CN108034058A - A kind of preparation method of in-situ cross-linked hyaluronic acid gel - Google Patents
A kind of preparation method of in-situ cross-linked hyaluronic acid gel Download PDFInfo
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- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
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- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
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- C08J3/075—Macromolecular gels
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- 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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- 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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- 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
- C08J2329/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal, or ketal radical; Hydrolysed polymers of esters of unsaturated alcohols with saturated carboxylic acids; Derivatives of such polymer
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- C08J2405/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2401/00 or C08J2403/00
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- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2429/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal, or ketal radical; Hydrolysed polymers of esters of unsaturated alcohols with saturated carboxylic acids; Derivatives of such polymer
- C08J2429/02—Homopolymers or copolymers of unsaturated alcohols
- C08J2429/04—Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids
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Abstract
The present invention relates to a kind of preparation method of in-situ cross-linked hyaluronic acid gel, belong to biology medical material technical field.The present invention has carried out part ring-opening oxidation using sodium metaperiodate to hyaluronic acid,Using hydroxyacetic acid grafting polyvinyl alcohol,Pass through schiff base reaction and sulfhydryl oxidase again,It is prepared for the interpenetrating double-network hydrogel of gelatinizing-in-situ,With high gel strength,High fracture toughness and fracture strength,The gel rubber material of high strength can be formed,And it successfully avoid using the cytotoxic small molecule crosslinking agent of tool,Also without addition catalyst,It is easy to operate,Compared with typical natural polymer hydrogel,Its mechanical performance and anti-degradation capability are improved,Caused inflammatory effector is relatively low,Retention time is grown,Cytotoxicity is low,Good biocompatibility,And the aquogel system of cross-linking reaction can be completed in vivo without the triggering of any specific condition,Can the novel tissue engineering rack in situ that plastic be administered so as to be provided for regeneration.
Description
Technical field
The present invention relates to a kind of preparation method of in-situ cross-linked hyaluronic acid gel, belongs to bio-medical material technology neck
Domain.
Background technology
Hydrogel is reticulated polymeric structures, and wherein polymer chain is very hydrophilic, causes them to be combined with substantial amounts of water
And do not dissolve.Water can combine closely with polymer network or be moved freely in polymer network, due to hydrogel water content
Greatly, many unique properties, such as swelling/deswelling, stimulate the reaction, damping, and low sliding friction are made it have.These are only
Special performance makes hydrogel be applied at many aspects, such as waste processing, organization bracket, insoluble drug release, stealthy eye
Mirror, cornea implant and is used as cartilage etc..However, most of hydrogels typically exhibit bad mechanical property and brittleness
Height, this greatly limits their applications in terms of high-mechanical property is needed, is used for example as the substitute of load-bearing soft tissue
Hydrogel cartilage, tendon and ligament.
Since most of hydrogel material is water, comparatively mechanical performance is poor, this just promotes many researchers
To study the mechanical performance of hydrogel, particularly in biomedical aspect, due to the bad mechanical property of hydrogel, significantly
Application of the hydrogel in medical domain is limited, particularly when hydrogel is being carried out with traditional engineering materials in mechanical properties
When comparing.Since these materials have relatively small elasticity modulus, it is set neither to show the characteristic of solid matter nor show
The substance characteristics of liquid, so the measurement and explanation of mechanical data are great challenges for researcher.
Syringeability hydrogel has vast potential for future development, it will grinding as people in the future for a long period of time
Study carefully hot spot.Hyaluronic acid gel and gelatin hydrogel are reported by majority in recent years, since it has higher biocompatibility,
Both materials are made to be widely used in medical domain, but the machinery of single network structure hydrogel that both materials are prepared
Performance is usually more fragile, this makes it be greatly restricted in the application of medicine and industrial circle.
The content of the invention
The technical problems to be solved by the invention:For single network structure hydrogel mechanical performance it is more fragile the problem of,
Provide a kind of preparation method of in-situ cross-linked hyaluronic acid gel.
