperature is 200 ℃, and air outlet temperature is 110 ℃, obtains colistine sulfate B.The spraying drying yield is 98.5%, and colistine sulfate B content is 80.9%.
Embodiment 3
(1) pre-treatment of fermented liquid
It is 2 that fermented liquid is transferred pH with sulfuric acid, adds the super-cell of 2%wt while stirring, by Plate Filtration, till not having filtrate and oozing, obtains first-time filtrate.The Plate Filtration yield is 97%.
(2) concentrating under reduced pressure
First-time filtrate is carried out concentrating under reduced pressure, and temperature is 90 ℃, and vacuum tightness is-0.097MPa that being concentrated into liquid content is 29840ug/ml, obtains concentrated solution.Concentrated yield is 97.5%.
(3) heating
Concentrated solution is heated to 100 ℃ while stirring, and insulation 15min is cooled to room temperature then, obtains turbid solution.
(4) suction filtration
Get 0.8g diatomite by every 100ml turbid solution, diatomite is added in the pure water, carry out suction filtration after the stirring and form cake layer, add step (3) gained turbid solution to cake layer again and carry out suction filtration, obtain secondary filtrate.
(5) precipitate and separate
It is 11 that secondary filtrate is transferred pH with ammoniacal liquor, stirs 0.5 h, static 4 h under 8 ℃ of conditions, the secondary filtrate suction filtration with post precipitation obtains filter cake, with pure water washing leaching cake 1 time, add while stirring in the filter cake after washing dilute sulphuric acid to pH be 7.Obtain acidizing fluid, the precipitate and separate yield is 88%.
(6) spraying drying
Acidizing fluid is carried out drying with spray-dryer, and inlet temperature is 180 ℃, and air outlet temperature is 120 ℃, obtains colistine sulfate B.The spraying drying yield is 96%, and colistine sulfate B content is 83.1%.
Embodiment 4
(1) pre-treatment of fermented liquid
It is 3.5 that fermented liquid is transferred pH with sulfuric acid, adds the pearlite filtering aid of 5%wt while stirring, by Plate Filtration, till not having filtrate and oozing, obtains first-time filtrate.The Plate Filtration yield is 98%.
(2) concentrating under reduced pressure
First-time filtrate is carried out concentrating under reduced pressure, and temperature is 50 ℃, and vacuum tightness is-0.096MPa that being concentrated into liquid content is 22400ug/ml, obtains concentrated solution.Concentrated yield is 95%.
(3) heating
Concentrated solution is heated to 95 ℃ while stirring, and insulation 30min is cooled to room temperature then, obtains turbid solution.
(4) suction filtration
Get the 1g perlite by every 100ml turbid solution, perlite is added in the pure water, carry out suction filtration after the stirring and form cake layer, add step (3) gained turbid solution to cake layer again and carry out suction filtration, obtain secondary filtrate.
(5) precipitate and separate
It is 12 that secondary filtrate is transferred pH with ammoniacal liquor, stirs 4 h, static 3 h under 6 ℃ of conditions, the secondary filtrate suction filtration with post precipitation obtains filter cake, with pure water washing leaching cake 2 times, add while stirring in the filter cake after washing dilute sulphuric acid to pH be 6.5, obtain acidizing fluid.The precipitate and separate yield is 87.5%.
(6) spraying drying
Acidizing fluid is carried out drying with spray-dryer, and inlet temperature is 170 ℃, and air outlet temperature is 70 ℃, obtains colistine sulfate B.The spraying drying yield is 97%, and colistine sulfate B content is 81.5%.
Embodiment 5
(1) pre-treatment of fermented liquid
Fermented liquid is transferred pH3.2 with sulfuric acid, add the pearlite filtering aid of 3.5%wt while stirring,, till not having filtrate and oozing, obtain first-time filtrate by Plate Filtration.The Plate Filtration yield is 95%.
(2) concentrating under reduced pressure
First-time filtrate is carried out concentrating under reduced pressure, and temperature is 65 ℃, and vacuum tightness is-0.098MPa that being concentrated into liquid content is 30000ug/ml, obtains concentrated solution.Concentrated yield is 96%.
(3) heating
Concentrated solution is heated to 85 ℃ while stirring, and insulation 20min is cooled to room temperature then, obtains turbid solution.
(4) suction filtration
Get the 0.5g perlite by every 100ml turbid solution, perlite is added in the pure water, carry out suction filtration after the stirring and form cake layer, add step (3) gained turbid solution to cake layer again and carry out suction filtration, obtain secondary filtrate.
(5) precipitate and separate
It is 11.5 that secondary filtrate is transferred pH with ammoniacal liquor, stirs 3.5h, static 3.5 h under 0 ℃ of condition, secondary filtrate suction filtration with post precipitation obtains filter cake, uses pure water washing leaching cake 3 times, add dilute sulphuric acid while stirring to pH6.0 in the filter cake after washing, obtain acidizing fluid.The precipitate and separate yield is 89.5%.
(6) spraying drying
Acidizing fluid is carried out drying with spray-dryer, and inlet temperature is 140 ℃, and air outlet temperature is 120 ℃, obtains colistine sulfate B.The spraying drying yield is 97%, and colistine sulfate B content is 82.4%.
