CN107043468A - Double cross-linking sodium hyaluronate gels of a kind of heterogeneous catalysis and preparation method thereof - Google Patents

Double cross-linking sodium hyaluronate gels of a kind of heterogeneous catalysis and preparation method thereof Download PDF

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CN107043468A
CN107043468A CN201611113550.XA CN201611113550A CN107043468A CN 107043468 A CN107043468 A CN 107043468A CN 201611113550 A CN201611113550 A CN 201611113550A CN 107043468 A CN107043468 A CN 107043468A
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sodium hyaluronate
linking
cross
heterogeneous catalysis
sodium
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周长江
许世生
唐小雄
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Wuhan Yijiabao Biomaterial Co Ltd
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Wuhan Yijiabao Biomaterial Co Ltd
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    • C08J3/00Processes of treating or compounding macromolecular substances
    • C08J3/24Crosslinking, e.g. vulcanising, of macromolecules
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C08J3/02Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
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Abstract

The invention discloses double cross-linking sodium hyaluronate gels of a kind of heterogeneous catalysis and preparation method thereof.The gel is in acetone, the mixed solution of sodium hydroxide and the crosslinking agent 1 containing epoxide group by Sodium Hyaluronate dry powder, 4 butanediol diglycidyl ethers are crosslinked through Catalyzed By Phase-transfer Catalyst multiphase, react after 2~8 h and filter in 30 DEG C~70 DEG C, cross-linking hyaluronic acid sodium powder is transferred into pH value to continue to react 72 h in the environment of 2~5.5, washing, dries, collect and filling after sieving powder is swelled sterilizing through high pressure obtains a kind of double cross-linking sodium hyaluronate gels of heterogeneous catalysis.New type gel prepared by the present invention has stronger resistance to enzymic degradation ability, and is a kind of surgical plastic tissue filling agent of great competitiveness with good viscoplasticity and syringeability.

Description

Double cross-linking sodium hyaluronate gels of a kind of heterogeneous catalysis and preparation method thereof
Technical field
The present invention relates to double cross-linking sodium hyaluronate gels of a kind of heterogeneous catalysis for tissue filling and preparation method thereof.
Background technology
Hyaluronic acid(Hyaluronic Acid, HA)For a kind of linear polysaccharide, by β -1,3- glucose acetamides(β-1, 3-N-acetylglucosamine)With β -1,4- gluconic acids(β-1,4-glucuronic acid)With β-Isosorbide-5-Nitrae glucosides key-shaped Into repetition disaccharide unit, this disaccharides repeat unit again with β -1,3 glycosidic bonds repeat connect, formed straight chain polymer polymer. Hyaluronic acid can absorb the moisture of more than 500 times of relative self-molecules present amount, at the same can influence the transfer of cell, differentiation, growth, Blood vessel transfer, immunological regulation and radicals scavenging etc..In addition, hyaluronic acid does not have kind sex differernce, with extremely excellent life Thing compatibility and biodegradability, are widely used in medicine and skin care item.
Current Sodium Hyaluronate is moistened in abdominopelvic cavity post-operation adhesion preventing, ophthalmologic operation with ophthalmology viscoelastic agent and knee joint It is used widely in terms of synovia.And these hyaluronic acids are all natural without modification, existence time is shorter in vivo, Degraded by interior free yl or Sodium Hyaluronate enzyme, generally two weeks to one month or so.However, certain fields may need The presence cycle of hyaluronic acid sodium gel in vivo is longer(Such as:Tissue filling needs to reach more than six months), it is unmodified Sodium Hyaluronate comparatively fast limits its application due to degraded.Accordingly, it would be desirable to by natural Sodium Hyaluronate by chemical crosslinking shape Into fine and close three-dimensional network-like structure, restraint of liberty base or Sodium Hyaluronate enzyme are to the degradation capability of Sodium Hyaluronate, Jin Eryan There is the cycle in vivo in long its.
