CN101532040B - Method for producing hyaluronic acid by continuous addition of glucose and fermentation according to acid output - Google Patents
Method for producing hyaluronic acid by continuous addition of glucose and fermentation according to acid output Download PDFInfo
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- CN101532040B CN101532040B CN2008100849963A CN200810084996A CN101532040B CN 101532040 B CN101532040 B CN 101532040B CN 2008100849963 A CN2008100849963 A CN 2008100849963A CN 200810084996 A CN200810084996 A CN 200810084996A CN 101532040 B CN101532040 B CN 101532040B
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 title claims abstract description 32
- 238000000855 fermentation Methods 0.000 title claims abstract description 32
- 230000004151 fermentation Effects 0.000 title claims abstract description 32
- 239000008103 glucose Substances 0.000 title claims abstract description 27
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 24
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 24
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 24
- 239000002253 acid Substances 0.000 title claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 title abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 29
- 239000003513 alkali Substances 0.000 claims abstract description 22
- 239000007788 liquid Substances 0.000 claims abstract description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 60
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 23
- 239000002609 medium Substances 0.000 claims description 16
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 13
- 229930006000 Sucrose Natural products 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- 239000005720 sucrose Substances 0.000 claims description 13
- 238000012262 fermentative production Methods 0.000 claims description 10
- 238000009923 sugaring Methods 0.000 claims description 10
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 6
- 238000011218 seed culture Methods 0.000 claims description 6
- 230000001954 sterilising effect Effects 0.000 claims description 6
- 238000004659 sterilization and disinfection Methods 0.000 claims description 6
- 239000001963 growth medium Substances 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 3
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 2
- 239000000758 substrate Substances 0.000 abstract description 15
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 abstract 1
- 238000007796 conventional method Methods 0.000 abstract 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 22
- 239000000243 solution Substances 0.000 description 17
- 239000011259 mixed solution Substances 0.000 description 7
- 239000011734 sodium Substances 0.000 description 6
- 239000001888 Peptone Substances 0.000 description 4
- 108010080698 Peptones Proteins 0.000 description 4
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 4
- 235000019319 peptone Nutrition 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000001360 synchronised effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- -1 hydrogen potassium oxide Chemical class 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 229910001950 potassium oxide Inorganic materials 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- NVNLLIYOARQCIX-MSHCCFNRSA-N Nisin Chemical compound N1C(=O)[C@@H](CC(C)C)NC(=O)C(=C)NC(=O)[C@@H]([C@H](C)CC)NC(=O)[C@@H](NC(=O)C(=C/C)/NC(=O)[C@H](N)[C@H](C)CC)CSC[C@@H]1C(=O)N[C@@H]1C(=O)N2CCC[C@@H]2C(=O)NCC(=O)N[C@@H](C(=O)N[C@H](CCCCN)C(=O)N[C@@H]2C(NCC(=O)N[C@H](C)C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCSC)C(=O)NCC(=O)N[C@H](CS[C@@H]2C)C(=O)N[C@H](CC(N)=O)C(=O)N[C@H](CCSC)C(=O)N[C@H](CCCCN)C(=O)N[C@@H]2C(N[C@H](C)C(=O)N[C@@H]3C(=O)N[C@@H](C(N[C@H](CC=4NC=NC=4)C(=O)N[C@H](CS[C@@H]3C)C(=O)N[C@H](CO)C(=O)N[C@H]([C@H](C)CC)C(=O)N[C@H](CC=3NC=NC=3)C(=O)N[C@H](C(C)C)C(=O)NC(=C)C(=O)N[C@H](CCCCN)C(O)=O)=O)CS[C@@H]2C)=O)=O)CS[C@@H]1C NVNLLIYOARQCIX-MSHCCFNRSA-N 0.000 description 1
- 108010053775 Nisin Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241001052560 Thallis Species 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000000600 disaccharide group Chemical group 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 239000004309 nisin Substances 0.000 description 1
- 235000010297 nisin Nutrition 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
Abstract
The invention relates to a method for producing hyaluronic acid, in particular to a method for producing hyaluronic acid by continuous addition of glucose and fermentation according to acid output. The method is characterized in that a conventional method is used to prepare and ferment slant strains and seed liquid; during the fermentation process, according to the proportional relationship of the sugar consumption and the output of the acid, the proportional sugar and alkali are added so as to maintain suitable pH and suitable sugar consistency of the fermentation solution, thus leading the solution neither to generate substrate inhibition nor to form restriction. The method of continuous addition of glucose improves the conversion rate of the sugar and obviously improves the productive rate of the hyaluronic acid.
