CN115124631A - Preparation method of silanized hyaluronic acid compound - Google Patents
Preparation method of silanized hyaluronic acid compound Download PDFInfo
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- CN115124631A CN115124631A CN202210568017.1A CN202210568017A CN115124631A CN 115124631 A CN115124631 A CN 115124631A CN 202210568017 A CN202210568017 A CN 202210568017A CN 115124631 A CN115124631 A CN 115124631A
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- -1 hyaluronic acid compound Chemical class 0.000 title claims abstract description 39
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 33
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000000243 solution Substances 0.000 claims abstract description 55
- 239000003054 catalyst Substances 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 40
- 239000002608 ionic liquid Substances 0.000 claims abstract description 27
- 239000002841 Lewis acid Substances 0.000 claims abstract description 25
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 25
- 229920003217 poly(methylsilsesquioxane) Polymers 0.000 claims abstract description 25
- 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 claims abstract description 24
- 238000003756 stirring Methods 0.000 claims abstract description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000001035 drying Methods 0.000 claims abstract description 19
- 238000010438 heat treatment Methods 0.000 claims abstract description 18
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 13
- 238000002156 mixing Methods 0.000 claims abstract description 13
- 239000012266 salt solution Substances 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 50
- 238000000746 purification Methods 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 230000008569 process Effects 0.000 claims description 13
- 229910004298 SiO 2 Inorganic materials 0.000 claims description 12
- 239000012528 membrane Substances 0.000 claims description 12
- 238000000926 separation method Methods 0.000 claims description 12
- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 claims description 10
- 229940014041 hyaluronate Drugs 0.000 claims description 10
- 238000005374 membrane filtration Methods 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 239000002131 composite material Substances 0.000 claims description 9
- 239000008367 deionised water Substances 0.000 claims description 9
- 229910021641 deionized water Inorganic materials 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 239000000919 ceramic Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 230000009967 tasteless effect Effects 0.000 claims description 3
- 229910001507 metal halide Inorganic materials 0.000 claims description 2
- 150000005309 metal halides Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 229920002385 Sodium hyaluronate Polymers 0.000 abstract description 37
- 229940010747 sodium hyaluronate Drugs 0.000 abstract description 37
- 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 abstract description 37
- SCPYDCQAZCOKTP-UHFFFAOYSA-N silanol Chemical compound [SiH3]O SCPYDCQAZCOKTP-UHFFFAOYSA-N 0.000 abstract description 17
- 230000000694 effects Effects 0.000 abstract description 14
- 230000003213 activating effect Effects 0.000 abstract description 9
- 230000009471 action Effects 0.000 abstract description 5
- 230000004888 barrier function Effects 0.000 abstract description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 5
- 238000005342 ion exchange Methods 0.000 abstract description 4
- 229920001296 polysiloxane Polymers 0.000 abstract description 4
- 230000000087 stabilizing effect Effects 0.000 abstract description 4
- 230000003335 steric effect Effects 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 23
- 229910052710 silicon Inorganic materials 0.000 description 16
- 239000010703 silicon Substances 0.000 description 16
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 239000002994 raw material Substances 0.000 description 7
- 210000003491 skin Anatomy 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000011521 glass Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000035699 permeability Effects 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000011068 loading method Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- NSGDYZCDUPSTQT-UHFFFAOYSA-N N-[5-bromo-1-[(4-fluorophenyl)methyl]-4-methyl-2-oxopyridin-3-yl]cycloheptanecarboxamide Chemical compound Cc1c(Br)cn(Cc2ccc(F)cc2)c(=O)c1NC(=O)C1CCCCCC1 NSGDYZCDUPSTQT-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 230000003020 moisturizing effect Effects 0.000 description 3
- 230000009965 odorless effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- GDCCFQMGFUZVKK-UHFFFAOYSA-N 1-butyl-2h-pyridine Chemical compound CCCCN1CC=CC=C1 GDCCFQMGFUZVKK-UHFFFAOYSA-N 0.000 description 2
- UZGLOGCJCWBBIV-UHFFFAOYSA-N 3-(chloromethyl)pyridin-1-ium;chloride Chemical compound Cl.ClCC1=CC=CN=C1 UZGLOGCJCWBBIV-UHFFFAOYSA-N 0.000 description 2
