CN107880288A - A kind of preparation method of hyaluronic acid sodium gel - Google Patents
A kind of preparation method of hyaluronic acid sodium gel Download PDFInfo
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- CN107880288A CN107880288A CN201711227101.2A CN201711227101A CN107880288A CN 107880288 A CN107880288 A CN 107880288A CN 201711227101 A CN201711227101 A CN 201711227101A CN 107880288 A CN107880288 A CN 107880288A
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- gel
- hyaluronic acid
- acid sodium
- sodium
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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
- 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
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/04—Oxygen-containing compounds
- C08K5/15—Heterocyclic compounds having oxygen in the ring
- C08K5/151—Heterocyclic compounds having oxygen in the ring having one oxygen atom in the ring
- C08K5/1545—Six-membered rings
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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
Abstract
The invention discloses a kind of preparation method of hyaluronic acid sodium gel, comprise the following steps：1) Sodium Hyaluronate dry powder is dissolved in sodium hydroxide solution, adds the Geniposide of Sodium Hyaluronate dry powder weight 0.01~0.05%, 5~8h is incubated at 35~50 DEG C, obtains gel X；2) gel X is suppressed into 1~3min under 500~1000MPa；3) pH value of the gel X after regulation compacting adds phosphate buffer and is swelled 18~36h to neutrality；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 network structure, can effectively improve the anti-degradability of hyaluronic acid, RT 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 preparation of hyaluronic acid sodium gel
Method.
Background technology
Hyaluronic acid is to repeat two pool construction unit β-D-Glucose aldehydic acid and the mutual chain of title of 2-Acetamido-2-deoxy-D-glucose
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
Composition is wanted, water conservation is played in vivo, maintains extracellular space, regulation osmotic pressure, lubrication, the important physiology work(for promoting cell repair
Energy.Because 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 RT in human body planted agent, even require longer-term persistence in vivo sometimes.Generally for the acquisition long period
Effective Sodium Hyaluronate filler, is transformed hyaluronan molecule using the method for modification and crosslinking, changes hyalomitome
Some attributes of acid.Cross-linking sodium hyaluronate gel is to be stirred hyaluronic acid in aqueous with crosslinking agent simultaneously, 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, the crosslinker component of residual 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
It is transparent after crosslinking the technical problem to be solved in the present invention is to provide a kind of preparation method of hyaluronic acid sodium gel
Matter acid sodium gel has more stable network structure, can effectively improve the anti-degradability of hyaluronic acid, retain in extension body
Time.
Technical scheme provided by the invention is a kind of preparation method of hyaluronic acid sodium gel, it is characterised in that：Including with
Lower step：
1) Sodium Hyaluronate dry powder is dissolved in sodium hydroxide solution, addition Sodium Hyaluronate dry powder weight 0.01~
0.05% Geniposide, 5~8h is incubated at 35~50 DEG C, obtains gel X；
2) gel X is suppressed into 1~3min under 500~1000MPa；
3) pH value of the gel X after regulation compacting adds phosphate buffer and is swelled 18~36h to neutrality；
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 Geniposide 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
The addition of connection agent is less, and the degree of cross linking between Sodium Hyaluronate and crosslinking agent is also insufficient, and now gel X is entered 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), because 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, macromolecular chain is caused 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 network structure, can effectively improve transparent
RT in the sour anti-degradability of matter, extension body.
2) present invention adds a small amount of crosslinking agent and can obtain sufficiently stable network 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 Geniposide of dry powder weight 0.01%, 5h is incubated at 35 DEG C, obtains gel X；
2) gel X is suppressed into 1min under 500MPa；
3) pH value of the gel X after regulation compacting adds phosphate buffer, 18h is swelled at 40 DEG C to neutrality；
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 method of testing：Precision weighs above-mentioned gel, is added to 0.1mogl/L phosphate buffers (pH7.0)
5ml and hyaluronic acid enzyme liquid (100U/ml) 5ml, it is well 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-added 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 determines：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 that the titer of viscosity known to measures；
T is torsional moment；
ω is angular speed.
3rd, intrinsic viscosity determines：Using determination of ubbelohde viscometer intrinsic viscosity, according to《Pharmacopoeia of People's Republic of China》
(2010 editions) two methods of annex VI G the 3rd measure.