Description
Technical field
The invention belongs to the fermentation engineering field, relate to the hyaluronic method of a kind of production, relate in particular to a kind of according to producing the hyaluronic method of acid amount stream sugaring fermentative production.
Background technology
Hyaluronic acid (HA), extensively is present in vertebrate soft tissue such as skin, knuckle synovia, the vitreum for the polymer straight chain mucopolysaccharide that disaccharide unit forms by glucuronic acid and N-n acetylglucosamine n.Because hyaluronic acid has characteristics such as viscosity height, moisture retention are good, has been widely used in fields such as medicine, makeup.Present hyaluronic production mainly contains extraction method and fermentation method.Because the fermentative Production hyaluronic acid is not subjected to advantages such as raw material restriction, the easy purifying of product, has become and produced hyaluronic main flow.
Hyaluronic acid fermentation is the fermentation of substrate inhibition type, and therefore high initial substrate concentration can produce the substrate inhibition, influences thalli growth.For addressing this problem, there is the scholar to adopt stream during the fermentation to add the method for feed liquid, promptly when beginning, only add an amount of substrate, continue to add substrate then in some way again, to keep concentration of substrate in suitable scope, make it neither to produce substrate and suppress, also be unlikely and cause substrate to lack.
Up to now, the hyaluronic document of research stream sugaring fermentative production mainly contains following several pieces.Be reported in the preceding sugar of inoculation among the patent JP09-056394 and add in the substratum, add 20%～40% sugar after 1 hour again,, remaining sugar is all mended, can obtain hyaluronic high yield like this after 5～6 hours with 20%～40%.Patent JP62-215397 has introduced the hyaluronic method of a kind of high yield, in the culturing process that produces bacterium, sugar is repeatedly added in the nutrient solution, makes sugared concentration remain on 0.1～3% (w/v).Introduce the inoculation back among the patent KR8903708 and cultivated 5 hours, slowly mend 70% glucose then, make sugared concentration keep 0.5%, continue to cultivate 24 hours, hyaluronic productive rate is 3.4 grams per liters.The stream sugaring mode of mentioning in the above document, some is simple to operate, and the concentration of substrate fluctuation is big, though some concentration of substrate fluctuation is little, but needs complicated calculations.
In addition, patent CN200410046394.0 discloses the potential of hydrogen (pH) that a kind of mixed flow liquid feeding by adding substrate sugar and alkali is controlled fermented liquid, the method for producing nisin.At present, about still not having report according to producing the hyaluronic method of acid amount stream sugaring fermentative production.
The invention provides a kind of according to producing the hyaluronic method of acid amount stream sugaring fermentative production.In the hyaluronic acid fermentation process, microorganism utilizes sugar to produce a large amount of organic acids, as acetate, lactic acid and hyaluronic acid etc., needs to add alkali and keeps fermented liquid pH in neutrality.The sugar consumption amount is proportional with product acid amount, and produce the acid amount and add alkali number and be directly proportional, therefore synchronous flow adds proportional liquid glucose when adding alkali lye, can make the suitable scope that is controlled at that substrate sugar concentration can be more stable, thereby hyaluronic fermentation production rate is improved significantly.
Summary of the invention
The purpose of this invention is to provide a kind of simple stream sugaring hydraulic control system method, control pH of fermented liquid and sugared concentration stabilize in a suitable scope, thereby hyaluronic acid productivity is obviously improved.
Provided by the invention according to producing the hyaluronic method of acid amount stream sugaring fermentative production, comprise and use ordinary method to prepare slant strains and seed liquor, ferment then, during the fermentation, utilize the sugar consumption amount and acid generation between proportionlity, (sugar and alkali must separately add to add proportional sugar and alkali, can not mix adding), keeping suitable pH, and the sugared concentration in the maintenance system is in a suitable scope, make it neither to produce substrate and suppress, also be not construed as limiting.
The concrete steps of this method are as follows:
1. slant strains preparation: the preparation slant medium, after the sterilization, will produce hyaluronic acid strain and be seeded on the slant medium and cultivate, obtain slant strains;
2. seed liquor preparation: the preparation seed culture medium, after the sterilization, the slant strains that 1. step is made changes in the seed culture medium cultivates, and obtains seed liquor;
3. fermentation culture: preparation fermention medium, after the sterilization, the seed liquor that 2. step is made inserts in the fermention medium carries out the fermentative production hyaluronic acid, during the fermentation, additional proportion is the alkali and the sugar of 0.3～5 moles base per mole sugar respectively synchronously, to keep fermented liquid pH 6.5～7.5.
