CN105232457B - A kind of preparation method of doractin sterile solution - Google Patents
A kind of preparation method of doractin sterile solution Download PDFInfo
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- CN105232457B CN105232457B CN201510787886.3A CN201510787886A CN105232457B CN 105232457 B CN105232457 B CN 105232457B CN 201510787886 A CN201510787886 A CN 201510787886A CN 105232457 B CN105232457 B CN 105232457B
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Abstract
The present invention relates to a kind of preparation method of doractin sterile solution, its technical process is：It will be pre-processed first using being mutated Avid kyowamycin as the doractin zymotic fluid that strain fermentation produces, the dry bacteria residue obtained after expansion drying is extracted with organic solvent A, cool down and add purified water and separate out, the doractin crude product of gained is dissolved with organic solvent B after filtering, ultrafiltration, crystallization, the solid doractin that obtains of gained is dissolved with organic solvent B after filtering again, and micro-filtration can obtain doractin sterile solution.The present invention realizes doractin in zymotic fluid and efficiently separates and purify, and more than 85%, product quality meets the requirements extraction total recovery, while reduces production cost；Be conducive to improve doractin competitiveness in the international market.
Description
Technical field
The invention belongs to antibiotic extractive technique field, more particularly to a kind of preparation side of doractin sterile solution
Method.
Background technology
Doractin is that by adding ring, ammonia carboxylic acid is sent out for precursor substance by the Avid kyowamycin new strains of genetic recombination
A kind of Avermectins antibiotic that ferment forms, belongs to third generation AVM hereinafter mushroom medicine.
In the prior art, the extraction of Duola's mycin is using Organic Alcohol extraction coupled ion switching technology or Organic Alcohol extraction
With reference to chromatographic technique extraction purification doractin zymotic fluid, its finished product is obtained, its existing main problem is：
1 extract yield is low.Average extract yield is only 70% or so.
2 do not pre-process doractin zymotic fluid, and moisture has exceeded 60% in wet bacteria slag, directly using organic
Solvent is extracted, and causes liquor capacity to increase, and adds the intractability of lower procedure.
3 production technologies are complex, production cycle length.
4 production costs are higher, contrast similar product, and the market competitiveness is weaker.
The content of the invention
It is an object of the invention to overcome it is above-mentioned in the prior art the defects of, there is provided one kind effectively improves extract yield, work
Skill is simple, with short production cycle, and reduces the preparation method of the doractin sterile solution of subsequent technique intractability.
The technical solution taken to achieve the above object is：
A kind of preparation method of doractin sterile solution, it is characterised in that its technical process is：First will be mutated Ah
Dimension streptomycete is pre-processed for the doractin zymotic fluid of strain fermentation production, and the dry bacteria residue obtained after expansion drying is with having
Solvent A is extracted, and is cooled down and is added purified water precipitation, the doractin crude product of gained is dissolved with organic solvent B after filtering, is surpassed
Filter, crystallization, the solid doractin that obtains of gained is dissolved with organic solvent B after filtering again, and micro-filtration can obtain doractin
Sterile solution；
The preprocessing process is：First, by doractin zymotic fluid acid solution tune pH2~3, stirring 10~
Filtered after 20min, gained wet bacteria slag is diluted with water, and continues 10~20min of stirring, filters again, and gained wet bacteria slag is diluted with water
Afterwards with alkaline solution tune pH9-10,20-40min is again stirring for, stands 80-100min, plate-frame filtering；
The organic solvent A is methanol or ethanol or butanol or isobutanol or acetone；
The organic solvent B is medicinal glycerin or PEG400.
The acid solution is the hydrochloric acid or sulfuric acid solution that mass concentration is 20-30%, and alkaline solution is that mass concentration is
The ammonium hydroxide or sodium hydroxide solution of 30-40%.
