CN101502677B - Crosslinking hyaluronic acid sodium gel for injection and preparation method thereof - Google Patents
Crosslinking hyaluronic acid sodium gel for injection and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a cross bonding sodium hyaluronate gel for injection and a preparation method thereof. The method is characterized in that sodium hyaluronate and glycidyl ether are mixed and react in alkaline solution to form water-insoluble gel, the gel is purified in deionized water and broken into particles of certain sizes; ionic strength of the deionized water is improved to contract the gel particles. The cross bonding sodium hyaluronate gel features asepsis, apyrogeneity and small and uniform particles; therefore the gel can be applied to prepare injection for beauty care and medical treatment.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of crosslinking hyaluronic acid sodium gel for injection and its preparation method.
Background technology
Hyaluronic acid (hyalouronic acid; hereinafter to be referred as HA) by (1-β-4) D-glucuronic acid and the multiply-connected a kind of chain polyanion mucopolysaccharide that forms that connects of (1-β-3) N-acetyl group-D-aminoglucose disaccharidase unit weight; be the important component that consists of skin, vitreous body, knuckle synovia and cartilaginous tissue, have unique physicochemical property and biological function.Commodity hyaluronate sodium (sodium hyaluronate, hereinafter to be referred as SH) be the sodium salt of HA, derive from animal tissue or microbial fermentation, be widely used in food, daily use chemicals and field of medicaments, due to the difference of purity, have the multiple grade product such as food stage, medical grade and cosmetics-stage.Through long-term research and development, highly purified medical grade SH has been made into injection, is applied to ophthalmologic operation, bone surgery, treatment osteoarthritis and rheumatoid arthritis and prevention of postoperative adhesion.In addition, owing to having good biocompatibility and unique viscoelasticity, HA is used to inject skin of face, alleviates wrinkle, improve skin appearance and structure (RU2272634, RU2194512) or improve lip shape, stop skin aging (RU2159111).But natural HA is easily by the enzymatic degradation in when injected organism tissue, and good water solublity easily is diffused it in tissue, so the time that it retains in the animal tissue part is also unsatisfactory.Natural HA easily disperses in order to overcome, degradation-labile defect, numerous compounds is used to modify or crosslinked natural HA (US4713448, US4582865, WO9009401, WO9515168, US2003114406, EP1265116 etc.), wherein adopt the compound crosslink HA that contains glycidyl ether (epoxy radicals), obtained that injectable, toxicity are little, the product of good biocompatibility, can be used for preparing that the ophthalmology vitreous body substitutes, anti, soft tissue is filled and the product such as slow releasing pharmaceutical bank.With the existing crosslinked listing of the crosslinked HA of BDDE (Isosorbide-5-Nitrae-butanediol diglycidyl ether, BDDE), as the ophthalmic product SKGEL of French CORNEAL company
Cosmetics RESTYLANE with U.S. Q-MED company
, in clinical practice for many years, rarely seen toxic and side effects report is the higher crosslinked HA product of safety.
open (the WO8600079 of the existing a plurality of patents of the technology of the crosslinked HA of glycidyl ether, WO8600912, WO9704012, US6852255, CN1590444 etc.), its Patent WO026350 discloses the technical process that BDDE crosslinked HA prepares injectable gel, cross-linking agent first is dissolved in aqueous slkali, again with solid HA hybrid reaction, obtain uniformity gel preferably, gel after purified obtains the granulated gel of certain particle size by the homogenizing disintegrating process, sterilization at last obtains finished product, under certain thrust, gel particle can (be released as 26～27G) through thinner syringe needle.
Patent CN1590444 discloses in acidity or alkaline solution, and glycidyl ether and HA (15 ℃～35 ℃) reaction under lower temperature conditions is conducive to protection HA macromolecular chain in course of reaction, reduces the degraded that it produces due to chain rupture.This patent is also mentioned especially and is adopted the BD of University Of Tianjin series deproteinization purifying products HA raw material simultaneously, can improve the quality of product.
