CN109010912B - Modified hyaluronic acid injectable filling material and preparation method thereof - Google Patents
Modified hyaluronic acid injectable filling material and preparation method thereof Download PDFInfo
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- CN109010912B CN109010912B CN201811133176.9A CN201811133176A CN109010912B CN 109010912 B CN109010912 B CN 109010912B CN 201811133176 A CN201811133176 A CN 201811133176A CN 109010912 B CN109010912 B CN 109010912B
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- hyaluronic acid
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical class CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 120
- 239000000463 material Substances 0.000 title claims abstract description 37
- 238000011049 filling Methods 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 97
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 97
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 32
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 32
- 239000007853 buffer solution Substances 0.000 claims abstract description 13
- 229930003231 vitamin Natural products 0.000 claims abstract description 8
- 235000013343 vitamin Nutrition 0.000 claims abstract description 8
- 239000011782 vitamin Substances 0.000 claims abstract description 8
- 229940088594 vitamin Drugs 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 239000000243 solution Substances 0.000 claims description 16
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 14
- 239000000600 sorbitol Substances 0.000 claims description 14
- 238000005303 weighing Methods 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000003431 cross linking reagent Substances 0.000 claims description 6
- 239000007795 chemical reaction product Substances 0.000 claims description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 229920006037 cross link polymer Polymers 0.000 claims description 2
- 125000003827 glycol group Chemical group 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 230000003416 augmentation Effects 0.000 abstract description 4
- 230000037303 wrinkles Effects 0.000 abstract description 3
- 210000000481 breast Anatomy 0.000 abstract description 2
- 238000005461 lubrication Methods 0.000 abstract description 2
- 230000000399 orthopedic effect Effects 0.000 abstract description 2
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- 239000007972 injectable composition Substances 0.000 abstract 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 18
- 229930003427 Vitamin E Natural products 0.000 description 9
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 9
- 235000019165 vitamin E Nutrition 0.000 description 9
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- 230000015556 catabolic process Effects 0.000 description 6
- 238000006731 degradation reaction Methods 0.000 description 6
- 108010003272 Hyaluronate lyase Proteins 0.000 description 3
- 102000001974 Hyaluronidases Human genes 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 229960002773 hyaluronidase Drugs 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- LUEWUZLMQUOBSB-FSKGGBMCSA-N (2s,3s,4s,5s,6r)-2-[(2r,3s,4r,5r,6s)-6-[(2r,3s,4r,5s,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5s,6r)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-4,5-dihydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@@H](O[C@@H]2[C@H](O[C@@H](OC3[C@H](O[C@@H](O)[C@@H](O)[C@H]3O)CO)[C@@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O LUEWUZLMQUOBSB-FSKGGBMCSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 229920002581 Glucomannan Polymers 0.000 description 2
- 210000004207 dermis Anatomy 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 229940046240 glucomannan Drugs 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 206010033675 panniculitis Diseases 0.000 description 2
- 238000003359 percent control normalization Methods 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 210000004304 subcutaneous tissue Anatomy 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- CYCBPQPFMHUATH-UHFFFAOYSA-N 4-(oxiran-2-ylmethoxy)butan-1-ol Chemical group OCCCCOCC1CO1 CYCBPQPFMHUATH-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 229930003270 Vitamin B Natural products 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 125000000600 disaccharide group Chemical group 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- -1 hyaluronic acid compound Chemical class 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000012844 infrared spectroscopy analysis Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 210000003954 umbilical cord Anatomy 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Classifications
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/20—Polysaccharides
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/52—Hydrogels or hydrocolloids
-
- 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
- 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
- A61L31/04—Macromolecular materials
- A61L31/042—Polysaccharides
-
- 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
- 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
- A61L31/04—Macromolecular materials
- A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- 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
- 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
-
- 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
- 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
-
- 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
- A61L2400/06—Flowable or injectable implant compositions
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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
- A61L2400/10—Materials for lubricating medical devices
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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
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction
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- Health & Medical Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Vascular Medicine (AREA)
- Surgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicinal Chemistry (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
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- Materials For Medical Uses (AREA)
Abstract
The invention discloses a modified hyaluronic acid injectable filling material and a preparation method thereof, wherein the modified hyaluronic acid injectable filling material comprises free transparent hyaluronic acid gel, cross-linked hyaluronic acid gel, water-soluble vitamins and buffer solution, and the hyaluronic acid-polyethylene glycol modified material has the following structure:
Description
Technical Field
The invention relates to the field of beauty treatment, in particular to the field of a modified hyaluronic acid injectable filling material crosslinked by polyethylene glycol.
Background
Hyaluronic acid (hyaluronic acid) is a polysaccharide of a straight chain macromolecule widely existing in human and animal bodies and composed of disaccharide units (glucuronic acid-N-ethinylglucose), and has a structural formula:
it is widely found in connective tissue, mucous tissue and bacterial tunica between vertebrates, and is also contained in high content in epidermis, dermis, umbilical cord, joint synovial fluid and cartilage tissue. Since 1934, Meyer et al in the united states first isolated hyaluronic acid from bovine vitreous humor, it was gradually discovered by people to have important properties such as good biocompatibility, high viscoelasticity, plasticity and permeability. Thus, the method is widely applied to the fields of medical treatment, cosmetology, bioengineering and the like. In the field of plastic cosmetology, hyaluronic acid is mainly used for filling facial depressions, removing wrinkles, enlarging nose and the like.
Hyaluronic acid has been widely used in medical cosmetology for over 10 years as a dermal filler, and injected under the dermis to increase the volume of subcutaneous tissue directly, so as to play a role of "cushion", and simultaneously absorb the water in the surrounding tissue to expand the volume, so as to re-plump the loose and sunken skin.
However, the hyaluronic acid for external use is maintained in vivo for a short time due to hyaluronidase, free radical degradation, etc. of human body, which limits the application of hyaluronic acid in subcutaneous tissue filling or skin. Therefore, how to improve the degradation period of hyaluronic acid in vivo by modifying the processing technology is a technical problem which needs to be solved urgently.
Patent document CN105131348B discloses a sterile injectable filling material formed by crosslinking hyaluronic acid gel and free hyaluronic acid solution, wherein the crosslinking agent is 1, 4-butanediol glycidyl ether, and although the degradation period can be increased and the stability can be improved, the requirement in industry can not be met.
Patent document CN104870479B discloses a polymer formed by bonding a hyaluronic acid compound and glucomannan via at least one ester linkage derived from a cross-linking agent, the formed spheres and polymer having a higher water trapping capacity, swelling better, faster, and being useful for improving skin or mucosal hydration. However, since glucomannan is expensive, the cost of application increases.
Polyethylene glycol is a non-ionic water-soluble polymer, since polyethylene glycol combines many excellent properties: water-solubility, non-volatility, physiological inertia and mildness, and is widely applied to surface modification of medical polymer materials.
There is no document in the prior art that discloses the application of hyaluronic acid to a subcutaneous filling material by forming a gel by ester-bonding hyaluronic acid to polyethylene glycol.
Disclosure of Invention
The invention provides an injectable filling material containing cross-linked hyaluronic acid gel formed by bonding hyaluronic acid and polyethylene glycol through ester bonds.
The technical problem of the invention is solved by the following technical scheme:
the modified hyaluronic acid injectable filling material is characterized in that: the hyaluronic acid gel comprises free transparent hyaluronic acid gel, cross-linked hyaluronic acid gel, water-soluble vitamins and a buffer solution, wherein the mass ratio of the free transparent hyaluronic acid gel to the cross-linked hyaluronic acid gel is 2:10-40: 1; wherein the molecular weight of the free transparent hyaluronic acid gel is 5K-200KDa, preferably 10K-100KDa, more preferably 50K-80 KDa; wherein the crosslinked hyaluronic acid gel has the following structure I:
wherein n is 10-5000, m is 100-5000; wherein the water-soluble vitamin is selected from one or any combination of vitamin B, vitamin C, vitamin E or their respective derivatives.
In a preferred embodiment of the invention, wherein the buffer solution maintains the pH of the composition between 5 and 8.5, more preferably between 6.8 and 8, most preferably between 7.0 and 8, suitable buffer solutions may be selected from phosphate buffer solutions, e.g. NaH2PO4-NaHPO4Acetate buffer solution, benzoate buffer solution, citrate buffer solution, maleate buffer solution, tartrate buffer solution;
in the preferable technical scheme of the invention, the molecular weight of the free transparent hyaluronic acid gel is 50K-80 KDa;
in the technical scheme of the invention, based on the weight of the free transparent hyaluronic acid gel, the weight percentage of the water-soluble vitamin is 1.0-5%, and preferably 2.5%;
in the technical scheme of the invention, the gel also comprises sorbitol, wherein the mass fraction of the sorbitol can be less than 3%, preferably 1% based on the weight of the free transparent hyaluronic acid gel;
in the technical scheme of the invention, the hyaluronic acid injectable filling material is subjected to sterile treatment before use.
In the technical scheme of the invention, the sterile treatment can be high-temperature sterilization and ultraviolet irradiation sterilization.
In the technical scheme of the invention, the modified hyaluronic acid injectable filling material can be applied to soft tissue filling, repairing and surgical operations, such as wrinkle removal, nose augmentation and breast augmentation, and can also be used for adhesion prevention and lubrication of orthopedic joints for medical surgical operations.
The invention also provides a preparation method of the modified hyaluronic acid injectable filling material, which comprises the following steps:
step (1) preparation of cross-linked hyaluronic acid gel: bonding the hydroxyl on the polyethylene glycol structure with one or more carboxyl on the hyaluronic acid skeleton, wherein the reaction process is as follows:
in a preferred embodiment, the method comprises the following steps of a, mixing a hyaluronic acid solution, a polyethylene glycol solution and a cross-linking agent, and continuously stirring; b. maintaining the pH of the reaction system at 4-6;
c. controlling the reaction temperature to be 60-80 ℃, and fully stirring for 12 h; d. dialyzing the reaction product, and drying to obtain hyaluronic acid-polyethylene glycol grafted cross-linked polymer;
in the preferable technical scheme of the step (1), the weight percentage of the hyaluronic acid and the polyethylene glycol is 10:1-1: 40; preferably 5: 1;
in the preferable technical scheme of step (1), the solvent of the hyaluronic acid solution and the polyethylene glycol solution is water, and the pH value of step b is preferably 5;
in a preferred embodiment of step (1), wherein said crosslinking agent is selected from EDC or HOBt, or a combination thereof;
step (2): weighing free transparent hyaluronic acid gel aqueous solution according to the proportion, adding the aqueous solution into the crosslinked hyaluronic acid gel prepared in the step (1), and fully mixing and stirring at room temperature;
and (3): weighing water-soluble vitamins and sorbitol according to a proportion, dissolving in water, fully stirring, and adding into the mixed solution of the free transparent hyaluronic acid gel and the cross-linked hyaluronic acid gel obtained in the step (2); adding buffer solution to maintain the pH of the system at 6-6.8;
and (4): dialyzing the mixture, and drying to obtain the modified hyaluronic acid injectable filling material.
The modified hyaluronic acid injectable filling material provided by the invention has the following advantages:
1. the injectability is good: the modified hyaluronic acid injectable filling material has good fluidity;
2. good biocompatibility: the modified hyaluronic acid injectable filling material provided by the invention has good biocompatibility, and does not cause inflammatory reaction or immune reaction of a subject after being implanted into a body;
3. the stability is good: the hyaluronic acid and the polyethylene glycol are bonded through covalent bonds to form the stable cross-linked hyaluronic acid material, so that the hyaluronic acid material is stable in metabolism in vivo and is not easy to degrade.
Detailed Description
Example 1
Step (1) preparation of cross-linked hyaluronic acid gel:
a. weighing hyaluronic acid/polyethylene glycol/HOBc/EDC (hyaluronic acid/polyethylene glycol/HOBt/EDC is 1g/0.5g/0.1/0.1, w/w) according to a certain proportion, respectively dissolving in 50mL deionized water, and fully stirring to mix uniformly;
b. adding NaH into the reaction system2PO4-NaHPO4Controlling the pH value of the reaction system to be 5;
c. controlling the reaction temperature to be 60-80 ℃, and fully stirring for 12 h;
d. and dialyzing the reaction product to obtain the cross-linked hyaluronic acid gel.
Step (2): weighing free transparent hyaluronic acid gel water solution (molecular weight is 50KDa) (free transparent hyaluronic acid gel: cross-linked hyaluronic acid gel is 0.8g/1g, w/w), adding into the prepared cross-linked hyaluronic acid gel in the step (1), and fully mixing and stirring at room temperature;
and (3): weighing water-soluble vitamin E (the water-soluble vitamin E: free transparent hyaluronic acid gel is 0.02g:1g, w/w) and sorbitol (the sorbitol: free transparent hyaluronic acid gel is 0.02g:1g, w/w) according to the proportion, dissolving in water, fully stirring, and adding into the mixed solution of the free transparent hyaluronic acid gel and the cross-linked hyaluronic acid gel obtained in the step (2); adding a buffer solution, and keeping the pH value of the system at 6.8;
and (4): dialyzing the mixture, and drying to obtain the modified hyaluronic acid injectable filling material.
Example 2
Step (1) preparation of cross-linked hyaluronic acid gel:
a. weighing hyaluronic acid/polyethylene glycol/HOBc/EDC (hyaluronic acid/polyethylene glycol/HOBt/EDC is 1g/1g/0.1/0.1, w/w) according to a certain proportion, respectively dissolving in 50mL deionized water, and fully stirring to mix uniformly;
b. adding NaH into the reaction system2PO4-NaHPO4Controlling the pH value of the reaction system to be 5;
c. controlling the reaction temperature to be 60-80 ℃, and fully stirring for 12 h;
d. and dialyzing the reaction product to obtain the cross-linked hyaluronic acid gel.
Step (2): weighing free transparent hyaluronic acid gel water solution (molecular weight is 50KDa) (free transparent hyaluronic acid gel: cross-linked hyaluronic acid gel is 0.5g/1g, w/w), adding into the prepared cross-linked hyaluronic acid gel in the step (1), and fully mixing and stirring at room temperature;
and (3): weighing water-soluble vitamin E (the water-soluble vitamin E: free transparent hyaluronic acid gel is 0.02g:1g, w/w) and sorbitol (the sorbitol: free transparent hyaluronic acid gel is 0.02g:1g, w/w) according to the proportion, dissolving in water, fully stirring, and adding into the mixed solution of the free transparent hyaluronic acid gel and the cross-linked hyaluronic acid gel obtained in the step (2); adding a buffer solution, and keeping the pH value of the system at 6.8;
and (4): dialyzing the mixture, and drying to obtain the modified hyaluronic acid injectable filling material.
Example 3
Step (1) preparation of cross-linked hyaluronic acid gel:
a. weighing hyaluronic acid/polyethylene glycol/HOBc/EDC (0.5 g/1/0.1/0.1, w/w of hyaluronic acid/polyethylene glycol/HOBt/EDC) according to a certain proportion, respectively dissolving in 50mL of deionized water, and fully stirring to uniformly mix; b. adding NaH into the reaction system2PO4-NaHPO4Controlling the pH value of the reaction system to be 5;
c. controlling the reaction temperature to be 60-80 ℃, and fully stirring for 12 h;
d. and dialyzing the reaction product to obtain the cross-linked hyaluronic acid gel.
Step (2): weighing free transparent hyaluronic acid gel water solution (molecular weight is 50KDa) (free transparent hyaluronic acid gel: cross-linked hyaluronic acid gel is 0.5g/1g, w/w), adding into the prepared cross-linked hyaluronic acid gel in the step (1), and fully mixing and stirring at room temperature;
and (3): weighing water-soluble vitamin E (the water-soluble vitamin E: free transparent hyaluronic acid gel is 0.02g:1g, w/w) and sorbitol (the sorbitol: free transparent hyaluronic acid gel is 0.02g:1g, w/w) according to the proportion, dissolving in water, fully stirring, and adding into the mixed solution of the free transparent hyaluronic acid gel and the cross-linked hyaluronic acid gel obtained in the step (2); adding a buffer solution, and keeping the pH value of the system at 6.8;
and (4): dialyzing the mixture, and drying to obtain the modified hyaluronic acid injectable filling material.
Comparative example 1
Step (1): weighing free transparent hyaluronic acid gel aqueous solution (molecular weight is 50KDa), water soluble vitamin E (water soluble vitamin E: free transparent hyaluronic acid gel is 0.02g:1g, w/w) and sorbitol (sorbitol: free transparent hyaluronic acid gel is 0.02g:1g, w/w), dissolving in water, and stirring thoroughly;
adding a buffer solution, and keeping the pH value of the system at 6.8;
and (3): dialyzing the mixture, and drying to obtain the modified hyaluronic acid injectable filling material.
Example 4: infrared spectroscopic analysis
The hyaluronic acid-polyethylene glycol modified materials obtained in examples 1 to 3 were subjected to infrared spectroscopic characterization. Wherein, polyethylene glycol and hyaluronic acid-polyethylene glycol have strong vibration absorption peaks of ester ether bonds at wave numbers of 1092, 1136 and 1186cm < -1 >, meanwhile, polyethylene glycol has free-OH vibration absorption near 3500cm < -1 >, but after reacting with hyaluronic acid, the vibration absorption peaks disappear, which indicates that the hydroxyl of polyethylene glycol also participates in chemical reaction in the modification process.
Example 5 analysis of rheological Properties
The rheological properties of the hyaluronic acid-polyethylene glycol modified materials obtained in examples 1-3 were analyzed by a rheometer, and the specific test method was performed by using a 30mm flat disc and a temperature gradient mode, wherein the temperature range was 10-50 ℃ and the temperature rise rate was 2 ℃/min.
The result of the rheological analysis can show that the obtained material has good temperature sensitivity for the hyaluronic acid-polyethylene glycol modified material. For example, the modified material of example 1 had a storage modulus (G') of 452Pa and a loss modulus (G ") of 218Pa at 25 ℃; the modified material of example 2 had a storage modulus (G ') of 446Pa and a loss modulus (G') of 202Pa at 25 ℃; the modified material of example 3 had a storage modulus (G ') of 468Pa and a loss modulus (G') of 176Pa at 25 ℃.
Example 6 injectable Performance analysis
The method comprises the following steps: 10-20% by weight of the aqueous solution of the material prepared in examples 1-3 was prepared, stirred sufficiently to dissolve it completely, and the sample was transferred to a syringe and tested using a 27 gauge needle. From the test results, it can be seen that the modified hyaluronic acid filling materials of examples 1-3 can easily pass through a 27-gauge needle at room temperature, thereby indicating that the material has better injectability.
Example 7 in vitro degradation Properties
This example compares the in vitro degradation performance of the hyaluronic acid-polyethylene glycol modified materials obtained in examples 1-3 (test groups 1-3) with unmodified hyaluronic acid (control group 1) and reland 2(Restylance) (control group 2), and the specific test method is as follows:
and (3) putting 1g of sample into a 1mL centrifuge tube, centrifugally leveling the liquid level in the tube, and then adding 50 mu L of hyaluronidase solution into each test tube to enable the action concentration of the hyaluronidase to reach 100 IU/mL. After the reaction, each tube was inverted, and the liquid sample was absorbed by a paper, and the weight of the sample remaining at the bottom of the tube was measured. The results of the sample weights and the theoretical residual sample percentages (%) for each test group are shown in table 1:
| group of | Hyaluronic acid concentration (mg/mL) | Percentage of |
| Example 1 | 34.2 | 84.2±0.2％ |
| Example 2 | 32.6 | 82.4±0.2％ |
| Example 3 | 31.4 | 80.6±0.2％ |
| Control group 1 | 24.2 | 64.1±0.2％ |
| Control group 2 | 18.6 | 50.4±0.2％ |
As can be seen from the results of table 1, the modified hyaluronic acid injectable filler material of the present invention has a significantly improved degradation cycle compared to unmodified hyaluronic acid or ruian No. 2.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention as defined in the appended claims. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (4)
1. The preparation method of the modified hyaluronic acid injectable filling material is characterized by comprising the following steps: step (1) preparation of cross-linked hyaluronic acid gel: bonding the hydroxyl on the polyethylene glycol structure with one or more carboxyl on the hyaluronic acid skeleton, wherein the reaction process is as follows:
the method comprises the following steps: a. mixing hyaluronic acid solution, polyethylene glycol solution and cross-linking agent, and stirring continuously; b. maintaining the pH of the reaction system at 4-6; c. controlling the reaction temperature to be 60-80 ℃, and fully stirring for 12 h; d. dialyzing the reaction product, and drying to obtain a hyaluronic acid-polyethylene glycol grafted cross-linked polymer, wherein in the step (a), the weight percentage of hyaluronic acid to polyethylene glycol is 10:1-1: 40; wherein, in the step (1), the solvent of the hyaluronic acid solution and the polyethylene glycol solution is water, and the pH value in the step (b) is 5; wherein the crosslinking agent is selected from EDC or HOBt, or a combination thereof;
step (2): weighing free transparent hyaluronic acid gel aqueous solution according to the proportion, adding the aqueous solution into the crosslinked hyaluronic acid gel prepared in the step (1), and fully mixing and stirring at room temperature; wherein the mass ratio of the free transparent hyaluronic acid gel to the cross-linked hyaluronic acid gel is 2:10-40: 1; wherein the molecular weight of the free transparent hyaluronic acid gel is 5K-200 KDa;
and (3): weighing water-soluble vitamins and sorbitol according to a proportion, dissolving in water, fully stirring, and adding into the mixed solution of the free transparent hyaluronic acid gel and the cross-linked hyaluronic acid gel obtained in the step (2); adding buffer solution to maintain the pH of the system at 6-6.8; the weight percentage of the water-soluble vitamins in the free transparent hyaluronic acid gel is 1.0-5%; the sorbitol accounts for less than 3% of the free transparent hyaluronic acid gel by weight;
and (4): dialyzing the mixture, and drying to obtain the hyaluronic acid injectable filling material.
2. The method of claim 1, wherein the weight ratio of hyaluronic acid to polyethylene glycol is 5: 1.
3. The method of claim 1, wherein said water soluble vitamin is present in an amount of 2.5% by weight of said free transparent hyaluronic acid gel.
4. The method of claim 1, wherein said sorbitol comprises 1% by weight of said free transparent hyaluronic acid gel.
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| CN103360633A (en) * | 2012-03-26 | 2013-10-23 | 株式会社杰内沃 | Implantation material comprising biocompatible polymer |
| CN103834053A (en) * | 2014-02-28 | 2014-06-04 | 陕西佰傲再生医学有限公司 | Injectable crosslinked hyaluronic acid gel and preparation method thereof |
| CN105107018A (en) * | 2015-08-19 | 2015-12-02 | 李媚 | Method for preparing sterile injectable materials |
| CN105131348A (en) * | 2015-08-19 | 2015-12-09 | 李媚 | Aseptic injectable material |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103360633A (en) * | 2012-03-26 | 2013-10-23 | 株式会社杰内沃 | Implantation material comprising biocompatible polymer |
| CN103834053A (en) * | 2014-02-28 | 2014-06-04 | 陕西佰傲再生医学有限公司 | Injectable crosslinked hyaluronic acid gel and preparation method thereof |
| CN105107018A (en) * | 2015-08-19 | 2015-12-02 | 李媚 | Method for preparing sterile injectable materials |
| CN105131348A (en) * | 2015-08-19 | 2015-12-09 | 李媚 | Aseptic injectable material |
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