- 239000005046 Chlorosilane Substances 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 150000004819 silanols Chemical class 0.000 description 2
- 150000003377 silicon compounds Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 102000016942 Elastin Human genes 0.000 description 1
- 108010014258 Elastin Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 102000016611 Proteoglycans Human genes 0.000 description 1
- 108010067787 Proteoglycans Proteins 0.000 description 1
- 208000028990 Skin injury Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- DCAADTQUFYNVHS-UHFFFAOYSA-N [SiH3]O.[Na] Chemical compound [SiH3]O.[Na] DCAADTQUFYNVHS-UHFFFAOYSA-N 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- QABCGOSYZHCPGN-UHFFFAOYSA-N chloro(dimethyl)silicon Chemical compound C[Si](C)Cl QABCGOSYZHCPGN-UHFFFAOYSA-N 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 210000004177 elastic tissue Anatomy 0.000 description 1
- 229920002549 elastin Polymers 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- LWIGVRDDANOFTD-UHFFFAOYSA-N hydroxy(dimethyl)silane Chemical compound C[SiH](C)O LWIGVRDDANOFTD-UHFFFAOYSA-N 0.000 description 1
- AIPVRBGBHQDAPX-UHFFFAOYSA-N hydroxy(methyl)silane Chemical compound C[SiH2]O AIPVRBGBHQDAPX-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001095 inductively coupled plasma mass spectrometry Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 239000009438 liyan Substances 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002366 mineral element Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 150000001367 organochlorosilanes Chemical class 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 229920002050 silicone resin Polymers 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/42—Block-or graft-polymers containing polysiloxane sequences
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
The invention discloses a preparation method of a silanized hyaluronic acid compound, belonging to the technical field of sodium hyaluronate preparation, and characterized in that the preparation method comprises the following steps: the method comprises the following steps of uniformly mixing a hyaluronic acid salt solution and an active compound solution according to a preset proportion, stirring at normal temperature, reacting under the condition of a catalyst after heating, and obtaining a silanized hyaluronic acid compound by post-treating, separating, purifying and drying reaction liquid, wherein the silanized hyaluronic acid compound has the following beneficial effects: activating polymethylsilsesquioxane by adopting Lewis acid, treating active silanol molecules step by step, stabilizing the active silanol molecules by using steric effect, and breaking through the energy barrier of steric hindrance to form a silicone base by the carboxyl activity of hyaluronic acid; the sodium hyaluronate is reduced into ionic liquid and water through ion exchange under the action of a supported ionic liquid catalyst, and the effect of easily reacting with the sodium hyaluronate is realized.
Description
The technical field is as follows:
the invention belongs to the technical field of sodium hyaluronate preparation, and particularly relates to a preparation method of a silanized hyaluronic acid compound.
Background art:
sodium hyaluronate, also known as sodium hyaluronate, is a polysaccharide composed of repetitive connections of glucuronic acid and glucosamine disaccharide units, is one of the main components constituting the extracellular matrix of skin, has extremely high hydrophilicity and viscoelasticity, and is known as an ideal natural moisturizing factor. When applied to the surface of skin, the sodium hyaluronate has the physiological effects of moisturizing and lubricating, nourishing, repairing, preventing injury and the like, but has poor permeability and strong sticky and wet feeling. Silicon element, which is a necessary mineral element for the survival and development of living organisms, exists in the state of monomethylsilanol and dimethylsilanol in the organisms and is mainly present in macromolecules such as proteoglycan, collagen, elastin and the like of extracellular connective tissue. The form of in vivo natural silicon element is simulated by exogenous silanol (soluble organic silicon), and the silanol is applied to local skin, which proves that the silanol has no toxic or side effect, can help the reconstruction and repair of damaged connective tissue, promote the proliferation of fibroblast, is beneficial to the regeneration of collagen fiber and elastic fiber, and has the functions of repair and compaction. Silanol can also bind water molecules to keep moisture, and stimulate fat cells to release glycerol fatty acid to reduce fat. However, silanol is easy to be condensed to form water-insoluble polysiloxane or silicone resin, so that the bioactivity is lost, the storage is difficult, and the direct use is inconvenient.
