CN104725529A - Hyaluronic acid derivative synthesis method - Google Patents
Hyaluronic acid derivative synthesis method Download PDFInfo
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- CN104725529A CN104725529A CN201310699386.5A CN201310699386A CN104725529A CN 104725529 A CN104725529 A CN 104725529A CN 201310699386 A CN201310699386 A CN 201310699386A CN 104725529 A CN104725529 A CN 104725529A
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- hyaluronic acid
- solution
- benzyl ester
- butyl ammonium
- karb
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Abstract
The present invention discloses a hyaluronic acid derivative synthesis method, wherein a cation exchange resin is adopted and is subjected to ion exchange with hyaluronic acid in an ion exchange column to obtain a hyaluronic acid tetrabutylammonium salt, and the hyaluronic acid tetrabutylammonium salt and an alkylation reagent react in a N-methylpyrrolidone solvent to generate the hyaluronic acid derivative hyaluronic acid benzyl ester. The synthesis method of the present invention has characteristics of simple process and easy control, is suitable for industrial production, and has wide application prospects.
Description
Technical field
The invention belongs to the synthetic method of a kind of derivatives of hyaluronic acids of biological technical field.
Background technology
Hyaluronic acid be tissue naturally exist and indispensable a kind of be the straight chain polymer polysaccharide that dissacharide units forms by glucuronic acid-NAG, extensively be present in reticular tissue as joint, vitreum, synovia, in umbilical cord, cartilage, skin, cockscomb, A race and C race Hemolytic streptococcus and jelly of Wharton, to meet some important functions as the Metabolism regulation of toughness, underwork and cell.Hyaluronic acid has the key properties such as biological adsorbability, biocompatibility, vicidity and water-retentivity, is widely used in the fields such as cardiovascular surgery, sacroiliitis, surgical operation anti, drug delivery, cancer therapy, ophthalmology, esthetic surgery, diagnostics, animal doctor and beauty and health care.Although hyaluronic acid with its good biocompatibility and biological degradability of many uses, particularly in technical field of biological material, there is DEVELOPMENT PROSPECT widely, but hyaluronic acid is soluble in water, absorb the physics such as the rapidly and in the tissue residence time is short and biological nature also limit it for the preparation of the biomaterial that has certain requirements to hardness, physical strength and stability, therefore need to carry out chemically modified to hyaluronic acid, to make more stable solid-state material.
4 sites can carrying out chemically modified in hyaluronan molecule are respectively carboxyl, hydroxyl, N-ethanoyl and reduction end, and main modifying method has esterification, crosslinked, grafting (comprising end reduction) etc.Through the derivatives of hyaluronic acids that chemically modified is formed, not only maintain the original biocompatibility of hyaluronic acid, cell adhesion ability and to human non-toxic, the advantage such as non-stimulated, other good characteristics a series of are also endowed, as suitable physical strength, special rheological properties, antihyaluronidase degraded, targeting etc.Hyaluronic esterification can be carried out on its carboxyl or hydroxyl, general comparatively common with the esterification of carboxyl, do not changing under hyaluronic acid backbone prerequisite by esterification, hyaluronic physico-chemical property is as polymer stabilisation, water-soluble and biological property, as cell adhesion ability will largely be changed, hyaluronic acid benzyl ester is a kind of derivatives of hyaluronic acids, is a kind of biomaterial of semi-synthetic absorbability.Hyaluronic acid benzyl ester is considerable as a kind of novel biomaterial potentiality, various types of preparation can be made as pharmaceutical carrier, as microballoon, film, tablet etc., also can be used for artificial cartilage, artificial skin development and be applied in antibiont adhesion and anti-corruption in, medicine can also be widely used in as medical dressing and implantable material.
Summary of the invention
The object of this invention is to provide the synthetic method of a kind of derivatives of hyaluronic acids-hyaluronic acid benzyl ester.
The present invention adopts Zeo-karb to carry out ion-exchange with hyaluronic acid in ion exchange column and obtains hyaluronic acid 4-butyl ammonium, and hyaluronic acid 4-butyl ammonium and alkylating agent react and generate hyaluronic acid benzyl ester in N-Methyl pyrrolidone solvent.Concrete steps take hyaluronic acid powder to be dissolved in distilled water, by hyaluronic acid solution through processed (C
4h
9)
4n
+zeo-karb, uses the hyaluronic acid solution wash-out (C of 0.1%
4h
9)
4n
+zeo-karb, collect hyaluronic acid TBuA salts solution, namely lyophilize obtains hyaluronic acid 4-butyl ammonium dry powder; Take hyaluronic acid 4-butyl ammonium powder and be dissolved in the hyaluronic acid TBuA salts solution that N-Methyl pyrrolidone makes 20mg/ml, slowly inject above-mentioned solution by with the alkylating agent after N-Methyl pyrrolidone dilution, 37 DEG C are incubated more than 60 hours; Add sodium-chlor after reaction terminates, stir slowly to add in the acetone of 5 times of volumes after half an hour and generate precipitation, filtering-depositing, with acetone water (80: 20) solution washing 3 times, under final 30 DEG C of conditions, namely drying obtains hyaluronic acid benzyl ester at least 48 hours.This technique is simple, easy to control, is suitable for industrial production, is with a wide range of applications.
