CN101759881A - Medical cross-linking sodium hyaluronate gel derivative product and preparation method thereof - Google Patents
Medical cross-linking sodium hyaluronate gel derivative product and preparation method thereof Download PDFInfo
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- CN101759881A CN101759881A CN200810200895A CN200810200895A CN101759881A CN 101759881 A CN101759881 A CN 101759881A CN 200810200895 A CN200810200895 A CN 200810200895A CN 200810200895 A CN200810200895 A CN 200810200895A CN 101759881 A CN101759881 A CN 101759881A
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- hyaluronic acid
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Abstract
The invention provides a medical cross-linking sodium hyaluronate gel derivative product and a preparation method thereof. The preparation contains cross-linking hyaluronic acid and non-crosslinked hyaluronic acid; the cross-linking hyaluronic acid reacts with hyaluronic acid molecules by using a cross-linking agent under the alkaline environment and forms cross-linking hyaluronic acid gel, and then the cross-linking agent is removed to prepare the medical cross-linking sodium hyaluronate gel derivative product. The product has good biocompatibility and longer half-life period and is suitable for tissue filling, bone articular lubrication or medicine sustained-release preparation and the like.
Description
Technical field
The present invention relates to a kind of medical cross-linking sodium hyaluronate gel derivative product and preparation method thereof.
Background technology
Hyaluronic acid (Hyaluronic Acid is called for short HA) gel is widely used in fields such as ophthalmology, orthopaedics, gynecological surgery, plastic surgery, and it is in the history of clinical existing more than ten years, and its security and validity have obtained the generally approval of medical science all circles.Natural ectogenic hyaluronan molecule amount is greatly about 100,000～5,000,000 Dalton, and retention time in vivo about about 3～15 days, has limited its application in some field greatly to a great extent.For example on tissue filling, be used to improve facial wrinkles and folding line, improve lip and correct face contour etc.; Perhaps be used for osteoarthrosis when lubricated the effect time length too short, need injection continuously.
Cross-linked hyaluronic acid gel is the cross-linking products of hyaluronic acid and linking agent, have excellent biological compatibility and good biodegradability, according to the above-mentioned character of cross-linked hyaluronic acid gel, be applied to that anti, osteoarthrosis are lubricated, fields such as medicament slow release preparation and tissue filling agent.
Conventional cross-linking method in the past is that hyaluronic acid and linking agent are mixed in the aqueous solution, makes the incompatible preparation of chemical bond between the hyaluronic acid macromolecular chain by linking agent.But when bestowing organism, residual linking agent causes inflammatory reaction in the body easily, reduce the linking agent usage quantity with ordinary method, the cross-linked hyaluronic acid gel visco-elasticity that obtains reduces, not soft, filling effect is undesirable or to keep the effect time during as medicament slow release preparation undesirable during as tissue filler.
Summary of the invention
The purpose of this invention is to provide a kind of medical cross-linking sodium hyaluronate gel derivative product and preparation method thereof, to overcome the above-mentioned defective that prior art exists.
Method of the present invention comprises the steps:
(1) with hyaluronic acid in alkaline substance solution, mixed 2～5 hours, making concentration is the hyaluronic basic solution of 0.08～0.15g/mL;
Said hyaluronic molecular weight is 500,000～3,000,000 dalton;
Said alkaline substance solution is the NaOH aqueous solution, the KOH aqueous solution or Na
2CO
3A kind of in the aqueous solution etc., concentration is 0.001～2.0M, preferred 0.25M;
(2) linking agent is added in the hyaluronic acid basic solution of step (1), then solution is placed 37～60 ℃ to descend 2～5 hours;
In the hyaluronic acid basic solution, the concentration of linking agent is 0.0002～0.02g/mL;
Said linking agent is selected from having the compound of 2 above functional groups, carboxyl, hydroxyl, kharophen isoreactivity functional group reactions that its functional group can be had with hyaluronan molecule and the functional group that forms covalent linkage;
Preferably, said linking agent is more than one in epoxide, aldehyde, diglycidylether or the divinyl sulfone etc., consider linking agent to the side effect of human body and in conjunction with the LD50 index, most preferably toxicity less 1,4-butanediol diglycidyl ether (BDDE).
