WO2023202613A1 - 一种透明质酸锌的制备方法和应用 - Google Patents
一种透明质酸锌的制备方法和应用 Download PDFInfo
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- WO2023202613A1 WO2023202613A1 PCT/CN2023/089192 CN2023089192W WO2023202613A1 WO 2023202613 A1 WO2023202613 A1 WO 2023202613A1 CN 2023089192 W CN2023089192 W CN 2023089192W WO 2023202613 A1 WO2023202613 A1 WO 2023202613A1
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- Prior art keywords
- zinc
- hyaluronate
- zinc hyaluronate
- molecular weight
- skin
- Prior art date
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- 239000012916 chromogenic reagent Substances 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229940028356 diethylene glycol monobutyl ether Drugs 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- MFGZXPGKKJMZIY-UHFFFAOYSA-N ethyl 5-amino-1-(4-sulfamoylphenyl)pyrazole-4-carboxylate Chemical compound NC1=C(C(=O)OCC)C=NN1C1=CC=C(S(N)(=O)=O)C=C1 MFGZXPGKKJMZIY-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 210000000245 forearm Anatomy 0.000 description 1
- 210000001061 forehead Anatomy 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000008233 hard water Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 239000005453 ketone based solvent Substances 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
- 229960003987 melatonin Drugs 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000006916 nutrient agar Substances 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- JCGNDDUYTRNOFT-UHFFFAOYSA-N oxolane-2,4-dione Chemical compound O=C1COC(=O)C1 JCGNDDUYTRNOFT-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000012449 sabouraud dextrose agar Substances 0.000 description 1
- 239000012898 sample dilution Substances 0.000 description 1
- 210000001732 sebaceous gland Anatomy 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 230000009759 skin aging Effects 0.000 description 1
- 230000037380 skin damage Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 230000035483 skin reaction Effects 0.000 description 1
- 231100000430 skin reaction Toxicity 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- WGIWBXUNRXCYRA-UHFFFAOYSA-H trizinc;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O WGIWBXUNRXCYRA-UHFFFAOYSA-H 0.000 description 1
- BIKXLKXABVUSMH-UHFFFAOYSA-N trizinc;diborate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]B([O-])[O-].[O-]B([O-])[O-] BIKXLKXABVUSMH-UHFFFAOYSA-N 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- 230000037314 wound repair Effects 0.000 description 1
- YZYKBQUWMPUVEN-UHFFFAOYSA-N zafuleptine Chemical compound OC(=O)CCCCCC(C(C)C)NCC1=CC=C(F)C=C1 YZYKBQUWMPUVEN-UHFFFAOYSA-N 0.000 description 1
- 239000011667 zinc carbonate Substances 0.000 description 1
- 235000004416 zinc carbonate Nutrition 0.000 description 1
- 229910000010 zinc carbonate Inorganic materials 0.000 description 1
- 239000011746 zinc citrate Substances 0.000 description 1
- 235000006076 zinc citrate Nutrition 0.000 description 1
- 229940068475 zinc citrate Drugs 0.000 description 1
- XKKVXDJVQGBBFQ-UHFFFAOYSA-L zinc ethanol diacetate Chemical compound C(C)O.C(C)(=O)[O-].[Zn+2].C(C)(=O)[O-] XKKVXDJVQGBBFQ-UHFFFAOYSA-L 0.000 description 1
- SRWMQSFFRFWREA-UHFFFAOYSA-M zinc formate Chemical compound [Zn+2].[O-]C=O SRWMQSFFRFWREA-UHFFFAOYSA-M 0.000 description 1
- 239000011670 zinc gluconate Substances 0.000 description 1
- 235000011478 zinc gluconate Nutrition 0.000 description 1
- 229960000306 zinc gluconate Drugs 0.000 description 1
- 229940032991 zinc picolinate Drugs 0.000 description 1
- XSMMCTCMFDWXIX-UHFFFAOYSA-N zinc silicate Chemical compound [Zn+2].[O-][Si]([O-])=O XSMMCTCMFDWXIX-UHFFFAOYSA-N 0.000 description 1
- 235000019352 zinc silicate Nutrition 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- VRGNUPCISFMPEM-ZVGUSBNCSA-L zinc;(2r,3r)-2,3-dihydroxybutanedioate Chemical compound [Zn+2].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O VRGNUPCISFMPEM-ZVGUSBNCSA-L 0.000 description 1
- JNPQFTCBVDSMDO-UHFFFAOYSA-L zinc;2,3-dihydroxypropanoate Chemical compound [Zn+2].OCC(O)C([O-])=O.OCC(O)C([O-])=O JNPQFTCBVDSMDO-UHFFFAOYSA-L 0.000 description 1
- MCOGTQGPHPAUJN-UHFFFAOYSA-L zinc;2-hydroxyacetate Chemical compound [Zn+2].OCC([O-])=O.OCC([O-])=O MCOGTQGPHPAUJN-UHFFFAOYSA-L 0.000 description 1
- WDHVIZKSFZNHJB-UHFFFAOYSA-L zinc;butanoate Chemical compound [Zn+2].CCCC([O-])=O.CCCC([O-])=O WDHVIZKSFZNHJB-UHFFFAOYSA-L 0.000 description 1
- XDWXRAYGALQIFG-UHFFFAOYSA-L zinc;propanoate Chemical compound [Zn+2].CCC([O-])=O.CCC([O-])=O XDWXRAYGALQIFG-UHFFFAOYSA-L 0.000 description 1
- NHVUUBRKFZWXRN-UHFFFAOYSA-L zinc;pyridine-2-carboxylate Chemical compound C=1C=CC=NC=1C(=O)O[Zn]OC(=O)C1=CC=CC=N1 NHVUUBRKFZWXRN-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/18—Antioxidants, e.g. antiradicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
- C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
- C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present application relates to a preparation method and application of zinc hyaluronate, belonging to the technical field of hyaluronate.
- Hyaluronic acid is a polysaccharide composed of glucuronic acid and acetylglucosamine disaccharide units. It has physiological functions such as moisturizing, nutrition, repairing and preventing damage, and is widely used in the field of cosmetics. Studies have shown that in an aqueous solution with a pH value of 6.0 to 6.5, Zn 2+ can combine with the oxygen-containing donor group in HA to form a zinc hyaluronate (Zn-HA) complex.
- Zn-HA zinc hyaluronate
- zinc hyaluronate is obtained by exchanging sodium ions in sodium hyaluronate and zinc ions in zinc salts.
- the Hungarian patent reports the preparation process of powdered Zn-HA: Dissolve Na-HA in water, add zinc salt, precipitate with an organic solvent, and then use an organic solvent to dehydrate and dry it.
- the ion exchange resin method is commonly used in China: sodium hyaluronate is dissolved and put on an ion exchange column to convert Na-HA into Zn-HA, which is then precipitated by ethanol, dehydrated and dried. What the two have in common is that Na-HA is dissolved first and ions are exchanged in the solution.
- the former has a simpler path, but the sodium ion content in the product is higher; the latter occupies a lot of equipment and is more complex to operate, but the product has a higher zinc ion content.
- Patent CN100355790C a method for preparing zinc hyaluronate, provides a method for preparing powdered zinc hyaluronate, which is to use zinc salt as Na-HA solid in an alcohol solution to generate hyaluronic acid through direct ion exchange. zinc.
- Patent CN111647100A is a preparation method of high molecular weight zinc hyaluronate.
- the optimal preparation conditions were obtained by exploring preparation conditions such as replacement solution pH, replacement times, washing pH, washing times, dehydration solution pH, and dehydration times.
- the molecular weight of the obtained zinc hyaluronate can reach more than 1 million Da, the light transmittance is greater than 99.5%, and the zinc content is greater than 7.0%.
- Zinc hyaluronate is a zinc salt of hyaluronic acid. In addition to the moisturizing properties of hyaluronic acid, it also It also has the following effects: anti-inflammation, barrier repair, repair of skin damage, improvement of skin texture, melatonin and whitening, etc., and can be used in the field of cosmetics. In addition, zinc hyaluronate also has physiological functions such as lubrication, antimicrobial effects, preventing and treating peptic ulcers, and promoting wound repair, and is widely used in the medical field.
- Patent CN112691049A is a shampoo composition containing zinc hyaluronate, in which zinc hyaluronate is added.
- Zinc hyaluronate is mainly used to significantly inhibit Malassezia on the scalp and play the role of removing dandruff and relieving itching. And used in combination with other ingredients to control oil and soothe.
- Patent CN102961396A uses hyaluronate in the preparation of drugs for treating skin diseases, its drug combination and its preparation method. It provides a pharmaceutical composition (cream) containing zinc hyaluronate/or sodium hyaluronate, wherein Hyaluronic acid metal salts, especially preparations containing zinc hyaluronate as the main active ingredient, are very effective in treating skin barrier dysfunction, and can regulate skin physiological functions and repair skin barrier function.
- the present invention is based on the solid replacement method and optimizes the concentration of zinc salt in the replacement liquid, the volume of the replacement liquid, the replacement time, and the number of replacements, greatly shortening the production cycle and improving the replacement efficiency. , reducing the contact time between raw materials and acid replacement liquid, and avoiding a significant reduction in the molecular weight of the product.
- the present invention provides a method for producing zinc hyaluronate quickly and efficiently, which is suitable for large-scale production of zinc hyaluronate.
- a preparation method of zinc hyaluronate which includes the following steps:
- Sodium hyaluronate is added to the acidic aqueous organic medium containing zinc salt, and a replacement is performed to obtain zinc hyaluronate precipitation.
- Low molecular weight zinc hyaluronate prepared by the method described in any one of items 1 to 6.
- the molecular weight of the low molecular weight zinc hyaluronate is less than or equal to 1000 kDa.
- High molecular weight zinc hyaluronate prepared by the method described in any one of items 1 to 6.
- the molecular weight of the high molecular weight zinc hyaluronate is greater than 1000 kDa.
- a zinc hyaluronate wherein the molecular weight of the zinc hyaluronate is 2 kDa to 2500 kDa, and the zinc hyaluronate has a light transmittance of ⁇ 88.1%, preferably ⁇ 99.1%, in an aqueous solution with a concentration of 0.5 wt%.