In order to solve the above technical problems, the technical solution adopted by the present invention is:
(1)Take hyaluronic acid to add in deionized water to be uniformly mixed, then sodium periodate solution is added dropwise, rear lucifuge stirring is added dropwise
20~24h is reacted, ethylene glycol is added and terminates dialysis purification after reaction, be freeze-dried to obtain oxidized hyaluronic acid;
(2)To take hydroxyacetic acid, mass fraction be 36% acetum, acetic anhydride, mass fraction are 98% sulfuric acid solution, mass fraction
60~70h of reaction is mixed for 5% poly-vinyl alcohol solution, then alcohol precipitation filters to obtain filter residue, filter residue alcohol washes drying, obtains the poly- second of sulfydryl
Enol;
(3)It is 0.9% sodium chloride solution for mixing sterilization treatment by the mass fraction that oxidized hyaluronic acid addition acid-base value is 7.4
Obtain A liquid;
(4)It is 0.9% sodium chloride solution for mixing sterilization treatment by the mass fraction that sulfydryl polyvinyl alcohol addition acid-base value is 7.4
Obtain B liquid;
(5)By A liquid and B liquid in mass ratio 1:1 mixing stands crosslinking, obtains in-situ cross-linked hyaluronic acid gel.
Step(1)The hyaluronic acid and the mass ratio of deionized water are 1:100.
Step(1)The mass fraction of the sodium periodate solution is 3%, and dosage is 8~33 times of hyaluronic acid quality.
Step(1)The dialysis purification process is dialysed 2~3 days to be fitted into the bag filter of 10000~15000D.
Step(2)The hydroxyacetic acid, mass fraction are 36% acetum, acetic anhydride, mass fraction are that 98% sulfuric acid is molten
Liquid, mass fraction are that the parts by weight of 5% poly-vinyl alcohol solution are 5~10 parts of hydroxyacetic acids, and 5~10 parts of mass fractions are 36% acetic acid
Solution, 10~20 parts of acetic anhydrides, 0.2~0.4 part of mass fraction are 98% sulfuric acid solution, and 20~40 parts of mass fractions are 5% poly- second
Enolate solution.
Step(3)The oxidized hyaluronic acid is 1 with the mass ratio that mass fraction is 0.9% sodium chloride solution:100~1:
400。
Step(4)The sulfydryl polyvinyl alcohol is 1 with the mass ratio that mass fraction is 0.9% sodium chloride solution:100~1:
400。
Compared with other methods, advantageous effects are the present invention:
(1)The present invention has carried out part ring-opening oxidation using sodium metaperiodate to hyaluronic acid, using hydroxyacetic acid grafted polyethylene
Alcohol, then by schiff base reaction and sulfhydryl oxidase, the interpenetrating double-network hydrogel of gelatinizing-in-situ is prepared for, the network is distinctive
Force mutual tolerance to act on, make the very big or different function polymer of two kinds of performance differences, stable combination is formed, so as to fulfill each
Performance complement between component, at the same time, two-phase continuously wait structural form feature to be effectively reduced the macroscopic view between component
Phase separation degree, the characteristics of retaining each component each, make to produce special collaboration between different component in performance and function and make
With, there is high gel strength, high fracture toughness and fracture strength, the gel rubber material of high strength can be formed, and successfully
Avoid using the cytotoxic small molecule crosslinking agent of tool, it is not required that catalyst is added, it is easy to operate, it is natural high with typical case
Molecule hydrogel is compared, its mechanical performance and anti-degradation capability are improved, and caused inflammatory effector is relatively low, when retaining
Between it is long, cytotoxicity is low, good biocompatibility, and can complete the water of cross-linking reaction in vivo without the triggering of any specific condition
Gel rubber system, can the novel tissue engineering rack in situ that plastic be administered so as to be provided for regeneration;
(2)Preparation method of the present invention is simple and efficient, swelling behavior rate is high, and stability is good, gel time and rheologic behavio(u)r can
Control, there is preferable medicament slow release performance, can potential application in fields such as drug delivery system, cell scaffold materials.