Among the present invention, the usage quantity of linking agent is not particularly limited, but consider the organism adaptability of cross-linked hyaluronic acid gel, preferentially select for use a small amount of as far as possible linking agent to carry out crosslinking reaction, the concentration of linking agent in mixture is preferably 0.0002～0.02g/mL;
(3) adding pH subsequently in the product of step (2) is 7.1～7.7 PBS damping fluid or deionized water, soaking and washing gel, soaking and washing, soaking and washing 2～4 days;
(4) remove PBS damping fluid or deionized water, then with cross-linked hyaluronic acid gel at 7～8kg/cm
2Pressure under, be the extrusion cavities of 450～550 μ m by bore dia, be extruded into microgranular gel;
(5) then microgranular hyaluronic acid derivatives is mixed with hyaluronic acid, obtain said cross-linked hyaluronic acid gel, wherein, hyaluronic acid concentration is 0.5～3mg/ml, preferred 1～2mg/ml;
Said BDDE can adopt the commercially available prod;
The cross-linked hyaluronic acid gel molecular structure is:
Wherein: n=1 * 10
6～5 * 10
6, and be integer;
Said hyaluronic acid for the straight chain polymer polysaccharide that disaccharide unit forms, comprises hyaluronate sodium, hyaluronic acid magnesium or Calcium hyaluronate etc. by N-n acetylglucosamine n-D-glucuronic acid;
Among the present invention, the hyaluronic acid raw material select for use the fermentation using bacteria method produce or tissue extraction all can, for reducing antigenicity, preferentially select fermentation using bacteria method raw material for use, adopt as hyaluronic acid and fermentative production thereof are summarized the method for (Guo Xue equality);
In the present invention, contain 8～15% above-mentioned hyaluronic acid in the mixture of crosslinking reaction, like this, its molecular chain of the hyaluronic acid of high density exists with the state of very complicated mutual winding, therefore partial cross-linked between the hyaluronic acid chain, by spatial constraint mutually, can make the network structure firm stable between the molecular chain.Also can prepare excellent viscoelastic cross-linked hyaluronic acid gel even select less linking agent like this for use.
Among the present invention, hyaluronic reactivity during for the raising crosslinking reaction, the pH value that can regulate mixture is preferably added NaOH, KOH, Na
2CO
3, preferably add the NaOH of 0.25M, pH=10～12;
The medical cross-linking sodium hyaluronate gel derivative product that the present invention obtains contains uncrosslinked hyaluronic acid and cross-linked hyaluronic acid gel, so both has been convenient to injection, can keep good effect and persistence again after injection.
The cross-linked hyaluronic acid gel that the present invention obtains has favorable tissue consistency and biodegradability, and is easy to injection, long half time, and filling effect is good, is fit to the preparation tissue filling agent, osteoarthrosis lubricant or medicament slow release preparation etc.
Embodiment
Below provide embodiments of the invention, further the present invention is described in detail, but the present invention is not limited to this.
Embodiment 1
With molecular weight is that the smart powder 3.3g of 2,000,000 daltonian hyaluronic acids places the container that fills 30ml 0.25M NaOH solution, mixes 3 hours;
In whipping process, add 0.3ml 1,4-butanediol diglycidyl ether (BDDE) places solution 45 ℃ water-bath 5 hours then, forms cross-linked hyaluronic acid gel;
Add 500mLpH subsequently and be 7.3 PBS damping fluid, soaking and washing is 6 times repeatedly, cleans 2.5 days.
Then hyaluronic acid derivatives is placed the pressure extrusion device, it is 500 μ m that bore dia is set, pressurization 7kg/cm
2, hyaluronic acid derivatives is extruded into microgranular gel.
