CN1563108A - Method for preparing transparent calcium hyaIuronate in low molecular weight - Google Patents
Method for preparing transparent calcium hyaIuronate in low molecular weight Download PDFInfo
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- CN1563108A CN1563108A CN 200410024013 CN200410024013A CN1563108A CN 1563108 A CN1563108 A CN 1563108A CN 200410024013 CN200410024013 CN 200410024013 CN 200410024013 A CN200410024013 A CN 200410024013A CN 1563108 A CN1563108 A CN 1563108A
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- hyaluronate
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Abstract
The invention discloses a method for preparing calcium hyaluronate with low molecular weight. Said method utilizes the acid instability and thermal instability of hyaluronic acid to make the molecular weight of the hyaluronic acid by degraded into 5000-10000, then adds the inorganic calcium salt to make the hyaluronic acid be converted into the calcium hyaluronate, then utilizes the organic solvent obtained by mixing ethyl alcohol and acetone, etc. with water to make the calcium hyaluronate be precipitated and separated out. The technological process of said preparation method is relatively simple, its period is short, and is about 10 hr. and it is suitable for industrial large scale production. Said calcium hyaluronate has high water solubility, and aqueous solution stability.
Description
1, technical field
The present invention relates to a kind of preparation technology of Calcium hyaluronate, specifically a kind of method for preparing low-molecular-weight hyaluronic acid calcium.
2, technical background
At present, the method that obtains Calcium hyaluronate mainly is fermentation method or extraction method, and the hyaluronic acid that obtains from fermentation method or extraction method is its sodium-salt form, and molecular weight is generally greater than 5 * 10
5After exchanging with calcium salt, the Calcium hyaluronate that obtains is because molecular weight is big, and the solubleness in the aqueous solution is little, and stability is bad, separates out precipitation when placing easily.Current methods has just been used a kind of in hyaluronic acid labile and thermolability two specific characters, and hyaluronic acid is degraded, and becomes calcium salt again, the process procedure of this technology is many, the complete processing complexity, and the cycle is long, about 2-4 days, be difficult to control, the tooling cost height.
3, summary of the invention
The purpose of this invention is to provide a kind of method for preparing low-molecular-weight hyaluronic acid calcium.
The objective of the invention is to realize in the following manner: with hyaluronate sodium crude product under 70-80 ℃ of temperature vacuum-drying 4-5 hour, make dried hyaluronate sodium dissolving crude product is added in the ionized water, concentration is controlled at 0.05%-3.0%; The pH value 3.0-6.0 of regulator solution is heated to 70-80 ℃ of insulation 3-5 hour, adds activated carbon decolorizing 0.5-1 hour of 0.05-2% (m/v) in the solution, helps filter with soil, obtains sodium hyaluronate solution; Solution is regulated pH value 3.0-6.0, and solution is smooth by the acid type Zeo-karb, and exchange liquid pH value is perhaps used the membrane filter appts of the molecular weight 5000-10000 that dams between 1.2-4.5, and fully concentrating and desalinating obtains hyaluronic acid filtrate; Add the doubly water-soluble Ca salt of (mol ratio) amount of 1.0-1.5 in the middle of filtrate, be heated to 50-70 ℃ and make it fully to react 1-3 hour, filtrate is regulated pH value 4.5-6.0 with calcium hydroxide, reduces pressure 50-60 ℃ to concentrate, and concentration is controlled at 1%-10%; Gac 60-70 ℃ that adds 0.05%-1% in the filtrate decoloured 0.5 hour, and filtered; In filtrate, slowly add 2-3 water-miscible organic solvent doubly while stirring, can obtain the Powdered unformed solid of Calcium hyaluronate; Solids fully dewaters with organic solvent, centrifugation, and solid vacuum-drying under 60-80 ℃ of temperature obtains the Calcium hyaluronate finished product.Being used to help the soil of filter is kaolin, diatomite or white bole; Water-soluble Ca salt is calcium chloride, Calcium Bromide or nitrocalcite; Water-miscible organic solvent is ethanol, acetone and acetonitrile.
This preparation method's complete processing is simple relatively, and the cycle is short, about 10 hours, is fit to large-scale industrialization production, has not only reduced production cost, and the Calcium hyaluronate that so makes has very big water-solublely, and aqueous stability is good.
