CN104771331A - Hyaluronic acid elastomer and applications thereof - Google Patents
Hyaluronic acid elastomer and applications thereof Download PDFInfo
- Publication number
- CN104771331A CN104771331A CN201510109114.4A CN201510109114A CN104771331A CN 104771331 A CN104771331 A CN 104771331A CN 201510109114 A CN201510109114 A CN 201510109114A CN 104771331 A CN104771331 A CN 104771331A
- Authority
- CN
- China
- Prior art keywords
- gel
- hyaluronic acid
- cross
- acid elastomer
- linking
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 71
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 70
- 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 title claims abstract description 69
- 229920001971 elastomer Polymers 0.000 title claims abstract description 38
- 239000000806 elastomer Substances 0.000 title claims abstract description 35
- 239000003431 cross linking reagent Substances 0.000 claims abstract description 36
- 238000004132 cross linking Methods 0.000 claims abstract description 25
- 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 claims abstract description 21
- 239000002245 particle Substances 0.000 claims abstract description 20
- 229920002385 Sodium hyaluronate Polymers 0.000 claims abstract description 16
- 229940010747 sodium hyaluronate Drugs 0.000 claims abstract description 16
- 238000002156 mixing Methods 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 238000000502 dialysis Methods 0.000 claims abstract description 10
- 230000007935 neutral effect Effects 0.000 claims abstract description 9
- 239000002537 cosmetic Substances 0.000 claims abstract description 8
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- SHKUUQIDMUMQQK-UHFFFAOYSA-N 2-[4-(oxiran-2-ylmethoxy)butoxymethyl]oxirane Chemical compound C1OC1COCCCCOCC1CO1 SHKUUQIDMUMQQK-UHFFFAOYSA-N 0.000 claims description 8
- 238000011049 filling Methods 0.000 claims description 4
- 239000008187 granular material Substances 0.000 claims description 4
- 230000002421 anti-septic effect Effects 0.000 claims description 3
- 230000003796 beauty Effects 0.000 claims description 3
- 150000001718 carbodiimides Chemical class 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- UWFRVQVNYNPBEF-UHFFFAOYSA-N 1-(2,4-dimethylphenyl)propan-1-one Chemical compound CCC(=O)C1=CC=C(C)C=C1C UWFRVQVNYNPBEF-UHFFFAOYSA-N 0.000 claims description 2
- 230000000845 anti-microbial effect Effects 0.000 claims description 2
- 230000002141 anti-parasite Effects 0.000 claims description 2
- 239000003963 antioxidant agent Substances 0.000 claims description 2
- 230000003078 antioxidant effect Effects 0.000 claims description 2
- 235000006708 antioxidants Nutrition 0.000 claims description 2
- 239000003096 antiparasitic agent Substances 0.000 claims description 2
- 230000003750 conditioning effect Effects 0.000 claims description 2
- 239000000645 desinfectant Substances 0.000 claims description 2
- GYZLOYUZLJXAJU-UHFFFAOYSA-N diglycidyl ether Chemical class C1OC1COCC1CO1 GYZLOYUZLJXAJU-UHFFFAOYSA-N 0.000 claims description 2
- 239000004744 fabric Substances 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 235000015097 nutrients Nutrition 0.000 claims description 2
- 239000000419 plant extract Substances 0.000 claims description 2
- 239000003223 protective agent Substances 0.000 claims description 2
- 230000004044 response Effects 0.000 claims description 2
- 230000000475 sunscreen effect Effects 0.000 claims description 2
- 239000000516 sunscreening agent Substances 0.000 claims description 2
- 235000013343 vitamin Nutrition 0.000 claims description 2
- 239000011782 vitamin Substances 0.000 claims description 2
- 229940088594 vitamin Drugs 0.000 claims description 2
- 229930003231 vitamin Natural products 0.000 claims description 2
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims 1
- 239000007924 injection Substances 0.000 claims 1
- 239000011148 porous material Substances 0.000 claims 1
- 230000037303 wrinkles Effects 0.000 abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract 1
- 238000000518 rheometry Methods 0.000 abstract 1
- 239000000499 gel Substances 0.000 description 88
- 238000000034 method Methods 0.000 description 15
- 239000000523 sample Substances 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 230000003013 cytotoxicity Effects 0.000 description 11
- 231100000135 cytotoxicity Toxicity 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 9
- 230000007515 enzymatic degradation Effects 0.000 description 8
- 150000003384 small molecules Chemical class 0.000 description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 230000002255 enzymatic effect Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000004971 Cross linker Substances 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 230000035807 sensation Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012531 culture fluid Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 229940097043 glucuronic acid Drugs 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- HPILSDOMLLYBQF-UHFFFAOYSA-N 2-[1-(oxiran-2-ylmethoxy)butoxymethyl]oxirane Chemical compound C1OC1COC(CCC)OCC1CO1 HPILSDOMLLYBQF-UHFFFAOYSA-N 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000035126 Facies Diseases 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 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
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000000245 forearm Anatomy 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 238000000694 mesotherapy Methods 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 230000037394 skin elasticity Effects 0.000 description 1
- 230000036548 skin texture Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005491 wire drawing Methods 0.000 description 1
Landscapes
- Cosmetics (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
The invention relates to the technical field of sodium hyaluronate gel, and especially relates to a hyaluronic acid elastomer. The hyaluronic acid elastomer is prepared by the following steps: reacting hyaluronic acid with a crosslinking agent to obtain crosslinked sodium hyaluronate gel (A); granulating the obtained crosslinked sodium hyaluronate gel (A) to obtain gel (B) and gel (C) with different particle sizes; mixing the gel (B) and gel (C) to carry out crosslinking reactions again, adjusting the pH value to a neutral area, and carrying out dialysis to obtain the hyaluronic acid elastomer. The provided hyaluronic acid elastomer has an excellent rheology performance, can be used as a cosmetic raw material, can be used to eliminate skin wrinkles physically, maintain the skin water, slowly release the effective component, and improve the feeling. The invention further discloses applications of the hyaluronic acid elastomer.