Then microgranular hyaluronic acid derivatives and hyaluronic acid are mixed, obtain product, wherein, the hyaluronic acid ultimate density is 2mg/ml.High pressure steam sterilization (121 ℃, 30 minutes) is carried out in can.
Embodiment 2
With molecular weight is that the smart powder 4g of 2,000,000 daltonian hyaluronic acids places the container that fills 30ml 0.25M NaOH solution, mixes 4 hours;
In whipping process, add 0.4ml 1,4-butanediol diglycidyl ether (BDDE) places solution 50 ℃ water-bath 5 hours then, forms cross-linked hyaluronic acid gel;
Add 500mL deionized water soaking and washing 8 times repeatedly subsequently, cleaned 3 days.
Then hyaluronic acid derivatives is placed the pressure extrusion device, it is 550 μ m that bore dia is set, pressurization 8kg/cm
2, hyaluronic acid derivatives is extruded into microgranular gel.Then microgranular hyaluronic acid derivatives and hyaluronic acid are mixed, the hyaluronic acid ultimate density is 2mg/ml.High pressure steam sterilization (121 ℃, 30 minutes) is carried out in can.
Embodiment 3
With molecular weight is that the smart powder 2.6g of 2,000,000 daltonian hyaluronic acids places the container that fills 30ml 0.25M NaOH solution, mixes 4 hours;
In whipping process, add 0.3ml 1,4-butanediol diglycidyl ether (BDDE) places solution 40 ℃ water-bath 3 hours then, forms cross-linked hyaluronic acid gel;
Add 500mL deionized water soaking and washing 6 times repeatedly subsequently, cleaned 2.5 days.
Then hyaluronic acid derivatives is placed the pressure extrusion device, it is 550 μ m that bore dia is set, pressurization 8kg/cm
2, hyaluronic acid derivatives is extruded into microgranular gel.
Then microgranular hyaluronic acid derivatives and hyaluronic acid are mixed, the hyaluronic acid ultimate density is 1mg/ml.High pressure steam sterilization (121 ℃, 30 minutes) is carried out in can.
Claims (9)
1. the preparation method of a medical cross-linking sodium hyaluronate gel derivative product is characterized in that, comprises the steps:
(1) with hyaluronic acid in alkaline substance solution, mixed 2～5 hours, making concentration is the hyaluronic acid basic solution of 0.08～0.15g/mL;
(2) linking agent is added in the hyaluronic acid basic solution of step (1), then solution is placed 37～60 ℃ to descend 2～5 hours;
Said linking agent is more than one in epoxide, aldehyde, diglycidylether or the divinyl sulfone;
(3) adding pH subsequently in the product of step (2) is 7.1～7.7 PBS damping fluid or deionized water, soaking and washing gel, soaking and washing;
(4) remove PBS damping fluid or deionized water, then with cross-linked hyaluronic acid gel at 7～8kg/cm
2Pressure under, be the extrusion cavities of 450～550 μ m by bore dia, be extruded into microgranular gel;
(5) then microgranular hyaluronic acid derivatives is mixed with hyaluronic acid, obtain said cross-linked hyaluronic acid gel, wherein, hyaluronic acid concentration is 0.5～3mg/ml.
2. method according to claim 1 is characterized in that, said hyaluronic molecular weight is 500,000～3,000,000 dalton.
3. method according to claim 1 is characterized in that, said alkaline substance solution is the NaOH aqueous solution, the KOH aqueous solution or Na
2CO
3A kind of in the aqueous solution, concentration is 0.001～2.0M.
4. method according to claim 1 is characterized in that, in the hyaluronic acid basic solution, the concentration of linking agent is 0.0002～0.02g/mL.
5. method according to claim 1 is characterized in that, said linking agent is 1, the 4-butanediol diglycidyl ether.
6. method according to claim 1 is characterized in that, the concentration of linking agent in mixture is 0.0002～0.02g/mL.
7. according to each described method of claim 1～6, it is characterized in that, select the hyaluronic acid of fermentation using bacteria method production or the hyaluronic acid of tissue extraction for use.
8. according to each described method of claim 1～6, it is characterized in that hyaluronic acid is hyaluronate sodium, hyaluronic acid magnesium or Calcium hyaluronate.
9. according to the medical cross-linking sodium hyaluronate gel derivative product of each described method preparation of claim 1～8.
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| CN200810200895A CN101759881A (en) | 2008-10-08 | 2008-10-08 | Medical cross-linking sodium hyaluronate gel derivative product and preparation method thereof |
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|---|---|---|---|
| CN200810200895A CN101759881A (en) | 2008-10-08 | 2008-10-08 | Medical cross-linking sodium hyaluronate gel derivative product and preparation method thereof |
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| CN101759881A true CN101759881A (en) | 2010-06-30 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552974A (en) * | 2012-02-17 | 2012-07-11 | 上海白衣缘生物工程有限公司 | Gel composition for injection filling of skins and preparation method for gel composition |
| CN102952275A (en) * | 2011-08-19 | 2013-03-06 | 上海建华精细生物制品有限公司 | Hyaluronic acid gel employing biphasic technology, and preparation method thereof |
| CN103923328A (en) * | 2014-04-16 | 2014-07-16 | 常州药物研究所有限公司 | High-quality cross-linked sodium hyaluronate gel and preparation method thereof |
| 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 |
| CN104014174A (en) * | 2014-06-18 | 2014-09-03 | 常州药物研究所有限公司 | Product purification device for cross-linked sodium hyaluronate production |
| CN104194008A (en) * | 2014-08-08 | 2014-12-10 | 陕西佰傲再生医学有限公司 | Cross-linked hyaluronic acid gel microparticle and preparation method thereof |
| CN104592420A (en) * | 2014-12-25 | 2015-05-06 | 上海景峰制药有限公司 | Method for preparing intermediate HA-VS of cross-linked sodium hyaluronate |
| CN106924818A (en) * | 2017-02-16 | 2017-07-07 | 南方医科大学珠江医院 | One kind carries medicinal gel and its preparation method and application |
| CN107349476A (en) * | 2017-06-13 | 2017-11-17 | 爱美客技术发展股份有限公司 | Bionic joint synovia and preparation method thereof |
| CN107522881A (en) * | 2017-08-16 | 2017-12-29 | 杭州协合医疗用品有限公司 | The method for preparing single-phase modification hyaluronic acid sodium gel |
| CN108047351A (en) * | 2017-12-15 | 2018-05-18 | 浙江景嘉医疗科技有限公司 | A kind of preparation method of low crosslinking degree Sodium Hyaluronate |
| CN108250457A (en) * | 2017-05-08 | 2018-07-06 | 上海利康瑞生物工程有限公司 | Controllable two-phase cross-linking sodium hyaluronate gel of a kind of shear viscosity and preparation method thereof and preparation |
| CN108264581A (en) * | 2017-02-20 | 2018-07-10 | 上海昊海生物科技股份有限公司 | A kind of self-crosslinking Sodium Hyaluronate and preparation method thereof |
| CN109513043A (en) * | 2017-09-20 | 2019-03-26 | 刘宏飞 | A kind of injection modification hyaluronic acid sodium gel and preparation method thereof |
| CN110078978A (en) * | 2013-03-27 | 2019-08-02 | 株式会社Lg化学 | It is used to prepare the composition of viscoplasticity cross-linked-hyaluronic acid and utilizes cross-linked-hyaluronic acid made from the composition |