The expansion drying uses flash dryer to bacteria residue moisture less than 5%, and control inlet air temperature 100~
120 DEG C, 70~90 DEG C of leaving air temp, charging rotating speed is 50~400r/min.
The dry bacteria residue is extracted twice with organic solvent A, and extraction for the first time is organic molten according to the dry bacteria residue addition 4-5L of every 1kg
Agent A, second according to the dry bacteria residue addition 2-2.5L organic solvent As of every 1kg, each extraction time 100-150min.
It is described to cool down and add purified water precipitation process and be：Organic solvent leaching liquor is cooled to 0-5 DEG C, adds its volume
4.5-5 times of purified water, stand 150-190min, filtering, obtain doractin crude product.
The doractin crude product or solid doractin are dissolved in organic solvent B, control its mass concentration 20-30%.
In the ultra-filtration process, pressure is controlled in 0.2-0.3MPa, and the material of ultrafiltration membrane is vinylidene, and aperture is
100nm。
The crystallization process is：Under stirring, the doractin ultrafiltrate obtained by ultrafiltration is cooled to -10-0 DEG C,
Cooling rate is controlled in 2-3 DEG C/h, when there is crystalline polamer, adds crystal seed doractin, dosage is doractin ultrafiltration liquid
Long-pending 0.1-0.3%, continues to stir 60-100min, then growing the grain 180-200min, and filtering can obtain solid doractin.
The micro-filtration uses membrane filter system, which is separately installed with the filter core that specification is 0.45um and 0.22um, mistake
During filter, pressure control terminates in 0.2-0.3MPa, filtering, collects filtrate, obtains sterile doractin solution.
The preprocessing process is：First time dilutes the 20-30% that purifying water consumption used is fermentating liquid volume, for the second time
Dilution purifying water consumption used is the 40-50% of fermentating liquid volume.
The technical advantage of the present invention is embodied in：
1 extract yield is higher, has reached more than 85%.
2 present invention replace ion exchange and chromatographic technique using filtering technique, reduce the difficulty of production technology, shorten
Production cycle.
3 present invention first pre-process zymotic fluid, so as to reduce the intractability of subsequent technique（Reason：It is more
Draw rhzomorph zymotic fluid after pretreatment, can remove most of insoluble granule, insoluble granule account for the 80% of total impurities with
On）.
The preparation of 4 doractin clinical practices is mainly injection.According to external veterinary drug Doramectin injection fluid quality mark
Standard, the present invention provides a kind of method for preparing doractin sterile solution, by the doractin solution that this method obtains into
Row compatibility, its solution quality meet quality standard.
Specific implementation method
The present invention is explained with example, it should be understood that example is to be used to illustrate rather than to this below
The limitation of invention.The scope of the present invention is determined with core content according to claims.
Zymotic fluid source in following embodiments：
Using second order fermentation mode of manufacture doractin, it produces strain as mutation Avid kyowamycin, doractin fermentation
Culture medium seed formula is cornstarch, and soybean cake powder, glucose, cottonseed meal, fermentative medium formula is cornstarch, yellow
Beancake powder, dusty yeast, sodium chloride, dipotassium hydrogen phosphate, magnesium sulfate, calcium carbonate, amylase, precursor cyclohexanecarboxylic acid.Doractin is sent out
Ferment temperature is 28 DEG C, and fermentation period is 11 days, and fermentation unit is generally in 1200mg/L.
The material of ultrafiltration membrane is vinylidene, aperture 100nm.
The filter core used in micro-filtration provides membrane filter system by Co., Ltd in Mi Libo, which is separately installed with rule
Lattice are the filter core of 0.45um and 0.22um, and in filter process, pressure is controlled in 0.2-0.3MPa.
The crystal seed is sterile bulk drug doractin.
Embodiment 1
Doractin zymotic fluid 10m3, potency 1324mg/L.