The inventive method is having unique distinction aspect gel-purified and granule preparation (fragmentation).The present invention utilizes crosslinked HA jel product different characteristic of the coefficient of expansion in the different ionic strength aqueous solution, allow cross-linking products fully expand in deionized water, then improve deionized water intermediate ion intensity gel is shunk, fully removed unreacted reactant and other impurity; Make gel by a certain size screen cloth under the adequately expanded state of gel, form particle diameter than the homogeneous granule, after improving deionized water intermediate ion intensity, but make it shrink form the flow-gel granule of uniform and smooth, compare with the technique (WO0206350) that the mechanical homogenizing of direct employing is made fine particle with gel, have a gel particle even, particle size distribution range is little, purity is high, and impurity is few, does not increase the advantages such as content of beary metal.
The present invention adopts medical grade SH raw material, and glycidyl ether is cross-linking agent, under alkali condition, carries out cross-linking reaction and purification at 40～80 ℃.Compare with the method for CN1590444, medical grade SH raw materials market is on sale, and its purity is high, protein residue is extremely low, need not deproteinization again, has reduced the feed purification step; The pyroreaction that the inventive method adopts, high temperature purification are compared with its normal-temperature reaction, room temperature purification, have advantages of that technique is simple, consuming time short, are conducive to keep in process of production that product is aseptic, apyrogeneity, can reduce the step of finished product depyrogenation.Evidence, under alkali condition, lower temperature, for a long time reaction is to the palliating degradation degree of SH and be not less than the reaction of higher temperatures, short time.
Summary of the invention
The preparation method that the purpose of this invention is to provide a kind of crosslinked SH gel of injection, and use gel preparation beauty treatment that the method makes or the injection of medical application.
The preparation method of the crosslinked SH gel of injection of the present invention comprises the steps:
1.: SH and glycidyl ether hybrid reaction in sodium hydroxide (NaOH) solution forms gel;
2.: the gel that 1. step is obtained soaks the gel particle that is broken for a certain size after purification in deionized water;
3.: improve the 2. ionic strength of middle deionized water of step, gel particle is shunk.
More specifically, the preparation method of the crosslinked SH gel of injection of the present invention comprises the steps:
1.: glycidyl ether and SH are mixed at 0.5%～2% NaOH solution, in 40～80 ℃ of insulations 2～8 hours, obtain the water-insoluble gel;
2.: the gel that 1. step is obtained is soaked in deionized water, and purification 6～12 hours obtains the aqueous gel of volumetric expansion;
3.: collect the aqueous gel that 2. step obtains, making it is the screen cloth of 100～400 μ m by the sieve aperture internal diameter, obtains the aqueous gel granule;
4.: the ionic strength of deionized water in the aqueous gel granule that 3. the raising step obtains, 40～80 ℃ are incubated 2～8 hours, and the aqueous gel granule shrinks, sedimentation, the aqueous gel granule that obtains shrinking;
5.: collect the 4. middle aqueous gel granule that shrinks of step, sterilization, packing makes finished product.
The glycidyl ether that uses in preparation method of the present invention be a class with the compound of epoxy radicals active group, be called as epoxy resin diluent in a lot of occasions.
Glycidyl ether described in preparation method of the present invention can be selected BDDE, also can select Ethylene glycol diglycidyl ether.Wherein BDDE refers to be the compound of 2425-79-8 No. CA, English can be expressed as Isosorbide-5-Nitrae-butanediol diglycidyl ether, Isosorbide-5-Nitrae-Bis (2,3-epoxypropoxy) butane or Isosorbide-5-Nitrae-bisglycidyloxybutane.In addition, also has in the literature multiple title or abbreviation (abbreviation) expression, as BDO glycidyl ether, butanediol glycidyl ether, epoxide diluent D-1402, AralaiteRD-2, Eqodie750, WSR-622, G96, JX-023, BDGE and BDDE etc.Ethylene glycol diglycidyl ether refers to be the compound of 2224-15-9 No. CA, English can be expressed as Ethylene glycol diglycidyl ether, 1,2-bis (2,3-epoxypropoxy) ethylene, Glycol diglycidyl ether or 2,2 '-[Ethylenebis (oxymethylene)] bisoxirane.In addition, also has in the literature multiple title or abbreviation (abbreviation) expression, as diglycidyl ether of ethylene glycol epoxide diluent D-669, Quetol651, EGDGE etc.