4, embodiment
Embodiment 1:
Get hyaluronate sodium crude product 30g (the about 1.8 * 106-2.0 of viscosity-average molecular weight * 106 dalton), be dissolved in the 3000ml deionized water, regulate pH value 4.3-4.7, be heated to 60-70 ℃, fully dissolving, insulated and stirred 2-3 hour; Add the 6-10g gac, fully stirred 0.5 hour; Solution helps filter with diatomite, and filtrate is cooled to room temperature, regulates filtrate pH value 4.3-4.7, and is smooth by strongly acidic cation-exchange (001 * 7), and exchange liquid pH value is 1.8; In exchange liquid, add 7.0g calcium chloride CaCl
2(mol ratio is about 1.25), be heated to 60-70 ℃ of stirring reaction 2 hours, with calcium hydroxide Ca (OH)
2Regulate pH value 4.3-4.7; Reacting liquid filtering, the filtering solid insoluble, 60-70 ℃ of vacuum decompression is concentrated into 30ml; Concentrated solution adds 60-70 ℃ of decolouring of 0.3g gac 30 minutes, filters; Filtrate is reduced to room temperature, adds 60-90ml ethanol under the agitation condition in filtrate, separates out white Calcium hyaluronate solid; Solid filters with 60ml ethanol dehydration 2-3 time; Solid 60-70 ℃ vacuum-drying 4 hours obtains hyaluronic acid calcium product 17g; Yield 56.7%; With the gel chromatography molecular weight is 7100.
Embodiment 2:
Get hyaluronate sodium crude product 20g (the about 1.2 * 106-1.4 of viscosity-average molecular weight * 106 dalton), be dissolved in the 2000ml deionized water, regulate pH value 4.3-4.6, be heated to 60-65 ℃, fully dissolving, insulated and stirred 2-3 hour; Add the 4-6g gac, fully stirred 0.5 hour; Solution helps filter with kaolin, and filtrate is cooled to room temperature, regulates filtrate pH value 4.3-4.5, smooth film filter by the molecular weight 5000-10000 that dams, fully concentrating and desalinating; In exchange liquid, add 4.5g calcium chloride CaCl
2(mol ratio is about 1.2), be heated to 60-70 ℃ of stirring reaction 1.5 hours, with calcium hydroxide Ca (OH)
2Regulate pH value 4.5-4.7; Reaction solution filtering solid insoluble, 60-70 ℃ of vacuum decompression is concentrated into 20ml; Concentrated solution adds 60-70 ℃ of decolouring of 0.15g gac 30 minutes, filters; Filtrate is reduced to room temperature, adds 40-60ml ethanol under the agitation condition in filtrate, separates out white Calcium hyaluronate solid; Solid filters with 40ml ethanol dehydration 2-3 time; Solid 60-70 ℃ vacuum-drying 4 hours obtains hyaluronic acid calcium product 11.7g; Yield is 58.5%; With the gel chromatography molecular weight is 6400.
Claims (4)
1, a kind of method for preparing low-molecular-weight hyaluronic acid calcium, it is characterized in that the preparation method is: with hyaluronate sodium crude product under 70-80 ℃ of temperature vacuum-drying 4-5 hour, make dried hyaluronate sodium dissolving crude product is added in the ionized water, concentration is controlled at 0.05%-3.0%; The pH value 3.0-6.0 of regulator solution is heated to 70-80 ℃ of insulation 3-5 hour, adds activated carbon decolorizing 0.5-1 hour of 0.05-2% (m/v) in the solution, helps filter with soil, obtains sodium hyaluronate solution; Solution is regulated pH value 3.0-6.0, and solution is smooth by the acid type Zeo-karb, and exchange liquid pH value is perhaps used the membrane filter appts of the molecular weight 5000-10000 that dams between 1.2-4.5, and fully concentrating and desalinating obtains hyaluronic acid filtrate; Add the doubly water-soluble Ca salt of (mol ratio) amount of 1.0-1.5 in the middle of filtrate, be heated to 50-70 ℃ and make it fully to react 1-3 hour, filtrate is regulated pH value 4.5-6.0 with calcium hydroxide, reduces pressure 50-60 ℃ to concentrate, and concentration is controlled at 1%-10%; Gac 60-70 ℃ that adds 0.05%-1% in the filtrate decoloured 0.5 hour, and filtered; In filtrate, slowly add 2-3 water-miscible organic solvent doubly while stirring, can obtain the Powdered unformed solid of Calcium hyaluronate; Solids fully dewaters with organic solvent, centrifugation, and solid vacuum-drying under 60-80 ℃ of temperature obtains the Calcium hyaluronate finished product.
2, method according to claim 1, it is characterized in that being used to help the soil of filter is kaolin, diatomite or white bole.