Embodiment
The present invention is the synthetic method of derivatives of hyaluronic acids-hyaluronic acid benzyl ester, adopt Zeo-karb to carry out ion-exchange with hyaluronic acid in ion exchange column and obtain hyaluronic acid 4-butyl ammonium, hyaluronic acid 4-butyl ammonium and alkylating agent react and generate hyaluronic acid benzyl ester in N-Methyl pyrrolidone solvent.
Below citing further illustrates the technological process adopting the present invention to synthesize hyaluronic acid benzyl ester.
embodiment 1
Taking hyaluronic acid 25g is dissolved in 1.5L distilled water, by hyaluronic acid solution through processed (C
4h
9)
4n
+zeo-karb, uses the hyaluronic acid solution wash-out (C of 0.1%
4h
9)
4n
+zeo-karb, collect hyaluronic acid TBuA salts solution, namely lyophilize obtains hyaluronic acid 4-butyl ammonium dry powder and is about 35g;
Take hyaluronic acid 4-butyl ammonium 5g and be dissolved in the hyaluronic acid TBuA salts solution making 20mg/ml in the N-Methyl pyrrolidone of 250ml, hyaluronic acid TBuA salts solution is slowly injected, 37 DEG C of insulation 60h after measuring the dilution of alkylating agent 1.2ml to 10mlN-methyl-2-pyrrolidone;
After reaction terminates, take 2g sodium-chlor and add in reaction soln, slowly add after stirring half an hour in the acetone of 5 times of volumes and generate precipitation, filtering-depositing, with acetone water (80: 20) solution washing 3 times, dry 48h under 30 DEG C of conditions, obtains hyaluronic acid benzyl ester.
embodiment 2
Taking hyaluronic acid 69g is dissolved in 4L distilled water, by hyaluronic acid solution through processed (C
4h
9)
4n
+zeo-karb, uses the hyaluronic acid solution wash-out (C of 0.1%
4h
9)
4n
+zeo-karb, collect hyaluronic acid TBuA salts solution, namely lyophilize obtains hyaluronic acid 4-butyl ammonium dry powder and is about 100g;
Take hyaluronic acid 4-butyl ammonium 15g and be dissolved in the hyaluronic acid TBuA salts solution making 20mg/ml in the N-Methyl pyrrolidone of 750ml, hyaluronic acid TBuA salts solution is slowly injected, 37 DEG C of insulation 72h after measuring the dilution of alkylating agent 3.1ml to 20mlN-methyl-2-pyrrolidone;
After reaction terminates, take 6g sodium-chlor and add in reaction soln, slowly add after stirring half an hour in the acetone of 5 times of volumes and generate precipitation, filtering-depositing, with acetone water (80: 20) solution washing 3 times, dry 60h under 30 DEG C of conditions, obtains hyaluronic acid benzyl ester.
embodiment 3
Taking hyaluronic acid 48g is dissolved in 3L distilled water, by hyaluronic acid solution through processed (C
4h
9)
4n
+zeo-karb, uses the hyaluronic acid solution wash-out (C of 0.1%
4h
9)
4n
+zeo-karb, collect hyaluronic acid TBuA salts solution, namely lyophilize obtains hyaluronic acid 4-butyl ammonium dry powder and is about 65g;
Take hyaluronic acid 4-butyl ammonium 12g and be dissolved in the hyaluronic acid TBuA salts solution making 20mg/ml in the N-Methyl pyrrolidone of 600ml, hyaluronic acid TBuA salts solution is slowly injected, 37 DEG C of insulation 65h after measuring the dilution of alkylating agent 2.5ml to 15mlN-methyl-2-pyrrolidone;
After reaction terminates, take 4g sodium-chlor and add in reaction soln, slowly add after stirring half an hour in the acetone of 5 times of volumes and generate precipitation, filtering-depositing, with acetone water (80: 20) solution washing 3 times, dry 50h under 30 DEG C of conditions, obtains hyaluronic acid benzyl ester.