| CN111840638A (en) * | 2020-07-21 | 2020-10-30 | 华熙生物科技股份有限公司 | Preparation method of crosslinked hyaluronic acid filler for injection |
-
2008
- 2008-10-08 CN CN200810200895A patent/CN101759881A/en not_active Withdrawn
Cited By (21)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102952275A (en) * | 2011-08-19 | 2013-03-06 | 上海建华精细生物制品有限公司 | Hyaluronic acid gel employing biphasic technology, and preparation method thereof |
| CN102552974A (en) * | 2012-02-17 | 2012-07-11 | 上海白衣缘生物工程有限公司 | Gel composition for injection filling of skins and preparation method for gel composition |
| CN110078978A (en) * | 2013-03-27 | 2019-08-02 | 株式会社Lg化学 | It is used to prepare the composition of viscoplasticity cross-linked-hyaluronic acid and utilizes cross-linked-hyaluronic acid made from the composition |
| CN103923328A (en) * | 2014-04-16 | 2014-07-16 | 常州药物研究所有限公司 | High-quality cross-linked sodium hyaluronate gel and preparation method thereof |
| 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 |
| CN103923328B (en) * | 2014-04-16 | 2016-01-20 | 常州药物研究所有限公司 | High quality cross-linking sodium hyaluronate gel and preparation method thereof |
| CN104014174A (en) * | 2014-06-18 | 2014-09-03 | 常州药物研究所有限公司 | Product purification device for cross-linked sodium hyaluronate production |
| CN104194008A (en) * | 2014-08-08 | 2014-12-10 | 陕西佰傲再生医学有限公司 | Cross-linked hyaluronic acid gel microparticle and preparation method thereof |
| CN104592420A (en) * | 2014-12-25 | 2015-05-06 | 上海景峰制药有限公司 | Method for preparing intermediate HA-VS of cross-linked sodium hyaluronate |
| CN106924818A (en) * | 2017-02-16 | 2017-07-07 | 南方医科大学珠江医院 | One kind carries medicinal gel and its preparation method and application |
| CN108264581A (en) * | 2017-02-20 | 2018-07-10 | 上海昊海生物科技股份有限公司 | A kind of self-crosslinking Sodium Hyaluronate and preparation method thereof |
| CN108250457A (en) * | 2017-05-08 | 2018-07-06 | 上海利康瑞生物工程有限公司 | Controllable two-phase cross-linking sodium hyaluronate gel of a kind of shear viscosity and preparation method thereof and preparation |
| CN107349476A (en) * | 2017-06-13 | 2017-11-17 | 爱美客技术发展股份有限公司 | Bionic joint synovia and preparation method thereof |
| CN107349476B (en) * | 2017-06-13 | 2020-09-08 | 爱美客技术发展股份有限公司 | Bionic joint synovial fluid and preparation method thereof |
| CN107522881A (en) * | 2017-08-16 | 2017-12-29 | 杭州协合医疗用品有限公司 | The method for preparing single-phase modification hyaluronic acid sodium gel |
| WO2019033596A1 (en) * | 2017-08-16 | 2019-02-21 | 杭州协合医疗用品有限公司 | Method for preparing single-phase modified sodium hyaluronate gel |
| CN107522881B (en) * | 2017-08-16 | 2020-05-05 | 杭州协合医疗用品有限公司 | Method for preparing single-phase modified sodium hyaluronate gel |
| CN109513043A (en) * | 2017-09-20 | 2019-03-26 | 刘宏飞 | A kind of injection modification hyaluronic acid sodium gel and preparation method thereof |
| CN108047351A (en) * | 2017-12-15 | 2018-05-18 | 浙江景嘉医疗科技有限公司 | A kind of preparation method of low crosslinking degree Sodium Hyaluronate |
| CN111840638A (en) * | 2020-07-21 | 2020-10-30 | 华熙生物科技股份有限公司 | Preparation method of crosslinked hyaluronic acid filler for injection |
| CN111840638B (en) * | 2020-07-21 | 2022-04-12 | 华熙生物科技股份有限公司 | Preparation method of crosslinked hyaluronic acid filler for injection |
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Open date: 20100630 |