JPS62289197A - Production of sodium hyaluronate powder - Google Patents
Production of sodium hyaluronate powderInfo
- Publication number
- JPS62289197A JPS62289197A JP13115886A JP13115886A JPS62289197A JP S62289197 A JPS62289197 A JP S62289197A JP 13115886 A JP13115886 A JP 13115886A JP 13115886 A JP13115886 A JP 13115886A JP S62289197 A JPS62289197 A JP S62289197A
- Authority
- JP
- Japan
- Prior art keywords
- precipitate
- hyaluronic acid
- water
- dried
- sodium hyaluronate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229920002385 Sodium hyaluronate Polymers 0.000 title claims abstract description 19
- 229940010747 sodium hyaluronate Drugs 0.000 title claims abstract description 19
- 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 title claims abstract description 19
- 239000000843 powder Substances 0.000 title claims abstract description 16
- 238000004519 manufacturing process 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 34
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 34
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 34
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 21
- 239000002244 precipitate Substances 0.000 claims abstract description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000011780 sodium chloride Substances 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 238000004108 freeze drying Methods 0.000 claims abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 229960004592 isopropanol Drugs 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 3
- 239000000047 product Substances 0.000 abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract description 4
- 239000001888 Peptone Substances 0.000 abstract description 4
- 108010080698 Peptones Proteins 0.000 abstract description 4
- 239000008103 glucose Substances 0.000 abstract description 4
- 235000019319 peptone Nutrition 0.000 abstract description 4
- 239000000706 filtrate Substances 0.000 abstract description 3
- 239000007864 aqueous solution Substances 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 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 abstract 2
- 229940014041 hyaluronate Drugs 0.000 abstract 2
- 239000011734 sodium Substances 0.000 abstract 2
- 241000120569 Streptococcus equi subsp. zooepidemicus Species 0.000 abstract 1
- 230000000813 microbial effect Effects 0.000 abstract 1
- 235000002639 sodium chloride Nutrition 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 241000194017 Streptococcus Species 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 244000005700 microbiome Species 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940041514 candida albicans extract Drugs 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 239000012138 yeast extract Substances 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- LPUQAYUQRXPFSQ-DFWYDOINSA-M monosodium L-glutamate Chemical compound [Na+].[O-]C(=O)[C@@H](N)CCC(O)=O LPUQAYUQRXPFSQ-DFWYDOINSA-M 0.000 description 2
- 235000013923 monosodium glutamate Nutrition 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- -1 polypeptone Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 description 1
- BWLBGMIXKSTLSX-UHFFFAOYSA-N 2-hydroxyisobutyric acid Chemical compound CC(C)(O)C(O)=O BWLBGMIXKSTLSX-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000194042 Streptococcus dysgalactiae Species 0.000 description 1
- 241000194048 Streptococcus equi Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229940099596 manganese sulfate Drugs 0.000 description 1
- 239000011702 manganese sulphate Substances 0.000 description 1
- 235000007079 manganese sulphate Nutrition 0.000 description 1
- SQQMAOCOWKFBNP-UHFFFAOYSA-L manganese(II) sulfate Chemical compound [Mn+2].[O-]S([O-])(=O)=O SQQMAOCOWKFBNP-UHFFFAOYSA-L 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000013379 molasses Nutrition 0.000 description 1
- 239000004223 monosodium glutamate Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000011218 seed culture Methods 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 229940073490 sodium glutamate Drugs 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 235000013547 stew Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940115920 streptococcus dysgalactiae Drugs 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
Description
【発明の詳細な説明】
３、発明の詳細な説明
産業上の利用分野
本発明は比容積が小さく、溶解性の良好なヒアルロン酸
す） ＩＪウム粉末ならびにその製造法に関する。Detailed Description of the Invention 3. Detailed Description of the Invention Field of Industrial Application The present invention relates to hyaluronic acid powder having a small specific volume and good solubility, and a method for producing the same.
