KR101061911B1 - PEGylated betulin derivatives and cosmetic compositions comprising the same - Google Patents
PEGylated betulin derivatives and cosmetic compositions comprising the same Download PDFInfo
- Publication number
- KR101061911B1 KR101061911B1 KR1020090027959A KR20090027959A KR101061911B1 KR 101061911 B1 KR101061911 B1 KR 101061911B1 KR 1020090027959 A KR1020090027959 A KR 1020090027959A KR 20090027959 A KR20090027959 A KR 20090027959A KR 101061911 B1 KR101061911 B1 KR 101061911B1
- Authority
- KR
- South Korea
- Prior art keywords
- betulin
- pegylated
- derivative according
- sunscreen
- betulin derivative
- 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.)
- Active
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- 239000000203 mixture Substances 0.000 title claims abstract description 84
- FVWJYYTZTCVBKE-ROUWMTJPSA-N betulin Chemical class C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(CO)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C FVWJYYTZTCVBKE-ROUWMTJPSA-N 0.000 title claims abstract description 53
- 239000002537 cosmetic Substances 0.000 title claims abstract description 35
- DSNLMYRCHYFVDO-UHFFFAOYSA-N [5a,5b,8,8,11a-pentamethyl-9-(oxan-2-yloxy)-1-prop-1-en-2-yl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysen-3a-yl]methyl 4-methylbenzenesulfonate Chemical compound C1CC(C2(CCC3C(C)(C)C(OC4OCCCC4)CCC3(C)C2CC2)C)(C)C2C2C(C(=C)C)CCC21COS(=O)(=O)C1=CC=C(C)C=C1 DSNLMYRCHYFVDO-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000009472 formulation Methods 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 239000000243 solution Substances 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 7
- 239000006071 cream Substances 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000007921 spray Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000839 emulsion Substances 0.000 claims description 3
- 239000000499 gel Substances 0.000 claims description 3
- 239000006072 paste Substances 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 230000037072 sun protection Effects 0.000 claims 1
- 239000000516 sunscreening agent Substances 0.000 abstract description 44
- 230000000475 sunscreen effect Effects 0.000 abstract description 43
- MVIRREHRVZLANQ-UHFFFAOYSA-N betulin Natural products CC(=O)OC1CCC2(C)C(CCC3(C)C2CC=C4C5C(CCC5(CO)CCC34C)C(=C)C)C1(C)C MVIRREHRVZLANQ-UHFFFAOYSA-N 0.000 abstract description 30
- JYDNKGUBLIKNAM-UHFFFAOYSA-N Oxyallobutulin Natural products C1CC(=O)C(C)(C)C2CCC3(C)C4(C)CCC5(CO)CCC(C(=C)C)C5C4CCC3C21C JYDNKGUBLIKNAM-UHFFFAOYSA-N 0.000 abstract description 29
- 230000003020 moisturizing effect Effects 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 4
- 230000000903 blocking effect Effects 0.000 abstract 2
- 230000006320 pegylation Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- QGJZLNKBHJESQX-FZFNOLFKSA-N betulinic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C QGJZLNKBHJESQX-FZFNOLFKSA-N 0.000 description 44
- 229920001223 polyethylene glycol Polymers 0.000 description 38
- QGJZLNKBHJESQX-UHFFFAOYSA-N 3-Epi-Betulin-Saeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(=C)C)C5C4CCC3C21C QGJZLNKBHJESQX-UHFFFAOYSA-N 0.000 description 32
- CLOUCVRNYSHRCF-UHFFFAOYSA-N 3beta-Hydroxy-20(29)-Lupen-3,27-oic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C(O)=O)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C CLOUCVRNYSHRCF-UHFFFAOYSA-N 0.000 description 32
- DIZWSDNSTNAYHK-XGWVBXMLSA-N Betulinic acid Natural products CC(=C)[C@@H]1C[C@H]([C@H]2CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]34C)[C@@H]12)C(=O)O DIZWSDNSTNAYHK-XGWVBXMLSA-N 0.000 description 32
- PZXJOHSZQAEJFE-UHFFFAOYSA-N dihydrobetulinic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(C)C)C5C4CCC3C21C PZXJOHSZQAEJFE-UHFFFAOYSA-N 0.000 description 32
- MQYXUWHLBZFQQO-UHFFFAOYSA-N nepehinol Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C MQYXUWHLBZFQQO-UHFFFAOYSA-N 0.000 description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 24
- 210000003491 skin Anatomy 0.000 description 18
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 12
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 239000004408 titanium dioxide Substances 0.000 description 12
- 230000036572 transepidermal water loss Effects 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- -1 methoxyphenyl Chemical group 0.000 description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000000454 talc Substances 0.000 description 8
- 229910052623 talc Inorganic materials 0.000 description 8
- 235000011187 glycerol Nutrition 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 235000015112 vegetable and seed oil Nutrition 0.000 description 7
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 6
- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 description 6
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 6
- LVKVQZBPJNTQQC-UHFFFAOYSA-N CCCCCCC(=C(C1=CC=CC=C1CC)C(=O)O)OC Chemical compound CCCCCCC(=C(C1=CC=CC=C1CC)C(=O)O)OC LVKVQZBPJNTQQC-UHFFFAOYSA-N 0.000 description 6
- XMSXQFUHVRWGNA-UHFFFAOYSA-N Decamethylcyclopentasiloxane Chemical compound C[Si]1(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O1 XMSXQFUHVRWGNA-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 229920001214 Polysorbate 60 Polymers 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 235000021355 Stearic acid Nutrition 0.000 description 6
- 235000019486 Sunflower oil Nutrition 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 6
- 230000002421 anti-septic effect Effects 0.000 description 6
- 229940081733 cetearyl alcohol Drugs 0.000 description 6
- 229940086555 cyclomethicone Drugs 0.000 description 6
- 229940075529 glyceryl stearate Drugs 0.000 description 6
- UBHWBODXJBSFLH-UHFFFAOYSA-N hexadecan-1-ol;octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO.CCCCCCCCCCCCCCCCCCO UBHWBODXJBSFLH-UHFFFAOYSA-N 0.000 description 6
- DWMMZQMXUWUJME-UHFFFAOYSA-N hexadecyl octanoate Chemical compound CCCCCCCCCCCCCCCCOC(=O)CCCCCCC DWMMZQMXUWUJME-UHFFFAOYSA-N 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- LDHBWEYLDHLIBQ-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide;hydrate Chemical compound O.[OH-].[O-2].[Fe+3] LDHBWEYLDHLIBQ-UHFFFAOYSA-M 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 6
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 6
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 6
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 6
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 6
- 229940113124 polysorbate 60 Drugs 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 229960005078 sorbitan sesquioleate Drugs 0.000 description 6
- 229940032094 squalane Drugs 0.000 description 6
- 239000008117 stearic acid Substances 0.000 description 6
- 239000002600 sunflower oil Substances 0.000 description 6
- 239000000230 xanthan gum Substances 0.000 description 6
- 229920001285 xanthan gum Polymers 0.000 description 6
- 229940082509 xanthan gum Drugs 0.000 description 6
- 235000010493 xanthan gum Nutrition 0.000 description 6
- 235000018185 Betula X alpestris Nutrition 0.000 description 5
- 235000018212 Betula X uliginosa Nutrition 0.000 description 5
- CAHKINHBCWCHCF-UHFFFAOYSA-N N-acetyltyrosine Chemical compound CC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 CAHKINHBCWCHCF-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000008591 skin barrier function Effects 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000000691 measurement method Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- LSRUBRSFDNKORM-UHFFFAOYSA-N 1,1-diaminopropan-1-ol Chemical compound CCC(N)(N)O LSRUBRSFDNKORM-UHFFFAOYSA-N 0.000 description 2
- BLCJBICVQSYOIF-UHFFFAOYSA-N 2,2-diaminobutanoic acid Chemical compound CCC(N)(N)C(O)=O BLCJBICVQSYOIF-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 235000010140 Betula sp Nutrition 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000006750 UV protection Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 238000010533 azeotropic distillation Methods 0.000 description 2
- 235000012216 bentonite Nutrition 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 210000004209 hair Anatomy 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 210000000434 stratum corneum Anatomy 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000002834 transmittance Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 150000003648 triterpenes Chemical class 0.000 description 2
- 235000014692 zinc oxide Nutrition 0.000 description 2
- 239000011787 zinc oxide Substances 0.000 description 2
- FHLXUWOHGKLDNF-UHFFFAOYSA-N (2-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=CC=C1OC(Cl)=O FHLXUWOHGKLDNF-UHFFFAOYSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
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- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 1
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- JGUMTYWKIBJSTN-UHFFFAOYSA-N 2-ethylhexyl 4-[[4,6-bis[4-(2-ethylhexoxycarbonyl)anilino]-1,3,5-triazin-2-yl]amino]benzoate Chemical compound C1=CC(C(=O)OCC(CC)CCCC)=CC=C1NC1=NC(NC=2C=CC(=CC=2)C(=O)OCC(CC)CCCC)=NC(NC=2C=CC(=CC=2)C(=O)OCC(CC)CCCC)=N1 JGUMTYWKIBJSTN-UHFFFAOYSA-N 0.000 description 1
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- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
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- 238000006809 Jones oxidation reaction Methods 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000219745 Lupinus Species 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
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- 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
- A61K8/63—Steroids; Derivatives 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
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
- A61K8/86—Polyethers
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Birds (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Cosmetics (AREA)
Abstract
본 발명은 페길레이션(PEGylation)된 베튤린 유도체 및 그를 포함하는 화장료 조성물에 관한 것이다. 본 발명의 페길레이션(PEGylation)된 베튤린 유도체는 수용성이면서 우수한 자외선 차단 효과, 백탁 방지 효과 및 보습 효과를 가져 화장료 조성물, 특히 자외선 차단용 화장료 조성물에 효과적으로 사용될 수 있다.The present invention relates to a PEGylated betulin derivative and a cosmetic composition comprising the same. The PEGylated betulin derivative of the present invention is water-soluble and has excellent UV blocking effect, anti-whitening effect and moisturizing effect, so that it can be effectively used in cosmetic compositions, particularly cosmetic compositions for blocking UV rays.
