CN118512359A - Concentrated hyaluronic acid stock solution and preparation method thereof - Google Patents
Concentrated hyaluronic acid stock solution and preparation method thereof Download PDFInfo
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- CN118512359A CN118512359A CN202410615897.2A CN202410615897A CN118512359A CN 118512359 A CN118512359 A CN 118512359A CN 202410615897 A CN202410615897 A CN 202410615897A CN 118512359 A CN118512359 A CN 118512359A
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- hyaluronic acid
- stock solution
- acid stock
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- sodium hyaluronate
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical 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 66
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 66
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 66
- 239000011550 stock solution Substances 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title abstract description 14
- 229920002385 Sodium hyaluronate Polymers 0.000 claims abstract description 56
- 229940010747 sodium hyaluronate Drugs 0.000 claims abstract description 56
- 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 56
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 36
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 claims abstract description 33
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 33
- 238000000855 fermentation Methods 0.000 claims abstract description 22
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- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims abstract description 17
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- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims abstract description 17
- 229940094978 bis-peg-18 methyl ether dimethyl silane Drugs 0.000 claims abstract description 16
- 229940015975 1,2-hexanediol Drugs 0.000 claims abstract description 13
- FHKSXSQHXQEMOK-UHFFFAOYSA-N hexane-1,2-diol Chemical compound CCCCC(O)CO FHKSXSQHXQEMOK-UHFFFAOYSA-N 0.000 claims abstract description 13
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 11
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229960001631 carbomer Drugs 0.000 claims abstract description 11
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims abstract description 5
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- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 2
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- 239000010905 bagasse Substances 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
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- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical compound CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
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- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- 229940035437 1,3-propanediol Drugs 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 1
- 229920002498 Beta-glucan Polymers 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 206010010726 Conjunctival oedema Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 208000006069 Corneal Opacity Diseases 0.000 description 1
- 208000028006 Corneal injury Diseases 0.000 description 1
- 206010011039 Corneal perforation Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 1
- 241001558929 Sclerotium <basidiomycota> Species 0.000 description 1
- 206010070835 Skin sensitisation Diseases 0.000 description 1
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- 230000002378 acidificating effect Effects 0.000 description 1
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- 210000002159 anterior chamber Anatomy 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229960002233 benzalkonium bromide Drugs 0.000 description 1
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960002152 chlorhexidine acetate Drugs 0.000 description 1
- 229960003333 chlorhexidine gluconate Drugs 0.000 description 1
- YZIYKJHYYHPJIB-UUPCJSQJSA-N chlorhexidine gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(Cl)=CC=C1NC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)NC1=CC=C(Cl)C=C1 YZIYKJHYYHPJIB-UUPCJSQJSA-N 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
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- NJDNXYGOVLYJHP-UHFFFAOYSA-L disodium;2-(3-oxido-6-oxoxanthen-9-yl)benzoate Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=CC(=O)C=C2OC2=CC([O-])=CC=C21 NJDNXYGOVLYJHP-UHFFFAOYSA-L 0.000 description 1
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- 239000000419 plant extract Substances 0.000 description 1
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- MCSINKKTEDDPNK-UHFFFAOYSA-N propyl propionate Chemical compound CCCOC(=O)CC MCSINKKTEDDPNK-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides concentrated hyaluronic acid stock solution and a preparation method thereof, which relate to the field of cosmetics and comprise the following components: purified concentrate of yeast fermentation product, bis-PEG-18-methylether dimethyl silane, glycerol, propylene glycol, 1, 2-hexanediol, sodium hyaluronate, p-hydroxyacetophenone, hydroxyethyl cellulose, carbomer, and triethanolamine. The product finally prepared by the synergistic combination of the raw materials has high skin compatibility, high stability and no eye irritation.
Description
Technical Field
The invention relates to the field of cosmetics, in particular to concentrated hyaluronic acid stock solution and a preparation method thereof.