The silanized sodium hyaluronate is a silanized sodium hyaluronate derivative, has the biological activities of sodium hyaluronate and silanol, has strong moisturizing and sticky feeling eliminating effects on skin (US6197986B1), has strong stability at high temperature, and has the effects of preventing and repairing skin injury (MC200122A 1). According to the literature report, the silanized sodium hyaluronate has no irritation to skin, has little or no cytotoxicity, and can remarkably promote the growth and proliferation of keratinocytes (Liyan and the like, daily chemical industry, 2014,44(9): 5).
One of the prior art methods for preparing silanized sodium hyaluronate is an organic synthesis method, for example, chinese patent CN201310317104.0 discloses a method for preparing silanized hyaluronic acid ester compound, which comprises reacting sodium hyaluronate and dimethylchlorosilane in an organic solvent under a protective gas, separating and purifying the reaction solution, and drying under reduced pressure to obtain the product. US20130029934a1 discloses a synthesis scheme of silicon-based derivatives of polysaccharides, also using organochlorosilanes and hyaluronic acid to obtain silanized sodium hyaluronate through organic synthesis reaction. The early-stage reaction of the method requires an organic solvent for suspension, the subsequent treatment requires a large amount of ethyl acetate and ethanol for precipitating the product, a large amount of the organic solvent is consumed, and the method is not environment-friendly.
Another method is a solution mixing method, such as FR2961915, in which a hyaluronic acid solution and a sodium silanol solution are mixed and reacted, and then the pH is adjusted by using a cation exchange resin, and then an aqueous solution of the complex is obtained. Patent EP0867445 discloses a method for preparing a solid bioactive silicon compound, in which an organic silicon compound and hyaluronic acid are mixed and reacted in an aqueous solution of ethanol, and then the solvent is removed by reduced pressure evaporation to obtain a solid compound, wherein the water in the product is difficult to remove due to good hydrophilic property of the product during the reduced pressure evaporation process, so that the product is sticky, the stability of the product is reduced, and the subsequent product is inconvenient to use.
The invention content is as follows:
in order to solve the problems and overcome the defects of the prior art, the preparation method of the silanized hyaluronic acid compound has the advantages of safe and environment-friendly reaction raw materials, mild reaction process, no organic solvent, simple separation and purification steps, and stable product quality and storage performance.
The specific technical scheme for solving the technical problems comprises the following steps: a method for preparing a silylated hyaluronic acid compound, comprising: uniformly mixing a hyaluronic acid salt solution and an active compound solution according to a preset proportion, stirring at normal temperature, heating, reacting under the condition of a catalyst, and carrying out post-treatment, separation, purification and drying on a reaction solution to obtain the silanized hyaluronic acid compound.
Further, the preparation method comprises the following steps:
step 1: preparation of hyaluronic acid salt solution: dissolving hyaluronic acid salt in deionized water to obtain a hyaluronic acid salt solution;
step 2: preparation of active complex solution: mixing a polymethylsilsesquioxane ethanol solution with a Lewis acid aqueous solution, and heating for reaction to obtain an active compound solution;
and step 3: silanized hyaluronate reaction: uniformly mixing a hyaluronic acid salt solution and an active compound solution according to a preset proportion, stirring at normal temperature, heating, reacting under the condition of a supported ionic liquid catalyst, and carrying out post-treatment, separation, purification and drying on a reaction solution to obtain a silanized hyaluronic acid compound.
Further, the supported ionic liquid catalyst is a solid carrier and an ionic liquid composite catalyst; the supported ionic liquid catalyst is SiO 2 N-butylpyridine hexafluorophosphate ionic liquid supported composite catalyst or SiO 2 The supported 1-butyl-3-methylimidazole tetrafluoroborate ionic liquid composite catalyst has the mass ratio of the hyaluronate to the catalyst of 1:0.02-1: 0.10.
Further, the concentration of the hyaluronic acid salt solution in the step 1 is 0.5-30%, and the average molecular weight of the hyaluronate is 10-2000 KDa.
