CN114306126A - Water-in-oil nano emulsion and preparation method thereof - Google Patents
Water-in-oil nano emulsion and preparation method thereof Download PDFInfo
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- CN114306126A CN114306126A CN202111629352.XA CN202111629352A CN114306126A CN 114306126 A CN114306126 A CN 114306126A CN 202111629352 A CN202111629352 A CN 202111629352A CN 114306126 A CN114306126 A CN 114306126A
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- hyaluronic acid
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- 239000007908 nanoemulsion Substances 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims description 8
- 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 claims abstract description 154
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 154
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 154
- 239000000203 mixture Substances 0.000 claims abstract description 76
- 239000012071 phase Substances 0.000 claims abstract description 31
- 239000004480 active ingredient Substances 0.000 claims abstract description 25
- 239000008346 aqueous phase Substances 0.000 claims abstract description 22
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims description 75
- 239000003921 oil Substances 0.000 claims description 37
- 235000019198 oils Nutrition 0.000 claims description 22
- 239000004615 ingredient Substances 0.000 claims description 17
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
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- 235000019438 castor oil Nutrition 0.000 claims description 13
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 13
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 claims description 8
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 8
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 claims description 8
- UIVPNOBLHXUKDX-UHFFFAOYSA-N 3,5,5-trimethylhexyl 3,5,5-trimethylhexanoate Chemical compound CC(C)(C)CC(C)CCOC(=O)CC(C)CC(C)(C)C UIVPNOBLHXUKDX-UHFFFAOYSA-N 0.000 claims description 6
- 230000003712 anti-aging effect Effects 0.000 claims description 6
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims description 6
- BJRNKVDFDLYUGJ-RMPHRYRLSA-N hydroquinone O-beta-D-glucopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-RMPHRYRLSA-N 0.000 claims description 6
- 229940100554 isononyl isononanoate Drugs 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- YUZJJFWCXJDFOQ-UHFFFAOYSA-K manganese(3+);2-methoxy-6-[2-[(3-methoxy-2-oxidophenyl)methylideneamino]ethyliminomethyl]phenolate;chloride Chemical compound [Cl-].[Mn+3].COC1=CC=CC(C=NCCN=CC=2C(=C(OC)C=CC=2)[O-])=C1[O-] YUZJJFWCXJDFOQ-UHFFFAOYSA-K 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 230000003020 moisturizing effect Effects 0.000 claims description 6
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 claims description 6
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- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 claims description 4
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- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 claims description 3
- FYGDTMLNYKFZSV-URKRLVJHSA-N (2s,3r,4s,5s,6r)-2-[(2r,4r,5r,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5r,6s)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1[C@@H](CO)O[C@@H](OC2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-URKRLVJHSA-N 0.000 claims description 3
- 229920002498 Beta-glucan Polymers 0.000 claims description 3
- KNFLNGRLKALWRF-LDXSYGEZSA-N CSCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(N)=O)CC1=CC=CC=C1 Chemical compound CSCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(N)=O)CC1=CC=CC=C1 KNFLNGRLKALWRF-LDXSYGEZSA-N 0.000 claims description 3
- QRYRORQUOLYVBU-VBKZILBWSA-N Carnosic acid Natural products CC([C@@H]1CC2)(C)CCC[C@]1(C(O)=O)C1=C2C=C(C(C)C)C(O)=C1O QRYRORQUOLYVBU-VBKZILBWSA-N 0.000 claims description 3
- 108010087806 Carnosine Proteins 0.000 claims description 3
- 102000008186 Collagen Human genes 0.000 claims description 3
- 108010035532 Collagen Proteins 0.000 claims description 3
- 108010024636 Glutathione Proteins 0.000 claims description 3
- CQOVPNPJLQNMDC-UHFFFAOYSA-N N-beta-alanyl-L-histidine Natural products NCCC(=O)NC(C(O)=O)CC1=CN=CN1 CQOVPNPJLQNMDC-UHFFFAOYSA-N 0.000 claims description 3
- 235000019774 Rice Bran oil Nutrition 0.000 claims description 3
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 claims description 3
- 229960000271 arbutin Drugs 0.000 claims description 3
- CQOVPNPJLQNMDC-ZETCQYMHSA-N carnosine Chemical compound [NH3+]CCC(=O)N[C@H](C([O-])=O)CC1=CNC=N1 CQOVPNPJLQNMDC-ZETCQYMHSA-N 0.000 claims description 3
- 229940044199 carnosine Drugs 0.000 claims description 3
- 239000003240 coconut oil Substances 0.000 claims description 3
- 235000019864 coconut oil Nutrition 0.000 claims description 3
- 229920001436 collagen Polymers 0.000 claims description 3
- 229940008099 dimethicone Drugs 0.000 claims description 3
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims description 3
- 239000004205 dimethyl polysiloxane Substances 0.000 claims description 3
- 229940091557 ethylbisiminomethylguaiacol manganese chloride Drugs 0.000 claims description 3
- 229960003180 glutathione Drugs 0.000 claims description 3
