CN102321258A - High-crosslinking-degree hyaluronic acid through synthesis involved by quaternary ammonium base and process method thereof - Google Patents
High-crosslinking-degree hyaluronic acid through synthesis involved by quaternary ammonium base and process method thereof Download PDFInfo
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Abstract
The invention relates to a high-crosslinking-degree hyaluronic acid through synthesis involved by quaternary ammonium base and a process method thereof. According to the invention, a crosslinking agent for crosslinking reaction of hyaluronic acid (HA) is 1,2,7,8-diepoxyoctane (DEO); the quaternary ammonium base is used as a combination of a base catalyst and a phase transfer catalyst; the quaternary ammonium base is synthesized by using an oxidation method or an ethanol method; and regulation is carried out with hydrochloric acid until subacidity is formed. In the invention, the crosslinking process of first base and later acid can ensure that the hydroxyl and carboxyl of HA participate in crosslinking. The invention has the advantages that reaction conditions are simple, the crosslinking agent utilization is high, and the thermal stability of gel is good and has sterility, no toxicity, no pyrogen, biocompatibility and the like.
Description
Technical field
The present invention relates to a kind of quaternary ammonium hydroxide and participate in synthetic high-crosslinking-degree mucinase and process method thereof, the linking agent that the crosslinking reaction of mucinase (HA) adopts is 1,2; 7,8-diepoxy octane (DEO) is with the combination of quaternary ammonium hydroxide as alkaline catalysts and phase-transfer catalyst; Adopt behind the first alkali acid method of concentrating under reduced pressure again; Synthesis of hydroxy and carboxyl double cross couplet and degree of crosslinking are high, and stability is strong, and the hyaluronic acid derivatives of high-biocompatibility or hyaluronic acid membrane.It is simple that the present invention has a reaction conditions, and the linking agent utilization ratio is high, the better heat stability of gel, aseptic nontoxic pyrogen-free, advantages such as biocompatibility.
Background technology
Mucinase (Hyaluronic acid, HA) has another name called Hyaluronic Acid, and mucinase is a kind of acidic mucopolysaccharide, and the ophthalmology professor Meyer of Columbia Univ USA in 1934 etc. at first isolate this material from bovine vitreous body.Mucinase demonstrates multiple important physical function with its distinctive molecular structure and physico-chemical property in body, like lubricated joint, regulate the permeability of vessel wall, regulates protein, and Water-Electrolyte diffusion and running promote wound healing etc.Particularly importantly; Mucinase has special water retention; It is the best material of finding at present of occurring in nature moisture retention; (Natural moisturizing factor, NMF), for example: the water-soluble fluid power of 2% pure hyaluronic acid keeps 98% moisture securely to be called as the ideal natural moisturizing factor.Mucinase is a kind of multi-functional matrix, and mucinase (HA) is distributed widely in the partes corporis humani position.Wherein skin also contains a large amount of mucinases.Human skin maturation and weathering process are also along with hyaluronic content changes with metabolism; It can improve the skin-nourishing metabolism; Make skin tender, smooth, go wrinkle, increase elasticity, prevent aging, be again the good transdermal absorption enhancer when preserving moisture.Be used with other nutritive ingredients, can play the better effect that promotes dietetic alimentation.And hyaluronic acid derivatives is used for subcutaneous injection, but moment deep moisturizing, increase skin elasticity and tension force, help and recover the normal oil-water balance of skin, improve dry and lax skin.
Exploitation can be used and clinical dermal filler, just must carry out a series of chemically modified and treating processes to mucinase.If adopt noncrosslinking mucinase as dermal filler, so, the hyaluronan molecule that naturally occurring Unidasa and radical will cut-out polymerization one by one get up in skin, the noncrosslinking mucinase of degrading fast.The result makes mucinase have only one day to two days in the in-house transformation period, passes through the dilution of water then, in liver, progressively is degraded to water and carbonic acid gas.Like this, product the injection the position will be very fast lose effectiveness (one the week in), the result makes the residence time of noncrosslinking mucinase in skin receive very big restriction.Therefore, noncrosslinking mucinase does not have a curative effect that should play as dermal filler.