Wherein, contain glucose or sucrose in the fermention medium, its concentration (this concentration is initial concentration) is 0.01～80 grams per liter.
Described alkali and sugar dissolving back separately add simultaneously with the form of alkali lye and liquid glucose, and wherein the concentration of liquid glucose is 1～900 grams per liter.
Described sugar is glucose or sucrose.Described alkali is sodium hydroxide or potassium hydroxide.
The present invention finds that if add with the alkali of aforementioned proportion and the mixed solution of sugar, hyaluronic productive rate there is no obvious raising, has only both separately to add and just can improve hyaluronic productive rate.The present invention adds respectively in the fermented liquid after alkali and sugar are dissolved, and makes the alkali and the sugar maintenance specified proportion (0.3～5 moles base per mole sugar) that add in the unit time.This method adds sugar when stream in fermentation system adds alkali control pH, and makes the sugar of adding just in time replenish the sugar that consumes, thus indirect control the sugared concentration in the fermented liquid, make the sugared concentration in the fermented liquid maintain certain limit.Therefore, provided by the inventionly produce hyaluronic method, can control concentration of substrate more accurately according to producing the sugaring of acid amount stream, simple to operate, and can obviously improve hyaluronic productive rate.
Embodiment
Following examples are in order to further specify the present invention, but never are limitations of the present invention.
Embodiment 1
1) inclined-plane preparation: will produce hyaluronic acid strain and be seeded on the slant medium, the slant culture based formulas: peptone 10g, yeast powder 10g, Na
2HPO
412H
2O 2g, MgSO
47H
2O 0.5g, glucose 10g is dissolved in water and is settled to 1L.During the preparation solid medium, need add 2% agar.In incubator, cultivate, cultivated 24 hours for 32～39 ℃.
2) seed liquor preparation: cultured bacterial classification is changed in the seed culture medium, the same slant medium of seed culture based formulas, 32～39 ℃, 200rpm cultivated 24 hours.
3) fermentation culture: seed liquor inserted in the fermentor tank ferment fermentative medium formula: peptone 10g, yeast powder 10g, Na
2HPO
412H
2O 2g, MgSO
47H
2O 0.5g, glucose 5g is dissolved in water and is settled to 1L.Culture condition: air flow 20vvm, 32～39 ℃, 250rpm, pH are controlled between 6～8, and best 6.5～7.5.Synchronously add glucose solution respectively and alkali lye carries out the control of pH.Glucose solution concentration is 700 grams per liters, and concentration of sodium hydroxide solution is 260 grams per liters, and the sodium hydroxide that adds is 1.7 molar sodium hydroxides/mole glucose with the ratio of sugar synchronously.When pH is lower than 7.0, beginning auto-feeding sodium hydroxide solution to 7.0, synchronous flow adds glucose solution during stream hydro-oxidation sodium solution.Remaining sugar concentration maintains 4～6 grams per liters in the fermenting process, and hyaluronic acid productivity is 8.5 grams per liters during fermentation ends.
Embodiment 2
Other fermentation conditions are with embodiment 1.Fermentative medium formula: peptone 10g, yeast powder 10g, Na
2HPO
412H
2O2g, MgSO
47H
2O 0.5g, sucrose 10g is dissolved in water and is settled to 1L.Synchronously add sucrose solution respectively and alkali lye carries out the control of pH.Sucrose solution concentration is 800 grams per liters, and concentration of sodium hydroxide solution is 300 grams per liters, and the sodium hydroxide that adds is 3.2 molar sodium hydroxides/mole sucrose with the ratio of sugar synchronously.When pH is lower than 7.2, beginning auto-feeding sodium hydroxide solution to 7.2, synchronous flow adds sucrose solution during stream hydro-oxidation sodium solution.Remaining sugar concentration maintains 8～12 grams per liters in the fermenting process, and hyaluronic acid productivity is 8.0 grams per liters during fermentation ends.