ヒアルロン酸は多糖類の一種であり、ニワ） ＩＪのト
サカ、ｖ！帯、関節液、皮膚などに存在し、保水剤、潤
滑剤的な役割をはだすとともに、バクテリアの侵入から
生体を保護する役割もはたし、生体にとって１要な物質
である。またヒアルロン酸は化粧品や医薬品として用途
開発中の物質である。Hyaluronic acid is a type of polysaccharide (Niwa) IJ crest, v! It exists in the bands, synovial fluid, skin, etc., and plays the role of a water-retaining agent and lubricant, as well as protecting living organisms from invasion by bacteria, and is an essential substance for living organisms. Hyaluronic acid is also a substance currently under development for use in cosmetics and pharmaceuticals.
従来の技術
ヒアルロン酸の製造法は、生体から抽出する方法〔特開
昭６０−２４１９４．メソッヅ・イン・エンチモロジイ
（！、Ｉｅｔｈｏｄｓ ｉｎ Ｅｎｚｙｍｏｌｏｇｙ）
’１ｇ。Conventional technology A method for producing hyaluronic acid is a method of extracting it from a living body [Japanese Patent Application Laid-Open No. 60-24194. Methods in Enzymology (!, Methods in Enzymology)
'1g.
９５〜９８ （１９７２） ：］ 、 ヒアルロン酸
生産能を有する微生物を培地に培養して製造する方法〔
ジャーナル・オブ・バイオロジカル・ケミストリイ （
Ｊ。95-98 (1972):], Method for producing microorganisms capable of producing hyaluronic acid by culturing them in a medium [
Journal of Biological Chemistry (
J.
Ｂｉｏｌ、 Ｃｈｅｍ、） ２３９． Ｎ（１３，７２
６〜７２８ （１９６４）、特開昭５８−５６６９２Ｅ
などが知られている。Biol, Chem, ) 239. N(13,72
6-728 (1964), JP-A-58-56692E
etc. are known.
発明が解決しようとする問題点
現在、ヒアルロン酸はヒアルロン酸ナトリウムとして市
販されているが、極めて高価であり、製品が綿状で比容
積の大きな溶解性の悪い乾燥物である。Problems to be Solved by the Invention At present, hyaluronic acid is commercially available as sodium hyaluronate, but it is extremely expensive and the product is a dried product with a large specific volume and poor solubility.
生体由来ならびに微生物の産生ずるヒアルロン酸は本来
粘性が高いため溶液を凍結乾燥して１辱られる乾燥物は
比容積が大きく、取り扱い上、輸送の面で問題がある。Hyaluronic acid derived from living organisms and produced by microorganisms is inherently highly viscous, so the dried product obtained by freeze-drying the solution has a large specific volume, which poses problems in terms of handling and transportation.
さらにこれら比容積の大きい乾燥物を化粧品の基材や医
薬品原末などとして使用する目的で、水などの溶媒に溶
解することを検討したところ、極めて溶解性が悪く、完
全に溶解させる際に長時間要する。Furthermore, when we considered dissolving these dry products with large specific volumes in solvents such as water for the purpose of using them as base materials for cosmetics or bulk pharmaceutical powders, we found that the solubility was extremely poor and it took a long time to completely dissolve them. It takes time.
これは、ヒアルロン酸を分離、精製する際に、得られる
ヒアルロン酸ナトリウム沈殿を水に溶解して、凍結乾燥
を行うためである。また溶液をスプレードライヤーで乾
燥すると、加熱によりヒアルロン酸が低分子化する。一
方、沈殿物を真空乾燥すると乾燥物は固化し、溶解性は
先の凍結乾燥物よりさらに悪い状態になる。This is because when separating and purifying hyaluronic acid, the obtained sodium hyaluronate precipitate is dissolved in water and freeze-dried. Furthermore, when the solution is dried with a spray dryer, the hyaluronic acid is reduced in molecular weight by heating. On the other hand, when the precipitate is vacuum-dried, the dried product solidifies and its solubility becomes even worse than that of the freeze-dried product.
