CN110698700A - Method for preparing sodium hyaluronate gel by tannin crosslinking and sodium hyaluronate gel - Google Patents
Method for preparing sodium hyaluronate gel by tannin crosslinking and sodium hyaluronate gel Download PDFInfo
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- CN110698700A CN110698700A CN201911032170.7A CN201911032170A CN110698700A CN 110698700 A CN110698700 A CN 110698700A CN 201911032170 A CN201911032170 A CN 201911032170A CN 110698700 A CN110698700 A CN 110698700A
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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
- C08J3/244—Stepwise homogeneous crosslinking of one polymer with one crosslinking system, e.g. partial curing
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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 belongs to the technical field of preparation of medicines and cosmetics, and relates to a method for preparing sodium hyaluronate gel by tannin crosslinking and the sodium hyaluronate gel. The method comprises the following steps: (1) mixing sodium hyaluronate with sodium hydroxide solution until the sodium hyaluronate is completely dissolved; (2) adding tannin into the sodium hyaluronate solution obtained in the step (1) to perform a crosslinking reaction; adjusting the pH value of the crosslinking reaction solution to be neutral, and stopping the crosslinking reaction; (3) adding a phosphate buffer solution into the solution of which the crosslinking reaction is ended in the step (2), and naturally swelling to prepare crosslinked sodium hyaluronate gel; (4) mixing the cross-linked sodium hyaluronate gel with a precipitator, and precipitating; (5) and (4) carrying out vacuum drying on the precipitate obtained in the step (4) to obtain sodium hyaluronate gel powder. The invention adopts tannin as a cross-linking agent, can prepare gel with water absorption and swelling properties, and better meets different requirements in the fields of medicine, beauty treatment, cosmetics and the like.
Description
Technical Field
The invention belongs to the technical field of preparation of medicines and cosmetics, and particularly relates to a method for preparing sodium hyaluronate gel by tannin crosslinking and the sodium hyaluronate gel prepared by the method.
Background
Hyaluronic Acid (HA) is a linear polyanionic mucopolysaccharide (formula I) formed by repeatedly connecting D-glucuronic acid and N-acetyl-D-glucosamine disaccharide units, widely exists in connective tissues such as joint synovial fluid, eyeball vitreous body, skin, intercellular space, cockscomb and the like of animals and human beings, is an important component for forming joint synovial fluid, vitreous body, skin and cartilage tissue, and HAs unique physicochemical properties and wide biological functions.
Hyaluronic acid is typically present in the form of a hyaluronate salt, namely Sodium Hyaluronate (SH). SH can be extracted from animal tissues and also can be produced by a microbial fermentation method, is widely applied to the fields of food, daily chemicals and medicines, and can be divided into various grades such as food grade, medical grade, cosmetic grade and the like according to different molecular weights. Through long-term research and development, high-purity medical-grade SH has been prepared into injections for application in ophthalmic surgery, orthopedic surgery, treatment of osteoarthritis and rheumatoid arthritis, prevention of postoperative adhesion and the like. In addition, since hyaluronic acid HAs good biocompatibility, unique viscoelasticity and excellent water retention, HA is also used for injection into facial skin, wrinkle reduction, skin appearance improvement and skin aging prevention.
The natural sodium hyaluronate is easy to biodegrade, has short retention time in organisms and insufficient hardness and mechanical strength, and limits the application of the natural sodium hyaluronate. In view of the above defects, sodium hyaluronate is usually prepared into gels with different molecular weights by using a proper cross-linking agent, the molecular weight of the cross-linked and modified sodium hyaluronate gel is increased, and the cross-linked and modified sodium hyaluronate gel with more complex molecular structure, stronger viscoelasticity and obviously improved enzymolysis resistance and mechanical properties can be developed on the basis of keeping the original biocompatibility, so that the application of the gel is wider.
Most of the currently used crosslinking agents are chemical agents, which have irritation and even cytotoxicity to skin, and the residue of the crosslinking agents has great potential harm to users, so the application of the crosslinking agents is limited, and therefore, the preparation of the sodium hyaluronate gel by using the safe and nontoxic natural biological crosslinking agents is an effective method for solving the problem.