페길레이션, 베튤린, 화장료 조성물, 자외선 차단제 Pegylation, betulin, cosmetic composition, sunscreen
Description
본 발명은 페길레이션(PEGylation)된 베튤린 유도체 및 그를 포함하는 화장료 조성물에 관한 것이다. 보다 구체적으로 본 발명은 수용성이면서 우수한 자외선 차단 효과, 백탁 방지 효과 및 보습 효과를 가지는 페길레이션(PEGylation)된 베튤린 유도체 및 그를 포함하는 화장료 조성물에 관한 것이다.The present invention relates to a PEGylated betulin derivative and a cosmetic composition comprising the same. More specifically, the present invention relates to a PEGylated betulin derivative having water solubility and excellent sunscreen effect, anti-clouding effect and moisturizing effect, and a cosmetic composition comprising the same.
하기 화학식 1로 나타내는 베튤린(betulin)은 루판(lupine) 계의 천연 5환 트리테르펜(triterpene) 알코올로서, 베튤리놀(betulilnol) 및 루프-20(29)-엔-3β,28-디올(lup-20(29)-ene-3β,28-diol)로서도 알려져 있다. 베튤린은 몇몇 나무종의 나무껍질, 특히 자작나무(Betula sp.) 껍질에 많이 존재하며, 자작나무 껍질로부터 추출에 의해 베튤린을 분리하는 방법들이 공지되어 있다. Betulin represented by Chemical Formula 1 is a lupine-based natural 5-ring triterpene alcohol, which is betulinol and loop-20 (29) -ene-3β, 28-diol (lup). -20 (29) -ene-3β, 28-diol). Betulin is present in many bark of tree species, especially in the bark of Betula sp., And methods for separating betulin by extraction from birch bark are known.
한편, 하기 화학식 3으로 나타내는 베튤린산(betulinic acid)은 자작나무(Betula sp.) 껍질 또는 황병나무(Quercus suber L.)의 코르크로부터 추출에 의해 분리하거나, 베튤린 또는 자작나무 껍질의 직접 산화에 의한 방법들에 의해 제조할 수 있는 것으로 알려져 있다. 예를 들어 하기 반응식 1에 도시된 바와 같이, 미국특허 제6,280,778호에 개시된 존스(Jones) 산화 방법에 따라 베튤린(1)을 산화크롬(VI) 촉매의 존재하에 산화시켜 베튤로닉산(betulonic acid; 2)를 수득한 다음, 수득된 베튤로닉론산(2)를 수소화붕소나트륨으로 선택적 환원반응시켜 베튤린산(3)을 수득할 수 있는 것으로 보고되어 있다.Meanwhile, betulinic acid (betulinic acid) represented by the following formula (3) is isolated by extraction from the cork of the birch ( Betula sp.) Bark or Quercus suber L., or by direct oxidation of the betulin or birch bark It is known that it can be prepared by the methods. For example, as shown in Scheme 1, betulin (1) is oxidized in the presence of a chromium (VI) catalyst according to the Jones oxidation method disclosed in US Pat. No. 6,280,778 to betuonic acid. 2) is obtained, and then, it is reported that betulinic acid (3) can be selectively reduced with sodium borohydride to obtain betulinic acid (3).
[반응식 1]Scheme 1
또한 미국 특허 제5,804,575호에는 베튤린의 3-β-히드록시기를 아세틸화에 의해 보호한 다음, 산화반응시키는 단계를 포함하는 베튤린산의 다른 제조방법이 개시되어 있다. U. S. Patent No. 5,804, 575 also discloses another method for preparing betulinic acid comprising protecting the 3-β-hydroxy group of betulin by acetylation and then oxidizing.
상기 베튤린 및 그의 유도체는 의약 및 화장품 용도로 사용될 수 있는 것으로 알려져 있으며, 그들의 항균활성 등이 연구되어 왔다.The betulin and its derivatives are known to be used in medicine and cosmetics, their antimicrobial activity has been studied.
예를 들어 국제공개 WO 00/03749호에는 베튤린 및 베튤린산을 모발 성장 및 생성의 촉진제 및 피부 크림과 같은 화장품에 사용할 수 있는 것으로 공지되어 있다. For example in WO 00/03749 it is known that betulin and betulinic acid can be used in cosmetics such as skin creams and accelerators of hair growth and production.
또한 국제공개 WO 01/74327호에는 베튤린산을 UV 광의 유해한 영향을 방지하기 위하여 선크림에 사용할 수 있는 것으로 개시되어 있다.International publication WO 01/74327 also discloses that betulinic acid can be used in sunscreens to prevent the harmful effects of UV light.
유럽특허 제0 717 983호에는 베튤린산을 약학적 조성물 또는 피부 관리용 화장료 조성물에서, 단독으로 또는 아스코르브산과 함께 사용할 수 있다고 개시되어 있다. 조성물에서 베튤린산은 피부의 콜라겐 합성을 촉진하고, 광에 의해 주름이 형성되고 늘어진 피부를 관리하고 셀룰라이트를 치료하는데 적합한 것으로 보고되어 있다.EP 0 717 983 discloses that betulinic acid can be used alone or in combination with ascorbic acid in pharmaceutical compositions or cosmetic compositions for skin care. It is reported that betulinic acid in the composition promotes collagen synthesis of the skin, is suitable for treating wrinkled and loosened skin and treating cellulite by light.
미국특허 제6,207,711호에는 광으로 인한 노화 방지에 사용되는 트리테르페노이드 유도체 및 그의 염이 개시되어 있다. 상기 유도체에서, 베튤린산의 28 위치에 있는 수소는 -CHR1R2 기로 치환되는데, R1은 페닐, 메톡시페닐, 에톡시페닐, 부톡시페닐, 니트로페닐, 디페닐 또는 나프틸기를 나타내고, R2는 수소원자 또는 페닐기를 나타낸다. U. S. Patent No. 6,207, 711 discloses triterpenoid derivatives and salts thereof which are used to prevent aging due to light. In this derivative, the hydrogen at position 28 of the betulinic acid is substituted with a -CHR 1 R 2 group, wherein R 1 represents a phenyl, methoxyphenyl, ethoxyphenyl, butoxyphenyl, nitrophenyl, diphenyl or naphthyl group, R 2 represents a hydrogen atom or a phenyl group.
국제공개 WO 2006/050158호에는 피부 및 모발 관리용 조성물에서 통상적으로 사용되는 오일에 가용성인 베튤린의 부가물(additive) 및 에스테르 또는 에테르를 함유하는 피부 및 모발 관리용 화장료 조성물이 보고되어 있다. International publication WO 2006/050158 reports cosmetic compositions for skin and hair care containing additives and esters or ethers of betulin soluble in oils commonly used in skin and hair care compositions.
미국특허 제6,642,217호에는 베튤린 및 그의 특정 유도체를 살균제 및 항효모제로 사용할 수 있다고 기재되어 있다.U.S. Patent No. 6,642,217 discloses that betulin and certain derivatives thereof can be used as fungicides and anti yeasts.