Further, the average molecular weight of the polymethylsilsesquioxane in the step 2 is 200Da-2000 Da; the material-liquid ratio of the polymethylsilsesquioxane in ethanol is 1:5-1: 20.
Further, in the step 2, the Lewis acid is a metal halide comprising AlCl 3 、BF 3 、SbCl 5 、FeBr 3 、FeCl 3 、SnCl 4 、TiCl 4 Or ZnCl 2 The concentration range of the Lewis acid solution is 0.01 percent to 1 percent, and the heating reaction temperature in the step 2The reaction time is 5-15h at the temperature of 30-100 ℃.
Further, in the step 3, the stirring time is 3-7h, the temperature rise is 30-100 ℃, and the temperature rise reaction time is 15-30 h.
Further, the post-treatment process comprises the following steps: and filtering to remove the carrier of the supported ionic liquid catalyst by adopting a filtering method.
Further, the separation and purification process comprises: and (3) performing membrane filtration and purification on the reaction liquid until the fraction is colorless and tasteless, adjusting the pH of the reaction liquid to 5.0-7.0 by using alkali liquor after separation and purification, wherein the membrane for membrane filtration is an organic membrane or a ceramic membrane, and the aperture of the membrane is 500D-2000D.
Furthermore, the drying process adopts low-temperature drying at the temperature of 0-25 ℃.
The invention has the beneficial effects that:
the raw materials are safe and environment-friendly: the preparation method does not use chlorosilane, silanol and other easily-degradable and polymerizable raw materials, adopts polymethylsilsesquioxane high-molecular polymer as a raw material, and has the advantages of stable performance, safety, environmental protection, and easiness in storage and transportation;
the reaction process is mild: activating polymethylsilsesquioxane by adopting Lewis acid, treating active silanol molecules step by step, stabilizing the active silanol molecules by using steric effect, and breaking through the energy barrier of steric hindrance to form a silicone base by the carboxyl activity of hyaluronic acid; ion exchange is carried out to reduce the sodium hyaluronate into ionic liquid and water under the action of a supported ionic liquid catalyst, so that the sodium hyaluronate can easily react;
the separation and purification steps are simple: the membrane filtration purification is adopted, a small amount of water is added in the process for many times, the introduced Lewis acid is removed, a large amount of ethanol and ethyl acetate precipitation are not needed, and the consumption is reduced;
the product has strong stability and efficacy: because the reaction is controllable, the process is mild, the catalyst can be recycled, side reactions are basically avoided, the product is uniform and stable, the permeability can be increased, the product can enter deeper skin tissues, and the effects of increasing the permeability and keeping moisture in a deep layer are achieved.
The specific implementation mode is as follows:
in the description of the invention, specific details are given only to enable a full understanding of the embodiments of the invention, but it should be understood by those skilled in the art that the invention is not limited to these details for the implementation. In other instances, well-known structures and functions have not been described or shown in detail to avoid obscuring the points of the embodiments of the invention. The specific meanings of the above terms in the present invention can be understood in specific cases to those skilled in the art.
The specific implementation mode of the invention is as follows:
a method for preparing a silylated hyaluronic acid compound, comprising the steps of:
the method comprises the following steps of reacting a hyaluronic acid salt solution with polymethylsilsesquioxane activated by a Lewis acid solution together, adding a catalyst in the reaction process, and carrying out post-treatment, separation, purification and drying on the reaction solution to obtain the silanized hyaluronic acid compound.
Further, the specific reaction is as follows:
step 1: preparation of hyaluronate solution: dissolving hyaluronate in deionized water to obtain a solution C1;
and 2, step: preparing a composite reactant required by the reaction: mixing the polymethylsilsesquioxane ethanol solution with the Lewis acid aqueous solution, and then heating to react to obtain the active compound. Finally obtaining a solution C2;
and step 3: silanized hyaluronate reaction: mixing C1 and C2 uniformly, stirring for several hours at normal temperature, and then heating to react under the condition of a supported ionic liquid catalyst.
The reaction formula is as follows:
reaction (1) stabilizing and activating silanol molecules by using steric effect through large cations of ionic liquid; the carboxyl activity of the hyaluronic acid breaks through the energy barrier of steric hindrance to form a silicon ester group in the reaction formula (2); the catalyst of the reaction formula (3) is reduced into ionic liquid and water by ion exchange.
And 4, step 4: post-treatment, purification and drying: and (3) filtering the reaction liquid in the step (3) to remove the catalyst carrier, and then performing membrane filtration and purification on the filtrate, wherein a small amount of water is added for many times in the purification process until the fraction is colorless and tasteless. Adding alkali for neutralization, and performing freeze drying treatment after neutralization to pH5.0-7.0, and drying to obtain the product;
furthermore, the drying process adopts low-temperature drying at the temperature of 0-25 ℃.
Further, in the step 1, the concentration of the hyaluronic acid salt solution C1 is 0.5% -30%, and the average molecular weight of the hyaluronic acid salt is 10KDa-2000KDa, preferably 20KDa-200 KDa.
Further, the average molecular weight of the polymethylsilsesquioxane in the step 2 is 200Da-2000 Da; the material-liquid ratio of the polymethylsilsesquioxane in ethanol is 1:5-1: 20.
Further, the Lewis acid activator in the step 2 is MgCl 2 、ZnCl 2 The concentration range of the Lewis acid solution is 0.01-1 percent.
Further, the heating reaction temperature in the step 2 is 30-100 ℃, and the reaction time is 5-15 h.
Further, in the step 3, the stirring time is 3-7h, the temperature rise is 30-100 ℃, and the temperature rise reaction time is 15-30 h.
Further, the supported ionic liquid catalyst in the step 3 is SiO 2 Loading N-butyl pyridine hexafluorophosphate or 1-butyl-3-methylimidazole tetrafluoroborate. Catalyst carrier SiO 2 Can be crushed but does not participate in the reaction, and can be removed by one-step filtration; the mass ratio of the hyaluronate to the catalyst is 1:0.02-1: 0.10.
Further, the membrane used for separating and purifying the reaction liquid in the reaction step 4 is an organic membrane or a ceramic membrane, and the pore diameter of the membrane is 500D-2000D.
Further, in the reaction step 4, the alkali liquor is at least one of a sodium hydroxide solution, a sodium carbonate solution and a sodium bicarbonate solution.
Further, the drying process in the reaction step 4 adopts low-temperature drying at the temperature of 0-25 ℃.
In order to better understand the present invention, specific embodiments are described, it is emphasized that the effects of the embodiments are not substantially different from the various embodiments within the scope of the present invention, and the described effects of the present invention and the above-mentioned problems can be achieved;
example 1
The preparation method of the silanized sodium hyaluronate comprises the following steps:
(1) weighing 10.00g of sodium hyaluronate with the molecular weight of 1000KDa in a 5000mL reaction bottle, adding 2000mL of deionized water, stirring at room temperature until the sodium hyaluronate is completely dissolved into a homogeneous phase to obtain 0.5% sodium hyaluronate solution C1;
(2) 2.85g MgCl was weighed in a glass reactor 2 Adding 5700mL of deionized water, stirring at room temperature to dissolve, and obtaining 0.05% MgCl 2 A Lewis acid solution; dissolving 5.05g of polymethylsilsesquioxane by using 30mL of ethanol solution, dropwise adding the dissolved polymethylsilsesquioxane into a Lewis acid solution, heating to 30 ℃, reacting for 14 hours to obtain an active compound C2, and then cooling the reaction system to room temperature;
(3) adding the solution C1 into a glass reaction kettle, stirring and mixing uniformly, adding 0.50g of SiO 2 Loading N-butylpyridine hexafluorophosphate, stirring at normal temperature for 3 hours, heating to 60 ℃, and reacting for 15 hours to obtain a target product reaction solution A1;
(4) filtering the reaction liquid to remove the catalyst carrier, then performing membrane filtration purification, adding a small amount of water for many times in the purification process until the fraction is colorless and odorless, and finally completing the purification, wherein the volume of the reaction liquid is 200 mL;
(5) adjusting pH of the reaction solution to 5.0-6.0 with sodium hydroxide solution, and freeze drying;
(6) drying to obtain crystalline product.