The mass volume ratio of SH described in preparation method of the present invention and NaOH solution can be 5%～50%, and is preferred 10%～25%, and more preferably 15%～20%.
Deionized water described in preparation method of the present invention is the deionized water of 40～80 ℃, the deionized water of preferred 45～75 ℃, the more preferably deionized water of 60～70 ℃.
The method that improves the ionic strength of deionized water in gel described in preparation method of the present invention is to add osmotic pressure higher than phosphate buffered solution (PBS) or sodium chloride (NaCl) solution of 300mOsmol/L, or directly adds solid NaCl.
The method of collecting moisture hydrogel particle described in preparation method of the present invention can adopt the method for filtration, also can adopt centrifugal method.For example, filter method can adopt the screen filtration of 80～200 orders (sieve aperture internal diameter 180～75 μ m), and centrifugal method can adopt 2000～5000rpm centrifugal 5～30 minutes.
Sterilizing methods described in preparation method of the present invention can be moist heat sterilization, and preferred sterilising conditions is 115 ℃～125 ℃ sterilizations 15～30 minutes, and more preferably sterilising conditions is 121 ℃ of sterilizations 15 minutes.
Preparation method technique of the present invention is simple, consuming time short, and the gel for preparing is aseptic, apyrogeneity, and impurity is few, uniform particles is fine and smooth, is suitable for preparing the injection of beauty treatment and medical application.
The specific embodiment
Following examples are for the present invention is described better, are not restriction the present invention.
Embodiment 1
Get the 1%NaOH solution mix homogeneously that 10g SH (mean molecule quantity 1,800,000 dalton) and 68ml contain 0.5g BDDE, the gained reactant liquor was in 50 ℃ of insulations 3 hours, and reaction forms the water-insoluble gel.For the advantage of technique of the present invention is described, the gel that reaction is obtained is divided into 2 parts, 1 part by the inventive method preparation (A), press the disclosed method preparation of WO026350 (B) for another 1 part, for the ease of comparing, gel B has adopted cleansing temp and the phosphate buffer identical with gel A.
A: in 70 ℃ of purification after 10 hours, extruding makes gel pass through 60 mesh sieves (sieve aperture internal diameter 250 μ m) with deionized water, collects gel particle, and (every 1000ml contains NaH to add the grade of 2 times of concentration of equal-volume to ooze PBS
2PO
42H
2O 90mg, Na
2HPO
412H
2O 1.12g, NaCl 17g), 65 ℃ are incubated 4 hours, and centrifugal 15 minutes of 2000rpm collects gel precipitation, sterilizes 15 minutes for 121 ℃, and sterile filling is in the disposable syringe of prior sterilization.
B: (every 1000ml contains NaH to ooze PBS with the grade of pH 7.2
2PO
42H
2O 45mg, Na
2HPO
412H
2O0.56g, NaCl 8.5g), filter and collect gel after 10 hours in 70 ℃ of purification, will smash with homogenizer, be not more than 0.5mm to the particle diameter of gel the largest particles, 121 ℃ of sterilizations 15 minutes, sterile filling is in the disposable syringe of prior sterilization.
In order to compare the different qualities of gained gel, by the following method gel is tested:
1. content (c) is measured: get the 0.5g gel, add 0.5M sulphuric acid 10ml, boiling water bath hydrolysis 15 minutes adds water to 100ml.Carbazole method is measured glucuronic acid content, and multiplying factor (2.07) is SH content.
2. yield is measured: the amount of the front SH of the amount of SH/reaction, i.e. c * w/5 * 100% in jel product (w/g).
