CN1837265A - Process for composite modification of hyaluronic acid and carboxymethyl cellulose - Google Patents
Process for composite modification of hyaluronic acid and carboxymethyl cellulose Download PDFInfo
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- CN1837265A CN1837265A CN 200610039972 CN200610039972A CN1837265A CN 1837265 A CN1837265 A CN 1837265A CN 200610039972 CN200610039972 CN 200610039972 CN 200610039972 A CN200610039972 A CN 200610039972A CN 1837265 A CN1837265 A CN 1837265A
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- hyaluronic acid
- carboxymethyl cellulose
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Abstract
The invention discloses a composite modified method of hyaluronic acid-carboxymethyl cellulose, which comprises the following steps: letting two or more amino polymer or oligomer and hyaluronic acid, carboxymethyl cellulose reacts to produce non-aqueous composite modified material of hyaluronic acid-carboxymethyl cellulose.
Description
Technical field
A kind of method of composite modification of hyaluronic acid and carboxymethyl cellulose, the present invention relates to a kind of new composite modified method of hyaluronic acid, the cross-linked composite that particularly relates to a kind of non-water-soluble hyaluronic acid and carboxymethyl cellulose, to be hyaluronic acid and carboxymethyl cellulose make linking agent by the product that the amidation crosslinking reaction obtains with diamines or polyamines superpolymer or oligopolymer to described mixture, belongs to technological field of biochemistry.
Technical background
Hyaluronic acid (hyaluronic acid, HA) have another name called hyaluronic acid or glass acid, be with β-1 by glucuronic acid (GlcA) and N-acetylglucosamine (GlcNAc), 3 and β-1, the disaccharide unit that 4 glycosidic links connect into repeats to make up the straight chain line style negatively charged ion mucopolysaccharide that forms, and its molecular weight order of magnitude is 10
4-10
7Hyaluronic acid extensively is present in organism soft junction base of a fruit histocyte epimatrix (ECM), organism synovia and the umbilical cord, have good water retention and lubrication, can regulate the synthetic of collagen, suppress the surface of a wound and shrink, reduce scar and generate, and in clinical application, be confirmed.In addition, HA is as the polymerization anion electrolyte, on the molecule with a large amount of negative charges can regulate negative ion concentrations on every side, the activity of inhibitory enzyme.Composition (with the solution of different viscosity, different viscoelastic gel, sponge, film or membranous form) with hyaluronate sodium of different molecular weight is applied in people's the medical treatment and surgical operation, for example it is as the substitute of synovia, the agent of structure again of artificial tears, carrier tissue (giving birth to and the formation in immediately calcification Hou Gu district as moving for scleroblast as extracellular matrix) is handled or attitude shape surgery is used as the material of artificial skin burning; The coating agent that has the blood vessel of physiological compatibility to repair, in the sustained release prescription as the slow-released carrier of medicine etc.
Although yet HA is of many uses with its excellent biological compatibility and biological degradability, particularly has DEVELOPMENT PROSPECT widely in technical field of biological material, but then, physics and biological natures such as pure HA is soluble in water, absorb rapidly and the residence time is short in tissue, also limited it and be used for preparation hardness, physical strength and the stability biomaterial that has certain requirements, need carry out chemically modified, to make more stable solid-state material.In addition, have only HA is carried out careful chemically modified, could keep inertia and the non-inflammatory reaction of the pure HA of its high-molecular weight, just can maximize favourable factors and minimize unfavourable ones, make HA biomaterial broader applications.HA has functional groups such as hydroxyl, carboxyl and kharophen, can carry out modification by crosslinked, esterification, grafting, molecular modification and method such as compound.
Some documents were once reported synthetic many examples crosslinked, non-water-soluble derivatives of hyaluronic acids such as various employing bifunctional compound such as divinylsulfone, diepoxide, dihalide, formaldehyde.