Description
Technical field
The present invention relates to a kind of hyaluronic acid elastomer.The present invention has excellent viscoelasticity, can be used as cosmetic material, for physics smooth out wrinkles, keeps moisture of skin, slow release functional component, improvement use sensation etc.Meanwhile, the invention still further relates to its application.
Background technology
Hyaluronic acid (hyalouronic acid, HA) is repeated a kind of straight chain polymer mucopolysaccharide formed by glucuronic acid and n acetylglucosamine n dissacharide units.Hyaluronic acid is the endogenous material itself had in human body, has good biocompatibility; There is high viscoelasticity and non-Newtonian rheological characteristic; Nontoxic, without immunogenicity, nonirritant, there is very high safety.
The extensive use in cosmetics of noncrosslinking hyaluronic acid derivatives, but be mainly used in moisture-keeping function, the amount of interpolation is also little, otherwise solution is more glutinous, easily wire drawing after being coated with, a mud.Hyaluronic acid that is crosslinked or that modify has different rheologic behavio(u)rs, can protect skin, physics smooths/fill wrinkle etc.The application of hyaluronic acid in cosmetics that be crosslinked or that modify is less at present.
Publication number is that CN 101056891 B patent provides and can prepare the few and method of the crosslinked HA gel that viscoelasticity is good of content of crosslinking agent easily.It is characterized in that, under acid or alkaline conditions by containing hyaluronic acid 10%(W/V) more than, the mixture of cross-linking agent and water is uniformly mixed.This patent is mainly by increasing the mode of hyaluronic concentration, and reduce dosage of crosslinking agent, the method is single step reaction and does not consider the impact of other reacting substances.
Publication number is the method disclosing the cross-linked-hyaluronic acid in a kind of emulsion in the patent of CN 101878230 B, the steps include: that (a) providing package contains the alkaline aqueous solution of hyaluronic acid or its salt; B (), in organic facies or oil phase, forms the microdroplet with desired size, to form the emulsion of Organic substance bag water or Water-In-Oil (W/O) from the mixed solution of step (a); C () adds the solution comprising cross-linking agent in emulsion, hyaluronic acid and described cross-linking agent react to provide crosslinked hyaluronic acid microballon thus; And (d) the optionally dispersion of the crosslinked hyaluronic acid microballon of gained in procedure of processing (c).Need in the method reaction system to add organic reagent, organic reagent may be brought to remain equivalent risk.
Publication number is mention multiple cross-linked hyaluronic acid technology in the patent of invention of CN1200951C, utilize two or more functional group being selected from hydroxyl, carboxyl and amino and cross-linking hyaluronic acids, adopt glutaraldehyde, carbodiimides, butanediol diglycidyl ether etc. to be cross-linking agent.The cross-linked hyaluronic acid gel obtained in patent, the gel not mixing different-grain diameter is cross-linked again, and with organic reagent washings such as acetone, pollutes larger.
Publication number is propose a kind of biodegradable cohesive hydrogel in the patent of CN101925348 A, and preparation method is polymer intimate mixing X kind with the identical or different degree of cross linking.The method is only that X kind polymer is carried out physical mixed, does not have cross-bond, can not form cross-linked network structure between polymer.
Publication number is that patent discloses of CN101909597A a kind ofly comprises the fractal net work of nano-particle and the gel rubber system of macroscopic particles.This gel rubber system can be formed " optical gel ", and described gel is fuzzy wrinkle line and wrinkle effectively due to the size field difference between fractal particle and macroscopic particles.This patent proposes the concept with there being the fuzzy wrinkle of the gel rubber system of granule, and gel is applicable to cosmetics but gel in patent is the materials such as silicon dioxide, aluminium oxide, silicone elastomer, does not use the hyaluronic acid gellike of good biocompatibility.
Summary of the invention
In order to solve above technical problem, the invention provides a kind of hyaluronic acid elastomer.It can be used as cosmetic material, for physics smooth out wrinkles, keeps moisture of skin, slow release functional component, improvement use sensation etc.
The present invention is achieved by the following measures:
A kind of hyaluronic acid elastomer, is obtained by following steps:
(1) hyaluronic acid and cross-linking agent are reacted, obtain cross-linking sodium hyaluronate gel A;
(2) select the screen cloth with suitable aperture, cross-linking sodium hyaluronate gel A is granulated, obtains the different gel B of size and gel C;
(3) by gel B and gel C mixing, again carry out cross-linking reaction, adjust ph is to neutral, and dialysis, obtains hyaluronic acid elastomer.
Described hyaluronic acid elastomer, preferred cross-linking agent is the one in carbodiimide, divinylsulfone, Ethylene glycol diglycidyl ether, BDDE, the many glycidyl ethers of polyglycereol.
Cross-linking reaction can be acid condition in step (3), pH value 2 ~ 6, more preferably 2 ~ 4, and also can be alkali condition, pH value 9 ~ 14, more preferably 11 ~ 14.
Described hyaluronic acid elastomer, in preferred steps (1), cross-linking agent and hyaluronic quality accounting are 0.02 ~ 3.0%.
Described hyaluronic acid elastomer, in preferred steps (3), gel B and gel C mixed proportion are 1-9:9-1.
Described hyaluronic acid elastomer, in preferred steps (1) (3), cross-linking reaction temperature is 10 DEG C ~ 60 DEG C, preferably 15 DEG C ~ 50 DEG C; Response time 1 ~ 50 h, preferably 2 ~ 24 h.
