CN105504313B - A kind of preparation method and applications of hyaluronic acid plural gel - Google Patents
A kind of preparation method and applications of hyaluronic acid plural gel Download PDFInfo
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- A—HUMAN NECESSITIES
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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
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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
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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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Abstract
The present invention relates to a kind of hyaluronic acid plural gel fields, more particularly to a kind of preparation method of hyaluronic acid plural gel, provide a kind of homogeneous realized cross-linking system using Multi-parameter Combined Tool in more periods He prepare gel, early period realizes the abundant mixing of system by low temperature and high frequency oscillation, middle and later periods improves temperature and sets different frequency of oscillation promotion reaction production gels and reduce destruction of the preparation process to gel, so as to obtain a kind of new plural gel.The present invention also provides application of the plural gel in terms of medical treatment or prevention.
Description
Technical field
The present invention relates to a kind of hyaluronic acid plural gel field, more particularly to a kind of system of hyaluronic acid plural gel
Preparation Method, so as to obtain a kind of new plural gel.The new gel has the application in terms of medical treatment.
Background technology
A kind of straight chain polymer that hyaluronic acid is made of glucuronic acid and N-acetylglucosamine dissacharide units
Glutinous polysaccharide prepares gel in medical field extensive use by it, gel for cross-linking hyaluronic acid is modified into infinite networks and
It prepares.Performance to promote gel is combined hyaluronic acid with other soft tissues implantation viscoelastic medium with expanding its application
Prepare plural gel.Viscosity is larger after being dissolved because of hyaluronic acid, is also easy to produce the problems such as system homogenieity is poor, reaction is uneven, with
The difficulty that the above problem solves is increased after the implantation viscoelastic medium mixing of other soft tissues, simple dilution can promote system homogeneous
Property, but cross-linking reaction can be produced bigger effect, reduce gel mechanical performance.
The patent application of 104086788 A of publication number CN proposes substep crosslinking and prepares injection modification Sodium Hyaluronate
Gel, respectively by hyaluronic acid and crosslinking agent in PH>Gel X is reacted to obtain under conditions of 10, hyaluronic acid and crosslinking agent are existed
PH>Gel X with gel Y is mixed, carries out cross-linking reaction again, while the patent application is also by the gel Y reacted under conditions of 9
Including vitamin, amino acid etc. are added in gel.The crosslinking of two steps can promote gelling performance, but it is poor to increase gel homogenieity
The problem of, while the substances such as vitamin, amino acid are added in after gel-forming, it is merged with gel poor, it is difficult to realize to gelation
The promotion of energy.
The patent application of Publication No. CN 1190974A provides a kind of method for preparing cross-linked polysaccharide gel composition.
Including：Form the aqueous solution of water-soluble, crosslinkable polysaccharide；Start the friendship of the polysaccharide in the presence of polyfunctional crosslinking agent
Connection；Before gel reaction generation, steric hindrance cross-linking reaction prevents its termination, so as to obtain activated polysaccharide；To the activation
Polysaccharide in be re-introduced into the condition of non-steric hindrance with continue its cross-linking reaction until formed viscoelastic gel.But the method need pair
System is diluted and concentrates, more, cumbersome using step, is unfavorable for medical product production, exists simultaneously intermediate steps pair
Raw material causes the problems such as degradation.
Invention content
The object of the present invention is to provide a kind of systems for preparing good, gelling performance stabilization the hyaluronic acid plural gel of homogenieity
Standby technique, while the technological operation is convenient, the production available for treatment purpose product.
In order to achieve the above object, the technical scheme is that：
A kind of preparation process of hyaluronic acid plural gel, it is characterised in that：
（1）Hyaluronic acid is dissolved with crosslinking agent in alkaline aqueous solution, it is fully dispersed；
（2）Soft tissue implantation viscoelastic medium is added in above-mentioned solution；
（3）Using the concussion of more period different conditions, to realize solution and gel-forming stage system before cross-linking reaction
Homogeneous, wherein, first segment reduces cross-linking reaction incidence before the non-mixing of system by low temperature and high frequency oscillation, second
Section promotes system during system cross-linking reaction early period that can keep homogeneous state by high temperature and high frequency oscillation；Third section passes through height
Mild low frequency oscillation promotes the formation of gel and reduces destruction of the oscillation to gel result；
（4）Acidification and dialysis equilibrium are carried out using acid balanced salt solution, is prepared into hyaluronic acid plural gel.
Step（1）In, preferably clear matter acid molecule amount is 0.3MDa to 1.5MDa.
The soft tissue implantation viscoelastic medium is chitosan, collagen, dextran, acrylate and its copolymer
In one or more combinations.
The crosslinking agent is selected from epoxides, Geniposide, polyethylene glycol, divinylsulfone, glycidol ether.
The first segment, second segment, third Duan Junke are divided into one or more periods, wherein, belong to second segment
Period can recycle progress with the period for belonging to third section, until generation plural gel；Each period when it is a length of
0.5-12 hours.In same section of different time sections, temperature and/or concussion frequency can be identical or different, the time
Total hop count of section is 5-9 sections, preferably 7 sections, more preferably 5 sections.
Step（3）Setting low temperature, high oscillation frequency condition are so that hyaluronic acid, crosslinking agent, soft tissue in middle first segment
Be implanted into viscoelastic medium abundant homogeneous in system, the low temperature be 2 DEG C to 25 DEG C, preferably 5 DEG C to 23 DEG C, more preferably
7 DEG C to 20 DEG C；The high oscillation frequency is 150rpm to 600rpm.
Step（3）In in the section setting high-temperature, high oscillation frequency condition so that cross-linking reaction fully occurs.The high temperature
Spend is 35 DEG C to 60 DEG C；The high oscillation frequency is 150rpm to 600rpm.
Step（3）Setting high-temperature in middle third section, low frequency of oscillation condition reduce oscillation pair so that gel is sufficiently formed
Form the destruction of gel result.The high-temperature is 35 DEG C to 60 DEG C；The low frequency of oscillation is 5rpm to 50rpm.
Step（4）Middle acidity balanced salt solution pH value is 1 to 4.5, and the acidification time is 0.2 to 6 hour, preferably
0.4 to 5 hour, more preferably 0.6 to 4 hour.
Step（4）Middle dialysis equilibrium makes gel to swelling equilibrium for dialysis.
In the prior art, match in advance using solution is dilute, complete system homogeneous after concentration prepare gel, gained gel strength
Difference, homogenieity is undesirable instead, caused in later stage concentration process raw molecule amount reduce, local bolus poly and crosslinked it is uneven existing
As.
To improve gel problem of non-uniform, the present invention abandons first mixing, then stands the conventional method of reaction, select to anti-
The method for answering system persistent oscillation, it is found through experiment that there are still the problem of uneven and persistent oscillation destroys gel structure is crosslinked,
It improves, has obtained compound to prepare hyaluronic acid using the method for different condition oscillation in more periods through repetition test and method
The method of gel.It is an advantage of the invention that：
（1）The plural gel homogenieity of preparation is good, and each component is uniformly distributed, and crosslinking is uniform.
（2）The plural gel of preparation is with good stability, is resistant to moist heat sterilization.
（3）Plural gel preparation process is easy to operate, is suitble to the sterile production operation of product.
（4）The plural gel finally obtained has close to physiological pH value, osmotic pressure etc., and with good bio-compatible
Property.
The purpose of the present invention additionally provides the purposes of hyaluronic acid plural gel prepared by a kind of any of the above-described method, is used for
Orthopaedics injection supplement substitutes synovia.
The gel can be used for repairing damaged skin tissue by mesotherapy, improve skin texture and elasticity.
The gel can be used as filler, enhance local organization by injecting method.
Specific embodiment
In order to better understand the present invention, it is further illustrated with reference to specific embodiment.
Embodiment 1
The reaction system for preparing gel is established.Those skilled in the art are selected it is known that 1%NaOH solution is as lye,
Glycidol ether is crosslinking agent, uniform mixing equipment constant-temperature table.10.0g hyaluronic acids are dissolved in 200ml lye, according to saturating
Bright matter acid：Crosslinking agent quality is than 2:1 to 20:1 adds in crosslinking agent, adds in collagen, is mixed under 22 DEG C, frequency of oscillation 300rpm
It is even.
Embodiment 2
The reaction system for preparing gel is established.Those skilled in the art are selected it is known that 1%NaOH solution is as lye,
Glycidol ether is crosslinking agent, uniform mixing equipment constant-temperature table.10.0g hyaluronic acids are dissolved in 200ml lye, according to saturating
Bright matter acid：Crosslinking agent quality is than 2:1 to 18:1 adds in crosslinking agent, dextran particle is added in, in 20 DEG C, frequency of oscillation 220rpm
Lower mixing.
Embodiment 3
The reaction system for preparing gel is established.Those skilled in the art are selected it is known that 1%NaOH solution is as lye,
Glycidol ether is crosslinking agent, uniform mixing equipment constant-temperature table.10.0g hyaluronic acids are dissolved in 200ml lye, according to saturating
Bright matter acid：Crosslinking agent quality is than 2:1 to 18:1 adds in crosslinking agent, adds in chitosan, is mixed under 20 DEG C, frequency of oscillation 350rpm
It is even.
Embodiment 4
The preparation of hyaluronic acid plural gel.
（1）The reaction system obtained in embodiment 1 to 3 is put into constant-temperature table, point five periods prepare gel, and first
5 hours periods, 15 DEG C of temperature, frequency of oscillation 550rpm；Second time period 5 hours, 55 DEG C of temperature, frequency of oscillation 550rpm；
5 hours third periods, 55 DEG C of temperature, frequency of oscillation 35rpm；4th 5 hours periods, 55 DEG C of temperature, frequency of oscillation
550rpm；5th 5 hours periods, 55 DEG C of temperature, frequency of oscillation 35rpm.
（2）Compound will be prepared through 2.0 pickle pickling of pH value 4 hours, balanced salt solution is dialysed to swelling equilibrium, damp and hot
Composite transparent matter acid gel is obtained after sterilizing.
The plural gel of preparation preferably homogenizes because realizing, and performance is stablized, gel viscoelastisity before and after moist heat sterilization
Variation is smaller, while product syringe handle pushing force is can be controlled in relatively low range, and changes smaller.Data are shown in Table 1.
Assay method is as follows：
Gel viscoelastisity, using rheometer,（25±0.2）At DEG C, in the range of 0.01~10Hz, springform is drawn
Measure G ' and the logarithm of viscous modulus G " and the logarithmic plot of frequency, it is indicated that viscous modulus and elasticity modulus under 1Hz frequencies
Value.
Syringe handle pushing force installs 23G injection needles, pushes syringe and excludes a small amount of air in front end to the appearance of needle point position
Gel droplet.Syringe is installed on universal testing machine, setting driving velocity 12mm/min is measured, record injection
Device handle is averaged pushing force.
Table 1 sterilizes（Moist heat sterilization）Front and rear pushing force, modulus change
The plural gel prepared simultaneously, pH value and homeo-osmosis, close to physiological level.Data are shown in Table 2.
Table 2 sterilizes（Moist heat sterilization）Front and rear pH value and osmotic pressure
Claims (4)
1. a kind of preparation method of hyaluronic acid plural gel, it is characterised in that：
(1) hyaluronic acid is dissolved with crosslinking agent in alkaline aqueous solution, it is fully dispersed；
(2) soft tissue implantation viscoelastic medium is added in above-mentioned solution, the soft tissue implantation viscoelastic medium includes the right side
The wherein at least one of the sugared acid anhydride of rotation, dextran copolymer；
(3) using the concussion of more period different conditions, to realize the equal of solution and gel-forming stage system before cross-linking reaction
Matter, wherein, first segment reduces cross-linking reaction incidence before the non-mixing of system, second segment leads to by low temperature and high frequency oscillation
Excessively high mild high frequency oscillation promotes system during system cross-linking reaction early period that can keep homogeneous state；Third section by high temperature and
Low frequency oscillation promotes the formation of gel and reduces destruction of the oscillation to gel result；
(4) acidification and dialysis equilibrium are carried out using acid balanced salt solution, is prepared into hyaluronic acid plural gel；
Setting low temperature, high oscillation frequency condition are so that hyaluronic acid, crosslinking agent, soft tissue implantation viscoplasticity in first time period
Medium abundant homogeneous in system；The low temperature is 2 DEG C to 25 DEG C, and high oscillation frequency is 150rpm to 600rpm；
Setting high-temperature, high oscillation frequency condition are so that cross-linking reaction fully occurs in second segment；The high-temperature for 35 DEG C extremely
60 DEG C, high oscillation frequency is 150rpm to 600rpm；
Setting high-temperature, low frequency of oscillation condition are so that gel is sufficiently formed, and reduces oscillation to forming gel knot in third section
The destruction of structure；The high-temperature is 35 DEG C to 60 DEG C, and low frequency of oscillation is 5rpm to 50rpm；
Crosslinking agent is selected from Geniposide, polyethylene glycol, divinylsulfone, glycidol ether.
2. the preparation method of Sodium Hyaluronate plural gel according to claim 1, it is characterised in that：The hyalomitome of selection
Acid molecule amount is in 0.3MDa to 1.5MDa.
3. the preparation method of hyaluronic acid plural gel according to claim 1 or 2, it is characterised in that：Described first
Section, second segment, third Duan Junke are divided into one or more periods, wherein, belong to the period of second segment and belong to third section
Period can recycle progress, until generation plural gel；Each period when it is 0.5-12 hours a length of.
4. the preparation method of hyaluronic acid plural gel according to claim 1 or 2, it is characterised in that：It is sour in step (4)
Sexual balance salting liquid pH is 1-4.5, and the acidification time is 0.2-6 hours.
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| KR101710639B1 (en) * | 2016-06-07 | 2017-03-08 | 주식회사 파마리서치프로덕트 | Filler composition comprising nucleic acid, chitosan and hyaluronic acid for tissue augmentation and process for producing the same |
| CN105997859B (en) * | 2016-07-08 | 2019-01-15 | 上海建华精细生物制品有限公司 | Facet joint treatment nano injection liquid and preparation method thereof |
| CN106167549A (en) * | 2016-08-10 | 2016-11-30 | 浙江美华鼎昌医药科技有限公司 | A kind of preparation method of slow degraded cross-linked hyaluronic acid gel |
| CN110343193B (en) * | 2019-08-26 | 2020-12-25 | 华南理工大学 | High-emulsion-stability beet pectin and preparation method thereof |
| CN112791238B (en) * | 2020-12-22 | 2022-07-01 | 浙江景嘉医疗科技有限公司 | Compound gel for treating bladder ureteral reflux and preparation method thereof |
| CN114395144B (en) * | 2022-01-28 | 2024-09-06 | 上海瑞凝生物科技有限公司 | Hyaluronic acid-polyethylene glycol-layered silicon dioxide composite hydrogel and application thereof |
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|---|---|---|---|---|
| CN1200299A (en) * | 1997-05-22 | 1998-12-02 | 吴湘君 | Cohesive and hydrophilic gel for medical use, and method for preparing same |
| CN1927912A (en) * | 2006-09-21 | 2007-03-14 | 上海大学 | Physical cross-linking hydrogel and preparation method thereof |
| CN101537209A (en) * | 2008-03-28 | 2009-09-23 | 杭州嘉伟生物制品有限公司 | Preparation process and application of three-dimensional network structure medical use hydrogel particles |
| CN101537205A (en) * | 2009-04-10 | 2009-09-23 | 暨南大学 | Degradable medical hemostatic non-viscous material and preparation method thereof |
| CN102757570A (en) * | 2011-04-25 | 2012-10-31 | 颜先琴 | Preparation method of sodium hyaluronate gel |
| CN103333349A (en) * | 2013-06-28 | 2013-10-02 | 陕西巨子生物技术有限公司 | Hyaluronic acid-collagen composite hydrogel for injection and preparation method thereof |
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