- the zinc hyaluronate prepared by the method described in any one of items 1 to 8 or the zinc hyaluronate described in item 9 is useful in skin moisturizing, skin oil control, inhibiting harmful skin bacteria, antioxidant, scar repair, inhibiting Used in scars and preventing skin wound infection,
- the use in inhibiting harmful skin bacteria includes uses in acne removal and dandruff removal;
- the use in preventing skin wound infection includes preventing skin wound infection caused by water-light needles and microneedles.
- a method for skin moisturizing, skin oil control, inhibiting harmful skin bacteria, anti-oxidation, scar repair, inhibiting scars or preventing skin wound infection comprising applying the method described in any one of items 1 to 8 to a subject.
- zinc hyaluronate or zinc hyaluronate described in item 9
- the inhibition of harmful skin bacteria includes acne and dandruff removal
- the prevention of skin wound infection includes preventing skin wound infection caused by water-light needles and microneedles.
- zinc hyaluronate in reducing the oil content of the skin, preferably the zinc hyaluronate is a low molecular weight zinc hyaluronate,
- the molecular weight of the low molecular weight zinc hyaluronate is 2kDa-1000kDa, preferably Select 5kDa ⁇ 500kDa.
- zinc hyaluronate in reducing the porphyrin content in skin oil.
- the zinc hyaluronate is a low molecular weight zinc hyaluronate.
- the molecular weight of the low molecular weight zinc hyaluronate is 2kDa-1000kDa, preferably 5kDa-500kDa.
- zinc hyaluronate in scavenging hydroxyl free radicals on the skin surface.
- the zinc hyaluronate is a low molecular weight zinc hyaluronate.
- the molecular weight of the low molecular weight zinc hyaluronate is 2kDa-1000kDa, preferably 5kDa-500kDa.
- zinc hyaluronate in scavenging superoxide anion free radicals on the skin surface.
- the zinc hyaluronate is a high molecular weight zinc hyaluronate.
- the molecular weight of the high molecular weight zinc hyaluronate is 1000kDa to 2500kDa, preferably 1100kDa to 2000kDa.
- this application optimizes the concentration of zinc salt in the replacement liquid, the volume of the replacement liquid, the replacement time, and the number of replacements, which greatly shortens the production cycle, improves the replacement efficiency, and reduces the replacement of raw materials and acid
- the contact time of the liquid avoids a significant reduction in the molecular weight of the product.
- This application provides a method for quickly and efficiently producing zinc hyaluronate, which is suitable for large-scale production of zinc hyaluronate.
- the zinc hyaluronate prepared by this application has the effects of moisturizing, inhibiting harmful skin bacteria, repairing damage, controlling oil, antioxidant, removing fine lines, etc., and can be used for skin care.
- Zinc hyaluronate is weakly acidic and can ensure a weakly acidic environment for the skin (including the scalp). It can also inhibit the growth of some pathogenic microorganisms, resist the invasion of various fungi, and repair inflammation and damage to the skin. .
- zinc hyaluronate can maintain skin moisture, protect and enhance the skin's natural protective barrier, has a certain oil control effect, regulates the secretion of oil by sebaceous glands, and maintains the balance of water and oil. Therefore, zinc hyaluronate plays an important role in maintaining a healthy skin (including scalp) ecological environment.
- Figure 3A Effect of zinc hyaluronate I on porphyrin content in T zone
- Figure 3B Effect of zinc hyaluronate II on porphyrin content in T zone
- Figure 6B Changes in collagen III content.
- the method for quickly and efficiently producing zinc hyaluronate described in this application includes the following steps:
- the product After washing, the product is dehydrated and then dried under vacuum to obtain zinc hyaluronate.
- the zinc salt refers to a salt that can at least partially dissociate in an aqueous solution to produce zinc ions.
- Exemplary zinc salts may include, but are not limited to, zinc lactate, zinc oxide, zinc chloride, Zinc phosphate, zinc citrate, zinc acetate, zinc sulfate, zinc nitrate, zinc borate, zinc butyrate, zinc carbonate, zinc formate, zinc gluconate, zinc glycerate, zinc glycolate, zinc oxide, zinc phosphate, zinc picolinate , zinc propionate, zinc salicylate, zinc silicate, zinc stearate, zinc tartrate, zinc undecenoate and mixtures thereof.
- the zinc salt is zinc chloride, zinc acetate, zinc sulfate, zinc nitrate or zinc lactate.
- the organic medium is an organic medium that has good compatibility with water but in which sodium hyaluronate or zinc hyaluronate is insoluble or slightly soluble, such as alcohol organic solvents, ketone organic solvents, amides
- the solvent or acetonitrile is preferably an alcoholic organic solvent or a ketone organic solvent.
- Exemplary alcoholic organic solvents include, but are not limited to, methanol, ethanol, isopropyl alcohol, propanol, n-butanol, diacetone alcohol, ethylene glycol ethyl ether, ethylene glycol butyl ether, propylene glycol butyl ether, propylene glycol monomethyl ether, and Diethylene glycol monobutyl ether, etc.
- the alcoholic organic solvents are methanol and ethanol.
- Exemplary ketone solvents include, but are not limited to, methyl ethyl ketone, methyl isobutyl ketone, 1-methyl-2-pyrrolidone, cyclohexanone or acetone.
- the ketone organic solvent is acetone.
- Exemplary amide solvents include, but are not limited to, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone or formamide, etc.
- the acidic aqueous organic medium refers to any organic medium as mentioned above dissolved in water and configured into a certain proportion of aqueous organic medium.
- the pH value of the aqueous organic medium is adjusted to make it acidic.
- the pH value of the aqueous organic medium can be hydrochloric acid, glacial acetic acid, sulfuric acid, phosphoric acid, etc.
- the pH value of the acidic aqueous organic medium ranges from 5.0 to 6.9.
- the pH value can be 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 ,6.0,6.1,6.2,6.3,6.4,6.5,6.6,6.7,6.8,6.9.
- the sodium hyaluronate solid In an acidic environment, the sodium hyaluronate solid has a high degree of dissociation of sodium ions, making it easier to replace ions.
- the pH is too low, sodium hyaluronate will be degraded, affecting the molecular weight of the product; and the longer the product is in contact with the acidic aqueous medium, the more the molecular weight will decrease. Therefore, it is very important to control the appropriate pH and production cycle.
- the mass concentration of the organic medium is 55-95wt%, preferably 55-70wt%.
- sodium hyaluronate is insoluble in it and is in solid form.
- concentration of the aqueous medium the higher the degree of dispersion of sodium hyaluronate in it, but the sedimentation is slow, the loss is large, and the cycle is long; conversely, the degree of dispersion is Low, less loss and fast settling.
- the zinc ion concentration in the acidic aqueous organic medium containing zinc salt is 1 to 3wt%, for example, it can be 1wt%, 1.1wt%, 1.2wt%, 1.3wt%, 1.4wt%, 1.5wt%, 1.6wt% , 1.7wt%, 1.8wt%, 1.9wt%, 2.0wt%, 2.1wt%, 2.2wt%, 2.3wt%, 2.4wt%, 2.5wt%, 2.6wt%, 2.7wt%, 2.8wt%, 2.9 wt%, 3wt%.
- the concentration of zinc ions is related to the concentration of the organic medium in the acidic aqueous organic medium.
- the sodium hyaluronate is a white or off-white solid, and the molecular weight and uronic acid content of the sodium hyaluronate can be any value.
- the molecular weight of the sodium hyaluronate is 1 kDa to 3000 kDa, preferably 10 kDa to 2500 kDa, and the uronic acid content is 40 to 50 wt%, preferably 45 to 50 wt%.
- the molecular weight of the selected sodium hyaluronate is higher than the required molecular weight of zinc hyaluronate.
- the ratio of sodium hyaluronate input mass to zinc salt mass is 1:0.5-1:3.5, for example, it can be 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1 , 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1 :2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, preferably 1 :1-1:3.
- the time of stirring and substitution is 1-24h, preferably 5-16h.
- Sodium hyaluronate is subjected to a displacement reaction in an acidic aqueous organic medium containing zinc salts.
- the volume of the replacement liquid is controlled by controlling the total amount of zinc salt.
- the replacement time is controlled between 1 and 24 hours, and more preferably, the replacement time is between 5 and 16 hours.
- the pH of the acidic aqueous organic medium during the washing process is greater than or equal to 5.0 and less than 6.9, the concentration of the organic medium is 70-85wt%, and the number of washings is 2-6 times.
- the product is washed to wash away excess unbound ions and at the same time make the bound ions more stable. Washing is carried out with an acidic aqueous organic medium.
- the organic medium is an organic medium that has good compatibility with water but in which sodium hyaluronate or zinc hyaluronate is insoluble or slightly soluble, preferably Alcoholic organic solvents or ketone organic solvents, commonly used are ethanol, methanol, acetone, etc.
- the concentration of the organic medium is 70 to 85 wt%, and the pH is 5.0 to 6.9.
- Washing is based on the removal of excess ions.
- washing can be carried out through multiple washing, stirring and soaking.
- the product is dehydrated using a neutral aqueous organic medium, and the concentration of the organic medium is greater than or equal to 90wt%; the organic medium has good compatibility with water, but sodium hyaluronate or transparent
- the organic medium in which zinc phosphate is insoluble or slightly soluble is preferably an alcoholic organic solvent or a ketone organic solvent, and commonly used ones are ethanol, methanol, acetone, etc.
- the drying method is vacuum drying, and the drying temperature can be adjusted according to the molecular weight requirements and drying weight loss requirements of the product, generally 20 to 75°C.
- the zinc ion content of zinc hyaluronate obtained through the above preparation method is 6.0-9.0wt%, the replacement rate is 75%-100%, and the remaining indicators are: pH 5.5-7.5; weight loss on drying ⁇ 15.0%, light transmittance ⁇ 99.0%, heavy metals ⁇ 20ppm, protein ⁇ 0.1%, zinc hyaluronate content is more than 90wt%, and zinc hyaluronate yield is more than 90%.
- a step of degrading sodium hyaluronate may also be included, and this degradation step is performed before stirring and replacing.