3, method according to claim 1 is characterized in that water-soluble Ca salt is calcium chloride, Calcium Bromide or nitrocalcite.
4, method according to claim 1 is characterized in that water-miscible organic solvent is ethanol, acetone and acetonitrile.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410024013 CN1563108A (en) | 2004-04-13 | 2004-04-13 | Method for preparing transparent calcium hyaIuronate in low molecular weight |
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| CN 200410024013 CN1563108A (en) | 2004-04-13 | 2004-04-13 | Method for preparing transparent calcium hyaIuronate in low molecular weight |
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| CN1563108A true CN1563108A (en) | 2005-01-12 |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1326883C (en) * | 2005-11-04 | 2007-07-18 | 山东福瑞达生物化工有限公司 | Method for preparing calcium hyauronate |
| CN1329414C (en) * | 2005-12-02 | 2007-08-01 | 凌沛学 | Bismuth potassium hyalurate and its preparation method and uses |
| CN102489193A (en) * | 2011-11-28 | 2012-06-13 | 上海景峰制药有限公司 | Dissolving method of sodium hyaluronate for solution preparation |
| WO2013123791A1 (en) * | 2012-02-21 | 2013-08-29 | 华熙福瑞达生物医药有限公司 | Bacillus, hyaluronic acid enzyme, and uses thereof |
| CN103936882A (en) * | 2013-01-21 | 2014-07-23 | 上海昊海生物科技股份有限公司 | Method for rapid preparation of sodium hyaluronate from sodium hyaluronate fermentation broth |
| US8933054B2 (en) | 2005-03-22 | 2015-01-13 | Q.P. Corporation | Low molecular weight hyaluronic acid and/or salt thereof, method for producing same, and cosmetic preparation and food composition containing same |
| CN105524188A (en) * | 2015-12-14 | 2016-04-27 | 中国海洋大学 | Hyaluronan odd oligosaccharide monomer and preparation method thereof |
| WO2023125789A1 (en) * | 2021-12-31 | 2023-07-06 | 华熙生物科技股份有限公司 | Calcium hyaluronate, and preparation method therefor and use thereof |
-
2004
- 2004-04-13 CN CN 200410024013 patent/CN1563108A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8933054B2 (en) | 2005-03-22 | 2015-01-13 | Q.P. Corporation | Low molecular weight hyaluronic acid and/or salt thereof, method for producing same, and cosmetic preparation and food composition containing same |
| CN1326883C (en) * | 2005-11-04 | 2007-07-18 | 山东福瑞达生物化工有限公司 | Method for preparing calcium hyauronate |
| CN1329414C (en) * | 2005-12-02 | 2007-08-01 | 凌沛学 | Bismuth potassium hyalurate and its preparation method and uses |
| CN102489193A (en) * | 2011-11-28 | 2012-06-13 | 上海景峰制药有限公司 | Dissolving method of sodium hyaluronate for solution preparation |
| WO2013123791A1 (en) * | 2012-02-21 | 2013-08-29 | 华熙福瑞达生物医药有限公司 | Bacillus, hyaluronic acid enzyme, and uses thereof |
| US9493755B2 (en) | 2012-02-21 | 2016-11-15 | Bloomage Freda Biopharm Co., Ltd. | Bacillus, hyaluronidase, and uses thereof |
| CN103936882A (en) * | 2013-01-21 | 2014-07-23 | 上海昊海生物科技股份有限公司 | Method for rapid preparation of sodium hyaluronate from sodium hyaluronate fermentation broth |
| CN105524188A (en) * | 2015-12-14 | 2016-04-27 | 中国海洋大学 | Hyaluronan odd oligosaccharide monomer and preparation method thereof |
| CN105524188B (en) * | 2015-12-14 | 2018-04-03 | 中国海洋大学 | A kind of hyaluronic acid odd number oligosaccharide monomer and preparation method thereof |
| WO2023125789A1 (en) * | 2021-12-31 | 2023-07-06 | 华熙生物科技股份有限公司 | Calcium hyaluronate, and preparation method therefor and use thereof |
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Effective date of registration: 20060609 Address after: 257506 Shandong city of Dongying province Kenli County Shengtuo town government resident Shandong Dongchen Industrial Group Co. Ltd. Applicant after: Shandong Dongchen Group Company Ltd. Address before: 602, room 1, building 7, Hong Lou District, Licheng District, Shandong, Ji'nan 250100, China Applicant before: Ruan Chunxue |
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