So the particle diameter (X of gel B
50) select 100 ~ 800 μm.
So the particle diameter (X of gel C
50) select 70 ~ 100 μm.
Hyaluronic acid sodium gel after crosslinked is made the gel that particle diameter varies in size by the present invention, then carries out two steps and be cross-linked, and different hyaluronic acid network structure is interted together, and gel has excellent rheologic behavio(u)r.
The present invention stops crosslinked being completed by dialysis removing cross-linking agent and unreacted small-molecule substance.
Object of the present invention additionally provides the purposes of this gel, and in cosmetics, physics smooth out wrinkles, keeps moisture of skin, slow release functional component.
This gel can be used for filling fine, moderate or deep wrinkles, and tissue filling.
This gel can be used for recovering skin beauty water balance by mesotherapy, improves skin texture and elasticity.
This gel can be used for supplementing or alternative synovial fluid.
A kind of or the wherein several combination in the additive of noncrosslinking hyaluronic acid, sunscreen, light protective agent, antioxidant, nutrient, vitamin, skin conditioning agent, irritated inhibitor, disinfectant, antiseptic, antimicrobial, antiparasitic, plant extract, special efficacy can be added in this gel.
According to embodiment of the present invention, this gel can sterilizing or add antiseptic, and moist heat sterilization mode is selected in sterilizing.
Beneficial effect of the present invention:
Hyaluronic acid elastomer of the present invention, be again cross-linked with the cross-linking sodium hyaluronate gel of two kinds of different-grain diameters, dosage of crosslinking agent is few, pollutes few, is easy to realize industrialization; Gel of the present invention has excellent rheologic behavio(u)r and biocompatibility, can physics smooth out wrinkles, keeps moisture of skin, slow release functional component, improves and use sensation.
Detailed description of the invention
In order to better the present invention is described, further illustrate below in conjunction with specific embodiment.
Embodiment 1
The gel B size difference that the present embodiment is investigated is on the impact of invention gelling properties, and preparation method is as follows:
(1) by 10 g hyaluronic acid dissolves in the NaOH solution of 100 ml (pH value is 11 ~ 13), after mixing, add cross-linking agent 1,4-butanediol diglycidyl ether, cross-linking agent and hyaluronic quality accounting are 1%, stirring and evenly mixing, reacts 6 h in 35 DEG C of water-baths, obtains cross-linking sodium hyaluronate gel A;
(2) granulated by cross-linking sodium hyaluronate gel A, the particle diameter of gel B is as shown in table 1, and the particle diameter of gel C is 72 μm of (X
50);
(3) gel B and gel C are pressed 1: 1(w: w) mix, adjust ph to 2 ~ 4, add BDDE, and cross-linking agent and hyaluronic quality accounting are react 8 h in 0.8%, 30 DEG C of water-baths.Adjust ph is to neutral, and dialysis removes unreacted small-molecule substance.
The viscoelasticity of the gel that the gel B comparing different-grain diameter prepares and resistance to enzymatic, assay method is as follows:
Viscoelasticity method of testing: match to write from memory flying generation that science and technology (China) company with Haake RS6000() Instrument measuring viscoelasticity, condition is: rotor: P20 Ti L; Gap value: 1.00 mm; Temperature: 25 DEG C; Mode determination; Oscillation frequency sweep CD; Stress; 1%; Frequency range: 0.01 ~ 1 Hz.Elastic modelling quantity when recording 0.1 Hz and viscous modulus.
Resistance to enzymatic: precision takes the gel obtained in embodiment, and (hyaluronic acid contents is 0.5 g), add 0.1 mol/L phosphate buffer (pH 7.0) 9 mL and hyaluronidase liquid (100 U/mL) 1 mL, mix homogeneously, be placed in 37 DEG C of water-bath enzymolysis 8 h, then boil 10 min deactivations at 100 DEG C.0.45 μm of filtering with microporous membrane, gets filtrate 1.0 ml, adds water and be settled to 10 ml.Adopt improvement carbazole development process (list of references: Bitter .T, Muir H.M, (1962) A modified uronic acid carbarbazole reation .Anal.Biochem.4,330-333.) measuring glucuronic acid content, after being multiplied by 2.07, converting the content a of cross-linking hyaluronic acid sodium in the sample for adding enzyme liquid; Cross-linking hyaluronic acid sodium content in not enzyme-added liquid sample is b, calculates enzymatic degradation rate=a/b × 100%.Enzymatic degradation rate is lower, and show that the ability of the slow release functional component of gel is stronger, the functional component maintainable time is long.
The impact of the gel B of table 1 different-grain diameter
Gel B selects viscoelasticity to be suitable for, and degradation rate is moderate.When the granule of gel B is greater than 800 μm, the resistance to enzymatic of final gained gel is poor, and effect is held time short, so the particle diameter of gel B selects 100 ~ 800 μm.
Embodiment 2
The gel C size difference that the present embodiment is investigated is on the impact of invention gelling properties, and preparation method is as follows:
(1) by 10 g hyaluronic acid dissolves in 100 ml NaOH solution in (pH value is 11 ~ 13), after mixing, add cross-linking agent 1,4-butanediol diglycidyl ether, cross-linking agent and hyaluronic quality accounting are 1.0%, stirring and evenly mixing, reacts 6 h in 35 DEG C of water-baths, obtains cross-linking sodium hyaluronate gel A;
(2) cross-linking sodium hyaluronate gel A is granulated, gel B particle diameter be 198 μm of (X
50), the particle diameter of gel C is as shown in table 2;
(3) gel B and gel C are pressed 1: 1(w: w) mix, adjust ph to 2 ~ 4, add BDDE, and cross-linking agent and hyaluronic quality accounting are react 8 h in 0.8%, 30 DEG C of water-baths.Adjust ph is to neutral, and dialysis removes unreacted small-molecule substance.