- the degradation of sodium hyaluronate can be achieved by any method disclosed in the prior art, such as enzymatic hydrolysis, alkaline hydrolysis, etc.
- sodium hyaluronate will degrade in an acidic environment
- sodium hyaluronate when preparing zinc hyaluronate with a lower molecular weight, sodium hyaluronate is first degraded in an acidic aqueous organic medium. , degrade the molecular weight of sodium hyaluronate to the required molecular weight, and then stir and replace the degraded sodium hyaluronate to prepare zinc hyaluronate.
- the pH of degradation is different from the pH of stirring displacement.
- the pH of degradation is less than 5, and a larger pH is preferred. 1 is less than 5.
- the sodium hyaluronate whose pH has been adjusted with sodium hydroxide is added to the acidic aqueous organic medium containing zinc salt for stirring and replacement.
- the preparation method of zinc hyaluronate is based on the existing preparation method of zinc hyaluronate and has been further optimized after many experimental attempts.
- the mass ratio of the sodium and zinc salt replacement process reaches an appropriate ratio, so that sodium hyaluronate and zinc salt can achieve a good replacement effect through only one replacement, avoiding the need to repeatedly add zinc salt for multiple replacements in the existing technology.
- this application further optimizes the concentration of the solvent used in the preparation process and the molecular weight of sodium hyaluronate, strengthens the process parameters, and further ensures the quality of the prepared zinc hyaluronate.
- the preparation method of zinc hyaluronate of the present application simplifies the preparation steps, saves resources, and the prepared zinc hyaluronate is effective and has obvious advantages in light transmittance and yield.
- zinc hyaluronate with different molecular weights in the range of 1kDa to 2000kDa can be obtained, such as 1kDa-5kDa, 5kDa-10kDa, 10kDa-200kDa, 200kDa-500kDa, 500kDa- 1000kDa, 1000kDa-2000kDa.
- the zinc hyaluronate prepared in this application has functions such as moisturizing, inhibiting harmful skin bacteria, repairing damage, controlling oil, antioxidant, and removing fine lines, maintains a healthy skin (including scalp) ecological environment, and can be used as a raw material for cosmetics. field.
- Zinc hyaluronate is a zinc salt of hyaluronic acid. It not only has the excellent characteristics of HA, but also has unique physiological functions and effects. Zinc hyaluronate with different molecular weights has different biological activities. Among them, low molecular weight zinc hyaluronate, also called hydrolyzed zinc hyaluronate, refers to zinc hyaluronate with a molecular weight lower than 1000kDa, which is obtained by the replacement reaction of hydrolyzed sodium hyaluronate and zinc ions.
- Zinc hyaluronate has a significant inhibitory effect on a variety of skin surface bacteria (such as Staphylococcus epidermidis, Malassezia, acnes, etc.), and high molecular weight zinc hyaluronate is more effective than hydrolyzed zinc hyaluronate.
- Zinc hyaluronate also has the effect of reducing oil on the skin epidermis.
- Porphyrin is a product of microbial metabolism. There is a certain correlation between skin porphyrin content and oil content.
- the zinc hyaluronate can be used to prepare skin care products.
- the skin care includes moisturizing, antibacterial, anti-inflammatory, oil control, anti-aging and repair.
- the skin care products include toner, essence, gel, lotion, cream, facial mask, makeup, soap, facial cleanser, shampoo, conditioner and shower gel.
- the zinc hyaluronate prepared by this application is used in skin moisturizing, skin oil control, inhibiting harmful skin bacteria, antioxidant, scar repair, scar inhibition, and preventing skin wound infection.
- the zinc hyaluronate prepared by this application can significantly maintain the skin porphyrin content at a low level, thereby effectively controlling the skin oil content.
- the molecular weight of the zinc hyaluronate is between 2kDa and 1000kDa.
- the zinc hyaluronate prepared in this application has a very good effect in removing acne and dandruff; further research in this application found that the zinc hyaluronate has a high inhibitory rate against Staphylococcus epidermidis, which can reach about 50%. At the same time, The inhibition rate of Malassezia furfur can reach more than 70%. Malassezia furfur mainly causes dandruff and dandruff problems. Therefore, the zinc hyaluronate of the present application has a good use in removing dandruff; so The above-mentioned zinc hyaluronate also has an inhibitory rate of more than 60% against Propionibacterium acnes, which mainly causes skin acne. Therefore, the zinc hyaluronate of the present application also has a good use in removing acne. Furthermore, the present application can also prevent the infection of skin wounds caused by water-light needles, micro-needles, etc.
- the hyaluronic acid prepared in this application has a very good use in antioxidants.
- the zinc hyaluronate has a significant effect on scavenging hydroxyl free radicals, and the low molecular weight zinc hyaluronate has a higher scavenging rate of hydroxyl free radicals. It can reach more than 80%.
- the molecular weight of the low molecular weight zinc hyaluronate is between 2kDa and 1000kDa.
- the molecular weight is 2kDa, 5kDa, 10kDa, 20kDa, 30kDa, 40kDa, 50kDa.
- 60kDa, 70kDa, 80kDa, 90kDa 100kDa, 150kDa, 200kDa, 250kDa, 300kDa, 350kDa, 350kDa, 400kDa, 450kDa, 500kDa, 550kDa, 600kDa, 650kDa, 700kDa, 750kDa, 800kDa, 850kDa, 900kDa, 950kDa, 1000kDa, More preferably, it is 5 kDa to 500 kDa.
- the zinc hyaluronate has a good use in scavenging superoxide anion free radicals on the skin surface.
- the zinc hyaluronate has a significant effect on scavenging superoxide anion free radicals, among which polymer hyaluronic acid Zinc scavenging ability is higher, and the scavenging rate can reach more than 70%.
- the high molecular weight zinc hyaluronate has a better effect if its molecular weight is between 1000kDa and 2500kDa.
- the molecular weight is 1100kDa, 1150kDa, 1200kDa, 1250kDa, 1300kDa, 1350kDa, 1400kDa, 1450kDa, 1500kDa, 1550kDa.
- the preparation of zinc hyaluronate can be achieved through only one replacement, and the zinc ion content in the prepared zinc hyaluronate is greater than 4wt%, the replacement rate is greater than 56%, and the light transmittance is greater than 88.0%. The rate is over 89%.
- the preparation of zinc hyaluronate in this application is rapid and efficient, saving a lot of production time and manpower and material costs.
- the obtained zinc hyaluronate has a high yield and is suitable for large-scale industrial production.
- the sodium hyaluronate raw materials used are from Bloomage Biotechnology Co., Ltd.
- the uronic acid content is detected by the sulfuric acid-carbazole colorimetric method
- the sodium content and zinc content are detected by the atomic absorption spectrophotometry
- the molecular weight is detected by the intrinsic viscosity method.
- the replacement rate refers to the replacement efficiency of zinc ions in zinc hyaluronate.
- the replacement rate The calculation method is: the ratio of the actual detection value of zinc ions in zinc hyaluronate to the theoretical value of complete replacement of zinc ions.
- the yield is the ratio of the discharge amount to the feed amount
- the calculation formula is:
- a spectrophotometer was used to measure the light transmittance of a 0.5% aqueous solution at 550 nm.
- Glacial acetic acid Glacial acetic acid, Sinopharm Chemical Reagent Co., Ltd.;
- the drying temperature was 45°C
- the vacuum degree was 0.10MPa
- the drying time was 18h
- 28.33kg of zinc hyaluronate was obtained.
- the zinc hyaluronate of Examples 2-17 was prepared according to the method of Example 1.
- the amounts of each substance and the technical parameters in the method are as shown in the table.
- the technical parameters not mentioned in the table are the same as those of Example 1.
- the product performance and quality of the zinc hyaluronate prepared in Examples 1-18 were measured. Each index is shown in Table 2. It can be seen from the table that by adjusting the reasonable ratio and concentration of each component and appropriate parameter indicators, the preparation of zinc hyaluronate can be achieved through only one substitution in this application, and the prepared transparent.
- the zinc ion content in zinc phosphate is greater than 4wt%, the replacement rate is greater than 56%, the light transmittance is greater than 88.0%, and the yield is more than 89%.
- the quality indicators of the product meet the requirements.
- Zinc hyaluronate (Example 9, molecular weight 1270kD), sodium hyaluronate (Huaxi Biotechnology Co., Ltd., molecular weight 1230kD)
- Sample 1 High molecular weight zinc hyaluronate sample (Example 9, 1270kD);
- Purified water was used as a control.
- Sample 1 and sample 2 were respectively prepared with purified water to a concentration of 1.0% and 0.5%.
- Emulsion containing 0.5% zinc hyaluronate I (Example 9); emulsion containing 0.5% zinc hyaluronate II (embodiment 10); blank emulsion (without zinc hyaluronate)
- Group A Use emulsion containing high molecular weight zinc hyaluronate (Example 9) on the left face, and use blank emulsion on the right face;
- Group B Use emulsion containing low molecular weight zinc hyaluronate (Example 10) on the left face, and use it on the right face Blank lotion; test the water content of the stratum corneum in the apple muscle area of the subject's face before and after use.
- Group A Use emulsion containing high molecular weight zinc hyaluronate (Example 9) on the left face, and use blank emulsion on the right face;
- Group B Use emulsion containing low molecular weight zinc hyaluronate (Example 10) on the left face, and use it on the right face Blank lotion; test subjects' forehead oil secretion, T-zone porphyrin content, and facial apple muscle area texture area before and after use.
- Porphyrin is a product of microbial metabolism. There is a certain correlation between skin porphyrin content and oil content. In areas with higher oil content, microbial metabolic activity is usually stronger, and more porphyrins are produced.
- the results of Group A and Group B are shown in Figures 3A and 3B respectively, and the initial value before use was set to 100%.
- Figure 3A compared with the blank group, zinc hyaluronate I can reduce the porphyrin content in the T zone to a certain extent (reduced by 4%-6%) only after 2 weeks of use; in Figure 3B, compared with the blank group , Zinc Hyaluronate II always maintains a lower T-zone porphyrin content (reduced by 7%-14%) within 4 weeks of use.