Embodiment
Take 6~12g hyaluronic acids, add in 600~1200mL deionized waters, with 300~400r/min stirrings 20~
30min, then 100~200g mass fractions are added dropwise as 3% sodium periodate solution using 1~2g/min, it is anti-that rear lucifuge stirring is added dropwise
20~24h is answered, adds 4.5~9.0g ethylene glycol, 1~2h is stirred with 200~300r/min, and load 10000~15000D
Bag filter in dialyse 2~3 days, dialysis purification is placed in freeze drying box, at -50~-30 DEG C be freeze-dried 10~
12h, obtains oxidized hyaluronic acid, takes 5~10g hydroxyacetic acids, and 5~10g mass fractions are 36% acetum, 10~20g acetic acid
Acid anhydride, 0.2~0.4g mass fractions are 98% sulfuric acid solution, and it is in 5% poly-vinyl alcohol solution, 30 to add 20~40g mass fractions
60~70h of stirring reaction under~35 DEG C of waters bath with thermostatic control, then be settled down to for 95% ethanol solution with mass fraction and produced without precipitation
It is raw, filter residue is filtered to obtain, wash filter residue with absolute ethyl alcohol is placed in vacuum drying chamber for 2~3 times, and drying is to perseverance at 50~60 DEG C
Weight, obtains sulfydryl polyvinyl alcohol, takes 0.5~1.0g oxidized hyaluronic acid, adds the mass fraction that 100~200g acid-base values are 7.4
In 0.9% sodium chloride solution, to stir 20~30min with 200~300r/min, then be placed in sterilization treatment 15 in high-pressure sterilizing pot
~20min, obtains A liquid, takes 3~6g sulfydryl polyvinyl alcohol, and it is 0.9% chlorine to add the mass fraction that 100~200g acid-base values are 7.4
Change in sodium solution, 200~300r/min stirs 20~30min, then is placed in 15~20min of sterilization treatment in high-pressure sterilizing pot, obtains B
Liquid, by A liquid and B liquid in mass ratio 1:1 mixing, 30~40min of crosslinking is stood at 35~38 DEG C, obtains in-situ cross-linked hyaluronic acid
Hydrogel.
Example 1
6g hyaluronic acids are taken, are added in 600mL deionized waters, 20min are stirred with 300r/min, then 100g matter is added dropwise with 1g/min
Amount fraction is 3% sodium periodate solution, and rear lucifuge stirring reaction 20h is added dropwise, 4.5g ethylene glycol is added, with 200r/min
1h is stirred, and is fitted into the bag filter of 10000D and dialyses 2~3 days, dialysis purification is placed in freeze drying box, at -50 DEG C
10h is freeze-dried, obtains oxidized hyaluronic acid, takes 5g hydroxyacetic acids, 5g mass fractions are 36% acetum, 10g acetic anhydrides,
0.2g mass fractions are 98% sulfuric acid solution, and it is in 5% poly-vinyl alcohol solution, under 30 DEG C of waters bath with thermostatic control to add 20g mass fractions
Stirring reaction 60h, then be settled down to for 95% ethanol solution with mass fraction and produced without precipitation, filter residue is filtered to obtain, with anhydrous second
Alcohol washing filter residue is placed in vacuum drying chamber for 2 times, is dried at 50 DEG C to constant weight, is obtained sulfydryl polyvinyl alcohol, take 0.5g to aoxidize
Hyaluronic acid, it is in 0.9% sodium chloride solution to add the mass fraction that 100g acid-base values are 7.4, and 20min is stirred with 200r/min,
Sterilization treatment 15min in high-pressure sterilizing pot is placed in again, obtains A liquid, takes 3g sulfydryl polyvinyl alcohol, and it is 7.4 to add 100g acid-base values
Mass fraction is 200r/min stirring 20min in 0.9% sodium chloride solution, then is placed in sterilization treatment 15min in high-pressure sterilizing pot,
B liquid is obtained, by A liquid and B liquid in mass ratio 1:1 mixing, crosslinking 30min is stood at 35 DEG C, obtains in-situ cross-linked hyaluronic acid water-setting
Glue.
