CN106167549A - A kind of preparation method of slow degraded cross-linked hyaluronic acid gel - Google Patents
A kind of preparation method of slow degraded cross-linked hyaluronic acid gel Download PDFInfo
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- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/145—Hydrogels or hydrocolloids
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- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
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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
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
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- C08J2471/00—Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
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Abstract
The present invention relates to the preparation method of a kind of slow degraded cross-linked hyaluronic acid gel, belong to the process of polymer substance or the technical process technical field of dispensing.Adjust the pH to 5.9 6.1 of purified water, SH is dissolved in wherein formation SH solution；Glycidyl ether is dissolved in this SH solution, at room temperature reaction 58 hours；It is placed in surface plate and is dried；Product is soaked in deionized water, and purification obtains the aqueous gel expanded；It is passed to screen cloth, obtains aqueous gel granule；Improve the ionic strength of deionized water in aqueous gel granule, aqueous gel particle collapses, precipitate, obtain the aqueous gel granule that shrinks；Collecting, sterilizing, packaging makes finished product.The advantages such as the application being applied to skin injection, has gel particle uniform, particle size distribution range is little, and purity is high, and impurity is few.
Description
Technical field
The present invention relates to the preparation method of a kind of slow degraded cross-linked hyaluronic acid gel, belong to polymer substance process or
The technical process technical field of dispensing.
Background technology
Hyaluronic acid (hyaluronic acid is called for short HA) is widely present in skin, ligament, joint fluid and eyes
A kind of mucopolysaccharide in the tissue such as vitreous body, it is by (1-β-4) D-Glucose aldehydic acid and (1-β-3) N-acetyl group-D-amino
The multiply-connected a kind of wire polyanion mucopolysaccharide connecing composition of glucose disaccharide unit weight, is to constitute skin, vitreous body, knuckle synovia
With the important component of cartilaginous tissue, there is physicochemical property and the biological function widely of uniqueness.Human body be exactly one the most smart
Close machine, joint is a vitals of this machine, and HA is exactly joint lubrication oil, plays lubrication and make in articular cavity
With, it is ensured that the normal function in joint.Joint lacks HA, can cause joint bone injury (arthritis etc.), people even can be made to lose
Locomotor activity.Showing according to statistics, China's arthritic rate remains high, and arthritic's number is more than 100,000,000, due to people
, through long-term operating, there is the result caused after " abrasion " in the machine of this precision of body.The up-to-date way for the treatment of of arthritis is exactly
Viscosupple mentation, namely gives joint artificial supplementation HA, improves the content of HA in knuckle synovia, eliminates arthralgia, extensive
Compound joint function, as the disease such as knee osteoarthritis, scapulohumeral periarthritis；When gonarthritis, Injection in knuckle articular cavity；For shoulder
Time scorching, shoulder joint chamber or subacromial intracapsular injection；In joint disease treatment, by supplemented with exogenous hyaluronic acid, Ke Yiqi
To the lubricating function of recovery lubricating fluid, for the time of joint one self-regeneration of creation of pathological changes, the reparation in promotion joint and merit
The improvement of energy, and HA is the material that human body self exists, the toxic and side effects that it enters after human body is very little.
But natural HA is easily by the enzymatic degradation in body tissue, and good water solublity makes it the most easily be expanded
Dissipating, therefore it is the longest in animal tissue's time of retaining of local, in order to overcome natural HA easily to disperse, degradation-labile defect, many
Many compounds are used for modifying or cross-linking natural HA, such as patent 2006100653261, carry out HA modification, as used containing shrinking
The compound crosslink HA of glycerin ether (epoxy radicals), obtains injectable, product that toxicity small biocompatible is good, but it is the most very
Fast diffusion and degraded, it is difficult to maintain ideal effect.
