CN116284495A - All-trans retinoic acid low-molecular hyaluronate derivative and preparation method and application thereof - Google Patents
All-trans retinoic acid low-molecular hyaluronate derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN116284495A CN116284495A CN202310286693.4A CN202310286693A CN116284495A CN 116284495 A CN116284495 A CN 116284495A CN 202310286693 A CN202310286693 A CN 202310286693A CN 116284495 A CN116284495 A CN 116284495A
- Authority
- CN
- China
- Prior art keywords
- retinoic acid
- trans retinoic
- hyaluronate
- derivative
- skin
- 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
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 title claims abstract description 103
- 229930002330 retinoic acid Natural products 0.000 title claims abstract description 97
- 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 class 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 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 35
- 229920002674 hyaluronan Polymers 0.000 claims description 27
- 230000037303 wrinkles Effects 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 23
- 229960003160 hyaluronic acid Drugs 0.000 claims description 23
- 235000010413 sodium alginate Nutrition 0.000 claims description 23
- 239000000661 sodium alginate Substances 0.000 claims description 23
- 229940005550 sodium alginate Drugs 0.000 claims description 23
- 239000002537 cosmetic Substances 0.000 claims description 22
- CCOXXLBCWNALRU-UHFFFAOYSA-N CC([Na])=O Chemical compound CC([Na])=O CCOXXLBCWNALRU-UHFFFAOYSA-N 0.000 claims description 21
- -1 hyaluronic acid ester Chemical class 0.000 claims description 18
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 17
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 17
- 238000009472 formulation Methods 0.000 claims description 15
- 229940014041 hyaluronate Drugs 0.000 claims description 15
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 11
- 206010061218 Inflammation Diseases 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 9
- 230000004054 inflammatory process Effects 0.000 claims description 8
- 230000032683 aging Effects 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 235000013305 food Nutrition 0.000 claims description 6
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003729 cation exchange resin Substances 0.000 claims description 5
- WOWHHFRSBJGXCM-UHFFFAOYSA-M cetyltrimethylammonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)C WOWHHFRSBJGXCM-UHFFFAOYSA-M 0.000 claims description 5
- 230000000699 topical effect Effects 0.000 claims description 5
- 230000006872 improvement Effects 0.000 claims description 4
- 239000004615 ingredient Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 230000008591 skin barrier function Effects 0.000 claims description 3
- 230000033228 biological regulation Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 3
- 239000001110 calcium chloride Substances 0.000 claims 1
- 229910001628 calcium chloride Inorganic materials 0.000 claims 1
- 230000008833 sun damage Effects 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 37
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract description 15
- 206010040880 Skin irritation Diseases 0.000 abstract description 5
- 230000036556 skin irritation Effects 0.000 abstract description 5
- 231100000475 skin irritation Toxicity 0.000 abstract description 5
- 210000003491 skin Anatomy 0.000 description 46
- 239000000243 solution Substances 0.000 description 24
- 230000000694 effects Effects 0.000 description 20
- 238000012360 testing method Methods 0.000 description 20
- 229960001727 tretinoin Drugs 0.000 description 20
- 239000000499 gel Substances 0.000 description 17
- 239000008367 deionised water Substances 0.000 description 13
- 229910021641 deionized water Inorganic materials 0.000 description 13
- 238000002474 experimental method Methods 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 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 description 10
- 239000007787 solid Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 210000004207 dermis Anatomy 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 108090001005 Interleukin-6 Proteins 0.000 description 7
- 108090001007 Interleukin-8 Proteins 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 238000010907 mechanical stirring Methods 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- KIUKXJAPPMFGSW-MNSSHETKSA-N hyaluronan Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(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-MNSSHETKSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- 102000008186 Collagen Human genes 0.000 description 5
- 108010035532 Collagen Proteins 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 230000003712 anti-aging effect Effects 0.000 description 5
- 230000003110 anti-inflammatory effect Effects 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 229920001436 collagen Polymers 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 230000002757 inflammatory effect Effects 0.000 description 5
- 238000012423 maintenance Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 208000002874 Acne Vulgaris Diseases 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 102000012422 Collagen Type I Human genes 0.000 description 4
- 108010022452 Collagen Type I Proteins 0.000 description 4
- 206010000496 acne Diseases 0.000 description 4
- 210000001124 body fluid Anatomy 0.000 description 4
- 239000010839 body fluid Substances 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 229940099552 hyaluronan Drugs 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- 230000007794 irritation Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000003711 photoprotective effect Effects 0.000 description 4
- 230000004224 protection Effects 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- 201000004624 Dermatitis Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 210000002615 epidermis Anatomy 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 230000001815 facial effect Effects 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000005017 polysaccharide Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- 206010013786 Dry skin Diseases 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 206010040844 Skin exfoliation Diseases 0.000 description 2
- 229960002916 adapalene Drugs 0.000 description 2
- LZCDAPDGXCYOEH-UHFFFAOYSA-N adapalene Chemical compound C1=C(C(O)=O)C=CC2=CC(C3=CC=C(C(=C3)C34CC5CC(CC(C5)C3)C4)OC)=CC=C21 LZCDAPDGXCYOEH-UHFFFAOYSA-N 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 230000001153 anti-wrinkle effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000035618 desquamation Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000037336 dry skin Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000037072 sun protection Effects 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- JCERKCRUSDOWLT-UHFFFAOYSA-N 1-bromopropan-1-ol Chemical compound CCC(O)Br JCERKCRUSDOWLT-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 235000005459 Digitaria exilis Nutrition 0.000 description 1
- 240000008570 Digitaria exilis Species 0.000 description 1
- 238000011891 EIA kit Methods 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029412 Nightmare Diseases 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 235000010575 Pueraria lobata Nutrition 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000028990 Skin injury Diseases 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000004347 all-trans-retinol derivatives Chemical class 0.000 description 1
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003255 anti-acne Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003367 anti-collagen effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940096422 collagen type i Drugs 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 229940000033 dermatological agent Drugs 0.000 description 1
- 239000003241 dermatological agent Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000000600 disaccharide group Chemical group 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 125000005608 naphthenic acid group Chemical class 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 230000035910 sensory benefits Effects 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 230000009759 skin aging Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 230000037394 skin elasticity Effects 0.000 description 1
- 210000001626 skin fibroblast Anatomy 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000000475 sunscreen effect Effects 0.000 description 1
- 239000000516 sunscreening agent Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Images
Classifications
-
- 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
- A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/203—Retinoic acids ; Salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- 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
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/67—Vitamins
- A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
-
- 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
- A61P17/18—Antioxidants, e.g. antiradicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
- A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
-
- 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
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Birds (AREA)
- Polymers & Plastics (AREA)
- Gerontology & Geriatric Medicine (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Molecular Biology (AREA)
- Materials Engineering (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Cosmetics (AREA)
Abstract
The application provides an all-trans retinoic acid low-molecular hyaluronate derivative, and a preparation method and application thereof, wherein the structure of the all-trans retinoic acid low-molecular hyaluronate derivative is shown as a formula I:
wherein R is 1 、R 2 、R 3 、R 4 Each independently selected from hydrogen and acetyl, m is greater than or equal to 1, n is greater than or equal to 0. The derivative has better stability and water solubility, and reduces the possibility of skin irritation.