Fermentation liquor pretreatment：First, zymotic fluid pH is adjusted to 2 with 20% hydrochloric acid solution, stirs 10min, obtained after filtering wet
Bacteria residue.Then, purified water 2m is added in the wet bacteria slag3, 10min is stirred, is filtered again.Finally, obtained by filtering again
Purified water 4m is added in wet bacteria slag3, pH to 9 is adjusted with 30% ammonia spirit, 20min is stirred, then stands 80min.Stand knot
Zymotic fluid is subjected to plate-frame filtering after beam, obtains doractin wet bacteria slag.
Expansion drying：Using flash dryer, 100~120 DEG C of inlet air temperature, 70~90 DEG C of leaving air temp, charging are controlled
Rotating speed is 50~400r/min.Expansion drying terminates, and obtains the dry bacteria residue 756kg of doractin, and wherein moisture is 4.1%.
Organic solvent A extracts：Extract for the first time, add methanol 3050L；Second of extraction, adds methanol 1550L, merges
Leaching liquor twice.
Cool down and add purified water and separate out：Leaching liquor cooling temperature is down to 0 DEG C, adds purified water 20700L, stands 150-
180min.Filtered after standing, obtain doractin crude product 12.5kg.
Dissolving：Doractin crude product is dissolved in medicinal glycerin, concentration is controlled 20%.
Ultrafiltration：In ultra-filtration process, pressure is controlled in 0.2-0.3MPa.Ultrafiltration terminates, and collects filtrate 62L.
Crystallization：Under stirring, doractin ultrafiltrate is cooled to -10 DEG C, cooling rate is controlled in 2-3 DEG C/h.
When there is crystalline polamer, crystal seed 62g is added.Continue to stir 60min, then growing the grain 180min.Filtered after growing the grain, consolidate
Body doractin 11.4kg.
Dissolving：Solid doractin is dissolved in medicinal glycerin, concentration is controlled 20%.
Micro-filtration：Doractin solution is crossed into micro-filtration using membrane filter system, it is 0.45um which, which is separately installed with specification,
With the filter core of 0.22um.In filter process, pressure is controlled in 0.2-0.3MPa.Filtering terminates, and collects filtrate, it is sterile to obtain 20%
Doractin solution.
Extract total recovery：85.6%.
Embodiment 2
Doractin fermentation 10m3, potency 1296mg/L.
Fermentation liquor pretreatment：First, zymotic fluid pH is adjusted to 2.3 with 23% sulfuric acid solution, stirs 13min, obtained after filtering
Wet bacteria slag.Secondly, purified water 2.3m is added in the wet bacteria slag3, 13min is stirred, is filtered again；Finally, institute is being filtered again
Obtain and purified water 4.2m is added in wet bacteria slag3, doractin zymotic fluid pH to 9.3, stirring are adjusted with 33% sodium hydroxide solution
25min, then stands 85min.Zymotic fluid is subjected to plate-frame filtering after standing, obtains doractin wet bacteria slag.
Expansion drying：Using flash dryer, 100~120 DEG C of inlet air temperature, 70~90 DEG C of leaving air temp, charging are controlled
Rotating speed is 50~400r/min.Expansion drying terminates, and obtains the dry bacteria residue 731kg of doractin, and wherein moisture is 4.0%.
Organic solvent extracts：Extract for the first time, add methanol 3080L；Second of extraction, adds methanol 1535L, merges two
Secondary leaching liquor.
Cool down and add purified water and separate out：Organic solvent leaching liquor temperature is down to 1 DEG C, adds purified water 21300L, it is quiet
Put 160min.Filtered after standing, obtain doractin crude product 12.2kg.
Dissolving：Doractin crude product is dissolved in PEG400, concentration is controlled 22%.
Ultrafiltration：In ultra-filtration process, pressure is controlled in 0.2-0.3MPa.Ultrafiltration terminates, and collects filtrate 55.3L.
