CN109513043A - A kind of injection modification hyaluronic acid sodium gel and preparation method thereof - Google Patents

A kind of injection modification hyaluronic acid sodium gel and preparation method thereof Download PDF

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CN109513043A
CN109513043A CN201710877910.1A CN201710877910A CN109513043A CN 109513043 A CN109513043 A CN 109513043A CN 201710877910 A CN201710877910 A CN 201710877910A CN 109513043 A CN109513043 A CN 109513043A
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hyaluronic acid
gel
acid sodium
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microgel particle
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刘宏飞
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/20Polysaccharides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52Hydrogels or hydrocolloids
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00Processes of treating or compounding macromolecular substances
    • C08J3/02Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075Macromolecular gels
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2400/00Materials characterised by their function or physical properties
    • A61L2400/06Flowable or injectable implant compositions
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2305/00Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
    • C08J2305/08Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Dermatology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a kind of injection modification hyaluronic acid sodium gels and preparation method thereof, belong to hyaluronic acid sodium gel technical field.This method is characterized in that hyaluronic acid and crosslinking agent 1,4- butanediol diglycidyl ether reacts to obtain water-insoluble gel under conditions of pH > 10, after broken, low-molecular-weight hyaluronic acid solution is added, after mixing, the reaction was continued, pH value is adjusted to neutrality, phosphate buffer solution is added, adjusts solid content, obtains injection modification hyaluronic acid sodium gel.This method is not necessarily to dialysis procedure, and gained injection, which modifies hyaluronic acid sodium gel, has good biocompatibility and stability, and is easy to inject, and can be used for beauty or medical field.

Description

A kind of injection modification hyaluronic acid sodium gel and preparation method thereof
Technical field
The present invention relates to hyaluronic acid sodium gel technical field, in particular to a kind of injection modifies hyaluronic acid sodium gel And preparation method thereof.
Background technique
Hyaluronic acid (hyalouronic acid, HA) is made of glucuronic acid and n acetylglucosamine n disaccharide units A kind of linear polymeric polysaccharide has splendid biological safety, is widely used in medical treatment and beauty treatment fields, HA has become at present The soft tissue filler of usage amount first.
Since that there are degradation speeds is very fast for noncrosslinking HA gel, the disadvantage that the filling effect time is short, therefore normal open are maintained It crosses cross-linking reaction and obtains crosslinking HA gel, to obtain more longlasting filling effect.Common crosslinking agent has: 1,4-butanediol two contracts Water glycerin ether (Isosorbide-5-Nitrae-butanediol diglycidyl ether, BDDE) and divinylsulfone (divinyl sulfone, DVS) etc..These crosslinking agents have very strong bio-toxicity, for the biological safety for ensureing gel, need strict control crosslinking HA solidifying The content (< 2ppm) of crosslinking agent in glue.At present frequently with unreacted crosslinking agent in dialysis removal gel, dialysis procedure increases Process flow and product cost are added.
A kind of preparation process for being crosslinked HA gel particle of the patented invention of Publication No. CN 101264348A, step It include: cross-linking reaction preparation crosslinking HA gel;Dialysis treatment is crosslinked HA gel;Gel particle classification obtains crosslinking HA gel Grain.Patent 1g is crosslinked HA gel and need to be dialysed 15~60 hours with the dialyzate of 500~5000ml, to remove unreacted crosslinking Agent.
Publication No. CN 104086788A patent provides that a kind of dosage of crosslinking agent is few, injection of good rheological property is repaired Adorn the preparation method of HA gel.It is characterized by: HA is reacted to obtain gel X with crosslinking agent under conditions of pH > 10;By HA with Crosslinking agent reacts to obtain gel Y under conditions of pH > 9;Gel X is mixed with gel Y, cross-linking reaction is carried out again, through overregulating PH value obtains injection modification HA gel to neutral and dialysis.Although this patent dosage of crosslinking agent is less, still needed to after cross-linking reaction Dialysis treatment is carried out, crosslinking agent and unreacted small-molecule substance are removed.
Publication No. CN 103923328A discloses a kind of high quality cross-linking sodium hyaluronate gel and preparation method thereof, After obtaining cross-linking hyaluronic acid sodium dry powder, washed with DMSO;By the powder ethanol washing after DMSO is washed;It will be through ethyl alcohol The dry acquisition cross-linking hyaluronic acid sodium powder of powder under vacuum after washing;Powder is sufficiently swollen, is purified 6~10 hours in room temperature Afterwards, homogeneous treatment with micron is carried out with high speed disperser, obtains cross-linking sodium hyaluronate gel particle.The method, which need to use, largely to be had Machine reagent, there are the remaining risks of organic reagent, and preparation process is complicated.
But the above-mentioned prior art cannot have both, and preparation process is simple, product without dialysis purification, HA gel plasticity it is good and The advantages that stable, internal retention time is long.
Summary of the invention
It cannot have both that preparation process is simple, product is without dialysis purification, HA to solve the HA gel of prior art preparation Gel plasticity is good and stablize, the advantages that internal retention time is long the problem of, that the present invention provides a kind of preparation processes is simple, produces Product are without dialysis purification, the injection modification HA gel that gel plasticity is good, stability is good, internal retention time is long and its side Method.
The present invention is realized by following measures:
A kind of preparation method of injection modification hyaluronic acid sodium gel, includes the following steps:
(1) hyaluronic acid and 1,4-butanediol diglycidyl ether are mixed in 1.0~1.5% NaOH solution, in 30~50 DEG C insulation reaction 2-6 hours, obtain water-insoluble gel;
(2) gel for obtaining step (1) is broken, crosses 60 mesh screens, obtains microgel particle A;
(3) microgel particle A is uniformly mixed with the hyaluronic acid solution of low molecular weight, in 30~50 DEG C reaction 2-5 hours, Obtain microgel particle B;
(4) microgel particle B is neutralized to system pH with 1.0~1.5% HCl solution is neutrality, obtains microgel particle C;
(5) microgel particle C is uniformly mixed with the phosphate buffer solution of pH=7, regulates and controls hyaluronic acid in microgel particle Content be 16-20mg/mL;
(6) microgel particle that step (5) obtain is pressed through to the sieve of 120 mesh, it is filling in syringe, it is damp and hot in 121 DEG C Sterilizing 15~20 minutes, obtains finished product.
The preparation method of the injection modification hyaluronic acid sodium gel, it is characterised in that hyaluronic acid in step (1) Molecular weight be 1000~4000kDa.
The preparation method of the injection modification hyaluronic acid sodium gel, it is characterised in that hyaluronic acid in step (1) Mass volume ratio with NaOH solution is 5%~30%, preferably 10%~20%.
The preparation method of the injection modification hyaluronic acid sodium gel, it is characterised in that Isosorbide-5-Nitrae-fourth two in step (1) The mass ratio of alcohol diglycidyl ether and hyaluronic acid is 5~40%, preferably 5%~20%.
The preparation method of the injection modification hyaluronic acid sodium gel, it is characterised in that low molecular weight in step (3) The molecular weight of hyaluronic acid is 1.0~5.0kDa, preferably 1.0~3.0kDa;Solution concentration be 0.5%~3%, preferably 1%~ 2%.
The preparation method of the injection modification hyaluronic acid sodium gel, it is characterised in that microgel particle A in step (3) Mass ratio with the hyaluronic acid solution of low molecular weight is 1: 1~4: 1, preferably 1: 1~2: 1.
A kind of injection modification hyaluronic acid sodium gel prepared such as above-mentioned preparation method.
The injection modifies hyaluronic acid sodium gel, it is characterised in that: the content of crosslinking agent B DDE is lower than in gel 2ppm。
The purpose of the present invention additionally provides the purposes of the gel, for filling fine, moderate or deep wrinkles, and tissue Filling.
Beneficial effects of the present invention:
1. injection of the invention modifies hyaluronic acid sodium gel, there is good plasticity, be easy to inject, retains in vivo Time is long, is able to maintain biocompatibility.
2. preparation process of the present invention is simple, product is not necessarily to dialysis purification, low energy consumption, and pollution-free, process cycle is short, is easy to produce Industry metaplasia produces.
Specific embodiment
For a better understanding of the invention, it further illustrates combined with specific embodiments below.
Embodiment 1
(1) 5.0g hyaluronic acid (molecular weight 4000kDa) is dissolved in 50ml, in 1.0% NaOH solution, mixed Afterwards, crosslinking agent 1,4-butanediol diglycidyl ether is added, crosslinking agent and hyaluronic acid mass ratio are 5%, are stirred and evenly mixed, 30 6h is reacted in DEG C water-bath, obtains water-insoluble gel;
(2) gel for obtaining step (1) is broken, crosses 60 mesh screens, obtains microgel particle A;
(3) by microgel particle A and 25ml, 1% hyaluronic acid (molecular weight 1.0kDa) solution is uniformly mixed, in 50 DEG C reaction 2 hours, obtain microgel particle B;
(4) microgel particle B is neutralized to system pH with 1.0% HCl solution is neutrality, obtains microgel particle C;
(5) microgel particle C is uniformly mixed with the phosphate buffer solution of pH=7, regulates and controls hyaluronic acid in microgel particle Content be 16mg/mL;
(6) microgel particle that step (5) obtain is pressed through to the sieve of 120 mesh, it is filling in syringe, it is damp and hot in 121 DEG C Sterilizing 15 minutes obtains injection modification hyaluronic acid sodium gel;
(7) gas chromatography of YY/T0962-2014 annex is used to measure BDDE residual quantity as 0.79ppm.
Embodiment 2
(1) 5.0g hyaluronic acid (molecular weight 1000kDa) is dissolved in 25ml, in 1.5% NaOH solution, mixed Afterwards, crosslinking agent 1,4-butanediol diglycidyl ether is added, crosslinking agent and hyaluronic acid mass ratio are 20%, it stirs and evenly mixs, 2h is reacted in 50 DEG C of water-baths, obtains water-insoluble gel;
(2) gel for obtaining step (1) is broken, crosses 60 mesh screens, obtains microgel particle A;
(3) by microgel particle A and 25ml, 2% hyaluronic acid (molecular weight 1.0kDa) solution is uniformly mixed, in 30 DEG C reaction 5 hours, obtain microgel particle B;
(4) microgel particle B is neutralized to system pH with 1.5% HCl solution is neutrality, obtains microgel particle C;
(5) microgel particle C is uniformly mixed with the phosphate buffer solution of pH=7, regulates and controls hyaluronic acid in microgel particle Content be 18mg/mL;
(6) microgel particle that step (5) obtain is pressed through to the sieve of 120 mesh, it is filling in syringe, it is damp and hot in 121 DEG C Sterilizing 20 minutes obtains injection modification hyaluronic acid sodium gel;
(7) gas chromatography of YY/T0962-2014 annex is used to measure BDDE residual quantity as 1.26ppm.
Embodiment 3
(1) 5.0g hyaluronic acid (molecular weight 2000kDa) is dissolved in 35ml, in 1.25% NaOH solution, mixed Afterwards, crosslinking agent 1,4-butanediol diglycidyl ether is added, crosslinking agent and hyaluronic acid mass ratio are 15%, it stirs and evenly mixs, 4h is reacted in 40 DEG C of water-baths, obtains water-insoluble gel;
(2) gel for obtaining step (1) is broken, crosses 60 mesh screens, obtains microgel particle A;
(3) by microgel particle A and 20ml, 1.5% hyaluronic acid (molecular weight 2.0kDa) solution is uniformly mixed, in 40 DEG C are reacted 3 hours, and microgel particle B is obtained;
(4) microgel particle B is neutralized to system pH with 1.25% HCl solution is neutrality, obtains microgel particle C;
(5) microgel particle C is uniformly mixed with the phosphate buffer solution of pH=7, regulates and controls hyaluronic acid in microgel particle Content be 20mg/mL;
(6) microgel particle that step (5) obtain is pressed through to the sieve of 120 mesh, it is filling in syringe, it is damp and hot in 121 DEG C Sterilizing 18 minutes obtains injection modification hyaluronic acid sodium gel;
(7) gas chromatography of YY/T0962-2014 annex is used to measure BDDE residual quantity as 0.87ppm.
Embodiment 4
(1) 5.0g hyaluronic acid (molecular weight 3000kDa) is dissolved in 40ml, in 1.0% NaOH solution, mixed Afterwards, crosslinking agent 1,4-butanediol diglycidyl ether is added, crosslinking agent and hyaluronic acid mass ratio are 10%, it stirs and evenly mixs, 2h is reacted in 50 DEG C of water-baths, obtains water-insoluble gel;
(2) gel for obtaining step (1) is broken, crosses 60 mesh screens, obtains microgel particle A;
(3) by microgel particle A and 30ml, 1.5% hyaluronic acid (molecular weight 3.0kDa) solution is uniformly mixed, in 50 DEG C are reacted 2.5 hours, and microgel particle B is obtained;
(4) microgel particle B is neutralized to system pH with 1.5% HCl solution is neutrality, obtains microgel particle C;
(5) microgel particle C is uniformly mixed with the phosphate buffer solution of pH=7, regulates and controls hyaluronic acid in microgel particle Content be 18mg/mL;
(6) microgel particle that step (5) obtain is pressed through to the sieve of 120 mesh, it is filling in syringe, it is damp and hot in 121 DEG C Sterilizing 20 minutes obtains injection modification hyaluronic acid sodium gel;
(7) gas chromatography of YY/T0962-2014 annex is used to measure BDDE residual quantity as 0.93ppm.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by the limit of embodiment System, other any changes made without departing from the spirit and principles of the present invention, combination, substitution, simplification should be equivalent Alternative is included within the scope of the present invention.

Claims (8)

1. a kind of preparation method of injection modification hyaluronic acid sodium gel, it is characterised in that include the following steps:
(1) hyaluronic acid and 1,4-butanediol diglycidyl ether are mixed in 1.0~1.5% NaOH solution, in 30~ 50 DEG C insulation reaction 2-6 hours, obtain water-insoluble gel;
(2) gel for obtaining step (1) is broken, crosses the sieve of 60 mesh, obtains microgel particle A;
(3) microgel particle A is uniformly mixed with the hyaluronic acid solution of low molecular weight, in 30~50 DEG C reaction 2-5 hours, obtain solidifying Glue particles B;
(4) microgel particle B is neutralized to system pH with 1.0~1.5% HCl solution is neutrality, obtains microgel particle C;
(5) microgel particle C is uniformly mixed with the phosphate buffer solution of pH=7, hyaluronic acid contains in regulation microgel particle Amount is 16-20mg/mL;
(6) microgel particle that step (5) obtain is pressed through to the sieve of 120 mesh, it is filling in syringe, in 121 DEG C of moist heat sterilizations 15~20 minutes, obtain finished product.
2. a kind of preparation method of injection modification hyaluronic acid sodium gel according to claim 1, it is characterised in that step Suddenly the molecular weight of hyaluronic acid is 1000~4000kDa in (1).
3. a kind of preparation method of injection modification hyaluronic acid sodium gel according to claim 1, it is characterised in that step Suddenly hyaluronic acid and the mass volume ratio of NaOH solution are 5%~30% in (1).
4. a kind of preparation method of injection modification hyaluronic acid sodium gel according to claim 1, it is characterised in that step Suddenly the mass ratio of 1,4-butanediol diglycidyl ether and hyaluronic acid is 5~40% in (1).
5. a kind of preparation method of injection modification hyaluronic acid sodium gel according to claim 1, it is characterised in that step Suddenly the molecular weight of low-molecular-weight hyaluronic acid is 1~5kDa in (3), and solution concentration is 0.5%~3%.
6. a kind of preparation method of injection modification hyaluronic acid sodium gel according to claim 1, it is characterised in that step Suddenly the mass ratio of microgel particle A and the hyaluronic acid solution of low molecular weight is 1: 1~4: 1 in (3).
7. injection prepared by preparation method according to claim 1 modifies hyaluronic acid sodium gel.
8. injection according to claim 7 modifies hyaluronic acid sodium gel, it is characterised in that: crosslinking agent B DDE in gel Content be lower than 2ppm.
CN201710877910.1A 2017-09-20 2017-09-20 A kind of injection modification hyaluronic acid sodium gel and preparation method thereof Pending CN109513043A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112791238A (en) * 2020-12-22 2021-05-14 浙江景嘉医疗科技有限公司 Compound gel for treating bladder ureteral reflux and preparation method thereof
RU2750000C1 (en) * 2019-12-25 2021-06-21 Акционерное общество «Медтехнопроект» Method for synthesis of modified hyaluronan and application thereof in medicine, including in endoprosthetics

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CN101538377A (en) * 2008-03-20 2009-09-23 上海昊海生物科技有限公司 Cross-linked hyaluronic acid gel and preparation method thereof
CN101759881A (en) * 2008-10-08 2010-06-30 上海建华精细生物制品有限公司 Medical cross-linking sodium hyaluronate gel derivative product and preparation method thereof
CN102065849A (en) * 2008-04-24 2011-05-18 麦德托尼克公司 Protective gel based on chitosan and oxidized polysaccharide
US20120225842A1 (en) * 2010-01-13 2012-09-06 Allergan, Inc. Hyaluronic acid compositions for dermatological use
US20130209532A1 (en) * 2007-11-30 2013-08-15 Allergan, Inc. Polysaccharide gel formulation having increased longevity
CN107029281A (en) * 2017-04-17 2017-08-11 江苏昌吉永生物科技股份有限公司 A kind of preparation method of Absorbable hemostatic material

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US20130209532A1 (en) * 2007-11-30 2013-08-15 Allergan, Inc. Polysaccharide gel formulation having increased longevity
CN101538377A (en) * 2008-03-20 2009-09-23 上海昊海生物科技有限公司 Cross-linked hyaluronic acid gel and preparation method thereof
CN102065849A (en) * 2008-04-24 2011-05-18 麦德托尼克公司 Protective gel based on chitosan and oxidized polysaccharide
CN101759881A (en) * 2008-10-08 2010-06-30 上海建华精细生物制品有限公司 Medical cross-linking sodium hyaluronate gel derivative product and preparation method thereof
US20120225842A1 (en) * 2010-01-13 2012-09-06 Allergan, Inc. Hyaluronic acid compositions for dermatological use
CN107029281A (en) * 2017-04-17 2017-08-11 江苏昌吉永生物科技股份有限公司 A kind of preparation method of Absorbable hemostatic material

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2750000C1 (en) * 2019-12-25 2021-06-21 Акционерное общество «Медтехнопроект» Method for synthesis of modified hyaluronan and application thereof in medicine, including in endoprosthetics
WO2021133190A1 (en) * 2019-12-25 2021-07-01 Акционерное общество "Медтехнопроект" Method for producing modified hyaluronan
CN112791238A (en) * 2020-12-22 2021-05-14 浙江景嘉医疗科技有限公司 Compound gel for treating bladder ureteral reflux and preparation method thereof

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Application publication date: 20190326