Description
Technical Field
The application relates to the technical field of biological medicine, in particular to an all-trans retinoic acid low-molecular hyaluronic acid ester derivative, and a preparation method and application thereof.
Background
Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
The development of functional cosmetics has now become the subject of the development of the cosmetic industry today, wherein the added bioactive ingredients have an important regulatory effect on the growth and metabolism of cells. Among the multifunctional raw materials, anti-aging and anti-acne are always hot topics in the skin care community, and consumers and brands are exploring the nightmares of 'true life components' in the heart to change and resist skin aging and acne.
The hyaluronic acid has a molecular structure of a repeated structure of disaccharide units consisting of D-glucuronic acid and N-acetylglucosamine, has a plurality of important physiological functions, including preventing and repairing skin injury, promoting wound healing and the like, has the functions of locking water and improving skin metabolism, can be used as a good transdermal absorption promoter, and is widely used in cosmetic skin care products. The macromolecular hyaluronic acid is difficult to permeate into the skin, is mainly used for external application, is easy to penetrate cell membranes to reach dermis layers, has low viscosity, and can promote proliferation and differentiation of epidermis cells and remove oxygen free radicals, thereby achieving the functions of eliminating wrinkles and enhancing skin elasticity. In addition, hyaluronan (Acetylated hyaluronic acid, acHA) is an acetylated modified derivative of hyaluronic acid, has hydrophilicity and lipophilicity, can soften the stratum corneum highly, has strong affinity to skin, and has a water-retaining capacity and a skin care effect far exceeding those of hyaluronic acid.
All-trans retinoic acid (ATRA) is a vitamin A derivative, belongs to a lipophilic molecule, can be combined with a specific nuclear receptor, can regulate gene expression involved in cell proliferation and differentiation, can increase generation of subcutaneous collagen, and has an anti-wrinkle function; meanwhile, the all-trans retinoic acid can inhibit the production of proinflammatory cytokines, such as IL-6 and IL-8 in cells, reduce other proinflammatory mediators and has obvious anti-inflammatory effect. In addition, oral and topical retinoic acid has been clinically used for treating dermatoses such as acne, psoriasis, etc. In medicine, retinoic acid and its compounds are also applied to tumor research, for example, the combination of all-trans retinoic acid and camptothecin anticancer drugs can improve the bioavailability and anticancer effect of anticancer drugs; all-trans retinoic acid in combination with paclitaxel can induce apoptosis of glioblastoma cells.
Although all-trans retinoic acid is very attractive in pharmaceutical and cosmetic aspects, it also has significant drawbacks. Because it has a series of fragile double bonds, the molecular structure is unstable and retinoic acid is degraded by many different factors. The baseline retinoic acid concentration was 60-80% degraded within 24 hours when exposed to normal sunlight. Products containing retinoic acid, such as medicines or cosmetics, fail over a period of weeks up to months as retinoic acid degrades once they are contacted with air or light. In addition, the degradation products of retinoic acid have high irritation, are easy to damage skin, and have the phenomena of erythema, desquamation, dryness, burning, itching and the like. In addition, the poor water solubility of retinoic acid also limits its use to some extent. Therefore, the defects of poor stability, strong irritation, poor water solubility and the like limit the development and application of all-trans retinoic acid.
To avoid the above drawbacks, researchers have been working for many years to search for improved methods, including methods to improve the stability of retinoic acid to maintain its activity, e.g., US Skinvisible Pharmaceuticals company in US20090264527A1 discloses a method of stabilizing all-trans retinoic acid by mixing retinoic acid with a hydrophobic/hydrophilic polymer in an oxygen-containing atmosphere to form a retinoic acid-containing composition. The composition can maintain stability and activity of retinoic acid, but has high potential safety hazard due to the fact that the hydrophobic and hydrophilic materials are required to be mixed in an anhydrous molten state at a high temperature and oxygen atmosphere protection is required, and the composition is high in cost and unfavorable for mass production. And researchers are also looking for alternative compounds to retinoic acid, hopefully to develop a compound with retinoic acid efficacy but with little irritation and side effects. For example Adapalene (Adapalene), a naphthenic acid derivative with retinoid activity, can increase the efficacy and penetration of drugs for treating local acne, and accelerate the improvement of pigmentation after acne inflammation, but there are still disadvantages such as high susceptibility to local skin erythema, dryness, desquamation. In addition, polysaccharides are easy to chemically modify due to the fact that they contain hydroxyl, carboxyl, amino and other active groups, and are widely used in the fields of biopharmaceuticals and cosmetics, for example, ireland company Eurand Pharmaceuticals in US6897203B2 utilizes halogenated acyl groups of retinoic acid to react with alcoholized hydroxyl groups of polysaccharides to prepare all-trans retinoic acid polysaccharide esters, and the products overcome the disadvantages of unstable and high irritation of retinoic acid, but still require light-shielding conditions, and have complex preparation process and harsh conditions.