Example 2
The preparation method of the sodium hyaluronate silanized by the embodiment comprises the following steps:
(1) weighing 20.00g of sodium hyaluronate with molecular weight of 200KDa in a 1000mL reaction bottle, adding 400mL of deionized water, stirring at room temperature until the sodium hyaluronate is completely dissolved to be homogeneous, and obtaining 5% sodium hyaluronate solution C1;
(2) on glass9.50g MgCl was weighed in a glass reactor 2 Adding 950mL of deionized water, stirring at room temperature to dissolve the mixture to obtain 1.0% MgCl 2 A Lewis acid solution; dissolving 16.80g of polymethylsilsesquioxane by using 150mL of ethanol solution, dropwise adding the dissolved polymethylsilsesquioxane into a Lewis acid solution, heating to 90 ℃, reacting for 8 hours to obtain an active compound C2, and then cooling the reaction system to room temperature;
(3) adding the solution C1 into a glass reaction kettle, stirring and mixing uniformly, adding 2.00g of SiO 2 Loading N-butyl pyridine hexafluorophosphate, stirring for 7 hours at normal temperature, then heating to 80 ℃, and reacting for 24 hours to obtain a target product reaction solution A1;
(4) filtering the reaction liquid to remove the catalyst carrier, then performing membrane filtration purification, adding a small amount of water for multiple times in the purification process until the fraction is colorless and odorless, and finally completing the purification, wherein the volume of the reaction liquid is 500 mL;
(7) adjusting pH of the reaction solution to 5.0-6.0 with sodium carbonate solution, and freeze drying;
(8) drying to obtain crystalline product.
Example 3
The preparation method of the silanized sodium hyaluronate comprises the following steps:
(1) weighing 50.00g of sodium hyaluronate with molecular weight of 10KDa in a reaction kettle, adding 10000mL of deionized water, and stirring at room temperature until the sodium hyaluronate is completely dissolved to be homogeneous, so as to obtain 0.5% sodium hyaluronate solution C1;
(2) weighing 20.40g of ZnCl in a glass reaction kettle 2 4080mL of deionized water was added and dissolved at room temperature with stirring to obtain 0.5% MgCl 2 A Lewis acid solution; dissolving 25.20g of polymethylsilsesquioxane by using 500mL of ethanol solution, dropwise adding the dissolved polymethylsilsesquioxane into a Lewis acid solution, heating to 50 ℃, reacting for 10 hours to obtain an active compound C2, and cooling the reaction system to room temperature;
(3) adding the solution C1 into a glass reaction kettle, stirring and mixing evenly, adding 2.50g SiO 2 Loading 1-butyl-3-methylimidazole tetrafluoroborate, stirring at normal temperature for 5 hours, then heating to 40 ℃, and reacting for 20 hours to obtain a target product reaction solution A1;
(4) filtering the reaction liquid to remove the catalyst carrier, then performing membrane filtration purification, adding a small amount of water for many times in the purification process until the fraction is colorless and odorless, and finally completing the purification, wherein the volume of the reaction liquid is 800 mL;
(9) adjusting pH of the reaction solution to 5.0-6.0 with sodium bicarbonate solution, lyophilizing, and drying to obtain crystalline product.
And the crystalline substance obtained in the above examples 1 to 3 was subjected to a silicon content measurement by inductively coupled plasma mass spectrometry in accordance with technical specifications for cosmetic safety (2015 th edition);
table 1: results of measuring content of silanized sodium hyaluronate and silicon
| Activating agent | Ionic liquid composite catalyst | Silicon content | |
| Example 1 | Lewis acid | SiO 2 N-butylpyridine supported hexafluorophosphate | 3.01％ |
| Example 2 | Lewis acid | SiO 2 N-butylpyridine supported hexafluorophosphate | 3.53％ |
| Example 3 | Lewis acids | SiO 2 Supported 1-butyl-3-methylimidazole tetrafluoroborate | 3.18％ |
According to the data analysis in the table 1, the following data can be obtained:
the embodiments of the invention have relatively excellent silicon content, which shows that the lewis acid is adopted to activate the polymethylsilsesquioxane, so that the active silanol molecules can be treated step by step and can be easily reacted with the sodium hyaluronate under the action of the supported ionic liquid catalyst;
in order to more intuitively show the process advantages of the invention, the process method adopting the activating agent and the ionic liquid composite catalyst is compared with the equivalent replacement method adopted by the same process,
comparative example 1
The preparation method is the same as example 1, except that the activating agent is not added in the process method;
comparative example 2
The preparation method is the same as example 1, except that no catalyst is added in the process method;
comparative example 3
The preparation method is the same as example 1, except that the process method is not added with an activating agent and a catalyst;
comparative example 4
The procedure is as in example 1, except that the catalyst is replaced by the conventional 3-chloromethylpyridine hydrochloride.