After testing, the enzyme degradation rate of hyaluronic acid sodium gel is 3.5%, and dynamic viscosity is 50.1 × 104MPas, characteristic
Glutinous number is 4478.8cm3/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 Geniposide of dry powder weight 0.01%, 5h is incubated at 35 DEG C, obtains gel X；
2) gel X pH value is adjusted to neutrality, is added phosphate buffer, is swelled 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 13.6%, and dynamic viscosity is
31.1×104MPas, intrinsic viscosity 2682.6cm3/g。
Embodiment 2
1) Sodium Hyaluronate dry powder is dissolved in the sodium hydroxide solution that mass concentration is 20%, adds Sodium Hyaluronate
The Geniposide of dry powder weight 0.05%, 8h is incubated at 50 DEG C, obtains gel X；
2) gel X is suppressed into 3min under 1000MPa；
3) pH value of the gel X after regulation compacting adds phosphate buffer, 36h is swelled at 50 DEG C to neutrality；
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 3.4%, and dynamic viscosity is
51.7×104MPas, intrinsic viscosity 4541.8cm3/g。
Embodiment 3
1) Sodium Hyaluronate dry powder is dissolved in the sodium hydroxide solution that mass concentration is 15%, adds Sodium Hyaluronate
The Geniposide of dry powder weight 0.02%, 6h is incubated at 45 DEG C, obtains gel X；
2) gel X is suppressed into 2min under 800MPa；
3) pH value of the gel X after regulation compacting adds phosphate buffer, 24h is swelled at 45 DEG C to neutrality；
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 3.1%, and dynamic viscosity is
55.6×104MPas, intrinsic viscosity 4668.3cm3/g。
Embodiment 4
1) Sodium Hyaluronate dry powder is dissolved in the sodium hydroxide solution that mass concentration is 10%, adds Sodium Hyaluronate
The Geniposide of dry powder weight 0.05%, 8h is incubated at 35 DEG C, obtains gel X；
2) gel X is suppressed into 3min under 500MPa；
3) pH value of the gel X after regulation compacting adds phosphate buffer, 36h is swelled at 40 DEG C to neutrality；
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 3.6%, and dynamic viscosity is
52.0×104MPas, intrinsic viscosity 4411.7cm3/g。
Claims (5)
- A kind of 1. preparation method of hyaluronic acid sodium 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% Geniposide, at 35~50 DEG C be incubated 5~8h, obtain gel X；2) gel X is suppressed into 1~3min under 500~1000MPa；3) pH value of the gel X after regulation compacting adds phosphate buffer and is swelled 18~36h to neutrality；4) the gel X after swelling is cooled to -4 DEG C, and 1~3h of isothermal holding, obtains hyaluronic acid sodium gel.
- A kind of 2. preparation method of hyaluronic acid sodium gel according to claim 1, it is characterised in that：Sodium hydroxide solution Mass concentration be 10~20%.
- A kind of 3. preparation method of hyaluronic acid sodium gel according to claim 1, it is characterised in that：Swelling temperature is 40 ~50 DEG C.
- A kind of 4. preparation method of hyaluronic acid sodium gel according to claim 1, it is characterised in that：Swelling time is 24h。
- A kind of 5. preparation method of hyaluronic acid sodium gel according to claim 1, it is characterised in that：The dosage of Geniposide For the 0.02% of Sodium Hyaluronate weight.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108514056A (en) * | 2018-04-24 | 2018-09-11 | 常州市蒽盗钟情生物科技有限公司 | A kind of compound fish guano of slow-release and preparation method thereof |
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2017
- 2017-11-29 CN CN201711227101.2A patent/CN107880288A/en active Pending
Patent Citations (5)
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| CN101264348A (en) * | 2008-05-19 | 2008-09-17 | 山东凯乐普生物工程有限公司 | Preparation technique of sodium hyaluronate gel granule |
| CN102573913A (en) * | 2009-07-31 | 2012-07-11 | 阿森迪斯药物股份有限公司 | Biodegradable polyethylene glycol based water-insoluble hydrogels |
| EP2529764A1 (en) * | 2011-05-31 | 2012-12-05 | Curasan AG | Biodegradable composite material |
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| CN108514056A (en) * | 2018-04-24 | 2018-09-11 | 常州市蒽盗钟情生物科技有限公司 | A kind of compound fish guano of slow-release and preparation method thereof |
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