従って、比容積が小さく溶解性の良好なヒアルロン酸の
製造法の開発が望まれている。Therefore, it is desired to develop a method for producing hyaluronic acid which has a small specific volume and good solubility.
問題点を解決するための手段
本発明者は、ヒアルロン酸乾燥物を、比容積が小さく溶
解性の良好な乾燥粉末に改善し、１工業的利用価値の高
いものにするため鋭意研究を重ねた。Means for Solving the Problems The present inventor has conducted intensive research to improve dried hyaluronic acid into a dry powder with a small specific volume and good solubility, and to make it highly valuable for industrial use. .
その結果、ヒアルロン酸を精製する際、塩化ナトリウｌ
、含有のヒアルロン酸水溶液に水溶性有機溶媒を加えて
ヒアルロン酸す） ＋Ｊウムとして沈殿させ、該沈殿物
を直接凍結乾燥することにより、比容積が小さく溶解性
の良好な乾燥粉末が得られることを見出した。As a result, when purifying hyaluronic acid, sodium chloride
By adding a water-soluble organic solvent to an aqueous hyaluronic acid solution containing hyaluronic acid to precipitate it as hyaluronic acid and directly freeze-drying the precipitate, a dry powder with a small specific volume and good solubility can be obtained. I found out.
以下に、本発明の詳細な説明する。The present invention will be explained in detail below.
本発明は、ヒアルロン酸を製造する方法において、ヒア
ルロン酸を精製する際、塩化ナトリウム含有のヒアルロ
ン酸水溶液に水溶性有機溶媒を加えてヒアルロン酸ナト
リウムを沈殿させ、該沈殿物を分離し、該沈殿物を直接
凍結乾燥することを特徴とするヒアルロン酸ナトリウム
粉末の製造法を提供する。The present invention provides a method for producing hyaluronic acid in which, when purifying hyaluronic acid, a water-soluble organic solvent is added to a hyaluronic acid aqueous solution containing sodium chloride to precipitate sodium hyaluronate, the precipitate is separated, and the precipitate is Provided is a method for producing sodium hyaluronate powder, which is characterized by directly freeze-drying the product.
本発明に用いる塩化ナトリウム含有のヒアルロン酸水溶
液は、ヒアルロン酸生産能を有する微生物を栄養培地に
培養した培養液より得ることができるが、生体抽出ヒア
ルロン酸ナトリウムも用いることができる。The sodium chloride-containing aqueous hyaluronic acid solution used in the present invention can be obtained from a culture solution obtained by culturing microorganisms capable of producing hyaluronic acid in a nutrient medium, but biologically extracted sodium hyaluronate can also be used.
ヒアルロン酸を得るために本発明に使用する微生物は、
ヒアルロン酸を菌体外に蓄積する菌株であればいずれも
使用可能であるが、とくにランセフイールド（Ｌａｎｃ
ｅｆ １ｅｌｄ） による血清学的分類〔バーシーズ・
マニュアル・オブ・デタミネイティブ・バタテリオロジ
イ（Ｂｅｒｇｅｙ’ｓ Ｍａｎｕａｌ ｏｆＤｅｔｅｒ
ｍｉｎａｔｉｖｅ Ｂａｃｔｅｒｉｏｌ、） ４９１．
１９７４ 〕のＡ群および０群のストレプトコツカス属
菌種が望ましい。具体的な例としては、ストレプトコッ
カス・ピオゲネス、ストレプトコッカス・エクイ、スト
レプトコッカス・エクインミリス、ストレプトコッカス
・ディスガラクティアエ、ストレプトコフカス・ズーエ
ビデミクスなどが用いられる。とくに好適にはストレプ
トコッカス・ズーエビデミクス（Ｓｔｒｅｐｔｏｃｏｃ
ｃｕｓ ｚｏｏｅｐ、ｉｄｅｍｉｃｕｓ） ＮＣＴＣ７
０２３〔ジャーナル・オブ・ジェネラル・ミクロバイオ
ロジイ（Ｊ、Ｇｅｎ、Ｍｉｃｒｏｂｉｏｌ、） １５．
４８５〜４９１ （１９５６）］があげられる。The microorganisms used in the present invention to obtain hyaluronic acid are:
Any strain that accumulates hyaluronic acid outside the bacterial body can be used, but Lansefield (Lancefield) can be used in particular.