3. granularity inspection: get gel 0.1g, contain the normal saline dilution of serge blue with 10ml after, at 50～100 times of optical microphotograph Microscopic observations, counting.
4. heavy metal inspection: with reference to the method for 2005 editions two appendix of Chinese Pharmacopoeia, get gel 1g, 60 ℃ of oven dry, blazing to carbonization, add 0.5ml sulphuric acid heating evaporate to dryness, add again 0.5ml nitric acid heating evaporate to dryness, make ashing 500～600 ℃ of heating, add 2ml hydrochloric acid, water bath method, add the 15ml distilled water, be adjusted to neutrality with 4% ammonia, the acetate buffer that adds 2ml pH 3.5, be diluted to 25ml after dissolving, after getting simultaneously the agents useful for same evaporate to dryness, add equivalent acetate buffer solution and distilled water, add the plumbous test solution of appropriate standard, be diluted to 25ml, carry out audit by comparison after adding respectively the colour developing of thioacetamide test solution
5. anti-enzyme mensuration: gel 0.5g adds the hyaluronic acid enzymatic solution that 2ml concentration is 300U/ml, 37 ℃ of enzymolysis 65 hours, the PBS to 5ml that adds pH 7.2, get 1ml and add dehydrated alcohol 4ml, centrifugal 15 minutes of 10000rpm, get the 2ml supernatant and be settled to 5ml with the PBS of pH 7.2, adopt improvement carbazole development process (list of references: Bitter T., and MuirH.M. (1962) A modified uronic acid carbarbazole reation.Anal.Biochem.4,330～333.) measure glucuronic acid content, convert into SH content (
*2.07), being a value, SH content (c) as the b value, calculates a/b in the gel.
The determination data of two kinds of gels sees Table 1.
Two kinds of gel determination data of table 1 relatively
| Project | Content (%) | Yield (%) | Particle size range/mean diameter (μ m) | Heavy metal (ppm) | Anti-enzyme (a/b) |
| A B | 1.78 1.81 | 84.2 85.1 | 100～250/150 5～500/150 | ＜10 ＞100 | 0.406 0.412 |
Result of the test from table 1 can find out, in the essentially identical situation of other character, and the heavy metal severe overweight of B gel, the A gel particle is more even, and B gel particle size range is larger, and the A good fluidity is more conducive to injection in B.
Embodiment 2
Getting 10g SH (mean molecule quantity 1,200,000 dalton) is dissolved in the 1.5%NaOH solution that 90ml contains 0.8g BDDE.For the advantage of technique of the present invention is described, reactant liquor is divided into 2 parts, 1 part of reaction condition preparation (C) by the inventive method is pressed the disclosed reaction condition preparation of CN1590444 (D) for another 1 part.
The C reactant liquor was in 50 ℃ of insulations 2 hours, and reaction forms the water-insoluble gel.
The D reactant liquor was in 20 ℃ of insulations 24 hours, and reaction forms the water-insoluble gel.
For the ease of comparing, the gel aftertreatment technology that C and D reaction obtain (purification, granule preparation and sterilization etc.) all adopts the preparation method of embodiment 1A gel.
In order to compare the different qualities of gained gel, by the method for describing in embodiment 1, gel is tested, the results are shown in Table 2.
Two kinds of gel determination data of table 2 relatively
| Project | Content (%) | Yield (%) | Particle size range/mean diameter (μ m) | Heavy metal (ppm) | Anti-enzyme (a/b) |
| C D | 1.42 1.15 | 80.5 78.6 | 100～250/150 100～250/150 | ＜10 ＜10 | 0.597 0.810 |
Result of the test from table 2 can be found out, both yield and particle diameter are suitable, and D gel content and anti-enzyme are starkly lower than the C gel, illustrate that the outer resistance to enzymic degradation of C gelinite is significantly better than the D gel, mean that C gel retention time in vivo is longer than the D gel, can think the reaction condition of D gel to the palliating degradation degree of HA and be not less than the reaction condition of C gel, compared in 2 hours with 50 ℃ of reactions in other words, 20 ℃ of reactions can not significantly reduce the macromolecular chain rupture of HA in 24 hours.