The derivative of HA has been developed a lot of purposes, as prevents the aspects such as viscosity additives of rectification, skin growth, organizational project and the osteoarthritis of tissue adhesion, facial wrinkles after the surgical operation.As one of hyaluronic method of modifying, composite modifiedly can give hyaluronic acid multi-biological activity and physico-chemical property, be one of hyaluronic acid modified direction.Situation from present research, the compound research of hyaluronic acid and collagen protein, poly(lactic acid) or chitosan more, also do not appear in the newspapers and hyaluronic acid and carboxymethyl cellulose are compound, hyaluronic acid and carboxymethyl cellulose are carried out composite modified having a dual effect: carboxymethyl cellulose is given the hyaluronic acid favorable mechanical, and hyaluronic acid then can be given carboxymethyl cellulose with excellent biological compatibility.
Summary of the invention
The purpose of this invention is to provide a kind of non-water-soluble, hyaluronic acid and the composite modified method of carboxymethyl cellulose, undertaken hyaluronic acid and carboxymethyl cellulose composite modified by amidate action by having two or more amino superpolymer or oligopolymer in the molecular structure.
Another object of the present invention provides with non-water-soluble, the hyaluronic acid of method for preparing and carboxymethyl cellulose crosslinked mixture.
Technical scheme of the present invention: in the presence of carboxyl activator and coagent with hyaluronic acid, carboxymethyl cellulose and linking agent carry out crosslinking reaction, its technology is: with hyaluronic acid, carboxymethyl cellulose successively is dissolved in the distilled water, be made into the hyaluronic acid solution of 1-4mg/ml and the cmc soln of 4-50mg/ml, add linking agent, make the carboxyl of carboxymethyl cellulose: the mole proportioning of linking agent is 1: 0.1-1: 10, transfer pH to 4-6 with dilute hydrochloric acid, add carboxyl activator and coagent then, the addition of carboxyl activator is 1-5mg/ml, the addition of coagent is 1-5mg/ml, crosslinking reaction 2-20h under 10-40 ℃ of temperature, regulate in the reaction process and maintenance pH4-6, reaction finishes, with the reaction solution 24h that dialyses, dialysis finishes, and adds the dehydrated alcohol precipitation, lyophilize obtains the composite modified product of hyaluronic acid and carboxymethyl cellulose.
Described linking agent is to have two or more amino superpolymer or oligopolymer in the molecular structure.
Described carboxyl activator is the water-soluble carbodiimide compounds.
Described coagent is succimide class, phentriazine class or benzotriazole compound.
According to the present invention, the example that has two or more amino superpolymer or oligopolymer in the molecular structure can be selected from: 1, and 6-hexanediamine, adipic dihydrazide, have two or more and can react and can accept the amino acid of amino of proton or polypeptide etc.
Add the example that is used for the carboxyl promoting agent of activated carboxyl in the amidate action water-soluble carbodiimide compounds is arranged.Preferred carbodiimide is selected from compound soluble in water, as EDC[1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride], have 1-propyl group-3-(3-dimethyl aminopropyl) carbodiimide or the CMC (1-cyclohexyl-3-(2-morpholino ethyl) carbodiimide) of analog structure with EDC.
More preferably, above-mentioned amidate action optionally adds coagent.Water soluble, the material that can form active ester all can be used as the coagent of above-mentioned amidate action.The example of coagent can be selected from: NHS (N-maloyl imines), HOBt (I-hydroxybenzotriazole), HOOBt (3,4-dihydro-3-hydroxyl-4-oxo-1,2,3-phentriazine), HOAt (1-hydroxyl-7-azepine benzotriazole) and Sulfo-NHS (N-hydroxyl sulfo group succimide).
Compare with not making used additives, make used additives such as NHS, can reduce the generation of by product such as O-uride and N-uride, the material behavior of resulting in both cases composite modification of hyaluronic acid and carboxymethyl cellulose thing and there was no significant difference.
Beneficial effect of the present invention: the purposes of the composite modification of hyaluronic acid and carboxymethyl cellulose thing that makes aspect medicine, surgical operation, makeup is very extensive, can be used as the rectification material of weighting agent, facial wrinkles of cartilaginous tissue and shaping and beauty packing material, can also be used as slow releasing carrier of medication.
Non-water-soluble, the composite modification of hyaluronic acid and carboxymethyl cellulose thing that make according to the present invention have following feature: this mixture not only has higher thermostability, has the characteristic of acceptable material biologically, promptly have biocompatibility, a class has overcome the novel biomaterial that existing derivatives of hyaluronic acids is easy to degrade and is easy to shortcomings such as dissolving under severe condition such as acidity especially.