Background
Hyaluronic acid is a component of the environment in the human body, and the hyaluronic acid in a commercialized form is also called hyaluronic acid, is an acidic mucopolysaccharide, is an important basic substance for skin tendering, and has a water-retaining effect. When the hyaluronic acid is applied to human bodies, the molecular weight span of hyaluronic acid can be extremely large, the minimum molecular weight can be only 5000 daltons, the highest molecular weight can be 2000 ten thousand daltons or more, the molecular weight of hyaluronic acid products for injection is 500 ten thousand-1000 ten thousand daltons, and the hyaluronic acid products can be biocompatible with human body healthy tissues. Hyaluronic acid in a human body is not regenerated after losing, so that the hyaluronic acid needs to be externally supplemented, and the problems of skin wrinkle aging and the like are solved.
The hyaluronic acid related product, such as patent CN113181079A, discloses a hyaluronic acid stock solution and a preparation method thereof, and the hyaluronic acid stock solution comprises the following components in percentage by mass: 0.1-1% of macromolecular sodium hyaluronate, 0.1-1% of medium molecular sodium hyaluronate, 0.1-1% of small molecular sodium hyaluronate, 1-10% of sodium hyaluronate cross-linked polymer, 0.2-2% of hydrolyzed sodium hyaluronate, 30-60% of glycerin, 1-10% of butanediol, 1-10% of 1, 3-propanediol, 1-2% of 1, 2-hexanediol and the balance of water. Wherein the molecular weight of the macromolecular sodium hyaluronate is more than or equal to 100 Da, the molecular weight of the medium molecular sodium hyaluronate is 20-60 Da, and the molecular weight of the small molecular sodium hyaluronate is less than or equal to 10 Da. The hyaluronic acid stock solution has good moisturizing effect, can permeate into skin, and can supplement sodium hyaluronate in human skin, so that the loss of sodium hyaluronate is delayed.
Also as disclosed in patent CN109260095A is a small molecule hyaluronic acid stock solution comprising the following components: sodium hyaluronate cross-linked polymer, sodium hyaluronate, hydrolyzed sodium hyaluronate, organic solvents, and plant extracts. The finally prepared product has the functions of repairing and water retention, has no anti-corrosion system, and is safe and has no stimulation. Patent CN109620752a discloses a hyaluronic acid stock solution and a preparation method thereof, comprising the following components in percentage by weight: 4-10% of butanediol, 2-7% of glycerol, 0.05-0.5% of sodium hyaluronate, 0.2-0.8% of hydroxyethyl cellulose, 0.5-2% of betaine, 1-5% of hydrolyzed chitin, 0.3-1.2% of p-hydroxyacetophenone, 0.5-2% of oat-beta glucan, 0.1-0.8% of a mixture of sclerotium gum and phenoxyethanol, 0.2-1% of 1, 2-hexanediol, and the balance of water. The invention utilizes the small molecular weight hyaluronic acid precursor to permeate into the skin, promotes the synthesis speed of hyaluronic acid in the skin, and has fresh and non-sticky texture, and can supplement water and preserve moisture.
However, at present, most hyaluronic acid stock solutions are complex in preparation method, and the prepared product is poor in compatibility with skin or has eye irritation. Aiming at the problems existing in the prior art, it is necessary to find a concentrated hyaluronic acid stock solution with high compatibility with skin and no eye irritation and a preparation method thereof.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides the concentrated hyaluronic acid stock solution and the preparation method thereof, and the prepared product has high skin compatibility, high stability and no eye irritation through the synergistic compounding of the raw materials.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
The invention provides concentrated hyaluronic acid stock solution, which comprises the following components: the purified concentrated solution of the saccharomycete fermentation product, bis-PEG-18-methyl ether dimethyl silane, glycerol, propylene glycol, 1, 2-hexanediol, sodium hyaluronate, p-hydroxyacetophenone, hydroxyethyl cellulose, carbomer, triethanolamine and water.