Reference example 1 method measures gel viscoelastisity and resistance to enzymatic, and data are in table 2.
The impact of the gel C of table 2 different-grain diameter
Gel C selects viscoelasticity to be suitable for, and degradation rate is moderate.When the granule of gel C is less than 60 μm, final gained gel elastomer is comparatively large, is difficult to smear, so the particle diameter (X of gel C
50) select 70 ~ 100 μm.
Embodiment 3
Gel B(198 μm by embodiment 2) and gel C (72 μm) with different quality than after mix homogeneously, pH value is transferred to 2 ~ 4, and add 1,4-butanediol diglycidyl ether, cross-linking agent and hyaluronic quality accounting are 0.8%(w/w), in 30 DEG C of water-baths, react 6 h, then adjust ph is to neutral, the unreacted small-molecule substance of dialysis removing.
Reference example 1 method measures gel viscoelastisity and resistance to enzymatic, and viscoelasticity test data is in table 3.
The ratio of table 3 gel X and gel Y
Can see from above-mentioned data, the ratio of gel B is larger, and enzymatic degradation rate is higher, and functional component discharges faster, elasticity and viscosity lower, be easy to smear; The ratio of gel C is larger, and enzymatic degradation rate is lower, and resistance to enzymatic is better, and functional component discharges slower.Suitable ratio can be selected according to functional component release time and viscoelastic needs.
Embodiment 4
The present embodiment investigates the impact of the crosslinker ratio that a step is cross-linked, and method is as follows:
(1) by 10 g hyaluronic acid dissolves in 100 ml NaOH solution in (pH value is 13 ~ 14), after mixing, add cross-linking agent divinylsulfone (DVS), cross-linking agent and hyaluronic mass ratio as shown in table 4, stirring and evenly mixing, in 25 DEG C of water-baths, react 8 h, obtain cross-linking sodium hyaluronate gel A;
(2) cross-linking sodium hyaluronate gel A is granulated, gel B particle diameter be 198 μm of (X
50), the particle diameter of gel C is 81 μm of (X
50);
(3) gel B and gel C are pressed 1: 1(w: w) mix, adjust ph to 11 ~ 12, add divinylsulfone (DVS), and cross-linking agent and hyaluronic acid mass ratio are react 30 h in 1.0%, 25 DEG C of water-baths.Adjust ph is to neutral, and dialysis removes unreacted small-molecule substance.
Table 4 one step is cross-linked the impact of crosslinker ratio
When the cross-linking agent that one step is crosslinked and hyaluronic acid mass ratio are 0.02 ~ 3.0%, the viscoelasticity of gel is moderate, and enzymatic degradation rate is adjustable; When cross-linking agent and hyaluronic acid mass ratio are less than 0.02%, the viscoelasticity of gel is very poor, and enzymatic degradation obtains very fast, so the crosslinked cross-linking agent of a step and hyaluronic acid mass ratio are decided to be 0.02 ~ 3.0%.
Embodiment 5
The present embodiment investigates the impact of the crosslinker ratio that two steps are cross-linked, and method is as follows:
(1) by 10 g hyaluronic acid dissolves in the NaOH solution of 100 ml (pH value is 13 ~ 14), after mixing, add cross-linking agent divinylsulfone (DVS), cross-linking agent and hyaluronic acid mass ratio are 1.0%, stirring and evenly mixing, reacts 8 h in 25 DEG C of water-baths, obtains cross-linking sodium hyaluronate gel A;
(2) cross-linking sodium hyaluronate gel A is granulated, gel B particle diameter be 198 μm of (X
50), the particle diameter of gel C is 81 μm of (X
50);
(3) by gel B and gel C by 1: 1(w: w) mix, adjust ph to 11 ~ 12, add divinylsulfone (DVS), cross-linking agent and hyaluronic mass ratio as shown in table 5, react 30 h in 25 DEG C of water-baths.Adjust ph is to neutral, and dialysis removes unreacted small-molecule substance.
Table 5 two step is cross-linked the impact of crosslinker ratio
When the cross-linking agent that two steps are crosslinked and hyaluronic acid mass ratio are 0.1 ~ 3.0%, the viscoelasticity of gel is moderate, and enzymatic degradation rate is adjustable; When cross-linking agent and hyaluronic acid mass ratio are less than 0.1%, the viscoelasticity of gel is very poor, and enzymatic degradation obtains very fast, so the crosslinked cross-linking agent of two steps and hyaluronic acid mass ratio are decided to be 0.1 ~ 3.0%.
Embodiment 6
The present embodiment investigates the elastomeric moisture retention of hyaluronic acid, and method is as follows:
Gel B(198 μm by embodiment 2) and gel C (72 μm) by 1: 1(w: w) after mix homogeneously, pH value is transferred to 2 ~ 4, and add 1,4-butanediol diglycidyl ether, cross-linking agent and hyaluronic acid mass ratio are 0.8%(w/w), in 15 DEG C of water-baths, react 30 h, then adjust ph is to neutral, and the unreacted small-molecule substance of dialysis removing obtains hyaluronic acid elastomer sample.
The sample of 5% and the HA solution of 0.1% is prepared respectively with the essence containing polyhydric alcohol, thickening agent and gels such as glycerol.Bend the pilot region of side labelling 5 4cm × 4cm at 10 left and right forearms of experimenter, smear the essence (w/w) containing 5% sample respectively, 0.1%HA essence (w/w) and contrast (essence), applying amount is 3.0 ± 0.1 mg/cm
2, be massaged into absorption of sample gently.Use moisture of skin analyzer and skin water loss analyzer to measure to smear front and skin moisture content after being coated with when 30min, 1h, 3h, 6h, 8h and 24h in each region and skin water loss amount.