It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative. Throughout the specification and claims, the words "comprise," "include," and the like are to be construed in an inclusive sense, rather than an exclusive or exhaustive sense, unless the context clearly requires otherwise; that is, it is interpreted in the light of "including, but not limited to".
Disclosure of Invention
The invention provides an all-trans retinoic acid low molecular hyaluronic acid ester derivative, a preparation method and application thereof, wherein the structure of the all-trans retinoic acid low molecular hyaluronic acid ester derivative simultaneously contains a hydrophobic all-trans retinoic acid structure and a hydrophilic hyaluronic acid or hyaluronan structure, and the two structures are combined through covalent bonds, and particularly, a three-carbon short chain exists between the two structures, so that the all-trans retinoic acid low molecular hyaluronic acid ester derivative has better stability and water solubility on the whole, and the possibility of skin irritation is reduced; meanwhile, the skin and dermis can be penetrated efficiently, and then the ester bond and the ether bond in the structure are opened under the action of body fluid, so that the effective release of all-trans retinoic acid and low-molecular hyaluronic acid or hyaluronan in the dermis layer is realized, and the anti-inflammatory and anti-aging effects are better exerted.
Specifically, the invention provides the following technical scheme:
in a first aspect of the invention, the invention provides an all-trans retinoic acid low molecular weight hyaluronate derivative, which has the structure shown in formula I:
wherein R is 1 、R 2 、R 3 、R 4 Each independently selected from hydrogen and acetyl, m is greater than or equal to 1, n is greater than or equal to 0.
In an embodiment of the invention, the average molecular weight of the derivative structure of formula I is less than 200kDa; preferably from 10kDa to 100kDa.
In an embodiment of the present invention, the degree of substitution of the all-trans retinoic acid structure in formula I is from 0.01 to 0.1, preferably from 0.01 to 0.05.
In some embodiments of the invention, R 1 、R 2 、R 3 、R 4 All are hydrogen; or in some embodiments, R 1 、R 2 、R 3 、R 4 One or more of the above is acetyl, wherein the content of acetyl is 23-29%.
The all-trans retinoic acid low molecular weight hyaluronate derivative is formed by covalently connecting all-trans retinoic acid derivative with low molecular weight sodium hyaluronate or sodium hyaluronateThe trans-retinoic acid derivative is all-trans-retinoic acid
(X is a leaving group such as halogen, e.g. bromine or chlorine) which gives the derivatives of formula I of the present invention better stability, water solubility and reduced potential for skin irritation; meanwhile, the derivative shown in the formula I can penetrate epidermis and dermis efficiently, and then ester bonds and ether bonds in the structure of the derivative are opened under the action of body fluid (hydrolytic enzyme exists in the body fluid), so that the effective release of all-trans retinoic acid and low-molecular hyaluronic acid or hyaluronan in dermis is realized, the anti-inflammatory and anti-aging effects are better exerted, in particular, UVB-induced skin inflammation can be effectively reduced, I-type collagen synthesis is promoted, and the derivative has good skin photoprotection and skin maintenance effects.
In a second aspect of the invention, the invention provides an intermediate having the structural formula II:
where X is a leaving group, or leaving group, generally refers to an atom or functional group that is detached from a larger molecule in a chemical reaction (generally referred to as a nucleophilic substitution or elimination reaction), such as a halogen, preferably halogen in the present invention, preferably bromine or chlorine.
In an embodiment of the present invention, there is provided a process for the preparation of a compound of formula II, comprising: all-trans retinoic acid
The esterification reaction is carried out and X is a leaving group such as halogen, e.g. bromine or chlorine.
In a third aspect of the present invention there is provided the use of an intermediate as described in the second aspect above for the preparation of an all-trans retinoic acid low molecular hyaluronate derivative as described in the first aspect above.
In a fourth aspect of the present invention, there is provided a process for preparing the all-trans retinoic acid low molecular weight hyaluronate derivative as described in the first aspect, which comprises performing a coupling reaction of an intermediate compound represented by formula II with hyaluronate in the presence of a base, and then performing a salt shift to prepare a compound of formula I;
wherein X is a leaving group, preferably halogen.
In some embodiments of the invention, the hyaluronate is obtained from the reaction of sodium hyaluronate or sodium hyaluronate with cetyltrimethylammonium chloride (western Qu Lvan). Specifically, the preparation method of the hyaluronate comprises the following steps: dissolving sodium hyaluronate or hyaluronate in water, adding cetyltrimethylammonium chloride, stirring, filtering, and oven drying.
In some embodiments of the present invention, the method for preparing the all-trans retinoic acid low molecular weight hyaluronate derivative comprises: the intermediate shown in the formula II, hyaluronate and alkali such as sodium carbonate are subjected to coupling reaction in a solvent such as dimethyl sulfoxide, and are added into 95% ethanol after the reaction is finished, and the compound shown in the formula I is prepared by filtering, washing, drying, dissolving in water, and then performing salt conversion through cation exchange resin.
In a fifth aspect of the present invention, there is provided a composition comprising an all-trans retinoic acid low molecular weight hyaluronate derivative as described in the first aspect above; the composition is a pharmaceutical composition, a cosmetic composition or a food composition.
In embodiments of the invention, the composition may be a formulation which may further comprise other suitable ingredients and necessary adjuvants, for example, the formulation comprises a cosmetically, pharmaceutically, dermatologically or food suitable carrier, and optionally other suitable ingredients, depending on the desired property profile.
In some embodiments of the invention, the formulation is generally a topically applicable formulation, such as a cosmetic or dermatological agent or medical product. By "topical application" in the sense of the present invention is meant that the formulation is topical, i.e. the formulation must be adapted to the skin or hair etc. The formulations according to the invention are therefore preferably used as cosmetic or dermatological preparations, particularly preferably as cosmetic preparations. In some embodiments of the invention, the formulation may be administered orally or by injection.