Tannin is also called tannin and tannin, is a polyphenol compound (see formula II) with a relatively complex structure, exists in bark, wood, leaves, roots, fruits and other parts of various plants, is particularly common in bark, can be combined with protein to form water-insoluble precipitate, and can be used for tanning. Has astringency and strong reducibility, has the functions of stopping bleeding, promoting scab, coagulating protein, inhibiting bacteria, resisting virus, resisting oxidation, resisting allergy, resisting inflammation, expelling parasites, lowering blood pressure and the like, and has increasingly expanded application range. At present, tannin commodities in the market are sufficient in supply, low in price and easy to obtain. As a polyphenol compound, the tannin structure contains a plurality of active functional groups such as hydroxyl, ester group, ether bond and the like, and the tannin is considered to be suitable to be used as a novel biological cross-linking agent in the fields of food, daily chemicals, medicines and the like due to the characteristics of natural non-toxicity, oxidation resistance, bacteriostasis, easy obtaining of products and the like.
However, there is currently no method for preparing sodium hyaluronate gel by crosslinking tannin.
Disclosure of Invention
The invention aims to provide a method for preparing sodium hyaluronate gel by tannin crosslinking and the sodium hyaluronate gel.
The first aspect of the invention provides a method for preparing sodium hyaluronate gel by tannin crosslinking, which comprises the following steps:
(1) dissolution
Mixing sodium hyaluronate with sodium hydroxide solution until the sodium hyaluronate is completely dissolved;
(2) crosslinking reaction
Adding tannin into the sodium hyaluronate solution obtained in the step (1), and carrying out crosslinking reaction for 2-24 h at 30-80 ℃; adjusting the pH value of the crosslinking reaction solution to be neutral, and stopping the crosslinking reaction;
(3) swelling of the composition
Adding a phosphate buffer solution into the solution of which the crosslinking reaction is ended in the step (2), and naturally swelling to prepare crosslinked sodium hyaluronate gel;
(4) precipitation of
Mixing the cross-linked sodium hyaluronate gel obtained in the step (3) with a precipitator for precipitation;
(5) drying
And (4) carrying out vacuum drying on the precipitate obtained in the step (4) to obtain sodium hyaluronate gel powder with the crosslinking degree of 1-10%.
According to a preferred embodiment of the present invention, in the step (1), the mass concentration of the sodium hydroxide solution is 0.5% to 5%.
According to a preferred embodiment of the invention, in the step (1), the mass ratio of the sodium hyaluronate to the sodium hydroxide is 1-10: 1-10;
according to a preferred embodiment of the present invention, in the step (1), the mixing conditions include: stirring for 1-4 h at 20-60 ℃.
In the invention, the tannin is used as a cross-linking agent, and according to a preferred embodiment of the invention, in the step (2), the mass ratio of the tannin to the sodium hyaluronate in the sodium hyaluronate solution is 1-10: 10-100.
According to a preferred embodiment of the present invention, in the step (2), the pH of the crosslinking reaction solution is adjusted by adding an acidic solution to the crosslinking reaction solution; the acid solution is preferably 0.01-0.03 mol/L hydrochloric acid solution.
According to a preferred embodiment of the present invention, in the step (3), the phosphate buffer solution has a concentration of 0.05mol/L to 0.5mol/L and a pH of 6.0 to 8.0; the volume ratio of the phosphate buffer solution to the solution of which the crosslinking reaction is terminated in the step (2) is 1: 1-5: 1.
According to a preferred embodiment of the present invention, in the step (3), the natural swelling time is 1 to 5 hours.
According to a preferred embodiment of the invention, in the step (4), the volume ratio of the cross-linked sodium hyaluronate gel to the precipitant is 1: 1-1: 5.
According to a preferred embodiment of the present invention, in the step (4), the precipitant is 92 to 97% ethanol.