- Test Example 2.4 Inhibition of harmful skin bacteria
- test bacterial suspension Dilute the test bacterial suspension appropriately with PBS solution. The required concentration is: drop 0.1mL into 5.0mL control sample solution (PBS phosphate buffer solution), and the number of recovered bacteria is 1 ⁇ 10 4 to 9 ⁇ 10 4 cfu/mL.
- control sample solution PBS phosphate buffer solution
- test sample original solution or its dilution Take 5.0 mL of the test sample original solution or its dilution into a sterilized test tube, and keep it at a constant temperature of 20°C for 5 minutes.
- test bacterial solution Add 0.1 mL of the test bacterial solution into the test tube containing 5.0 mL of sample, mix quickly, and time immediately.
- test bacteria After the set time, take 0.5 mL of the test bacteria and sample mixture, add it to a test tube containing 4.5 mL of sterilized PBS, and mix thoroughly.
- zinc hyaluronate has an inhibitory effect on harmful bacteria on the skin surface, and can prevent infection of skin wounds caused by water-light needles, micro-needle, etc.; it can also be used to remove dandruff (caused by Malassezia furfur) and acne. (caused by Propionibacterium acnes).
- the salicylic acid method was used to determine the hydroxyl radical scavenging ability of zinc hyaluronate samples. Mix a certain amount of H 2 O 2 with FeSO 4 to cause Fenton reaction to generate hydroxyl radicals. Adding salicylic acid to the reaction system can capture hydroxyl radicals and produce 3-hydroxysalicylic acid and 5-hydroxywater. Cylic acid, both products have strong absorption at 510nm.
- the reaction equation is as follows: H 2 O 2 +Fe 2+ ⁇ OH+OH - +Fe 3+
- sample will compete with salicylic acid to react with ⁇ OH, thereby reducing the production of 3-hydroxysalicylic acid and 5-hydroxysalicylic acid.
- S is the clearance rate
- a 0 is the absorbance value of the blank control
- a x is the absorbance value when the sample is added
- a x0 is the absorbance value without adding chromogenic reagent.
- pyrogallol autoxidation method Under weakly alkaline conditions, pyrogallol can undergo an auto-oxidation reaction to generate superoxide anions and a colored intermediate product, which has a characteristic absorption peak at 320nm. In the preliminary stage, the amount of intermediate products has a linear relationship with time. Since the auto-oxidation rate depends on the concentration of superoxide anions, when a superoxide anion scavenger is added, it can quickly react with superoxide anions and inhibit the auto-oxidation reaction, thereby preventing the accumulation of intermediate products and weakening the light absorption of the solution at 320nm. . Therefore, the scavenging effect of scavengers on superoxide anions can be evaluated by measuring the A320 value.
- HA-Zn has a significant effect on scavenging superoxide anion free radicals, among which the polymer zinc hyaluronate has a higher scavenging ability, with a scavenging rate of more than 70%.
- zinc acetate has a certain scavenging ability of superoxide anion free radicals, it is significantly lower than that of HA-Zn, while HA-Na has almost no scavenging ability of superoxide anion free radicals. Therefore, zinc hyaluronate has a significant effect in scavenging superoxide anion free radicals, which reflects that zinc hyaluronate has a good antioxidant effect.
- collagen can be divided into four types: I, II, III, and IV.
- Normal skin collagen is mainly type I and type III, and the content ratio of the two is about 3.5:1.
- Type I collagen is a thick fiber and is the material basis of scar tissue fibrosis;
- type II collagen is a thin fiber and is the main component of reticular fibers.
- type II fibers are gradually They are replaced by thick type I fibers, which destroys the network structure of normal skin and changes the biological characteristics of normal skin.
- the ratio of type I/III collagen decreases significantly, the collagen fibers are arranged disorderly, and the fibers become thicker, thus manifesting Gives the signature look of scarring.
- Fibroblasts were treated with TGF- ⁇ 1 to establish an in vitro scar model.
- the scar repair efficacy was evaluated by observing changes in the CollagenI and CollagenIII contents of fibroblasts. (This test was conducted by Guangdong Boxi Biotechnology Co., Ltd.)
- BC is the positive control and NC is the negative (blank) control.
- NC is the negative (blank) control.