Serological classification according to ef 1eld)
Bergey's Manual of Determination
minative Bacteriol, ) 491.
Streptococcus species of groups A and 0 of [1974] are preferred. Specific examples include Streptococcus pyogenes, Streptococcus equi, Streptococcus equimillis, Streptococcus dysgalactiae, and Streptococcus zooevidemicus. Particularly preferred is Streptococcus zooevidemicus.
cus zooep, idemicus) NCTC7
023 [Journal of General Microbiology (J, Gen, Microbiol,) 15.
485-491 (1956)].
本発明に用いる培地としては、炭素源、窒素源。The culture medium used in the present invention includes a carbon source and a nitrogen source.
ｆｌｔｔｌ物その他の栄養物を程よく含有するものであ
れば、合成培地、天然培地いずれも使用できる。Both synthetic and natural media can be used as long as they contain appropriate amounts of flttl and other nutrients.
炭素源としてはグルコース、ンユクロース、廃糖蜜、で
ん粉加水分解物などが使用できる。窒素源としてはペプ
トン、ポリペプトン、酵母エキス。Glucose, sugar syrup, blackstrap molasses, starch hydrolyzate, etc. can be used as carbon sources. Nitrogen sources include peptone, polypeptone, and yeast extract.
コーンスチーブリカー、カゼイン加水分解物、プレイン
・ハート・インヒユージョン、馬血清などの有機栄養源
の添加が望ましく、硫酸アンモニウム、硝酸アンモニウ
ム、塩化アンモニウム、アンモニアなどを併用すること
も可能である。無機塩としては例えば、塩化ナトリウム
、リン酸ナトリウム、リン酸カリウム、硫酸マグネシウ
ム、チオ硫酸す） ＩＪウム、硫酸第１鉄、硫酸マンガ
ン、塩化カルシウム、炭酸カルシウムなどが使用できる
。It is desirable to add an organic nutrient source such as corn steep liquor, casein hydrolyzate, plain heart injection, horse serum, etc. Ammonium sulfate, ammonium nitrate, ammonium chloride, ammonia, etc. can also be used in combination. Examples of inorganic salts that can be used include sodium chloride, sodium phosphate, potassium phosphate, magnesium sulfate, thiosulfate, ferrous sulfate, manganese sulfate, calcium chloride, and calcium carbonate.
もちろん天然栄養源を用いたときなどに天然物中に含有
する無機塩のみで満足させることが可能なときもある。Of course, there are times when it is possible to satisfy the needs only with inorganic salts contained in natural products, such as when using natural nutritional sources.
また必要に応じて、各種ビタミン。Also various vitamins as needed.
アミノ酸塩、例えばチアミン、ニコチン酸、ビオチン、
パントテン酸、グルタミン酸ナトリウムなどが使用でき
る。Amino acid salts such as thiamine, nicotinic acid, biotin,
Pantothenic acid, monosodium glutamate, etc. can be used.
培養は、振盪培養１通気培養などの好気的条件下で行う
。培養温度は２５〜４２℃、好ましくは３０〜３８℃が
適当である。培養時のｐＨは５〜９が適当である。ｐＨ
調節はアンモニア水、水酸化ナトリウム、水酸化カリウ
ム、炭酸カルシウムなどによって行う。Cultivation is performed under aerobic conditions such as shaking culture 1 aerated culture. The appropriate culture temperature is 25-42°C, preferably 30-38°C. A suitable pH during culturing is 5 to 9. pH
Adjustments are made with aqueous ammonia, sodium hydroxide, potassium hydroxide, calcium carbonate, etc.