According to a preferred embodiment of the present invention, in the step (4), the precipitation manner is to add the gel into the precipitant, stir to generate a precipitate, and then stand for 1 to 12 hours.
According to a preferred embodiment of the present invention, in the step (5), the temperature of the vacuum drying is 20 to 60 ℃.
According to a preferred embodiment of the invention, the method further comprises:
(6) sterilization
And (3) mixing the powder obtained in the step (5) with a phosphate buffer solution to prepare gel with the mass fraction of 1% -10%, and sterilizing at high temperature for a short time to obtain the granulated cross-linked sodium hyaluronate gel.
According to a preferred embodiment of the present invention, in the step (6), the phosphate buffer solution has a concentration of 0.05mol/L to 0.5mol/L and a pH of 6.0 to 8.0; the mass ratio of the powder to the phosphate buffer solution is 1: 20-1: 100.
According to the method of the invention, the sodium hyaluronate can be prepared by a conventional fermentation method or an extraction method.
The second aspect of the present invention provides a sodium hyaluronate gel prepared by the above method.
The invention has the following technical effects:
(1) tannin is used as a cross-linking agent, and gel with water absorption and swelling properties can be prepared.
(2) Because the tannin is natural and non-toxic, the process of eluting the cross-linking agent at the later stage of the gel can be greatly simplified, the preparation efficiency is improved, and the elution cost is reduced.
(3) On the basis of adopting tannin as a cross-linking agent, the sodium hyaluronate gel with specific cross-linking degree can be customized according to requirements in a certain range by further optimizing the molecular weight of the sodium hyaluronate raw material, adjusting the proportion of the cross-linking agent and the sodium hyaluronate raw material in the cross-linking reaction and cross-linking reaction conditions, and different requirements in the fields of medicine, beauty, cosmetics and the like can be better met.
Additional features and advantages of the invention will be set forth in the detailed description which follows.
Detailed Description
Preferred embodiments of the present invention will be described in more detail below. While the following describes preferred embodiments of the present invention, it should be understood that the present invention may be embodied in various forms and should not be limited by the embodiments set forth herein.
The sodium hyaluronate raw material selected in the following examples is produced by a fermentation method, and has a molecular weight of 80-200 ten thousand daltons.
The phosphate buffer was composed of deionized water solutions containing sodium phosphate dibasic and sodium phosphate monobasic in different proportions.
Example 1
Weighing 1g of sodium hydroxide, dissolving the sodium hydroxide in 100mL of distilled water to prepare a 1% sodium hydroxide solution, adding 2g of sodium hyaluronate raw material, stirring and dissolving for 2 hours at 25 ℃ until the sodium hyaluronate is completely dissolved. 0.1g of tannin is added into the solution, and the mixture is stirred and reacted for 24 hours at the temperature of 30 ℃. After the reaction is finished, adding 0.02mol/L hydrochloric acid solution to adjust the pH value to be neutral, and stopping the crosslinking reaction. 100mL of phosphate buffer (concentration 0.1mol/L, pH7.0) was added, and the mixture was allowed to stand and swell for 4 hours. And dropwise adding 200mL of 95% ethanol into the swollen gel under stirring, collecting the precipitate, and performing vacuum drying at 25 ℃ for 24 hours to obtain sodium hyaluronate gel powder with the crosslinking degree of 3.7%. The gel powder was added to 100mL of phosphate buffer (concentration 0.1mol/L, pH7.0) to prepare gel particles, which were sterilized at 120 ℃ for 10 min.