아울러 국제공개 WO 02/6792호에는 베튤린 및 그의 특정 유도체의 항균활성이 제시되어 있다. In addition, WO 02/6792 discloses the antimicrobial activity of betulin and certain derivatives thereof.
그러나, 현재까지 공지된 베튤린 및 그의 유도체는 물에 용해, 유화 및/또는 제형화되기가 어렵고, 의약 및 화장품 용도로 안정하고 적합한 제형으로 전환되기 어려운 문제점이 있다.However, betulin and its derivatives known to date are difficult to be dissolved, emulsified and / or formulated in water and difficult to convert into stable and suitable formulations for medicinal and cosmetic uses.
한편, 자외선으로부터 피부를 보호하기 위한 통상적인 자외선 차단제는 (i) 이산화티탄 (titanium dioxide), 아연백 (zinc white) 등의 무기 자외선 차단제와 (ii) 옥틸 메톡시신나메이트 (ethylhexyl methoxycinnamate), 부틸 메톡시디벤조일메탄 (butyl methoxydibenzoylmethane), 옥틸 트리아존 (ethylhexyl triazone), 글리세릴 파바 (glyceryl PABA), 드로메트리졸 (drometrizole), 벤조페논-3 (benzophenone-3), 벤조페논-4 (benzophenone-4), 벤조페논-8 (benzophenone-8), 시녹세이트 (cinoxate), 옥토크릴렌 (octocrylene), 옥틸 디메틸 파바 (ethylhexyl dimethyl PABA), 2-페닐벤즈이미다졸-5-설폰산 (phenylbenzimidazole sulfonic acid), 옥틸 살리실레이트 (ethylhexyl salicylate), 호모살레이트 (homosalate) 등의 유기 자외선 차단제로 분류되며, 통상적으로 이들을 혼용하고 있다. 이렇게 유기 자외선 차단제와 무기 자외선 차단제를 혼용하는 이유는 유기 자외선 차단물질은 자외선을 흡수함으로써 자외선을 차단하는데 반해, 무기 자외선 차단물질은 자외선을 산란 및 반사시킴으로써 자외선을 차단하기 때문이다. 특히, 무기 자외선 차단제는 자외선 차단력이 탁월하고 안전성이 우수하여 널리 이용되어 왔다. 그 중에서도 이산화티탄은 UVB 영역을 효과적으로 차단하고 가격이 저렴하며 커버력이 높아, 자외선 차단 제품 뿐만 아니라 메이크업 화장료에도 널리 이용되고 있다. 그러나, 이산화티탄은 광활성이 높아 피부에 자극을 주고, 피부에 도포시 허옇게 되는 백탁현상을 야기하며, 특정의 유기 자외선 차단물질과 혼용시 콤플렉스를 형성하여 역가를 저하시키고, 또한 그 구조 (morphology)가 사면체 (tetrahedral)라 사용성이 거칠은 단점이 있다.Meanwhile, conventional sunscreens for protecting the skin from ultraviolet rays include (i) inorganic sunscreens such as titanium dioxide and zinc white, and (ii) ethylhexyl methoxycinnamate and butyl. Butyl methoxydibenzoylmethane, octyl triazone, glyceryl PABA, drometrizole, benzophenone-3, benzophenone-4 ), Benzophenone-8, cinoxate, octocrylene, ethylhexyl dimethyl PABA, 2-phenylbenzimidazole-5-sulfonic acid , Octyl salicylate (ethylhexyl salicylate), homo sunlate (homosalate) and the like are classified into organic sunscreens, these are commonly used. The reason why the organic sunscreen is mixed with the inorganic sunscreen is that organic sunscreens block ultraviolet rays by absorbing ultraviolet rays, whereas inorganic sunscreens block ultraviolet rays by scattering and reflecting ultraviolet rays. In particular, inorganic sunscreens have been widely used because of their excellent ultraviolet protection and excellent safety. Among them, titanium dioxide effectively blocks the UVB area, is inexpensive, and has a high coverage, and is widely used in makeup cosmetics as well as UV protection products. Titanium dioxide, however, has high photoactivity, irritates the skin, causes white clouding when applied to the skin, forms complexes when mixed with certain organic sunscreens, lowers the titer, and also its morphology. It is a tetrahedron (tetrahedral) and has a rough usability disadvantage.
본 발명자들은 상기한 베튤린 및 그의 유도체와 자외선 차단제의 문제점을 해결하고자 예의 연구 검토한 결과, 하기 화학식 4의 페길레이션(PEGylation)된 베튤린 유도체가 수용성이면서 우수한 자외선 차단 효과, 백탁 방지 효과 및 보습 효과를 가지는 것을 발견하고 본 발명을 완성하게 되었다. The present inventors have studied diligently to solve the problems of the above-mentioned betulin and its derivatives and the sunscreen, and as a result, the PEGylated betulin derivative of the formula (4) is water-soluble, excellent sunscreen effect, anti-clouding effect and moisturizing It has been found to have an effect and to complete the present invention.
따라서, 본 발명의 목적은 기능성 화장품 원료로 사용될 수 있는 하기 화학식 4의 페길레이션된 베튤린 유도체를 제공하는 것이다.Accordingly, it is an object of the present invention to provide a pegylated betulin derivative of formula (4) which can be used as a functional cosmetic raw material.
본 발명의 다른 목적은 하기 화학식 4의 페길레이션된 베튤린 유도체를 함유하는 화장료 조성물을 제공하는 것이다. Another object of the present invention to provide a cosmetic composition containing a pegylated betulin derivative of the formula (4).
본 발명은 기능성 화장품 원료로 사용될 수 있는 하기 화학식 4의 페길레이션(PEGylation)된 베튤린 유도체에 관한 것이다. The present invention relates to a PEGylated betulin derivative of the formula (4) which can be used as a functional cosmetic raw material.
[화학식 4][Formula 4]
상기 식에서,Where
L은 CH2OCO(CH2)mX, CH2OCOCHR'(CH2)pY, COX 또는 COOCHR'(CH2)qY이고,L is CH 2 OCO (CH 2 ) m X, CH 2 OCOCHR ′ (CH 2 ) p Y, COX or COOCHR '(CH 2 ) q Y,
R'는 수소 또는 (CH2)rY(CH2CH2O)nR이며,R 'is hydrogen or (CH 2 ) r Y (CH 2 CH 2 O) n R,
X는 O, NH 또는 S이고,X is O, NH or S,
Y는 NHCOO이며,Y is NHCOO,
R은 수소 또는 C1-C6의 저급 알킬기, 바람직하게는 수소 또는 메틸기, 가장 바람직하게는 메틸기이고,R is hydrogen or a lower alkyl group of C 1 -C 6 , preferably hydrogen or methyl, most preferably methyl
n은 4 내지 800, 바람직하게는 10 내지 400, 보다 바람직하게는 40 내지 200의 정수이며,n is an integer of 4 to 800, preferably 10 to 400, more preferably 40 to 200,
m은 1 내지 10, 바람직하게는 1 내지 6, 보다 바람직하게는 1 내지 3의 정수이고,m is an integer of 1 to 10, preferably 1 to 6, more preferably 1 to 3,
p, q 및 r은 각각 독립적으로 0 내지 10, 보다 바람직하게는 0 내지 3의 정수이다.p, q, and r are each independently an integer of 0 to 10, more preferably 0 to 3;
본 명세서에서 C1-C6의 저급 알킬기는 탄소수 1 내지 6개로 구성된 직쇄형 또는 분지형 탄화수소를 의미하며, 예를 들어 메틸, 에틸, n-프로필, n-부틸, n-펜틸, n-헥실 등이 포함되나 이에 한정되는 것은 아니다.Lower alkyl group of C 1 -C 6 herein means a straight or branched hydrocarbon consisting of 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl And the like, but are not limited thereto.
본 발명의 화합물은 예를 들어 하기 반응식 1 내지 9에 나타낸 방법에 따라 제조될 수 있다. 하기 반응식에 기재된 방법은 본 발명에서 대표적으로 사용된 방법을 예시한 것일 뿐 단위조작의 순서, 반응시약, 반응조건 등은 경우에 따라 얼마 든지 변경될 수 있다. Compounds of the present invention can be prepared, for example, according to the methods shown in Schemes 1-9 below. The method described in the following reaction scheme is merely exemplary of the method used in the present invention, the order of the unit operation, the reaction reagent, the reaction conditions and the like may be changed at any time.