The inventive method has the feature that reaction is easy, the separation and purification operation simply and not needs to use deleterious organic solvent.
Specific embodiments
Embodiment 1: use the crosslinked hyaluronic acid of adipic dihydrazide and the preparation of carboxymethyl cellulose mixture
Taking by weighing hyaluronic acid 0.1g and carboxymethyl cellulose 0.4g (0.00166mol carboxyl) respectively is dissolved in the distilled water of 100ml, after dissolving finishes, add 2.884g (0.0166mol) adipic dihydrazide (ADH), fully after the dissolving, hydrochloric acid with 0.1mol/L is regulated pH to 4.0-5.0, add 0.5g carbodiimide (EDC) and 0.5gNHS then, 40 ℃ were reacted 2 hours down, regulated the pH value in reaction process between 4.0-5.0.After reaction finishes, reaction solution was dialysed 24 hours, dialysis finishes, and adds the dehydrated alcohol precipitation, and lyophilize obtains membranaceous hyaluronic acid and carboxymethyl cellulose mixture.
Embodiment 2: with 1, and the preparation of hyaluronic acid that the 6-hexanediamine is crosslinked and carboxymethyl cellulose mixture
Divide hyaluronic acid and the 3g carboxymethyl cellulose (0.0124mol carboxyl) of another name 0.2g to be dissolved in the distilled water of 100ml, after dissolving finishes, add 1.438g1,6-hexanediamine (0.0124mol), fully after the dissolving, regulate pH to 5.0-5.5, add 0.1g 1-cyclohexyl-3-(2-morpholino ethyl) carbodiimide and 0.1g HOOBt then with the hydrochloric acid of 0.1mol/L, 30 ℃ were reacted 7 hours down, regulated the pH value in reaction process between 5.0-5.5.After reaction finishes, reaction solution was dialysed 24 hours, dialysis finishes, and adds the dehydrated alcohol precipitation, and lyophilize obtains membranaceous hyaluronic acid and carboxymethyl cellulose mixture.
Embodiment 3: use the crosslinked hyaluronic acid of arginine and the preparation of carboxymethyl cellulose mixture
Divide another name 0.4g hyaluronic acid and 5g carboxymethyl cellulose (0.021mol carboxyl) to be dissolved in the distilled water of 100ml, after dissolving finishes, add 0.365g arginine (0.0021mol), fully after the dissolving, hydrochloric acid with 0.1mol/L is regulated pH to 5.5-6.0, add 0.3g1-alkyl-3-(3-dimethyl aminopropyl) carbodiimide and 0.3g HOAt then, 10 ℃ were reacted 20 hours down, regulated the pH value in reaction process between 5.5-6.0.After reaction finishes, reaction solution was dialysed 24 hours, dialysis finishes, and adds the dehydrated alcohol precipitation, and lyophilize obtains membranaceous hyaluronic acid and carboxymethyl cellulose mixture.
Claims (4)
1, a kind of method of composite modification of hyaluronic acid and carboxymethyl cellulose, it is characterized in that in the presence of carboxyl activator and coagent hyaluronic acid, carboxymethyl cellulose and linking agent carry out crosslinking reaction, its technology is: with hyaluronic acid, carboxymethyl cellulose successively is dissolved in the distilled water, be made into the hyaluronic acid solution of 1-4mg/ml and the cmc soln of 4-50mg/ml, add linking agent, make the carboxyl of carboxymethyl cellulose: the mole proportioning of linking agent is 1: 0.1-1: 10, transfer pH to 4-6 with dilute hydrochloric acid, add carboxyl activator and coagent then, the addition of carboxyl activator is 1-5mg/ml, the addition of coagent is 1-5mg/ml, crosslinking reaction 2-20h under 10-40 ℃ of temperature, regulate in the reaction process and keep pH4-6, reaction finishes, with the reaction solution 24h that dialyses, dialysis finishes, add the dehydrated alcohol precipitation, lyophilize obtains the composite modified product of hyaluronic acid and carboxymethyl cellulose;
Described linking agent is to have two or more amino superpolymer or oligopolymer in the molecular structure;
Described carboxyl activator is the water-soluble carbodiimide compounds;
Described coagent is succimide class, phentriazine class or benzotriazole compound.
