CN1229071A - Water-soluble heparin type chitosan sulfanilamide anticoagulation agent - Google Patents
Water-soluble heparin type chitosan sulfanilamide anticoagulation agent Download PDFInfo
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- CN1229071A CN1229071A CN 97109356 CN97109356A CN1229071A CN 1229071 A CN1229071 A CN 1229071A CN 97109356 CN97109356 CN 97109356 CN 97109356 A CN97109356 A CN 97109356A CN 1229071 A CN1229071 A CN 1229071A
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- Prior art keywords
- scs
- water
- sulfanilamide
- soluble
- coagulant
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Abstract
A water-soluble heparin-type chitosan sulfanilamide as anticoagulant (SCS) is prepared from purified chitosamine or the chitosamine after direct deacylation as raw material, urea and fuming sulfuric acid as sulfonating agent, and one quanternary ammonium salt as phase-transfer catalyst through sulfonating reaction to obtain SCS, as well as deformed chitosamine with high bioactivity. Its advantages include simple process, lower cost and no environmental pollution.
Description
Water-soluble heparin type chitosan sulfanilamide (Sulfamic Chitosan is abbreviated as SCS) anti-coagulant is a kind of medicine that obtains with chemical process, is used for blood transfusion, vascular surgery and treatment thrombosis, phlebitis and embolism.Therefore, the invention belongs to carefully refine worker or pharmaceutical chemistry technical field, also belong to the biomedical engineering technology field.
After chemical modification and can directly be dissolved in the Viartril-S of water (chitonsan is abbreviated as CS, chemical formula C
6H
11O
4N) purified solution, in the molecular structure biologically active-NH
2The base group fully comes out.High more its physiologically active of person of CS purity is also good more.Water-soluble CS can remove the radioelement that has been deposited in the mouse bone, and sulfonated CS then has function (shojiroKyotani et al., Chen.Pharm.BUll., 1992,4 (10): 267 of preventing cancer metastasis; 2814).Usually, adopt chlorsulfonic acid, under the protonated severe condition of 2 amidos as sulphonating agent, obtain 6 water-soluble CS products of sulfonated (Zhao Wenwei etc., chemistry circular, 1994, (4): 31-34), but do not see that so far grafting introducing sulfonic group (report SO3H) on 2 amidos of CS is arranged.And only 2 introduce sulfonic groups with 3 after, this sulfonated products just has and heparin (Heparin, chemical formula C
6H
12O
10NS
2, a kind of anti-coagulant that from animal liver, lung, extracts) and similar structure, prevent just that also hemoglutinin is transformed into zymoplasm, prevent that Parenogen is transformed into the fibrin protein, the blood coagulation of prevention and antithrombotic function are promptly arranged.
The objective of the invention is: select the sulphonating agent under a kind of mild conditions for use, Direct Sulfonation root on 2,3,6 of CS, thereby become water-soluble heparin type chitosan sulfanilamide, and in reaction process, make and do not give that part of CS molecular chain degradation of sulfonated, having strengthened the part wetting ability, made the CS that only can be dissolved in the diluted acid can be scattered in water---in the ethanol liquid, the biological activity of amine groups is stronger.
As follows for realizing the technical measures that purpose of the present invention adopts:
The present invention is with deacylated tRNA degree 80～90%, the CS of ashes 1.0～1.5%, further made with extra care purification as follows: 20～40g/L CS is dissolved in the acetum of 0.17～0.33mol/L, slowly splash into the 0.125～0.25mol/LNaOH solution that is equivalent to 1～2 times of volume of acetum while stirring, make till the pH value of solution ≈ 7.2～7.8, leave standstill 2～4h after, divide the aqueous solution that removes to contain sodium-acetate as far as possible, obtain deacylated tRNA degree＞90%, the pure white cotton-shaped CS of ash＜1.0% makes with extra care thing.
With the CS of refining purifying, with 200～400g/L dithiocarbamic acid (SA) sulfonation reaction 4～6h under 115 ± 5 ℃ of temperature, leave standstill the back layering: solution is partly used CaCO
3Get water-soluble SCS behind the purifying; Precipitation is partly with 2.77～4.36mol/L NaOH solution quaternization 0.5～0.6h under 65 ± 5 ℃ of temperature, layering after the furnishing neutrality.The solution part that obtains after the layering for the second time gets white powdery SCS, yield 15～25% through concentrate drying; The precipitation part promptly gets pure white loose CS through cryodrying.Obtain to change shape CS with this method, the CS powder that vacuum-drying that its biological activity ratio adopts at present or vacuum lyophilization make is much higher, and its cost then only is the latter's 1/2～1/3.
The molecular structure characterization of SCS is as follows:
N=100-1000
The invention will be further described below in conjunction with example.Example one, produce SCS by one step of following proportioning:
CS urea oleum PTC
20～40g/L 5～15g/L 10～30g/L 1.0～1.5g/L
All the other ethanol.By above proportioning, the urea soln and the CS ethanol liquid that will be dissolved in earlier in a small amount of vitriol oil mix, add phase-transfer catalyst (PTC) dodecyl dixylyl bromide, under room temperature isolation condition, add oleum, stirring reaction 1～2h under 60～80 ℃ of temperature then, after then being warming up to 115 ± 5 ℃ of reactions, separate, concentrate, drying obtains SCS respectively and changes shape CS.