[반응식 2] Scheme 2
상기 화학식 4-1의 페길레이션된 베튤린 유도체는 상기 화학식 1의 베튤린과 상기 화학식 5-1의 PEG 유도체를 결합반응시켜 제조한다.The pegylated betulin derivative of Formula 4-1 is prepared by combining the betulin of Formula 1 with the PEG derivative of Formula 5-1.
상기 베튤린은 자작나무 수피(birch bark)로부터 당업계에 공지된 방법에 따라 추출에 의해 분리할 수 있다. The betulin can be separated from the birch bark by extraction according to methods known in the art.
상기 화학식 5-1의 PEG 유도체는 PEG의 말단 히드록시기에 알킬렌 연결부를 통해 카르복시기가 결합되어 있는 화합물로서, 상업적으로 입수하거나 당업계에 공지된 방법에 의해 용이하게 제조할 수 있다[참조: 미국 특허 제5,672,662호 등].The PEG derivative of Chemical Formula 5-1 is a compound in which a carboxyl group is bonded through an alkylene linkage to a terminal hydroxy group of PEG, and can be easily obtained by commercially available methods or known in the art. 5,672,662, and the like.
[반응식 3]Scheme 3
상기 화학식 4-2의 분지된 PEG 유도체로 페길레이션된 베튤린 유도체는 상기 화학식 1의 베튤린과 상기 화학식 5-2의 분지된 PEG 유도체를 결합반응시켜 제조한다.The betulin derivative pegylated with the branched PEG derivative of Formula 4-2 is prepared by combining the betulin of Formula 1 with the branched PEG derivative of Formula 5-2.
[반응식 4]Scheme 4
상기 화학식 5-2의 분지된 PEG 유도체는 공지된 방법에 따라 상기 화학식 6의 활성화된 PEG 유도체와 상기 화학식 7의 디아미노카르복실산을 결합반응시켜 제조할 수 있다.The branched PEG derivative of Formula 5-2 may be prepared by combining the activated PEG derivative of Formula 6 with the diaminocarboxylic acid of Formula 7 according to a known method.
[반응식 5]Scheme 5
한편, 상기 화학식 6의 활성화된 PEG 유도체는 공지된 방법에 따라 상기 화학식 5-3의 PEG와 상기 화학식 8의 니트로페닐클로로퍼메이트(4-nitrophenyl chloroformate)를 반응시켜 제조할 수 있다. Meanwhile, the activated PEG derivative of Chemical Formula 6 may be prepared by reacting PEG of Chemical Formula 5-3 with nitrophenyl chloroformate of Chemical Formula 8 according to a known method.
상기 PEG는 공지의 수용성 고분자로서 상업적으로 입수하거나 공지된 방법[참고문헌: Sandler and Karo, Polymer Synthesis, Academic Press, New York, Vol.3, pages 138-161]에 따라 에틸렌 글리콜을 개환 중합반응시켜 제조할 수 있다. The PEG is commercially available as a known water-soluble polymer or by ring-opening polymerization of ethylene glycol according to a known method [Ref. Sandler and Karo, Polymer Synthesis, Academic Press, New York, Vol. 3, pages 138-161]. It can manufacture.
[반응식 6] Scheme 6
상기 화학식 4-3의 페길레이션된 베튤린 유도체는 상기 화학식 3의 베튤린산과 상기 화학식 5-3의 PEG를 결합반응시켜 제조한다.The pegylated betulin derivative of Chemical Formula 4-3 is prepared by combining the betulinic acid of Chemical Formula 3 with PEG of Chemical Formula 5-3.
[반응식 7]
상기 화학식 4-4의 분지된 PEG로 페길레이션된 베튤린 유도체는 상기 화학식 3의 베튤린산과 상기 화학식 5-4의 분지된 PEG유도체를 결합반응시켜 제조한다.The betulin derivative PEGylated with branched PEG of Formula 4-4 is prepared by combining the betulinic acid of Formula 3 with the branched PEG derivative of Formula 5-4.
[반응식 8] Scheme 8
상기 화학식 5-4의 분지된 PEG 유도체는 공지된 방법에 따라 상기 화학식 6의 활성화된 PEG 유도체와 상기 화학식 9의 디아미노알코올을 결합반응시켜 제조할 수 있다. The branched PEG derivative of Chemical Formula 5-4 may be prepared by combining the activated PEG derivative of Chemical Formula 6 with the diamino alcohol of Chemical Formula 9 according to a known method.
[반응식 9] Scheme 9
상기 화학식 4-5의 아미드 결합으로 페길레이션된 베튤린 유도체는 상기 화학식 3의 베튤린산과 상기 화학식 5-5의 말단에 아민기를 가지는 PEG 유도체를 결합반응시켜 제조한다.The betulin derivative PEGylated by the amide bond of Formula 4-5 is prepared by combining the betulinic acid of Formula 3 with a PEG derivative having an amine group at the terminal of Formula 5-5.
상기 말단에 아민기를 가지는 PEG 유도체는 상업적으로 입수하거나 공지된 방법[참고문헌: Makromol. Chem., 1981, vol. 182, pages 1379-1384 등]에 따라 PEG로부터 제조할 수 있다. PEG derivatives having an amine group at the terminal are commercially available or known methods [Ref. Makromol. Chem., 1981 , vol. 182, pages 1379-1384, etc.].
상기 반응식 2, 3, 6, 7 및 9에서 결합반응은 4-디메틸아미노피리딘(4-dimethylaminopyridine: DMAP)과 디시클로헥실카보디이미드(dicyclohexylcarbodiimide: DCC)의 존재하에 수행하는 것이 바람직하다. In the
반응용매로는 디클로로메탄, 클로로포름 등을 사용하는 것이 바람직하며, 반응온도는 실온이 바람직하다.Dichloromethane, chloroform, or the like is preferably used as the reaction solvent, and the reaction temperature is preferably room temperature.
상기 반응식 2, 3, 6, 7 및 9에서 PEG 및 PEG 유도체들의 분자량은 페길레이션된 베튤린 유도체의 화장료 조성물에서의 사용 목적, 사용량, 화장료 조성물의 형태 등에 따라 적절히 선택될 수 있다. The molecular weights of PEG and PEG derivatives in
다른 한편으로, 본 발명은 상기 화학식 4의 페길레이션된 베튤린 유도체를 포함하는 화장료 조성물, 특히 자외선 차단용 화장료 조성물에 관한 것이다.On the other hand, the present invention relates to a cosmetic composition, particularly a sunscreen cosmetic composition comprising a pegylated betulin derivative of the formula (4).
본 발명의 화장료 조성물은 상기 화학식 4의 페길레이션된 베튤린 유도체를 유효성분으로서 0.01 내지 20.0 중량%, 바람직하게는 0.1 내지 10.0 중량%로 포함한다. 유효성분의 함량은 그의 사용 목적에 따라 적절하게 결정될 수 있다.The cosmetic composition of the present invention comprises a PEGylated betulin derivative of the formula (4) as an active ingredient 0.01 to 20.0% by weight, preferably 0.1 to 10.0% by weight. The content of the active ingredient can be appropriately determined according to the purpose of use thereof.
본 발명의 화장료 조성물은 유효성분으로서 상기 화학식 4의 페길레이션된 베튤린 유도체 이외에 화장료 조성물에 통상적으로 사용되는 성분들, 예를 들어 항산화제, 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제, 그리고 담체를 포함한다.The cosmetic composition of the present invention is a component commonly used in cosmetic compositions in addition to the pegylated betulin derivatives of the formula (4) as an active ingredient, for example, such as antioxidants, stabilizers, solubilizers, vitamins, pigments and flavorings Phosphorus aids, and carriers.
본 발명의 화장료 조성물은 당업계에서 통상적으로 사용되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어, 용액, 현탁액, 유탁액, 페이스트, 겔, 크림, 파우더, 스프레이 등으로 제형화될 수 있다. Cosmetic compositions of the present invention may be prepared in any formulation commonly used in the art, and may be formulated, for example, in solutions, suspensions, emulsions, pastes, gels, creams, powders, sprays, and the like.
본 발명의 제형이 페이스트, 크림 또는 겔인 경우에는 담체 성분으로서 동물성유, 식물성유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크, 산화아연 등이 이용될 수 있다.When the formulation of the present invention is a paste, cream or gel, animal oils, vegetable oils, waxes, paraffins, starches, trachants, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicas, talc, zinc oxide and the like may be used as carrier components. Can be.