Commodity hyaluronate sodium (sodium hyaluronate, hereinafter referred to as SH) is the sodium salt of HA, derives from animal groups
Knit or fermentable, be widely used in food, daily use chemicals and field of medicaments, owing to purity is different, have food stage, medical grade and
The multiple rank such as cosmetics-stage.It is made into injection through long-term highly purified medical grade SH of research and development, is applied to eye
Section's operation, bone surgery, treatment diarthrodial joint inflammation and prevention of postoperative adhesion.Existing procucts such as sodium hyaluronate injection, glass
Acid sodium injection is the thick liquid of achromaticity and clarification, and glycidyl ether crosslinking HA existing multiple patents disclosure (W0860079,
W08600912, W09704012, US6852255, CN1590444), wherein, patent CN1590444 discloses at alkaline solution
In, glycidyl ether and HA (15 DEG C-35 DEG C) reaction under lower temperature conditions is conducive to protecting in course of reaction HA macromole
Chain, reduces its degraded produced due to chain rupture, but when being applied to human body, owing to it is the reaction occurred in the basic conditions,
Poor with the compatibility of human body, especially cannot adapt to the acid-base value situation of human body.
Based on this, make the application.
Summary of the invention
For drawbacks described above existing during overcoming existing hyaluronic acid derivatives to use, the application provides a kind of injection
The preparation method of crosslinking SH gel, by allowing SH crosslink reaction in acid condition with glycidyl ether, SH is entered
Row chemical modification.
For achieving the above object, the technical scheme that this year, application was taked is as follows:
The preparation method of a kind of slow degraded cross-linked hyaluronic acid gel, comprises the steps:
1. the pH (adding HCl or NaOH) to 5.9-6.1 of purified water is adjusted.
2. SH is dissolved in the water that 1. step obtains, forms the SH solution that concentration is 0.5%-3% (w/v).
3. being dissolved in by glycidyl ether in step solution 2., making HA is 1:1-1:10 with the mass ratio of glycidyl ether,
At room temperature reaction 5-8 hour.
4. the solution that 3. step obtains is placed in surface plate, drying at room temperature 3-5 days.
5. by step 4. can to product be soaked in deionized water, purification 6-12 hour, obtain expand aqueous gel.
6. collect step 5. in the gel that obtains so that it is by the screen cloth that sieve aperture internal diameter is 100-400 μm, obtain containing water-setting
Glue granule.
7. improving the ionic strength of deionized water in the aqueous gel granule that 6. step obtains, 40-80 DEG C of insulation 2-8 is little
Time, aqueous gel particle collapses, precipitate, obtain shrink aqueous gel granule.
8. collecting the step 7. middle aqueous gel granule shunk, sterilizing, packaging makes finished product.
Further, as preferably:
Described glycidyl ether is polyethyleneglycol diglycidylether or BDDE.Wherein, polyethylene glycol diglycidyl
Ether refers to No. CAS compound being 39443-66-8, and BDDE refers to No. CAS compound for 2425-79-8.
Step 1. in, the pH of described purified water is 5.0-6.1, preferably 6.0-6.1.
Step 2. in, the molecular weight of described SH can 200,000-300 ten thousand, preferably 900,000-150 ten thousand.
Described SH is 1%-2% with the mass volume ratio of purified water.
Described SH and glycidyl ether mass volume ratio are 1:2.
Step 8. in, sterilizing use moist heat sterilization, sterilising conditions 115 DEG C-130 DEG C sterilizing 15-30min, more preferably conditions
It is 121 DEG C of sterilizing 15min.
Compared with prior art, operation principle and the beneficial effect of the application is analyzed as follows:
The application can cover with Saving cortilage tissue, improve lubricating function, by penetrating into the cartilage of degeneration, suppression cartilage
Degeneration changes and improves the cartilage metabolism in degeneration cartilage, meanwhile, shows slow by suppressing the effect of pain mediator on synovial membrane
Solve the effect of pain, so the application energy alleviating pain, improving patient's daily routines and range of motion, be mainly reflected in
Lower four aspects:
(1) effect to articular cartilage
1. there is affinity with articular cartilage, can cover and protect cartilage surface
2. suppression cartilage degeneration change
3. this product suppression proteoglycan oozes out from cartilage matrix and improves the metabolism of cartilage
(2) effect to synovial membrane
Act on synovial cell, promote the synthesis of macromolecule Hyaluronic Acid
(3) effect to joint fluid
Increase Hyaluronic Acid concentration and the molecular weight of pathologic joint fluid, improve spinnability etc..