Contain multiple hydroxyls and multiple carboxyls on the linear molecule chain of Sodium Hyaluronate, can be by selecting suitable crosslinking agent (Such as:Glutaraldehyde, ether epoxy, carbodiimides etc.)Carry out cross-linking reaction.When the usage amount of crosslinking agent is less, crosslink density is not Enough, the presence cycle of prepared cross-linking sodium hyaluronate gel in vivo is shorter;And when the usage amount of crosslinking agent is more, though The three-dimensional net structure so formed is very close, extends degradation time in vivo, but prepared cross-linking sodium hyaluronate gel Quality is partially hard, and Swelling Capacity is poor, reduces its injectivity.Meanwhile, Sodium Hyaluronate is after the completion of crosslinking, possible residual fraction Unreacted(Including:Single-ended be not bonded is not bonded with two ends)Crosslinking agent be covered by three-dimensional net structure, influence it to give birth to Thing compatibility, rejection is caused to human body.Product on the market, is substantially by crosslinked dose of crosslinking shape of Sodium Hyaluronate at present Into after gel, the purpose of control residual cross-linker is reached by tedious steps such as dialysis, purifying, such technology mode is not only Production cycle length, cost are high, and the control of residual volume is also not ideal.
Chinese patent literature CN 101502677(Application number 200810009194.6)Disclose a kind of injection crosslinking saturating Sour sodium gel of bright matter and preparation method thereof.First, by Sodium Hyaluronate and crosslinking agent BDO diglycidyl ether (BDDE)Reaction prepares water-insoluble cross-linking sodium hyaluronate gel;Then, obtained cross-linking sodium hyaluronate gel is placed in Sieved after being fully swelled in deionized water, the purpose of reduction residual cross-linker is reached by diffusion;Finally, the ion of solution is improved Intensity shrinks gel particle, collects aqueous gel particle, cross-linking sodium hyaluronate gel product is obtained after sterilizing.The program In, cross-linking sodium hyaluronate gel is first swelled after-contraction, whole complex production process, inefficiency, production cost are higher, together When be difficult to ensure that prepared cross-linking sodium hyaluronate gel particle infiltration flattens weighing apparatus.
Chinese patent literature CN 102731801(Application number 201210245094.X)A kind of surgical plastic is disclosed to hand over Join hyaluronic acid sodium gel and preparation method thereof.First, by Sodium Hyaluronate dry powder dispersion in the hydrogen by the wt% of 10 wt%~20 In the mixed solution of sodium oxide molybdena and acetone composition, addition crosslinking agent reaction prepares water and is impermissible for cross-linking hyaluronic acid sodium powder;So Afterwards, obtained cross-linking hyaluronic acid sodium powder is washed with acetone, the residual quantity of crosslinking agent is controlled;Finally, it is swelled after crossing sieve classification And sterilize, prepare surgical plastic cross-linking sodium hyaluronate gel.In the program, because Sodium Hyaluronate dry powder is in acetone It is insoluble with the mixed solution of sodium hydroxide, and crosslinking agent is solvable, forms heterogeneous reaction system.Crosslinking agent and Sodium Hyaluronate Dry powder contact area is small, reacts not abundant enough, and prepared cross-linking sodium hyaluronate gel is partially soft, moulding ability is poor, degraded It hurry up.
Chinese patent literature CN 102863631(Application number 201210372786.0)Disclose a kind of surgical plastic group Knit filler cross-linking sodium hyaluronate gel and preparation method thereof.The art solutions are handed over using epoxy ether crosslinking agent While connection, the appropriate long chain alkane containing epoxy radicals is introduced(The carbon atom number of long chain alkane is 6~18), show simultaneously:Profit It is produced from the hydrophobicity and hydrophobic association of long chain alkane and sticks cluster formed by self aggregation function to increase resistance to enzymic degradation Effect.But introduce the also worth discussion of long-term influence that the long chain alkane of 6~18 carbon numbers is caused on human body, and single-ended crosslinking Close network structure and then the more enzymolysis sites of exposure can not be formed, to internal resistance to enzymic degradation effect promoting and are failed to understand It is aobvious.
In summary, the present invention proposes double cross-linking sodium hyaluronate gels of a kind of heterogeneous catalysis and preparation method thereof.First, Increase the contact area of cross-linking reaction by phase transfer catalyst, it is full cross-linked in the basic conditions to prepare cross-linking hyaluronic acid sodium Obtained cross-linking sodium hyaluronate gel, is then placed under acid condition and carries out second of crosslinking, make to be coated on network by gel Residual cross-linker in structure carries out the second secondary response, and detection crosslinking agent residual quantity is less than 2 ppm, i.e.,:Need not move through dialysis, The techniques such as purifying just can inject human body, and external resistance to enzymic degradation ability is excellent and with good injection property.Therefore, the present invention is excellent Change existing preparation technology, improve its production efficiency, it is significant.
The content of the invention
It is an object of the invention to provide double cross-linking sodium hyaluronate gels of a kind of heterogeneous catalysis and preparation method thereof.
The technical scheme for realizing the object of the invention is a kind of double cross-linking sodium hyaluronate gels of heterogeneous catalysis and its preparation side Method, comprises the following steps:
Sodium Hyaluronate is obtained in the mixed solution that 1. Sodium Hyaluronate dry powder evenly spread to sodium hydroxide and acetone Acetone alkaline solution, crosslinking agent and phase transfer catalyst, stirring mixing are added into above-mentioned Sodium Hyaluronate acetone alkaline solution After uniform 15 min, it is placed at 30 DEG C~70 DEG C and is incubated the h of catalytic reaction 2 h~8, reaction is filtrated to get cross-linked transparent after terminating Matter acid sodium A powder;
2. cross-linking hyaluronic acid sodium A powder is transferred into pH value to filter to continue in the environment of 2~5.5 to react after 72 h, obtained The Hyal powder that double cross joins under to acid condition;
3. by step 2. in obtained double cross join Hyal powder through phosphate buffer and purifying water washing, dry It is dry, collect sieving powder and cross 80 mesh stainless steels steel sieve, add water for injection and fully molten under the kPa of 101 kPa~303 It is swollen, collect that filling after the hyaluronic acid sodium gel that the gel particle after being swelled is crosslinking is swelled sterilizing through high pressure to obtain one kind more Mutually it is catalyzed double cross-linking sodium hyaluronate gels.
Above-mentioned steps 1. in phase transfer catalyst be:Benzyltrimethylammonium hydroxide, TBAB and the tetradecane One kind in base trimethyl ammonium chloride.
Above-mentioned steps 1. in crosslinking agent be the 1,4- butanediol diglycidyl ethers containing epoxide group(BDDE).
Above-mentioned steps 1. in sodium hydroxide and the volume ratio of acetone be(2:8)~(6:4).
Above-mentioned steps 1. in Sodium Hyaluronate dry powder molecular weight distribution between the kDa of 800 kDa~2200.
Above-mentioned steps 1. in the mass ratio of crosslinking agent and Sodium Hyaluronate dry powder be(1:10)~(1:1).
Above-mentioned steps 2. in pH value be 2~5.5 environment be one kind in watery hydrochloric acid, acetic acid or citric acid, react bar Part is normal temperature.
The solution have the advantages that:Increase the contact area of cross-linking reaction by phase transfer catalyst, in alkalescence condition Under it is full cross-linked prepare cross-linking sodium hyaluronate gel, then obtained cross-linking sodium hyaluronate gel is placed under acid condition Carry out second to be crosslinked, the residual cross-linker of cladding in the network architecture is carried out the second secondary response, detect crosslinking agent residual quantity Less than 2 ppm, i.e.,:Needing not move through the techniques such as dialysis, purifying just can inject human body.The present invention has found simultaneously, then turns by phase Move after catalytic crosslinking, the secondary cross-linking under acid condition is carried out using other decorating sites of Sodium Hyaluronate so that the present invention Cross-linking sodium hyaluronate gel resistance to enzymic degradation ability in vitro add more than twice, when extending its reservation in vivo Between and effect stability.Exception, soft texture, multiple injection after cross-linking sodium hyaluronate gel prepared by the present invention is swelled through high pressure Result of the test shows that injectability is excellent, is relatively easy to the disposable sterilized stainless steel syringe needle by 30G.