본 발명의 제형이 파우더 또는 스프레이인 경우에는 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄 히드록시드, 칼슘 실리케이트, 폴리아미드 파우더 등이 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카 본, 프로판/부탄 또는 디메틸 에테르와 같은 추진체를 포함할 수 있다.When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder, and the like may be used, and in particular, in the case of a spray, additionally chlorofluorohydrocarbons. Propellant such as propane / butane or dimethyl ether.
본 발명의 제형이 용액 또는 유탁액인 경우에는 담체 성분으로서 용매, 용해화제 또는 유탁화제, 예를 들어 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸글리콜 오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜, 소르비탄의 지방산 에스테르 등이 이용될 수 있다.When the formulation of the present invention is a solution or emulsion, a carrier, solubilizing or emulsifying agent as carrier component, for example water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylglycol oil, glycerol aliphatic ester, polyethylene glycol, fatty acid ester of sorbitan and the like can be used.
본 발명의 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상의 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 또는 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가, 트라칸트 등이 이용될 수 있다.When the formulation of the present invention is a suspension, a liquid diluent such as water, ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester or polyoxyethylene sorbitan ester, and microcrystals are used as carrier components. Castle cellulose, aluminum metahydroxy, bentonite, agar, tracant and the like can be used.
본 발명의 화장료 조성물은 스킨, 로션, 크림, 팩, 색조화장품, 선크림, 투웨이케이크, 페이스파우더, 콤팩트, 메이크업베이스, 스킨커버, 아이쉐도우, 립스틱, 립글로스, 립픽스, 아이브로우 펜슬 등의 화장품에 적용될 수 있다. The cosmetic composition of the present invention is applied to cosmetics such as skins, lotions, creams, packs, color cosmetics, sun creams, two-way cakes, face powders, compacts, makeup bases, skin covers, eye shadows, lipsticks, lip gloss, lip fixes, eyebrow pencils, and the like. Can be applied.
본 발명의 페길레이션된 베튤린 유도체는 수용성이므로 안정한 화장료 조성물로 용이하게 제형화될 수 있고, PEG 부분에 존재하는 산소원자 당 2분자의 물을 흡수함으로써 보습효과가 뛰어날 뿐만 아니라, PEG 부분에 존재하는 산소원자들이 이산화티탄 등 무기 자외선 차단제의 금속과 착체를 형성하여 무기 자외선 차단제의 백탁현상을 방지할 수 있다. The pegylated betulin derivatives of the present invention are water soluble and can be easily formulated into stable cosmetic compositions, and are excellent in moisturizing effects by absorbing two molecules of water per oxygen atom present in the PEG moiety, as well as being present in the PEG moiety. Oxygen atoms may form a complex with a metal of an inorganic sunscreen agent such as titanium dioxide to prevent clouding of the inorganic sunscreen agent.
따라서 본 발명의 화합물은 기능성 화장품 원료로서 화장료 조성물, 특히 자외선 차단용 화장료 조성물에 효과적으로 사용될 수 있다.Therefore, the compound of the present invention can be effectively used in cosmetic compositions, particularly UV-protective cosmetic composition as a functional cosmetic raw material.
이하, 실시예에 의해 본 발명을 보다 구체적으로 설명하고자 한다. 이들 실시예는 오직 본 발명을 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업자에게 있어서 자명하다. Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it is obvious to those skilled in the art that the scope of the present invention is not limited to these examples.
실시예 1: 페길레이션된 베튤린(4-1; R=메틸기)의 제조Example 1 Preparation of Pegylated Vetulin (4-1; R = Methyl Group)
자작나무 수피(birch bark; 학명: Betula platyphylla var. japonica)를 클로로포름에 넣고 1~2 시간 동안 환류 교반하였다. 그런 다음, 혼합물을 냉각한 후 여과하여 얻어진 여과액을 감압 농축하고 진공 건조시켜 백색 분말의 베튤린(betulin; 1)을 수득하였다.Birch bark (Berula platyphylla var. Japonica) was put in chloroform and stirred under reflux for 1-2 hours. Then, after cooling the mixture, the filtrate obtained by filtration was concentrated under reduced pressure and dried in vacuo to obtain white powder of betulin (betulin) 1.
베튤린(1) 0.17 g(0.38 mmol)과 mPEG-PA(5-1) 1.92 g(0.38 mmol)을 건조 디클로로메탄(DCM)에 녹이고, 4-디메틸아미노피리딘(4-dimethylaminopyridine: DMAP) 0.047 g(0.038 mmol)을 첨가하였다. 그런 다음, 반응 용액에 디시클로헥실카보디이미드(dicyclohexylcarbodiimide: DCC) 0.095 g(0.46 mmol)을 얼음 중탕 하에서 첨가한 후 실온에서 12 시간 동안 교반하였다. 생성된 부유물(DCU)을 여과하여 제거한 후 여과액을 0.1 N HCl(aq)으로 세척하였다. 분리된 유기층을 무수 MgSO4로 건조한 후 여과시키고, 감압 농축한 다음 진공 건조하였다. 잔류물을 DCM(5 ml)에 녹이고 디에틸 에테르(500 ml)에 가한 다음, 30분 동안 냉장 보관한 후 여과하였다. 잔류물을 디에틸 에테르로 충분히 세척하고 진공 건조시켰다. 그런 다음, 생성된 분말을 에틸 아세테이트(250 ml)에 가열하면서 녹이고, 1 시간 동안 냉동 보관한 후 여과하였다. 잔류물을 에틸 아세테이트로 충분히 세척하고 진공 건조시켰다. 얻어진 고형물을 DCM에 녹이고 탄산수소나트륨(NaHCO3) 포화 수용액으로 세척한 다음, 유기층을 무수 MgSO4로 건조한 후 여과시키고, 감압 농축한 다음 진공 건조하여 백색 고체인 페길레이션된 베튤린(4-1; 1.6 g)을 수득하였다. 0.17 g (0.38 mmol) of betulin (1) and 1.92 g (0.38 mmol) of mPEG-PA (5-1) were dissolved in dry dichloromethane (DCM), and 0.047 g of 4-dimethylaminopyridine (DMAP). (0.038 mmol) was added. Then, 0.095 g (0.46 mmol) of dicyclohexylcarbodiimide (DCC) was added to the reaction solution under an ice bath, followed by stirring at room temperature for 12 hours. The resulting suspension (DCU) was filtered off and the filtrate was washed with 0.1 N HCl (aq). The separated organic layer was dried over anhydrous MgSO 4 , filtered, concentrated under reduced pressure, and dried in vacuo. The residue was taken up in DCM (5 ml) and added to diethyl ether (500 ml), then refrigerated for 30 minutes and filtered. The residue was washed sufficiently with diethyl ether and dried in vacuo. The resulting powder was then dissolved in heating with ethyl acetate (250 ml), frozen for 1 hour and filtered. The residue was washed sufficiently with ethyl acetate and dried in vacuo. The obtained solid was dissolved in DCM, washed with a saturated aqueous solution of sodium hydrogen carbonate (NaHCO 3 ), and then the organic layer was dried over anhydrous MgSO 4 , filtered, concentrated under reduced pressure, and dried under vacuum to yield a white solid pegylated betulin (4-1). 1.6 g) was obtained.
제조예 1: 활성화된 PEG 유도체(6; R=메틸기)의 합성Preparation Example 1 Synthesis of Activated PEG Derivative (6; R = Methyl Group)
mPEG-OH(5-3) 10g을 톨루엔 100 ml에 용해한 후 공비증류를 통해 건조시켰다. 건조된 mPEG-OH를 디클로로메탄 50 ml에 용해한 혼합물에 피리딘 1.2 ml를 첨가하고, 니트로페닐클로로퍼메이트(4-nitrophenyl chloroformate) 3.0 g을 첨가한 다음 실온에서 18시간 동안 교반하였다. 생성된 혼합물의 부유물을 여과하여 제거하고 여과액을 감압 농축하였다. 과량의 디에틸에테르에 넣어 침전시킨 후 디에틸에테르로 충분히 씻어주면서 여과하였다. 잔류물을 에틸아세테이트로 재결정하여 mPEG-NPC(6) 10.4 g을 수득하였다.10 g of mPEG-OH (5-3) was dissolved in 100 ml of toluene and dried by azeotropic distillation. 1.2 ml of pyridine was added to a mixture of dried mPEG-OH in 50 ml of dichloromethane, and 3.0 g of 4-nitrophenyl chloroformate were added, followed by stirring at room temperature for 18 hours. The suspended matter in the resulting mixture was filtered off and the filtrate was concentrated under reduced pressure. The precipitate was added to an excess of diethyl ether and precipitated, followed by filtration with sufficient washing with diethyl ether. The residue was recrystallized from ethyl acetate to give 10.4 g of mPEG-NPC (6).
실시예 2: 분지된 PEG 유도체로 페길레이션된 베튤린(4-2; R=메틸기)의 제조Example 2: Preparation of betulin (4-2; R = methyl group) PEGylated with branched PEG derivatives
디아미노뷰티릭 엑시드(7) 0.57 g을 0.1 M 소듐보레이트 완충용액(pH 9.0)에 용해하고, 상기 제조예 1에서 수득한 mPEG-NPC(6) 2.0 g을 2시간 동안 나눠서 첨가한 후 15시간 동안 실온에서 교반하였다. 반응 혼합물에 0.1 N 염산 수용액을 천천히 가하면서 pH를 2-3 정도로 낮추고, 디클로로메탄으로 추출하여 마그네슘설페이트 무수물로 건조하고 여과한 후, 얻어진 여과액을 감압 농축하였다. GPC를 통해 분리하여 분지된 PEG 유도체(5-2) 1.4 g (72%)를 수득하였다.0.57 g of diaminobutyric acid (7) was dissolved in 0.1 M sodium borate buffer (pH 9.0), and 2.0 g of mPEG-NPC (6) obtained in Preparation Example 1 was added for 2 hours, followed by 15 hours. Stirred at room temperature. The pH was lowered to 2-3 while slowly adding 0.1 N aqueous hydrochloric acid solution to the reaction mixture, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered, and the resulting filtrate was concentrated under reduced pressure. Separation via GPC gave 1.4 g (72%) of the branched PEG derivative (5-2).
베튤린(1) 0.17 g을 디클로로메탄에 용해하고, 분지된 PEG 유도체(5-2) 1.5 g과 DMAP 0.05 g을 가한 용액에 DCC 0.09 g을 첨가하고, 실온에서 24 시간 동안 교반하였다. 반응 혼합물의 부유물(DCU)을 여과하여 제거한 후, 여과액을 0.1M 염산 수용액으로 씻어주고, 다시 소듐비카보네이트 포화 수용액으로 유기층을 씻어서 추출한 다음, 마그네슘 설페이트 무수물로 건조하고 여과한 후 여과액을 감압 농축하였다. 잔류물을 에틸아세테이트로 재결정하여 분지된 PEG 유도체로 페길레이션된 베튤린(4-2) 1.36 g (80%)을 수득하였다.0.17 g of betulin (1) was dissolved in dichloromethane, 0.09 g of DCC was added to a solution of 1.5 g of branched PEG derivative (5-2) and 0.05 g of DMAP, and stirred at room temperature for 24 hours. After removing the suspended solids (DCU) of the reaction mixture by filtration, the filtrate was washed with 0.1M aqueous hydrochloric acid solution, washed with an aqueous saturated sodium bicarbonate solution and extracted with organic layer, dried over anhydrous magnesium sulfate, filtered and the filtrate was decompressed Concentrated. The residue was recrystallized from ethyl acetate to give 1.36 g (80%) of betulin (4-2) PEGylated with a branched PEG derivative.
실시예 3: 페길레이션된 베튤린산(4-3; R=메틸기)의 제조Example 3 Preparation of Pegylated Betulinic Acid (4-3; R = Methyl Group)
베튤린(1) 3 g을 아세톤 20 ml에 용해한 용액에, 산화크롬(CrO3) 26.7 g을 황산(H2SO4) 23 ml에 녹이고 물로 최종 부피를 100 ml로 하여 만든 존스 시약(Jone's reagent) 6 ml를 가하고, 실온에서 24 시간 동안 교반하였다. 반응 혼 합물을 감압 농축하고 CH2Cl2로 희석하여 여과하였다. 여과액을 물로 세척하고 다시 NaHCO3 수용액과 물로 세척한 다음, 유기층을 MgSO4로 건조하고 여과한 후 감압 농축하고 건조하여 베튤로닉산(betulonic acid) 3.06 g (100%)을 정량적으로 얻었다.To a solution of 3 g of betulin (1) dissolved in 20 ml of acetone, 26.7 g of chromium oxide (CrO 3 ) was added to sulfuric acid (H 2 SO 4 ). 6 ml of Jones's reagent, which was dissolved in 23 ml and had a final volume of 100 ml with water, was added and stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, diluted with CH 2 Cl 2 and filtered. The filtrate was washed with water and again washed with NaHCO 3 aqueous solution and water, and then the organic layer was dried over MgSO 4 , filtered, concentrated under reduced pressure and dried to obtain 3.06 g (100%) of betuonic acid quantitatively.
베튤로닉산 2 g을 THF에 용해하여 0 ℃로 냉각하고 NaBH4 1.76 g을 첨가하였다. 생성된 혼합물을 실온에서 10 시간 동안 교반하였다. 2 N HCl 수용액으로 반응을 종결시키고 감압 농축하여 THF를 제거한 후, 농축된 용액을 에틸아세테이트로 희석하고 물과 식염수(brine)로 세척하였다. 에틸아세테이트 층을 마그네슘설페이트로 건조하고 여과한 후 감압 농축하여 정량적으로 얻어진 백색 부유물을 메탄올을 사용하여 재결정하여 베튤린산(betulinic acid; 3) 1.52 g (76%)을 수득하였다.2 g of betuonic acid were dissolved in THF, cooled to 0 ° C. and 1.76 g of NaBH 4 was added. The resulting mixture was stirred at rt for 10 h. The reaction was terminated with 2 N HCl aqueous solution, concentrated under reduced pressure to remove THF, and the concentrated solution was diluted with ethyl acetate and washed with water and brine. The ethyl acetate layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The white suspension, which was obtained quantitatively, was recrystallized from methanol to obtain 1.52 g (76%) of betulinic acid (betulinic acid).
베튤린산(3) 1 g을 디클로로메탄에 용해하고, mPEG-OH(5-3) 3.2 g과 DMAP 0.26 g을 가한 용액에 DCC 0.53 g을 첨가하고, 실온에서 24 시간 동안 교반하였다. 반응 혼합물의 부유물(DCU)을 여과하여 제거하고, 여과액을 감압 농축하였다. 잔류물을 실리카겔 컬럼크로마토그래피(디클로로메탄:메탄올 = 10:1)로 정제하여 무색 고체인 페길레이션된 베튤린산(4-3) 2.8g (67%)을 수득하였다.1 g of betulinic acid (3) was dissolved in dichloromethane, 0.53 g of DCC was added to a solution to which 3.2 g of mPEG-OH (5-3) and 0.26 g of DMAP were added, and stirred at room temperature for 24 hours. The suspended solids (DCU) of the reaction mixture were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to give 2.8 g (67%) of pegylated betulinic acid (4-3) as a colorless solid.
실시예 4: 분지된 PEG 유도체로 페길레이션된 베튤린산(4-4; R=메틸기)의 제 조Example 4 Preparation of Betulinic Acid (4-4; R = Methyl Group) Pegylated with Branched PEG Derivatives
디아미노프로판올(9) 0.27 g을 1M 소듐포스페이트 완충용액(pH 8.0)에 용해하고, 상기 제조예 1에서 수득한 mPEG-NPC(6) 2.0 g을 2시간 동안 나눠서 첨가한 후 15시간 동안 실온에서 교반하였다. 반응 혼합물에 0.1 N 염산 수용액을 천천히 가하면서 pH를 2-3 정도로 낮추고, 디클로로메탄으로 추출하여 마그네슘설페이트 무수물로 건조하고 여과한 후, 얻어진 여과액을 감압 농축하였다. GPC를 통해 분리하여 분지된 PEG 유도체(5-4) 1.3 g (63%)을 수득하였다.0.27 g of diaminopropanol (9) was dissolved in 1M sodium phosphate buffer (pH 8.0), and 2.0 g of mPEG-NPC (6) obtained in Preparation Example 1 was added in portions for 2 hours, followed by 15 hours at room temperature. Stirred. The pH was lowered to 2-3 while slowly adding 0.1 N aqueous hydrochloric acid solution to the reaction mixture, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered, and the resulting filtrate was concentrated under reduced pressure. Separation via GPC gave 1.3 g (63%) of the branched PEG derivative (5-4).