培養期間は通常２〜４日間でヒアルロン酸は主として菌
体外に蓄積する。The culture period is usually 2 to 4 days, and hyaluronic acid is mainly accumulated outside the bacterial cells.
培養物からのヒアルロン酸の精製は、以下の方法で行う
。Purification of hyaluronic acid from culture is performed by the following method.
水酸化す） ＩＪウムなどでｐＨを５〜９に調節を行っ
て得た培養物に粉末活性炭ならびに一過助剤を加えて一
過を行い泥液を得る。この泥液に塩化ナトリウムを加え
た後にアセトン、メタノール。Powdered activated carbon and a passing aid are added to the culture obtained by adjusting the pH to 5 to 9 using IJum (hydroxide), etc., and passing is carried out to obtain a slurry. Add sodium chloride to this slurry, then acetone and methanol.
エタノール、ｎ−プロパノール、イソ−プロパノール、
アセトニトリルなどの水溶性有機溶媒を泥液に対して１
〜４倍量添加して、粗ヒアルロン酸す） ＩＪウムの沈
殿を析出させる。沈殿を分離した後、０．２モル／ｐ程
度の食塩水に溶解し、再度アセトン、メタノール、エタ
ノール、ｎ−プロパノール、イソ−プロパノール、アセ
トニ） ＋Ｊルナトの水溶性有機溶媒を添加してヒアル
ロン酸す） ＩＪウムの沈殿を析出させ、母液と沈殿を
分離する。ethanol, n-propanol, iso-propanol,
Add a water-soluble organic solvent such as acetonitrile to the slurry
Add up to 4 times the amount of crude hyaluronic acid to precipitate IJum. After separating the precipitate, it was dissolved in a saline solution of about 0.2 mol/p, and a water-soluble organic solvent (acetone, methanol, ethanol, n-propanol, iso-propanol, acetonate) + J Lunato was added again to dissolve hyaluronic acid. ) Precipitate IJum and separate the mother liquor and precipitate.
このようにして得られたヒアルロン酸ナトリウム沈殿物
を５０〜１００％濃度のメタノール、エタノール、ｎ−
プロパノール、イソーブロパノール、アセトン、アセト
ニトリル溶液で洗浄し、沈殿物のまま０℃以下、好まし
くは一１０℃以下に冷却し、さらに棚温度を０℃以下、
好ましくは一２０℃以下に冷却した状態で凍結乾燥を行
うと、比容積が１〜２ｍｌ／ｇと小さなヒアルロン酸ナ
トリウム乾燥物を得ることができる。さらにこの乾燥物
は粉砕機などにより容易に粉砕でき粉末化できる。また
粉砕したヒアルロン酸ナトリウム粉末は水などの溶媒に
対する溶解速度が予想外に速い。The sodium hyaluronate precipitate thus obtained was mixed with methanol, ethanol, n-
Wash with propanol, isopropanol, acetone, and acetonitrile solutions, cool the precipitate to below 0°C, preferably below -10°C, and then lower the shelf temperature to below 0°C.
If freeze-drying is preferably carried out at a temperature of -20° C. or lower, a dried sodium hyaluronate product with a small specific volume of 1 to 2 ml/g can be obtained. Furthermore, this dried product can be easily crushed and powdered using a crusher or the like. Furthermore, the pulverized sodium hyaluronate powder has an unexpectedly high dissolution rate in solvents such as water.
本発明により得られるヒアルロン酸ナトリウム粉末と通
常の方法にて得られるヒアルロン酸ナトリウム乾燥物と
の溶解性ならびに比容積の比較を行った結果を第１表に
示した。Table 1 shows the results of a comparison of the solubility and specific volume between the sodium hyaluronate powder obtained by the present invention and the dried sodium hyaluronate obtained by a conventional method.