Date processing (averaging):
Skin moisture content increment rate (%)=
× 100
Skin water loss increment rate (%)=
× 100
Hyaluronate sodium elastomer sample on the impact of skin moisture content in table 6, table 7.
Front and back skin moisture content increment rate (%) smeared by table 6
Result show, all sustainable 24h of the effect that 5% sample makes skin beauty water content increase, and moistening effect always than 0.1%HA and blank good.
Front and back moisture of skin windage increment rate (%) smeared by table 7
Result shows, and within 3 h, 5% sample solution effectively can suppress moisture loss, and effect is better than 0.1%HA and blank.
Embodiment 7
The wrinkle that the present embodiment investigates hyaluronic acid elastomer (sample of embodiment 6) fills efficacy assessments, and method is as follows:
Experimenter smears at left and right canthus sample and contrast (essence containing the polyhydric alcohol such as glycerol, thickening agent and gel) respectively, and applying amount is 3.0 ± 0.1 mg/cm2, is massaged into absorption of sample gently.3D skin fast imaging system on probation (PRIMOS, Germany) is evaluated and is smeared front and smear the change of canthus wrinkle mean depth of rear 30min, 1h, 3h and 6h.
Wrinkle mean depth Sa increment rate (%)=
× 100
Table 8 canthus wrinkle mean depth increment rate
| Sa relative value (%) | 30min | 1h | 3h | 6h |
| 5% sample | -2.67 | -2.24 | -1.96 | -1.85 |
| Contrast | 1.28 | 2.40 | 2.36 | 2.72 |
Hyaluronic acid elastomer, uses rear canthus wrinkle mean depth increment rate comparison to throw light on and shows reduction, so hyaluronic acid elastomer of the present invention has good wrinkle filling effect.
Embodiment 8
The present embodiment investigates the elastomeric cytotoxicity of hyaluronic acid, and according to EN ISO 10993-5: 2009 " biological assessment of medical apparatus and instruments--the 5th part: vitro cytotoxicity is tested " standard, detect cell proliferation rate, concrete grammar is as follows:
(1) prepare hyaluronic acid elastomer sample according to the method for embodiment 4, sample is added RPMI1640 culture fluid (0.2 g/ml), at 37 DEG C, lixiviate 72 h under 5% carbon dioxide conditions after mixing, 0.22 μm of membrane filtration is degerming, obtains lixiviating solution.
(2) by 1 × 10
5the L929 cell suspending liquid of individual/mL is inoculated in 96 porocyte culture plates, is placed in 37 DEG C of CO2 gas incubator and cultivates 24 hours, after cell attachment growth, removes supernatant, is divided into matched group and experimental group two groups.
(3) matched group adds RPMI1640 culture fluid; Experimental group adds the RPMI1640 culture fluid containing 50% above-mentioned lixiviating solution; Matched group and experimental group are placed in respectively 37 DEG C of CO2 gas incubator to continue to cultivate, took out after 2 days, the every hole of culture plate adds MTT solution (5mg/ml) 20 μ L, continues cultivation 4 h in 37 DEG C, stops cultivating.
(4) careful suction abandons culture supernatant in hole, and every hole adds 200 μ L DMSO, vibrates after mixing in 10 minutes, measures its absorbance with enzyme-linked immunosorbent assay instrument respectively under 630 nm.
(5) according to the relative appreciation rate of formulae discovery cell (RCR) below:
RCR(%)=(experimental group mean absorbance values/matched group mean absorbance values) × 100%.
Cell relative to appreciation rate RCR and cytotoxicity classification relationship as follows:
RCR is not less than 100%, and cytotoxicity is classified as 0 grade;
RCR is 75 ~ 99%, and cytotoxicity is classified as 1 grade;
RCR is 50 ~ 74%, and cytotoxicity is classified as 2 grades;
RCR is 25 ~ 49%, and cytotoxicity is classified as 3 grades;
RCR is 1 ~ 24%, and cytotoxicity is classified as 4 grades;
RCR is 0%, and cytotoxicity is classified as 5 grades;
The cell recorded with said method judges the elastomeric biocompatibility of hyaluronate sodium relative to appreciation rate.RCR is higher, shows that the elastomeric biocompatibility of cross-linked-hyaluronic acid to be measured is better.
Hyaluronic acid elastomer cytotoxicity testing result: the relative rate of increase of cell is the cell proliferation rate of 93.49%(negative control is 100%), cytotoxicity is I level.The elastomeric biocompatibility of gained hyaluronic acid of the present invention is very good.
To sum up, gained gel of the present invention has excellent viscoelasticity, moisture-retaining capacity, physics fill wrinkle ability, can slow release functional component, improve and use sensation, and there is good biocompatibility.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not by the restriction of embodiment; other is any do not deviate from spirit of the present invention and principle under make change, modification, combination, substitute, simplify and all should be equivalent substitute mode, be included within protection scope of the present invention.
Claims (10)
1. a hyaluronic acid elastomer, is characterized in that, is obtained by following steps:
(1) hyaluronic acid and cross-linking agent are reacted, obtain cross-linking sodium hyaluronate gel A;
(2) get cross-linking sodium hyaluronate gel A, select the screen cloth of different pore size to granulate respectively, obtain the different gel B of particle diameter and gel C;
(3) by gel B and gel C mixing, again carry out cross-linking reaction, adjust ph is to neutral, and dialysis, obtains hyaluronic acid elastomer.
2. hyaluronic acid elastomer according to claim 1, is characterized in that, cross-linking agent is the one in carbodiimide, divinylsulfone, Ethylene glycol diglycidyl ether, BDDE, the many glycidyl ethers of polyglycereol.