Specifically, the preparation of the present invention may be, for example, an injection, a liniment, a liquid preparation, a paste, a dressing, a powder injection, or the like; or some form of application to cosmetics such as creams, lotions, aquas, gels, solids, powder bars, freeze-dried forms, etc., examples of specific products for these forms include, but are not limited to, lotions, essences, emulsions, gels, powder bars, creams, foundations, masks, sunscreens (pre-sun or post-sun formulations), solid sticks, or washes (e.g., shampoos, body washes, etc.), etc.
The other suitable components may be, for example, substances which do not react with or at least do not affect the active structure of the all-trans-retinoic acid low molecular hyaluronate derivative according to the present invention.
The all-trans retinoic acid low molecular weight hyaluronic acid ester derivative has good stability, water solubility, very low or almost no skin irritation, can penetrate epidermis and dermis with high efficiency, and better plays roles of resisting inflammation and inhibiting aging, so that in a preferable implementation mode, the all-trans retinoic acid low molecular weight hyaluronic acid ester derivative or the composition containing the derivative can be prepared into cosmetics with the functions of sun protection, moisture preservation, skin nutrition supplementing, anti-inflammation, oxidation resistance, wrinkle removal, aging resistance, skin repair and the like, and the application range of the cosmetics comprises but is not limited to head washing and maintenance, face washing and maintenance, body washing and maintenance products.
For example, in some embodiments of the present invention, the present invention provides a functional cosmetic that is a gel formulation comprising an all-trans retinoic acid low molecular hyaluronate derivative and acetylsodium alginate, wherein the acetylsodium alginate is used as an encapsulation carrier. In one embodiment provided herein, a method of preparing the gel formulation is provided, comprising: mixing the all-trans retinoic acid low molecular weight hyaluronic acid ester derivative solution with the acetyl sodium alginate solution, and then adding the calcium chloride solution.
In these embodiments, the method of preparing the gel formulation comprises: dissolving acetyl sodium alginate in deionized water to prepare a solution; adding the all-trans retinoic acid low molecular weight hyaluronic acid ester derivative into an acetyl sodium alginate solution under stirring, adding a calcium chloride solution, stirring and standing to obtain the all-trans retinoic acid low molecular weight hyaluronic acid ester derivative.
The acetyl sodium alginate can be obtained by purchasing or modifying sodium alginate by acetic anhydride, wherein the substitution degree of acetyl in the acetyl sodium alginate is 10-25%.
In a sixth aspect of the present invention, there is provided the use of an all-trans retinoic acid low molecular weight hyaluronate derivative as described in the above first aspect or a composition as described in the above fifth aspect for the preparation of a medicament, cosmetic or food for treating skin conditions; the medicament comprises an external skin preparation, a dermal filler and a surgical implant; the cosmetic comprises but not limited to cosmetics with the functions of sun protection, moisture preservation, skin nutrition supplementation, inflammation resistance, oxidation resistance, wrinkle removal, aging resistance, skin repair and the like, the application range of the cosmetic comprises but not limited to products such as head washing and caring, face washing and caring and body washing and caring, and the cosmetic dosage forms comprise but not limited to cream, emulsion, water agent, gel, solid, block powder, freeze-drying and the like.
The treatment of skin conditions includes the care of the skin, intended for topical application to the skin to achieve conditions of regulation and/or improvement of the skin condition. Such as may be used to treat a variety of skin conditions, such as those associated with or resulting from inflammation; exposing ultraviolet rays; solar damage; aging (intrinsic or extrinsic); damaged skin barrier (e.g., dry skin); the texture is rough; wrinkles, and the like.
In a seventh aspect of the present invention, there is provided a method of treating a skin condition comprising topically applying to the skin (principally human skin) the all-trans-retinoic acid low molecular hyaluronate derivative of the present invention or a composition comprising the all-trans-retinoic acid low molecular hyaluronate derivative in an effective amount for modulating and/or improving the skin condition.
Wherein the skin condition of the present invention includes, but is not limited to, a skin condition associated with or resulting from inflammation; exposing ultraviolet rays; solar damage; aging (intrinsic or extrinsic); damaged skin barrier (e.g., dry skin); the texture is rough; wrinkles, and the like.
By effective amount is meant that amount of a compound or composition that can significantly induce a positive effect on the skin during treatment (e.g., during use). Such as appearance and/or sensory benefits, such as, in one embodiment, improving wrinkles, roughness, etc. In some cases, an effective amount may be displayed using ex vivo and/or in vitro methods.
Compared with the prior art, the invention has the advantages that:
the structure of the all-trans retinoic acid low molecular hyaluronic acid ester derivative contains a hydrophobic all-trans retinoic acid structure and a hydrophilic hyaluronic acid or hyaluronan structure, and the two structures are combined through covalent bonds, and particularly, a three-carbon short chain exists between the two structures, so that the all-trans retinoic acid low molecular hyaluronic acid ester derivative has better stability and water solubility on the whole, and the possibility of skin irritation is reduced; meanwhile, the skin and dermis can be penetrated efficiently, and then the ester bond and ether bond in the structure are opened under the action of body fluid, so that the effect of effectively releasing all-trans retinoic acid and low-molecular hyaluronic acid or hyaluronan in the dermis layer is realized, the effects of resisting inflammation and inhibiting aging are better exerted, in particular, the UVB-induced skin inflammation can be effectively reduced, the synthesis of I-type collagen is promoted, and the skin photoprotection effect and the skin maintenance effect are good.
Drawings
The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this application, illustrate embodiments of the application and together with the description serve to explain the application and do not constitute an undue limitation to the application. Embodiments of the present application are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 shows nuclear magnetic resonance hydrogen spectra of all-trans retinoic acid low molecular weight hyaluronate derivatives according to the present invention.
Fig. 2 shows the dissolution of all-trans retinoic acid low molecular weight hyaluronate derivative and trans retinoic acid in water according to the present invention.