Chinese patent CN200710171444.1, CN00804641.7 discloses among the CN00804642.5 with 1,2; 7,8-diepoxy octane (DEO) is used as linking agent with cross-linking hyaluronic acid, but because 1,2; 7, the carbochain of 8-diepoxy octane (DEO) is longer, and molecular polarity is less, makes 1; 2,7, the solubleness of 8-diepoxy octane (DEO) in water is very little; Generally be no more than 1% (massfraction), this also caused its aqueous phase and hyaluronic crosslinking activity specific energy and water miscible 1,4-butyleneglycol bisglycidyl ether (BDDE) is poor.So these three patents all are the cross-linked hyaluronic acid gels than low crosslinking degree (＜10%) that has utilized its solubleness faint in water to prepare; If the consumption of linking agent is increased more than the twice; Fail to dissolve the linking agent that gets into water in a large number owing to exist; Be present in that linking agent in the oil phase just can not fully react with the mucinase of aqueous phase and the utilization ratio very low (＜20%) that causes linking agent, can't obtain expecting the mucinase of high-crosslinking-degree.
Adopt 1,2,7; 8-diepoxy octane (DEO) is as hyaluronic linking agent; Hyaluronic hydroxyl and carboxyl is all crosslinked, improved the stability of hyaluronan molecule, prevented the hyaluronic Degradation of Unidasa and radical pair effectively; Improved the residence time of mucinase in skin significantly, had good as the due curative effect of dermal filler.
Summary of the invention
The object of the present invention is to provide a kind of quaternary ammonium hydroxide to participate in synthetic high-crosslinking-degree mucinase and process method thereof.The linking agent that adopts is 1,2,7,8-diepoxy octane (DEO); With the combination of quaternary ammonium hydroxide, increased by 1,2,7 as alkaline catalysts and phase-transfer catalyst; The solubleness (＞20%, massfraction) of 8-diepoxy octane (DEO) in water lets it can be dissolved in equably in the hyaluronic solution simultaneously, further increases 1; 2,7, the utilization ratio (＞90%) of 8-diepoxy octane (DEO) makes the cross-linked-hyaluronic acid of high-crosslinking-degree (＞20%) be able to synthesize.The sour method of concentrating under reduced pressure again behind elder generation's alkali, synthesis of hydroxy and carboxyl double cross couplet and degree of crosslinking are high, and stability is strong, and the hyaluronic acid derivatives of high-biocompatibility or hyaluronic acid membrane.It is simple that the present invention has a reaction conditions, and the linking agent utilization ratio is high, the better heat stability of gel, aseptic nontoxic pyrogen-free, advantages such as biocompatibility.
It is with mucinase, linking agent 1,2,7 that the present invention provides a kind of quaternary ammonium hydroxide to participate in synthetic high-crosslinking-degree mucinase, and 8-diepoxy octane (DEO) and quaternary ammonium hydroxide are that raw material is synthetic, and concrete process method comprises the steps:
In the quaternary ammonium alkali solution of mucinase (HA), add linking agent 1,2; 7,8-diepoxy octane (DEO) carries out crosslinking reaction, with sour conditioned reaction solution to subacidity; Vacuum concentration to reaction soln is half one-tenth gel of original volume; Use the alkaline ethanol aqueous solution soaking, filter, vacuum-drying gets hyaluronic acid derivatives.HA and DEO mass ratio are 1: 0.2～1: 3, and the consumption of quaternary ammonium hydroxide accounts for 0.5%～30% (mass percent) of reaction system total mass; Adopt the synthetic quaternary ammonium hydroxide of oxidation style or Ethanol Method; Be adjusted to subacidity with hydrochloric acid.Behind this first alkali the cross-linking process of acid guaranteed hyaluronic hydroxyl and carboxyl equal can participate in crosslinked.
Quaternary ammonium hydroxide is participated in hyaluronic crosslinking reaction and is represented as follows:
The present invention provides a kind of quaternary ammonium hydroxide to participate in the synthetic hyaluronic process method of high-crosslinking-degree and comprises the steps:
1) mucinase is dissolved with in oxidation style or the new synthetic quaternary ammonium alkali solution of Ethanol Method, add linking agent 1,2,7 then under the room temperature, 8-diepoxy octane carries out crosslinking reaction 24-30h, and hyaluronic hydroxyl is reacted with linking agent earlier;
2) with hydrochloric acid conditioned reaction solution to subacidity (pH=5-6), vacuum concentration removes the water in the removal system, to half gel of original volume, remaining little amount of crosslinking agent and mucinase is reacted completely; Behind this first alkali the cross-linking process of acid guaranteed hyaluronic hydroxyl and carboxyl equal can participate in crosslinked.
