CN1486993A - Prepn process of chondroitin sulfate with medium molecule weight - Google Patents
Prepn process of chondroitin sulfate with medium molecule weight Download PDFInfo
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- CN1486993A CN1486993A CNA031527728A CN03152772A CN1486993A CN 1486993 A CN1486993 A CN 1486993A CN A031527728 A CNA031527728 A CN A031527728A CN 03152772 A CN03152772 A CN 03152772A CN 1486993 A CN1486993 A CN 1486993A
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- chondroitin sulfate
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Abstract
Animal cartilage and/or marketable common chondroitin sulfate as material is prepared into serial chondroitin sulfate products with molecular weight of 10-30 KD through conventional alkali solution treatment, enzymolysis, hydrolysis, superfiltering membrane and nanofiltering membrane separation, purification, concentration, etc. Compared with available chondroitin sulfate products, the present invention has high purity, easy absorption, high bioavailability in body, high bioactivity, powerful pharmacological effect and other features. It may be used as material for health article, cosmetics, food, etc.
Description
[technical field]
The present invention relates to a kind of preparation method of middle molecular weight chondroitin sulfate series product.
[background technology]
Chondroitin sulfate (Chondroitin Sulfate, be called for short CS) is that a kind of waste material with fishery products such as animal cartilage tissue such as pig, ox, sheep and shark suft bones is starting material, the macromole acid mucopolysaccharides that utilizes biochemical extraction process technology extraction to obtain.Its sodium salt, sylvite, calcium salt, zinc salt etc. are widely used in making medicine, medicines and health protection product, food, makeup, feed for pet etc.As hypolipidemic, China is existing should be in the chondroitin sulfate tablet and the injection of clinical treatment hyperlipidemia.Chondroitin sulfate also has different physiological roles, plays an important role keeping function of joint and keeping on the immunity function, is used to prevent and treat neuropathic pains such as coronary heart disease, treatment migraine, improves senile function of joint degeneration etc.As food supplement, the chondroitin sulfate preparation of the U.S. (comprising tablet, capsule, solution etc.) is widely used in delaying senile function of joint and degenerates, improves the joint motion function.
The production method of chondroitin sulfate mainly contains three kinds: salt solution, alkaline hydrolysis method, enzymolysis process; Its sodium salt is comparatively common, also can produce chondroitin sulfate calcium salt, sylvite or zinc salt as required, is 99112553.3,99112554.1 " chondroitin sulfate and production method thereof " as number of patent application.
The chondroitin sulfate molecular weight difference that the different process method is produced.Generally speaking, low-molecular weight chondroitin sulfate is meant that molecular-weight average is less than 10,000 daltonian chondroitin sulfates; Middle molecular weight chondroitin sulfate then is meant molecular-weight average 10,000-30, the chondroitin sulfate of 000 dalton's scope.The molecular-weight average of common molecular weight chondroitin sulfate product is all greater than 30,000 dalton.
And different, its pharmacologically active and molecular weight have confidential relation to the biological activity of chondroitin sulfate with the molecular weight difference, and the size of molecular weight is also fairly obvious to the influence of oral back stomach and intestine specific absorption.
U.S. Pat P 3,405, and 120 have proved, and molecular weight is 5,300-3, and during 500 dalton, the pharmacologically active of chondroitin sulfate is the strongest, has better therapeutic to preventing and treating atherosclerosis, rheumatic inflammation and wound healing etc.
After the oral administration administration, the less chondroitin sulfate of molecular weight is easier to be absorbed by stomach and intestine, and this is also confirmed by the modern medicine experiment.Univ Maryland-Coll Park USA is an absorption model with the Caco-2 cell, and the molecular-weight average that Spain Bioiberica company is produced is that 16,900,8,000,4,000 daltonian material samples have carried out experimental study (Spring 2000, Vol.3, No.1 JANA).Represent the membrane permeability coefficient (Permeability Coefficient) of stomach and intestine specific absorption to be respectively 10.1 * 10
-6Cm/sec, 12.5 * 10
-6Cm/sec, 16.2 * 10
-6Cm/sec.And the membrane permeability coefficient of several commercially available common molecular weight chondroitin sulfate raw materials is respectively 0.00,1.03,3.63 * 10
-6Cm/sec.Experimental result shows, absorbs the product that all obviously is better than common molecular weight in the body of middle molecular weight, small molecular weight chondroitin sulfate product, and the more little specific absorption of molecular weight is high more.