Example 2
9g hyaluronic acids are taken, are added in 900mL deionized waters, 25min are stirred with 350r/min, then 150g matter is added dropwise with 1g/min
Amount fraction is 3% sodium periodate solution, and rear lucifuge stirring reaction 22h is added dropwise, 6.5g ethylene glycol is added, with 250r/min
1h is stirred, and is fitted into the bag filter of 12500D and dialyses 2 days, dialysis purification is placed in freeze drying box, is freezed at -40 DEG C
Dry 11h, obtains oxidized hyaluronic acid, takes 7g hydroxyacetic acids, and 7g mass fractions are 36% acetum, 15g acetic anhydrides, 0.3g matter
Amount fraction is 98% sulfuric acid solution, and it is in 5% poly-vinyl alcohol solution to add 30g mass fractions, is stirred under 32 DEG C of waters bath with thermostatic control anti-
65h is answered, then is settled down to for 95% ethanol solution with mass fraction and is produced without precipitation, filter residue is filtered to obtain, is washed with absolute ethyl alcohol
Filter residue is placed in vacuum drying chamber for 3 times, is dried at 55 DEG C to constant weight, is obtained sulfydryl polyvinyl alcohol, takes 0.75g to aoxidize hyalomitome
Acid, it is in 0.9% sodium chloride solution to add the mass fraction that 150g acid-base values are 7.4, stirs 25min with 250r/min, then be placed in
Sterilization treatment 17min in high-pressure sterilizing pot, obtains A liquid, takes 5g sulfydryl polyvinyl alcohol, adds the quality point that 150g acid-base values are 7.4
Number is 250r/min stirring 25min in 0.9% sodium chloride solution, then is placed in sterilization treatment 17min in high-pressure sterilizing pot, obtains B liquid,
By A liquid and B liquid in mass ratio 1:1 mixing, crosslinking 35min is stood at 36 DEG C, obtains in-situ cross-linked hyaluronic acid gel.
Example 3
12g hyaluronic acids are taken, are added in 1200mL deionized waters, 30min are stirred with 400r/min, then 200g is added dropwise with 2g/min
Mass fraction is 3% sodium periodate solution, and rear lucifuge stirring reaction 24h is added dropwise, 9.0g ethylene glycol is added, with 300r/
Min stirs 2h, and is fitted into the bag filter of 15000D and dialyses 3 days, and dialysis purification is placed in freeze drying box, at -30 DEG C
12h is freeze-dried, obtains oxidized hyaluronic acid, takes 10g hydroxyacetic acids, 10g mass fractions are 36% acetum, 20g acetic anhydrides,
0.4g mass fractions are 98% sulfuric acid solution, and it is in 5% poly-vinyl alcohol solution, under 35 DEG C of waters bath with thermostatic control to add 40g mass fractions
Stirring reaction 70h, then be settled down to for 95% ethanol solution with mass fraction and produced without precipitation, filter residue is filtered to obtain, with anhydrous second
Alcohol washing filter residue is placed in vacuum drying chamber for 3 times, is dried at 60 DEG C to constant weight, is obtained sulfydryl polyvinyl alcohol, take 1.0g to aoxidize
Matter acid, it is in 0.9% sodium chloride solution to add the mass fraction that 200g acid-base values are 7.4, stirs 30min with 300r/min, then put
The sterilization treatment 20min in high-pressure sterilizing pot, obtains A liquid, takes 6g sulfydryl polyvinyl alcohol, adds the quality that 200g acid-base values are 7.4
Fraction is 300r/min stirring 30min in 0.9% sodium chloride solution, then is placed in sterilization treatment 20min in high-pressure sterilizing pot, obtains B
Liquid, by A liquid and B liquid in mass ratio 1:1 mixing, crosslinking 40min is stood at 38 DEG C, obtains in-situ cross-linked hyaluronic acid gel.
A kind of in-situ cross-linked hyaluronic acid gel prepared by the present invention and the hyalomitome water-setting of Guangzhou company production
Glue is detected, specific testing result such as following table table 1:
The in-situ cross-linked hyaluronic acid gel performance characterization of table 1
The in-situ cross-linked hyaluronic acid gel that as shown in Table 1 prepared by the present invention, compression ratio is smaller, and compressive strength is high, incompressible
Performance is good, and swelling behavior rate is high, and stability is good, gel time is controllable, has broad application prospects.
Claims (7)
1. a kind of preparation method of in-situ cross-linked hyaluronic acid gel, it is characterised in that specifically preparation process is:
(1)Take hyaluronic acid to add in deionized water to be uniformly mixed, then sodium periodate solution is added dropwise, rear lucifuge stirring is added dropwise
20~24h is reacted, ethylene glycol is added and terminates dialysis purification after reaction, be freeze-dried to obtain oxidized hyaluronic acid;
(2)To take hydroxyacetic acid, mass fraction be 36% acetum, acetic anhydride, the concentrated sulfuric acid, mass fraction are that 5% polyvinyl alcohol is molten
60~70h of reaction is mixed in liquid, then alcohol precipitation filters to obtain filter residue, and filter residue alcohol washes drying, obtains sulfydryl polyvinyl alcohol;
(3)Oxidized hyaluronic acid is added into mixing sterilization treatment in the physiological saline that acid-base value is 7.4 and obtains A liquid;
(4)Sulfydryl polyvinyl alcohol is added into mixing sterilization treatment in the physiological saline that acid-base value is 7.4 and obtains B liquid;
(5)By A liquid and B liquid in mass ratio 1:1 mixing stands crosslinking, obtains in-situ cross-linked hyaluronic acid gel.
A kind of 2. preparation method of in-situ cross-linked hyaluronic acid gel as claimed in claim 1, it is characterised in that step
(1)The hyaluronic acid and the mass ratio of deionized water are 1:100.
A kind of 3. preparation method of in-situ cross-linked hyaluronic acid gel as claimed in claim 1, it is characterised in that step
(1)The mass fraction of the sodium periodate solution is 3%, and dosage is 8~33 times of hyaluronic acid quality.
A kind of 4. preparation method of in-situ cross-linked hyaluronic acid gel as claimed in claim 1, it is characterised in that step
(1)The dialysis purification process is dialysed 2~3 days to be fitted into the bag filter of 10000~15000D.
A kind of 5. preparation method of in-situ cross-linked hyaluronic acid gel as claimed in claim 1, it is characterised in that step
(2)The hydroxyacetic acid, mass fraction are 36% acetum, acetic anhydride, the concentrated sulfuric acid, mass fraction are 5% poly-vinyl alcohol solution
Parts by weight be 5~10 parts of hydroxyacetic acids, 5~10 parts of mass fractions are 36% acetum, 10~20 parts of acetic anhydrides, 0.2~
0.4 part of concentrated sulfuric acid, 20~40 parts of mass fractions are 5% poly-vinyl alcohol solution.
A kind of 6. preparation method of in-situ cross-linked hyaluronic acid gel as claimed in claim 1, it is characterised in that step
(3)The mass ratio of the oxidized hyaluronic acid and physiological saline is 1:100~1:400.
A kind of 7. preparation method of in-situ cross-linked hyaluronic acid gel as claimed in claim 1, it is characterised in that step
(4)The mass ratio of the sulfydryl polyvinyl alcohol and physiological saline is 1:100~1:400.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102441137B1 (en) * | 2022-02-07 | 2022-09-06 | 김환철 | A biocompatible polymer hydrogel comprising an ether group capable of controlling the degradation rate |
CN115715745A (en) * | 2022-12-01 | 2023-02-28 | 湖州紫金生物科技有限公司 | Oil-control acne-removing gel based on sustained release of 3-hydroxy medium-chain fatty acid, preparation method and application |
-
2017
- 2017-12-18 CN CN201711363319.0A patent/CN108034058A/en not_active Withdrawn
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102441137B1 (en) * | 2022-02-07 | 2022-09-06 | 김환철 | A biocompatible polymer hydrogel comprising an ether group capable of controlling the degradation rate |
CN115715745A (en) * | 2022-12-01 | 2023-02-28 | 湖州紫金生物科技有限公司 | Oil-control acne-removing gel based on sustained release of 3-hydroxy medium-chain fatty acid, preparation method and application |
CN115715745B (en) * | 2022-12-01 | 2024-02-27 | 湖州紫金生物科技有限公司 | Oil-control acne-removing gel based on 3-hydroxy medium-chain fatty acid slow release, preparation method and application |
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