第１表 以下に、本発明の実施例を示す。Table 1 Examples of the present invention are shown below.
実施例１゜
ストレプトコブカス・ズーエビデミクスＮＣＴＣ７０２
３をプレイン・ハート・インヒユージョン寒天培地（田
水製薬社製）で３７℃、１６時間培養した菌体を、グル
コース１％、ペプトン１．５％。Example 1 Streptococcus zooevidemics NCTC702
3 was cultured on Plain Heart Infusion Agar medium (manufactured by Tasumi Seiyaku Co., Ltd.) at 37°C for 16 hours, and the cells were incubated with 1% glucose and 1.5% peptone.
酵母エキス０．５％、コーンスチー７’ ＩＪ カー
１％。Yeast extract 0.5%, corn stew 7' IJ car
1%.
グルタミン酸ナトリウム０，３％、リン酸２カリウム０
．２％、硫酸マグネシウム０．０５％、チオ硫酸ナトリ
ウム０．１％、炭酸力ルンウム２％からなる種培地（ｐ
Ｈ７，０）３０ Ｑｍｌに接種し、３７℃。Sodium glutamate 0.3%, dipotassium phosphate 0
．． Seed medium (p
H7,0) Inoculated into 30 Qml and kept at 37°C.
１６時間振盪培養した。この種培養液１５ Ｑｍｌをグ
ルコース２．５％、ペプトン１．５％、酵母エキス０．
５％、コーンスチーブリ力−〇、５％、リン酸２カリウ
ム０．２％、硫酸マグネシウム０．００５％。The culture was incubated with shaking for 16 hours. 15 Qml of this seed culture was mixed with 2.5% glucose, 1.5% peptone, and 0.0% yeast extract.
5%, Cohn-Steebly force - 5%, dipotassium phosphate 0.2%, magnesium sulfate 0.005%.
チオ硫酸ナトリウム０．１％からなる発酵培地（ｐＨ７
，２）３ｆを含む５Ｉ！容ジャーファーメンタ−に接種
し、３７℃９通気量Ｑ、３ｖｖｍ、ｐＨ７，０にて２６
時間培養して、培養液中にヒアルロン酸を４、５ ｇ
／ １蓄積させた。培養液３１に水６β、塩化ナトリウ
ム７０ｇ、濾過助剤ラジオライト＃５００（昭和化工社
製）１５０ｇ、粉末活性炭タイコ−ＣＴ−５Ａ−Ｉ Ｇ
Ｑ Ｏ（二相化学社製）５０ｇを加え約１時間攪拌し
た後、ヌッチェにて濾過し泥液を得た。Ｐ液９，５ｆｌ
にエタノール２０１を加え、粗ヒアルロン酸ナトリウム
を沈殿化し、母液と分離した後、沈殿を食塩３０ｇを含
む水１０ｐに溶解し、粉末活性炭２０ｇを加えた後ヌブ
チェにて濾過を行い精製ヒアルロン酸Ｆ液を得た。この
ろ液２１にエタノール４１を加えてヒアルロン酸ナトリ
ウムの沈殿を析出させた後、沈殿を分離し、８０％エタ
ノール水で洗浄し、沈殿を一２０℃にて５時間冷却した
。冷却した沈殿を真空度２トール以下、棚温−４０℃に
て１０時間凍結乾燥した。Fermentation medium consisting of 0.1% sodium thiosulfate (pH 7)
, 2) 5I including 3f! Inoculated into a jar fermenter and incubated at 37°C, 9 aeration volume Q, 3vvm, pH 7.0 for 26 hours.
After culturing for an hour, add 4 to 5 g of hyaluronic acid to the culture solution.