- Figure 6A and Figure 6B compared with the NC group, after zinc hyaluronate was used for 24 hours at a concentration of 0.05mg/mL, the Collagen I content was extremely significant. Decreased (P ⁇ 0.05); Collagen III content decreased, but there was no significant difference.
- the sample zinc hyaluronate can significantly inhibit the synthesis of Collagen I at a concentration of 0.05 mg/mL, thereby affecting the protein expression ratio of Collagen I and Collagen III, and inhibiting scarring caused by overexpression of Collagen I. .
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Abstract
本申请提供了一种透明质酸锌的制备方法，包括以下步骤：将透明质酸钠加入到含锌盐的酸性含水有机介质中，进行一次置换，得到透明质酸锌沉淀；用洗涤液洗涤所述沉淀；将洗涤后的所述沉淀用脱水液进行脱水，干燥，得到透明质酸锌粉末。本申请基于固体置换法，对置换液中锌盐浓度、置换液体积、置换时间、置换次数进行了优化，解决了目前透明质酸锌生产工艺中置换次数多、耗时长、分子量消耗大、锌盐利用率低的问题，大大缩短了生产周期，提高了置换效率，减少了原料与酸性置换液的接触时间，避免了产品分子量的大幅降低。本申请提供了一种快速高效生产透明质酸锌的方法，适用于透明质酸锌的大规模生产。
Description
本申请涉及一种透明质酸锌的制备方法和应用，属于透明质酸盐技术领域。
透明质酸(hyaluronic acid，HA)是由葡萄糖醛酸和乙酰氨基葡萄糖双糖单位组成的多糖，具有保湿、营养、修复和预防损伤等生理作用，广泛用于化妆品领域。研究表明，在pH值为6.0～6.5的水溶液中，Zn2+可与HA中含氧的供体基团结合形成透明质酸锌(Zinc hyaluronate，Zn-HA)复合物。
通常情况下，透明质酸锌是由透明质酸钠中的钠离子和锌盐中的锌离子交换得到的。
匈牙利专利报道了粉末状Zn-HA的制备工艺：将Na-HA溶解于水，加入锌盐后用有机溶剂沉淀，再用有机溶剂脱水干燥制得。目前国内普遍使用的是离子交换树脂法：将透明质酸钠溶解后上离子交换柱，使Na-HA转化为Zn-HA，再经乙醇沉淀、脱水干燥制得。两者的共同点是先溶解Na-HA，在溶液中离子交换。前者路径较简单，但产品中钠离子含量较高；后者占用设备多，操作较复杂，但产品锌离子含量较高。
专利CN100355790C一种透明质酸锌的制备方法中，提供了一种粉末状透明质酸锌的制备方法，是在醇溶液中将Na-HA固体用锌盐以直接离子交换的方式生成透明质酸锌。
专利CN111647100A一种高分子量透明质酸锌的制备方法，通过对置换液pH、置换次数、洗涤pH、洗涤次数、脱水液pH、脱水次数等制备条件进行了探索，得到最佳的制备条件。得到的透明质酸锌的分子量可达100万Da以上，透光率大于99.5％，锌含量大于7.0％。
上述工艺均采用多次置换，存在周期长、有机溶剂用量大、锌盐利用率低、产品分子量降低幅度大的问题。
而透明质酸锌是透明质酸的锌盐，它除了具有透明质酸的保湿性能外，
还具有以下功效：抗炎、屏障修复、修复皮肤损伤、改善肤质、褪黑美白等，可用在化妆品领域。另外，透明质酸锌还具有润滑、抗微生物作用、预防和治疗消化性溃疡、促进创伤修复等生理功能，在医药领域广泛应用。
专利CN102834417A透明质酸金属盐的制造方法、包含透明质酸金属盐的化妆品的制造方法以及透明质酸锌及其制造方法中，通过胶带剥离法处理皮肤，从而破坏皮肤的屏障功能，涂抹含有透明质酸锌0.1％浓度的精华水，由实验结果可知，透明质酸锌具有优异的经表皮水分蒸散量的恢复效果，能够有效修护皮肤屏障。同时，对皮肤发红的情况具有良好的改善效果。
专利CN112691049A一种含透明质酸锌的香波组合物，其中添加了透明质酸锌，主要应用透明质酸锌对头皮马拉色菌明显的抑制作用，起到去屑、止痒的作用。并与其他成分联合使用，起到控油、舒缓的作用。
专利CN102961396A透明质酸盐在制备治疗皮肤病药物中的应用、其药物组合及其制备方法，提供了一种含透明质酸锌/或透明质酸钠的药物组合物(乳膏)，其中的透明质酸金属盐尤其是透明质酸锌为主活性成分的制剂，对于治疗皮肤屏障功能紊乱疗效确切，且能够调节皮肤生理功能，修复皮肤屏障功能。
发明内容
针对透明质酸锌生产中长期存在的问题，本发明基于固体置换法，对置换液中锌盐浓度、置换液体积、置换时间、置换次数进行了优化，大大缩短了生产周期，提高了置换效率，减少了原料与酸性置换液的接触时间，避免了产品分子量的大幅降低。
针对目前透明质酸锌制备方法中存在的问题，本发明提供了一种快速高效生产透明质酸锌的方法，适用于透明质酸锌的大规模生产。
具体的，本申请采用如下技术方案：
1.一种透明质酸锌的制备方法，其中，包括以下步骤：
将透明质酸钠加入到含锌盐的酸性含水有机介质中，进行一次置换，得到透明质酸锌沉淀。
2.根据项1所述的制备方法，其中，所述透明质酸钠的加入量与所述锌盐的质量比为1：0.5-1：3.5，优选为1：1-1：3。
3.根据项1或2所述的制备方法，其中，所述含锌盐的酸性含水有机介
质中有机溶剂浓度为55％～95％(v/v)，优选为55％～70％(v/v)，锌离子浓度为1％～3％(w/v)，所述含锌盐的酸性含水有机介质的pH为5.0～6.9。
4.根据项1-3中任一项所述的制备方法，其中，所述透明质酸钠的分子量为1kDa-3000kDa。
5.根据项1-4中任一项所述的制备方法，其中，所述置换时间为1～24h。
6.根据项1-5中任一项所述的制备方法，其中，还包括用洗涤液洗涤所述透明质酸锌沉淀，然后用脱水液对洗涤后的沉淀进行脱水，干燥，得到透明质酸锌粉末。
7.项1-6中任一项所述的方法制备的低分子量的透明质酸锌，优选，所述低分子量的透明质酸锌的分子量小于等于1000kDa。
8.项1-6中任一项所述的方法制备的高分子量的透明质酸锌，优选，所述高分子量的透明质酸锌的分子量大于1000kDa。
9.一种透明质酸锌，其中，透明质酸锌的分子量为2kDa～2500kDa，所述透明质酸锌在浓度为0.5wt％的水溶液中，透光率≥88.1％，优选≥99.1％。
10.项1-8中任一项所述的方法制备的透明质酸锌或项9中所述的透明质酸锌在皮肤保湿、皮肤控油、抑制皮肤有害菌、抗氧化、疤痕修复、抑制瘢痕、防止皮肤创伤感染方面的用途，
优选所述抑制皮肤有害菌方面的用途包括祛痘和去屑方面的用途；
优选所述防止皮肤创伤感染方面的用途包括防止水光针和微针引起的皮肤创伤感染。
11.一种皮肤保湿、皮肤控油、抑制皮肤有害菌、抗氧化、疤痕修复、抑制瘢痕或防止皮肤创伤感染的方法，包括向受试者施用项1-8中任一项所述的方法制备的透明质酸锌或项9中所述的透明质酸锌，
优选所述抑制皮肤有害菌包括祛痘和去屑；
优选所述防止皮肤创伤感染包括防止水光针和微针引起的皮肤创伤感染。
12.项1-8中任一项所述的方法制备的透明质酸锌或项9中所述的透明质酸锌在皮肤护理品中的用途。
13.透明质酸锌在减少皮肤油脂含量方面的用途，优选所述透明质酸锌是低分子量的透明质酸锌，
进一步优选，所述低分子量透明质酸锌的分子量为2kDa-1000kDa，优
选为5kDa～500kDa。
14.透明质酸锌在减少皮肤油脂中卟啉含量方面的用途，优选所述透明质酸锌是低分子量的透明质酸锌,
进一步优选，所述低分子量透明质酸锌的分子量为2kDa-1000kDa，优选为5kDa～500kDa。
15.透明质酸锌在清除皮肤表面羟基自由基方面的用途，优选所述透明质酸锌是低分子量的透明质酸锌,
进一步优选，所述低分子量透明质酸锌的分子量为2kDa-1000kDa，优选为5kDa～500kDa。
16.透明质酸锌在清除皮肤表面超氧阴离子自由基方面的用途，优选所述透明质酸锌是高分子量的透明质酸锌,
进一步优选，所述高分子量透明质酸锌的分子量为1000kDa～2500kDa，优选为1100kDa～2000kDa。
发明效果
1.工艺改进，本申请基于固体置换法，对置换液中锌盐浓度、置换液体积、置换时间、置换次数进行了优化，大大缩短了生产周期，提高了置换效率，减少了原料与酸性置换液的接触时间，避免了产品分子量的大幅降低。本申请提供了一种快速高效生产透明质酸锌的方法，适用于透明质酸锌的大规模生产。
2.护肤功效：本申请制备的透明质酸锌具有保湿、抑制皮肤有害菌、修复损伤、控油、抗氧化、去细纹等功效，能够用于皮肤护理。透明质酸锌呈弱酸性，可以确保皮肤(包括头皮)的弱酸性环境，同时可抑制一些致病类微生物的生长，为皮肤抵抗各种菌类的入侵，并对皮肤的炎症和损伤进行修复。另外，透明质酸锌能够维持皮肤水润，保护和增强皮肤的天然保护屏障，具有一定的控油效果，调节皮脂腺对油脂的分泌，保持水油平衡。因此，透明质酸锌对维持健康的皮肤(包括头皮)生态环境具有重要的作用。
3.透明质酸锌的功效越来越多被发现，但在医药领域的研究和应用较多。对于透明质酸锌原料的作用没有***的、全面的研究，因此本申请对不同分子量透明质酸锌的功效进行了一系列的研究，对透明质酸锌的应用和行业的发展，具有更深远的意义。
图1A透明质酸锌I对角质层含水量的影响；
图1B透明质酸锌II对角质层含水量的影响；
图2A透明质酸锌I对皮肤油脂含量的影响；
图2B透明质酸锌II对皮肤油脂含量的影响；
图3A透明质酸锌I对T区卟啉含量的影响；
图3B透明质酸锌II对T区卟啉含量的影响；
图4透明质酸锌对羟基自由基的清除效果；
图5透明质酸锌对超氧阴离子自由基的清除效果；
图6A胶原蛋白Ⅰ的含量变化情况；
图6B胶原蛋白Ⅲ的含量变化情况。
下面结合实施例进一步说明本申请，应当理解，实施例仅用于进一步说明和阐释本申请，并非用于限制本申请。
除非另外定义，本说明书中有关技术的和科学的术语与本领域内的技术人员所通常理解的意思相同。虽然在实验或实际应用中可以应用与此间所述相似或相同的方法和材料，本文还是在下文中对材料和方法做了描述。在相冲突的情况下，以本说明书包括其中定义为准，另外，材料、方法和例子仅供说明，而不具限制性。以下结合具体实施例对本申请作进一步的说明，但不用来限制本申请的范围。
本申请所述的快速高效生产透明质酸锌的方法，包括以下步骤：
配制含锌盐的酸性含水有机介质；
将透明质酸钠固体浸泡于含锌盐的酸性含水有机介质中，进行搅拌置换，通过控制置换时间使锌离子含量达到要求；
锌离子含量达到要求后，向去掉上清液的剩余物中加入酸性含水有机介质进行洗涤，洗去多余的离子；
洗涤后，将产物脱水，然后进行真空干燥，得到透明质酸锌。
在本申请中，所述锌盐是指可以在水溶液中至少部分地解离以产生锌离子的盐。作为示例性锌盐可以包括但不限于乳酸锌、氧化锌、氯化锌、
磷酸锌、柠檬酸锌、乙酸锌、硫酸锌、硝酸锌、硼酸锌、丁酸锌、碳酸锌、甲酸锌、葡萄糖酸锌、甘油酸锌、乙醇酸锌、氧化锌、磷酸锌、吡啶甲酸锌、丙酸锌、水杨酸锌、硅酸锌、硬脂酸锌、酒石酸锌、十一碳烯酸锌及其混合物。
在某些优选的实施例中，所述锌盐为氯化锌、乙酸锌、硫酸锌、硝酸锌或乳酸锌。
在本申请中，所述有机介质为与水相容性好、但透明质酸钠或透明质酸锌在其中不溶或微溶的有机介质，例如醇类有机溶剂、酮类有机溶剂、酰胺类溶剂或者乙腈，优选为醇类有机溶剂或酮类有机溶剂。
作为示例性醇类有机溶剂包括但不限于甲醇、乙醇、异丙醇、丙醇、正丁醇、二丙酮醇、乙二醇***、乙二醇丁醚、丙二醇丁醚、丙二醇单甲醚和二乙二醇单丁醚等。
在本申请某些优选的实施方式中，所述醇类有机溶剂为甲醇和乙醇。
作为示例性酮类溶剂包括但不限于甲基乙基酮、甲基异丁基酮、1-甲基-2-吡咯烷酮、环己酮或丙酮等。
在本申请中某些优选的实施方式中，所述酮类有机溶剂为丙酮。
作为示例性酰胺类溶剂包括但不限于N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、二甲亚砜、N-甲基吡咯烷酮或甲酰胺等。
在本申请中，所述酸性含水有机介质是指如上所述的任一有机介质溶于水中配置为一定比例的含水有机介质，同时通过调节含水有机介质的pH值使其呈酸性，所述调节含水有机介质pH值的物质可以为盐酸、冰乙酸、硫酸、磷酸等。
在本申请某些优选的实施方式中，所述酸性含水有机介质的pH值范围为5.0-6.9，例如pH值可以为5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9。
在酸性环境中，透明质酸钠固体的钠离子解离程度高，更易进行离子的置换。但pH过低，则会降解透明质酸钠，影响产品分子量；且产品与酸性含水介质接触的时间越久，分子量则会降低越多，因此，控制合适的pH和生产周期非常重要。
在本申请某些优选的实施方式中，所述有机介质的质量浓度为55～95wt％，优选为55～70wt％。
在此浓度范围内，透明质酸钠在其中不溶，呈固体形态，含水介质浓度越低，透明质酸钠在其中的分散程度越高，但沉降慢，损耗多，周期长；反之则分散程度低，损耗少，沉降快。
所述含锌盐的酸性含水有机介质中的锌离子浓度为1～3wt％，例如可以为1wt％、1.1wt％、1.2wt％、1.3wt％、1.4wt％、1.5wt％、1.6wt％、1.7wt％、1.8wt％、1.9wt％、2.0wt％、2.1wt％、2.2wt％、2.3wt％、2.4wt％、2.5wt％、2.6wt％、2.7wt％、2.8wt％、2.9wt％、3wt％。
锌离子的浓度与酸性含水有机介质中有机介质的浓度有关，有机介质浓度越高，锌离子溶解度越低。因此，在合适的含水有机介质浓度下，锌离子浓度优选为1～3wt％，此浓度既能保证锌离子浓度达到一定水平，又能很好的促进置换反应的进行，又能保证锌盐完全的溶于酸性含水有机介质中。
在本申请中，所述透明质酸钠为白色或类白色固体，所述透明质酸钠的分子量和糖醛酸含量可以是任意数值。在本申请优选的实施方式中，所述透明质酸钠的分子量为1kDa～3000kDa，优选为10kDa～2500kDa，所述糖醛酸含量为40～50wt％，优选为45～50wt％。
因为在制备的过程中存在降解的情况，因此所选的透明质酸钠的分子量要高于所需透明质酸锌的分子量。
透明质酸钠投料质量与锌盐质量比值为1：0.5-1：3.5，例如可以为1:0.5、1:0.6、1:0.7、1:0.8、1:0.9、1:1、1:1.1、1:1.2、1:1.3、1:1.4、1:1.5、1:1.6、1:1.7、1:1.8、1:1.9、1:2.0、1:2.1、1:2.2、1:2.3、1:2.4、1:2.5、1:2.6、1:2.7、1:2.8、1:2.9、1:3、1:3.1、1:3.2、1:3.3、1:3.4、1:3.5，优选为1：1-1：3。
搅拌置换的时间为1-24h，优选为5～16h。
将透明质酸钠在含锌盐的酸性含水有机介质中进行置换反应，酸性含水有机介质中锌离子浓度越高、所用锌盐总量越大、置换的时间越长，则产物中锌离子含量越高，即置换率越高。根据酸性含水介质中锌盐的含量，通过控制锌盐的总用量来控制置换液的体积，透明质酸钠投料质量与锌盐质量比值为1：(0.5-3.5)时，置换效率较高。置换的搅拌时间越长，置换效率越高，但时间越长，产品降解越多，分子量降低越多，因此置换时间控制在1～24h，更优选的，置换时间在5～16h。
进一步的，上述制备方法中，洗涤过程酸性含水有机介质的pH大于等于5.0小于6.9，有机介质的浓度为70～85wt％，洗涤次数为2～6次。
进一步的，置换至锌离子符合要求后，对产物进行洗涤，以洗去多余的未结合的离子，同时使结合上的离子更稳固。用酸性含水有机介质进行洗涤，所述酸性含水有机介质中，所述有机介质为与水相容性好、但透明质酸钠或透明质酸锌在其中不溶或微溶的有机介质，优选为醇类有机溶剂或酮类有机溶剂，常用的为乙醇、甲醇、丙酮等。
酸性含水有机介质中，有机介质的浓度为70～85wt％，pH为5.0～6.9。
洗涤以多余离子清除干净为标准。
为了提高洗涤效果、减少废水的产生，可以通过多次洗涤、搅拌浸泡等方式来进行洗涤。
进一步的，洗涤完成后，将产物进行脱水，脱水用中性的含水有机介质，有机介质的浓度为大于等于90wt％；所述有机介质为与水相容性好、但透明质酸钠或透明质酸锌在其中不溶或微溶的有机介质，优选为醇类有机溶剂或酮类有机溶剂，常用的为乙醇、甲醇、丙酮等。
脱水后，除去上清中的含水有机介质，进行干燥，获得透明质酸锌固体。
干燥方式为真空干燥，干燥温度可根据产物的分子量要求和干燥失重要求进行调节，一般为20～75℃。
进一步的，通过上述制备方法所得透明质酸锌的锌离子含量为6.0～9.0wt％，置换率为75％～100％，其余指标：pH5.5～7.5；干燥失重≤15.0％，透光率≥99.0％，重金属≤20ppm，蛋白质≤0.1％，透明质酸锌含量为90wt％以上，透明质酸锌收率为90％以上。
进一步的，在透明质酸锌的制备过程中，除了搅拌置换、洗涤、脱水、干燥的步骤外，还可以包括将透明质酸钠进行降解的步骤，该降解步骤在搅拌置换前进行。
可以采用现有技术中公开的任意方法实现透明质酸钠的降解，例如酶解法、碱解法等。
因为透明质酸钠在酸性环境下会发生降解，因此在本申请某一具体实施方式中，在制备较低分子量的透明质酸锌时，先将透明质酸钠在酸性含水有机介质中进行降解，将透明质酸钠的分子量降解至所需的分子量，然后再将降解后的透明质酸钠进行搅拌置换，制备透明质酸锌。
降解的pH与搅拌置换的pH不同，降解的pH为小于5，优选pH大
于1小于5。
降解完成后，再用氢氧化钠调整pH后的透明质酸钠中加入含锌盐的酸性含水有机介质中进行搅拌置换。
本申请中，所述透明质酸锌的制备方法，在现有的透明质酸锌的制备方法的基础上，经过多次实验尝试，进一步进行了优化，通过在制备过程中，调整透明质酸钠和锌盐置换过程的质量比到合适的比例，使得透明质酸钠和锌盐仅仅通过一次置换就可以达到良好的置换效果，避免了现有技术中需要反复的加入锌盐进行多次置换，耗费人力物力，本申请进一步优化了制备过程中用的溶剂的浓度以及透明质酸钠的分子量，加强了工艺参数，更加保证了制备得到的透明质酸锌的质量。本申请的透明质酸锌的制备方法简化了制备步骤，节约资源，且制备的透明质酸锌效果好，透光率和收率都具有明显的优势。
通过降解步骤的调控，以及透明质酸钠分子量的选择，可以得到1kDa～2000kDa范围内不同分子量段的透明质酸锌，例如1kDa-5kDa、5kDa-10kDa、10kDa-200kDa、200kDa-500kDa、500kDa-1000kDa、1000kDa-2000kDa。
进一步的，本申请制备的透明质酸锌具有保湿、抑制皮肤有害菌、修复损伤、控油、抗氧化、去细纹等功能，维持健康的皮肤(包括头皮)生态环境，可作为原料用于化妆品领域。
透明质酸锌是透明质酸的锌盐，既具有HA的优良特性，还具有独特的生理功能和功效，且不同分子量的透明质酸锌具有不同的生物活性。其中，低分子透明质酸锌，又叫水解透明质酸锌，是指分子量低于1000kDa的透明质酸锌，是由水解透明质酸钠与锌离子的置换反应得到的。经实验验证，透明质酸锌对多种皮肤表面菌(如表皮葡萄球菌、马拉色菌、痤疮杆菌等)具有明显抑制作用，高分子量透明质酸锌比水解透明质酸锌效果更好。透明质酸锌还具有降低皮肤表皮的油脂的效用，卟啉是微生物代谢产物，皮肤卟啉含量与油脂含量有一定的相关性，油脂含量较高的区域，微生物代谢活动通常比较旺盛，产生的卟啉量就多；透明质酸锌能够在一定程度上降低T区卟啉含量，而低分子透明质酸锌效果更显著。另外，低分子透明质酸锌还可以减少细纹，改善肤质，延缓皮肤衰老。另外，透明质酸锌能够显著抑制CollagenⅠ的合成，从而影响CollagenⅠ和CollagenⅢ
蛋白表达比例，抑制因CollagenⅠ过量表达造成的瘢痕发生。
进一步的，所述的透明质酸锌可用于制备皮肤护理产品。所述皮肤护理为保湿、抑菌、消炎、控油、抗衰、修复。
进一步的，所述皮肤护理产品为柔肤水、精华液、啫喱、乳液、膏霜、面膜、彩妆、香皂、洗面奶、洗发水、护发素及沐浴露。
进一步的，含有透明质酸锌的各种剂型的皮肤护理产品均在本申请保护之列。
本申请制备的透明质酸锌在皮肤保湿、皮肤控油、抑制皮肤有害菌、抗氧化、疤痕修复、抑制瘢痕、防止皮肤创伤感染方面的用途。
本申请通过大量试验研究发现，皮肤卟啉含量与油脂含量有一定的相关性，油脂含量较高的区域，微生物代谢活动通常比较旺盛，产生的卟啉量就多。而本申请制备的透明质酸锌可以显著保持皮肤卟啉含量在一个较低的水平，从而有效控制皮肤油脂含量，在一个优选的实施方式中，所述透明质酸锌的分子量在2kDa-1000kDa之间具有更好控油效果，例如分子量为2kDa，5kDa，10kDa，20kDa，30kDa，40kDa，50kDa，60kDa，70kDa，80kDa，90kDa，100kDa，150kDa，200kDa，250kDa，300kDa，350kDa，350kDa，400kDa，450kDa，500kDa，550kDa，600kDa，650kDa，700kDa，750kDa，800kDa，850kDa，900kDa，950kDa，1000kDa，进一步优选为5kDa～500kDa。