Crystallization：Under stirring, doractin ultrafiltrate is cooled to -8 DEG C, cooling rate is controlled in 2-3 DEG C/h.Go out
During existing crystalline polamer, crystal seed 83g is added.Continue to stir 70min, then growing the grain 185min.Filtered after growing the grain, obtain solid
Doractin 11.29kg.
Dissolving：Solid doractin is dissolved in PEG400, concentration is controlled 23%.
Micro-filtration：By doractin solution membrane filter system micro-filtration, the equipment be separately installed with specification for 0.45um and
The filter core of 0.22um.In filter process, pressure is controlled in 0.2-0.3MPa.Filtering terminates, and collects filtrate, it is sterile more to obtain 23%
Draw rhzomorph solution.
Extract total recovery：86.5%.
Embodiment 3
Doractin fermentation 10m3, potency 1247mg/L.
Fermentation liquor pretreatment：First, zymotic fluid pH is adjusted to 2.5 with 25% hydrochloric acid solution, stirs 15min, obtained after filtering
Wet bacteria slag.Secondly, purified water 2.5m is added in the wet bacteria slag3, 15min is stirred, is filtered again；Finally, institute is being filtered again
Obtain and purified water 4.5m is added in wet bacteria slag3, doractin zymotic fluid pH to 9.5 is adjusted with 35% ammonia spirit, stirs 30min,
Then 90min is stood.Zymotic fluid is subjected to plate-frame filtering after standing, obtains doractin wet bacteria slag.
Expansion drying：Using flash dryer, 100~120 DEG C of inlet air temperature, 70~90 DEG C of leaving air temp, charging are controlled
Rotating speed is 50~400r/min.Expansion drying terminates, and obtains the dry bacteria residue 747kg of doractin, and wherein moisture is 3.9%.
Organic solvent extracts：Extract for the first time, add methanol 3365L；Second of extraction, adds methanol 1718L, merges two
Secondary leaching liquor.
Cool down and add purified water and separate out：Organic solvent leaching liquor is down to 3 DEG C, adds purified water 23890L, it is quiet
Put 170min.Filtered after standing, obtain doractin crude product 12kg.
Dissolving：Doractin crude product is dissolved in medicinal glycerin, concentration is controlled 25%.
Ultrafiltration：In ultra-filtration process, pressure is controlled in 0.2-0.3MPa.Ultrafiltration terminates, and collects filtrate 48L.
Crystallization：In whipping process, doractin ultrafiltrate is cooled to -5 DEG C, cooling rate is controlled in 2-3 DEG C/h.Occur
During crystalline polamer, crystal seed 96g is added.Continue to stir 80min, then growing the grain 190min.Filtered after growing the grain, it is more to obtain solid
Draw rhzomorph 10.86kg.
Dissolving：Doractin solid is dissolved in medicinal glycerin, and concentration is controlled 25%.
Micro-filtration：By doractin solution membrane filter system, it is 0.45um's and 0.22um which, which is separately installed with specification,
Filter core.In filter process, pressure is controlled in 0.2-0.3MPa.Filtering terminates, and collects filtrate, it is molten to obtain 25% sterile doractin
Liquid.
Extract total recovery：87.1%.
Embodiment 4
Doractin fermentation 10m3, potency 1301mg/L.
Fermentation liquor pretreatment：First, zymotic fluid pH is adjusted to 2.7 with 28% hydrochloric acid solution, stirs 18min, obtained after filtering
Wet bacteria slag.Secondly, purified water 2.7m is added in the wet bacteria slag3, 18min is stirred, is filtered again；Finally, institute is being filtered again
Obtain and purified water 4.7m is added in wet bacteria slag3, doractin zymotic fluid pH to 9.7, stirring are adjusted with 38% sodium hydroxide solution
35min, then stands 95min.Zymotic fluid is subjected to plate-frame filtering after standing, obtains doractin wet bacteria slag.
Expansion drying：Using flash dryer, 100~120 DEG C of inlet air temperature, 70~90 DEG C of leaving air temp, charging are controlled
Rotating speed is 50~400r/min.Expansion drying terminates, and obtains the dry bacteria residue 750kg of doractin, and wherein moisture is 3.9%.
Organic solvent extracts：Extract for the first time, add methanol 3525L；Second of extraction, adds methanol 1800L, merges two
Secondary leaching liquor.
Cool down and add purified water and separate out：Organic solvent leaching liquor temperature is down to 4 DEG C, adds purified water 23890L, it is quiet
Put 170min.Filtered after standing, obtain doractin crude product 12.21kg.
Dissolving：Doractin crude product is dissolved in PEG400, and concentration is controlled 28%.
Ultrafiltration：In ultra-filtration process, pressure is controlled in 0.2-0.3MPa.Ultrafiltration terminates, and collects filtrate 43.6L.
Crystallization：Under stirring, doractin ultrafiltrate is cooled to -3 DEG C, cooling rate is controlled in 2-3 DEG C/h.Go out
During existing crystalline polamer, crystal seed 110g is added.Continue to stir 90min, then growing the grain 195min.Filtered after growing the grain, consolidate
Body doractin 11.28kg.
Dissolving：Doractin solid is dissolved in PEG400, and concentration is controlled 28%.
Micro-filtration：By doractin solution membrane filter system, it is 0.45um's and 0.22um which, which is separately installed with specification,
Filter core.In filter process, pressure is controlled in 0.2-0.3MPa.Filtering terminates, and collects filtrate, it is molten to obtain 28% sterile doractin
Liquid.
Extract total recovery：86.7%.
Embodiment 5
Doractin fermentation 10m3, potency 1290mg/L.
Fermentation liquor pretreatment：First, zymotic fluid pH is adjusted to 3 with 30% sulfuric acid solution, stirs 20min, obtained after filtering wet
Bacteria residue.Secondly, purified water 3m is added in wet bacteria slag3, 18min is stirred, is filtered again；Finally, purified water 5m is added in wet bacteria slag3,
Doractin zymotic fluid pH to 10 is adjusted with 40% ammonia spirit, 40min is stirred, then stands 100min.Will after standing
Zymotic fluid carries out plate-frame filtering, obtains doractin wet bacteria slag.
Expansion drying：Using flash dryer, 100~120 DEG C of inlet air temperature, 70~90 DEG C of leaving air temp, charging are controlled
Rotating speed is 50~400r/min.Expansion drying terminates, and obtains the dry bacteria residue 753kg of doractin, and wherein moisture is 4.0%.
Organic solvent extracts：Extract for the first time, add methanol 3765L；Second of extraction, adds methanol 1882L, merges two
Secondary leaching liquor.
Cool down and add purified water and separate out：Organic solvent leaching liquor temperature is down to 5 DEG C, adds purified water 28237L, it is quiet
Put 180min.Filtered after standing, obtain doractin crude product 12.12kg.
Dissolving：Doractin crude product is dissolved in medicinal glycerin, and concentration is controlled 30%.
Ultrafiltration：In ultra-filtration process, pressure is controlled in 0.2-0.3MPa.Ultrafiltration terminates, and collects filtrate 40.4L.
Crystallization：Under stirring, doractin ultrafiltrate is cooled to 0 DEG C, cooling rate is controlled in 2-3 DEG C/h.Go out
During existing crystalline polamer, crystal seed 120g is added.Continue to stir 100min, then growing the grain 200min.Filtered after growing the grain, consolidate
Body doractin 11.13kg.
Dissolving：Doractin solid is dissolved in medicinal glycerin, and concentration is controlled 30%.
Micro-filtration：By doractin solution membrane filter system, it is 0.45um's and 0.22um which, which is separately installed with specification,
Filter core.In filter process, pressure is controlled in 0.2-0.3MPa.Filtering terminates, and collects filtrate, it is molten to obtain 30% sterile doractin
Liquid.
Extract total recovery：86.2%.
Claims (9)
1. a kind of preparation method of doractin sterile solution, it is characterised in that its technical process is：First will be to be mutated AVM hereinafter
Streptomycete is pre-processed for the doractin zymotic fluid of strain fermentation production, then expansion drying, and obtained dry bacteria residue is used
Organic solvent A extracts, and cools down and adds purified water precipitation, the doractin crude product of gained is dissolved with organic solvent B after filtering, is surpassed
Filter, crystallization, the solid doractin of gained continues to be dissolved with organic solvent B after filtering again, and micro-filtration can obtain doractin
Sterile solution；
The preprocessing process is：First, by doractin zymotic fluid acid solution tune pH2~3, after stirring 10~20min
Filtering, gained wet bacteria slag are diluted with water, continue 10~20min of stirring, filter again, and gained wet bacteria slag uses alkalescence after being diluted with water
Solution tune pH9-10, is again stirring for 20-40min, stands 80-100min, plate-frame filtering；
The organic solvent A is methanol or ethanol or butanol or isobutanol or acetone；
The organic solvent B is medicinal glycerin or PEG400；
The crystallization process is：Under stirring, the doractin ultrafiltrate obtained by ultrafiltration is cooled to -10-0 DEG C, cooling
Speed control is in 2-3 DEG C/h, when there is crystalline polamer, adds crystal seed doractin, dosage is doractin ultrafiltrate volume
0.1-0.3%, continues to stir 60-100min, then growing the grain 180-200min, and filtering can obtain solid doractin.
2. the preparation method of doractin sterile solution described in accordance with the claim 1, it is characterised in that the acid solution is
Mass concentration is the hydrochloric acid or sulfuric acid solution of 20-30%, and alkaline solution is that the ammonium hydroxide that mass concentration is 30-40% or sodium hydroxide are molten
Liquid.
3. the preparation method of doractin sterile solution described in accordance with the claim 1, it is characterised in that the expansion drying makes
With flash dryer to bacteria residue moisture less than 5%, 100~120 DEG C of inlet air temperature of control, 70~90 DEG C of leaving air temp,
Charging rotating speed is 50~400r/min.
4. the preparation method of doractin sterile solution described in accordance with the claim 1, it is characterised in that the dry bacteria residue is with having
Solvent A is extracted twice, and extraction for the first time adds 4-5L organic solvent As according to the dry bacteria residues of every 1kg, is done for the second time according to every 1kg
Bacteria residue adds 2-2.5L organic solvent As, each extraction time 100-150min.
5. the preparation method of doractin sterile solution described in accordance with the claim 1, it is characterised in that the cooling simultaneously adds
Purified water precipitation process is：Organic solvent leaching liquor is cooled to 0-5 DEG C, adds 4.5-5 times of purified water of its volume, is stood
150-190min, filtering, obtains doractin crude product.
6. the preparation method of doractin sterile solution described in accordance with the claim 1, it is characterised in that the doractin is thick
Product or solid doractin are dissolved in organic solvent B, control its mass concentration 20-30%.
7. the preparation method of doractin sterile solution described in accordance with the claim 1, it is characterised in that in the ultra-filtration process,
Pressure control is in 0.2-0.3MPa, and the material of ultrafiltration membrane is vinylidene, aperture 100nm.
8. the preparation method of doractin sterile solution described in accordance with the claim 1, it is characterised in that the micro-filtration uses film
Filter plant, which is separately installed with the filter core that specification is 0.45um and 0.22um, and in filter process, pressure is controlled in 0.2-
0.3MPa, filtering terminate, and collect filtrate, obtain sterile doractin solution.
9. the preparation method of doractin sterile solution described in accordance with the claim 1, it is characterised in that the preprocessing process
For：20-30% of the purifying water consumption used for fermentating liquid volume is diluted for the first time, and it is hair that second, which dilutes purifying water consumption used,
The 40-50% of zymotic fluid volume.
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