/ Accumulated 1. Culture solution 31, water 6β, sodium chloride 70g, filter aid Radiolite #500 (manufactured by Showa Kako Co., Ltd.) 150g, powdered activated carbon Tyco-CT-5A-IG
After adding 50 g of QO (manufactured by Nisho Kagaku Co., Ltd.) and stirring for about 1 hour, the mixture was filtered using a Nutsche filter to obtain a slurry. P liquid 9.5 fl
Add ethanol 201 to the solution to precipitate crude sodium hyaluronate, separate it from the mother liquor, dissolve the precipitate in 10 parts of water containing 30 g of common salt, add 20 g of powdered activated carbon, and filter with Nubuche to obtain purified hyaluronic acid solution F. I got it. After adding ethanol 41 to this filtrate 21 to precipitate sodium hyaluronate, the precipitate was separated, washed with 80% ethanol water, and cooled at -20°C for 5 hours. The cooled precipitate was freeze-dried for 10 hours at a vacuum level of 2 torr or less and a shelf temperature of -40°C.
その後さらに棚温を室温にして、１０時間凍結乾燥して
、ヒアルロン酸ナトリウム乾燥物２．５ｇを得た。この
乾燥物をメノウ製乳針にて粉砕し、ヒアルロン酸す）
ＩＪウム粉末を得た。Thereafter, the shelf temperature was further raised to room temperature, and freeze-drying was performed for 10 hours to obtain 2.5 g of dried sodium hyaluronate. This dried product is crushed with an agate milk needle and mixed with hyaluronic acid)
IJum powder was obtained.
得られた乾燥粉末の比容積は１．８ｍｌ／ｇ、溶解性は
２２分であった。The resulting dry powder had a specific volume of 1.8 ml/g and a solubility of 22 minutes.
実施例２゜
実施例１．で示した方法にて得た、精製ヒアルロン酸泥
液２ｆ！にアセトン３１を添加して、ヒアルロン酸す）
ＩＪウムを析出させた後、沈殿を分離し、８０％アセ
トン水で洗浄し、沈殿を一４０℃にて３時間冷却した。Example 2゜Example 1. Purified hyaluronic acid slurry obtained by the method shown in 2f! Add acetone 31 to hyaluronic acid)
After IJium was precipitated, the precipitate was separated and washed with 80% acetone water, and the precipitate was cooled at -40°C for 3 hours.
冷却した沈殿を真空度２トール以下、棚温−３θ℃にて
６時間凍結乾燥した。その後、棚温を室温にして１０時
間凍結乾燥して、ヒアルロン酸ナトリウム乾燥物２．６
ｇを得た。この乾燥物をメノウ製乳針にて粉砕し、ヒア
ルロン酸す） ＩＪウム粉末を１等だ。The cooled precipitate was freeze-dried for 6 hours at a vacuum level of 2 torr or less and a shelf temperature of -3θ°C. Thereafter, the shelf temperature was raised to room temperature and lyophilized for 10 hours to obtain a dried sodium hyaluronate product of 2.6
I got g. This dried product is crushed with an agate milk needle and hyaluronic acid powder is used.
得られた乾燥粉末の比容積は２．０ｍｌ／ｇ、溶解性は
２６分であった。The specific volume of the obtained dry powder was 2.0 ml/g, and the solubility was 26 minutes.
発明の効果
本発明によれば、比容積が小さく溶解性の良好なヒアル
ロン酸ナトリウム粉末を安価に供給することができる。Effects of the Invention According to the present invention, sodium hyaluronate powder having a small specific volume and good solubility can be supplied at low cost.
Claims (2)
性有機溶媒を加えてヒアルロン酸ナトリウムを沈殿させ
、該沈殿物を分離し、該沈殿物を凍結乾燥することを特
徴とするヒアルロン酸ナトリウム粉末の製造法。(1) Production of sodium hyaluronate powder, which is characterized by adding a water-soluble organic solvent to an aqueous hyaluronic acid solution containing sodium chloride to precipitate sodium hyaluronate, separating the precipitate, and freeze-drying the precipitate. Law.