(4) inhibition of pain effect.
The application carries out cross-linking reaction in acid condition by hyaluronic acid and epoxide, obtains one and has
The effect of bright matter acid, but the injection of the degradation speed that can slow down, apply in arthritis disease, can play in articular cavity
Lubrication, while reducing the friction between tissue, plays elastic reaction, buffers the stress effect to articular cartilage, play
Due physiological function；Hyaluronan molecule contains hydroxyl, carboxyl, N-acetamido and reduction end, therefore can be to transparent
Matter acid is chemically modified.The application, by modifying the hydroxyl of hyaluronan molecule, makes the hyaluronic acid after chemical modification derive
Thing not only maintains the feature such as original biocompatibility, cell adhesion ability, but also gives other good characteristics a series of,
As suitable mechanical strength, special rheological properties and the degradability of antihyaluronidase, free radical resisting degradability and
Targeting feature.
The product that employing the application method obtains degradation rate under hyaluronidase effect is less than in alkalescence condition
Under the product that obtains.It uses medical grade HA raw material, and glycidyl ether is cross-linking agent, carries out under acidity, normal temperature condition
Cross-linking reaction and purification.Compared with the method for CN1590444, having gel particle uniform, particle size distribution range is little, and purity is high,
The advantages such as impurity is few, preparation method technique is simple, it is adaptable to prepare the injection of medical application.
Detailed description of the invention
Embodiment 1
Take 2.7g polyethyleneglycol diglycidylether and contain 2g SH (mean molecule quantity 120 dalton) but pH with 200ml
(pH is 5.0,5.5,6.0,6.1) different solution at room temperature reacts 5 hours, is then transferred in surface plate by solution, room
Temperature is lower to be dried, and is dipped in water by dried product, is received through ionic strength of sieving, improve, gel particle contraction, precipitation etc.
The aqueous gel granule of contracting.
In order to compare the different qualities of gained gel, by the following method gel is tested.
1. assay: take 1g gel, adds 0.5M sulphuric acid 20ml, and boiling water bath hydrolyzes 15 minutes, adds water to 100ml, carbazole
Method measures glucuronic acid content, and multiplying factor (2.07) is SH content.
2. yield measures: the amount of HA before the amount/reaction of HA in jel product.
The most resistance to enzymatic determination: take gel 1g and add the hyaluronidase solution that 2ml concentration is 300U/ml, 37 DEG C of enzymolysis 65 hours,
Adding the PBS to 5ml of pH 7.2, take 1ml and add dehydrated alcohol 4ml, 1000rpm is centrifuged 15min, takes 2ml supernatant pH7.2's
PBS is settled to 5ml, and with the content of improvement carbazole determination of color glucuronic acid, conversion HA content (* 2.07) is a value, with solidifying
In glue, HA content is b value, calculates a/b.
4. heavy metal inspection: with reference to the method for 2015 editions two annex of Chinese Pharmacopoeia, takes gel 1g, and 60 DEG C of drying are blazing
To carbonization, add 0.5ml sulphuric acid and add and be evaporated, then add 0.5ml nitration acid heat and be evaporated, make carbonization 500～600 DEG C of heating, add 2ml
Hydrochloric acid, water bath method, add 15ml distilled water, add 4% ammonia and be adjusted to neutrality, add the acetate buffer solution of 2ml pH=3.5, molten
It is diluted to 25ml after solution, takes after agents useful for same is evaporated simultaneously, add equivalent acetate buffer solution and distilled water, add the examination of appropriate standard lead
Liquid, is diluted to 25ml, carries out audit by comparison after being separately added into the colour developing of thioacetamide test solution.
The determination data of two kinds of gels is shown in Table 1.