Table 2: results of measuring content of silanized sodium hyaluronate and silicon
According to the data analysis in the table 2, the following data can be obtained:
comparing example 1 with comparative example 1, it can be seen that: the activator is not added, the exposed hydroxyl of the polymethylsilsesquioxane can hardly react with the sodium hyaluronate under the action of the catalyst, and the silicon content is only 0.14%;
comparing example 1 with comparative example 2, it can be seen that: under the condition of not adding a catalyst, the activated silanol molecules and the sodium hyaluronate are subjected to esterification reaction, but the silicon content is lower and is only 1.13%; the reason for this is probably due to the polyanionic effect of the sodium hyaluronate carboxyl group which prevents further reaction with silanol molecules;
comparing example 1 with comparative example 3, it can be seen that: under the condition of not adding an activating agent and a catalyst, the polymethylsilsesquioxane cannot generate esterification reaction with sodium hyaluronate, and the silicon content is only 0.01%;
example 1 and comparative example 4 compare to see that: the catalyst was replaced with 3-chloromethylpyridine hydrochloride to give a product having a silicon content of 1.43%. The result shows that when the catalyst is replaced by other ionic liquid catalysts, the polymethylsilsesquioxane has esterification reaction with sodium hyaluronate, but the silicon content of the product is low, so that the catalyst cannot effectively stabilize activated silanol molecules by virtue of steric hindrance effect, and the carboxyl group of hyaluronic acid cannot further break through the energy barrier of steric hindrance to form a silicone ester group.
In summary, the following steps: the raw materials are safe and environment-friendly: the preparation method does not use chlorosilane, silanol and other easily-degradable and polymerizable raw materials, adopts polymethylsilsesquioxane high-molecular polymer as a raw material, and has the advantages of stable performance, safety, environmental protection, and easiness in storage and transportation;
the reaction process is mild: activating polymethylsilsesquioxane by adopting Lewis acid, processing active silanol molecules step by step, stabilizing the active silanol molecules by using steric effect, and breaking through the energy barrier of steric hindrance to form a silicon ester group by the carboxyl activity of hyaluronic acid; ion exchange is carried out to reduce the sodium hyaluronate into ionic liquid and water under the action of a supported ionic liquid catalyst, so that the sodium hyaluronate can easily react;
the separation and purification steps are simple: the membrane filtration purification is adopted, a small amount of water is added in the process for many times, the introduced Lewis acid is removed, a large amount of ethanol and ethyl acetate are not needed for precipitation, and the consumption is reduced;
the product has strong stability and efficacy: because the reaction is controllable, the process is mild, the catalyst can be recycled, side reactions are basically avoided, the product is uniform and stable, the permeability can be increased, the product can enter deeper skin tissues, and the effects of increasing the permeability and keeping moisture in a deep layer are achieved.
Claims (10)
1. A method for preparing a silylated hyaluronic acid compound, comprising: uniformly mixing a hyaluronic acid salt solution and an active compound solution according to a preset proportion, stirring at normal temperature, heating, reacting under the condition of a catalyst, and carrying out post-treatment, separation, purification and drying on a reaction solution to obtain the silanized hyaluronic acid compound.