The preparation method of external existing low-molecular weight chondroitin sulfate, comprise acid-hydrolysis method (U.S. Pat P3,405,120 Patented Oct.8,1968), ion-exchange-resin process (Japan special permission 70-04734,74-30817) and enzymolysis process (Japan speciallys permit 73-14078) etc.China's number of patent application is the patent of invention of 03114375.X, also discloses the preparation method of low-molecular weight chondroitin sulfate first.
The be on sale to America raw material of chondroitin sulfate in market of the commercially available and main exit of China, molecular-weight average is mostly greater than 45,000 dalton.Recently, we have detected 14 parts of the common molecular weight chondroitin sulfate products that domestic different company produces with GPC method (two appendix VH of Chinese Pharmacopoeia version in 2000), comprise ox, pig, shark chondroitine, molecular-weight average is 47,500-85, between 700 dalton (table 1), we are easy to draw such conclusion, China produces the also aching and limp ossein product of common sulfur molecule amount of the main exit U.S. at present, big, the shortcomings such as oral absorption is poor, bioavailability is low, curative effect instability of ubiquity molecular weight fluctuation.
At present, we have not still seen the report or the data of the production technology aspect of Central Shanxi Plain molecular weight (30,000-10 is between 0000 dalton) chondroitin sulfate product, there is not molecular weight to be lower than 30,000 daltonian middle molecular weight chondroitin sulfate production marketings on the market yet.
[summary of the invention]
The technological method that the present invention relates to is with commercially available common molecular weight chondroitin sulfate (molecular weight 45,000 roads
The molecular-weight average of table 1 commercial sulfuric acid chrondroitin raw material
Sample number into spectrum cartilage source and purity molecular-weight average
1 N, 90% 69,400
2 sharks, 90% 85,700
3 Ns, 90% 57,600
4 Ns, 90% 59,900
5 Ns, 90% 54,800
6 sharks, 90% 83,400
7 Ns, 90% 59,900
8 Ns, 90% 62,500
9 Ns, 85% 45,700
10 Ns, 90% 51,100
11 Ns, 90% 73,600
12 Ns, 95% 51,100
13 sharks, 90% 47,500
14 Ns, 90% 62,400 you more than) or animal cartilage be raw material, adopt processing methodes such as conventional alkali lye extraction, enzymolysis, acid hydrolysis condition and hydrolysis time by the control chondroitin sulfate, ultra-filtration membrane, the nanofiltration membrane of using PSPP carries out that molecular weight is held back, purifying, special process such as concentrate, the molecular weight of molecular weight chondroitin sulfate product can stably be controlled at 10 in resulting, 000-30 is between 0000 dalton.The present invention adopts ultrafiltration, Nanofiltering membrane grading purification chondroitin sulfate, is the new technique of middle molecular weight chondroitin sulfate suitability for industrialized production, has characteristics such as efficient, energy-conservation, pollution-free.Molecular weight cut-off 30,000 daltonian ultra-filtration membranes can remove impurity such as deproteinize, macromolecular polysaccharide; Molecular weight cut-off 500 daltonian nanofiltration membrane can concentrate, remove small molecular weight impurity.The production process reaction temperature and, the yield height, cost is low, the three wastes are few, easy and simple to handle, technology is reasonable, very suitable suitability for industrialized production.
The object of the present invention is achieved like this:
1. will put in the interlayer reactor through the animal cartilage of pulverizing, and add an amount of 15-20% sodium hydroxide solution, 40 ℃ are stirred extraction, filtration, and residue extracts with proper quantity of lye again, merges filtrate twice.Regulate pH to 8.0-9.0 with hydrochloric acid, add the 0.2-0.8% pancreatin, 45-48 ℃ hydrolysis 4-6 hour, hydrochloric acid is regulated pH to 6.5-7.0, is heated to 70-80 ℃, adds white bole or talcum powder, gac whip attachment 30 minutes, filters.