1 two kinds of gel determination data of table compare
| Gel | Content (%) | Yield (%) | Resistance to enzyme (a/b) | Heavy metal (ppm) | Resistance to enzyme |
| PH=6.1 | 1.78 | 84.2 | 100-250/150 | <10 | 0.406 |
| PH=5.5 | 1.81 | 85.1 | 5-500/150 | >100 | 0.412 |
By the result of the test in table 1 it can be seen that in the case of other character is identical, the gel that pH=5.5 obtains is with much money
Belonging to severe overweight, the gel that pH=5.5 obtains is relatively big from footpath scope, and pH=6.1 gel particle is more uniform, cuts mobility preferably,
It is more conducive to injection.
Embodiment 2
SH (mean molecule quantity 990,000, the 1200000 dalton) 2g of different molecular weight is dissolved in 200ml pH be 6.1 pure
Changing in water, wherein pH value dilute hydrochloric acid or dilute sulfuric acid regulation, stirring adds 2.7g polyethylene glycol diglycidyl after dissolving completely
Ether, reacts 5 hours under room temperature, is then transferred in surface plate by solution, is dried, dried product is dipped in water under room temperature
In, through ionic strength of sieving, improve, gel particle contraction, precipitation etc. obtain shrink aqueous gel granule.The survey of two kinds of gels
Given data is shown in Table 2.
2 two kinds of gel determination data of table compare
As shown in Table 2, the SH of different molecular weight, through the colloid that identical technique is made, its content, yield and resistance to enzyme
It is more or less the same.
Embodiment 3
Being dissolved in the purified water that 200ml pH is 6.1 by 2g (mean molecule quantity 1,200,000 dalton) SH, wherein pH value is used
Dilute hydrochloric acid or dilute sulfuric acid regulation, stirring to add after dissolving completely different amounts of polyethyleneglycol diglycidylether (2g, 2.7g,
3g), at room temperature reaction 5 hours, are then transferred to solution in surface plate, be dried, be dipped in by dried product under room temperature
In water, through ionic strength of sieving, improve, gel particle contraction, precipitation etc. obtain shrink aqueous gel granule.Three kinds of gels
Determination data is shown in Table 3.
3 three kinds of gel determination data of table compare
As shown in Table 3, in the case of other character are identical, when adding polyethyleneglycol diglycidylether 2.7g, obtain
Gel content of beary metal is relatively low, and gel is less from footpath scope, and gel particle is more uniform, cuts mobility preferably, is more conducive to injection.
Above content be the preferred implementation combining the invention provided technical scheme is made further in detail
Describe in detail bright, it is impossible to assert that the invention is embodied as being confined to these explanations above-mentioned, for technology belonging to the invention
For the those of ordinary skill in field, without departing from the concept of the premise of the invention, it is also possible to make some simple deductions
Or replace, all should be considered as belonging to the protection domain of the invention.
Claims (10)
1. the preparation method of a slow degraded cross-linked hyaluronic acid gel, it is characterised in that comprise the steps:
1. the pH to 5.9-6.1 of purified water is adjusted；
2. SH is dissolved in the water that 1. step obtains, forms the SH solution that concentration is 0.5%-3%；
3. being dissolved in by glycidyl ether in step solution 2., making HA is 1:1-1:10 with the mass ratio of glycidyl ether,
React 5-8 hour under room temperature；
4. the solution that 3. step obtains is placed in surface plate, drying at room temperature 3-5 days；
5. by step 4. can to product be soaked in deionized water, purification 6-12 hour, obtain expand aqueous gel；
6. collect step 5. in the gel that obtains so that it is by the screen cloth that sieve aperture internal diameter is 100-400 m, obtain containing water-setting
Glue granule；
7. improving the ionic strength of deionized water in the aqueous gel granule that 6. step obtains, 40-80 DEG C is incubated 2-8 hour,
Aqueous gel particle collapses, precipitate, obtain shrink aqueous gel granule；
8. collecting the step 7. middle aqueous gel granule shunk, sterilizing, packaging makes finished product.
The preparation method of a kind of slow degraded cross-linked hyaluronic acid gel the most as claimed in claim 1, it is characterised in that: described
Glycidyl ether is polyethyleneglycol diglycidylether or BDDE.