Embodiment 3
SH (mean molecule quantity 300,000,420,000,570,000, the 780000 dalton) 5g of different molecular weight is dissolved in the 1.0%NaOH solution that 35ml contains 0.25g BDDE.Press the preparation method of embodiment 1A gel, obtain respectively 4 kinds and have gel of different nature, by the method for describing in embodiment 1, gel is tested, the results are shown in Table 3.
4 kinds of gel determination data of table 3 relatively
| Gel | I | II | III | IV |
| The anti-enzyme of mean molecule quantity (dalton) content (%) yield (%) (a/b) | 300,000 0.6242.90.89 | 420,000 0.87 56 0.77 | 570,000 1.14 66.1 0.60 | 780,000 1.35 78.4 0.46 |
The SH of different molecular weight is prepared into the water-insoluble gel particle through same process, and its content, yield and anti-enzyme increase with the increase of molecular weight.
Embodiment 4
SH (mean molecule quantity 300,000,420,000,570,000, the 780000 dalton) 5g of different molecular weight is dissolved in the 1.0%NaOH solution that contains 0.25g BDDE.Press the preparation method of embodiment 1A gel, obtain respectively 4 kinds of gels, by the method for describing in embodiment 1, gelling properties is tested, the results are shown in Table 4.
4 kinds of gel determination data of table 4 relatively
| Gel | V | VI | VII | VIII |
| The anti-enzyme of mean molecule quantity (dalton) NaOH solution (ml) content (%) yield (%) (a/b) | 300,000 26.81.8772.50.41 | 420,000 28.5 1.85 78.4 0.39 | 570,000 30.5 1.84 82.3 0.38 | 780,000 32.2 1.79 85.1 0.40 |
The SH of different molecular weight through adjusting the consumption of NaOH solution, can obtain the similar gel of anti-enzymatic property, and yield improves with the increase of molecular weight.
Claims (13)
1. the preparation method of a crosslinking hyaluronic acid sodium gel for injection, comprise the steps:
1. hyaluronate sodium and BDO glycidyl ether mix in 1% NaOH solution, and wherein the mass volume ratio of hyaluronate sodium and NaOH solution in the scope greater than 15%, less than or equal to 20%, in 50 ℃ of insulations 3 hours, obtains the water-insoluble gel;
2. the gel that 1. step is obtained is soaked in the deionized water of 60 ℃～70 ℃, and purification 6～12 hours obtains the aqueous gel of volumetric expansion;
3. collect the aqueous gel that 2. step obtains, making it is the screen cloth of 100～400 μ m by the sieve aperture internal diameter, obtains the aqueous gel granule;
4. improve the ionic strength of deionized water in the aqueous gel granule that 3. step obtain, 65 ℃ of insulations 4 hours, the aqueous gel granule shrinks, sedimentation, the aqueous gel granule that obtains shrinking;
5. collect the aqueous gel granule that 4. step obtains, sterilized 15～30 minutes for 115 ℃～125 ℃, packing makes finished product.
2. preparation method claimed in claim 1, the method that is further characterized in that the ionic strength of described raising deionized water is to add osmotic pressure higher than phosphate buffered solution or the sodium chloride solution of 300mOsmol/L, or directly adds solid sodium chloride.
3. preparation method claimed in claim 1, be further characterized in that the method for collecting gel particle described in step 5. is filtration or centrifugal.
4. preparation method claimed in claim 1, be further characterized in that step 5. collected aqueous gel granule adopt 121 ℃ of sterilizations 15 minutes.
5. preparation method claimed in claim 1, be further characterized in that step 1. the mass volume ratio of described hyaluronate sodium and NaOH solution be 100: 536.