베튤린산(3) 0.14 g을 디클로로메탄에 용해하고, 분지된 PEG 유도체(5-4) 1.0 g과 DMAP 0.03 g을 가한 용액에 DCC 0.06 g을 첨가하고, 실온에서 24 시간 동안 교반하였다. 반응 혼합물의 부유물(DCU)을 여과하여 제거한 후, 여과액을 0.1M 염산 수용액으로 씻어주고, 다시 소듐비카보네이트 포화 수용액으로 유기층을 씻어서 추출한 다음, 마그네슘 설페이트 무수물로 건조하고 여과한 후 여과액을 감압 농축하였다. 잔류물을 에틸아세테이트로 재결정하여 분지된 PEG 유도체로 페길레이션된 베튤린산(4-4) 1.02 g (75%)을 수득하였다.0.14 g of betulinic acid (3) was dissolved in dichloromethane, 0.06 g of DCC was added to a solution of 1.0 g of branched PEG derivatives (5-4) and 0.03 g of DMAP, and stirred at room temperature for 24 hours. After removing the suspended solids (DCU) of the reaction mixture by filtration, the filtrate was washed with 0.1M aqueous hydrochloric acid solution, washed with an aqueous saturated sodium bicarbonate solution and extracted with organic layer, dried over anhydrous magnesium sulfate, filtered and the filtrate was decompressed Concentrated. The residue was recrystallized from ethyl acetate to give 1.02 g (75%) of betulinic acid (4-4) pegylated with a branched PEG derivative.
실시예 5: 아미드 결합으로 페길레이션된 베튤린산(4-5; R=메틸기)의 제조Example 5 Preparation of Betulinic Acid (4-5; R = Methyl Group) Pegylated with Amide Bonds
mPEG-OH(5-3) 27.5 g을 톨루엔 150 ml에 용해한 후 공비증류를 통해 건조시켰다. 건조된 mPEG-OH(5-3)를 무수 톨루엔에 용해한 혼합물에 무수 피리딘 4.3 ml를 첨가하고 저온에서 티오닐 클로라이드 3.7 ml를 30분 이상 적가한 후, 첨가 완 료된 혼합물을 4시간 동안 환류 교반하였다. 반응물을 실온으로 냉각하고 침전된 피리딘 염산염을 여과한 다음, 여과액을 감압 농축하여 톨루엔을 제거하였다. 잔류물을 디클로로메탄에 용해하여 포타슘카보네이트 무수물로 건조하고 여과하였다. 여과액을 50 g의 알루미나로 처리하고 여과한 후 감압 농축하여 mPEG-Cl 28 g을 수득하였다.27.5 g of mPEG-OH (5-3) was dissolved in 150 ml of toluene and dried by azeotropic distillation. 4.3 ml of anhydrous pyridine was added to the mixture of dried mPEG-OH (5-3) in anhydrous toluene and 3.7 ml of thionyl chloride was added dropwise at least 30 minutes at low temperature, and then the mixture was stirred under reflux for 4 hours. . The reaction was cooled to room temperature, the precipitated pyridine hydrochloride was filtered off, and the filtrate was concentrated under reduced pressure to remove toluene. The residue was dissolved in dichloromethane, dried over anhydrous potassium carbonate and filtered. The filtrate was treated with 50 g of alumina, filtered and concentrated under reduced pressure to give 28 g of mPEG-Cl.
mPEG-Cl 28 g을 디메틸포름아미드 150 ml에 용해한 혼합물에 소듐아지드 25.6 g을 첨가하고 3시간 동안 120℃에서 가열하였다. 반응 혼합물을 냉각하여 여과한 후 감압 농축하여 디메틸포름아미드를 제거하였다. 잔류물을 디클로로메탄에 용해하고 물로 씻어주어 유기층을 추출하였다. 마그네슘 설페이트 무수물로 건조하고 여과한 후 감압 농축하여 mPEG-N3 27.5 g을 수득하였다. To a mixture of 28 g of mPEG-Cl in 150 ml of dimethylformamide was added 25.6 g of sodium azide and heated at 120 ° C. for 3 hours. The reaction mixture was cooled, filtered and concentrated under reduced pressure to remove dimethylformamide. The residue was dissolved in dichloromethane and washed with water to extract the organic layer. Dried over magnesium sulfate anhydride, filtered and concentrated under reduced pressure to give 27.5 g of mPEG-N 3 .
mPEG-N3 27.5 g과 트리페닐 포스핀 28.4 g을 테트라히드로퓨란 150 ml에 용해하고 물 1.5 ml를 첨가하였다. 반응 혼합물을 실온에서 8시간 동안 교반하였다. 반응 혼합물을 감압 농축하여 용매를 제거하고 잔류물을 디클로로메탄에 용해한 다음, 물로 씻어주고 유기층을 추출하여 마그네슘설페이트 무수물로 건조하고 여과한 후 감압 농축하였다. 얻어진 혼합물을 실리카 겔 150 g으로 여과하여 부산물을 제거하고 감압 농축하여 mPEG-NH2(5-5) 22.5 g을 수득하였다. 27.5 g of mPEG-N 3 and 28.4 g of triphenyl phosphine were dissolved in 150 ml of tetrahydrofuran and 1.5 ml of water was added. The reaction mixture was stirred at rt for 8 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, the residue was dissolved in dichloromethane, washed with water, the organic layer was extracted, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting mixture was filtered through 150 g of silica gel to remove byproducts and concentrated under reduced pressure to give 22.5 g of mPEG-NH 2 (5-5).
베튤린산(3) 1 g을 디클로로메탄에 용해하고, mPEG-NH2(5-5) 1.2 g과 DMAP 0.10 g을 가한 용액에 DCC 0.19 g을 첨가하고, 실온에서 24 시간 동안 교반하였다. 반응 혼합물의 부유물(DCU)을 여과하여 제거하고, 여과액을 감압 농축하였다. 잔류물을 실리카겔 컬럼크로마토그래피(디클로로메 탄:메탄올 = 10:1)로 정제하여 무색 고체인 아미드 결합으로 페길레이션된 베튤린산(4-5) 1.04 g (68%)을 수득하였다.1 g of betulinic acid (3) was dissolved in dichloromethane, 0.19 g of DCC was added to a solution to which 1.2 g of mPEG-NH 2 (5-5) and 0.10 g of DMAP were added, and stirred at room temperature for 24 hours. The suspended solids (DCU) of the reaction mixture were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to yield 1.04 g (68%) of betulinic acid (4-5) pegylated with an amide bond as a colorless solid.
제형실시예 1: 페길레이션된 베튤린을 포함하는 자외선 차단제의 제조Formulation Example 1 Preparation of Sunscreen Containing Pegylated Bettulin
상기 실시예 1에서 수득한 페길레이션된 베튤린을 포함하는 자외선 차단제를 하기에 기재된 조성과 함량(중량%)으로 제조하였다. A sunscreen comprising pegylated betulin obtained in Example 1 was prepared in the composition and content (% by weight) described below.
표 1TABLE 1
제형실시예 2: 분지된 PEG 유도체로 페길레이션된 베튤린을 포함하는 자외선 차단제의 제조Formulation Example 2 Preparation of Sunscreen Comprising Bettulin Pegylated with Branched PEG Derivatives
상기 실시예 2에서 수득한 분지된 PEG 유도체로 페길레이션된 베튤린을 포함하는 자외선 차단제를 하기에 기재된 조성과 함량(중량%)으로 제조하였다. A sunscreen comprising betulin pegylated with the branched PEG derivative obtained in Example 2 was prepared in the composition and content (% by weight) described below.
표 2Table 2
제형실시예 3: 페길레이션된 베튤린산을 포함하는 자외선 차단제의 제조Formulation Example 3 Preparation of Sunscreen Containing Pegylated Betulinic Acid
상기 실시예 3에서 수득한 페길레이션된 베튤린산을 포함하는 자외선 차단제를 하기에 기재된 조성과 함량(중량%)으로 제조하였다. A sunscreen comprising pegylated betulinic acid obtained in Example 3 was prepared in the composition and content (% by weight) described below.
표 3TABLE 3
제형실시예 4: 분지된 PEG 유도체로 페길레이션된 베튤린산을 포함하는 자외선 차단제의 제조Formulation Example 4 Preparation of Sunscreen Containing Betulinic Acid Pegylated with Branched PEG Derivatives
상기 실시예 4에서 수득한 분지된 PEG 유도체로 페길레이션된 베튤린산을 포함하는 자외선 차단제를 하기에 기재된 조성과 함량(중량%)으로 제조하였다. A sunscreen comprising betulinic acid pegylated with the branched PEG derivative obtained in Example 4 was prepared in the composition and content (% by weight) described below.