FIG. 3 shows the inhibition of inflammatory factors (12 h IL-6 and IL-8 concentration changes) in the samples tested in the different experimental groups.
Fig. 4 shows the skin wrinkle area reduction (%) at different times after using different experimental groups of test samples.
Detailed Description
The present application is further illustrated below in conjunction with specific embodiments. It should be understood that these examples are illustrative only of the present application and are not intended to limit the scope of the present application. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or materials used in this application are all commercially available in conventional manners, and unless specifically indicated otherwise, are all used in conventional manners in the art or according to the product specifications. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present application. The preferred methods and materials described herein are presented for illustrative purposes only.
The invention provides an all-trans retinoic acid low-molecular hyaluronate derivative, which has a structure shown in a formula I:
wherein R is 1 、R 2 、R 3 、R 4 Each independently selected from hydrogen and acetyl, m is greater than or equal to 1, n is greater than or equal to 0; the average molecular weight of the derivative structure shown in the formula I is less than 200kDa; in a preferred embodiment, the molecular weight is from 10kDa to 100kDa.
The degree of substitution of the all-trans retinoic acid structure in formula I is from 0.01 to 0.1, and in a preferred embodiment, from 0.01 to 0.05.
In some embodiments of the invention, R 1 、R 2 、R 3 、R 4 All of which may be hydrogen; in some embodiments, R 1 、R 2 、R 3 、R 4 One or more of the above is acetyl, wherein the content of acetyl is 23-29%.
Specifically, the preparation and properties of the derivatives of the present invention will be schematically illustrated in the following examples, and it should be understood that the examples are merely illustrative and are not exhaustive, and those skilled in the art can easily prepare derivatives having the structures of the present invention or other derivatives similar to the structures of the present invention according to the present invention, and perform structural verification through nuclear magnetic resonance spectroscopy.
Example 1: preparation of hyaluronate
Wherein m is more than or equal to 1, and n is more than or equal to 0; r is R 1 、R 2 、R 3 、R 4 All being hydrogen, or, R 1 、R 2 、R 3 、R 4 One or more of the components is acetyl, and the content of the acetyl is 23-29%.
The molecular weight of the raw material sodium hyaluronate or sodium hyaluronate is 10kDa-100kDa.
1) 400g of sodium hyaluronate was dissolved in 10L of deionized water for further use. 312g of cetyltrimethylammonium chloride was dissolved in 6L of deionized water, and then sodium hyaluronate solution was added dropwise. A white solid precipitated after the reaction was carried out at 40℃for 16 hours. Filtering, and drying the solid at 50-55 ℃ under reduced pressure to obtain the hyaluronate (the yield is 512 g).
2) 490g of sodium hyaluronate (25% acetyl content) was dissolved in 10L of deionized water for further use. 346g of cetyltrimethylammonium chloride was dissolved in 6L of deionized water, and then sodium hyaluronate solution was added dropwise. A white solid precipitated after the reaction was carried out at 40℃for 16 hours. Filtering, and drying the solid under reduced pressure at 50-55 ℃ to obtain the hyaluronate (yield is 633 g).
Example 2: preparation of intermediate compounds of formula II
X is a leaving group such as halogen, e.g., bromine or chlorine.
300g of all-trans retinoic acid and 150g of bromopropanol are added into 1L of dichloromethane under the protection of light-shielding condition of nitrogen, and the mixture is stirred until the mixture is fully dissolved, and the temperature of the brine ice bath is reduced to about 0 ℃. 30g of 4-dimethylaminopyridine was added to the reaction solution, and 150g of N, N' -diisopropylcarbodiimide was added dropwise. After the completion of the dropwise addition, the temperature was raised to 20 to 30℃and stirred for 4 hours. And (5) detecting the completion of the reaction by thin layer chromatography. The reaction was concentrated to no solvent and a white solid was obtained by dropping out. The resulting white solid was dissolved in methylene chloride and purified by column chromatography to give the intermediate of formula II as a colorless oil (yield 399 g).
EXAMPLE 3 preparation of all-trans retinoic acid low molecular weight hyaluronate derivative
Wherein m is more than or equal to 1, and n is more than or equal to 0; r is R 1 、R 2 、R 3 、R 4 All being hydrogen, or, R 1 、R 2 、R 3 、R 4 One or more of the components is acetyl, and the content of the acetyl is 23-29%; x is a leaving group such as halogen, e.g., bromine or chlorine.
1) 10g of the intermediate compound of the formula II prepared in the example 2, 110g of the hyaluronate prepared in the example 1 and 35g of sodium carbonate are placed in 500mL of dimethyl sulfoxide, stirred for 8 hours at 20-30 ℃, then stirred for 40 hours, added into 95% ethanol after the reaction is finished, filtered, washed, dried, dissolved in water, subjected to salt conversion by cation exchange resin to prepare a compound of the formula I, and freeze-dried to obtain an all-trans retinoic acid low molecular hyaluronate derivative (hereinafter referred to as compound 1), wherein a nuclear magnetic hydrogen spectrum is shown in figure 1; the detection is carried out by adopting an ultraviolet-visible spectrophotometry, wherein the substitution degree of all-trans retinoic acid is 0.036.
2) 10g of the intermediate compound of the formula II prepared in the example 2, 200g of hyaluronate prepared in the example 1 and 35g of sodium carbonate are placed in 1000mL of dimethyl sulfoxide, stirred for 8 hours at 20-30 ℃, stirred for 40 hours, added into 95% ethanol after the reaction is finished, filtered, washed, dried, dissolved in water, subjected to salt conversion by a cation exchange resin to prepare a compound of the formula I, and subjected to freeze-drying to obtain an all-trans retinoic acid low molecular hyaluronate derivative (hereinafter referred to as compound 2), and detected by an ultraviolet-visible spectrophotometry, wherein the substitution degree of all-trans retinoic acid is 0.020.