6. preparation method claimed in claim 1, be further characterized in that step 1. the mass volume ratio of described hyaluronate sodium and NaOH solution be 100: 570.
7. preparation method claimed in claim 1, be further characterized in that step 1. the mass volume ratio of described hyaluronate sodium and NaOH solution be 100: 610.
8. preparation method claimed in claim 1, be further characterized in that step 1. the mass volume ratio of described hyaluronate sodium and NaOH solution be 100: 644.
9. preparation method claimed in claim 1, be further characterized in that step 1. the concentration of described NaOH solution be 1.5%.
10. preparation method claimed in claim 1 after being further characterized in that step 1. described hyaluronate sodium and BDO glycidyl ether mixing, in 50 ℃ of insulations 2 hours, obtains the water-insoluble gel in 1% NaOH solution.
11. preparation method claimed in claim 1 was further characterized in that in the deionized water that during step 2., the gel that obtains is soaked in 70 ℃ purification 10 hours, obtained the aqueous gel of volumetric expansion.
12. the gel that preparation method claimed in claim 1 makes.
13. the described gel of claim 12 is for the preparation of the injection of beauty treatment or medical application.
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| CN102120833A (en) * | 2011-01-10 | 2011-07-13 | 深圳市资福药业有限公司 | Hyaluronate gel particle and preparation method thereof |
| CN102226011B (en) * | 2011-04-26 | 2013-01-02 | 北京爱美客生物科技有限公司 | Hyaluronic acid-hydroxypropylmethylcellulose compound non-water gel and preparation method thereof |
| CN102731801B (en) * | 2012-07-13 | 2013-12-25 | 常州药物研究所有限公司 | Cross-linked sodium hyaluronate hydrogel for plastic surgery and preparation method thereof |
| CN102727424B (en) * | 2012-07-13 | 2013-08-21 | 常州药物研究所有限公司 | Sodium hyaluronate gel injection for bone joint cavity and preparation method thereof |
| CN103630536B (en) * | 2013-12-09 | 2016-05-25 | 河南工业大学 | A kind of method of measuring polyethylene glycol residual quantity in cross-linking sodium hyaluronate gel |
| TWI727014B (en) * | 2016-03-24 | 2021-05-11 | 德商梅茲製藥有限兩合公司 | Modified hyaluronic acid, method for making same and uses thereof |
| CN107540763B (en) * | 2016-06-24 | 2020-08-11 | 宁夏妙朗生物科技有限公司 | Method for preparing injection type long-acting hyaluronic acid gel by using biological cross-linking agent |
| KR101922711B1 (en) * | 2016-12-28 | 2018-11-27 | 주식회사 유영제약 | A method for purification of cross-linked hyaluronic acid gel |
| WO2019210496A1 (en) * | 2018-05-04 | 2019-11-07 | 上海其胜生物制剂有限公司 | Preparation method for and application of injectable hydrogel |
| CN108853569B (en) * | 2018-06-27 | 2021-06-11 | 湖南玉津医疗科技有限公司 | Covalent cross-linked hyaluronic acid aerogel, hydrogel thereof and preparation method |
| CN112442199B (en) * | 2019-08-29 | 2023-01-10 | 上海其胜生物制剂有限公司 | Flexible high-stability gel and preparation method thereof |
| CN113274314B (en) * | 2021-05-07 | 2023-02-03 | 山东省药学科学院 | Application of salt-sensitive hydrogel as intelligent water control and water supplement material |
| CN113413484B (en) * | 2021-06-21 | 2023-02-10 | 浙江苏嘉医疗器械股份有限公司 | Implant material for human soft tissue filling |
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Address after: 250101 888 Xinjie street, Ji'nan high tech Zone, Shandong Co-patentee after: Ling Peixue Patentee after: Shandong Freda Pharmaceutical Group Co., Ltd. Address before: 250101 888 Xinjie street, Ji'nan high tech Zone, Shandong Co-patentee before: Ling Peixue Patentee before: Shandong Fu Ruida Pharmaceutical Group company |