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 3
- 229940049964 oleate Drugs 0.000 claims description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 3
- BJRNKVDFDLYUGJ-UHFFFAOYSA-N p-hydroxyphenyl beta-D-alloside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 230000035699 permeability Effects 0.000 claims description 3
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims description 3
- 239000008165 rice bran oil Substances 0.000 claims description 3
- 229960005078 sorbitan sesquioleate Drugs 0.000 claims description 3
- SHWIJIJNPFXOFS-UHFFFAOYSA-N thiotaurine Chemical compound NCCS(O)(=O)=S SHWIJIJNPFXOFS-UHFFFAOYSA-N 0.000 claims description 3
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 claims description 3
- 229960000401 tranexamic acid Drugs 0.000 claims description 3
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 claims description 3
- PLISWQKGWPUZID-UHFFFAOYSA-N 2-hydroxy-4-methoxybenzoic acid;potassium Chemical compound [K].COC1=CC=C(C(O)=O)C(O)=C1 PLISWQKGWPUZID-UHFFFAOYSA-N 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 210000003491 skin Anatomy 0.000 abstract description 23
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- 239000002245 particle Substances 0.000 abstract description 3
- 229920002385 Sodium hyaluronate Polymers 0.000 description 27
- 229940010747 sodium hyaluronate Drugs 0.000 description 27
- 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 description 27
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- 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 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
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- MRIXVKKOHPQOFK-UHFFFAOYSA-N 4-methoxysalicylic acid Chemical compound COC1=CC=C(C(O)=O)C(O)=C1 MRIXVKKOHPQOFK-UHFFFAOYSA-N 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Cosmetics (AREA)
Abstract
The present invention provides a water-in-oil nanoemulsion comprising an oil phase, an aqueous phase, and an emulsifier, wherein the aqueous phase comprises a hyaluronic acid composition. The hyaluronic acid composition is added into the formula of the water-in-oil nanoemulsion and serves as an internal phase of the nanoemulsion, so that a storage effect can be realized in a dermis layer, the storage of active ingredients in a skin is enhanced, and the active ingredients can be conveyed to a skin deep layer with better hydrophilicity by combining the characteristics of small particle size and easiness in permeation of the nanoemulsion, so that the transdermal absorption effect is synergistically enhanced; meanwhile, the water-in-oil nano emulsion can wrap water-soluble active ingredients with poor stability, so that the stability is enhanced, and the problem of irritation is solved.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to a water-in-oil nano emulsion and a preparation method thereof.
Background
The nano emulsion is a transparent or semitransparent system consisting of a water phase, an oil phase, a surfactant and a cosurfactant. Compared with the traditional emulsion, most of the nano-emulsion can effectively prevent unstable processes such as layering, sedimentation, aggregation and the like, so that the nano-emulsion is widely applied to petroleum, food and cosmetics.
In practical applications of skin care products, the active ingredient must penetrate to the specific skin site to be effective. The transdermal capacity of the active substance is related to the molecular weight, and the components with the molecular weight more than 500 are not easy to permeate into the skin, and the transdermal of the active ingredients can be promoted by adopting nano preparations such as nano emulsion, micro emulsion, liposome and the like. In addition, the stratum corneum of the human body is lipophilic, oil-soluble ingredients are more easily taken into the skin than water-soluble active ingredients, the outer phase of the water-in-oil nanoemulsion is an oil phase and has better affinity with the skin, and the water-in-oil nanoemulsion is an effective way for promoting the absorption of the active ingredients.
However, the conventional water-in-oil preparation only can improve the absorption of oil-soluble ingredients in the external phase and has no obvious effect on promoting the absorption of water-soluble active ingredients in the internal water phase. Therefore, the water-in-oil nano emulsion obtained by the invention has good stability and good transdermal absorption effect, and has important significance for enhancing the skin care effect.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a water-in-oil nano emulsion and a preparation method thereof.
Specifically, the present invention relates to the following aspects:
1. a water-in-oil nanoemulsion comprising an oil phase, an aqueous phase, and an emulsifier, wherein the aqueous phase comprises a hyaluronic acid composition.
2. The nanoemulsion according to item 1, characterized in that the oil phase in the nanoemulsion ranges from 5 to 80% by mass, preferably from 10 to 60% by mass, the hyaluronic acid composition ranges from 0.01% to 10% by mass, preferably from 0.01% to 1% by mass, more preferably from 0.01% to 0.5% by mass, and the emulsifier ranges from 0.01% to 20% by mass, preferably from 0.5% to 10% by mass.