2. be about 5% with above-mentioned filtrate with the concentration that nanofiltration equipment is concentrated into chondroitin sulfate, or commercially available common molecular weight chondroitin sulfate put in the interlayer reactor, it is 5% that the adding deionized water makes the concentration of chondroitin sulfate, add an amount of concentrated hydrochloric acid, the acidity that makes hydrolyzed solution is 0.1-1.0N, under 35-95 ℃ of condition, stir hydrolysis 2-12 hour, use sodium hydroxide, yellow soda ash or lime carbonate are regulated pH to 4.5-5.5, carry out multi-ultrafiltration with the ultra-filtration equipment of PSPP, nanofiltration concentrates, and adds 95% ethanol sedimentation, vacuum-drying, obtain molecular-weight average 30,000-10, the middle molecular weight chondroitin sulfate product in 000 dalton's scope.
Preparation method of the present invention by control acid hydrolysis condition (as acidity, temperature etc.) and hydrolysis time, uses the ultra-filtration membrane of PSPP, can obtain the middle molecular weight chondroitin sulfate of different molecular weight specification.For example molecular-weight average is the middle molecular weight chondroitin sulfate product that 30,000,20,000,16,000,12,000 dalton wait different size or purposes.
The middle molecular weight chondroitin sulfate that the present invention produced is compared with commercially available common chondroitin sulfate, characteristics such as have bioavailability height in the purity height, oral easy absorption, body, biological activity is good, pharmacological action is strong, it is the important source material of series products such as pharmaceutical prod, healthcare product, makeup, food, added value is higher than common chondroitin sulfate, and economic benefit is fairly obvious.
The middle molecular weight chondroitin sulfate that the present invention obtains can according to common process, prepare its sodium salt, sylvite, calcium salt, zinc salt, bismuth salt, magnesium salts, aluminium salt etc. as required.
The main physical and chemical index of the middle molecular weight chondroitin sulfate that production technique of the present invention makes is as follows:
Proterties: white or off-white powder
Molecular weight ranges: 30,000-10,000 dalton
Purity: 〉=90%
Weight loss on drying :≤10%
Albumen :≤3.0%
[embodiment]
The following examples are provided,, but do not limit the present invention in any way so that be described in detail scope of the present invention in all fields.
Embodiment 1
4.5 liters of deionized waters are placed glass beaker, and heating in water bath to 70 ℃ adds 250 gram commercial sulfuric acid chrondroitin (molecular-weight average 48,000 dalton), stirring and dissolving, solution adds 145 milliliters of 36% hydrochloric acid, add deionized water to 5 liter, make the concentration of hydrochloric acid of solution be about 0.3N.Insulation and stirring reaction are after 6 hours, cooling rapidly, add 500 milliliters of 10% aqueous sodium hydroxide solutions, the pH value that makes solution is about 4.8, with molecular weight cut-off 10,000 daltonian ultra-filtering element (polysulfone hollow fibre ultra-filtration membrane, Yiming Filtering Technology Co., Ltd., Shanghai) three grades of ultrafiltration, nanofiltration element (Hangzhou Water Treatment Technology Development Center, State Oceanic Administration) concentrates, concentrated solution adds 95% ethanol, crystallization, vacuum-drying, obtain molecular weight chondroitin sulfate (molecular-weight average 11,200) in the 215.6 gram whites.
Embodiment 2
4.5 liters of deionized waters are placed glass beaker, and heating in water bath to 80 ℃ adds 300 gram commercial sulfuric acid chrondroitin (molecular-weight average 51,000 dalton) crude product, stirring and dissolving, solution adds 45 gram oxalic acid, add deionized water to 5 liter, make the concentration of oxalic acid of solution be about 0.1N.Insulation and stirring reaction are after 8 hours, cooling rapidly adds 50 gram lime carbonate, behind the separation calcium oxalate precipitation, the pH value of solution is about 5.1, with molecular weight cut-off 20,000 daltonian ultrafiltration membrance filters, nanofiltration membrane concentrates, concentrated solution adds 95% alcohol crystal, 60 ℃ of vacuum-dryings obtain molecular weight chondroitin sulfate (molecular weight 16,300) in the 276.8 gram whites.
Embodiment 3
650 liters of deionized waters are placed in the interlayer retort, be heated to 73 ℃, add 40 kilograms of commercially available common molecular weight chondroitin sulfate (molecular-weight average 48,000 dalton) crude product, stirring and dissolving, solution add 11.2 liters of 36% hydrochloric acid, make the concentration of hydrochloric acid of solution be about 0.2N.Insulation and stirring reaction are after 4 hours, cooling rapidly, add 6.8 kilograms of yellow soda ash, the pH value that makes solution is about 4.6, with molecular weight cut-off 20,000 daltonian ultrafiltration membrance filter, nanofiltration membrane concentrates, and concentrated solution adds 95% alcohol crystal, 60 ℃ of vacuum-dryings, obtain molecular weight chondroitin sulfate in 37 kilograms of whites (molecular weight 19,400).
Embodiment 4
To put in the interlayer reactor for 40 kilograms through the fresh animal cartilage of pulverizing (self-conceit pipe), and add 100 liter of 20% sodium hydroxide solution, 40 ℃ are stirred 4 hours after-filtration of extraction, and residue extracts once more with proper quantity of lye, merges filtrate twice.Regulate pH to 8.0-9.0 with HCl, add 0.5% pancreatin, 45-48 ℃ hydrolysis 4-6 hour, HCl regulates pH to 6.5-7.0, is heated to 70-80 ℃, adds white bole or talcum powder, gac whip attachment 30 minutes, filtration.Above-mentioned filtrate is concentrated with nanofiltration equipment, and making the concentration of chondroitin sulfate is about 5%, adds an amount of concentrated hydrochloric acid, the acidity that makes hydrolyzed solution is 0.3N, under 75 ℃ of conditions, stir hydrolysis 5 hours, regulate pH to 4.5-5.5 with yellow soda ash, with molecular weight cut-off is 20,000 ultra-filtration equipment carries out three grades of ultrafiltration, nanofiltration concentrates, and adds 95% ethanol sedimentation, 60 ℃ of vacuum-dryings, obtain molecular-weight average and be among 13,500 dalton 1.05 kilograms of molecular weight chondroitin sulfate products.
Claims (10)
1. the preparation method of molecular weight chondroitin sulfate series product in a kind, it is characterized in that utilizing animal cartilage and/or commercially available common molecular weight chondroitin sulfate, through production technique such as conventional alkali lye extraction, enzymolysis, acid hydrolysis condition and hydrolysis time by the control chondroitin sulfate, use that ultra-filtration membrane, nanofiltration membrane separate, purifying, technology such as concentrate, can obtain molecular-weight average 30,000-10, the chondroitin sulfate series product of the different molecular-weight average in 000 dalton's scope.
2. preparation method according to claim 1, the molecular weight that it is characterized in that the chondroitin sulfate series product that obtain is 30, and 000-10 is between 000 dalton.
3. preparation method according to claim 1, the acid that it is characterized in that the acid hydrolysis use can be but be not limited to hydrochloric acid, sulfuric acid, nitric acid, acetic acid, oxalic acid.The employed alkali of neutralizing acid hydrolyzed solution can be but be not limited to sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, lime carbonate, sodium bicarbonate.
4. preparation method according to claim 1 is characterized in that acid-hydrolyzed temperature is between 30-99 ℃.The acid concentration of hydrolyzed solution is 0.01-5N.
5. preparation method according to claim 1 is characterized in that hydrolysis time is 0.5-48 hour.