Brief description of the drawings
Fig. 1 is the double cross-linking sodium hyaluronate gels of heterogeneous catalysis1H-NMR spectrum(a), unmodified Sodium Hyaluronate Gel1H-NMR spectrum(b), crosslink density with BDDE contents change curve(c).
Fig. 2 is the external resistance to enzymic degradation ability of the double cross-linking sodium hyaluronate gels of heterogeneous catalysis(XHA45、XHA67、XHA90 Represent embodiment 2, embodiment 3, embodiment 4 and embodiment 5 respectively with XHA112).
Fig. 3 is the swelling behavior in water and PBS solution(XHA45, XHA67, XHA90 and XHA112 represent embodiment respectively 2nd, embodiment 3, embodiment 4 and embodiment 5).
Fig. 4 for Sodium Hyaluronate strand on can decorating site figure.
Fig. 5 is the crosslinking schematic diagram of the double cross-linking sodium hyaluronate gels of heterogeneous catalysis.
Embodiment
Below in conjunction with specific embodiment, the present invention is further illustrated, but is not limited only to this.
Embodiment 1
1. by 1 g Sodium Hyaluronate dry powder(Mean molecule quantity is 180 w)Evenly spread to the M of 90 mL 0.5 hydroxide Sodium Hyaluronate acetone alkaline solution is obtained in the mixed solution of sodium and 210 mL acetone, to above-mentioned Sodium Hyaluronate acetone alkalescence 0.22 g BDO diglycidyl ether and 2.3 g phase transfer catalyst benzyl trimethyl hydrogen-oxygen are added in solution Change ammonium, be uniformly mixed after 15 min, be placed in the insulation h of catalytic reaction 2 at 45 DEG C, reaction is filtrated to get crosslinking after terminating saturating The sour sodium A powder of bright matter;
Wherein, Sodium Hyaluronate:BDO diglycidyl ether:The mass ratio of benzyltrimethylammonium hydroxide is 1:0.22:2.3, the volume ratio of sodium hydroxide and acetone is 3:7;
2. the M of 30 mL 0.25 watery hydrochloric acid is added to above-mentioned cross-linking hyaluronic acid sodium A powder, 25 DEG C are continued to react after 72 h Filtering, obtains the Hyal powder that double cross joins under acid condition.
3. by step 2. in obtained double cross join Hyal powder through phosphate buffer and purifying water washing to pH It is worth for neutrality, dries, collects sieving powder and cross 80 mesh stainless steels steel sieve, add water for injection simultaneously fully molten under 303 kPa It is swollen, collect that filling after the hyaluronic acid sodium gel that the gel particle after being swelled is crosslinking is swelled sterilizing through high pressure to obtain one kind more Mutually it is catalyzed double cross-linking sodium hyaluronate gels.
2~embodiment of embodiment 7
Specific steps are substantially the same manner as Example 1, and difference is:Step in embodiment 1 1. middle Sodium Hyaluronate: BDO diglycidyl ether:The mass ratio of benzyltrimethylammonium hydroxide is 1:0.22:2.3, and embodiment 2~reality Apply in example 6, Sodium Hyaluronate:BDO diglycidyl ether:The mass ratio of benzyltrimethylammonium hydroxide presses table one It is shown to be added, obtain the cross-linking sodium hyaluronate gel under different phase transfer catalysis (PTC) agent contents and crosslinker ratio.
Sodium Hyaluronate, BDDE, the rate of charge of benzyltrimethylammonium hydroxide in the embodiment of table one
Detect the crosslink density of cross-linking sodium hyaluronate gel made from embodiment 1 to embodiment 7, enzyme degradation rate, water and Swellbility, syringeability energy in PBS solution(The disposable sterile stainless steel syringe needles of 30G)And cytotoxicity.
Specific detection method is as follows:
The detection of the crosslink density of the double cross-linking sodium hyaluronate gels of heterogeneous catalysis
Cross-linking sodium hyaluronate gel is handled at pH=2,70 DEG C, is then neutral, mistake with sodium dihydrogen phosphate regulation pH D is used after filter again2O dissolves, and is detected with H-NMR, and detection spectrogram is as shown in Figure of description 1, by comparing O-CH2CH2Peak The areal calculation degree of cross linking.
Figure of description 11In H-NMR spectrum, embodiment 1 after chemical crosslinking at the ppm of chemical shift 1.6 relative to Embodiment 7 newly increases a peak, shows after being crosslinked through multiple chemical ,-CH on Sodium Hyaluronate ring2OH reacts shape with epoxide group Into ehter bond.Crosslink density is obtained by peak area contrast, change curve of the crosslink density with BDDE contents is drawn(Fig. 3), from reality Example 1 is applied to embodiment 5 to show:Crosslink density is proportionate with BDDE contents.And phase transfer catalyst benzyl trimethyl hydroxide The content of ammonium is not lost during the course of the reaction, therefore influences little to crosslink density.
The detection of the double cross-linking sodium hyaluronate gel antibody exoenzyme degradation capabilities of heterogeneous catalysis.
Take 0.5 g through the double cross-linking sodium hyaluronate gels of heterogeneous catalysis, add the hyaluronic acid that 2 mL concentration are 30 U/mL Sodium bull testis enzyme solutions, add the mL of PBS 3 that pH value is 7, in 37 DEG C of enzymolysis, and enzymolysis time is 0~13 day.Digest Cheng Houyong ultracentrifuges centrifuge 10 min under the rpm of rotating speed 15000, take the mL of supernatant 1, and it is 7 to add 4 mL pH value PBS.Using improvement carbazole method(With reference to Bitter .t.A modified hyaluronic acid Carbarbozole reaction.1962.4,330~333)Glucuronic acid content is determined, is multiplied by after coefficient 2.07 as enzymolysis Hyaluronic acid sodium content, divided by hyaluronic acid sodium content can obtain external resistance to enzymic degradation rate in cross-linked gel.
As can be seen that embodiment 2 is degraded completely, as crosslinking agent B DDE is used for external about 1 day from Figure of description 4 The increase of amount, the external resistance to enzymic degradation performance of embodiment 5 can extend to 13 days.
Double Study on Swelling Properties of the cross-linking sodium hyaluronate gel in water and PBS solution of heterogeneous catalysis
Using classical weighing method, precision weighs the g of cross-linking sodium hyaluronate gel 1, is swelled in purified water or PBS solution After 48 h balances, the gel quality m weighed after surface moisture after being swelled is gently wiped away with filter paper1, then by gel in 70 DEG C of bakings Drying claims to obtain quality m in case2, the swellability of the double cross-linking sodium hyaluronate gels of heterogeneous catalysis is equal to m1/m2×100。
Result shows in Figure of description 5, from embodiment 2 to embodiment 5, and with the increase of content of crosslinking agent, crosslinking is saturating Swellbility of the sour sodium gel of bright matter in purified water and PBS solution is gradually reduced, and due to containing certain ion in PBS solution Intensity, so the swellbility in PBS solution is small relative to purified water.And embodiment 7 can dissolve each other with the water of arbitrary proportion, Embodiment 6(Swelling ratio is 82)It is higher relative to embodiment 3, under same Sodium Hyaluronate and crosslinking agent usage amount, it is not added with Phase transfer catalyst, cross-linking reaction efficiency is substantially less than normal.
The double cross-linking sodium hyaluronate gel injectable performance studies of heterogeneous catalysis
The double cross-linking sodium hyaluronate gels of the heterogeneous catalysis being encapsulated in glass pre-encapsulated injector, which are loaded onto, disposably to be made With the sterile stainless steel injection needles of 30G and push handle, gel is extruded with normal occupation mode with hand propelled push rod, is judged to note with hand Penetrate and be difficult to degree.
The double cross-linking sodium hyaluronate gel syringeability energy of the heterogeneous catalysis of table two
Group Embodiment 1 Embodiment 2 Embodiment 3 Embodiment 4 Embodiment 5 Embodiment 6 Embodiment 7
Syringeability Easily Easily Easily Easily It is difficult Easily Easily
As can be seen from Table II, in addition to embodiment 5 has certain pushing difficulty, other embodiment, which is pushed, compares appearance Easily, therefore, the double cross-linking sodium hyaluronate gels of the bigger heterogeneous catalysis of selective cross-linking degree under the conditions of pushing readily, can be effective Extend its presence cycle in vivo.
The Study of cytotoxicity of the double cross-linking sodium hyaluronate gels of heterogeneous catalysis
According to standard《GB/T 16886.5-2003 BiologicalEvaluationofMedicalDevice Part V:Vitro cytotoxicity is tried Test》, by detecting that the cell proliferation rate of the double cross-linking sodium hyaluronate gels of heterogeneous catalysis carries out Study of cytotoxicity.Multiphase is urged Change double cross-linking sodium hyaluronate gels to be mixed for 0.2 g/mLRPMI1640 with mass-volume concentration and extract 72 h, pass through After 0.22 μm of polyethersulfone membranes filtering, cultivated after 10 w/mL L929 cell suspending liquids are inoculated with, treat cell attachment Supernatant is removed after growth;Control group is added into RPMI1640 nutrient solutions, experimental group adds the RPMI1640 trainings of 50% above-mentioned extraction Nutrient solution, two groups are placed in 37 DEG C of CO2gas incubator and cultivates 48 h, and culture finishes the rear MTT that 5 mg/mL are added per hole The mL of solution 0.02, continues to cultivate stopping culture after 5 h;Added per hole after 0.2 mL DMSO solution with ELIASA measure 630 Absorbance under nm, cell is experimental group mean absorbance values divided by control group mean absorbance values with respect to appreciation rate, then Classification processing is carried out according to table three.
The cell of table three is with respect to appreciation rate RCR and the relation of cytotoxicity
Cell is with respect to appreciation rate RCR Cytotoxicity
≥100% 0 grade
75%≤RCR≤99% 1 grade
50%≤RCR≤74% 2 grades
25%≤RCR≤49% 3 grades
1%≤RCR≤24% 4 grades
0 5 grades
The vitro cytotoxicity result of study of 1~embodiment of embodiment 7 is as shown in Table 4:
The Study of cytotoxicity of the double cross-linking sodium hyaluronate gels of the heterogeneous catalysis of table four
Group Embodiment 1 Embodiment 2 Embodiment 3 Embodiment 4 Embodiment 5 Embodiment 6 Embodiment 7
Cytotoxicity 1 grade 1 grade 1 grade 1 grade 2 grades 1 grade 1 grade
As a result show:The test stone of biocompatibility is met through the double cross-linking sodium hyaluronate gels of heterogeneous catalysis.

Claims (9)

1. double cross-linking sodium hyaluronate gels of a kind of heterogeneous catalysis and preparation method thereof, it is characterised in that it is Sodium Hyaluronate Dry powder is in the acetone soln containing crosslinking agent under alkaline environment after 30 DEG C~70 DEG C h of catalytic reaction 2~8 of phase transfer catalyst Filtering, cross-linking hyaluronic acid sodium powder is transferred to pH value to continue in the environment of 2~5.5 to react 72 h, then scrubbed, dry Dry, collection sieving powder is filling after being swelled sterilizing through high pressure to obtain a kind of double cross-linking sodium hyaluronate gels of heterogeneous catalysis.
2. the double cross-linking sodium hyaluronate gels of heterogeneous catalysis according to claim 1, it is characterised in that described crosslinking agent For the 1,4- butanediol diglycidyl ethers containing epoxide group(BDDE).
3. the double cross-linking sodium hyaluronate gels of heterogeneous catalysis according to claim 1, it is characterised in that described phase transfer Catalyst is:One kind in benzyltrimethylammonium hydroxide, TBAB and tetradecyl trimethyl ammonium chloride.
4. the double cross-linking sodium hyaluronate gels of heterogeneous catalysis according to claim 1, it is characterised in that described hyalomitome Sour sodium dry powder molecular weight distribution is between the kDa of 800 kDa~2200.
5. the double cross-linking sodium hyaluronate gels of heterogeneous catalysis according to claim 1, it is characterised in that the alkalescence condition Acetone soln pH value between 9~14, be adjusted by the M of 0.2 M~0.5 sodium hydroxide solution, and sodium hydroxide with The volume ratio of acetone exists(2:8)~(6:4)Between.
6. the double cross-linking sodium hyaluronate gels of heterogeneous catalysis according to claim 1, it is characterised in that described pH value is 2~5.5 environment is one kind in watery hydrochloric acid, acetic acid or citric acid, and reaction condition is normal temperature.
7. the double cross-linking sodium hyaluronate gels of heterogeneous catalysis according to claim 1, it is characterised in that specific preparation process It is as follows:Sodium Hyaluronate dry powder dispersion is obtained saturating after the M of 0.2 M~0.5 sodium hydroxide solution and the mixed solution of acetone The sour sodium alkaline solution of bright matter, then adds the crosslinking agent B DDE containing epoxide group into Sodium Hyaluronate alkaline solution, and mixing is equal Phase transfer catalyst is added after even, under the conditions of 30 DEG C~70 DEG C after the h of stirring at low speed catalytic reaction 2~8, filtering is adjusted with diluted acid The pH value of cross-linking hyaluronic acid sodium powder is to continue to react 72 h after 2~5.5 under normal temperature, filtering, with phosphate buffer and pure Change water washing to solution to be dried in vacuo after neutrality, resulting white dry powder is cross-linking hyaluronic acid sodium powder;
The cross-linking hyaluronic acid sodium powder that 1. step is prepared crosses 80 mesh stainless steels steel sieve after crushing, add water for injection simultaneously Fully it is swelled under the kPa of 101 kPa~303, collects the hyaluronic acid sodium gel that the gel particle after being swelled is crosslinking;
The hyaluronic acid sodium gel that 2. step is collected is filling in the disposable pre-encapsulated injector sterilized in advance, and 115 DEG C~134 DEG C at the min of the min of high-temp steam sterilizing 5~30, you can obtain a kind of can be used for surgical plastic tissue filling agent many Mutually it is catalyzed double cross-linking sodium hyaluronate gels.
8. the specific preparation process of the double cross-linking sodium hyaluronate gels of heterogeneous catalysis according to claim 7, it is characterised in that By adding the contact area of phase transfer catalyst, increase solid phase and liquid phase, intensified response efficiency makes the cross-linked transparent matter of preparation Sour sodium gel network structure is more fine and close, and viscoplasticity is more preferable.
9. the cross-linking hyaluronic acid sodium powder prepared under alkalescence condition simultaneously, is placed in into secondary cross-linking under acid condition, both improved The crosslink density of Sodium Hyaluronate, again solves the residue problem of cladding crosslinking agent in the network architecture, eliminates dialysis pure Change this tedious steps, improve production efficiency.
CN201611113550.XA 2016-12-07 2016-12-07 Double cross-linking sodium hyaluronate gels of a kind of heterogeneous catalysis and preparation method thereof Pending CN107043468A (en)

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CN109939612A (en) * 2019-03-11 2019-06-28 上海发凯化工有限公司 Guerbet alcohol alkyl glucoside surfactant and preparation method thereof
CN110016152A (en) * 2019-05-10 2019-07-16 山东华皙梦生物科技有限公司 It is crosslinked the preparation method of filling hyaluronic acid sodium gel
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CN111363171A (en) * 2020-04-02 2020-07-03 南昌大学第二附属医院 Antibacterial hydrogel and preparation method and application thereof
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