3. The nanoemulsion as set forth in item 1, wherein the hyaluronic acid composition comprises medium molecular weight hyaluronic acid or a salt thereof, acetylated hyaluronic acid or a salt thereof, and hydrolyzed hyaluronic acid or a salt thereof, preferably the medium molecular weight hyaluronic acid or a salt thereof has a molecular weight of 200-700kDa, preferably 200-400kDa, more preferably the acetylated hyaluronic acid or a salt thereof has a molecular weight of 20-40kDa, and still more preferably the hydrolyzed hyaluronic acid or a salt thereof has a molecular weight of 3-18 kDa.
4. The nanoemulsion according to item 3, characterized in that the content of the medium molecular weight hyaluronic acid or the salt thereof is 20-60%, preferably 25-40%, the content of the acetylated hyaluronic acid or the salt thereof is 10-50%, preferably 20-35%, and the content of the hydrolyzed hyaluronic acid or the salt thereof is 30-70%, preferably 40-55%, in terms of mass percentage in the hyaluronic acid composition.
5. The nanoemulsion of item 1, wherein the aqueous phase also includes a water-soluble active ingredient.
6. The nanoemulsion according to claim 1, wherein the water-soluble active ingredient is one or more of a whitening functional ingredient, a moisturizing functional ingredient and an anti-aging functional ingredient, the whitening functional ingredient is one or more selected from nonapeptide-1, tranexamic acid, nicotinamide, thiotaurine, 4-methoxysalicylate, arbutin, glutathione and ethylbisiminomethylguaiacol manganese chloride (EUK-134), the moisturizing functional ingredient is one or more selected from ectoin, carnosine and beta-glucan, and the anti-aging functional ingredient is one or more selected from Polydeoxyribonucleotide (PDRN), gamma-aminobutyric acid and collagen.
7. The nanoemulsion according to claim 1, characterized in that the oil phase is selected from one or more of squalane, rice bran oil, caprylic/capric triglyceride, coconut oil, isononyl isononanoate (ISIS).
8. The nanoemulsion according to item 1, characterized in that the emulsifier is selected from one or more of polyglycerol-2 dipolyhydroxystearate, polyglycerol-2 oleate, polyglycerol-3 diisostearate, cetyl PEG/PPG-10/1 dimethicone, PEG40 hydrogenated castor oil, sorbitan sesquioleate, PEG-20 glycerol tristearate, preferably a mixture of polyglycerol-3 diisostearate and PEG40 hydrogenated castor oil, and further preferably the mass ratio of polyglycerol-3 diisostearate to PEG40 hydrogenated castor oil is 1:4-2: 3.
9. The method of preparing a nanoemulsion as set forth in any one of claims 1-8, characterized in that it comprises the following steps:
dissolving the emulsifier in the liquid oil to form an oil phase,
dissolving a hyaluronic acid composition in water to form an aqueous phase,
mixing and homogenizing the oil phase and the water phase at the same temperature to obtain nano emulsion;
preferably, the step of dissolving the hyaluronic acid composition in water to form an aqueous phase comprises:
the hyaluronic acid composition and the water-soluble active ingredient are dissolved in water to form an aqueous phase.
10. A cosmetic comprising the nanoemulsion of any one of items 1-8.
11. Use of a hyaluronic acid composition for increasing stability and/or permeability of a nanoemulsion, wherein the hyaluronic acid composition comprises medium molecular weight hyaluronic acid or a salt thereof, acetylated hyaluronic acid or a salt thereof and hydrolysed hyaluronic acid or a salt thereof;
preferably, the molecular weight of the medium molecular weight hyaluronic acid or the salt thereof is 200-700kDa, preferably 200-400kDa, the molecular weight of the acetylated hyaluronic acid or the salt thereof is 20-40kDa, and the molecular weight of the hydrolyzed hyaluronic acid or the salt thereof is 3-18 kDa;
further preferably, the content of the medium molecular weight hyaluronic acid or the salt thereof is 20 to 60%, preferably 25 to 40%, the content of the acetylated hyaluronic acid or the salt thereof is 10 to 50%, preferably 20 to 35%, and the content of the hydrolyzed hyaluronic acid or the salt thereof is 30 to 70%, preferably 40 to 55%, in terms of mass percentage in the hyaluronic acid composition.