3) soak with the aqueous ethanolic solution of the 20-40% of pH=8-9 and concentrate gel 1-3 time that the back forms; Make acid residual in the gel by neutralization fully, filtration makes gel separate with ethanolic soln, gel vacuum-drying; Solidifying and setting obtains the hyaluronic acid derivatives of degree of crosslinking at 20%-300%.
Mucinase (HA) and 1,2,7,8-diepoxy octane (DEO) mass ratio is 1: 0.2-3.
Vacuum concentration condition: be 30-35 ℃, 0.1MPa;
Vacuum-drying condition: be 50-60 ℃, dry 10-12h under the condition of 0.08-0.09MPa.
Described quaternary ammonium hydroxide can synthesize with two kinds of methods:
1) oxidation style, this method are with simple substance silver and halogenation quaternary amine aqueous solution thorough mixing, add ydrogen peroxide 50 again as oxygenant; At room temperature just can synthesize the quaternary ammonium hydroxide aqueous solution fast; Promptly can be used to dissolve mucinase after removing by filter silver halide precipitation, these method materials are few, do not introduce foreign ion and organic solvent; The deposition silver halide can recycling, environmental protection simple to operation; Described quaternary amine is preferably: Tetrabutyl amonium bromide.
X=Cl, Br; R1, R2, R3, R4 are four aliphatic groups identical or inequality or aryl.
Optional quaternary amine is a Tetrabutyl amonium bromide.
2) Ethanol Method; Prepare quaternary ammonium hydroxide with the solubleness bust and precipitating of sodium salt in ethanol: earlier halogenation quaternary amine and sodium hydroxide are dissolved in respectively in 90% ethanol; Again two kinds of solution are mixed and stir; Filter out the sodium halide post precipitation and obtain the quaternary ammonium alkali alcosol, through obtaining the quaternary ammonium alkali solution of high density behind the vacuum concentration.This method biggest advantage is exactly the quaternary ammonium hydroxide that can prepare high density, but has wherein introduced organic solvent impurity, and complicated operation.Described quaternary amine is preferably: trimethylammonium octyl group ammonium chloride.
X=Cl, Br; R1, R2, R3, R4 are four aliphatic groups identical or inequality or aryl.
Optional quaternary amine is a trimethylammonium octyl group ammonium chloride.
The benefit that adopts simple quaternary ammonium hydroxide to compare quaternary amine and sodium hydroxide combination is: the ionic strength of simple quaternary ammonium hydroxide will be lower than quaternary amine and sodium hydroxide combination; Because the increase of particle intensity can have influence on hyaluronic solubility property; And cause the mucinase can be excessive at partial concn; And caused the partial cross-linking of crosslinking reaction inhomogeneous, influenced the proterties of gel and the utilization ratio of linking agent.Therefore, the combination of quaternary ammonium hydroxide as phase-transfer catalyst and alkaline catalysts adopted in comprehensive above-mentioned consideration, make that crosslinked uniformity coefficient is better, and the utilization ratio of linking agent is higher.
The present invention adopts 1; 2,7,8-diepoxy octane (DEO) is as hyaluronic linking agent; Before the cross-linking hyaluronic acid reaction, mucinase is joined in the quaternary ammonium alkali solution; Hyaluronic hydroxyl and carboxyl is all crosslinked, improved the stability of hyaluronan molecule, prevented the hyaluronic Degradation of Unidasa and radical pair effectively.Reaction conditions of the present invention is simple, with the combination of quaternary ammonium hydroxide as alkaline catalysts and phase-transfer catalyst, has increased by 1,2; 7, the solubleness (＞20%, massfraction) of 8-diepoxy octane (DEO) in water lets it can be dissolved in the hyaluronic solution equably simultaneously; Further increase 1,2,7; The utilization ratio (＞90%) of 8-diepoxy octane (DEO), the linking agent utilization ratio is high, makes the cross-linked-hyaluronic acid of high-crosslinking-degree (＞20%) be able to synthesize.The sour method of concentrating under reduced pressure again behind elder generation's alkali, synthesis of hydroxy and carboxyl double cross couplet and degree of crosslinking are high, and stability is strong, and the hyaluronic acid derivatives of high-biocompatibility or hyaluronic acid membrane.The better heat stability of gel of the present invention, aseptic nontoxic pyrogen-free, advantages such as biocompatibility.The prepared cross-linked hyaluronic acid gel of the present invention is with gas chromatographic detection 1,2,7; The residual quantity of 8-diepoxy octane (DEO), its residual value all is lower than the detection limit of gc, and linking agent 1 has been described; 2,7, the utilization ratio of 8-diepoxy octane (DEO) in crosslinking reaction is very high.The present invention has improved the residence time of mucinase in skin significantly, has good in the due curative effect of dermal filler.
