CN108034060A - A kind of preparation method of Sodium Hyaluronate biomembrane - Google Patents
A kind of preparation method of Sodium Hyaluronate biomembrane Download PDFInfo
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- CN108034060A CN108034060A CN201711225619.2A CN201711225619A CN108034060A CN 108034060 A CN108034060 A CN 108034060A CN 201711225619 A CN201711225619 A CN 201711225619A CN 108034060 A CN108034060 A CN 108034060A
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- sodium hyaluronate
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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
- C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
- C08J5/18—Manufacture of films or sheets
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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
- C08J3/246—Intercrosslinking of at least two polymers
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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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- 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
- C08J2471/00—Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
- C08J2471/02—Polyalkylene oxides
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Abstract
The invention discloses a kind of preparation method of Sodium Hyaluronate biomembrane, comprise the following steps：1) Sodium Hyaluronate dry powder is dissolved in sodium hydroxide solution, adds the polyethylene glycol ether epoxy 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, be freeze-dried, compacting film forming, obtains Sodium Hyaluronate biomembrane.Sodium Hyaluronate biomembrane 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 system of Sodium Hyaluronate biomembrane
Preparation Method.
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
It is saturating after crosslinking the technical problem to be solved in the present invention is to provide a kind of preparation method of Sodium Hyaluronate biomembrane
Bright matter acid sodium biomembrane has more stable net structure, can effectively improve the anti-degradability of hyaluronic acid, in extension body
Retention time.
Technical solution provided by the invention is a kind of preparation method of Sodium Hyaluronate biomembrane, it is characterised in that：Including
Following steps：
1) Sodium Hyaluronate dry powder is dissolved in sodium hydroxide solution, addition Sodium Hyaluronate dry powder weight 0.01~
0.05% polyethylene glycol ether epoxy, 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, be freeze-dried, compacting film forming, obtains
Bright matter acid sodium biomembrane.
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 polyethylene glycol ether epoxy 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 refined biometric film is soft.
Compared with prior art, the invention has the advantages that：
1) the Sodium Hyaluronate biomembrane after present invention crosslinking has more stable net structure, can effectively improve
Retention time in the anti-degradability of bright 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 polyethylene glycol ether epoxy of dry powder weight 0.01%, 5h is kept the temperature 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, be freeze-dried, compacting film forming, obtains hyalomitome
Sour sodium biomembrane.
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 Sodium Hyaluronate biomembrane is 3.8%, and dynamic viscosity is 54.8 × 104MPas, it is special
It is 4871.8cm that property, which sticks number,3/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 polyethylene glycol ether epoxy of dry powder weight 0.01%, 5h is kept the temperature at 35 DEG C, obtains gel X；
2) pH value of gel X is adjusted to neutrality, adds phosphate buffer, 18h is swollen at 40 DEG C, be freeze-dried, press
Film is made, obtains Sodium Hyaluronate biomembrane.
Method according to embodiment 1 is detected, and the enzyme degradation rate of Sodium Hyaluronate biomembrane is 14.6%, dynamic viscosity
For 29.7 × 104MPas, intrinsic viscosity 2724.8cm3/g。
Embodiment 2
1) Sodium Hyaluronate dry powder is dissolved in the sodium hydroxide solution that mass concentration is 20%, adds Sodium Hyaluronate
The polyethylene glycol ether epoxy of dry powder weight 0.05%, 8h is kept the temperature 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, be freeze-dried, compacting film forming, obtains hyalomitome
Sour sodium biomembrane.
Method according to embodiment 1 is detected, and the enzyme degradation rate of Sodium Hyaluronate biomembrane is 3.9%, dynamic viscosity
For 55.4 × 104MPas, intrinsic viscosity 4776.8cm3/g。
Embodiment 3
1) Sodium Hyaluronate dry powder is dissolved in the sodium hydroxide solution that mass concentration is 15%, adds Sodium Hyaluronate
The polyethylene glycol ether epoxy of dry powder weight 0.02%, 6h is kept the temperature 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, be freeze-dried, compacting film forming, obtains hyalomitome
Sour sodium biomembrane.
Method according to embodiment 1 is detected, and the enzyme degradation rate of Sodium Hyaluronate biomembrane is 3.5%, dynamic viscosity
For 59.2 × 104MPas, intrinsic viscosity 4930.1cm3/g。
Embodiment 4
1) Sodium Hyaluronate dry powder is dissolved in the sodium hydroxide solution that mass concentration is 10%, adds Sodium Hyaluronate
The polyethylene glycol ether epoxy of dry powder weight 0.05%, 8h is kept the temperature 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, be freeze-dried, compacting film forming, obtains hyalomitome
Sour sodium biomembrane.
Method according to embodiment 1 is detected, and the enzyme degradation rate of Sodium Hyaluronate biomembrane is 4.0%, dynamic viscosity
For 57.6 × 104MPas, intrinsic viscosity 4611.7cm3/g。
Claims (5)
- A kind of 1. preparation method of Sodium Hyaluronate biomembrane, 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% Polyethylene glycol ether epoxy, 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, be freeze-dried, compacting film forming, obtains hyalomitome Sour sodium biomembrane.
- A kind of 2. preparation method of Sodium Hyaluronate biomembrane according to claim 1, it is characterised in that：Sodium hydroxide is molten The mass concentration of liquid is 10~20%.
- A kind of 3. preparation method of Sodium Hyaluronate biomembrane according to claim 1, it is characterised in that：Swelling temperature is 40~50 DEG C.
- A kind of 4. preparation method of Sodium Hyaluronate biomembrane according to claim 1, it is characterised in that：Swelling time is 24h。
- A kind of 5. preparation method of Sodium Hyaluronate biomembrane according to claim 1, it is characterised in that：Polyethylene glycol ring The dosage of oxygen ether is the 0.02% of Sodium Hyaluronate weight.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104004208A (en) * | 2014-04-16 | 2014-08-27 | 常州药物研究所有限公司 | Cross-linked sodium hyaluronate biomembrane and preparation method thereof |
| CN104814943A (en) * | 2015-04-15 | 2015-08-05 | 常州大学 | Preparing method for doxorubicin hydrochloride loaded cross-linked hyaluronic acid composite membrane |
-
2017
- 2017-11-29 CN CN201711225619.2A patent/CN108034060A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104004208A (en) * | 2014-04-16 | 2014-08-27 | 常州药物研究所有限公司 | Cross-linked sodium hyaluronate biomembrane and preparation method thereof |
| CN104814943A (en) * | 2015-04-15 | 2015-08-05 | 常州大学 | Preparing method for doxorubicin hydrochloride loaded cross-linked hyaluronic acid composite membrane |
Non-Patent Citations (1)
| Title |
|---|
| 孟甜甜: "新型交联透明质酸颗粒的制备及其性能研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
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Application publication date: 20180515 |