CN108250462A - A kind of resistance to enzymolysis cross-linking sodium hyaluronate gel and preparation method thereof and preparation - Google Patents
A kind of resistance to enzymolysis cross-linking sodium hyaluronate gel and preparation method thereof and preparation Download PDFInfo
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Abstract
The invention belongs to biomedicine fields, are related to a kind of resistance to enzymolysis cross-linking sodium hyaluronate gel and preparation method thereof and preparation.Specifically, the preparation method of the present invention includes the following steps：1) using two kind Sodium Hyaluronates of the lye dissolving with different molecular weight；2) crosslinking of two kinds of Sodium Hyaluronates；3) precipitation of cross-linking hyaluronic acid sodium, washing and drying；4) swelling of cross-linking hyaluronic acid sodium powder.Using high and low molecular weight hyaluronic acid sodium, crosslinked mode obtains resistance to enzymolysis cross-linking sodium hyaluronate gel to the present invention mutually, it has stable three-dimensional net structure, it heat resistanceheat resistant solution performance, resistance to enzymic degradation and injects fluency and is improved significantly, preparation method reduces processing step, production cost is saved, has the advantages that easy to operate, concentration is controllable.
Description
Technical field
The invention belongs to biomedicine field, be related to a kind of resistance to enzymolysis cross-linking sodium hyaluronate gel and preparation method thereof and
Preparation.
Background technology
Hyaluronic acid (also known as sodium hyaluronate) is that one kind is connected by glucuronic acid and N-acetylglucosamine by glycosidic bond
The linear macromolecule polysaccharide connect.Under physiological status, hyaluronic acid usually exists with sodium-salt form.Sodium Hyaluronate is thin
The important component of extracellular matrix has the transhipment for adjusting immune, barrier protection, adjusting osmotic pressure, regulating and controlling macromolecular substances
Etc. a variety of effects.Sodium Hyaluronate can be used for the auxiliary treatment of ophthalmologic operation adjuvant drug and osteoarthritis, and be repaiied in wound
Multiple, tissue generation etc. has important physiological function.
Conventional method for improving cross-linking hyaluronic acid sodium resistance to enzymolysis performance is by increasing crosslinker concentration, improving and hand over
It is realized the methods of starting transparent matter acid na concn during connection, but frequently can lead to cross-linking hyaluronic acid sodium transparency reduce, is biological
Poor compatibility injects the shortcomings of poor performance, is unfavorable for the clinical practice of product.
Invention content
For the resistance to enzymolysis performance of cross-linking sodium hyaluronate gel of the prior art it is bad and for improving crosslinking it is solidifying
The method of glue resistance to enzymolysis performance can lead to problems such as gel biological compatibility poor, the present invention is intended to provide a kind of novel resistance to enzymolysis is handed over
Join hyaluronic acid sodium gel and preparation method thereof and preparation.The present invention is made using two kinds of Sodium Hyaluronates with different molecular weight
It for raw material, is crosslinked in alkaline environment, after organic solvent deposit, washing, drying, swelling, it is saturating to obtain resistance to enzymolysis crosslinking
Bright matter acid sodium gel.The cross-linking sodium hyaluronate gel has many advantages, such as that controllable concentration, low cross-linking agent residual, resistance to enzymolysis are strong.
Entire preparation method is easy to operation, easily controllable.
Specifically, the present invention adopts the following technical scheme that：
A kind of preparation method of resistance to enzymolysis cross-linking sodium hyaluronate gel, includes the following steps：
1) Sodium Hyaluronate is dissolved using lye：
The mixture being made of high molecular weight sodium hyaluronate and low molecular weight sodium hyaluronate is dissolved in lye, is obtained
To the alkaline solution of Sodium Hyaluronate；
2) crosslinking of Sodium Hyaluronate：
Under agitation, crosslinking agent is added in the alkaline solution of the Sodium Hyaluronate obtained into step 1), in 25~
55 DEG C are reacted 1~6 hour, obtain the alkaline solution of cross-linking hyaluronic acid sodium；
3) precipitation of cross-linking hyaluronic acid sodium, washing and drying：
The pH value of the alkaline solution of the cross-linking hyaluronic acid sodium obtained in step 2) is adjusted to 6.5~7.5 using acid, then
Add in precipitating solvent, until until being no longer precipitated and precipitating, then using precipitating solvent by the washing of precipitate 5 times of precipitation with
On, low-temperature vacuum drying obtains cross-linking hyaluronic acid sodium powder；
4) swelling of cross-linking hyaluronic acid sodium powder：
Aseptically, the cross-linking hyaluronic acid sodium powder obtained in step 3) is added to phosphate buffer (PBS
Buffer solution) in, it is fully stirred evenly after swelling, obtains resistance to enzymolysis cross-linking sodium hyaluronate gel.
In a preferred technical solution, by weight percentage, mixture is by 10%~50% described in step 1)
The high molecular weight sodium hyaluronate and 50%~90% the low molecular weight sodium hyaluronate composition.
In a preferred technical solution, high molecular weight sodium hyaluronate described in step 1) and the low molecular weight are saturating
Bright matter acid sodium is made by bacterial fermentation process.
In a preferred technical solution, the molecular weight of high molecular weight sodium hyaluronate described in step 1) for 1.0 ×
106~4.0 × 106Dalton, preferably 1.5 × 106~3.0 × 106Dalton.
In a preferred technical solution, the molecular weight of low molecular weight sodium hyaluronate described in step 1) for 1.0 ×
105~1.0 × 106Dalton, preferably 2.0 × 105~5.0 × 105Dalton.
In a preferred technical solution, lye described in step 1) is water-soluble for sodium hydrate aqueous solution or potassium hydroxide
Liquid.
In a preferred technical solution, the molar concentration of lye described in step 1) is 0.1~0.5 mol/L, excellent
Select 0.25 mol/L.
In a preferred technical solution, the amount ratio of mixture described in step 1) and the lye is 1~2 gram:
10 milliliters, preferably 1 gram:10 milliliters.
In a preferred technical solution, crosslinking agent described in step 2) is 1,4-butanediol diglycidyl ether
(BDDE) or divinylsulfone (DVS).
In a preferred technical solution, the weight ratio of crosslinking agent described in step 2) and mixture described in step 1)
It is 1:5~100, preferably 1:10~50.
In a preferred technical solution, acid described in step 3) is hydrochloric acid.
In a preferred technical solution, precipitating solvent described in step 3) is alcohol or its aqueous solution, wherein described
Alcohol is methanol, ethyl alcohol or isopropanol.
In a preferred technical solution, the temperature of low-temperature vacuum drying described in step 3) is 0~4 DEG C.
In a preferred technical solution, under phosphate buffer described in step 4) includes by weight percentage
Row ingredient：0.65%~0.9% sodium chloride (NaCl), 0.05%~0.2% disodium hydrogen phosphate (Na2HPO4), 0.005%
~0.03% sodium dihydrogen phosphate (NaH2PO4) and surplus purified water, the pH value of the phosphate buffer is 6.5~7.5.
In a preferred technical solution, cross-linking hyaluronic acid sodium powder described in step 4) and the phosphate-buffered
The amount ratio of liquid is 15~30 milligrams:1 milliliter, preferably 20 milligrams:1 milliliter.
A kind of resistance to enzymolysis cross-linking sodium hyaluronate gel is made by above-mentioned preparation method.
A kind of resistance to enzymolysis cross-linking sodium hyaluronate gel preparation is passed through by above-mentioned resistance to enzymolysis cross-linking sodium hyaluronate gel
It dispenses and sterilizes and be made.
In a preferred technical solution, the detailed process of the packing is as follows：Aseptically, using full-automatic
The cross-linking sodium hyaluronate gel is distributed into prefilled syringe, and vacuum is jumped a queue by vacuum bottle placer of jumping a queue.
In a preferred technical solution, for high pressure steam sterilization, temperature is 110~130 DEG C for the sterilizing, and the time is
10~15 minutes.
Compared with prior art, using above-mentioned technical proposal the invention has the advantages that：
(1) present invention uses the high and low molecular weight hyaluronic acid sodium cross-linking hyaluronic acid sodium that crosslinked mode obtains mutually
Gel compared with existing cross-linked gel preparation process, reduces processing step, saves production cost；
(2) cross-linking sodium hyaluronate gel of the invention has stable three-dimensional net structure, with passing through two-phase gel system
The product that Preparation Method obtains is compared, and heat resistanceheat resistant solution performance, resistance to enzymic degradation and is injected fluency and is improved significantly；
(3) method that the present invention is precipitated using organic solvent ethyl alcohol or isopropanol and combines low-temperature vacuum drying obtains
Cross-linking hyaluronic acid sodium dry powder so that the gel for preparing any concentration is achieved, with taking in two-phase gel preparation method
Dialysis technique is compared, and has the advantages that easy to operate, concentration is controllable.
Description of the drawings
Fig. 1 be embodiment 1 to 5 in cross-linking sodium hyaluronate gel before sterilization after elasticity modulus comparison diagram.
Fig. 2 is the resistance to enzymolysis performance comparison figure of the cross-linking sodium hyaluronate gel and commercial product in embodiment 1 to 5.
Fig. 3 for different rinsing times to crosslinking agent in cross-linking sodium hyaluronate gel remaining impact effect figure.
Specific embodiment
Further description is made to the present invention below with reference to the drawings and specific embodiments.Unless otherwise indicated, it is following
Instrument, reagent, material used in embodiment etc. can be obtained by routine business means.
Embodiment 1：The preparation of resistance to enzymolysis cross-linking sodium hyaluronate gel and gel preparation.
Weigh the high molecular weight sodium hyaluronate as made from bacterial fermentation process (0.2g, 3.0 × 106Da) and low molecular weight is saturating
Bright matter acid sodium (1.8g, 4.0 × 105Da), it is dissolved in after mixing in 0.25M sodium hydrate aqueous solutions (20mL), obtains hyalomitome
The alkaline solution of sour sodium.
Under mechanical agitation, BDDE (0.2g) is added in into the alkaline solution of above-mentioned Sodium Hyaluronate, in 40 DEG C of water
3h is reacted in bath, obtains the alkaline solution of cross-linking hyaluronic acid sodium.
0.1M hydrochloric acid is added in into the alkaline solution of above-mentioned cross-linking hyaluronic acid sodium and is adjusted to pH=7.0, is slowly added to
95% ethyl alcohol is precipitated completely to white precipitate.The precipitation of precipitation is rinsed 5 times with 95% ethyl alcohol, in 4 DEG C of vacuum drying, is handed over
Join Hyal powder 1.84g.
According to 20mg:Above-mentioned dried powder is added to PBS buffer solution and (included with weight percent by the amount ratio of 1mL
Than the following ingredients of meter：0.65%~0.9% NaCl, 0.05%~0.2% Na2HPO4, 0.005%~0.03%
NaH2PO4With the purified water of surplus) in, it is fully stirred evenly after swelling, obtains resistance to enzymolysis cross-linking sodium hyaluronate gel.
Aseptically, above-mentioned single-phase cross-linking sodium hyaluronate gel is dispensed using fully automatic vacuum bottle placer of jumping a queue
Enter in prefilled syringe, and vacuum is jumped a queue, then in 121 DEG C of high pressure steam sterilization 15min, obtain resistance to enzymolysis cross-linked transparent matter
Sour sodium gel preparation.
Embodiment 2：The preparation of resistance to enzymolysis cross-linking sodium hyaluronate gel and gel preparation.
Weigh the high molecular weight sodium hyaluronate as made from bacterial fermentation process (1.0g, 3.0 × 106Da) and low molecular weight is saturating
Bright matter acid sodium (1.0g, 4.0 × 105Da), it is dissolved in after mixing in 0.25M sodium hydrate aqueous solutions (20mL), obtains hyalomitome
The alkaline solution of sour sodium.
Under mechanical agitation, BDDE (0.04g) is added in into the alkaline solution of above-mentioned Sodium Hyaluronate, in 40 DEG C of water
3h is reacted in bath, obtains the alkaline solution of cross-linking hyaluronic acid sodium.
0.1M hydrochloric acid is added in into the alkaline solution of above-mentioned cross-linking hyaluronic acid sodium and is adjusted to pH=6.5, is slowly added to
95% ethyl alcohol is precipitated completely to white precipitate.The precipitation of precipitation is rinsed 5 times with 95% ethyl alcohol, in 4 DEG C of vacuum drying, is handed over
Join Hyal powder 1.82g.
According to 20mg:Above-mentioned dried powder is added to PBS buffer solution and (included with weight percent by the amount ratio of 1mL
Than the following ingredients of meter：0.65%~0.9% NaCl, 0.05%~0.2% Na2HPO4, 0.005%~0.03%
NaH2PO4With the purified water of surplus) in, it is fully stirred evenly after swelling, obtains resistance to enzymolysis cross-linking sodium hyaluronate gel.
Aseptically, above-mentioned single-phase cross-linking sodium hyaluronate gel is dispensed using fully automatic vacuum bottle placer of jumping a queue
Enter in prefilled syringe, and vacuum is jumped a queue, then in 121 DEG C of high pressure steam sterilization 15min, obtain resistance to enzymolysis cross-linked transparent matter
Sour sodium gel preparation.
Embodiment 3：The preparation of resistance to enzymolysis cross-linking sodium hyaluronate gel and gel preparation.
Weigh the high molecular weight sodium hyaluronate as made from bacterial fermentation process (0.5g, 3.0 × 106Da) and low molecular weight is saturating
Bright matter acid sodium (1.5g, 4.0 × 105Da), it is dissolved in after mixing in 0.25M sodium hydrate aqueous solutions (20mL), obtains hyalomitome
The alkaline solution of sour sodium.
Under mechanical agitation, BDDE (0.1g) is added in into the alkaline solution of above-mentioned Sodium Hyaluronate, in 50 DEG C of water
2h is reacted in bath, obtains the alkaline solution of cross-linking hyaluronic acid sodium.
0.1M hydrochloric acid is added in into the alkaline solution of above-mentioned cross-linking hyaluronic acid sodium and is adjusted to pH=7.5, is slowly added to
Isopropanol is precipitated completely to white precipitate.The precipitation of precipitation is rinsed 5 times with isopropanol, in 4 DEG C of vacuum drying, it is saturating to obtain crosslinking
Bright matter acid sodium powder end 1.83g.
According to 20mg:Above-mentioned dried powder is added to PBS buffer solution and (included with weight percent by the amount ratio of 1mL
Than the following ingredients of meter：0.65%~0.9% NaCl, 0.05%~0.2% Na2HPO4, 0.005%~0.03%
NaH2PO4With the purified water of surplus) in, it is fully stirred evenly after swelling, obtains resistance to enzymolysis cross-linking sodium hyaluronate gel.
Aseptically, above-mentioned single-phase cross-linking sodium hyaluronate gel is dispensed using fully automatic vacuum bottle placer of jumping a queue
Enter in prefilled syringe, and vacuum is jumped a queue, then in 121 DEG C of high pressure steam sterilization 15min, obtain resistance to enzymolysis cross-linked transparent matter
Sour sodium gel preparation.
Embodiment 4：The preparation of resistance to enzymolysis cross-linking sodium hyaluronate gel and gel preparation.
Weigh the high molecular weight sodium hyaluronate as made from bacterial fermentation process (1.0g, 1.5 × 106Da) and low molecular weight is saturating
Bright matter acid sodium (1.0g, 4.0 × 105Da), it is dissolved in after mixing in 0.25M potassium hydroxide aqueous solutions (20mL), obtains hyalomitome
The alkaline solution of sour sodium.
Under mechanical agitation, DVS (0.2g) is added in into the alkaline solution of above-mentioned Sodium Hyaluronate, in 50 DEG C of water-baths
Middle reaction 2h, obtains the alkaline solution of cross-linking hyaluronic acid sodium.
0.1M hydrochloric acid is added in into the alkaline solution of above-mentioned cross-linking hyaluronic acid sodium and is adjusted to pH=7.0, is slowly added to
Isopropanol is precipitated completely to white precipitate.The precipitation of precipitation is rinsed 5 times with isopropanol, in 4 DEG C of vacuum drying, it is saturating to obtain crosslinking
Bright matter acid sodium powder end 1.86g.
According to 20mg:Above-mentioned dried powder is added to PBS buffer solution and (included with weight percent by the amount ratio of 1mL
Than the following ingredients of meter：0.65%~0.9% NaCl, 0.05%~0.2% Na2HPO4, 0.005%~0.03%
NaH2PO4With the purified water of surplus) in, it is fully stirred evenly after swelling, obtains resistance to enzymolysis cross-linking sodium hyaluronate gel.
Aseptically, above-mentioned single-phase cross-linking sodium hyaluronate gel is dispensed using fully automatic vacuum bottle placer of jumping a queue
Enter in prefilled syringe, and vacuum is jumped a queue, then in 121 DEG C of high pressure steam sterilization 15min, obtain resistance to enzymolysis cross-linked transparent matter
Sour sodium gel preparation.
Embodiment 5：The preparation of resistance to enzymolysis cross-linking sodium hyaluronate gel.
Weigh the high molecular weight sodium hyaluronate as made from bacterial fermentation process (0.2g, 1.5 × 106Da) and low molecular weight is saturating
Bright matter acid sodium (1.8g, 3.0 × 105Da), it is dissolved in after mixing in 0.25M potassium hydroxide aqueous solutions (20mL), obtains hyalomitome
The alkaline solution of sour sodium.
Under mechanical agitation, DVS (0.1g) is added in into the alkaline solution of above-mentioned Sodium Hyaluronate, in 50 DEG C of water-baths
Middle reaction 2h, obtains the alkaline solution of cross-linking hyaluronic acid sodium.
0.1M hydrochloric acid is added in into the alkaline solution of above-mentioned cross-linking hyaluronic acid sodium and is adjusted to pH=7.0, is slowly added to
95% ethyl alcohol is precipitated completely to white precipitate.The precipitation of precipitation is rinsed 5 times with 95% ethyl alcohol, in 4 DEG C of vacuum drying, is handed over
Join Hyal powder 1.85g.
According to 20mg:Above-mentioned dried powder is added to PBS buffer solution and (included with weight percent by the amount ratio of 1mL
Than the following ingredients of meter：0.65%~0.9% NaCl, 0.05%~0.2% Na2HPO4, 0.005%~0.03%
NaH2PO4With the purified water of surplus) in, it is fully stirred evenly after swelling, obtains resistance to enzymolysis cross-linking sodium hyaluronate gel.
Aseptically, above-mentioned single-phase cross-linking sodium hyaluronate gel is dispensed using fully automatic vacuum bottle placer of jumping a queue
Enter in prefilled syringe, and vacuum is jumped a queue, then in 121 DEG C of high pressure steam sterilization 15min, obtain resistance to enzymolysis cross-linked transparent matter
Sour sodium gel preparation.
Embodiment 6：The elastic modulus detection experiment of resistance to enzymolysis cross-linking sodium hyaluronate gel.
Resistance to enzymolysis cross-linking sodium hyaluronate gel obtained in Example 1 to 5 respectively, uses TA AR2000ex rheologies
Instrument opens air valve to 30bar, and set temperature is 25 DEG C, frequency 0.25Hz, the front and rear elasticity modulus of detection sterilizing, result
As shown in Figure 1.
As shown in Figure 1, the elasticity modulus of sample only than being declined slightly before sterilizing, is substantially protected in embodiment 1 to 5 after sterilizing
It is fixed to keep steady, and illustrates the structure of sample and has higher heat resistanceheat resistant solution performance.
Embodiment 7：The resistance to enzymolysis performance measurement experiment of resistance to enzymolysis cross-linking sodium hyaluronate gel.
Cross-linking sodium hyaluronate gel 4mg obtained in Example 1 to 5 respectively is added in saturating according to the ratio of 10U/mg
Bright matter acid enzyme solutions, 37 DEG C of water-bath 48h, 100 DEG C are heated 30min, are then centrifuged for taking supernatant, are detected according to carbazole development process
Absorbance value at 530nm, and calculate resistance to enzymolysis rate.Meanwhile commercial product Restylane is taken as reference substance, same treatment
After detect, the results are shown in Figure 2.
As shown in Figure 2, the uronic acid release rate of sample is significantly lower than commercialized product in embodiment 1 to 5
Restylane illustrates that sample has higher resistance to enzymolysis performance.
Embodiment 8：Crosslinking agent residues detecton experiment in resistance to enzymolysis cross-linking sodium hyaluronate gel.
The white precipitate being precipitated after 95% ethyl alcohol is added in using in embodiment 1 as detection sample, investigates different washing times
The crosslinking agent in gel (BDDE) remains afterwards, and the results are shown in Figure 3.
From the figure 3, it may be seen that after 5 rinsings, the crosslinking agent in gel is remained already below 2ppm, meets gel products
Related request.
Embodiment 9：The power of injecting of resistance to enzymolysis cross-linking sodium hyaluronate gel measures experiment.
Cross-linking sodium hyaluronate gel obtained uses universal testing machine as detection sample using in embodiment 1 to 5
With the driving velocity of 30mm/min, the syringe needle detection product of 27 1/2G injects power, and the results are shown in Table 1.
1 gel products of table inject power measurement result
| Embodiment is numbered | Inject power (N) |
| 1 | 16 |
| 2 | 15 |
| 3 | 17 |
| 4 | 16 |
| 5 | 14 |
By the result in table 1 it is found that the power of injecting of sample is respectively less than 20N in embodiment 1 to 5, illustrate have during Clinical practice
There is preferable feel, it is easily operated.
Claims (7)
1. a kind of preparation method of resistance to enzymolysis cross-linking sodium hyaluronate gel, it is characterised in that：
The preparation method includes the following steps：
1) Sodium Hyaluronate is dissolved using lye：
The mixture being made of high molecular weight sodium hyaluronate and low molecular weight sodium hyaluronate is dissolved in lye, is obtained
The alkaline solution of bright matter acid sodium；
2) crosslinking of Sodium Hyaluronate：
Under agitation, crosslinking agent is added in the alkaline solution of the Sodium Hyaluronate obtained into step 1), in 25~55 DEG C
Reaction 1~6 hour, obtains the alkaline solution of cross-linking hyaluronic acid sodium；
3) precipitation of cross-linking hyaluronic acid sodium, washing and drying：
The pH value of the alkaline solution of the cross-linking hyaluronic acid sodium obtained in step 2) is adjusted to 6.5~7.5 using acid, is added
Precipitating solvent is low then using precipitating solvent by washing of precipitate 5 times of precipitation or more until precipitation no longer is precipitated
Temperature vacuum drying, obtains cross-linking hyaluronic acid sodium powder；
4) swelling of cross-linking hyaluronic acid sodium powder：
Aseptically, the cross-linking hyaluronic acid sodium powder obtained in step 3) is added in phosphate buffer, fully
It is stirred evenly after swelling, obtains resistance to enzymolysis cross-linking sodium hyaluronate gel.
2. preparation method according to claim 1, it is characterised in that：
Mixture described in step 1) by 10%~50% by weight percentage the high molecular weight sodium hyaluronate and
50%~90% low molecular weight sodium hyaluronate composition；
The molecular weight of high molecular weight sodium hyaluronate described in step 1) is 1.0 × 106~4.0 × 106Dalton；
The molecular weight of low molecular weight sodium hyaluronate described in step 1) is 1.0 × 105~1.0 × 106Dalton；
Lye described in step 1) is sodium hydrate aqueous solution or potassium hydroxide aqueous solution；
The molar concentration of lye described in step 1) is 0.1~0.5 mol/L；
The amount ratio of mixture described in step 1) and the lye is 1~2 gram:10 milliliters.
3. preparation method according to claim 1, it is characterised in that：
Crosslinking agent described in step 2) is 1,4- butanediol diglycidyl ethers or divinylsulfone；
The weight ratio of crosslinking agent described in step 2) and mixture described in step 1) is 1:5~100.
4. preparation method according to claim 1, it is characterised in that：
Acid described in step 3) is hydrochloric acid；
Precipitating solvent described in step 3) is alcohol or its aqueous solution, wherein the alcohol is methanol, ethyl alcohol or isopropanol；
The temperature of low-temperature vacuum drying described in step 3) is 0~4 DEG C.
5. preparation method according to claim 1, it is characterised in that：
Phosphate buffer described in step 4) includes following ingredients by weight percentage：0.65%~0.9% chlorination
Sodium, 0.05%~0.2% disodium hydrogen phosphate, 0.005%~0.03% sodium dihydrogen phosphate and surplus purified water, the phosphorus
The pH value of phthalate buffer is 6.5~7.5；
The amount ratio of cross-linking hyaluronic acid sodium powder described in step 4) and the phosphate buffer is 15~30 milligrams:1 milli
It rises.
6. a kind of resistance to enzymolysis cross-linking sodium hyaluronate gel, passes through preparation side according to any one of claim 1 to 5
Method and be made.
7. a kind of resistance to enzymolysis cross-linking sodium hyaluronate gel preparation, by resistance to enzymolysis cross-linked transparent according to claim 6
Matter acid sodium gel is made by dispensing and sterilizing.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109805890A (en) * | 2018-12-03 | 2019-05-28 | 浙江景嘉医疗科技有限公司 | A method of the evaluation medical cross-linking sodium hyaluronate gel degradation in vivo period |
| 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 |
| CN113413484A (en) * | 2021-06-21 | 2021-09-21 | 浙江苏嘉医疗器械股份有限公司 | Implant material for human soft tissue filling |
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| CN101925348A (en) * | 2007-12-07 | 2010-12-22 | 实验室维维西公司 | Biodegradable single-phase cohesive hydrogel |
| CN102757572A (en) * | 2011-04-28 | 2012-10-31 | 上海其胜生物制剂有限公司 | Preparation method for agranular crosslinking sodium hyaluronate with high-temperature-resistant and enzymatic-hydrolysis-resistant characteristics |
| US20150065701A1 (en) * | 2003-04-10 | 2015-03-05 | Allergan Industrie Sas | Injectable monophase hydrogels |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20150065701A1 (en) * | 2003-04-10 | 2015-03-05 | Allergan Industrie Sas | Injectable monophase hydrogels |
| CN101925348A (en) * | 2007-12-07 | 2010-12-22 | 实验室维维西公司 | Biodegradable single-phase cohesive hydrogel |
| CN102757572A (en) * | 2011-04-28 | 2012-10-31 | 上海其胜生物制剂有限公司 | Preparation method for agranular crosslinking sodium hyaluronate with high-temperature-resistant and enzymatic-hydrolysis-resistant characteristics |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109805890A (en) * | 2018-12-03 | 2019-05-28 | 浙江景嘉医疗科技有限公司 | A method of the evaluation medical cross-linking sodium hyaluronate gel degradation in vivo period |
| 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 |
| CN113413484A (en) * | 2021-06-21 | 2021-09-21 | 浙江苏嘉医疗器械股份有限公司 | Implant material for human soft tissue filling |
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