embodiment 4
Taking hyaluronic acid 100g is dissolved in 6L distilled water, by hyaluronic acid solution through processed (C
4h
9)
4n
+zeo-karb, uses the hyaluronic acid solution wash-out (C of 0.1%
4h
9)
4n
+zeo-karb, collect hyaluronic acid TBuA salts solution, namely lyophilize obtains hyaluronic acid 4-butyl ammonium dry powder and is about 150g;
Take hyaluronic acid 4-butyl ammonium 25g and be dissolved in the hyaluronic acid TBuA salts solution making 20mg/ml in the N-Methyl pyrrolidone of 1250ml, hyaluronic acid TBuA salts solution is slowly injected, 37 DEG C of insulation 75h after measuring the dilution of alkylating agent 5.6ml to 25mlN-methyl-2-pyrrolidone;
After reaction terminates, take 10g sodium-chlor and add in reaction soln, slowly add after stirring half an hour in the acetone of 5 times of volumes and generate precipitation, filtering-depositing, with acetone water (80: 20) solution washing 3 times, dry 72h under 30 DEG C of conditions, obtains hyaluronic acid benzyl ester.
Claims (2)
1. the synthetic method of derivatives of hyaluronic acids-hyaluronic acid benzyl ester, this synthetic method adopts Zeo-karb to carry out ion-exchange with hyaluronic acid in ion exchange column and obtains hyaluronic acid 4-butyl ammonium, and hyaluronic acid 4-butyl ammonium and alkylating agent react and generate hyaluronic acid benzyl ester in N-Methyl pyrrolidone solvent.
2. hyaluronic acid benzyl ester synthetic method as claimed in claim 1, it is characterized in that, described method concrete steps take hyaluronic acid powder to be dissolved in distilled water, by hyaluronic acid solution through processed (C
4h
9)
4n
+zeo-karb, uses the hyaluronic acid solution wash-out (C of 0.1%
4h
9)
4n
+zeo-karb, collect hyaluronic acid TBuA salts solution, namely lyophilize obtains hyaluronic acid 4-butyl ammonium dry powder; Take hyaluronic acid 4-butyl ammonium powder and be dissolved in the hyaluronic acid TBuA salts solution that N-Methyl pyrrolidone makes 20mg/ml, slowly inject above-mentioned solution by with the alkylating agent after N-Methyl pyrrolidone dilution, 37 DEG C are incubated more than 60 hours; Add sodium-chlor after reaction terminates, stir slowly to add in the acetone of 5 times of volumes after half an hour and generate precipitation, filtering-depositing, with acetone water (80: 20) solution washing 3 times, under final 30 DEG C of conditions, namely drying obtains hyaluronic acid benzyl ester at least 48 hours.
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| CN201310699386.5A CN104725529A (en) | 2013-12-19 | 2013-12-19 | Hyaluronic acid derivative synthesis method |
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| CN201310699386.5A CN104725529A (en) | 2013-12-19 | 2013-12-19 | Hyaluronic acid derivative synthesis method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105693881A (en) * | 2016-02-24 | 2016-06-22 | 扬州大学 | Tertiary aliphatic amine grafted alginic acid derivative preparation method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1199343A (en) * | 1995-08-29 | 1998-11-18 | 菲迪亚高级生物聚合物公司 | Biomaterials for preventing post-surgical adhesions comprised of hyaluronic acid derivs. |
| WO1999024070A2 (en) * | 1997-11-06 | 1999-05-20 | Fidia Advanced Biopolymers, S.R.L. | Ester derivatives of hyaluronic acid with viscoelastic properties and their use in the biomedical and healthcare field |
-
2013
- 2013-12-19 CN CN201310699386.5A patent/CN104725529A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1199343A (en) * | 1995-08-29 | 1998-11-18 | 菲迪亚高级生物聚合物公司 | Biomaterials for preventing post-surgical adhesions comprised of hyaluronic acid derivs. |
| WO1999024070A2 (en) * | 1997-11-06 | 1999-05-20 | Fidia Advanced Biopolymers, S.R.L. | Ester derivatives of hyaluronic acid with viscoelastic properties and their use in the biomedical and healthcare field |
Non-Patent Citations (2)
| Title |
|---|
| 胡帼颖: ""透明质酸化学交联修饰及其衍生物的体外降解研究"", 《中国优秀博硕士学位论文全文数据库（硕士） 医药卫生科技辑》 * |
| 胡帼颖等: ""透明质酸交联、酯化衍生物的制备及医学应用进展"", 《透析与人工器官》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105693881A (en) * | 2016-02-24 | 2016-06-22 | 扬州大学 | Tertiary aliphatic amine grafted alginic acid derivative preparation method |
| CN105693881B (en) * | 2016-02-24 | 2017-12-08 | 扬州大学 | A kind of preparation method of the alginic acid derivative of fat tertiary amine grafting |
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