3. hyaluronic acid elastomer according to claim 1, is characterized in that, the pH value 2 ~ 4 of step (3) cross-linking reaction.
4. hyaluronic acid elastomer according to claim 1, is characterized in that, in step (3), the pH value of cross-linking reaction is 11 ~ 14.
5. hyaluronic acid elastomer according to claim 1, is characterized in that, in step (1), cross-linking agent and hyaluronic quality accounting are 0.02% ~ 3.0%, and in step (3), cross-linking agent and hyaluronic quality accounting are 0.1% ~ 3.0%.
6. hyaluronic acid elastomer according to claim 1, is characterized in that, in step (3), the mixed proportion of gel B and gel C is (1-9): (9-1).
7. hyaluronic acid elastomer according to claim 1, is characterized in that, in step (1), (3), cross-linking reaction temperature is 15 DEG C ~ 50 DEG C; Response time is 2 ~ 24 h.
8. hyaluronic acid elastomer according to claim 1, is characterized in that, the particle size range of gel B is 100 ~ 800 μm; The particle size range of gel C is 70 ~ 100 μm.
9. the compositions that the hyaluronic acid elastomers according to any one of a claim 1-8 becomes, it is characterized in that, also comprise in noncrosslinking hyaluronic acid, sunscreen, light protective agent, antioxidant, nutrient, vitamin, skin conditioning agent, irritated inhibitor, disinfectant, antiseptic, antimicrobial, antiparasitic or plant extract one or more.
10. the hyaluronic acid elastomer according to any one of a claim 1-8 is preparing the application in cosmetics, beauty treatment filling, orthopaedics injection or ophthalmology viscoelastic agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510109114.4A CN104771331B (en) | 2015-03-12 | 2015-03-12 | A kind of hyaluronic acid elastomer and its application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510109114.4A CN104771331B (en) | 2015-03-12 | 2015-03-12 | A kind of hyaluronic acid elastomer and its application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104771331A true CN104771331A (en) | 2015-07-15 |
| CN104771331B CN104771331B (en) | 2017-12-12 |
Family
ID=53613324
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510109114.4A Active CN104771331B (en) | 2015-03-12 | 2015-03-12 | A kind of hyaluronic acid elastomer and its application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104771331B (en) |
Cited By (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105194719A (en) * | 2015-10-28 | 2015-12-30 | 成都清科生物科技有限公司 | Facial wound restoration dressing and plaster, and preparation methods thereof |
| CN106580735A (en) * | 2016-10-26 | 2017-04-26 | 山东银河生物科技有限公司 | Skin care product containing sodium hyaluronate gel and preparing method thereof |
| CN107998437A (en) * | 2016-10-31 | 2018-05-08 | 常州药物研究所有限公司 | Nanometer cross-linking hyaluronic acid sodium gel and its preparation method and application |
| CN108395552A (en) * | 2017-12-15 | 2018-08-14 | 浙江景嘉医疗科技有限公司 | A kind of preparation method of single-phase cross-linking sodium hyaluronate gel |
| CN108743448A (en) * | 2018-08-30 | 2018-11-06 | 吉林省星空生物集团有限公司 | A kind of biological prosthetic facial mask and preparation method thereof |
| CN110200819A (en) * | 2019-06-05 | 2019-09-06 | 华熙生物科技股份有限公司 | A kind of hair sprays and preparation method thereof containing hyaluronic acid |
| CN110573190A (en) * | 2017-02-28 | 2019-12-13 | Cg生物技术有限公司 | Composition for skin injection |
| CN110573189A (en) * | 2017-02-28 | 2019-12-13 | Cg生物技术有限公司 | Composition for skin injection |
| CN110621355A (en) * | 2017-02-28 | 2019-12-27 | Cg生物技术有限公司 | Composition for skin injection |
| CN110893148A (en) * | 2018-09-13 | 2020-03-20 | 杭州维叶莫生物科技有限公司 | Composition containing dendrobium officinale and preparation method thereof |
| CN111603411A (en) * | 2020-05-26 | 2020-09-01 | 华熙生物科技股份有限公司 | Essence containing hyaluronic acid and preparation method thereof |
| CN112089643A (en) * | 2020-09-25 | 2020-12-18 | 华熙生物科技股份有限公司 | Oral care composition containing hyaluronic acid or salt thereof |
| CN112245366A (en) * | 2020-11-24 | 2021-01-22 | 山东华熙海御生物医药有限公司 | Permeation-promoting composition containing hyaluronic acid and application of permeation-promoting composition in cosmetics |
| FR3105922A1 (en) | 2020-01-08 | 2021-07-09 | Le Rouge Francais | Cosmetic composition for the treatment of the lips in the form of a compact solid containing at least one probiotic agent and at least one compound chosen from hyaluronic acid and its derivatives. |
| CN113164652A (en) * | 2018-12-20 | 2021-07-23 | 株式会社Lg化学 | Filler comprising hyaluronic acid hydrogel having excellent filler properties |
| CN114099409A (en) * | 2021-11-09 | 2022-03-01 | 优颜皮肤科学研究(广州)有限公司 | Soothing and repairing composition and application thereof |
| CN115245595A (en) * | 2022-07-28 | 2022-10-28 | 爱博诺德(北京)医疗科技股份有限公司 | Easily bolus hyaluronic acid-based gel composition |
| CN115572396A (en) * | 2022-12-08 | 2023-01-06 | 四川兴泰普乐医疗科技有限公司 | Sodium hyaluronate gel capable of being degraded in gradient manner and preparation method thereof |