The hyaluronic acid composition is added into the formula of the water-in-oil nanoemulsion and serves as an internal phase of the nanoemulsion, so that a storage effect can be realized in a dermis layer, the storage of active ingredients in a skin is enhanced, and the active ingredients can be conveyed to a skin deep layer with better hydrophilicity by combining the characteristics of small particle size and easiness in permeation of the nanoemulsion, so that the transdermal absorption effect is synergistically enhanced; meanwhile, the water-in-oil nano emulsion can wrap water-soluble active ingredients with poor stability, so that the stability is enhanced, and the problem of irritation is solved.
Detailed Description
The present invention is further illustrated by the following examples, which are intended to be purely exemplary of the invention and are not intended to be limiting.
Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in experimental or practical applications, the materials and methods are described below. In case of conflict, the present specification, including definitions, will control, and the materials, methods, and examples are illustrative only and not intended to be limiting. The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
The present invention provides a water-in-oil nanoemulsion, wherein the nanoemulsion comprises an oil phase, an aqueous phase encapsulating the oil phase, and an emulsifier, wherein the aqueous phase comprises a hyaluronic acid composition.
Further, the oil phase in the nanoemulsion may be 5 to 80% by mass, for example, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, preferably 10 to 60%. The hyaluronic acid composition may be 0.01% to 10% by mass, for example, 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, preferably 0.01% to 1%, and more preferably 0.01% to 0.5%. The emulsifier is 0.01 to 20% by mass, and may be, for example, 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, preferably 0.5 to 10% by mass.
The hyaluronic acid composition according to the invention may refer to any composition comprising hyaluronic acid or salts thereof in various forms.
In a particular embodiment, the hyaluronic acid composition comprises medium molecular weight hyaluronic acid or a salt thereof, acetylated hyaluronic acid or a salt thereof, and hydrolyzed hyaluronic acid or a salt thereof.
In a specific embodiment, the medium molecular weight hyaluronic acid or salt thereof has a molecular weight of 200-700kDa, preferably 200-400 kDa. For example, the molecular weight of the nucleic acid molecule may be 200kDa, 300kDa, 400kDa, 500kDa, 600kDa or 700 kDa.
Acetylated hyaluronic acid (AcHA) is obtained by acetylation of sodium Hyaluronate, and introduction of acetyl brings lipophilicity to hyaluronic acid.
In a specific embodiment, the acetylated hyaluronic acid or salt thereof has a molecular weight of 20-40 kDa. For example, the nucleic acid molecule may be 20kDa, 25kDa, 30kDa, 35kDa or 40 kDa.
The hydrolyzed hyaluronic acid or the salt thereof is small molecular weight hyaluronic acid obtained by enzymolysis of hyaluronic acid or the salt thereof, and the hydrolyzed hyaluronic acid with different molecular weights can be obtained by controlling enzymolysis conditions. The research finds that the physiological action of the hyaluronic acid is closely related to the molecular weight, and the hyaluronic acid with different molecular weights has different biological activities. The hyaluronic acid with small molecular weight has the functions of immunocompetence, promoting the proliferation of vascular endothelial cells, reversing the multidrug resistance of tumor cells and the like. Meanwhile, hydrolyzed hyaluronic acid can permeate into the epidermis due to small molecular weight.
In a particular embodiment, the hydrolyzed hyaluronic acid or salt thereof has a molecular weight of 3-18kDa, such as 3kDa, 4kDa, 5kDa, 6kDa, 7kDa, 8kDa, 9kDa, 10kDa, 11kDa, 12kDa, 13kDa, 14kDa, 15kDa, 16kDa, 17kDa, 18 kDa.
Further, in the hyaluronic acid composition, the content of the medium molecular weight hyaluronic acid or the salt thereof is 20 to 60% by mass percentage in the hyaluronic acid composition, and for example, may be 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, and preferably 25 to 40%. The content of the acetylated hyaluronic acid or salt thereof is 10 to 50%, and may be, for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%. Preferably 20 to 35%. The content of the hydrolyzed hyaluronic acid or a salt thereof is 30 to 70%, and for example, may be 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, and preferably 40 to 55%.
In a specific embodiment, the hyaluronic acid composition consists of medium molecular weight hyaluronic acid or a salt thereof, acetylated hyaluronic acid or a salt thereof, and hydrolyzed hyaluronic acid or a salt thereof.
In a specific embodiment, in the hyaluronic acid composition, the content of the medium molecular weight hyaluronic acid or the salt thereof is 25 to 40%, the content of the acetylated hyaluronic acid or the salt thereof is 20 to 35%, and the content of the hydrolyzed hyaluronic acid or the salt thereof is 40 to 55% by mass percentage in the hyaluronic acid composition.
In a specific embodiment, in the hyaluronic acid composition, the content of the medium molecular weight hyaluronic acid or the salt thereof is 30%, the content of the acetylated hyaluronic acid or the salt thereof is 25%, and the content of the hydrolyzed hyaluronic acid or the salt thereof is 45% by mass percentage in the hyaluronic acid composition.