2. The method of preparing a silylated hyaluronic acid compound according to claim 1, characterized in that: the preparation method comprises the following steps:
step 1: preparation of hyaluronic acid salt solution: dissolving hyaluronic acid salt in deionized water to obtain a hyaluronic acid salt solution;
step 2: preparation of active complex solution: mixing a polymethylsilsesquioxane ethanol solution with a Lewis acid aqueous solution, and heating for reaction to obtain an active compound solution;
and step 3: silanized hyaluronate reaction: uniformly mixing a hyaluronic acid salt solution and an active compound solution according to a preset proportion, stirring at normal temperature, heating, reacting under the condition of a supported ionic liquid catalyst, and performing post-treatment, separation, purification and drying on a reaction solution to obtain a silanized hyaluronic acid compound.
3. The method of preparing a silylated hyaluronic acid compound according to claim 2, characterized in that: the supported ionic liquid catalyst is a solid carrier and an ionic liquid composite catalyst; the supported ionic liquidThe bulk catalyst is SiO 2 N-butylpyridine hexafluorophosphate ionic liquid supported composite catalyst or SiO 2 The supported 1-butyl-3-methylimidazole tetrafluoroborate ionic liquid composite catalyst has the mass ratio of the hyaluronate to the catalyst of 1:0.02-1: 0.10.
4. The method of preparing a silylated hyaluronic acid compound according to claim 2, characterized in that: in the step 1, the concentration of the hyaluronic acid salt solution is 0.5-30%, and the average molecular weight of the hyaluronate is 10-2000 KDa.
5. The process for the preparation of silylated hyaluronic acid compound according to claim 2, characterized in that in step 2 the polymethylsilsesquioxane has an average molecular weight of 200Da-2000 Da; the material-liquid ratio of the polymethylsilsesquioxane in ethanol is 1:5-1: 20.
6. The method of preparing a silylated hyaluronic acid compound of claim 1, ch a ra cte rized in that the lewis acid in step 2 is a metal halide comprising AlCl 3 、BF 3 、SbCl 5 、FeBr 3 、FeCl 3 、SnCl 4 、TiCl 4 Or ZnCl 2 The concentration range of the Lewis acid solution is 0.01-1%, the heating reaction temperature in the step 2 is 30-100 ℃, and the reaction time is 5-15 h.
7. The method for preparing a silylated hyaluronic acid compound according to claim 2, characterized in that in step 3, the stirring is carried out for 3-7h, the temperature rise is 30-100 ℃, and the temperature rise reaction is carried out for 15-30 h.
8. The method for producing a silylated hyaluronic acid compound according to claim 2, characterized in that the post-treatment step is: and filtering to remove the carrier of the supported ionic liquid catalyst by adopting a filtering method.
9. The method for producing a silylated hyaluronic acid compound according to claim 2, characterized in that the separation and purification step is: and (3) performing membrane filtration and purification on the reaction liquid until the fraction is colorless and tasteless, adjusting the pH of the reaction liquid to 5.0-7.0 by using alkali liquor after separation and purification, wherein the membrane for membrane filtration is an organic membrane or a ceramic membrane, and the aperture of the membrane is 500D-2000D.
10. The method of preparing a silylated hyaluronic acid compound of claim 2 wherein the drying process is carried out at a low temperature of 0-25 ℃.
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| JP2010043138A (en) * | 2008-08-08 | 2010-02-25 | Shiseido Co Ltd | Silylated hyaluronic acid derivative and production method thereof |
| US20130029934A1 (en) * | 2010-03-05 | 2013-01-31 | Gaspare Aita | Silyl-derivatives of polysaccharides |
| CN103450368A (en) * | 2013-07-25 | 2013-12-18 | 山东福瑞达生物工程有限公司 | Preparation method of silanized hyaluronate compound |
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| JP2010043138A (en) * | 2008-08-08 | 2010-02-25 | Shiseido Co Ltd | Silylated hyaluronic acid derivative and production method thereof |
| US20130029934A1 (en) * | 2010-03-05 | 2013-01-31 | Gaspare Aita | Silyl-derivatives of polysaccharides |
| CN103450368A (en) * | 2013-07-25 | 2013-12-18 | 山东福瑞达生物工程有限公司 | Preparation method of silanized hyaluronate compound |
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| HO-YONG LEE ET AL: "One-pot synthesis of silane-modified hyaluronic acid hydrogels for effective antibacterial drug delivery via sol-gel stabilization" * |
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