Description of drawings
Fig. 1: quaternary ammonium hydroxide is participated in crosslinked mucinase and is participated in crosslinked hyaluronic infrared comparison diagram with no quaternary ammonium hydroxide.
Fig. 2: quaternary ammonium hydroxide is participated in crosslinked hyaluronic of crosslinked mucinase and no quaternary ammonium hydroxide participation
13C NMR solid state nmr comparison diagram.
Fig. 3: 1,2,7, the gas chromatogram of 8-diepoxy octane (DEO) standard.
Fig. 4: the gas chromatogram of cross-linked-hyaluronic acid elutriant.
Embodiment
Following examples are used to explain the present invention, but do not limit the present invention.
Embodiment 1: quaternary ammonium hydroxide synthetic
Embodiment 1a: oxidation style is synthesized quaternary ammonium hydroxide
That the quaternary ammonium halides salt in this reaction is selected for use is Tetrabutyl amonium bromide (TBAB).
The 6.44g Tetrabutyl amonium bromide is dissolved in the 100ml water, adds 2.5g simple substance silver powder, after in 25 ℃ of induction stirring, being uniformly dispersed rapidly, slowly drip 30% ydrogen peroxide 50 10ml, continue to react with this understanding 6h.Stop induction stirring, get 1ml left and right sides supernatant liquid,, do not occur, can confirm that then oxidizing reaction is complete if there is faint yellow Silver monobromide deposition this moment with dripping several Silver Nitrates with the back in the nitric acid.Reaction solution promptly can be used to dissolve mucinase removing by filter the Silver monobromide post precipitation, participates in crosslinking reaction.
By product Silver monobromide in the reaction can recycle after decomposition.
Embodiment 1b: Ethanol Method is synthesized quaternary ammonium hydroxide
That the quaternary ammonium halides salt in this reaction is selected for use is octyl group trimethyl ammonium chloride (OTMAC).
4.18g octyl group trimethyl ammonium chloride is dissolved in the ethanol of 100ml 90%, joins 100ml again and dissolved in 90% the ethanol of 0.8g NaOH, in 25 ℃ of induction stirring, mix rapidly, and react 12-18h with this understanding.Remove by filter NaCl deposition, in 35-40 ℃, vacuum tightness is to concentrate under the condition of 0.08～0.09MPa, obtains the quaternary ammonium alkali solution of high density, and ethanol content is no more than 5%.
Embodiment 2: high crosslinked the synthetic of phaneroplasm acid of spending
The quaternary ammonium hydroxide highly concentrated solution that any one method obtains among the embodiment 1, dilution is made into the quaternary ammonium alkali solution that concentration is 0.1mol/L, gets 100mL; Add 10g hyaluronate sodium (Shandong Fu Ruida products), stirring 12-14h is after being stirred to hyaluronate sodium and dissolving fully; In reaction system, add 3g 1,2,7 again; 8-diepoxy octane (DEO) stirs rapidly, reacts 24 hours down at 25 ℃.Reaction stops with 2mol/L hydrochloric acid, transfers to about pH=5, and simultaneously at 40 ℃, the water in the reaction system is removed in distillation under the vacuum degree condition of 0.1MPa, when the water that distills out reaches 50mL, stops underpressure distillation.Divide 3 ethanolic solns (NaOH preparation) of 30% to soak with 200mL pH=8-9, in and the hydrochloric acid of gel.Gel after the neutralization is changed in the vacuum drying oven, and in 60 ℃, dry 10h makes the gel solidification typing under the condition of 0.08-0.09MPa, and the gel water-intake rate is 45 times.The gained gel is at 90 ℃, and 0.09MPa vacuum-drying is to weight, and its Fourier infrared spectrum and 13C solid-state nuclear magnetic resonance spectrum are shown in Figure of description 1,2.600mL 30% ethanolic soln that is used in the reaction process soak gel behind concentrating under reduced pressure, through in the gas chromatographic analysis solution 1,2,7, the residual quantity of 8-diepoxy octane (DEO), its color atlas is shown in Figure of description 4.
Fig. 1, the 2nd, adopt ir spectra and 13C NMR solid-state nuclear magnetic resonance spectrum respectively to quaternary ammonium hydroxide cross-linked-hyaluronic acid of participating in and the characterization result that does not add the cross-linked-hyaluronic acid of quaternary ammonium hydroxide are arranged.From infrared and nuclear-magnetism, can both significantly find out: when not adding the quaternary ammonium hydroxide catalyzer, because 1,2; 7, the reactive behavior of 8-diepoxy octane (DEO) is lower, causes in the crosslinking reaction utilization ratio of linking agent low; Linking agent on actual and the cross-linking hyaluronic acid is less, therefore on nuclear-magnetism and ir spectra 1,2; 7, the characteristic peak of 8-diepoxy octane (DEO) is also not obvious; And after adding the quaternary ammonium hydroxide catalyzer, because 1,2,7; The solubleness of 8-diepoxy octane (DEO) in water increases, and its reactive behavior is strengthened, and the linking agent utilization ratio increases, and therefore on nuclear-magnetism and ir spectra, just can demonstrate tangible 1; 2,7, the characteristic peak of 8-diepoxy octane (DEO).So after having added quaternary ammonium hydroxide, can significantly improve 1,2,7, the reactive behavior of 8-diepoxy octane (DEO) improves its utilization ratio.
Fig. 3; 4 is 1,2,7; The gc contrast of 8-diepoxy octane (DEO) standard and cross-linked-hyaluronic acid elutriant; Can find out that from gas chromatogram the content of residual free cross-linker has been lower than the minimum detectability of gc in the mucinase, the utilization ratio that linking agent is described is more than 90%.
Comparative Examples: no quaternary ammonium hydroxide catalyzer, not synthetic through the cross-linked-hyaluronic acid of concentrating under reduced pressure
Get 100mL zero(ppm) water, add 10g hyaluronate sodium (Shandong Fu Ruida product), stir 12-14h; After being stirred to hyaluronate sodium and dissolving fully, add 10ml 10% NaOH solution stirring 0.5h, in reaction system, add 3g 1 again; 2,7,8-diepoxy octane (DEO); Stir rapidly, reacted 24 hours down at 25 ℃.Reaction stops with 2mol/L hydrochloric acid, transfers to about pH=5, continues reaction 4h.Divide 3 30% alcohol solution dippings with 200mL pH=8-9, in the hydrochloric acid of gel.The gained gel is at 90 ℃, and 0.09MPa vacuum-drying is to weight, and its Fourier infrared spectrum and 13C solid-state nuclear magnetic resonance spectrum are shown in Figure of description 1,2.600mL 30% ethanolic soln that is used in the reaction process soak gel is behind concentrating under reduced pressure, through in the gas chromatographic analysis solution 1,2; 7, the residual quantity of 8-diepoxy octane (DEO) is through chromatogram ration analysis; In the solution 1,2,7; The total content of 8-diepoxy octane (DEO) is 2.4g, explains that participating in crosslinked linking agent is 0.6g, and utilization ratio is 20%.
Claims (10)
1. a quaternary ammonium hydroxide is participated in synthetic high-crosslinking-degree mucinase, it is characterized in that it is with mucinase, linking agent 1,2,7, and 8-diepoxy octane (DEO) and quaternary ammonium hydroxide are that raw material is synthetic, and concrete process method comprises the steps:
In the quaternary ammonium alkali solution of mucinase (HA), add linking agent 1,2; 7,8-diepoxy octane (DEO) carries out crosslinking reaction, with sour conditioned reaction solution to subacidity; Vacuum concentration to reaction soln is half one-tenth gel of original volume; Use the alkaline ethanol aqueous solution soaking, filter, vacuum-drying gets the high-crosslinking-degree hyaluronic acid derivatives; HA and DEO mass ratio are 1: 0.2-1: 3, and the consumption of quaternary ammonium hydroxide accounts for the 0.5-30% of reaction system total mass.
2. high-crosslinking-degree mucinase according to claim 1 is characterized in that: described quaternary ammonium hydroxide is to adopt oxidation style or Ethanol Method to synthesize.
3. the described quaternary ammonium hydroxide of claim 1 is participated in the synthetic hyaluronic process method of high-crosslinking-degree, it is characterized in that it comprises the steps:
1) mucinase is dissolved in the new synthetic quaternary ammonium alkali solution, adds linking agent 1,2,7 then under the room temperature, 8-diepoxy octane carries out crosslinking reaction 24-30h, makes hyaluronic hydroxyl elder generation and linking agent reaction;
2) with hydrochloric acid conditioned reaction solution to subacidity, pH=5-6, vacuum concentration remove the water in the removal system, to half gel of original volume, remaining little amount of crosslinking agent and mucinase are reacted completely; Behind this first alkali the cross-linking process of acid guaranteed hyaluronic hydroxyl and carboxyl equal can participate in crosslinked;
3) soak with the aqueous ethanolic solution of the 20-40% of pH=8-9 and concentrate gel 1-3 time that the back forms; Make acid residual in the gel by neutralization fully, filtration makes gel separate with ethanolic soln, gel vacuum-drying; Solidifying and setting obtains the hyaluronic acid derivatives of degree of crosslinking at 20%-300%.
4. method according to claim 3 is characterized in that: described mucinase (HA) and 1,2,7, and 8-diepoxy octane (DEO) mass ratio is 1: 0.2-3; The consumption of quaternary ammonium hydroxide accounts for the 0.5-30% of reaction system total mass.
5. method according to claim 3 is characterized in that: described vacuum concentration condition: be 30-35 ℃, 0.1MPa.
6. method according to claim 3 is characterized in that: described vacuum-drying condition: be 50-60 ℃, dry 10-12h under the condition of 0.08-0.09MPa.
7. method according to claim 3 is characterized in that: described quaternary ammonium hydroxide oxidation style is synthetic:
With simple substance silver and halogenation quaternary amine aqueous solution thorough mixing, add ydrogen peroxide 50 again as oxygenant, at room temperature just can synthesize the quaternary ammonium hydroxide aqueous solution fast, promptly can be used to dissolve mucinase after removing by filter silver halide precipitation;
X=Cl, Br; R1, R2, R3, R4 are four aliphatic groups identical or inequality or aryl.
8. method according to claim 7 is characterized in that: described quaternary amine is a Tetrabutyl amonium bromide.
9. method according to claim 3 is characterized in that: described Ethanol Method prepares quaternary ammonium hydroxide: earlier halogenation quaternary amine and sodium hydroxide are dissolved in respectively in 90% ethanol, two kinds of solution are mixed stir again, filter out the sodium halide post precipitation
Obtain the quaternary ammonium alkali alcosol, through obtaining the quaternary ammonium alkali solution of high density behind the vacuum concentration;
X=Cl, Br; R1, R2, R3, R4 are four aliphatic groups identical or inequality or aryl.
10. method according to claim 9 is characterized in that: described quaternary amine is a trimethylammonium octyl group ammonium chloride.
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| PCT/CN2011/084096 WO2012146031A1 (en) | 2011-04-26 | 2011-12-16 | Composite gel of hyaluronic acid and hydroxypropyl methylcellulose and production method therefor |
| US13/844,842 US20130217872A1 (en) | 2011-04-26 | 2013-03-16 | Method for producing composite gel by cross-linking hyaluronic acid and hydroxypropyl methylcellulose |
| US15/202,664 US20160310522A1 (en) | 2011-04-26 | 2016-07-06 | Method for producing composite gel by cross-linking hyaluronic acid and hydroxylpropyl methylcellulose |
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| CN107043468A (en) * | 2016-12-07 | 2017-08-15 | 武汉医佳宝生物材料有限公司 | Double cross-linking sodium hyaluronate gels of a kind of heterogeneous catalysis and preparation method thereof |
| CN107556402A (en) * | 2017-10-18 | 2018-01-09 | 重庆工商大学 | Cationized hyaluronic acid and preparation method thereof |
| CN107739417A (en) * | 2017-11-03 | 2018-02-27 | 扬州中福生物技术有限公司 | A kind of preparation method of Cationized hyaluronic acid |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMI20120732A1 (en) * | 2012-05-03 | 2013-11-04 | B S Srl | POLYSACCHARIDES RETICULATED IN SHAPE MEMORY |
| WO2013164782A1 (en) * | 2012-05-03 | 2013-11-07 | Medical And Biotechnological Services Srl In Abbreviated Form M.B.S. Srl | Shape-memory cross-linked polysaccharides |
| CN107043468A (en) * | 2016-12-07 | 2017-08-15 | 武汉医佳宝生物材料有限公司 | Double cross-linking sodium hyaluronate gels of a kind of heterogeneous catalysis and preparation method thereof |
| CN107556402A (en) * | 2017-10-18 | 2018-01-09 | 重庆工商大学 | Cationized hyaluronic acid and preparation method thereof |
| CN107739417A (en) * | 2017-11-03 | 2018-02-27 | 扬州中福生物技术有限公司 | A kind of preparation method of Cationized hyaluronic acid |
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