Example 2
Weighing 1g of sodium hydroxide, dissolving the sodium hydroxide in 100mL of distilled water to prepare 1% sodium hydroxide solution, adding 1g of sodium hyaluronate raw material, stirring and dissolving at 50 ℃ for 1h until the sodium hyaluronate is completely dissolved. 0.2g of tannin is added into the solution, and the mixture is stirred and reacted for 3 hours at the temperature of 80 ℃. After the reaction is finished, adding 0.02mol/L hydrochloric acid solution to adjust the pH value to be neutral, and stopping the crosslinking reaction. 100mL of phosphate buffer (concentration 0.1mol/L, pH7.0) was added, and the mixture was allowed to stand and swell for 4 hours. And dropwise adding 100mL of 95% ethanol into the swollen gel under stirring, collecting the precipitate, and performing vacuum drying at 40 ℃ for 12 hours to obtain sodium hyaluronate gel powder with the crosslinking degree of 4.7%. The gel powder was added to 100mL of phosphate buffer (concentration 0.1mol/L, pH7.0) to prepare gel particles, which were sterilized at 120 ℃ for 10 min.
Example 3
Weighing 2g of sodium hydroxide, dissolving the sodium hydroxide in 100mL of distilled water to prepare a 2% sodium hydroxide solution, adding 1g of sodium hyaluronate raw material, stirring and dissolving at 40 ℃ for 1h until the sodium hyaluronate is completely dissolved. 0.1g of tannin is added into the solution, and the mixture is stirred and reacted for 12 hours at the temperature of 45 ℃. After the reaction is finished, adding 0.02mol/L hydrochloric acid solution to adjust the pH value to be neutral, and stopping the crosslinking reaction. 100mL of phosphate buffer (concentration 0.1mol/L, pH7.0) was added, and the mixture was allowed to stand and swell for 4 hours. And dropwise adding 100mL of 95% ethanol into the swollen gel under stirring, collecting the precipitate, and performing vacuum drying at 40 ℃ for 12 hours to obtain sodium hyaluronate gel powder with the crosslinking degree of 3.9%. The gel powder was added to 100mL of phosphate buffer (concentration 0.1mol/L, pH7.0) to prepare gel particles, which were sterilized at 120 ℃ for 10 min.
Test example
Viscoelastic property and swelling degree are important indexes reflecting gel physicochemical properties, and are main reference data of the sodium hyaluronate cross-linked gel different from non-cross-linked gel.
1. Dynamic viscosity determination:
the dynamic viscosity of the sample is calculated by a rotary viscometer measuring method according to the second method of VIG (video of the second supplement of pharmacopoeia of the people's republic of China) (2010 version), under the condition that the shearing rate is not less than 0.25Hz (25 +/-0.1) DEG C and according to the magnitude of the shearing stress acting on the liquid medium in the rotating process, and the dynamic viscosity of the sample is calculated by the following formula:
η＝K·(T/ω)
in the formula: k is a rotary viscometer constant measured with a standard fluid of known viscosity;
t is torque;
ω is the angular velocity.
2. Intrinsic viscosity measurement:
the characteristic viscosity number was measured by a Ubbelohde viscometer according to the third method of VIG, an appendix of pharmacopoeia of the people's republic of China (2015).
3. Degree of swelling
Accurately weighing a proper amount of cross-linked sodium hyaluronate gel, placing the cross-linked sodium hyaluronate gel in a culture dish, placing the culture dish in a drying box, adjusting the temperature to 70 ℃, and drying to constant weight. After removal, the mass m1 is accurately weighed. And soaking the dried cross-linked sodium hyaluronate gel into deionized water until the gel is completely expanded, taking out the gel, absorbing the water on the surface by using filter paper, and weighing the mass m2 of the expanded cross-linked sodium hyaluronate. The swelling degree of the crosslinked gel was calculated according to the formula Q ═ m2-m1)/m 1.
4. The above measurements were carried out on the crosslinked gels prepared in the 3 examples, and the measured performance parameters are shown in Table 1 below.
TABLE 1
Having described embodiments of the present invention, the foregoing description is intended to be exemplary, not exhaustive, and not limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments.