Example two, lower molecular weight full water-soluble SCS produces:
To be the CS that is directly obtained behind the concentrated base de-acyl reaction without refining the purification, with 46～60g/LH
2O
2Solution, under 60～80 ℃ of temperature, the quick stirring reaction 1.5～3.0h of stainless steel agitator arm, the elimination insolubles, promptly remove the not chitin of deacylated tRNA (chitin) of ashes and part, in the limpid lemon yellow liquid of gained content 50～100g/L CS, add 20～35g/L NH
2SO
3H solution reacts 3～5h under 60～80 ℃ of temperature, get the SCS viscous fluid of rice-pudding brown.
Claims (4)
1. one kind is raw material with the Viartril-S, and under sulphonating agent and phase-transfer catalyst effect, water-soluble heparin type chitosan sulfanilamide (SCS) anti-coagulant through sulfonation reaction obtains has following structural characterization:
N=100-1000
2. SCS anti-coagulant according to claim 1 is characterized in that: produce SCS by following one step of proportioning:
CS urea oleum PTC
20～40g/L 5～15g/L 10～30g/L 1.0～1.5g/L
3. SCS anti-coagulant according to claim 1 is characterized in that: use chitosan solution through hydrogen peroxide degraded to react with thionamic acid and make the SCS brown liquid of lower molecular weight full water-soluble.
4. SCS anti-coagulant according to claim 1, it is characterized in that: in refining neutralization reaction process of purifying, adopt rare Viartril-S acetate to remove the rare alkali lye of titration, thereby obtain the CS of pure white purifying, and form after sulfonation reaction and change shape CS, conventional drying just can obtain white loose CS powder at low temperatures.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 97109356 CN1229071A (en) | 1997-12-30 | 1997-12-30 | Water-soluble heparin type chitosan sulfanilamide anticoagulation agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 97109356 CN1229071A (en) | 1997-12-30 | 1997-12-30 | Water-soluble heparin type chitosan sulfanilamide anticoagulation agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1229071A true CN1229071A (en) | 1999-09-22 |
Family
ID=5171154
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 97109356 Pending CN1229071A (en) | 1997-12-30 | 1997-12-30 | Water-soluble heparin type chitosan sulfanilamide anticoagulation agent |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1229071A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6716970B2 (en) | 2000-04-21 | 2004-04-06 | Adjuvant Pharmaceuticals, Llc | Water soluble, randomly substituted partial N-partial O-acetylated chitosan, preserving compositions containing chitosan, and processes for making thereof |
| US7125967B2 (en) | 2003-10-08 | 2006-10-24 | Adjuvant Pharmaceuticals, Llc | Water-soluble chitosan having low endotoxin concentration and methods for making and using the same |
| CN100509860C (en) * | 2007-01-19 | 2009-07-08 | 中国科学院海洋研究所 | Chitin sulfuric-ester hydroxy-benzene disulfonic acid derivative and production thereof |
| CN100543040C (en) * | 2006-10-27 | 2009-09-23 | 中国科学院海洋研究所 | A kind of SULFAMIC CHITOSAN analog derivative and preparation method thereof |
| CN102805883A (en) * | 2012-08-03 | 2012-12-05 | 福州长庚医疗器械有限公司 | Method for preparing chitosan modified heparin lithium anticoagulant additive |
-
1997
- 1997-12-30 CN CN 97109356 patent/CN1229071A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6716970B2 (en) | 2000-04-21 | 2004-04-06 | Adjuvant Pharmaceuticals, Llc | Water soluble, randomly substituted partial N-partial O-acetylated chitosan, preserving compositions containing chitosan, and processes for making thereof |
| US7683039B2 (en) | 2000-04-21 | 2010-03-23 | Adjuvant Pharmaceuticals, Llc | Water soluble, randomly substituted partial N-, partial O-acetylated chitosan, preserving compositions containing chitosan, and processes for making thereof |
| US7125967B2 (en) | 2003-10-08 | 2006-10-24 | Adjuvant Pharmaceuticals, Llc | Water-soluble chitosan having low endotoxin concentration and methods for making and using the same |
| CN100543040C (en) * | 2006-10-27 | 2009-09-23 | 中国科学院海洋研究所 | A kind of SULFAMIC CHITOSAN analog derivative and preparation method thereof |
| CN100509860C (en) * | 2007-01-19 | 2009-07-08 | 中国科学院海洋研究所 | Chitin sulfuric-ester hydroxy-benzene disulfonic acid derivative and production thereof |
| CN102805883A (en) * | 2012-08-03 | 2012-12-05 | 福州长庚医疗器械有限公司 | Method for preparing chitosan modified heparin lithium anticoagulant additive |
| CN102805883B (en) * | 2012-08-03 | 2014-04-30 | 福州长庚医疗器械有限公司 | Method for preparing chitosan modified heparin lithium anticoagulant additive |
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| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |