CN107955194A - The preparation method of high quality cross-linking sodium hyaluronate gel - Google Patents
The preparation method of high quality cross-linking sodium hyaluronate gel Download PDFInfo
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- CN107955194A CN107955194A CN201711226854.1A CN201711226854A CN107955194A CN 107955194 A CN107955194 A CN 107955194A CN 201711226854 A CN201711226854 A CN 201711226854A CN 107955194 A CN107955194 A CN 107955194A
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
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Abstract
The invention discloses a kind of preparation method of high quality cross-linking sodium hyaluronate gel, comprise the following steps：1) Sodium Hyaluronate dry powder is dissolved in sodium hydroxide solution, adds the Isosorbide-5-Nitrae butanediol diepoxy ether of Sodium Hyaluronate dry powder weight 0.01~0.05%, 5~8h is kept the temperature at 35~50 DEG C, obtains gel X；2) gel X is suppressed into 1~3min under 500~1000MPa；3) pH value of pressed gel X is adjusted to neutrality, is added phosphate buffer and is swollen 18~36h；4) the gel X after swelling is cooled to 4 DEG C, and 1~3h of isothermal holding, obtains hyaluronic acid sodium gel.Hyaluronic acid sodium gel after crosslinking has more stable net structure, can effectively improve the anti-degradability of hyaluronic acid, retention time in extension body.
Description
Technical field
The present invention relates to a kind of hyaluronic acid sodium gel technical field, and in particular to a kind of high quality cross-linking hyaluronic acid sodium
The preparation method of gel.
Background technology
Hyaluronic acid is to repeat two pool construction unit β-D-Glucose aldehydic acid and the mutual chain of title of N-acetylglucosamine
Connect the linearly glutinous polysaccharide of composition.Hyaluronic acid is the master for forming the connective tissues such as human body cell interstitial, vitreum, knuckle synovia
Component is wanted, water conservation is played in vivo, maintains extracellular space, adjusts osmotic pressure, lubrication, the important physiology work(for promoting cell repair
Energy.Since hyaluronic acid has the characteristics such as viscoplasticity separation, viscoplasticity protection and viscoplasticity filling, it is made in department of general surgery and woman
Obstetrics prevent from being used widely in the medical domains such as the clinical medicine and burn of post-operation adhesion, wound and plastic surgery.But
It is due to that Natural hyaluronic acid is easily degraded in vivo, longer-term persistence in vivo, it is difficult to its excellent physicochemical characteristics is played,
Often limit the performance of its curative effect.In recent years in the application of preventing adhesions and Soft-tissue operation etc., it is desirable to hyaluronic acid
There is longer retention time in human body planted agent, even require longer-term persistence in vivo sometimes.Generally for the acquisition long period
Effective Sodium Hyaluronate filler, transforms hyaluronan molecule using modification and crosslinked method, changes hyalomitome
Some attributes of acid.Cross-linking sodium hyaluronate gel is to be stirred hyaluronic acid in aqueous with crosslinking agent at the same time, is led to
Crossing crosslinking agent makes between Sodium Hyaluronate macromolecular chain chemical bond and to prepare.Crosslinking agent used, when gel divides in vivo
Xie Hou, remaining crosslinker component are identified as foreign matter for organism, trigger the harmful effects such as inflammation.Therefore, to ensure
Biocompatible is, it is necessary to prepare the gel of the low degree of cross linking.But conventional cross-linking method, if reducing adding for crosslinking agent
Dosage, the gel viscoelastisity of gained reduces, not soft.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of preparation method of high quality cross-linking sodium hyaluronate gel, hands over
Hyaluronic acid sodium gel after connection has more stable net structure, can effectively improve the anti-degradability of hyaluronic acid, prolong
Long internal retention time.
Technical solution provided by the invention is the preparation method of high quality cross-linking sodium hyaluronate gel, it is characterised in that：
Comprise the following steps：
1) Sodium Hyaluronate dry powder is dissolved in sodium hydroxide solution, addition Sodium Hyaluronate dry powder weight 0.01~
0.05% 1,4-butanediol diepoxy ether, 5~8h is kept the temperature at 35~50 DEG C, obtains gel X；
2) gel X is suppressed into 1~3min under 500~1000MPa；
3) pH value of pressed gel X is adjusted to neutrality, is added phosphate buffer and is swollen 18~36h；
4) the gel X after swelling is cooled to -4 DEG C, and 1~3h of isothermal holding, obtains hyaluronic acid sodium gel.
In step 1), the mass concentration of sodium hydroxide solution is 10~20%.Sodium hydroxide in sodium hydrate aqueous solution
Mass percent is 10~20%.The dosage of 1,4- butanediol diepoxy ethers is the 0.02% of Sodium Hyaluronate weight.
In step 2), gel X not yet through overbalance and swelling period, also in the unstable stage, and is handed in the application
Join that the additive amount of agent is less, and the degree of cross linking between Sodium Hyaluronate and crosslinking agent is also insufficient, at this time to gel X at horizontal high voltage
Reason, can promote polymer segment to be orientated to form more disordered arrangements along pressure direction, cause polymer segment entangled to each other
Mutually penetrate, further formed and overlap close tridimensional network.
In step 3), swelling temperature is 40~50 DEG C.Swelling time is 24h.
In step 4), since the high pressure of step 2) acts on, promote macromolecular chain is entangled to each other to form the three-dimensional netted of stabilization
Structure, at the same time, a small amount of addition of crosslinking agent, causes macromolecular chain to be crosslinked very close, the free end of the chain of macromolecular chain
There occurs entangled to each other, this can cause gel network to produce defect and reduce elasticity.Therefore, gel X is cooled to -4 by the application
DEG C, and 1~3h of isothermal holding, macromolecular chain can be made to carry out conformation adjustment, the local motion of chain, which abreast queues, to be come, and promotes height
The free end disentanglement of strand so that ready gels are soft.
Compared with prior art, the invention has the advantages that：
1) hyaluronic acid sodium gel after present invention crosslinking has more stable net structure, can effectively improve transparent
Retention time in the anti-degradability of matter acid, extension body.
2) present invention adds a small amount of crosslinking agent and can obtain sufficiently stable net structure, and gels-soft is good.
Embodiment
The present invention is further elaborated for specific examples below, but not as a limitation of the invention.
Embodiment 1
1) Sodium Hyaluronate dry powder is dissolved in the sodium hydroxide solution that mass concentration is 10%, adds Sodium Hyaluronate
The 1,4-butanediol diepoxy ether of dry powder weight 0.01%, keeps the temperature 5h at 35 DEG C, obtains gel X；
2) gel X is suppressed into 1min under 500MPa；
3) pH value of pressed gel X is adjusted to neutrality, adds phosphate buffer, 18h is swollen at 40 DEG C；
4) the gel X after swelling is cooled to -4 DEG C, and isothermal holding 1h, obtains hyaluronic acid sodium gel.
1st, resistance to enzymatic test method：Precision weighs above-mentioned gel, is added to 0.1mogl/L phosphate buffers (pH7.0)
5ml and hyaluronic acid enzyme liquid (100U/ml) 5ml, is uniformly mixed, is placed in 37 DEG C of water-baths and digests 24h, then boiled at 100 DEG C
10min is inactivated.0.45 μm of filtering with microporous membrane, takes filtrate 1.0ml, adds water to be settled to 10ml.Surveyed using improvement carbazole development process
Determine glucuronic acid content, it is the content a of cross-linking hyaluronic acid sodium in the sample of addition enzyme liquid to be multiplied by conversion after 2.07；Not enzyme sample
In cross-linking hyaluronic acid sodium content be b, calculate enzyme degradation rate=a/b × 100%.Enzyme degradation rate is lower, shows the resistance to of gel
Enzyme is better, and what gel was filled in vivo holds time longer.
2nd, dynamic viscosity measures：Using Rotary Viscosimeter determination method, according to《Pharmacopoeia of People's Republic of China》(2010
Version) two the second methods of annex VI G measure, it is not less than 0.25HZ in shear rate, under the conditions of (25 ± 0.1) DEG C, according to rotating
During act on shearing stress size in liquid medium and complete measure, and be calculated as follows the dynamic viscosity of gel：
η=K (T/ ω)
In formula：K is the Rotary Viscosimeter constant measured with the titer of known viscosity；
T is torsional moment；
ω is angular speed.
3rd, intrinsic viscosity measures：Using determination of ubbelohde viscometer intrinsic viscosity, according to《Pharmacopoeia of People's Republic of China》
(2010 editions) two the 3rd methods of annex VI G measure.
After testing, the enzyme degradation rate of hyaluronic acid sodium gel is 3.4%, and dynamic viscosity is 51.5 × 104MPas, characteristic
Glutinous number is 4512.8cm3/g。
Reference examples 1
1) Sodium Hyaluronate dry powder is dissolved in the sodium hydroxide solution that mass concentration is 10%, adds Sodium Hyaluronate
The 1,4-butanediol diepoxy ether of dry powder weight 0.01%, keeps the temperature 5h at 35 DEG C, obtains gel X；
2) pH value of gel X is adjusted to neutrality, is added phosphate buffer, is swollen 18h at 40 DEG C, obtains hyaluronic acid
Sodium gel.
Method according to embodiment 1 is detected, and the enzyme degradation rate of hyaluronic acid sodium gel is 15.5%, and dynamic viscosity is
29.7×104MPas, intrinsic viscosity 2728.3cm3/g。
Embodiment 2
1) Sodium Hyaluronate dry powder is dissolved in the sodium hydroxide solution that mass concentration is 20%, adds Sodium Hyaluronate
The 1,4-butanediol diepoxy ether of dry powder weight 0.05%, keeps the temperature 8h at 50 DEG C, obtains gel X；
2) gel X is suppressed into 3min under 1000MPa；
3) pH value of pressed gel X is adjusted to neutrality, adds phosphate buffer, 36h is swollen at 50 DEG C；
4) the gel X after swelling is cooled to -4 DEG C, and isothermal holding 3h, obtains hyaluronic acid sodium gel.
Method according to embodiment 1 is detected, and the enzyme degradation rate of hyaluronic acid sodium gel is 3.6%, and dynamic viscosity is
55.0×104MPas, intrinsic viscosity 4467.8cm3/g。
Embodiment 3
1) Sodium Hyaluronate dry powder is dissolved in the sodium hydroxide solution that mass concentration is 15%, adds Sodium Hyaluronate
The 1,4-butanediol diepoxy ether of dry powder weight 0.02%, keeps the temperature 6h at 45 DEG C, obtains gel X；
2) gel X is suppressed into 2min under 800MPa；
3) pH value of pressed gel X is adjusted to neutrality, adds phosphate buffer, 24h is swollen at 45 DEG C；
4) the gel X after swelling is cooled to -4 DEG C, and isothermal holding 2h, obtains hyaluronic acid sodium gel.
Method according to embodiment 1 is detected, and the enzyme degradation rate of hyaluronic acid sodium gel is 3.0%, and dynamic viscosity is
57.4×104MPas, intrinsic viscosity 4618.4cm3/g。
Embodiment 4
1) Sodium Hyaluronate dry powder is dissolved in the sodium hydroxide solution that mass concentration is 10%, adds Sodium Hyaluronate
The 1,4-butanediol diepoxy ether of dry powder weight 0.05%, keeps the temperature 8h at 35 DEG C, obtains gel X；
2) gel X is suppressed into 3min under 500MPa；
3) pH value of pressed gel X is adjusted to neutrality, adds phosphate buffer, 36h is swollen at 40 DEG C；
4) the gel X after swelling is cooled to -4 DEG C, and isothermal holding 1h, obtains hyaluronic acid sodium gel.
Method according to embodiment 1 is detected, and the enzyme degradation rate of hyaluronic acid sodium gel is 3.5%, and dynamic viscosity is
54.9×104MPas, intrinsic viscosity 4492.0cm3/g。
Claims (5)
1. the preparation method of high quality cross-linking sodium hyaluronate gel, it is characterised in that：Comprise the following steps：
1) Sodium Hyaluronate dry powder is dissolved in sodium hydroxide solution, adds Sodium Hyaluronate dry powder weight 0.01~0.05%
1,4-butanediol diepoxy ether, at 35~50 DEG C keep the temperature 5~8h, obtain gel X；
2) gel X is suppressed into 1~3min under 500~1000MPa；
3) pH value of pressed gel X is adjusted to neutrality, is added phosphate buffer and is swollen 18~36h；
4) the gel X after swelling is cooled to -4 DEG C, and 1~3h of isothermal holding, obtains hyaluronic acid sodium gel.
2. the preparation method of high quality cross-linking sodium hyaluronate gel according to claim 1, it is characterised in that：Hydroxide
The mass concentration of sodium solution is 10~20%.
3. the preparation method of high quality cross-linking sodium hyaluronate gel according to claim 1, it is characterised in that：Swelling temperature
Spend for 40~50 DEG C.
4. the preparation method of high quality cross-linking sodium hyaluronate gel according to claim 1, it is characterised in that：During swelling
Between be 24h.
5. the preparation method of high quality cross-linking sodium hyaluronate gel according to claim 1, it is characterised in that：1,4- fourths
The dosage of glycol diepoxy ether is the 0.02% of Sodium Hyaluronate weight.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110698700A (en) * | 2019-10-28 | 2020-01-17 | 天津一安生物技术有限公司 | Method for preparing sodium hyaluronate gel by tannin crosslinking and sodium hyaluronate gel |
| CN110698699A (en) * | 2019-10-28 | 2020-01-17 | 天津一安生物技术有限公司 | Method for preparing sodium hyaluronate gel by puerarin crosslinking and sodium hyaluronate gel |
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| US20130023658A1 (en) * | 2007-07-30 | 2013-01-24 | Allergan, Inc. | Tunably crosslinked polysaccharide compositions |
| WO2010136694A2 (en) * | 2009-05-26 | 2010-12-02 | Anteis S.A. | Injectable hydrogel for the long-term supplementation of glycerol in the skin |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110698700A (en) * | 2019-10-28 | 2020-01-17 | 天津一安生物技术有限公司 | Method for preparing sodium hyaluronate gel by tannin crosslinking and sodium hyaluronate gel |
| CN110698699A (en) * | 2019-10-28 | 2020-01-17 | 天津一安生物技术有限公司 | Method for preparing sodium hyaluronate gel by puerarin crosslinking and sodium hyaluronate gel |
| CN110698699B (en) * | 2019-10-28 | 2022-03-11 | 天津一安生物技术有限公司 | Method for preparing sodium hyaluronate gel by puerarin crosslinking and sodium hyaluronate gel |
| CN110698700B (en) * | 2019-10-28 | 2022-03-11 | 天津一安生物技术有限公司 | Method for preparing sodium hyaluronate gel by tannin crosslinking and sodium hyaluronate gel |
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