Embodiment 3
Other fermentation conditions are with embodiment 1.Fermentative medium formula: peptone 10g, yeast powder 10g, Na
2HPO
412H
2O2g, MgSO
47H
2O 0.5g, glucose 10g is dissolved in water and is settled to 1L.Synchronously add glucose solution respectively and alkali lye carries out the control of pH.Glucose solution concentration is 700 grams per liters, and potassium hydroxide solution concentration is 270 grams per liters, and the potassium hydroxide that adds is 1.2 moles of hydrogen potassium oxide/mole glucose with the ratio of sugar synchronously.When pH is lower than 7.0, beginning auto-feeding potassium hydroxide solution to 7.0, synchronous flow adds glucose solution during stream hydro-oxidation potassium solution.Remaining sugar concentration maintains 8～12 grams per liters in the fermenting process, and hyaluronic acid productivity is 8.7 grams per liters during fermentation ends.
Embodiment 4
Other fermentation conditions are with embodiment 1.The mixed solution that stream adds glucose and sodium hydroxide in the fermenting process carries out the control of pH.Glucose concn is 700 grams per liters in the stream liquid feeding, and naoh concentration is 260 grams per liters, and sodium hydroxide is 1.7 molar sodium hydroxides/mole glucose with the ratio of sugar.When pH is lower than 7.0, the mixed solution to 7.0 of beginning auto-feeding glucose and sodium hydroxide.Remaining sugar concentration maintains 4～6 grams per liters in the fermenting process, and hyaluronic acid productivity is 5.8 grams per liters during fermentation ends.
Embodiment 5
Other fermentation conditions are with embodiment 2.Stream carries out the control of pH in the fermenting process with the mixed solution of sucrose and sodium hydroxide.Sucrose concentration is 400 grams per liters in the stream liquid feeding, and naoh concentration is 150 grams per liters, and sodium hydroxide is 3.2 molar sodium hydroxides/mole sucrose with the ratio of sugar.When pH is lower than 7.2, the mixed solution to 7.2 of beginning auto-feeding sucrose and sodium hydroxide.Remaining sugar concentration maintains 8～12 grams per liters in the fermenting process, and hyaluronic acid productivity is 6.2 grams per liters during fermentation ends.
Embodiment 6
Other fermentation conditions are with embodiment 3.The mixed solution that stream adds glucose and potassium hydroxide in the fermenting process carries out the control of pH.Glucose concn is 350 grams per liters in the stream liquid feeding, and concentration of potassium hydroxide is 135 grams per liters, and potassium hydroxide is 1.2 moles of hydrogen potassium oxide/mole glucose with the ratio of sugar.When pH is lower than 7.0, the mixed solution to 7.0 of beginning auto-feeding glucose and potassium hydroxide.Remaining sugar concentration maintains 8～12 grams per liters in the fermenting process, and hyaluronic acid productivity is 5.7 grams per liters during fermentation ends.
Embodiment 7
In the disposable adding substratum, other fermentation conditions are with embodiment 1 before the fermentation beginning for sugar in the substratum.Sugared concentration reduces gradually in the fermenting process, and hyaluronic acid productivity is 6.5 grams per liters during fermentation ends.
This shows, production method of the present invention, hyaluronic productive rate significantly improves.
Claims (1)
1. one kind according to producing the hyaluronic method of acid amount stream sugaring fermentative production, and it is characterized in that: this method may further comprise the steps:
1. slant strains preparation: the preparation slant medium, after the sterilization, will produce hyaluronic acid strain and be seeded on the slant medium and cultivate, obtain slant strains;
2. seed liquor preparation: the preparation seed culture medium, after the sterilization, the slant strains that 1. step is made changes in the seed culture medium cultivates, and obtains seed liquor;
3. fermentation culture: preparation fermention medium, after the sterilization, the seed liquor that 2. step is made inserts in the fermention medium carries out the fermentative production hyaluronic acid, during the fermentation, additional proportion is the alkali and the sugar of 0.3～5 moles base per mole sugar respectively synchronously, to keep fermented liquid pH 6.5～7.5;
Contain glucose or sucrose in the described fermention medium, its concentration is 0.01～80 grams per liter;
Described alkali and sugar dissolving back add respectively synchronously with the form of alkali lye and liquid glucose, and wherein the concentration of liquid glucose is 1～900 grams per liter;
Described sugar is glucose or sucrose;
Described alkali is sodium hydroxide or potassium hydroxide.
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| CN111778303B (en) * | 2020-06-15 | 2023-01-24 | 华熙生物科技股份有限公司 | Method for degrading hyaluronic acid or salt thereof by enzyme |
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Non-Patent Citations (2)
| Title |
|---|
| 叶华 等.透明质酸发酵流加过程的研究.《北京化工大学学报》.2006,第33卷(第1期),第20-21页. * |
| 郭学平.发酵法制备透明质酸.《日用化学工业》.1994,(第2期),第47页. * |
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