In a specific embodiment, in the hyaluronic acid composition, the content of the medium molecular weight hyaluronic acid or the salt thereof is 20%, the content of the acetylated hyaluronic acid or the salt thereof is 10%, and the content of the hydrolyzed hyaluronic acid or the salt thereof is 70% by mass percentage in the hyaluronic acid composition.
In a specific embodiment, in the hyaluronic acid composition, the content of the medium molecular weight hyaluronic acid or the salt thereof is 20%, the content of the acetylated hyaluronic acid or the salt thereof is 50%, and the content of the hydrolyzed hyaluronic acid or the salt thereof is 30% by mass percentage in the hyaluronic acid composition.
In a specific embodiment, in the hyaluronic acid composition, the content of the medium molecular weight hyaluronic acid or the salt thereof is 60%, the content of the acetylated hyaluronic acid or the salt thereof is 10%, and the content of the hydrolyzed hyaluronic acid or the salt thereof is 30% by mass percentage in the hyaluronic acid composition.
In a particular embodiment, the oil phase is selected from one or more of squalane, rice bran oil, caprylic/capric triglyceride, coconut oil, isononyl isononanoate (ISIS).
In a particular embodiment, the emulsifier is selected from one or more of polyglyceryl-2 dipolyhydroxystearate, polyglyceryl-2 oleate, polyglyceryl-3 diisostearate, cetyl PEG/PPG-10/1 dimethicone, PEG40 hydrogenated castor oil, sorbitan sesquioleate, PEG-20 glyceryl tristearate, preferably a mixture of polyglyceryl-3 diisostearate and PEG40 hydrogenated castor oil. Further preferably, the mass ratio of the polyglycerol-3 diisostearate to the PEG40 hydrogenated castor oil is 1:4 to 2:3, and may be, for example, 1:4, 1:3, 1:2, 1:1, 2:3, and the like.
The water-in-oil nanoemulsion of the present invention may further contain a water-soluble active ingredient in the aqueous phase. Wherein the water-soluble active ingredient is one or more of whitening functional ingredient, moisturizing functional ingredient and anti-aging functional ingredient.
The whitening functional component is one or more than two of nonapeptide-1, tranexamic acid, nicotinamide, thiotaurine, 4-methoxy potassium salicylate, arbutin, glutathione and ethyl bis-imino methyl guaiacol manganese chloride (EUK-134), the moisturizing functional component is one or more than two of ectoin, carnosine and beta-glucan, and the anti-aging functional component is one or more than two of Polydeoxyribonucleotide (PDRN), gamma-aminobutyric acid and collagen.
The invention also provides a preparation method of the nano emulsion, which comprises the following steps:
dissolving the emulsifier in the liquid oil to form an oil phase,
dissolving a hyaluronic acid composition in water to form an aqueous phase,
and mixing and homogenizing the oil phase and the water phase at the same temperature to obtain the nano emulsion.
Wherein the step of dissolving the hyaluronic acid composition in water to form an aqueous phase may further comprise:
the hyaluronic acid composition and the water-soluble active ingredient are dissolved in water to form an aqueous phase.
Wherein the composition and content of the hyaluronic acid composition, the water-soluble active ingredient and the like are as described above.
The invention also provides a cosmetic comprising the nanoemulsion.
The present invention also provides the use of a hyaluronic acid composition for increasing the stability and/or permeability of a nanoemulsion, wherein the hyaluronic acid composition comprises medium molecular weight hyaluronic acid or a salt thereof, acetylated hyaluronic acid or a salt thereof and hydrolysed hyaluronic acid or a salt thereof.
In a specific embodiment, the medium molecular weight hyaluronic acid or salt thereof has a molecular weight of 200-700kDa, preferably 200-400kDa, the acetylated hyaluronic acid or salt thereof has a molecular weight of 20-40kDa, and the hydrolyzed hyaluronic acid or salt thereof has a molecular weight of 3-18 kDa.
In a specific embodiment, the content of the medium molecular weight hyaluronic acid or the salt thereof is 20 to 60%, preferably 25 to 40%, the content of the acetylated hyaluronic acid or the salt thereof is 10 to 50%, preferably 20 to 35%, and the content of the hydrolyzed hyaluronic acid or the salt thereof is 30 to 70%, preferably 40 to 55%, by mass percentage in the hyaluronic acid composition
The present invention prepares a nanoemulsion using a hyaluronic acid composition, particularly a composition including medium molecular weight hyaluronic acid, acetylated hyaluronic acid and hydrolyzed hyaluronic acid, and a specific emulsifier, so that the nanoemulsion has higher stability at both low and high temperatures. The hyaluronic acid composition is used as the internal phase of the nano-emulsion, can play a role of storage in a dermis layer, enhances the storage of active ingredients in a skin, and can deliver the active ingredients to a skin deep layer with better hydrophilicity by combining the characteristics of small particle size and easy penetration of the nano-emulsion, thereby synergistically enhancing the transdermal absorption effect; meanwhile, the water-in-oil nano emulsion can wrap water-soluble active ingredients with poor stability, so that the stability is enhanced, and the problem of irritation is solved.