The preparation method of a kind of slow degraded cross-linked hyaluronic acid gel the most as claimed in claim 1, it is characterised in that: step is 1.
In, the pH of described purified water is 5.0-6.1.
The preparation method of a kind of slow degraded cross-linked hyaluronic acid gel the most as claimed in claim 3, it is characterised in that: step is 1.
In, the pH of described purified water is 6.0-6.1.
The preparation method of a kind of slow degraded cross-linked hyaluronic acid gel the most as claimed in claim 1, it is characterised in that: step is 2.
In, the molecular weight of described SH is 200,000-300 ten thousand.
The preparation method of a kind of slow degraded cross-linked hyaluronic acid gel the most as claimed in claim 5, it is characterised in that: step is 2.
In, the molecular weight of described SH is 900,000-150 ten thousand.
The preparation method of a kind of slow degraded cross-linked hyaluronic acid gel the most as claimed in claim 1, it is characterised in that: described
SH is 1%-2% with the mass volume ratio of purified water.
The preparation method of a kind of slow degraded cross-linked hyaluronic acid gel the most as claimed in claim 1, it is characterised in that: described
SH and glycidyl ether mass volume ratio are 1:2.
The preparation method of a kind of slow degraded cross-linked hyaluronic acid gel the most as claimed in claim 1, it is characterised in that: step is 8.
In, sterilizing uses moist heat sterilization, 115 DEG C-130 DEG C sterilizing 15-30min of sterilising conditions.
The preparation method of a kind of slow degraded cross-linked hyaluronic acid gel the most as claimed in claim 9, it is characterised in that: step
8., in, sterilising conditions is 121 DEG C of sterilizing 15min.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018121510A1 (en) * | 2016-12-29 | 2018-07-05 | 北京键凯科技股份有限公司 | Gel of sodium hyaluronate cross-linked by polyethylene glycol epoxy derivative for injection and preparation method thereof |
| WO2019001472A1 (en) * | 2017-06-28 | 2019-01-03 | 北京键凯科技股份有限公司 | Branched polyglycol epoxy derivative cross-linked sodium hyaluronate gel, preparation therefor, and application thereof |
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| CN101056891A (en) * | 2004-11-15 | 2007-10-17 | 株式会社资生堂 | Process for preparing crosslinked hyaluronic acid gel |
| CN104086788A (en) * | 2014-07-17 | 2014-10-08 | 华熙福瑞达生物医药有限公司 | Modified sodium hyaluronate gel for injection |
| CN104151572A (en) * | 2013-05-16 | 2014-11-19 | 吴学森 | Method for preparing medical cross-linking sodium hyaluronate gel |
| CN105504313A (en) * | 2016-01-22 | 2016-04-20 | 杭州协合医疗用品有限公司 | Preparation method and application of hyaluronic acid plural gel |
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2016
- 2016-08-10 CN CN201610658069.2A patent/CN106167549A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101056891A (en) * | 2004-11-15 | 2007-10-17 | 株式会社资生堂 | Process for preparing crosslinked hyaluronic acid gel |
| CN104151572A (en) * | 2013-05-16 | 2014-11-19 | 吴学森 | Method for preparing medical cross-linking sodium hyaluronate gel |
| CN104086788A (en) * | 2014-07-17 | 2014-10-08 | 华熙福瑞达生物医药有限公司 | Modified sodium hyaluronate gel for injection |
| CN105504313A (en) * | 2016-01-22 | 2016-04-20 | 杭州协合医疗用品有限公司 | Preparation method and application of hyaluronic acid plural gel |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018121510A1 (en) * | 2016-12-29 | 2018-07-05 | 北京键凯科技股份有限公司 | Gel of sodium hyaluronate cross-linked by polyethylene glycol epoxy derivative for injection and preparation method thereof |
| WO2019001472A1 (en) * | 2017-06-28 | 2019-01-03 | 北京键凯科技股份有限公司 | Branched polyglycol epoxy derivative cross-linked sodium hyaluronate gel, preparation therefor, and application thereof |
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