Claims (10)
1. A method for preparing sodium hyaluronate gel by tannin crosslinking is characterized by comprising the following steps:
(1) dissolution
Mixing sodium hyaluronate with sodium hydroxide solution until the sodium hyaluronate is completely dissolved;
(2) crosslinking reaction
Adding tannin into the sodium hyaluronate solution obtained in the step (1), and carrying out crosslinking reaction for 2-24 h at 30-80 ℃; adjusting the pH value of the crosslinking reaction solution to be neutral, and stopping the crosslinking reaction;
(3) swelling of the composition
Adding a phosphate buffer solution into the solution of which the crosslinking reaction is ended in the step (2), and naturally swelling to prepare crosslinked sodium hyaluronate gel;
(4) precipitation of
Mixing the cross-linked sodium hyaluronate gel obtained in the step (3) with a precipitator for precipitation;
(5) drying
And (4) carrying out vacuum drying on the precipitate obtained in the step (4) to obtain sodium hyaluronate gel powder with the crosslinking degree of 1-10%.
2. The method for preparing the sodium hyaluronate gel through tannin crosslinking according to claim 1, wherein in the step (1), the mass concentration of the sodium hydroxide solution is 0.5-5%;
the mass ratio of the sodium hyaluronate to the sodium hydroxide is 1-10: 1-10;
the mixing conditions include: stirring for 1-4 h at 20-60 ℃.
3. The method for preparing the sodium hyaluronate gel through tannin crosslinking according to claim 1, wherein in the step (2), the mass ratio of the tannin to the sodium hyaluronate in the sodium hyaluronate solution is 1-10: 10-100;
the pH value of the crosslinking reaction solution is adjusted by adding an acidic solution into the crosslinking reaction solution; the acid solution is preferably 0.01-0.03 mol/L hydrochloric acid solution.
4. The method for preparing sodium hyaluronate gel through tannin crosslinking according to claim 1, wherein in the step (3), the phosphate buffer solution is a phosphate buffer solution with concentration of 0.05-0.5 mol/L and pH of 6.0-8.0; the volume ratio of the phosphate buffer solution to the solution of which the crosslinking reaction is terminated in the step (2) is 1: 1-5: 1;
the natural swelling time is 1-5 h.
5. The method for preparing the sodium hyaluronate gel through tannin crosslinking according to claim 1, wherein in the step (4), the volume ratio of the crosslinked sodium hyaluronate gel to the precipitant is 1: 1-1: 5;
the precipitator is 92-97% ethanol;
the precipitation mode is that the gel is added into a precipitator, and the gel is stirred to generate precipitation and then is placed for 1 to 12 hours.
6. The method for preparing sodium hyaluronate gel by tannin crosslinking according to claim 1, wherein the temperature of vacuum drying in step (5) is 20 ℃ to 60 ℃.
7. The method for preparing sodium hyaluronate gel by tannin crosslinking according to claim 1, wherein the method further comprises:
(6) sterilization
And (3) mixing the powder obtained in the step (5) with a phosphate buffer solution to prepare gel with the mass fraction of 1% -10%, and sterilizing at high temperature for a short time to obtain the granulated cross-linked sodium hyaluronate gel.
8. The method for preparing the sodium hyaluronate gel through tannin crosslinking according to claim 7, wherein the phosphate buffer solution is a phosphate buffer solution with the concentration of 0.05-0.5 mol/L and the pH of 6.0-8.0; the mass ratio of the powder to the phosphate buffer solution is 1: 20-1: 100.
9. A method of tannin crosslinking to prepare a sodium hyaluronate gel according to any of claims 1 to 8, wherein the sodium hyaluronate is prepared by fermentation or extraction.
10. A sodium hyaluronate gel prepared by the method of any one of claims 1 to 9.
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| WO2014048168A1 (en) * | 2012-09-29 | 2014-04-03 | 杭州嘉伟生物制品有限公司 | Cross-linked sodium hyaluronate gel for tissue filler for plastic surgery and preparation method thereof |
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| WO2014048168A1 (en) * | 2012-09-29 | 2014-04-03 | 杭州嘉伟生物制品有限公司 | Cross-linked sodium hyaluronate gel for tissue filler for plastic surgery and preparation method thereof |
| CN107955194A (en) * | 2017-11-29 | 2018-04-24 | 桂林华诺威生物科技有限公司 | The preparation method of high quality cross-linking sodium hyaluronate gel |
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