Examples
The experimental methods used in the following examples are all conventional methods, unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified, and sodium hyaluronate used is commercially available from Huaxi Biotech Ltd.
Example 1
(1) Adding 2g of polyglycerol-3 diisostearate and 8g of PEG40 hydrogenated castor oil into 55g of squalane, heating to 80 ℃ to obtain an oil phase, dissolving 0.2g of a hyaluronic acid composition (wherein the hyaluronic acid composition contains 30% of sodium hyaluronate with a medium molecular weight, 400kDa of a molecular weight of 200, 25% of sodium acetylated hyaluronate with a molecular weight of 20-30kDa, 45% of sodium hydrolyzed hyaluronate with a molecular weight of 3-10kDa) and 3g of gamma-aminobutyric acid in 31.8g of ultrapure water, and heating to 80 ℃ to dissolve the gamma-aminobutyric acid to obtain a water phase;
(2) heating the two-phase substances to 80 ℃, mixing and stirring uniformly, and homogenizing by using a homogenizer to obtain a coarse emulsion;
(3) and (3) placing the obtained crude emulsion into a high-pressure homogenizer, and homogenizing for 2 times, 5min each time to obtain the nano emulsion.
Examples 2 to 5
Examples 2 to 5 differ from example 1 only in the amount of the hyaluronic acid composition and ultrapure water added. The addition amount of the hyaluronic acid composition in example 2 was 0.1g, the addition amount of the hyaluronic acid composition in example 3 was 0.5g, the addition amount of the hyaluronic acid composition in example 4 was 1g, the addition amount of the hyaluronic acid composition in example 5 was 0.005g, and the specific component contents are shown in table 1.
Examples 6 to 12
Examples 6-12 differ from example 1 only in the composition of the hyaluronic acid composition. The difference between the example 6 and the example 1 is that the contents of the medium molecular weight sodium hyaluronate, the acetylated sodium hyaluronate and the hydrolyzed sodium hyaluronate are different, wherein the content of the medium molecular weight sodium hyaluronate is 20%, the molecular weight is 200-400kDa, the content of the acetylated sodium hyaluronate is 10%, the molecular weight is 20-30kDa, and the content of the hydrolyzed sodium hyaluronate is 70%. Example 7 differs from example 1 in the content of medium molecular weight sodium hyaluronate, molecular weight 200-400kDa, acetylated sodium hyaluronate 50%, molecular weight 20-30kDa and hydrolyzed sodium hyaluronate 30%. Example 8 differs from example 1 in the content of medium molecular weight sodium hyaluronate, acetylated sodium hyaluronate and hydrolyzed sodium hyaluronate, wherein the content of medium molecular weight sodium hyaluronate is 60%, the molecular weight is 200-400kDa, the content of acetylated sodium hyaluronate is 10%, the molecular weight is 20-30kDa and the content of hydrolyzed sodium hyaluronate is 30%. The hyaluronic acid composition of example 9 contained only medium molecular weight sodium hyaluronate, which had a molecular weight of 200-400 kDa. The hyaluronic acid composition of example 10 contained only sodium hyaluronate acetylated, with a molecular weight of 20-30 kDa. The hyaluronic acid composition of example 11 contained only hydrolyzed sodium hyaluronate, which had a molecular weight of 3-10 kDa. Example 12 differs from example 1 in the content of medium molecular weight sodium hyaluronate, acetylated sodium hyaluronate, and hydrolyzed sodium hyaluronate, wherein the content of medium molecular weight sodium hyaluronate is 60%, the molecular weight is 200-400kDa, the content of acetylated sodium hyaluronate is 15%, the molecular weight is 20-30kDa, and the content of hydrolyzed sodium hyaluronate is 25%. The specific contents of the components are shown in table 1.
Examples 13 to 16
Examples 13-16 differ from example 1 only in the composition of the emulsifier. Wherein the emulsifier in example 13 is 4g of polyglyceryl-3 diisostearate and 6g of PEG40 hydrogenated castor oil, the emulsifier in example 14 is 10g of polyglyceryl-3 diisostearate, the emulsifier in example 15 is 10g of PEG40 hydrogenated castor oil, and the emulsifier in example 16 is 6g of polyglyceryl-3 diisostearate and 4g of PEG40 hydrogenated castor oil. The specific contents of the components are shown in table 1.
Comparative example 1
Comparative example 1 differs from example 1 only in that the aqueous phase does not contain the hyaluronic acid composition. That is, when preparing the aqueous phase in step 1, the hyaluronic acid composition was not added, and only 3g of gamma-aminobutyric acid was added.
Comparative example 2
Comparative example 2 is a solution obtained by directly dissolving 3g of gamma-aminobutyric acid in 97g of ultrapure water.
TABLE 1
Test examples
Test example 1 stability test
High-temperature test: the nano-emulsions prepared in examples and comparative examples were used as samples to be tested and placed in a suitable clean container at 55 ℃ for 10 days, and samples were taken on days 5 and 10 to observe the delamination of the samples.
And (3) low-temperature test: placing the sample to be tested in a proper clean container, placing the container for 5 days at the temperature of minus 20 ℃, sampling on the 5 th day, and observing the layering condition of the sample.
Centrifugal stability: the centrifuge tube was filled with the sample to be tested at about 2/3 height and stoppered. Then placing into an electric heating constant temperature incubator pre-adjusted to 38 ℃, keeping for 1h, immediately transferring into a centrifuge, adjusting the centrifuge to a centrifugal speed of 2000r/min, rotating for 30min, taking out and observing.
The test results are shown in the following table 2, and it can be known from the data in table 2 that the addition of the hyaluronic acid composition has an important influence on the stability of the emulsion, and the high-temperature stability of the water-in-oil nanoemulsion added with the hyaluronic acid composition is obviously improved; different emulsifier dosages in the system have important influence on the system stability.
TABLE 2
Test example 2 penetration-promoting test
The samples of examples 1 to 4, 6 to 8, 13 and comparative examples, which had no stability problems, were subjected to Franz diffusion cell permeation experiments to investigate the permeation promoting effect of hyaluronic acid compositions on active substances.
The in vitro pigskin is fixed between a supply pool and a receiving pool of a Phoenix DB-6 transdermal test system, and according to the liquid height of a sampling tube, about 15ml of PBS buffer solution is added into the sampling tube to exhaust air, so that the skin dermis layer is in close contact with the receiving liquid. Then 49 μ L of the sample to be tested was added to the skin surface and the sample was spread evenly from the center of the skin to the edge in a radial pattern using a stainless steel stir bar. Each sample was replicated in 3 replicates and was uniformly stirred while maintaining a constant temperature water bath at (32. + -. 1). degree.C.at a speed of 300 rpm/min. After diffusion for 20h, samples of the pigskin surface, the skin interior and the receiving liquid are collected and detected by high performance liquid chromatography to determine the in vitro transdermal efficiency.
Wherein,
relative retention (%). the skin partial assay/loading of test article%
Skin-to-skin retention ratio (part of skin detected amount of test substance/part of skin detected amount of comparative example 2)
TABLE 3 Retention ratio in skin test results
As can be seen from table 3, at the 20h node, the active retention in the skin was improved in the examples compared to the comparative examples. The most obvious improvement is shown in example 1, and the retention can be improved by 18%, which shows that the hyaluronic acid composition can promote the storage of the active substances, thereby further promoting the transdermal absorption of the active substances by the skin.
Test example 3 Patch test
The packaging of the plaque tester is torn off, and 0.025mL or 0.025g of the prepared sample to be tested of example 1, example 2, example 5, comparative example 1 and comparative example 2 is weighed and added into a chamber. The patch tester is applied to the curved side of the forearm of the subject and gently pressed with the palm to be uniformly applied to the skin for 24 h.
The reaction results were recorded at 30min, 24h and 48h after removal of the plaque tester as observed in Table 4. The results are shown in table 5, and it can be seen from the results in the table that the irritation is reduced after the addition of the hyaluronic acid composition, compared to the group without the addition of the hyaluronic acid composition; the addition of the active ingredient to a water-in-oil emulsion also significantly reduces its irritancy compared to a pure gamma-aminobutyric acid solution.
TABLE 4 skin reaction grading Standard for skin Enclosed Patch test
TABLE 5 Patch test results
| Group of | Results of the experiment |
| Example 1 | All 20 people are negative |
| Example 2 | All 20 people are negative |
| Example 5 | 1 person showed grade 1 reaction, and the rest were negative |
| Comparative example 1 | 2 people show grade 1 reaction, and the rest are negative |
| Comparative example 2 | 6 people showed grade 1 reaction, and the rest were negative |
Claims (10)
1. A water-in-oil nanoemulsion comprising an oil phase, an aqueous phase, and an emulsifier, wherein the aqueous phase comprises a hyaluronic acid composition.
2. The nanoemulsion of claim 1, wherein the oil phase in the nanoemulsion ranges from 5% to 80%, preferably from 10% to 60%, the hyaluronic acid composition ranges from 0.01% to 10%, preferably from 0.01% to 1%, more preferably from 0.01% to 0.5%, and the emulsifier ranges from 0.01% to 20%, preferably from 0.5% to 10%.
3. The nanoemulsion of claim 1, wherein the hyaluronic acid composition comprises medium molecular weight hyaluronic acid or a salt thereof, acetylated hyaluronic acid or a salt thereof and hydrolyzed hyaluronic acid or a salt thereof, preferably the medium molecular weight hyaluronic acid or a salt thereof has a molecular weight of 200-700kDa, preferably 200-400kDa, further preferably the acetylated hyaluronic acid or a salt thereof has a molecular weight of 20-40kDa, further preferably the hydrolyzed hyaluronic acid or a salt thereof has a molecular weight of 3-18 kDa.
4. The nanoemulsion of claim 3, wherein the medium molecular weight hyaluronic acid or a salt thereof is present in an amount of 20-60%, preferably 25-40%, the acetylated hyaluronic acid or a salt thereof is present in an amount of 10-50%, preferably 20-35%, and the hydrolyzed hyaluronic acid or a salt thereof is present in an amount of 30-70%, preferably 40-55%, by mass percentage in the hyaluronic acid composition.
5. The nanoemulsion of claim 1, wherein the aqueous phase further includes a water-soluble active ingredient, preferably, the water-soluble active ingredient is one or more of a whitening functional ingredient, a moisturizing functional ingredient and an anti-aging functional ingredient, wherein the whitening functional ingredient is one or more selected from nonapeptide-1, tranexamic acid, nicotinamide, thiotaurine, 4-methoxysalicylic acid potassium, arbutin, glutathione, ethyl bis-imino methyl guaiacol manganese chloride (EUK-134), the moisturizing functional ingredient is one or more selected from elcryptone, carnosine and beta-glucan, and the anti-aging functional ingredient is one or more selected from Polydeoxyribonucleotide (PDRN), gamma-aminobutyric acid and collagen.
6. The nanoemulsion of claim 1, wherein the oil phase is selected from one or more of squalane, rice bran oil, caprylic/capric triglyceride, coconut oil, isononyl isononanoate (ISIS).
7. The nanoemulsion of claim 1, wherein the emulsifier is selected from one or more of polyglycerol-2 dipolyhydroxystearate, polyglycerol-2 oleate, polyglycerol-3 diisostearate, cetyl PEG/PPG-10/1 dimethicone, PEG40 hydrogenated castor oil, sorbitan sesquioleate, PEG-20 glycerol tristearate, preferably a mixture of polyglycerol-3 diisostearate and PEG40 hydrogenated castor oil, more preferably the mass ratio of polyglycerol-3 diisostearate to PEG40 hydrogenated castor oil is 1:4-2: 3.
8. A process for the preparation of a nanoemulsion according to any of claims 1 to 7, characterized in that it comprises the following steps:
dissolving the emulsifier in the liquid oil to form an oil phase,
dissolving a hyaluronic acid composition in water to form an aqueous phase,
mixing and homogenizing the oil phase and the water phase at the same temperature to obtain nano emulsion;
preferably, the step of dissolving the hyaluronic acid composition in water to form an aqueous phase comprises:
the hyaluronic acid composition and the water-soluble active ingredient are dissolved in water to form an aqueous phase.
9. A cosmetic comprising the nanoemulsion of any one of claims 1-7.
10. Use of a hyaluronic acid composition for increasing stability and/or permeability of a nanoemulsion, wherein the hyaluronic acid composition comprises medium molecular weight hyaluronic acid or a salt thereof, acetylated hyaluronic acid or a salt thereof and hydrolysed hyaluronic acid or a salt thereof;
preferably, the molecular weight of the medium molecular weight hyaluronic acid or the salt thereof is 200-700kDa, preferably 200-400kDa, the molecular weight of the acetylated hyaluronic acid or the salt thereof is 20-40kDa, and the molecular weight of the hydrolyzed hyaluronic acid or the salt thereof is 3-18 kDa;
further preferably, the content of the medium molecular weight hyaluronic acid or the salt thereof is 20 to 60%, preferably 25 to 40%, the content of the acetylated hyaluronic acid or the salt thereof is 10 to 50%, preferably 20 to 35%, and the content of the hydrolyzed hyaluronic acid or the salt thereof is 30 to 70%, preferably 40 to 55%, in terms of mass percentage in the hyaluronic acid composition.
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