6. preparation method according to claim 1 is characterized in that utilizing the ultra-filtration membrane of PSPP, removes impurity, purification of sulphuric acids chrondroitins such as protein in the low-molecular weight chondroitin sulfate, macromolecular polysaccharide.
7. preparation method according to claim 1 is characterized in that utilizing the nanofiltration membrane of PSPP, and the low-molecular weight chondroitin sulfate hydrolyzed solution is concentrated and remove soluble small molecular impurity and inorganic salt, moisture etc.
8. preparation method according to claim 1, it is characterized in that controlling acid hydrolysis condition and hydrolysis time, utilize the ultra-filtration membrane of PSPP, can obtain the middle molecular weight chondroitin sulfate product of different molecular-weight average, can be but be not limited to molecular-weight average be 30,000,25,000,20,000,16,000,12,000 daltonian chondroitin sulfate products.
9. preparation method according to claim 1 is characterized in that the middle molecular weight chondroitin sulfate that obtains can be used for producing but is not limited to products such as medicine, healthcare product, makeup, food, animal-feed.
10. preparation method according to claim 1 is characterized in that the middle molecular weight chondroitin sulfate that obtains can be but is not limited to its sodium salt, sylvite, calcium salt, zinc salt, bismuth salt, magnesium salts, aluminium salt.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031527728A CN1486993A (en) | 2003-08-19 | 2003-08-19 | Prepn process of chondroitin sulfate with medium molecule weight |
| CNB2003101193037A CN1307203C (en) | 2003-05-07 | 2003-12-03 | Method fo preparing medium, low molecular weight chondroitin sulphate and obtained product |
| CNB2004100388155A CN100389777C (en) | 2003-08-19 | 2004-04-30 | Moderate molecular weighted chondroitin sulfate injection and its preparing process |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031527728A CN1486993A (en) | 2003-08-19 | 2003-08-19 | Prepn process of chondroitin sulfate with medium molecule weight |
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| Publication Number | Publication Date |
|---|---|
| CN1486993A true CN1486993A (en) | 2004-04-07 |
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|---|---|---|---|
| CNA031527728A Pending CN1486993A (en) | 2003-05-07 | 2003-08-19 | Prepn process of chondroitin sulfate with medium molecule weight |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1304430C (en) * | 2004-08-25 | 2007-03-14 | 淮阴工学院 | Production technology of chondroitin sulphate |
| CN100417728C (en) * | 2006-06-01 | 2008-09-10 | 扬州日兴生物化工制品有限公司 | Deacetylate chondroitin sulfate preparation technology |
| CN101230369B (en) * | 2007-01-25 | 2011-02-09 | 浙江海洋学院 | Extraction method for chondrin |
| CN102838691A (en) * | 2012-08-29 | 2012-12-26 | 宁波绿之健药业有限公司 | Extracting and purifying method of chondroitin sulfate |
| CN111662394A (en) * | 2019-03-05 | 2020-09-15 | 中国医学科学院药物研究所 | Semi-synthesis preparation method and application of chondroitin sulfate polysaccharide |
-
2003
- 2003-08-19 CN CNA031527728A patent/CN1486993A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1304430C (en) * | 2004-08-25 | 2007-03-14 | 淮阴工学院 | Production technology of chondroitin sulphate |
| CN100417728C (en) * | 2006-06-01 | 2008-09-10 | 扬州日兴生物化工制品有限公司 | Deacetylate chondroitin sulfate preparation technology |
| CN101230369B (en) * | 2007-01-25 | 2011-02-09 | 浙江海洋学院 | Extraction method for chondrin |
| CN102838691A (en) * | 2012-08-29 | 2012-12-26 | 宁波绿之健药业有限公司 | Extracting and purifying method of chondroitin sulfate |
| CN111662394A (en) * | 2019-03-05 | 2020-09-15 | 中国医学科学院药物研究所 | Semi-synthesis preparation method and application of chondroitin sulfate polysaccharide |
| CN111662394B (en) * | 2019-03-05 | 2022-11-04 | 中国医学科学院药物研究所 | Semi-synthesis preparation method and application of chondroitin sulfate polysaccharide |
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