本申请制备的透明质酸锌在祛痘和去屑方面的具有很好的作用；本申请进一步研究发现，所述透明质酸锌对表皮葡萄球菌抑制率较高，可以达到50％左右，同时对秕糠马拉色菌抑制率可以达到70％以上，秕糠马拉色菌主要会引起头屑、皮屑问题，因此本申请的透明质酸锌在去屑方面具有很好的用途；所述透明质酸锌对痤疮丙酸杆菌抑制率也达到了60％以上，而痤疮丙酸杆菌主要会引起皮肤起痘的问题。因此本申请的透明质酸锌在祛痘方面同样具有很好的用途进一步的，本申请还能够防止水光针、微针等引起的皮肤创伤的感染。
本申请所制备的透明质酸在抗氧化方面具有很好的用途，所述透明质酸锌对羟自由基的清除具有明显效果，且低分子透明质酸锌的羟基自由基清除率更高，可达80％以上，在一个优选的实施方式中，所述低分子量透明质酸锌的分子量为2kDa-1000kDa之间效果更佳，例如分子量为2kDa，5kDa，10kDa，20kDa，30kDa，40kDa，50kDa，60kDa，70kDa，80kDa，90kDa，
100kDa，150kDa，200kDa，250kDa，300kDa，350kDa，350kDa，400kDa，450kDa，500kDa，550kDa，600kDa，650kDa，700kDa，750kDa，800kDa，850kDa，900kDa，950kDa，1000kDa，进一步优选为5kDa～500kDa。
本申请进一步发现，所述透明质酸锌在清除皮肤表面超氧阴离子自由基方面具有很好的用途，所述透明质酸锌对超氧阴离子自由基清除具有显著作用，其中高分子透明质酸锌清除能力更高，清除率可达70％以上。在一个优选的实施方式中，所述高分子量透明质酸锌的分子量为1000kDa～2500kDa之间效果更佳，例如分子量为1100kDa,1150kDa，1200kDa,1250kDa，1300kDa,1350kDa,1400kDa,1450kDa,1500kDa,1550kDa,1600kDa,1650kDa,1700kDa,1750kDa,1800kDa,1850kDa,1900kDa,1950kDa,2000kDa,2050kDa,2100kDa,2150kDa,2200kDa,2250kDa,2300kDa,2350kDa,2400kDa,2450kDa,2500kDa，进一步优选为1100kDa～2000kDa。
1.本申请中仅通过一次置换就可以实现透明质酸锌的制备，且制备得到的透明质酸锌中锌离子含量为大于4wt％，置换率大于56％，透光率大于88.0％，收率为89％以上。
2.本申请透明质酸锌的制备快速高效，节省大量生产时间，节约了人力物力成本，所得透明质酸锌收率高适合大规模工业化生产。
实施例
以下利用实施例对本申请做以详细说明。然而应当理解，可以以各种形式实现本申请而不应被这里阐述的实施例所限制。相反，提供这些实施例是为了能够更透彻地理解本申请，并且能够将本申请的范围完整的传达给本领域的技术人员。在本申请中列举的数值范围均包括该数值范围的两个端点的数据，也包括该数值范围中具体的每一个数值，并且该数值可以与端点任意组合组成新的小范围。
下述实施例及对比例中，所用透明质酸钠原料均来自华熙生物科技股份有限公司。
下述实施例中，糖醛酸含量采用硫酸-咔唑比色法进行检测，钠含量、锌含量采用原子吸收分光光度法进行检测，分子量采用特性黏数法进行检测。
下述实施例中，置换率指的是透明质酸锌中锌离子的置换效率，置换率
的计算方式为：透明质酸锌中锌离子的实际检测值与锌离子全部置换的理论值之比。
下述实施例中，收率为出料量与投料量之比，计算公式为：
收率＝透明质酸锌出料量/透明质酸钠投料量×100％
下述实施例中，采用分光光度计在550nm下测定0.5％的水溶液的透光率。
下述实施例中，如无特别说明，所述浓度均为质量百分浓度。
实施例1
试剂：乙醇，华熙生物科技股份有限公司；
冰乙酸，国药集团化学试剂有限公司；
透明质酸钠，华熙生物科技股份有限公司；
乙酸锌，国药集团化学试剂有限公司；
氯化锌，国药集团化学试剂有限公司；
硫酸锌，国药集团化学试剂有限公司。
配制含有1.88wt％锌离子的乙酸锌-乙醇溶液170L，其中，乙醇浓度约55wt％，用冰乙酸调整pH为6.5。
准确称量30kg透明质酸钠(分子量2500kDa)固体，加入至上述置换液中，开启搅拌进行置换，搅拌置换8h。
静置至上清澄清，去掉上清液，加入800L浓度为70wt％的乙醇水溶液(pH 6.3)进行洗涤，洗涤搅拌3h，然后静置至上清澄清，去掉上清液，再加入800L浓度为70wt％的乙醇水溶液(pH 6.3)按照同样的方式进行洗涤，共洗涤4次。
最后一次洗涤后，静置除去上清，加入800L浓度为90wt％的乙醇溶液进行脱水操作，脱水2次，
然后转入三合一干燥机进行真空干燥，干燥温度为45℃，真空度为0.10MPa，干燥时间为18h，出料得到透明质酸锌28.33kg。
实施例2-17
按照实施例1的方法制备实施例2-17的透明质酸锌，方法中的各物质的量以及技术参数如表所示，表中未提到的技术参数与实施例1相同。
表1各实施例中物质的含量和技术参数
试验例1透明质酸锌的产品性能和质量
测定实施例1-18制备的透明质酸锌的产品性能和质量，各指标见表2。从表中可以看出，通过调整各组分的合理配比和浓度以及合适的参数指标，本申请中仅通过一次置换就可以实现透明质酸锌的制备，且制备得到的透明
质酸锌中锌离子含量为大于4wt％，置换率大于56％，透光率大于88.0％，收率为89％以上，产品的质量指标符合要求。
试验例2透明质酸锌性质研究
实验材料：
透明质酸锌(实施例9，分子量1270kD)，透明质酸钠(华熙生物科技有限公司，分子量1230kD)
实验过程：
配制0.5％浓度透明质酸锌和0.5％浓度透明质酸钠(含有0.13g二水乙酸锌)的水溶液，保证两样品中锌离子含量均为0.039％，样品名称分别为HA-Zn和HA-Na+Zn盐。对两种溶液的动力粘度、透光率和渗透压进行检测。
实验结果：
(1)动力粘度
0.5％浓度的样品溶液在25℃下测定动力粘度，结果如表3。
表3
(2)透光率
用分光光度计在550nm下测定样品透光率，结果如表4。
表4
(3)渗透压
以水的渗透压为0，测定样品的渗透压，结果如表5。
表5
由上述结果可以看出，与含有相同锌离子含量的透明质酸钠溶液相比，透明质酸锌的动力粘度、透光率较高，而渗透压较低。
试验例2.1斑贴试验
实验材料
样品1：高分子量透明质酸锌样品(实施例9、1270kD)；
样品2：低分子量透明质酸锌样品(实施例10、45kD)
实验过程：
(1)样品的制备
纯化水作为对照，样品1和样品2分别各自用纯化水配制成1.0％、0.5％的浓度。
(2)皮肤斑贴试验
撕开斑试器的包装，量取配置好的样品各0.025mL加入小室内。将斑试器贴敷于受试者的前臂曲侧，用手掌轻压使之均匀地贴敷于皮肤上，持续24h，受试者为30例。
3、结果分析
去除斑试器后30min、24h和48h按表6观察记录反应结果。
表6皮肤封闭型斑贴试验皮肤反应分级标准
注：参考《化妆品安全技术规范》-2015版。
表7斑贴试验结果统计(总例数：30)
结果如表7所示，30例受试者高、低分子量透明质酸锌1.0％、0.5％浓度的样品全为阴性反应，对人体无潜在不良反应。
试验例2.2保湿效果
实验材料：
含0.5％透明质酸锌Ⅰ(实施例9)的乳液；含0.5％透明质酸锌Ⅱ(实施例10)的乳液；空白乳液(不含透明质酸锌)
乳液配方中其他物质成分如下表8：
表8
实验过程：
采用半脸对照的方法，分A、B两组，每组10人；
A组：左脸使用高分子量透明质酸锌(实施例9)的乳液，右脸使用空白乳液；B组：左脸使用含低分子量透明质酸锌(实施例10)的乳液，右脸使用空白乳液；于使用前后分别检测受试者面部苹果肌区域的角质层含水量。
实验结果：
A组和B组的结果分别如图1A、1B所示，使用前初始值设为100％。与空白组相比，高分子量透明质酸锌和低分子量透明质酸锌使用4周的时间内，均能提高角质层含水量(4％-8％)。
试验例2.3：控油效果
实验材料：
试验例2.2所配制的两种乳液
实验过程：
采用半脸对照的方法，分A、B两组，每组10人；
A组：左脸使用高分子量透明质酸锌(实施例9)的乳液，右脸使用空白乳液；B组：左脸使用含低分子量透明质酸锌(实施例10)的乳液，右脸使用空白乳液；于使用前后分别检测受试者额头油脂分泌量、T区卟啉含量及面部苹果肌区域的纹理面积。
实验结果：
1.测试样品对皮肤油脂含量的影响
A组和B组的结果分别如图2A、2B所示，结果以与使用前皮肤油脂含量的差值表示。图2A中，与空白组相比，高分子量透明质酸锌组皮肤油脂含量略低，第4周时油脂含量平均值减少5.70μg/cm2；而图2B中，低分子量透明质酸锌组减少油脂的效果更显著，特别是使用1周后，皮肤油脂含量平均值比空白组减少13.11μg/cm2。
2.测试样品对T区卟啉含量的影响
卟啉是微生物代谢产物，皮肤卟啉含量与油脂含量有一定的相关性，油脂含量较高的区域，微生物代谢活动通常比较旺盛，产生的卟啉量就多。A组和B组的结果分别如图3A、3B所示，使用前初始值设为100％。图3A中，与空白组相比，透明质酸锌Ⅰ在使用2周之后，才能在一定程度上降低T区卟啉含量(降低4％-6％)；图3B中，与空白组相比，透明质酸锌Ⅱ在使用4周时间内始终保持较低的T区卟啉含量(降低7％-14％)。
试验例2.4：抑制皮肤有害菌
实验材料：
透明质酸锌样品(实施例9，1270kD)
实验过程：
1)用PBS液将试验菌悬液做适当稀释，要求浓度为：取0.1mL滴于5.0mL对照样液(PBS磷酸盐缓冲溶液)内，回收菌数为1×104～9×104cfu/mL。
2)将试验样品用无菌标准硬水稀释至规定的浓度。
3)吸取试验样品原液或其稀释液5.0mL放入灭菌试管中，20℃恒温5min。
4)吸取试验菌液0.1mL加入到含5.0mL样品的试管中，迅速混匀，并立即计时。
5)作用至设定时间后，取试验菌与样品混合液0.5mL，加入到含4.5mL经灭菌的PBS试管中，充分混匀。
6)放置10min后，吸取样液(或作适当稀释后，取其中2～3个稀释度的稀释液)1mL，置于灭菌平皿内，每个样液或稀释度接种两个灭菌平皿。用凉至40℃～45℃的营养琼脂培养基(细菌)或沙氏琼脂培养基(白色念株菌)15mL作倾注，转动平皿，使其充分均匀，琼脂凝固后翻转平皿，(35±2)℃培养48h(细菌)或72h(白色念株菌)后，做活菌菌落计数。
7)以PBS代替试验样品，同时按以上步骤操作，作为对照样品。
8)计算抑菌率
表9
结果如表9所显示：0.5％透明质酸锌溶液处理8h，对表皮葡萄球菌抑制率为50.03％，对秕糠马拉色菌抑制率为72.06％，对痤疮丙酸杆菌抑制率为62.10％。因此，透明质酸锌对皮肤表面有害菌均具有抑制作用，能够防止水光针、微针等引起的皮肤创伤的感染；还可用于去屑(秕糠马拉色菌引起的)、祛痘(痤疮丙酸杆菌引起的)的产品。
试验例2.5抗氧化功效
(1)羟基自由基清除效果
实验材料：0.5％透明质酸锌Ⅰ(实施例9、1270kD)溶液样品、0.5％透明质酸锌Ⅱ(实施例10、45kD)样品；0.5％透明质酸钠溶液样品(华熙生物科技股份有限公司，1230kD)，0.5％乙酸锌(二水)溶液；
实验方法：
采用水杨酸法测定透明质酸锌样品对羟基自由基清除能力。将一定量的H2O2与FeSO4混合,使之发生Fenton反应产生羟自由基,在反应体系中加入水杨酸,可捕获羟基自由基并产生3-羟基水杨酸和5-羟基水杨酸,两种产物在510nm处均有较强吸收,反应方程式如下:
H2O2+Fe2+→·OH+OH-+Fe3+
H2O2+Fe2+→·OH+OH-+Fe3+
样品的加入将和水杨酸竞争与·OH反应,从而使3-羟基水杨酸和5-羟基水杨酸的生成量减少。采用固定反应时间法，测量在510nm处反应液的吸光度值,并与空白液比较，以测定被测物对羟基自由基的清除作用。
清除率按下式计算:
S/％＝A0-(Ax-Ax0)/A0×100
S/％＝A0-(Ax-Ax0)/A0×100
式中,S为清除率,A0为空白对照吸光度值,Ax为加入样品时的吸光度值，Ax0为不加显色剂的吸光度值。
实验结果：
图4结果显示，HA-Zn对羟自由基的清除具有明显效果，且低分子透明质酸锌的羟基自由基清除率更高，可达85％；在同样浓度下，HA-Na和单独二水乙酸锌也具有一定清除羟基自由基的能力，但是清除率明显低于HA-Zn。因此，透明质酸锌具有清除羟基自由基的显著作用，反映了透明质酸锌抗氧
化效果较好，对维持机体正常的生理活动和抗衰老具有重要意义。
(2)超氧阴离子清除效果
实验材料：
0.5％透明质酸锌Ⅰ(实施例9、1270kD)溶液样品、0.5％透明质酸锌Ⅱ(实施例10、45kD)样品；0.5％透明质酸钠溶液样品(华熙生物科技股份有限公司，1230kD)，0.5％乙酸锌(二水)溶液
实验方法：
采用邻苯三酚自氧化法测定。在弱碱性条件下，邻苯三酚能发生自氧化反应，生成超氧阴离子，同时生成有色中间产物，该中间产物在320nm处有一特征吸收峰。在初试阶段，中间产物的量与时间成线性关系。由于自氧化速率依赖于超氧阴离子的浓度，当加入超氧阴离子清除剂时，它能迅速与超氧阴离子反应，抑制自氧化反应，从而阻止中间产物的积累，使溶液在320nm处光吸收减弱。故可以通过测定A320值来评价清除剂对超氧阴离子的清除作用。
清除率按下式计算：
超氧阴离子自由基清除率(％)＝(A0-Ax)/A0×100％
超氧阴离子自由基清除率(％)＝(A0-Ax)/A0×100％
由图5结果可知，HA-Zn对超氧阴离子自由基清除具有显著作用，其中高分子透明质酸锌清除能力更高，清除率可达70％以上。虽然乙酸锌具有一定的超氧阴离子自由基的清除能力，但明显低于HA-Zn，而HA-Na对超氧阴离子自由基几乎无清除能力。因此，透明质酸锌具有显著的清除超氧阴离子自由基的作用，可反映出透明质酸锌具有较好的抗氧化效果。
试验例2.6减少瘢痕形成
实验材料：透明质酸锌样品(实施例9、1270kD)
实验方法：
依据组成原胶原的三条肽链的氨基酸差异，可以将胶原分为I、II、Ⅲ、IV四种类型。正常皮肤胶原以I、Ⅲ型为主，二者含量比例约为3.5:1。在瘢痕形成过程中II型胶原纤维的绝对值以及相对比例均呈现降低趋势，I型胶原则呈现增加趋势。I型胶原是粗纤维，是瘢痕组织纤维化的物质基础；II型胶原是细纤维，是网状纤维的主要组成部分。随着瘢痕形成，II型纤维逐渐被
粗大的Ⅰ型纤维所替代，使得正常皮肤的网状结构遭到破坏，正常皮肤的生物学特性随之改变，I/Ⅲ型胶原比率大幅下降、胶原纤维排列紊乱，纤维变得粗大，从而表现出瘢痕形成的标志性外观。
采用TGF-β1处理成纤维细胞，建立体外瘢痕模型。采用0.05mg/ml的透明质酸锌受试物工作液处理瘢痕模型，48h内采用荧光显微镜进行图片采集，图片放大倍数为400倍(目镜10×，物镜40×)。通过观察成纤维细胞CollagenⅠ和CollagenⅢ含量的变化，评估瘢痕修复功效。(本测试由广东博溪生物科技有限公司进行。)
BC为阳性对照，NC为阴性(空白)对照，由图6A和图6B可知，与NC组相比，样品透明质酸锌在0.05mg/mL浓度下作用24h后，Collagen I的含量均极显著下降(P<0.05)；CollagenⅢ的含量有所下降，但无显著性差异。
综上所述，在体外培养体系中，样品透明质酸锌在0.05mg/mL浓度下能够显著抑制Collagen I的合成，从而影响Collagen I和CollagenⅢ蛋白表达比例，抑制因CollagenⅠ过量表达造成的瘢痕发生。
Claims (16)
- 一种透明质酸锌的制备方法，其中，包括以下步骤：将透明质酸钠加入到含锌盐的酸性含水有机介质中，进行一次置换，得到透明质酸锌沉淀。
- 根据权利要求1所述的制备方法，其中，所述透明质酸钠的加入量与所述锌盐的质量比为1：0.5-1：3.5，优选为1：1-1：3。
- 根据权利要求1或2所述的制备方法，其中，所述含锌盐的酸性含水有机介质中有机溶剂浓度为55％～95％(v/v)，优选为55％～70％(v/v)，锌离子浓度为1％～3％(w/v)，所述含锌盐的酸性含水有机介质的pH为5.0～6.9。
- 根据权利要求1-3中任一项所述的制备方法，其中，所述透明质酸钠的分子量为1kDa-3000kDa。
- 根据权利要求1-4中任一项所述的制备方法，其中，所述置换时间为1～24h。
- 根据权利要求1-5中任一项所述的制备方法，其中，还包括用洗涤液洗涤所述透明质酸锌沉淀，然后用脱水液对洗涤后的沉淀进行脱水，干燥，得到透明质酸锌粉末。
- 权利要求1-6中任一项所述的方法制备的低分子量的透明质酸锌，优选，所述低分子量的透明质酸锌的分子量小于等于1000kDa。
- 权利要求1-6中任一项所述的方法制备的高分子量的透明质酸锌，优选，所述高分子量的透明质酸锌的分子量大于1000kDa。
- 一种透明质酸锌，其中，透明质酸锌的分子量为2kDa～2500kDa，所述透明质酸锌在浓度为0.5wt％的水溶液中，透光率≥88.1％，优选≥99.1％。
- 权利要求1-8中任一项所述的方法制备的透明质酸锌或权利要求9中所述的透明质酸锌在皮肤保湿、皮肤控油、抑制皮肤有害菌、抗氧化、疤痕修复、抑制瘢痕、防止皮肤创伤感染方面的用途，优选所述抑制皮肤有害菌方面的用途包括祛痘和去屑方面的用途；优选所述防止皮肤创伤感染方面的用途包括防止水光针和微针引起的皮肤创伤感染。
- 一种皮肤保湿、皮肤控油、抑制皮肤有害菌、抗氧化、疤痕修复、抑制瘢痕或防止皮肤创伤感染的方法，包括向受试者施用权利要求1-8中任 一项所述的方法制备的透明质酸锌或权利要求9中所述的透明质酸锌，优选所述抑制皮肤有害菌包括祛痘和去屑；优选所述防止皮肤创伤感染包括防止水光针和微针引起的皮肤创伤感染。
- 权利要求1-8中任一项所述的方法制备的透明质酸锌或权利要求9中所述的透明质酸锌在皮肤护理品中的用途。
- 透明质酸锌在减少皮肤油脂含量方面的用途，优选所述透明质酸锌是低分子量的透明质酸锌，进一步优选，所述低分子量透明质酸锌的分子量为2kDa-1000kDa，优选为5kDa～500kDa。
- 透明质酸锌在减少皮肤油脂中卟啉含量方面的用途，优选所述透明质酸锌是低分子量的透明质酸锌,进一步优选，所述低分子量透明质酸锌的分子量为2kDa-1000kDa，优选为5kDa～500kDa。
- 透明质酸锌在清除皮肤表面羟基自由基方面的用途，优选所述透明质酸锌是低分子量的透明质酸锌,进一步优选，所述低分子量透明质酸锌的分子量为2kDa-1000kDa，优选为5kDa～500kDa。
- 透明质酸锌在清除皮肤表面超氧阴离子自由基方面的用途，优选所述透明质酸锌是高分子量的透明质酸锌,进一步优选，所述高分子量透明质酸锌的分子量为1000kDa～2500kDa，优选为1100kDa～2000kDa。
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| US20090215719A1 (en) * | 2005-03-22 | 2009-08-27 | Q.P. Corporation | Low molecular weight hyaluronic acid and/or salt thereof, method for producing same, and cosmetic preparation and food composition containing same |
| JP2016166133A (ja) * | 2015-03-09 | 2016-09-15 | キユーピー株式会社 | パック化粧料 |
| CN111647100A (zh) * | 2020-07-14 | 2020-09-11 | 山东华熙海御生物医药有限公司 | 一种高分子量透明质酸锌的制备方法 |
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| US20090215719A1 (en) * | 2005-03-22 | 2009-08-27 | Q.P. Corporation | Low molecular weight hyaluronic acid and/or salt thereof, method for producing same, and cosmetic preparation and food composition containing same |
| WO2006121210A1 (ja) * | 2005-05-13 | 2006-11-16 | Takata Seiyaku Co., Ltd. | 皮膚状態改善剤 |
| CN1760214A (zh) * | 2005-11-04 | 2006-04-19 | 山东福瑞达生物化工有限公司 | 一种透明质酸锌的制备方法 |
| JP2016166133A (ja) * | 2015-03-09 | 2016-09-15 | キユーピー株式会社 | パック化粧料 |
| CN111647100A (zh) * | 2020-07-14 | 2020-09-11 | 山东华熙海御生物医药有限公司 | 一种高分子量透明质酸锌的制备方法 |
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