Further, the concentrated hyaluronic acid stock solution comprises the following components in parts by weight: 0.5-1 part of saccharomycete fermentation product purification concentrated solution, 0.5-5 parts of bis-PEG-18-methyl ether dimethyl silane, 5-10 parts of glycerin, 5-12 parts of propylene glycol, 0.5-1 part of 1, 2-hexanediol, 0.3-1 part of sodium hyaluronate, 0.2-1 part of p-hydroxyacetophenone, 1-5 parts of hydroxyethyl cellulose, 1-5 parts of carbomer, 0.5-3 parts of triethanolamine and 50-60 parts of water.
Preferably, the concentrated hyaluronic acid stock solution comprises the following components in parts by weight: 0.6 part of yeast fermentation product purification concentrated solution, 3 parts of bis-PEG-18-methyl ether dimethyl silane, 8 parts of glycerol, 8 parts of propylene glycol, 1 part of 1, 2-hexanediol, 0.5 part of sodium hyaluronate, 0.4 part of p-hydroxyacetophenone, 1.5 parts of hydroxyethyl cellulose, 2 parts of carbomer, 1 part of triethanolamine and 52 parts of water.
Further, the components also comprise one or more of isopropanol, essence, preservative and bacteriostat.
Further, the concentrated hyaluronic acid stock solution provided by the invention comprises a secondary polishing concentrated hyaluronic acid stock solution and a daily polishing concentrated hyaluronic acid stock solution.
Further, the concentrated hyaluronic acid stock solution of the present invention includes an ophthalmic concentrated hyaluronic acid stock solution and a dermatological concentrated hyaluronic acid stock solution.
In some specific embodiments, when the concentrated hyaluronic acid stock solution is a concentrated hyaluronic acid stock solution for skin and is a daily throwing concentrated hyaluronic acid stock solution, the components of the stock solution further include a bacteriostatic agent.
Preferably, the antibacterial agent is 0.005-0.02 parts by weight. Preferably 0.01 parts.
Further, the bacteriostatic agent comprises one or more of benzalkonium chloride, benzalkonium bromide, chlorhexidine acetate, chlorhexidine gluconate and chlorobutanol.
Further, the weight ratio of the purified concentrated solution of the saccharomycete fermentation product to the bis-PEG-18-methyl ether dimethyl silane to the p-hydroxyacetophenone to the hydroxyethyl cellulose is (0.5-1) to (0.5-5) to (0.2-1) to (1-5).
Preferably, the weight ratio of the purified concentrated yeast fermentation product solution, the bis-PEG-18-methyl ether dimethyl silane, the p-hydroxyacetophenone and the hydroxyethyl cellulose is 0.6:3:0.4:1.5.
In some embodiments, the ratio of the total weight of the yeast fermentation product purification concentrate and bis-PEG-18-methyl ether dimethylsilane to the total weight of the p-hydroxyacetophenone and hydroxyethyl cellulose is (1-6): (1.2-6); preferably 3.6:5.5.
Further, the sodium hyaluronate comprises one or more of ultra-large molecular sodium hyaluronate, medium molecular sodium hyaluronate, small molecular sodium hyaluronate and ultra-small molecular sodium hyaluronate;
Further, the molecular weight of the ultra-large molecular sodium hyaluronate is more than 2200000Da, the molecular weight of the large molecular sodium hyaluronate is 1800000-2200000Da, the molecular weight of the medium molecular sodium hyaluronate is 1000000-1800000Da, the molecular weight of the small molecular sodium hyaluronate is 400000-1000000Da, and the molecular weight of the ultra-small molecular sodium hyaluronate is less than 400000Da.
Further, sodium hyaluronate with different molecular weights can be mixed in any proportion according to the actual dissolution condition; preferably, the super-large molecular sodium hyaluronate, the medium molecular sodium hyaluronate, the small molecular sodium hyaluronate and the super-small molecular sodium hyaluronate are mixed according to the weight ratio of 1:10:100 (100-1000): 100-5000. Further preferably 1:10:100 (300-500): 1000, by weight, by mixing one or more of them; even more preferably 1:10:100:300:1000.
Further, the invention also provides a preparation method of the concentrated hyaluronic acid stock solution, which comprises the following steps:
(1) Mixing propylene glycol, 1, 2-hexanediol and p-hydroxyacetophenone, and heating to obtain a mixture A;
(2) Mixing sodium hyaluronate, hydroxyethyl cellulose and glycerol to obtain a mixture B;
(3) Heating water, adding the mixture A and the mixture B, adding the bis-PEG-18-methyl ether dimethyl silane, carbomer and triethanolamine, stirring uniformly, cooling, adding the purified concentrated solution of the saccharomycete fermentation product, and stirring uniformly to obtain the product.
Further, the heating temperatures in the step (1) and the step (3) are both 85-90 ℃, preferably 90 ℃, and the cooling temperature in the step (3) is less than or equal to 40 ℃.
The invention has the technical effects that:
According to the concentrated hyaluronic acid stock solution, components such as saccharomycete fermentation product purified concentrated solution, bis-PEG-18-methyl ether dimethyl silane, sodium hyaluronate, p-hydroxyacetophenone, hydroxyethyl cellulose and the like are compounded, and various types of sodium hyaluronate such as super-macromolecular sodium hyaluronate, medium-molecular sodium hyaluronate, small-molecular sodium hyaluronate, super-small-molecular sodium hyaluronate and the like are mixed for use, so that a synergistic effect exists among the components, and finally the prepared product has high skin compatibility and no eye irritation.
Detailed Description
Other advantages and effects of the present invention will become apparent to those skilled in the art from the following disclosure, which describes the embodiments of the present invention with reference to specific examples. The invention may be practiced or carried out in other embodiments that depart from the specific details, and the details of the present description may be modified or varied from the spirit and scope of the present invention.
Before the embodiments of the invention are explained in further detail, it is to be understood that the invention is not limited in its scope to the particular embodiments described below; it is also to be understood that the terminology used in the examples of the invention is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention.
Where numerical ranges are provided in the examples, it is understood that unless otherwise stated herein, both endpoints of each numerical range and any number between the two endpoints are significant both in the numerical range. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The preparation method of the purified concentrated solution of the saccharomycete fermentation product used in the invention specifically comprises the following steps: inoculating bifidobacterium longum in a seed culture medium (such as 10g of bean dregs and 3g of bagasse, supplementing water to 1 kg), performing anaerobic activation to obtain a seed solution, inoculating the seed solution in a fermentation culture medium (such as 10g of bean dregs and 3g of bagasse, supplementing water to 1 kg), adjusting the pH to 7, performing anaerobic fermentation culture, centrifuging the fermentation solution, and filtering by an ultrafiltration membrane to obtain a purified concentrated solution of a saccharomycete fermentation product, wherein bifidobacterium longum can be selected from bifidobacterium longum ATCC15707, bifidobacterium longum ATCC15697 and the like, the bifidobacterium longum ATCC15697 is selected in the embodiment of the invention, and the rest raw materials are common commercial products, so the sources of the concentrated solution are not particularly limited.
Examples 1 to 4 and comparative examples 1 to 4
TABLE 1 composition of concentrated hyaluronic acid stock solutions in examples 1-4 and comparative examples 1-4 according to the invention (unit: parts by weight)
In the above table, the preparation method of the concentrated hyaluronic acid stock solution in examples 1 to 3 comprises the following steps:
(1) Mixing propylene glycol, 1, 2-hexanediol and p-hydroxyacetophenone, and heating to 90 ℃ to obtain a mixture A;
(2) Mixing sodium hyaluronate, hydroxyethyl cellulose and glycerol to obtain a mixture B;
(3) Heating water to 90 ℃, adding the mixture A and the mixture B, adding the bis-PEG-18-methyl ether dimethyl silane, carbomer and triethanolamine, uniformly stirring, cooling to below 40 ℃, adding the saccharomycete fermentation product purified concentrated solution, and uniformly stirring to obtain the product.
The preparation method of example 4 comprises the following steps:
(1) Mixing propylene glycol, 1, 2-hexanediol and p-hydroxyacetophenone, and heating to 90 ℃ to obtain a mixture A;
(2) Mixing sodium hyaluronate, hydroxyethyl cellulose and glycerol to obtain a mixture B;
(3) Heating water to 90 ℃, adding the mixture A and the mixture B, adding the bis-PEG-18-methyl ether dimethyl silane, carbomer, triethanolamine and benzalkonium chloride, uniformly stirring, cooling to below 40 ℃, adding the purified concentrated solution of the saccharomycete fermentation product, and uniformly stirring to obtain the microbial fermentation product.
The preparation method of concentrated hyaluronic acid stock solutions in comparative examples 1 to 4 is the same as in examples 1 to 3, except that specific raw materials are not added, the amounts are adjusted or the components are replaced according to the specific formulation.
1. Eye irritation test
Reference is made to GB/T16886.10-2017 medical device biological evaluation part 10, irritation and skin sensitization test eye irritation test.
1.1 Exclusion criteria for test samples
In skin tests it has been demonstrated that samples of materials and/or end products (finished products) which do have a significant corrosiveness or severe irritation should not be subjected to eye irritation tests. Nor should any materials and/or end products that exhibit skin irritants or a pH <3 or a pH >11.5 be tested, these materials and/or end products are identified as eye irritants.
1.2 Administration of test samples
The samples in each of the examples and comparative examples were diluted 10-fold with pure water and filled into spray bottles, respectively, and sprayed at a distance of about 10cm from the open eyes of the test animals for 1 s. The concentrated hyaluronic acid stock solution of example 4 was stock solution added with bacteriostat, and was suitable for skin without eye irritation test.
1.3 Animals and management
Healthy, primary adult albino rabbits should be used, without limitation to male and female, and the weight of the same strain is 2kg-3kg. The subject animals should be acclimatized and evaluated in accordance with GB/T16886.2-2011, "medical device biology: animal welfare claim, prescribing a farm animal. The pilot initial test should use 1 animal to evaluate the test material and/or the final product. If no reaction is expected, 4 animals will be used for each sample initial trial, and the total score value is counted to determine whether a positive result is present.
The material was tested using at least two more animals if no clear reaction occurred. After at least 3 animals are used, if the test reaction is still suspected or ambiguous, a retest should be considered.
1.4 Test procedure
Each rabbit was checked for abnormalities in both eyes within 24 hours prior to the test, and should be eliminated if abnormalities were found. The eye may be inspected for corneal damage using 2% sodium fluorescein, or an ophthalmoscope, slit lamp or other suitable instrument.
Filling a test material into a spray bottle, and spraying for 1s at a position 10cm away from the open eyes; if the material and/or the final product is expected to be repeatedly exposed to the human body during actual use and no significant reaction is found in the acute test, multiple contact tests may be performed. Multiple contact tests can only be performed after the acute contact test is completed (at least after 72 hours). The contact period should be similar to the clinical life of the test material/instrument.
1.5 Animal observations
Animals sprayed with the test material at a time were examined for both eyes of each animal about 1h, 12h, 24h, 48h, and 72h after instillation. If persistent lesions are present, the observation time should be extended to determine the progressive and reversible nature of the lesions, but the delay is at most 21d, and cannot exceed 21d. There is no meaning to observe the delay of animals with serious injury. The observed responses were scored and recorded as per the eye injury scoring system specified in table 2. Animals that were sprayed with the test material multiple times were examined for both eyes of each animal about 1h before and after each spray. If there is a stimulus after the last spraying/dripping, the observation time should be prolonged. The observation time should also be prolonged in the presence of persistent cornea involvement symptoms or other eye irritation reactions to determine the progressive and reversible nature of the injury. The observed responses were scored and recorded according to the eye injury grading system specified in table 2.
Animals should be immediately eliminated from the trial and sacrificed painlessly if one of the following symptoms appears:
a) Extremely severe eye injuries (conjunctival dementia or ulcers, corneal perforation, blood and pus in the anterior chamber, etc.);
b) Blood or pus discharge;
c) Obvious corneal ulcers.
Animals should also be eliminated from the trial as shown by the maximum response of the fractionation system in table 2, which response is: loss of light reflex (iris response score 2) or corneal haze (score 4) and no reversible signs over 24 h; or conjunctivitis (bulbar conjunctival edema score 4 with concomitant congestion score 3) with no reversible signs over 48 h.
The obsolete animals should be sacrificed painlessly.
1.6 Evaluation of results:
the variability between test eyes and control eyes should be judged and interpreted by the scoring system in table 2.
Acute contact:
if more than 1 animal tested eyes reacted positively at any stage of observation (a in Table 2), the material was considered an eye irritant and no further testing was necessary.
If only 1 animal in the test eyes has moderate response or suspected response, another animal should be taken for retest.
In the case of a retest, if the animal test eye responds more than half way positively at any stage of observation (a in Table 2), the test material and/or end product is considered to be an ocular irritant.
It was sufficient that only 1 animal showed severe response to confirm that the material was an eye irritant.
Repeated contact:
If more than half of the animals in the test group showed a positive response at any stage of observation (a in Table 2), the test material was considered an eye irritant.
TABLE 2 eye injury scoring system
The results were counted in the following table.
TABLE 3 results of the eye irritation test for each of the examples and comparative examples
| Examples | Example number (only) | Score (score) |
| Example 1 | 4 | 0 |
| Example 2 | 4 | 0 |
| Example 3 | 4 | 0 |
| Comparative example 1 | 4 | 5a |
| Comparative example 2 | 4 | 4a |
| Comparative example 3 | 1 | - |
| Comparative example 4 | 4 | 7a |
( And (3) injection: in the table, "-" indicates that the preliminary initial test has a positive reaction and is not scored; the results in the table are average values, a indicating the occurrence of a positive result. )
According to analysis of test results, the concentrated hyaluronic acid stock solutions of the diluted examples 1-3 in the invention have no eye irritation and are suitable for eyes. In comparison, the hyaluronic acid stock solutions in comparative examples 1 to 4 all had different degrees of ocular irritation.
2. Stability test
2.1 Test procedure:
20mL of the hyaluronic acid stock solutions prepared in each example and comparative example are respectively taken and placed under the conditions of high temperature (50 ℃ +/-1 ℃) and relative humidity of 75+/-5% for 30 days, 3 parallel samples are tested in each group, the layering and precipitation states of the liquids are observed, and meanwhile, the ultraviolet spectrophotometer is used for measuring the light transmittance at 550nm at the end of the test (the light transmittance before the test is measured to be 100%).
2.2 Evaluation of results:
the results were counted in the following table.
Table 4 stability test results for each of the examples and comparative examples
| Examples | Status of | Transmittance (%) |
| Example 1 | Non-layering | 100 |
| Example 2 | Non-layering | 100 |
| Example 3 | Non-layering | 100 |
| Example 4 | Non-layering | 100 |
| Comparative example 1 | Slight delamination | 90.2 |
| Comparative example 2 | Obvious delamination | 85.4 |
| Comparative example 3 | Obvious delamination | 80.5 |
| Comparative example 4 | With precipitation | 65.8 |
According to analysis of test results, the hyaluronic acid stock solutions of the embodiments of the invention have good stability, and can be stored at high temperature for a long time without layering. In contrast, the hyaluronic acid stock solutions of the comparative examples all showed a layered or precipitated state, and the transmittance was significantly reduced.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.
Claims (10)
1. A concentrated hyaluronic acid stock solution, which is characterized in that: the composition comprises the following components: the purified concentrated solution of the saccharomycete fermentation product, bis-PEG-18-methyl ether dimethyl silane, glycerol, propylene glycol, 1, 2-hexanediol, sodium hyaluronate, p-hydroxyacetophenone, hydroxyethyl cellulose, carbomer, triethanolamine and water.
2. The concentrated hyaluronic acid stock solution of claim 1, wherein: the composite material comprises the following components in parts by weight: 0.5-1 part of saccharomycete fermentation product purification concentrated solution, 0.5-5 parts of bis-PEG-18-methyl ether dimethyl silane, 5-10 parts of glycerin, 5-12 parts of propylene glycol, 0.5-1 part of 1, 2-hexanediol, 0.3-1 part of sodium hyaluronate, 0.2-1 part of p-hydroxyacetophenone, 1-5 parts of hydroxyethyl cellulose, 1-5 parts of carbomer, 0.5-3 parts of triethanolamine and 50-60 parts of water.
3. The concentrated hyaluronic acid stock solution of claim 2, wherein: the composite material comprises the following components in parts by weight: 0.6 part of yeast fermentation product purification concentrated solution, 3 parts of bis-PEG-18-methyl ether dimethyl silane, 8 parts of glycerol, 8 parts of propylene glycol, 1 part of 1, 2-hexanediol, 0.5 part of sodium hyaluronate, 0.4 part of p-hydroxyacetophenone, 1.5 parts of hydroxyethyl cellulose, 2 parts of carbomer, 1 part of triethanolamine and 52 parts of water.
4. The concentrated hyaluronic acid stock solution of claim 1, wherein: the components also comprise one or more of isopropanol, essence, preservative and bacteriostat.
5. The concentrated hyaluronic acid stock solution of claim 1, wherein: the concentrated hyaluronic acid stock solution comprises secondary polishing concentrated hyaluronic acid stock solution and daily polishing concentrated hyaluronic acid stock solution.
6. The concentrated hyaluronic acid stock solution of claim 1, wherein: the concentrated hyaluronic acid stock solution comprises concentrated hyaluronic acid stock solution for eyes and concentrated hyaluronic acid stock solution for skin.
7. The concentrated hyaluronic acid stock solution of claim 1, wherein: when the concentrated hyaluronic acid stock solution is concentrated hyaluronic acid stock solution for skin and is concentrated hyaluronic acid stock solution for daily throwing edition, the stock solution also comprises a bacteriostatic agent.
8. The concentrated hyaluronic acid stock solution of claim 1, wherein: the weight ratio of the purified concentrated solution of the saccharomycete fermentation product to the bis-PEG-18-methyl ether dimethyl silane to the hydroxyacetophenone to the hydroxyethyl cellulose is 0.6:3:0.4:1.5.
9. The concentrated hyaluronic acid stock solution of claim 1, wherein: the sodium hyaluronate comprises one or more of ultra-large molecular sodium hyaluronate, medium molecular sodium hyaluronate, small molecular sodium hyaluronate and ultra-small molecular sodium hyaluronate;
the molecular weight of the ultra-large molecular sodium hyaluronate is more than 2200000Da, the molecular weight of the large molecular sodium hyaluronate is 1800000-2200000Da, the molecular weight of the medium molecular sodium hyaluronate is 1000000-1800000Da, the molecular weight of the small molecular sodium hyaluronate is 400000-1000000Da, and the molecular weight of the ultra-small molecular sodium hyaluronate is less than 400000Da.
10. The method for preparing concentrated hyaluronic acid stock solution according to any of claims 1-9, characterized in that: the method comprises the following steps:
(1) Mixing propylene glycol, 1, 2-hexanediol and p-hydroxyacetophenone, and heating to obtain a mixture A;
(2) Mixing sodium hyaluronate, hydroxyethyl cellulose and glycerol to obtain a mixture B;
(3) Heating water, adding the mixture A and the mixture B, adding the bis-PEG-18-methyl ether dimethyl silane, carbomer and triethanolamine, stirring uniformly, cooling, adding the purified concentrated solution of the saccharomycete fermentation product, and stirring uniformly to obtain the product.
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