| FR3148720A1 (en) | 2023-05-18 | 2024-11-22 | Le Rouge Francais | Aqueous cosmetic composition containing a probiotic agent, a compound chosen from hyaluronic acid and its derivatives, a particular colorant and a vegetable oil. |
| FR3151215A1 (en) | 2023-07-23 | 2025-01-24 | Le Rouge Francais | Powdered anhydrous topical cosmetic composition comprising a probiotic agent, hyaluronic acid or one of its derivatives, a particular colorant and a particular mineral powder. |
| WO2025139905A1 (en) * | 2023-12-29 | 2025-07-03 | 爱美客技术发展股份有限公司 | Injectable interlocking cross-linked hydrogel of hyaluronan or salt thereof, preparation method therefor and use thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101153061A (en) * | 2006-09-29 | 2008-04-02 | 北京普麦迪克生物技术研究所 | Hyaluronic acid and method of secondary crosslinked gel formation thereof |
| CN101925348A (en) * | 2007-12-07 | 2010-12-22 | 实验室维维西公司 | Biodegradable single-phase cohesive hydrogel |
| US20130237315A1 (en) * | 2010-09-20 | 2013-09-12 | Igt | Preventing a media display from hijacking a gaming machine |
| CN103917256A (en) * | 2011-11-11 | 2014-07-09 | 米巴医疗股份有限公司 | Injectable filler |
| CN104086788A (en) * | 2014-07-17 | 2014-10-08 | 华熙福瑞达生物医药有限公司 | Modified sodium hyaluronate gel for injection |
-
2015
- 2015-03-12 CN CN201510109114.4A patent/CN104771331B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101153061A (en) * | 2006-09-29 | 2008-04-02 | 北京普麦迪克生物技术研究所 | Hyaluronic acid and method of secondary crosslinked gel formation thereof |
| CN101925348A (en) * | 2007-12-07 | 2010-12-22 | 实验室维维西公司 | Biodegradable single-phase cohesive hydrogel |
| US20130237315A1 (en) * | 2010-09-20 | 2013-09-12 | Igt | Preventing a media display from hijacking a gaming machine |
| CN103917256A (en) * | 2011-11-11 | 2014-07-09 | 米巴医疗股份有限公司 | Injectable filler |
| CN104086788A (en) * | 2014-07-17 | 2014-10-08 | 华熙福瑞达生物医药有限公司 | Modified sodium hyaluronate gel for injection |
Cited By (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105194719A (en) * | 2015-10-28 | 2015-12-30 | 成都清科生物科技有限公司 | Facial wound restoration dressing and plaster, and preparation methods thereof |
| CN105194719B (en) * | 2015-10-28 | 2018-03-16 | 成都清科生物科技有限公司 | A kind of facial wound repairs dressing, application and preparation method thereof |
| CN106580735A (en) * | 2016-10-26 | 2017-04-26 | 山东银河生物科技有限公司 | Skin care product containing sodium hyaluronate gel and preparing method thereof |
| CN107998437A (en) * | 2016-10-31 | 2018-05-08 | 常州药物研究所有限公司 | Nanometer cross-linking hyaluronic acid sodium gel and its preparation method and application |
| CN110573189B (en) * | 2017-02-28 | 2022-01-25 | Cg生物技术有限公司 | Composition for skin injection |
| CN110573190B (en) * | 2017-02-28 | 2022-01-25 | Cg生物技术有限公司 | Composition for skin infusion |
| US10980829B2 (en) | 2017-02-28 | 2021-04-20 | Cg Bio Co., Ltd. | Composition for dermal injection |
| CN110573190A (en) * | 2017-02-28 | 2019-12-13 | Cg生物技术有限公司 | Composition for skin injection |
| CN110573189A (en) * | 2017-02-28 | 2019-12-13 | Cg生物技术有限公司 | Composition for skin injection |
| CN110621355A (en) * | 2017-02-28 | 2019-12-27 | Cg生物技术有限公司 | Composition for skin injection |
| CN110621355B (en) * | 2017-02-28 | 2022-01-21 | Cg生物技术有限公司 | Composition for skin injection |
| AU2018228301B2 (en) * | 2017-02-28 | 2020-12-17 | Cg Bio Co., Ltd. | Composition For Dermal Injection |
| CN108395552A (en) * | 2017-12-15 | 2018-08-14 | 浙江景嘉医疗科技有限公司 | A kind of preparation method of single-phase cross-linking sodium hyaluronate gel |
| CN108395552B (en) * | 2017-12-15 | 2021-03-19 | 浙江景嘉医疗科技有限公司 | Preparation method of single-phase cross-linked sodium hyaluronate gel |
| CN108743448A (en) * | 2018-08-30 | 2018-11-06 | 吉林省星空生物集团有限公司 | A kind of biological prosthetic facial mask and preparation method thereof |
| CN110893148A (en) * | 2018-09-13 | 2020-03-20 | 杭州维叶莫生物科技有限公司 | Composition containing dendrobium officinale and preparation method thereof |
| CN113164652A (en) * | 2018-12-20 | 2021-07-23 | 株式会社Lg化学 | Filler comprising hyaluronic acid hydrogel having excellent filler properties |
| CN110200819A (en) * | 2019-06-05 | 2019-09-06 | 华熙生物科技股份有限公司 | A kind of hair sprays and preparation method thereof containing hyaluronic acid |
| FR3105922A1 (en) | 2020-01-08 | 2021-07-09 | Le Rouge Francais | Cosmetic composition for the treatment of the lips in the form of a compact solid containing at least one probiotic agent and at least one compound chosen from hyaluronic acid and its derivatives. |
| CN111603411A (en) * | 2020-05-26 | 2020-09-01 | 华熙生物科技股份有限公司 | Essence containing hyaluronic acid and preparation method thereof |
| CN112089643A (en) * | 2020-09-25 | 2020-12-18 | 华熙生物科技股份有限公司 | Oral care composition containing hyaluronic acid or salt thereof |
| CN112245366A (en) * | 2020-11-24 | 2021-01-22 | 山东华熙海御生物医药有限公司 | Permeation-promoting composition containing hyaluronic acid and application of permeation-promoting composition in cosmetics |
| CN114099409A (en) * | 2021-11-09 | 2022-03-01 | 优颜皮肤科学研究(广州)有限公司 | Soothing and repairing composition and application thereof |