2, preparation method according to claim 1 is characterized in that linking agent is selected from: 1, and 6-hexanediamine, adipic dihydrazide and have two or more amino amino acid or polypeptide.
3, preparation method according to claim 1 is characterized in that carboxyl activator is selected from: 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride, 1-propyl group-3-(3-dimethyl aminopropyl) carbodiimide or 1-cyclohexyl-3-(2-morpholino ethyl) carbodiimide.
4, preparation method according to claim 1, it is characterized in that coagent is selected from: N-maloyl imines, I-hydroxybenzotriazole, 3,4-dihydro-3-hydroxyl-4-oxo-1,2,3-phentriazine, 1-hydroxyl-7-azepine benzotriazole or N-hydroxyl sulfo group succimide.
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| CN 200610039972 CN1837265A (en) | 2006-04-25 | 2006-04-25 | Process for composite modification of hyaluronic acid and carboxymethyl cellulose |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012146031A1 (en) * | 2011-04-26 | 2012-11-01 | 北京爱美客生物科技有限公司 | Composite gel of hyaluronic acid and hydroxypropyl methylcellulose and production method therefor |
| CN102911380A (en) * | 2012-10-29 | 2013-02-06 | 北京爱美客生物科技有限公司 | Hyaluronan and biodegradable high polymer modified material and preparation method |
| CN105451786A (en) * | 2013-07-16 | 2016-03-30 | 埃里亚应用研究所有限责任公司 | Cross-linked hyaluronic acid, process for its preparation and use thereof in the aesthetic field |
| CN105833282A (en) * | 2016-03-25 | 2016-08-10 | 周荣 | Method of producing medicine carrier from ficus carica polysaccharides |
| CN108379112A (en) * | 2011-09-14 | 2018-08-10 | 阿勒根公司 | Dermal augmentation agent composition for microgroove treatment |
| CN108888591A (en) * | 2018-10-16 | 2018-11-27 | 杭州元研细胞生物科技有限公司 | A kind of drug and preparation method thereof for treating fibroid |
| CN110382193A (en) * | 2017-03-07 | 2019-10-25 | 株式会社真友生物 | The preparation method of hyaluronate film and the hyaluronate film thus prepared |
| WO2020242420A1 (en) * | 2019-05-27 | 2020-12-03 | Vsy Biyoteknoloji Ve Ilac Sanayi Anonim Sirketi | A hybrid hydrogel used as a dermal filler and its production method |
-
2006
- 2006-04-25 CN CN 200610039972 patent/CN1837265A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012146031A1 (en) * | 2011-04-26 | 2012-11-01 | 北京爱美客生物科技有限公司 | Composite gel of hyaluronic acid and hydroxypropyl methylcellulose and production method therefor |
| CN108379112A (en) * | 2011-09-14 | 2018-08-10 | 阿勒根公司 | Dermal augmentation agent composition for microgroove treatment |
| CN102911380A (en) * | 2012-10-29 | 2013-02-06 | 北京爱美客生物科技有限公司 | Hyaluronan and biodegradable high polymer modified material and preparation method |
| CN105451786A (en) * | 2013-07-16 | 2016-03-30 | 埃里亚应用研究所有限责任公司 | Cross-linked hyaluronic acid, process for its preparation and use thereof in the aesthetic field |
| CN105451786B (en) * | 2013-07-16 | 2020-06-05 | 埃里亚应用研究所有限责任公司 | Cross-linked hyaluronic acid, process for its preparation and use thereof in the aesthetic field |
| CN105833282A (en) * | 2016-03-25 | 2016-08-10 | 周荣 | Method of producing medicine carrier from ficus carica polysaccharides |
| CN110382193A (en) * | 2017-03-07 | 2019-10-25 | 株式会社真友生物 | The preparation method of hyaluronate film and the hyaluronate film thus prepared |
| CN108888591A (en) * | 2018-10-16 | 2018-11-27 | 杭州元研细胞生物科技有限公司 | A kind of drug and preparation method thereof for treating fibroid |
| WO2020242420A1 (en) * | 2019-05-27 | 2020-12-03 | Vsy Biyoteknoloji Ve Ilac Sanayi Anonim Sirketi | A hybrid hydrogel used as a dermal filler and its production method |
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