표 4Table 4
제형실시예 5: 아미드 결합으로 페길레이션된 베튤린산을 포함하는 자외선 차단제의 제조Formulation Example 5 Preparation of Sunscreen Comprising Bettulinic Acid Pegylated with Amide Bonds
상기 실시예 5에서 수득한 아미드 결합으로 페길레이션된 베튤린산을 포함하는 자외선 차단제를 하기에 기재된 조성과 함량(중량%)으로 제조하였다. A sunscreen comprising betulinic acid pegylated with the amide bond obtained in Example 5 was prepared in the composition and content (% by weight) described below.
표 5Table 5
비교예 1: 이산화티탄을 포함하는 자외선 차단제의 제조Comparative Example 1: Preparation of Sunscreen Agent Containing Titanium Dioxide
통상의 이산화티탄을 포함하는 자외선 차단제를 하기에 기재된 조성과 함량(중량%)으로 제조하였다. A sunscreen comprising conventional titanium dioxide was prepared in the composition and content (% by weight) described below.
표 6Table 6
시험예 1: 인 비트로(Test Example 1: In Vitro in vitroin vitro ) SPF 측정) SPF measurement
상기 제형실시예 1-5에서 수득한 본 발명의 자외선 차단제와 비교예 1에서 수득한 통상의 자외선 차단제의 인 비트로(in vitro) SPF(자외선 차단지수)를 측정하였다. 측정방법은 시료 2 ㎎/㎠를 폴리포어 테이프(polypore tape, 3M)에 도포한 후 20분간 건조시키고, 125W CW Xenon arc 램프가 장착된 SPF 290 분석기(Optometrics LLC.)를 이용하여 측정하였다. 그 결과를 하기 표 7에 나타내었다.The in vitro SPF (ultraviolet ray block index) of the sunscreen of the present invention obtained in Formulation Examples 1-5 and the conventional sunscreen obtained in Comparative Example 1 was measured. The measurement method was applied to a polypore tape (polypore tape, 3M) sample 2 mg / ㎠ and dried for 20 minutes, and measured using an SPF 290 analyzer (Optometrics LLC.) Equipped with a 125W CW Xenon arc lamp. The results are shown in Table 7 below.
표 7TABLE 7
상기 표 7에서 보는 바와 같이, 본 발명의 자외선 차단제가 통상의 자외선 차단제 보다 SPF 수치가 높음을 알 수 있었다. As shown in Table 7, it was found that the sunscreen of the present invention has a higher SPF value than the usual sunscreen.
시험예 2: 백탁현상 측정Test Example 2: Measurement of turbidity
피부에 도포시 허옇게 되거나 푸르스름하게 되는 백탁현상을 측정하기 위해 IR(적외선)을 이용하여 상기 제형실시예 1-5에서 수득한 본 발명의 자외선 차단제와 비교예 1에서 수득한 통상의 자외선 차단제의 흡광도를 측정하여 도 1에 그래프로 나타내었다(역으로는 투과도임). 가시광선 영역은 400-800 nm로서 이 영역에서의 흡수도가 높으면 백탁현상을 유발하는 것으로 알려져 있다. Absorbance of the sunscreen of the present invention obtained in Formulation Examples 1-5 and the conventional sunscreen obtained in Comparative Example 1 using IR (infrared ray) to measure the clouding phenomenon that becomes cloudy or bluish when applied to the skin. Was measured and represented graphically in FIG. 1 (inversely, transmittance). The visible light region is 400-800 nm, and high absorption in this region is known to cause cloudiness.
도 1의 흡광도 그래프를 통해, 본 발명의 자외선 차단제가 가시광선 영역에서의 흡수도가 낮아 투과도가 우수하여 백탁현상을 거의 유발하지 않음을 알 수 있었다.The absorbance graph of FIG. 1 shows that the sunscreen of the present invention has low absorption in the visible light region and thus has excellent transmittance and hardly causes cloudiness.
시험예 3: TEWL(trans-epidermal water loss) 측정Test Example 3 Measurement of Trans-epidermal Water Loss (TEWL)
TEWL(trans-epidermal water loss)은 피부를 통해 증발되는 수분 (땀은 제외)을 나타내는 지표로 각질층의 손상정도와 피부장벽 기능을 평가하는데 이용된다. 높은 수준의 TEWL은 피부장벽이 손상됐다는 것을 나타낸다.Trans-epidermal water loss (TEWL) is an indicator of moisture (except sweat) that evaporates through the skin and is used to assess the extent of damage to the stratum corneum and skin barrier function. High levels of TEWL indicate damage to the skin barrier.
상기 제형실시예 1-5에서 수득한 본 발명의 자외선 차단제와 비교예 1에서 수득한 통상의 자외선 차단제의 인체적용시 TEWL을 측정하였다. TEWL의 측정은 항 온(22℃) 및 항습(47%) 상태에서 이루어졌으며, 단위는 g/h/m2이다. 측정방법은 다음과 같다: 우선, 테이프-스트립핑(tape-stripping)을 30회 실시하여 피부장벽의 손상을 유발시켰다. 피부장벽의 손상을 유발한 후 시험 제품을 도포하기 전 TEWL 수치를 측정하였다. 제품을 적용하고 1시간 간격으로 4시간 동안 TEWL 수치의 변화를 Tewameter TM210(Courage+Khazaka, 독일)을 사용하여 측정하였다. 그 결과를 하기 표 8에 나타내었다.TEWL was measured in human application of the sunscreen of the present invention obtained in Formulation Examples 1-5 and the conventional sunscreen obtained in Comparative Example 1. The measurement of TEWL was made at constant temperature (22 ° C.) and constant humidity (47%) and the unit is g / h / m 2 . The measurement method was as follows: First, tape-stripping was performed 30 times to cause damage to the skin barrier. After causing damage to the skin barrier, the TEWL value was measured before application of the test product. Changes in TEWL values for 4 hours at 1 hour intervals after application of the product were measured using Tewameter TM210 (Courage + Khazaka, Germany). The results are shown in Table 8 below.
표 8Table 8
상기 표 8에서 보는 바와 같이, 본 발명의 자외선 차단제는 통상의 자외선 차단제 이상으로 수분 손실을 막을 수 있음을 알 수 있었다. As shown in Table 8, the sunscreen of the present invention was found to be able to prevent the loss of moisture than the usual sunscreen.
시험예 4: 인체적용시 수분 보유량 측정Test Example 4 Measurement of Water Retention in Human Application
TEWL 측정과 함께 피부보습에 관한 실험을 상기 제형실시예 1-5에서 수득한 본 발명의 자외선 차단제와 비교예 1에서 수득한 통상의 자외선 차단제를 사용하여 실시하였다. 피부보습은 코네어미터 (corneometer, CM820, Courage+Khazaka, 독일)를 사용하여 측정하였다. 측정방법은 다음과 같다: 시험물질을 적용하기 전 피부의 전기 전도도를 측정한 후 1일 2회씩 시험 제품을 4주간 적용하였다. 피부 보 습효과의 측정을 위해 1주 간격으로 코네어미터 수치를 측정하였다. 코네어미터는 피부의 최외각층인 각질층이 보유하는 수분의 양과 피부의 수분 보유 능력을 측정하는 기계로서 도포전 수분보유량을 기준으로 데이터를 표시하였다. 그 결과를 하기 표 9에 나타내었다.Experiments on skin moisturization with TEWL measurements were carried out using the sunscreen of the invention obtained in Formulation Examples 1-5 and the conventional sunscreen obtained in Comparative Example 1. Skin moisture was measured using a corneometer (CMeometer, CM820, Courage + Khazaka, Germany). The measurement method was as follows: The electrical conductivity of the skin was measured before application of the test substance, and the test product was applied twice a day for 4 weeks. In order to measure the skin moisturizing effect, the coronometer value was measured at a weekly interval. The cone meter is a machine that measures the amount of water retained by the stratum corneum, the outermost layer of the skin, and the ability of the skin to retain water, and displays data based on the amount of water retained before application. The results are shown in Table 9 below.
표 9Table 9
상기 표 9에서 보는 바와 같이, TEWL과 마찬가지로 본 발명의 자외선 차단제가 통상의 자외선 차단제 보다 탁월한 보습효과가 있음을 알 수 있었다.As shown in Table 9, it was found that the sunscreen of the present invention, like TEWL, has an excellent moisturizing effect than a conventional sunscreen.
도 1은 제형실시예 1-5에서 수득한 본 발명의 자외선 차단제와 비교예 1에서 수득한 통상의 자외선 차단제의 흡광도 그래프이다.1 is a graph of absorbance of the sunscreen of the present invention obtained in Formulation Examples 1-5 and the conventional sunscreen obtained in Comparative Example 1. FIG.
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