| CN114099409B (en) * | 2021-11-09 | 2024-08-06 | 优颜皮肤科学研究(广州)有限公司 | Relief repair composition and application thereof |
| CN115245595A (en) * | 2022-07-28 | 2022-10-28 | 爱博诺德(北京)医疗科技股份有限公司 | Easily bolus hyaluronic acid-based gel composition |
| CN115245595B (en) * | 2022-07-28 | 2024-05-24 | 爱博诺德(北京)医疗科技股份有限公司 | Hyaluronic acid-based gel compositions for easy bolus injection |
| CN115572396A (en) * | 2022-12-08 | 2023-01-06 | 四川兴泰普乐医疗科技有限公司 | Sodium hyaluronate gel capable of being degraded in gradient manner and preparation method thereof |
| CN115572396B (en) * | 2022-12-08 | 2023-03-24 | 四川兴泰普乐医疗科技有限公司 | Sodium hyaluronate gel capable of being degraded in gradient manner and preparation method thereof |
| FR3148720A1 (en) | 2023-05-18 | 2024-11-22 | Le Rouge Francais | Aqueous cosmetic composition containing a probiotic agent, a compound chosen from hyaluronic acid and its derivatives, a particular colorant and a vegetable oil. |
| FR3151215A1 (en) | 2023-07-23 | 2025-01-24 | Le Rouge Francais | Powdered anhydrous topical cosmetic composition comprising a probiotic agent, hyaluronic acid or one of its derivatives, a particular colorant and a particular mineral powder. |
| WO2025139905A1 (en) * | 2023-12-29 | 2025-07-03 | 爱美客技术发展股份有限公司 | Injectable interlocking cross-linked hydrogel of hyaluronan or salt thereof, preparation method therefor and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104771331B (en) | 2017-12-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104771331A (en) | Hyaluronic acid elastomer and applications thereof | |
| Pourjavadi et al. | Injectable chitosan/κ-carrageenan hydrogel designed with au nanoparticles: A conductive scaffold for tissue engineering demands | |
| US9872827B2 (en) | Cross-linked sodium hyaluronate gel for tissue filler for plastic surgery and preparation method thereof | |
| US8481080B2 (en) | Method of cross-linking hyaluronic acid with divinulsulfone | |
| CN102731801B (en) | Cross-linked sodium hyaluronate hydrogel for plastic surgery and preparation method thereof | |
| KR101868183B1 (en) | Process of preparing a cross linked gel | |
| Lee et al. | One-pot synthesis of silane-modified hyaluronic acid hydrogels for effective antibacterial drug delivery via sol–gel stabilization | |
| CN101502677B (en) | Crosslinking hyaluronic acid sodium gel for injection and preparation method thereof | |
| EP3412313A1 (en) | Temperature sensitive hydrogel composition including nucleic acid and chitosan | |
| CN104086788A (en) | Modified sodium hyaluronate gel for injection | |
| JP2002512087A (en) | Solid borate-diol reaction products for wounds | |
| US20100210587A1 (en) | Swellable Crosslinked Hyaluronan Powder And Method For Producing The Same | |
| CN101885853A (en) | Ripe cross-linked glutinous rice flour hydrogel and its preparation method and application | |
| CN105596367A (en) | Nano-silver antibacterial gel with chitosan-poloxamer as gel matrix and preparation method and application of nano-silver antibacterial gel | |
| CN101264348A (en) | Preparation technique of sodium hyaluronate gel granule | |
| CN104774337A (en) | Agarose microsphere-containing cross-linked sodium hyaluronate gel for injection and preparation method thereof | |
| La Gatta et al. | Hyaluronan dermal fillers via crosslinking with 1, 4‐butandiol diglycidyl ether: E xploitation of heterogeneous reaction conditions | |
| Tavakol et al. | Synthesis and characterization of an enzyme mediated in situ forming hydrogel based on gum tragacanth for biomedical applications | |
| CN113278170B (en) | A kind of chemically cross-linked hyaluronic acid hydrogel and preparation method and application thereof | |
| Dongre | Chitosan formulations: Chemistry, characteristics and contextual adsorption in unambiguous modernization of S&T | |
| CN109513043A (en) | A kind of injection modification hyaluronic acid sodium gel and preparation method thereof | |
| CN106999626B (en) | Biocompatible compositions and methods of preparation | |
| JP6372267B2 (en) | Phosphorylcholine group-containing sugar derivative and method for producing the same | |
| KR102163563B1 (en) | Method for preparing biocompatible poly-gamma-glutamate hydrogel using ultraviolet rays | |
| EP3533806A1 (en) | Gel composition and method for producing same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20180918 Address after: 250101 No. 3333, Century Avenue, high tech Zone, Ji'nan, Shandong Patentee after: SHANDONG BLOOMAGE HYINC BIOPHARM Corp.,Ltd. Address before: 250101 678 Tianchen street, hi tech Development Zone, Ji'nan, Shandong Patentee before: BLOOMAGE FREDA BIOPHARM Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20230621 Address after: Tianchen Avenue, Ji'nan hi tech Development Zone of Shandong Province, No. 678 250101 Patentee after: BLOOMAGE BIOTECH Co.,Ltd. Address before: 250101 No. 3333, Century Avenue, high tech Zone, Ji'nan, Shandong Patentee before: SHANDONG BLOOMAGE HYINC BIOPHARM Corp.,Ltd. |
|
| TR01 | Transfer of patent right |