Claims (10)
1. the preparation method of a colistine sulfate B is characterized in that described method in turn includes the following steps:
(1) pre-treatment of fermented liquid: the fermented liquid that will contain colistin B is 2.0 ~ 3.5 with acid accent pH, adds the flocculating aids after-filtration of 2 ~ 5%wt while stirring, obtains first-time filtrate;
(2) concentrating under reduced pressure: with first-time filtrate-0.095 ~-concentrate under the 0.098Mpa, temperature is 50 ~ 90 ℃, obtains the concentrated solution that liquid content is 20000 ~ 30000ug/ml after concentrating;
(3) heating: it is 80 ~ 100 ℃ that concentrated solution is heated to temperature while stirring, and insulation 10 ~ 30min is cooled to room temperature then, obtains turbid solution;
(4) suction filtration: get 0.5 ~ 1g flocculating aids by every 100ml turbid solution, flocculating aids is added in the pure water, carry out suction filtration after the stirring and form cake layer, add step (3) gained turbid solution to cake layer again and carry out suction filtration, obtain secondary filtrate;
(5) precipitate and separate: is 10.0 ~ 12.0 with secondary filtrate with adjusting PH with base, stir 0.5 ~ 4 h, static 2 ~ 4 h under 0 ~ 10 ℃ of condition, secondary filtrate suction filtration with post precipitation, obtain filter cake, with pure water washing leaching cake 2 ~ 3 times, add while stirring in the filter cake after washing dilute sulphuric acid to pH be 3.0 ~ 7.0, obtain acidizing fluid;
(6) spraying drying: will obtain colistine sulfate B after the acidizing fluid spraying drying, inlet temperature is 140 ~ 200 ℃ during spraying drying, and air outlet temperature is 70 ~ 120 ℃.
2. the preparation method of colistine sulfate B according to claim 1 is characterized in that the described acid of step (1) is one or more of oxalic acid, sulfuric acid, hydrochloric acid, phosphoric acid.
3. the preparation method of colistine sulfate B according to claim 1 is characterized in that step (1) and (3) described flocculating aids are one or more of perlite, diatomite, Mierocrystalline cellulose, acidic white earth, gac, asbestos.
4. the preparation method of colistine sulfate B according to claim 1 is characterized in that the described temperature of step (2) is 60 ~ 70 ℃.
5. the preparation method of colistine sulfate B according to claim 1 is characterized in that the described soaking time of step (3) is 15 ~ 20min.
6. the preparation method of colistine sulfate B according to claim 1 is characterized in that the described alkali of step (5) is one or more of sodium hydroxide, ammoniacal liquor, potassium hydroxide, yellow soda ash, sodium bicarbonate.
7. the preparation method of colistine sulfate B according to claim 1, it is characterized in that step (5) described be 10.5 ~ 11.5 with adjusting PH with base.
8. the preparation method of colistine sulfate B according to claim 1 is characterized in that described to transfer pH with dilute sulphuric acid be 6.0 ~ 7.0 to step (5).
9. the preparation method of colistine sulfate B according to claim 1 is characterized in that the described inlet temperature of step (6) is 170 ~ 180 ℃.
10. the preparation method of colistine sulfate B according to claim 1 is characterized in that the described air outlet temperature of step (6) is 90 ~ 100 ℃.
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| CN 201110192837 CN102250219B (en) | 2011-07-11 | 2011-07-11 | Method for preparing colistine sulfate B |
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| CN 201110192837 CN102250219B (en) | 2011-07-11 | 2011-07-11 | Method for preparing colistine sulfate B |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102250220A (en) * | 2011-07-11 | 2011-11-23 | 浙江升华拜克生物股份有限公司 | Preparation method of colistin sulphate |
| CN103641893A (en) * | 2013-11-18 | 2014-03-19 | 宁夏泰瑞制药股份有限公司 | Method for recovering colistin sulfate from colistin sulfate slag |
| CN106039283A (en) * | 2016-08-24 | 2016-10-26 | 浙江升华拜克生物股份有限公司 | Preparation method of colistin sulfate premix |
| CN106868079A (en) * | 2017-04-26 | 2017-06-20 | 山东鲁抗医药股份有限公司 | The method of fermentation aerosporin culture medium and fermenting and producing aerosporin |
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| CN100347188C (en) * | 2005-12-06 | 2007-11-07 | 河北工业大学 | Polymyxin E separation preparation method |
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| CN100347188C (en) * | 2005-12-06 | 2007-11-07 | 河北工业大学 | Polymyxin E separation preparation method |
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| 丁子狄: "粘菌素的制备方法", 《国外药学（抗生素分册）》 * |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102250220A (en) * | 2011-07-11 | 2011-11-23 | 浙江升华拜克生物股份有限公司 | Preparation method of colistin sulphate |
| CN102250220B (en) * | 2011-07-11 | 2013-02-13 | 浙江升华拜克生物股份有限公司 | Preparation method of colistin sulphate |
| CN103641893A (en) * | 2013-11-18 | 2014-03-19 | 宁夏泰瑞制药股份有限公司 | Method for recovering colistin sulfate from colistin sulfate slag |
| CN103641893B (en) * | 2013-11-18 | 2016-08-24 | 宁夏泰瑞制药股份有限公司 | A kind of method reclaiming colistine sulfate from colistine sulfate dreg |
| CN106039283A (en) * | 2016-08-24 | 2016-10-26 | 浙江升华拜克生物股份有限公司 | Preparation method of colistin sulfate premix |
| CN106868079A (en) * | 2017-04-26 | 2017-06-20 | 山东鲁抗医药股份有限公司 | The method of fermentation aerosporin culture medium and fermenting and producing aerosporin |
| CN106868079B (en) * | 2017-04-26 | 2020-12-08 | 山东鲁抗医药股份有限公司 | Culture medium for fermenting polymyxin B sulfate and method for producing polymyxin B sulfate through fermentation |
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Effective date of registration: 20171204 Address after: 313000 Zhejiang city of Huzhou province Deqing County Zhongguan town Hengtang Bridge No. 81 Patentee after: Zhejiang biok Biology Technology Co. Ltd. Address before: 313220 Huzhou City, Zhejiang Province, Deqing County Zhong Guan Town Industrial Zone Patentee before: Zhejiang Shenghua Biok Biology Co., Ltd. |