アセトン、ｎ−プロパノール、イソ−プロパノールまた
はアセトニトリルであることを特徴とする特許請求の範
囲第１項記載の製造法。(2) The water-soluble organic solvent is methanol, ethanol,
The method according to claim 1, characterized in that the solvent is acetone, n-propanol, iso-propanol or acetonitrile.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13115886A JPS62289197A (en) | 1986-06-06 | 1986-06-06 | Production of sodium hyaluronate powder |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13115886A JPS62289197A (en) | 1986-06-06 | 1986-06-06 | Production of sodium hyaluronate powder |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS62289197A true JPS62289197A (en) | 1987-12-16 |
Family
ID=15051353
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13115886A Pending JPS62289197A (en) | 1986-06-06 | 1986-06-06 | Production of sodium hyaluronate powder |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62289197A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2631344A1 (en) * | 1988-05-13 | 1989-11-17 | Chisso Corp | PROCESS FOR THE PREPARATION OF FINE HYALURONIC ACID POWDER OR SODIUM HYALURONATE AND FINE POWDER THUS OBTAINED |
| WO2007142285A1 (en) * | 2006-06-07 | 2007-12-13 | Kyowa Hakko Bio Co., Ltd. | Method for purification of hyaluronic acid salt |
| WO2008004530A1 (en) * | 2006-07-03 | 2008-01-10 | Kyowa Hakko Bio Co., Ltd. | Powder of hyaluronic acid or salt thereof, and method for producing the same |
| WO2015108029A1 (en) * | 2014-01-14 | 2015-07-23 | キユーピー株式会社 | Hyaluronic acid and/or salt thereof, method for producing same, and food, cosmetic, and pharmaceutical containing said hyaluronic acid and/or salt thereof |
| JP2017025157A (en) * | 2015-07-17 | 2017-02-02 | キユーピー株式会社 | Hyaluronic acid and/or salt thereof, foods, cosmetics and pharmaceuticals containing the hyaluronic acid and/or salt thereof |
| CN109851822A (en) * | 2018-12-07 | 2019-06-07 | 山东众山生物科技有限公司 | A kind of preparation method of instant Sodium Hyaluronate |
-
1986
- 1986-06-06 JP JP13115886A patent/JPS62289197A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2631344A1 (en) * | 1988-05-13 | 1989-11-17 | Chisso Corp | PROCESS FOR THE PREPARATION OF FINE HYALURONIC ACID POWDER OR SODIUM HYALURONATE AND FINE POWDER THUS OBTAINED |
| WO2007142285A1 (en) * | 2006-06-07 | 2007-12-13 | Kyowa Hakko Bio Co., Ltd. | Method for purification of hyaluronic acid salt |
| WO2008004530A1 (en) * | 2006-07-03 | 2008-01-10 | Kyowa Hakko Bio Co., Ltd. | Powder of hyaluronic acid or salt thereof, and method for producing the same |
| WO2015108029A1 (en) * | 2014-01-14 | 2015-07-23 | キユーピー株式会社 | Hyaluronic acid and/or salt thereof, method for producing same, and food, cosmetic, and pharmaceutical containing said hyaluronic acid and/or salt thereof |
| JP5824599B1 (en) * | 2014-01-14 | 2015-11-25 | キユーピー株式会社 | Method for producing hyaluronic acid and / or salt thereof |
| JP2017025157A (en) * | 2015-07-17 | 2017-02-02 | キユーピー株式会社 | Hyaluronic acid and/or salt thereof, foods, cosmetics and pharmaceuticals containing the hyaluronic acid and/or salt thereof |
| CN109851822A (en) * | 2018-12-07 | 2019-06-07 | 山东众山生物科技有限公司 | A kind of preparation method of instant Sodium Hyaluronate |
| CN109851822B (en) * | 2018-12-07 | 2022-02-11 | 山东众山生物科技有限公司 | Preparation method of instant sodium hyaluronate |
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