CN106496599A - High viscosity hyaluronic acid sodium gel and preparation method thereof - Google Patents
High viscosity hyaluronic acid sodium gel and preparation method thereof Download PDFInfo
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- CN106496599A CN106496599A CN201610884169.7A CN201610884169A CN106496599A CN 106496599 A CN106496599 A CN 106496599A CN 201610884169 A CN201610884169 A CN 201610884169A CN 106496599 A CN106496599 A CN 106496599A
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- hyaluronic acid
- gel
- high viscosity
- acid sodium
- sodium
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(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- Chemical compound [Na+].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 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 title claims abstract description 95
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- 238000001879 gelation Methods 0.000 title abstract description 4
- 229920002385 Sodium hyaluronate Polymers 0.000 claims abstract description 31
- 229940010747 sodium hyaluronate Drugs 0.000 claims abstract description 31
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 26
- 235000011187 glycerol Nutrition 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000008215 water for injection Substances 0.000 claims abstract description 11
- 239000003945 anionic surfactant Substances 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 238000000518 rheometry Methods 0.000 claims abstract description 9
- 230000001954 sterilising effect Effects 0.000 claims description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 14
- 230000003204 osmotic effect Effects 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- 230000003749 cleanliness Effects 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 7
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 6
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 6
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 238000004659 sterilization and disinfection Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical group OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- -1 alkyl sodium phosphate Chemical compound 0.000 claims description 2
- 230000003139 buffering effect Effects 0.000 claims description 2
- 229960001631 carbomer Drugs 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 4
- 239000012752 auxiliary agent Substances 0.000 abstract description 3
- 206010060932 Postoperative adhesion Diseases 0.000 abstract description 2
- 238000011049 filling Methods 0.000 description 20
- 229920002674 hyaluronan Polymers 0.000 description 19
- 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 compound 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 description 16
- 229960003160 hyaluronic acid Drugs 0.000 description 16
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 9
- 239000001103 potassium chloride Substances 0.000 description 8
- 235000011164 potassium chloride Nutrition 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- QZRMKGRPCTVXBS-UHFFFAOYSA-N 2,6,8-trimethylnonan-4-yl dihydrogen phosphate Chemical compound CC(C)CC(C)CC(CC(C)C)OP(O)(O)=O QZRMKGRPCTVXBS-UHFFFAOYSA-N 0.000 description 6
- 239000012467 final product Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 159000000000 sodium salts Chemical class 0.000 description 4
- 206010003246 arthritis Diseases 0.000 description 3
- 210000000845 cartilage Anatomy 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- KIUKXJAPPMFGSW-MNSSHETKSA-N hyaluronan Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(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-MNSSHETKSA-N 0.000 description 3
- 229940099552 hyaluronan Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000003252 repetitive effect Effects 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000000084 colloidal system Substances 0.000 description 2
- 150000002016 disaccharides Chemical class 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 210000000629 knee joint Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 238000010008 shearing Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 241000561734 Celosia cristata Species 0.000 description 1
- 208000022845 Cyclodialysis Clefts Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- 206010061876 Obstruction Diseases 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 238000004026 adhesive bonding Methods 0.000 description 1
- 230000001384 anti-glaucoma Effects 0.000 description 1
- 210000003567 ascitic fluid Anatomy 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 201000007391 chondromalacia patellae Diseases 0.000 description 1
- 210000001520 comb Anatomy 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 238000002316 cosmetic surgery Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- SEGLCEQVOFDUPX-UHFFFAOYSA-N di-(2-ethylhexyl)phosphoric acid Chemical compound CCCCC(CC)COP(O)(=O)OCC(CC)CCCC SEGLCEQVOFDUPX-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000005002 female reproductive tract Anatomy 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 201000006651 patellofemoral pain syndrome Diseases 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 210000000323 shoulder joint Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 238000012859 sterile filling Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 210000003954 umbilical cord Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- 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
- C08J3/075—Macromolecular gels
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
Landscapes
- Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses high viscosity hyaluronic acid sodium gel and preparation method thereof.Specifically, high viscosity hyaluronic acid sodium gel of the invention includes the following component in terms of mass concentration：The Sodium Hyaluronate of 20～40g/L, the anionic surfactant of 0.01～0.05g/L, the rheology control agent of 0.3～1.0g/L, the glycerine of 0.5～1.5g/L, balance of water for injection, wherein：The molecular weight of the Sodium Hyaluronate is 200～4,000,000 dalton.The gel is mainly prepared from by the Sodium Hyaluronate of high concentration, HMW, by adding multiple auxiliary agents such as anionic surfactant, rheology control agent, glycerine, so that the gel has higher viscoplasticity and more preferable rheological properties, can effectively prevent or reduce postoperative adhesions problem, there is good application prospect in field of medicaments.
Description
Technical field
The invention belongs to pharmaceutical technology field, is related to a kind of high viscosity hyaluronic acid sodium gel and preparation method thereof.
Background technology
1934, Karl professors Mayer extracted hyaluronic acid first in bovine vitreous body.Grinding through many decades
Study carefully, it has been found which is widely present in people and other vertebrate connective tissues, such as space between cells, movable joint group
Knit, all contain hyaluronic acid in the tissue such as umbilical cord, skin, cartilage, vascular wall, synovia and cockscomb and organ.
Hyaluronic acid belongs to linear polymeric polysaccharide, contains disaccharides repetitive, the glucose in repetitive in structure
Aldehydic acid is connected with N-Acetyl-D-glucosamine by β -1,3 glycosidic bonds, and thousands of disaccharides repetitive passes through β-Isosorbide-5-Nitrae glycosidic bond
It is connected, forms whole macromolecule linear chain structure, its structure is as follows.
In physiological conditions, the carboxyl in hyaluronan molecule is combined rear as hyalomitome in free state with sodium ion
Sour sodium.Sodium Hyaluronate intramolecular do not contain sulfate group, also not with protein covalent bond, can be in the form of free chain in body
Interior free presence, and which is random coil state in the solution, and with good hydrodynamic characteristics, it is heavy that this gives which
The physical characteristic that wants, i.e. height viscoplasticity, plasticity, permeability and good biocompatibility so as in medicine
Unique effect is played.
Hyaluronic acid sodium gel is widely used in fields such as orthopaedics, ophthalmology, gynaecology and department of plastic surgery.Except as eye-drops preparations
Carrier and as eye-drops preparations beyond, Sodium Hyaluronate also has important application in ophthalmologic operation.With deepening continuously for research,
Sodium Hyaluronate application clinically expanded to cataract extraction, detachment of retina, corneal transplantation, ophthalmic crystal be implanted into,
Anti-glaucoma, cornea preset, cyclodialysis cleft and eye traumas etc. more than 20 plant operation.Sodium Hyaluronate or knuckle synovia and cartilage
Important composition composition, by improve joint in Sodium Hyaluronate content, can increase joint fluid toughness and lubrication work(
Can, protection cartilage is played, promoted joint healing and regeneration, pain of alleviation, increased the effect such as range of motion.Report both at home and abroad
Knee joint osseous arthritis, the periarthritis of shoulderjoint, Kaschin-Beck disease, rheumatoid is treated using Sodium Hyaluronate replacement therapy in road
Arthritis, Chondromalacia of patella, especially treat knee joint osseous arthritis in intraarticular injection Sodium Hyaluronate and have taken
Obtain significant curative effect.Hyaluronic acid and its sodium salt content in peritoneal fluid, uterine fluid and Oviductal Fluid is decide to a great extent
Abdominal cavity, uterus and oviducal physiological function, the viscoelasticity of liquid affect the physiological function of female genital tract and preventing for itself
Imperial ability, and the quality of these liquid and how many molecular weight and concentration for depending on wherein hyaluronic acid and its sodium salt.Therefore,
When using laparoscope, hysteroscope, the postoperative obstruction that may occur and adhesion can be reduced using hyaluronic acid and its sodium salt
Complication, and the reparation on acceleration of wound surface.Substantial amounts of zoopery and clinical practice show, are preventing and reducing gynemetrics's hand
In terms of the adhesion that art is caused, hyaluronic acid and its sodium salt are a kind of safe and effective desirable materials.
Research shows, when hyaluronan molecule is sufficiently large, it becomes possible to form network structure, which forms cancellated energy
Power is affected by molecular weight.The hyaluronic acid of low-molecular-weight is only capable of the network structure to form fragment shape in low concentration, and high
The hyaluronic acid of molecular weight can form the network structure for covering whole system.When being mixed in the hyaluronic acid solution of HMW
During the hyaluronic acid of low-molecular-weight, can greatly change the rheological property of hyaluronic acid solution.Hyaluronic acid is molten in low concentration
In liquid, its molecule can arbitrarily be crimped and form viscoplasticity transparent colloid, and then there is in highly concentrated solution stronger film forming
Property.Therefore, in the urgent need to a kind of high concentration of offer, the hyaluronic acid sodium gel of HMW, the gel should have higher gluing
Elastic and more preferable rheological properties, and then preferably application is played in field of medicaments.
Content of the invention
For above-mentioned situation, it is an object of the invention to provide a kind of high viscosity hyaluronic acid sodium gel and its preparation side
Method.Sodium Hyaluronate containing high concentration, HMW in the hyaluronic acid sodium gel of the present invention, and made by adding auxiliary agent
Obtain gel of the invention and there are higher viscoplasticity and more preferable rheological properties.
To achieve these goals, the present invention adopts following technical proposal：
A kind of high viscosity hyaluronic acid sodium gel, which includes the following component in terms of mass concentration：20～40g/L's is transparent
Matter acid sodium, the anionic surfactant of 0.01～0.05g/L, the rheology control agent of 0.3～1.0g/L, 0.5～1.5g/L
Glycerine, balance of water for injection, wherein：The molecular weight of the Sodium Hyaluronate is 200～4,000,000 dalton.In shearing speed
Rate is 0.01Hz, under conditions of temperature is 25 DEG C, the shear viscosity of above-mentioned high viscosity hyaluronic acid sodium gel can reach 2 ×
106More than mPa s.
Preferably, in above-mentioned high viscosity hyaluronic acid sodium gel, the Sodium Hyaluronate extract from animal tissue or
Person is produced by bacterial fermentation process.
Preferably, in above-mentioned high viscosity hyaluronic acid sodium gel, the anionic surfactant is alkyl phosphoric acid
Ester sylvite or alkyl sodium phosphate.
Preferably, in above-mentioned high viscosity hyaluronic acid sodium gel, the rheology control agent is Carbomer.
In a preferred embodiment, above-mentioned high viscosity hyaluronic acid sodium gel also includes osmotic pressure regulator (such as
Sodium chloride, potassium chloride, glucose, sodium citrate etc.), which adjusts the osmotic pressure of the gel to 250～350mOsmol L-1.
Preferably, in above-mentioned high viscosity hyaluronic acid sodium gel, the osmotic pressure regulator is sodium chloride.
In a preferred embodiment, above-mentioned high viscosity hyaluronic acid sodium gel also includes pH value regulator (such as hydrogen
Sodium oxide molybdena, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium carbonate, sodium acid carbonate, hydrochloric acid etc.), its by the pH value of the gel adjust to
6.8～7.8.
Preferably, in above-mentioned high viscosity hyaluronic acid sodium gel, the pH value regulator is disodium hydrogen phosphate/di(2-ethylhexyl)phosphate
Hydrogen sodium buffering is right.
A kind of preparation method of above-mentioned high viscosity hyaluronic acid sodium gel, which comprises the steps：
1) according to formula in consumption weigh various components；
2) anionic surfactant, rheology control agent, glycerine are added in water for injection, are carried out after being completely dissolved
Aseptic filtration and high pressure steam sterilization, obtain gel carrier；
3) by step 2) in obtain gel carrier cooling, under clean environment, add in the gel carrier transparent
Matter acid sodium is simultaneously stirred, until Sodium Hyaluronate is completely dissolved, obtains high viscosity hyaluronic acid sodium gel.
Preferably, in above-mentioned preparation method, step 2) described in aseptic filtration using sterilized 0.22 μm of filter core come
Complete.
Preferably, in above-mentioned preparation method, step 2) described in the temperature of high pressure steam sterilization be 121 DEG C, the time is
30 minutes.
Preferably, in above-mentioned preparation method, step 3) described in cool down after temperature be 40～60 DEG C.
Preferably, in above-mentioned preparation method, step 3) described in clean environment cleanliness factor more than hundred grades.
Preferably, in above-mentioned preparation method, step 3) described in stir and completed using agitator tank, mixing speed exists
Below 200rpm.
In a preferred embodiment, above-mentioned preparation method also include by the high viscosity hyaluronic acid sodium gel without
Bacterium filling into preparation the step of.
Preferably, in above-mentioned preparation method, before the sterile filling, first the high viscosity Sodium Hyaluronate is coagulated
Glue is heated to 60～80 DEG C, its object is to the viscosity for reducing immediately product, so that follow-up filling operation can be smoothed out.
Compared with prior art, there are following advantages using the present invention of above-mentioned technical proposal：
The hyaluronic acid of low-molecular-weight is only capable of the network structure to form fragment shape in low concentration, and HMW is transparent
Matter acid molecule can form the network structure for covering whole system.In low concentration solution, hyaluronan molecule arbitrarily can be rolled up
Bent and form viscoelastic transparent colloid, and then there is in highly concentrated solution stronger film forming.Transparent when HMW
Be mixed in matter acid solution low-molecular-weight hyaluronic acid when, can greatly change hyaluronic acid solution rheological property.Therefore,
High viscosity hyaluronic acid sodium gel provided by the present invention is mainly prepared from by the Sodium Hyaluronate of high concentration, HMW,
By adding multiple auxiliary agents such as anionic surfactant, rheology control agent, glycerine so that the gel has higher viscoelastic
Property and more preferable rheological properties, can effectively prevent or reduce postoperative adhesions problem, there is well application in field of medicaments
Prospect.In addition, gel process for preparing provided by the present invention has the advantages that simple and convenient, equipment requirement is low, raw material are easy to get,
Solve high concentration, high molecular weight sodium hyaluronate and finely dispersed problem is difficult in course of dissolution, be suitable for extensive work
Industry metaplasia is produced.
Specific embodiment
Below in conjunction with specific embodiments to the present invention in technical scheme make further description, but following enforcement
Example should not be considered as limiting protection scope of the present invention.In addition to specified otherwise, instrument used in the following example,
Reagent, material etc. can pass through conventional commercial means and obtain.
Embodiment 1：The preparation of high viscosity hyaluronic acid sodium gel preparation.
(1) water for injection 1000mL is added in container, be subsequently adding 1-isobutyl-3,5-dimethylhexylphosphoric acid sylvite 0.01g, card
Ripple nurse 0.3g, glycerine 0.5g, disodium hydrogen phosphate 0.45g, sodium dihydrogen phosphate 0.20g and sodium chloride 7.0g, with after being completely dissolved
0.22 μm of filter core of sterilizing carries out aseptic filtration, is placed in high-pressure steam sterilizing pan sterilizing 30 minutes in 121 DEG C, obtains gel
Carrier；
(2) above-mentioned gel carrier is cooled to 40 DEG C, under hundred grades of cleanliness factor environment, gel carrier is added to stirring first
In tank, under 40 DEG C of heat-retaining conditions, then degerming for Sodium Hyaluronate that molecular weight is 3,560,000 dalton dry powder 20.0g is slowly added
Enter in agitator tank, mixing speed is slowly improved to 200rpm, until Sodium Hyaluronate is completely dissolved, obtain high viscosity hyaluronic acid
Sodium gel；
(3) aseptically above-mentioned gel is carried out filling, filling front hyaluronic acid sodium gel is heated to 60 DEG C first,
After the completion of filling, high viscosity hyaluronic acid sodium gel preparation is obtained final product.
The pH of the high viscosity hyaluronic acid sodium gel prepared by said method is 7.2, and osmotic pressure is 289mOsmol L-1.It is 0.01Hz in shear rate, under conditions of temperature is 25 DEG C, the shear viscosity of the gel is 2.578 × 106mPa·s.
Embodiment 2：The preparation of high viscosity hyaluronic acid sodium gel preparation.
(1) water for injection 1000mL is added in container, be subsequently adding 1-isobutyl-3,5-dimethylhexylphosphoric acid sylvite 0.03g, card
Ripple nurse 0.6g, glycerine 1.0g, disodium hydrogen phosphate 0.45g, sodium dihydrogen phosphate 0.20g and sodium chloride 7.0g, with after being completely dissolved
0.22 μm of filter core of sterilizing carries out aseptic filtration, is placed in high-pressure steam sterilizing pan sterilizing 30 minutes in 121 DEG C, obtains gel
Carrier；
(2) above-mentioned gel carrier is cooled to 50 DEG C, under hundred grades of cleanliness factor environment, gel carrier is added to stirring first
In tank, under 50 DEG C of heat-retaining conditions, then degerming for Sodium Hyaluronate that molecular weight is 2,880,000 dalton dry powder 30.0g is slowly added
Enter in agitator tank, mixing speed is slowly improved to 200rpm, until Sodium Hyaluronate is completely dissolved, obtain high viscosity hyaluronic acid
Sodium gel；
(3) aseptically above-mentioned gel is carried out filling, filling front hyaluronic acid sodium gel is heated to 70 DEG C first,
After the completion of filling, high viscosity hyaluronic acid sodium gel preparation is obtained final product.
The pH of the high viscosity hyaluronic acid sodium gel prepared by said method is 7.3, and osmotic pressure is 305mOsmol L-1.It is 0.01Hz in shear rate, under conditions of temperature is 25 DEG C, the shear viscosity of the gel is 4.103 × 106mPa·s.
Embodiment 3：The preparation of high viscosity hyaluronic acid sodium gel preparation.
(1) water for injection 1000mL is added in container, be subsequently adding 1-isobutyl-3,5-dimethylhexylphosphoric acid sylvite 0.05g, card
Ripple nurse 1.0g, glycerine 1.5g, disodium hydrogen phosphate 0.45g, sodium dihydrogen phosphate 0.20g and sodium chloride 7.0g, with after being completely dissolved
0.22 μm of filter core of sterilizing carries out aseptic filtration, is placed in high-pressure steam sterilizing pan sterilizing 30 minutes in 121 DEG C, obtains gel
Carrier；
(2) above-mentioned gel carrier is cooled to 60 DEG C, under hundred grades of cleanliness factor environment, gel carrier is added to stirring first
In tank, under 60 DEG C of heat-retaining conditions, then degerming for Sodium Hyaluronate that molecular weight is 2,120,000 dalton dry powder 38.0g is slowly added
Enter in agitator tank, mixing speed is slowly improved to 200rpm, until Sodium Hyaluronate is completely dissolved, obtain high viscosity hyaluronic acid
Sodium gel；
(3) aseptically above-mentioned gel is carried out filling, filling front hyaluronic acid sodium gel is heated to 80 DEG C first,
After the completion of filling, high viscosity hyaluronic acid sodium gel preparation is obtained final product.
The pH of the high viscosity hyaluronic acid sodium gel prepared by said method is 7.3, and osmotic pressure is 323mOsmol L-1.It is 0.01Hz in shear rate, under conditions of temperature is 25 DEG C, the shear viscosity of the gel is 5.578 × 106mPa·s.
Embodiment 4：The preparation of high viscosity hyaluronic acid sodium gel preparation.
(1) water for injection 1000mL is added in container, be subsequently adding 1-isobutyl-3,5-dimethylhexylphosphoric acid sylvite 0.03g, card
Ripple nurse 0.6g and glycerine 1.0g, carries out aseptic filtration with sterilized 0.22 μm of filter core after being completely dissolved, is placed in high steam
Sterilize 30 minutes in 121 DEG C in autoclave, obtain gel carrier；
(2) above-mentioned gel carrier is cooled to 50 DEG C, under hundred grades of cleanliness factor environment, gel carrier is added to stirring first
In tank, under 50 DEG C of heat-retaining conditions, then degerming for Sodium Hyaluronate that molecular weight is 3,560,000 dalton dry powder 30.0g is slowly added
Enter in agitator tank, mixing speed is slowly improved to 200rpm, until Sodium Hyaluronate is completely dissolved, obtain high viscosity hyaluronic acid
Sodium gel；
(3) aseptically above-mentioned gel is carried out filling, filling front hyaluronic acid sodium gel is heated to 70 DEG C first,
After the completion of filling, high viscosity hyaluronic acid sodium gel preparation is obtained final product.
The high viscosity hyaluronic acid sodium gel prepared by said method is 0.01Hz in shear rate, and temperature is 25 DEG C
Under the conditions of shear viscosity be 3.875 × 106mPa·s.
Embodiment 5：The preparation of high viscosity hyaluronic acid sodium gel preparation.
(1) water for injection 1000mL is added in container, be subsequently adding 1-isobutyl-3,5-dimethylhexylphosphoric acid sylvite 0.03g, card
Ripple nurse 0.6g, glycerine 1.0g, disodium hydrogen phosphate 0.45g and sodium dihydrogen phosphate 0.20g, with sterilized 0.22 μm after being completely dissolved
Filter core carries out aseptic filtration, is placed in high-pressure steam sterilizing pan sterilizing 30 minutes in 121 DEG C, obtains gel carrier；
(2) above-mentioned gel carrier is cooled to 50 DEG C, under hundred grades of cleanliness factor environment, gel carrier is added to stirring first
In tank, under 50 DEG C of heat-retaining conditions, then degerming for Sodium Hyaluronate that molecular weight is 3,560,000 dalton dry powder 30.0g is slowly added
Enter in agitator tank, mixing speed is slowly improved to 200rpm, until Sodium Hyaluronate is completely dissolved, obtain high viscosity hyaluronic acid
Sodium gel；
(3) aseptically above-mentioned gel is carried out filling, filling front hyaluronic acid sodium gel is heated to 70 DEG C first,
After the completion of filling, high viscosity hyaluronic acid sodium gel preparation is obtained final product.
The pH of the high viscosity hyaluronic acid sodium gel prepared by said method is 7.1.It is 0.01Hz in shear rate, warm
Under conditions of spending for 25 DEG C, the shear viscosity of the gel is 3.955 × 106mPa·s.
Embodiment 6：The preparation of high viscosity hyaluronic acid sodium gel preparation.
(1) water for injection 1000mL is added in container, be subsequently adding 1-isobutyl-3,5-dimethylhexylphosphoric acid sylvite 0.03g, card
Ripple nurse 0.6g, glycerine 1.0g and sodium chloride 7.0g, carry out aseptic filtration, juxtaposition with sterilized 0.22 μm of filter core after being completely dissolved
Sterilize 30 minutes in 121 DEG C in high-pressure steam sterilizing pan, obtain gel carrier；
(2) above-mentioned gel carrier is cooled to 50 DEG C, under hundred grades of cleanliness factor environment, gel carrier is added to stirring first
In tank, under 50 DEG C of heat-retaining conditions, then degerming for Sodium Hyaluronate that molecular weight is 3,560,000 dalton dry powder 30.0g is slowly added
Enter in agitator tank, mixing speed is slowly improved to 200rpm, until Sodium Hyaluronate is completely dissolved, obtain high viscosity hyaluronic acid
Sodium gel；
(3) aseptically above-mentioned gel is carried out filling, filling front hyaluronic acid sodium gel is heated to 70 DEG C first,
After the completion of filling, high viscosity hyaluronic acid sodium gel preparation is obtained final product.
The osmotic pressure of the high viscosity hyaluronic acid sodium gel prepared by said method is 311mOsmol L-1.In shearing
Speed is 0.01Hz, and under conditions of temperature is 25 DEG C, the shear viscosity of the gel is 4.126 × 106mPa·s.
Claims (10)
1. a kind of high viscosity hyaluronic acid sodium gel, which includes the following component in terms of mass concentration：The hyalomitome of 20～40g/L
Sour sodium, the anionic surfactant of 0.01～0.05g/L, the rheology control agent of 0.3～1.0g/L, 0.5～1.5g/L
Glycerine, balance of water for injection, wherein：The molecular weight of the Sodium Hyaluronate is 200～4,000,000 dalton.
2. high viscosity hyaluronic acid sodium gel according to claim 1, it is characterised in that：
The anionic surfactant is potassium alkyl phosphate or alkyl sodium phosphate.
3. high viscosity hyaluronic acid sodium gel according to claim 1, it is characterised in that：
The rheology control agent is Carbomer.
4. high viscosity hyaluronic acid sodium gel according to any one of claim 1 to 3, it is characterised in that：
The high viscosity hyaluronic acid sodium gel also includes osmotic pressure regulator, and the osmotic pressure regulator is oozed the gel
Pressure is adjusted to 250～350mOsmol L thoroughly-1.
5. high viscosity hyaluronic acid sodium gel according to claim 4, it is characterised in that：
The osmotic pressure regulator is sodium chloride.
6. high viscosity hyaluronic acid sodium gel according to any one of claim 1 to 3, it is characterised in that：
The high viscosity hyaluronic acid sodium gel also includes pH value regulator, and the pH value of the gel is adjusted by the pH value regulator
Save to 6.8～7.8.
7. high viscosity hyaluronic acid sodium gel according to claim 6, it is characterised in that：
The pH value regulator is that disodium hydrogen phosphate/sodium dihydrogen phosphate buffering is right.
8. a kind of preparation method of high viscosity hyaluronic acid sodium gel according to any one of claim 1 to 3, which includes
Following steps：
1) according to formula in consumption weigh various components；
2) anionic surfactant, rheology control agent, glycerine are added in water for injection, are carried out after being completely dissolved degerming
Filter and high pressure steam sterilization, obtain gel carrier；
3) by step 2) in obtain gel carrier cooling, under clean environment, in the gel carrier add hyaluronic acid
Sodium is simultaneously stirred, until Sodium Hyaluronate is completely dissolved, obtains high viscosity hyaluronic acid sodium gel.
9. preparation method according to claim 8, it is characterised in that：
Step 2) described in aseptic filtration completed using sterilized 0.22 μm of filter core；The temperature of the high pressure steam sterilization is
121 DEG C, the time is 30 minutes.
10. preparation method according to claim 8, it is characterised in that：
Step 3) described in cool down after temperature be 40～60 DEG C；The cleanliness factor of the clean environment is more than hundred grades；Described stir
Mix and completed using agitator tank, mixing speed is in below 200rpm.
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| CN116077671A (en) * | 2022-12-30 | 2023-05-09 | 稳得希林(沈阳)生物科技有限公司 | Preparation of hyaluronic acid matrix capable of being sterilized by irradiation |
| WO2023141614A1 (en) * | 2022-01-24 | 2023-07-27 | The Procter & Gamble Company | Skin care composition containing sodium hyaluronate and method of making the same |
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| CN108261562A (en) * | 2017-08-11 | 2018-07-10 | 上海建华精细生物制品有限公司 | A kind of Sodium Hyaluronate skin sparing film and its preparation method and application |
| WO2023141614A1 (en) * | 2022-01-24 | 2023-07-27 | The Procter & Gamble Company | Skin care composition containing sodium hyaluronate and method of making the same |
| CN116077671A (en) * | 2022-12-30 | 2023-05-09 | 稳得希林(沈阳)生物科技有限公司 | Preparation of hyaluronic acid matrix capable of being sterilized by irradiation |
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