EXAMPLE 4 stability, water solubility test
1. Stability test
The compound 1 and the compound 2 prepared in example 3 were subjected to light, heat and humidity stability experiments, and compared with all-trans retinoic acid, and the results showed significantly better stability than all-trans retinoic acid. The test method and the test result are as follows:
strong light stability test: all-trans retinoic acid and the two compounds prepared in example 3 were simultaneously placed in a test chamber and left for 8 days under an illuminance of 3000 lx. The decrease in all-trans retinoic acid content and the decrease in all-trans retinoic acid content of the two compounds prepared in example 3 were measured by sampling (uv-vis spectrophotometry), and the results are shown in table 1.
TABLE 1
Thermal stability test: all-trans retinoic acid and the two compounds prepared in example 3 were simultaneously placed in a dark vacuum oven at 40-45 ℃ for 8 days. The decrease in all-trans retinoic acid content and the decrease in all-trans retinoic acid content of the two compounds prepared in example 3 were measured by sampling (uv-vis spectrophotometry), and the results are shown in table 2. All-trans retinoic acid and the two compounds prepared in example 3 were simultaneously placed in a dark vacuum oven at 60-65 ℃ for 8 days. The decrease in all-trans retinoic acid content and the decrease in all-trans retinoic acid content of the two compounds prepared in example 3 were measured by sampling (uv-vis spectrophotometry), and the results are shown in table 3.
TABLE 2
TABLE 3 Table 3
Through the comparison of the stability tests, the all-trans retinoic acid low molecular hyaluronate derivative and the all-trans retinoic acid low molecular hyaluronate derivative have higher light and heat environmental stability and are far superior to the trans retinoic acid.
2. Water solubility test
Evaluation of solubility: the compound 1 and the compound 2 prepared in example 3 were dissolved in purified water at a concentration of 4mg/ml, respectively. All-trans retinoic acid was used as a control. It was confirmed that all-trans retinoic acid was hardly soluble in water at the same concentration and thus in an opaque state, whereas both compounds of the present invention were completely soluble in water (see fig. 2), showing significantly improved water solubility.
EXAMPLE 5 preparation of Compounds of formula III
Wherein m is more than or equal to 1, and n is more than or equal to 0; r is R 1 、R 2 、R 3 、R 4 All hydrogen.
The sodium hyaluronate and all-trans retinoic acid hyaluronate are directly esterified and coupled to obtain all-trans retinoic acid hyaluronate, which is shown as a formula III and comprises the following components: under the protection of nitrogen and in the dark, 11g of all-trans retinoic acid and 500mL of isopropanol are added into a reaction bottle 1, 35mL of triethylamine and 4.4mL of benzoyl chloride are added, and the mixture is stirred for 2 hours at 0-10 ℃ to obtain a reaction mixture. Into another reaction flask 2, 50g of sodium hyaluronate (molecular weight: 10kDa to 100 kDa), 1000mL of purified water, 500mL of isopropyl alcohol and 1g of 4-dimethylaminopyridine were added. Slowly dripping the reaction mixture of the reaction bottle 1 into the reaction bottle 2, stirring for 16 hours at the temperature of 0-10 ℃, adding into 95% ethanol after the reaction is finished, filtering, washing, drying, dissolving in water, performing salt conversion through cation exchange resin, preparing the compound of the formula III, and detecting the substitution degree of all-trans retinoic acid to be 0.030 by an ultraviolet-visible spectrophotometry.
EXAMPLE 6 preparation of functional gel
1) Dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; compound 1 (prepared according to example 3) was added to the sodium acetylalginate solution with mechanical stirring in an amount of 150 μg/mL; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain gel 1.
2) Dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; compound 2 (prepared according to example 3) was added to the sodium acetylalginate solution with mechanical stirring in an amount of 150 μg/mL; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain gel 2.
Wherein, the sodium acetylalginate used in the invention is obtained by modifying sodium alginate with acetic anhydride, the substitution degree of acetyl is 10-25%, and the preparation method of the sodium acetylalginate in the embodiment comprises the following steps: and (3) placing sodium alginate in an acetic anhydride solution, stirring the sodium alginate and the acetic anhydride solution at a mass volume ratio of 1:12, reacting for 10 hours at 50 ℃, pouring the reaction solution into deionized water for precipitation after the reaction is finished, washing the precipitate for 2-3 times, adding water for dissolving, and then freeze-drying the precipitate into powder to obtain the acetyl sodium alginate with the acetyl substitution degree of 15%.
Example 7
Dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; under the condition of mechanical stirring, adding all-trans retinoic acid hyaluronate (compound of formula III) obtained in the example 5 into an acetyl sodium alginate solution, wherein the addition amount is 150 mug/mL; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain gel 3.
Experimental example
The experimental example detects the anti-inflammatory, anti-aging and wrinkle-removing effects of the tested sample.
Experimental grouping and sample:
experiment group 1: dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; adding sodium hyaluronate into acetyl sodium alginate solution under the condition of mechanical stirring, wherein the addition amount is 150 mug/mL; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain sodium hyaluronate gel as sample of experiment group 1.
Experiment group 2: dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; under the condition of mechanical stirring, adding all-trans retinoic acid into an acetyl sodium alginate solution with the addition amount of 150 mug/mL; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain all-trans retinoic acid gel as the sample to be tested in experiment group 2.
Experiment group 3: dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; under the condition of mechanical stirring, adding sodium hyaluronate and trans-retinoic acid into an acetyl sodium alginate solution, wherein the addition amount is 150 mug/mL; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain sodium hyaluronate-trans retinoic acid gel as sample of experimental group 3.
Experiment group 4: gel 1 prepared in example 6 was used as a test sample for test group 4.
Experimental group 5: gel 2 prepared in example 6 was used as the test sample for test group 5.
Experiment group 6: gel 3 prepared in example 7 was used as a test sample for test group 6.
Blank 7: dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; under the condition of mechanical stirring, adding a calcium chloride solution with the concentration of 0.2 weight percent, stirring for 20min, and then standing for 24h to obtain a tested sample with gel as a blank group 7.
1. Photoprotection and anti-inflammatory effects
Inoculating human immortalized keratinocyte HaCaT cells in culture flask with DMEM containing 10% Fetal Bovine Serum (FBS) as culture medium, and placing into 37 deg.C and 5% CO 2 Culturing in an incubator with saturated humidity. When HaCaT cells in logarithmic growth phase grow to 80% -90% fusion degree, the HaCaT cells are grown according to the ratio of 1.5X10 4 Cells/well, 100 μl of each well was inoculated into 24 well plates, after cell attachment, the medium was discarded, randomly divided into 7 groups and each sample to be tested was added: experimental groups 1-6 and blank group 7, wherein the concentrations of the samples to be tested were all 0.01M.
After 12h of addition of each sample to be tested, the culture plate was placed at 300J/m 2 UVBIrradiating for 2h, 8h, and 12h, discarding the culture medium after irradiation, and adding the complete culture medium for further culturing for 24h.
After the cell culture is finished, the concentration and content of inflammatory factors IL-8 and IL-6 in the supernatant are respectively measured by adopting an ELISA method. The above assays were performed strictly according to ELISA kit instructions. The experimental results are shown in tables 4, 5 and 3.
TABLE 4 data on IL-8 concentration as a function of time of irradiation
TABLE 5 data on IL-6 concentration as a function of time of irradiation
Analysis of experimental results: as can be seen from Table 4, table 5 and FIG. 3, the blank group 7 showed no inhibition of the expression of both IL-8 and IL-6 inflammatory factors, and the expression level was increased. Compared with the blank group 7, the experimental group 1, the experimental group 2 and the experimental group 3 all show inhibition of the expression of two inflammatory factors of IL-8 and IL-6, but the inhibition effect is not obvious. The experimental groups 4, 5 and 6 show obvious inhibition effects on the expression of the IL-8 and IL-6 inflammatory factors, but the inhibition effects of the experimental groups 4 and 5 are obviously better, and the inhibition rate is obviously higher than that of the experimental group 6. This demonstrates that the test samples of experimental groups 4 and 5 have better photoprotection and are effective in reducing uv-induced skin inflammation.
2. Anti-aging and collagen regeneration promoting effects:
inoculating human skin fibroblast cells in culture flask with DMEM containing 10% Fetal Bovine Serum (FBS) as culture medium, and placing into 37 deg.C and 5% CO 2 Culturing in an incubator with saturated humidity. When HaCaT cells in logarithmic growth phase grow to 80% -90% fusion degree, the HaCaT cells are grown according to the ratio of 1.5X10 4 Cells/well, 100. Mu.L of each well was inoculated into 24 well plates, and after the cells had adhered to the walls, the medium was discarded, and experimental groups 1 to 6 and blank groups were used7 (test substance) to be tested. After 48h of treatment with the test substance, the supernatant was collected from the cell culture and the amount of synthesis of type I collagen was determined using the type 1C procollagen-peptide (PIP) EIA kit. The sample without the active ingredient was used as a control, and the collagen synthesis amount was 100%. The experimental results are shown in Table 6.
TABLE 6 Synthesis of collagen type I
As can be seen from table 6, the synthesis of type I collagen was promoted in comparison with the blank 7, but the promotion effect of the test group 1 and the test group 2 was not obvious, the promotion effect of the test group 4 and the test group 5 was particularly remarkable, and the synthesis of type I collagen was significantly increased.
3. Wrinkle removing effect:
the subject: 70 volunteers were selected, aged 35-55 years, and randomized into 7 groups of 10 persons each for skin experiments.
The using method comprises the following steps: the test samples of experimental groups 1 to 6 and blank group 7 were each applied at 0.5g uniformly to the facial skin of volunteers, once a day, for 4 weeks.
Prior to the experiment, the skin wrinkle area S of the face of the subject before the experiment is measured by a Visioline VL 650 wrinkle tester 0 The method comprises the steps of carrying out a first treatment on the surface of the Then, at each time point of 2 pm per day, the facial skin wrinkle area S was measured t The change of the silica gel replication membrane of the skin wrinkles is analyzed by software to obtain the change of the area of the facial skin wrinkles, and in the experiment, the environment temperature is ensured to be 20 ℃ and the relative humidity is ensured to be 50%. Finally, a skin wrinkle area reduction was calculated, wherein skin wrinkle area reduction (%) = (skin wrinkle area before test-average skin wrinkle area per week)/skin wrinkle area before test×100％＝(S 0 -S t )/S 0 X 100%. The results are shown in Table 7.
Table 7 comparison table of wrinkle removing effect
As can be seen from table 7 and fig. 4, the decrease in the skin wrinkle area of blank group 7 was almost unchanged, demonstrating that skin wrinkles on human face do not self-disappear after formation of self-wrinkles when no wrinkle-removing product is added; the effect of the experimental groups 1, 2 and 3 on the wrinkles is not obvious, and the experimental group 6 can reduce the area of the wrinkles to a certain extent, but is far less than the wrinkle removing effect of the experimental groups 4 and 5.
The foregoing description is only a preferred embodiment of the present application, and is not intended to limit the present application, but although the present application has been described in detail with reference to the foregoing embodiment, it will be apparent to those skilled in the art that modifications may be made to the technical solutions described in the foregoing embodiments, or that equivalents may be substituted for part of the technical features thereof. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application should be included in the protection scope of the present application.
Claims (10)
1. An all-trans retinoic acid low molecular weight hyaluronic acid ester derivative has a structure shown in a formula I:
wherein R is 1 、R 2 、R 3 、R 4 Each independently selected from hydrogen and acetyl, m is greater than or equal to 1, n is greater than or equal to 0.
2. The derivative according to claim 1, wherein the average molecular weight of the derivative structure of formula I is less than 200kDa;
preferably, the degree of substitution of the all-trans retinoic acid structure in formula I is 0.01-0.1;
preferably, R 1 、R 2 、R 3 、R 4 All being hydrogen, or R 1 、R 2 、R 3 、R 4 When one or more of the above are acetyl groups, the content of acetyl groups is 23-29%.
3. An intermediate of formula II:
wherein X is a leaving group, preferably halogen.
4. Use of the intermediate of claim 3 for the preparation of the all-trans retinoic acid low molecular hyaluronate derivative of claim 1 or 2.
5. A process for preparing the all-trans retinoic acid low molecular weight hyaluronate derivative as defined in claim 1 or 2, which comprises the steps of performing a coupling reaction between an intermediate represented by formula II and hyaluronate in the presence of a base, and then performing salt conversion to prepare a compound of formula I;
wherein X is a leaving group, preferably halogen.
6. The method of claim 5, wherein the hyaluronate is obtained by reacting sodium hyaluronate or sodium hyaluronate with cetyltrimethylammonium chloride.
7. The method of claim 5, wherein the salt conversion is performed by a cation exchange resin.
8. A composition comprising the all-trans retinoic acid low molecular hyaluronate derivative of claim 1 or 2; the composition is a pharmaceutical composition, a cosmetic composition or a food composition.
9. A formulation comprising an all-trans retinoic acid low molecular hyaluronate derivative as defined in claim 1 or 2 and optionally with or without other suitable ingredients;
preferably, the formulation is a pharmaceutical, cosmetic or food product;
preferably, the formulation is for oral, topical or injectable use;
preferably, the preparation is a gel preparation, and the raw materials of the preparation comprise all-trans retinoic acid low molecular hyaluronic acid ester derivatives, acetyl sodium alginate and calcium chloride;
preferably, the preparation method of the gel preparation comprises the following steps: mixing the all-trans retinoic acid low molecular weight hyaluronic acid ester derivative solution with the acetyl sodium alginate solution, and then adding the calcium chloride solution.
10. Use of an all-trans retinoic acid low molecular weight hyaluronate derivative according to claim 1 or 2 or a composition according to claim 8 or 9 for the preparation of a medicament, cosmetic or food for treating skin conditions;
preferably, the treating the skin condition includes the condition of caring for the skin to achieve regulation and/or improvement of the skin condition; the skin conditions include inflammation-related or inflammation-induced skin conditions, ultraviolet exposure, sun damage, aging, damaged skin barrier, rough texture, and wrinkles.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310286693.4A CN116284495A (en) | 2023-03-20 | 2023-03-20 | All-trans retinoic acid low-molecular hyaluronate derivative and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310286693.4A CN116284495A (en) | 2023-03-20 | 2023-03-20 | All-trans retinoic acid low-molecular hyaluronate derivative and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116284495A true CN116284495A (en) | 2023-06-23 |
Family
ID=86814746
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310286693.4A Pending CN116284495A (en) | 2023-03-20 | 2023-03-20 | All-trans retinoic acid low-molecular hyaluronate derivative and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116284495A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117964796A (en) * | 2024-03-29 | 2024-05-03 | 成都格纯生物医药有限公司 | Hyaluronic acid retinoic acid ester derivative and preparation method and application thereof |
-
2023
- 2023-03-20 CN CN202310286693.4A patent/CN116284495A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117964796A (en) * | 2024-03-29 | 2024-05-03 | 成都格纯生物医药有限公司 | Hyaluronic acid retinoic acid ester derivative and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI94767B (en) | For non-therapeutic use, complete and partial esters of hyaluronic acid are intended | |
| EP2522337B1 (en) | Hyaluronic acid esters, their preparation and use in dermatology | |
| CN108348560A (en) | Include the composition and its application method of silymarin and sulphur hydrocarbyl ether cyclodextrin | |
| KR101571385B1 (en) | Mixed butyric-formic esters of acid polysaccharides, and their preparation and use as skin cosmetics | |
| CN116284495A (en) | All-trans retinoic acid low-molecular hyaluronate derivative and preparation method and application thereof | |
| EP2906193B1 (en) | Modified hyaluronic acid derivatives and use thereof | |
| Fernandes et al. | The role of bacterial cellulose loaded with plant phenolics in prevention of UV-induced skin damage | |
| CN110251421B (en) | Cyclodextrin inclusion compound as active agent containing protamine and its prepn and application | |
| CN113599391A (en) | Application of carboxymethyl chitosan in promoting skin wound healing and repairing skin barrier | |
| CN113527537B (en) | Levo-vitamin C hyaluronic acid ester derivative and preparation method and application thereof | |
| KR100295875B1 (en) | Cosmetics Containing Green Bean Extract | |
| JP4726505B2 (en) | External preparation for skin and skin whitening method | |
| CN114555050A (en) | Composition comprising extract of leaves of Artemisia inflata for reducing skin damage | |
| JP2012201615A (en) | Elastase activity inhibitor | |
| JPH11171784A (en) | External preparation for skin | |
| JPH10182402A (en) | Agent for promoting synthesis of hyaluronic acid | |
| KR102539795B1 (en) | Cosmetic composition with water resistance comprising zwitterionic chitosan derivative | |
| CN118047884A (en) | Xylan tocopherol derivative, and preparation method and application thereof | |
| RU2745124C1 (en) | Bioactive composition based on a crosslinked hyaluronic acid salt containing resveratrol and a method of its preparation | |
| JP2002179578A (en) | Antioxidant converted into polymer and skin care preparation comprising the same | |
| JP2002363087A (en) | Super oxide dismutase-like agent, elastase inhibitor, collagenase inhibitor, collagen production-promoting agent, estrogen-like agent and hyaluronic acid production-promoting agent, and skin cosmetic | |
| KR20220046360A (en) | Cosmetic composition containing lauroyl methylglucamide laurate | |
| CN115300611A (en) | Hyaluronic acid-conotoxin polypeptide conjugate and application thereof in preparation of skin products | |
| AU2008329154B2 (en) | Mixed butyric-formic esters of acid polysaccharides, and their preparation and use as skin cosmetics | |
| CN116143851A (en) | Salicylic acid glucosamine and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |