KR20130140448A - Pharmaceutical compositions for prevention or treatment of diabetic complications comprising an extract of capsosiphon fulvescens or the compounds isolated from thereof - Google Patents
Pharmaceutical compositions for prevention or treatment of diabetic complications comprising an extract of capsosiphon fulvescens or the compounds isolated from thereof Download PDFInfo
- Publication number
- KR20130140448A KR20130140448A KR1020120063862A KR20120063862A KR20130140448A KR 20130140448 A KR20130140448 A KR 20130140448A KR 1020120063862 A KR1020120063862 A KR 1020120063862A KR 20120063862 A KR20120063862 A KR 20120063862A KR 20130140448 A KR20130140448 A KR 20130140448A
- Authority
- KR
- South Korea
- Prior art keywords
- diabetic
- extract
- diabetic complications
- preventing
- capsofulvesin
- Prior art date
Links
- 239000000284 extract Substances 0.000 title claims abstract description 105
- 208000002249 Diabetes Complications Diseases 0.000 title claims abstract description 64
- 206010012655 Diabetic complications Diseases 0.000 title claims abstract description 63
- 150000001875 compounds Chemical class 0.000 title claims abstract description 54
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 30
- 238000011282 treatment Methods 0.000 title claims description 17
- 230000002265 prevention Effects 0.000 title claims description 16
- 241001200842 Capsosiphon fulvescens Species 0.000 title abstract description 8
- 102000016912 Aldehyde Reductase Human genes 0.000 claims abstract description 38
- 108010053754 Aldehyde reductase Proteins 0.000 claims abstract description 38
- 239000004480 active ingredient Substances 0.000 claims abstract description 33
- 239000000203 mixture Substances 0.000 claims abstract description 33
- 230000036252 glycation Effects 0.000 claims abstract description 16
- 239000012454 non-polar solvent Substances 0.000 claims abstract description 15
- 239000000047 product Substances 0.000 claims abstract description 15
- 235000013305 food Nutrition 0.000 claims abstract description 10
- 235000015872 dietary supplement Nutrition 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- 230000002401 inhibitory effect Effects 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 239000000287 crude extract Substances 0.000 claims description 31
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 29
- 239000002904 solvent Substances 0.000 claims description 22
- 235000013376 functional food Nutrition 0.000 claims description 19
- 230000036541 health Effects 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 239000012046 mixed solvent Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 206010007749 Cataract diabetic Diseases 0.000 claims description 13
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 13
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 13
- 201000007025 diabetic cataract Diseases 0.000 claims description 13
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 238000004440 column chromatography Methods 0.000 claims description 10
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 206010012667 Diabetic glaucoma Diseases 0.000 claims description 8
- 235000009508 confectionery Nutrition 0.000 claims description 6
- 230000006872 improvement Effects 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 5
- 238000005194 fractionation Methods 0.000 claims description 4
- 235000013334 alcoholic beverage Nutrition 0.000 claims description 3
- 235000013361 beverage Nutrition 0.000 claims description 3
- 235000019219 chocolate Nutrition 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 235000015243 ice cream Nutrition 0.000 claims description 3
- 235000013372 meat Nutrition 0.000 claims description 3
- 235000012149 noodles Nutrition 0.000 claims description 3
- 235000013550 pizza Nutrition 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 239000000401 methanolic extract Substances 0.000 claims description 2
- 229940088594 vitamin Drugs 0.000 claims description 2
- 239000011782 vitamin Substances 0.000 claims description 2
- 235000013343 vitamin Nutrition 0.000 claims description 2
- 229930003231 vitamin Natural products 0.000 claims description 2
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 2
- 206010037660 Pyrexia Diseases 0.000 claims 1
- INDVLXYUCBVVKW-PXBBAZSNSA-N 24-methylenecholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCC(=C)C(C)C)[C@@]1(C)CC2 INDVLXYUCBVVKW-PXBBAZSNSA-N 0.000 abstract description 27
- 230000000694 effects Effects 0.000 abstract description 22
- 239000000126 substance Substances 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 4
- 230000001629 suppression Effects 0.000 abstract description 3
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 2
- 230000003013 cytotoxicity Effects 0.000 abstract description 2
- 239000005445 natural material Substances 0.000 abstract description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 34
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 22
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 16
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 15
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 15
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 15
- 239000008103 glucose Substances 0.000 description 15
- 239000000600 sorbitol Substances 0.000 description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 13
- 102000004877 Insulin Human genes 0.000 description 12
- 241000700159 Rattus Species 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 229940093499 ethyl acetate Drugs 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 108090001061 Insulin Proteins 0.000 description 11
- 238000000605 extraction Methods 0.000 description 11
- 229940125396 insulin Drugs 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 235000002639 sodium chloride Nutrition 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 8
- 239000011230 binding agent Substances 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- 230000037361 pathway Effects 0.000 description 8
- 229920005862 polyol Polymers 0.000 description 8
- 150000003077 polyols Chemical class 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 238000002835 absorbance Methods 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 239000007884 disintegrant Substances 0.000 description 7
- 201000001421 hyperglycemia Diseases 0.000 description 7
- 239000000314 lubricant Substances 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 208000002177 Cataract Diseases 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 229930186217 Glycolipid Natural products 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000000796 flavoring agent Substances 0.000 description 5
- 235000011187 glycerol Nutrition 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 5
- 241000195628 Chlorophyta Species 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 206010019133 Hangover Diseases 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 4
- OQVOZFPJUCUPLW-LURJTMIESA-N N-(1-Carboxymethyl)-L-lysine Chemical compound NCCCC[C@@H](C(O)=O)NCC(O)=O OQVOZFPJUCUPLW-LURJTMIESA-N 0.000 description 4
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 description 4
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 235000005911 diet Nutrition 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 235000013373 food additive Nutrition 0.000 description 4
- 239000002778 food additive Substances 0.000 description 4
- 230000013595 glycosylation Effects 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 229960001285 quercetin Drugs 0.000 description 4
- 235000005875 quercetin Nutrition 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 230000008961 swelling Effects 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 3
- 229930091371 Fructose Natural products 0.000 description 3
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 3
- 239000005715 Fructose Substances 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 206010029333 Neurosis Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 238000006206 glycosylation reaction Methods 0.000 description 3
- 239000007902 hard capsule Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000003914 insulin secretion Effects 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 208000017169 kidney disease Diseases 0.000 description 3
- -1 lens Chemical compound 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 208000015238 neurotic disease Diseases 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- AYEKKSTZQYEZPU-RYUDHWBXSA-N pentosidine Chemical compound OC(=O)[C@@H](N)CCCCN1C=CC=C2N=C(NCCC[C@H](N)C(O)=O)N=C12 AYEKKSTZQYEZPU-RYUDHWBXSA-N 0.000 description 3
- 210000000578 peripheral nerve Anatomy 0.000 description 3
- 239000008196 pharmacological composition Substances 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000012064 sodium phosphate buffer Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008223 sterile water Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 108010005094 Advanced Glycation End Products Proteins 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 208000018522 Gastrointestinal disease Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000012404 In vitro experiment Methods 0.000 description 2
- 208000002720 Malnutrition Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- INDVLXYUCBVVKW-UHFFFAOYSA-N Methylencholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(=C)C(C)C)C1(C)CC2 INDVLXYUCBVVKW-UHFFFAOYSA-N 0.000 description 2
- ZPFOMEYYYRDYJK-MDTVQASCSA-N NCCCC[C@@H](C(O)=O)N.NCCCC[C@@H](C(O)=O)N.C1=CN=CN1 Chemical compound NCCCC[C@@H](C(O)=O)N.NCCCC[C@@H](C(O)=O)N.C1=CN=CN1 ZPFOMEYYYRDYJK-MDTVQASCSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 208000017442 Retinal disease Diseases 0.000 description 2
- 206010038923 Retinopathy Diseases 0.000 description 2
- 239000002262 Schiff base Substances 0.000 description 2
- 150000004753 Schiff bases Chemical class 0.000 description 2
- 206010040880 Skin irritation Diseases 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
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N alpha-ketodiacetal Natural products O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 108010062796 arginyllysine Proteins 0.000 description 2
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 210000000695 crystalline len Anatomy 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 230000000378 dietary effect Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229930003935 flavonoid Natural products 0.000 description 2
- 150000002215 flavonoids Chemical class 0.000 description 2
- 235000017173 flavonoids Nutrition 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229930182830 galactose Natural products 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000004153 glucose metabolism Effects 0.000 description 2
- MNQZXJOMYWMBOU-UHFFFAOYSA-N glyceraldehyde Chemical compound OCC(O)C=O MNQZXJOMYWMBOU-UHFFFAOYSA-N 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002000 high resolution fast-atom bombardment mass spectrometry Methods 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229960000367 inositol Drugs 0.000 description 2
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000001071 malnutrition Effects 0.000 description 2
- 235000000824 malnutrition Nutrition 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 2
- WPHGSKGZRAQSGP-UHFFFAOYSA-N methylenecyclohexane Natural products C1CCCC2CC21 WPHGSKGZRAQSGP-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 208000015380 nutritional deficiency disease Diseases 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 208000033808 peripheral neuropathy Diseases 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 230000019612 pigmentation Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 239000006041 probiotic Substances 0.000 description 2
- 230000000529 probiotic effect Effects 0.000 description 2
- 235000018291 probiotics Nutrition 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000005057 refrigeration Methods 0.000 description 2
- 210000001525 retina Anatomy 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000036556 skin irritation Effects 0.000 description 2
- 231100000475 skin irritation Toxicity 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 2
- BOOXYSZJUWVNRE-JEDNCBNOSA-N (2s)-2,6-diaminohexanoic acid;2-oxopropanal Chemical class CC(=O)C=O.NCCCC[C@H](N)C(O)=O BOOXYSZJUWVNRE-JEDNCBNOSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical group CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- VTYFITADLSVOAS-NSHDSACASA-N 1-(L-norleucin-6-yl)pyrraline Chemical compound OC(=O)[C@@H](N)CCCCN1C(CO)=CC=C1C=O VTYFITADLSVOAS-NSHDSACASA-N 0.000 description 1
- UJOUHMMIDLYDDD-UHFFFAOYSA-N 1-phenyl-2-(1,3-thiazol-3-ium-2-yl)ethanone;bromide Chemical compound [Br-].C=1C=CC=CC=1C(=O)CC1=[NH+]C=CS1 UJOUHMMIDLYDDD-UHFFFAOYSA-N 0.000 description 1
- INDVLXYUCBVVKW-RNWIMVDMSA-N 24-Methylene cholesterol Natural products O[C@@H]1CC=2[C@@](C)([C@H]3[C@H]([C@H]4[C@@](C)([C@@H]([C@@H](CCC(C(C)C)=C)C)CC4)CC3)CC=2)CC1 INDVLXYUCBVVKW-RNWIMVDMSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- 241001200840 Capsosiphon Species 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- NBSCHQHZLSJFNQ-GASJEMHNSA-N D-Glucose 6-phosphate Chemical compound OC1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H](O)[C@H]1O NBSCHQHZLSJFNQ-GASJEMHNSA-N 0.000 description 1
- BDCFUHIWJODVNG-UHFFFAOYSA-N Desmosterol Natural products C1C=C2CC(O)C=CC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 BDCFUHIWJODVNG-UHFFFAOYSA-N 0.000 description 1
- 235000011511 Diospyros Nutrition 0.000 description 1
- 244000236655 Diospyros kaki Species 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- VFRROHXSMXFLSN-UHFFFAOYSA-N Glc6P Natural products OP(=O)(O)OCC(O)C(O)C(O)C(O)C=O VFRROHXSMXFLSN-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 102100031547 HLA class II histocompatibility antigen, DO alpha chain Human genes 0.000 description 1
- 102000005548 Hexokinase Human genes 0.000 description 1
- 108700040460 Hexokinases Proteins 0.000 description 1
- 101000866278 Homo sapiens HLA class II histocompatibility antigen, DO alpha chain Proteins 0.000 description 1
- 206010020649 Hyperkeratosis Diseases 0.000 description 1
- 206010020710 Hyperphagia Diseases 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 208000001126 Keratosis Diseases 0.000 description 1
- 108010009384 L-Iditol 2-Dehydrogenase Proteins 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 102000015731 Peptide Hormones Human genes 0.000 description 1
- 108010038988 Peptide Hormones Proteins 0.000 description 1
- 235000004347 Perilla Nutrition 0.000 description 1
- 244000124853 Perilla frutescens Species 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 102100026974 Sorbitol dehydrogenase Human genes 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003388 anti-hormonal effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 210000000467 autonomic pathway Anatomy 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
- 239000001354 calcium citrate Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 238000009535 clinical urine test Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 229940124301 concurrent medication Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 208000021921 corneal disease Diseases 0.000 description 1
- 125000004122 cyclic group Chemical class 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 125000004989 dicarbonyl group Chemical group 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000010459 dolomite Substances 0.000 description 1
- 229910000514 dolomite Inorganic materials 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000009207 exercise therapy Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000012812 general test Methods 0.000 description 1
- 210000005086 glomerual capillary Anatomy 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940091173 hydantoin Drugs 0.000 description 1
- 230000003345 hyperglycaemic effect Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- DXDRHHKMWQZJHT-FPYGCLRLSA-N isoliquiritigenin Chemical compound C1=CC(O)=CC=C1\C=C\C(=O)C1=CC=C(O)C=C1O DXDRHHKMWQZJHT-FPYGCLRLSA-N 0.000 description 1
- JBQATDIMBVLPRB-UHFFFAOYSA-N isoliquiritigenin Natural products OC1=CC(O)=CC=C1C1OC2=CC(O)=CC=C2C(=O)C1 JBQATDIMBVLPRB-UHFFFAOYSA-N 0.000 description 1
- 235000008718 isoliquiritigenin Nutrition 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229940069445 licorice extract Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 235000019462 natural additive Nutrition 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 235000020830 overeating Nutrition 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229940027779 persimmon extract Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 210000003635 pituitary gland Anatomy 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 229930008679 prenylflavonoid Natural products 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- VTYFITADLSVOAS-UHFFFAOYSA-N pyrraline Chemical compound OC(=O)C(N)CCCCN1C(CO)=CC=C1C=O VTYFITADLSVOAS-UHFFFAOYSA-N 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000002784 sclerotic effect Effects 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 208000006379 syphilis Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 238000002137 ultrasound extraction Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/02—Algae
- A61K36/05—Chlorophycota or chlorophyta (green algae), e.g. Chlorella
-
- 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
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/328—Foods, ingredients or supplements having a functional effect on health having effect on glycaemic control and diabetes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Chemical & Material Sciences (AREA)
- Alternative & Traditional Medicine (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Medicinal Chemistry (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Description
본 발명은 매생이 추출물 또는 이로부터 분리된 화합물들의 당뇨성 합병증 예방 또는 치료의 신규 용도에 관한 것으로, 자세하게는 매생이 조추출물, 비극성용매 가용 추출물 또는 이로부터 분리된 화합물을 유효성분으로 포함하는 당뇨성 합병증 예방 또는 치료용 약학조성물과 건강식품에 관한 것이다.The present invention relates to a novel use of the prophylaxis or treatment of diabetic complications of extracts or compounds isolated therefrom, and more specifically, diabetic complications comprising crude extracts, non-polar solvent soluble extracts or compounds isolated therefrom as active ingredients. It relates to a pharmaceutical composition and health food for prevention or treatment.
당뇨병은 대표적인 만성 성인병의 하나로, 우리나라의 당뇨병 환자는 전체 인구의 약 5% 정도로 최소한 250만 명으로 추정되고 있다. 선진국의 경우에 당뇨병 환자 수가 매년 급증하고 있으며, 우리나라도 생활수준의 향상과 더불어 생활양식이 서구화되면서 점차로 환자의 수가 증가되고 있다. 폴리펩티드성 호르몬인 인슐린은 췌장에 있는 랑게르한스섬의 베타세포에서 만들어지며, 체내의 대부분의 세포에서 포도당을 사용하는데 필요로 한다. 당뇨병은 인슐린의 부족으로 인해(인슐린의 절대량이 부족한 것은 아니며, 인슐린 이외의 다른 호르몬이 많이 분비되어 상대적으로 부족한 것을 의미) 체세포들이 포도당을 정상적으로 사용할 수 있는 능력에 장애가 생겨 혈당치가 증가하여, 과량의 당분이 소변으로 배설되는 대사성 질환이다. 췌장 호르몬인 인슐린은 뇌하수체, 부신, 갑상선 등 인슐린에 대항작용을 하는 호르몬으로 체내에서 균형이 이루어졌을 때, 혈당이 정상적으로 유지되도록 한다. 그러나 인슐린의 분비량이 부족하거나 인슐린 분비량은 거의 정상이나 대항 호르몬이 상대적으로 많아 인슐린 부족이 일어날 때 당뇨병이 발병하게 된다.Diabetes mellitus is one of the most common chronic diseases, and about 5% of the total population of the country is estimated to have at least 2.5 million people. In advanced countries, the number of diabetic patients is increasing rapidly. In Korea, the number of patients is gradually increasing as the living standard is improved and the lifestyle is westernized. Insulin, a polypeptide hormone, is made from beta cells in the island of Langerhans in the pancreas and is required for the use of glucose in most cells of the body. Diabetes is caused by a lack of insulin (not an absolute amount of insulin, but rather a relatively low amount of hormones other than insulin), which impairs the ability of somatic cells to use glucose normally and increases blood sugar levels. Sugar is a metabolic disorder in which urine is excreted. Pancreatic hormone insulin is a hormone that acts against the insulin, such as the pituitary gland, the adrenal glands, and the thyroid gland. When the body's balance is balanced, blood sugar is maintained normally. However, the amount of insulin secretion or insulin secretion is almost normal, but there is a relatively high number of anti-hormones, diabetes occurs when insulin deficiency occurs.
당뇨병은 크게 두 개로 나눌 수 있는데, 인슐린 의존형 당뇨병 (Type I. Insulin dependent diabetes mellitus, IDDM)은 당뇨병환자의 약 10%를 차지하며, 대개 20세 이하의 어린 연령층에 발병하므로 유전성인 것으로 보이며, 일명 소아당뇨병 (juvenile onset diavetes)이라고 한다. 이는 특정한 human lymphocyte antigen (HLA)과 바이러스 감염 등으로 랑겔한스섬의 β-세포가 파괴되어 인슐린의 분비가 되지 않아 발병하는 당뇨병으로, 일반적으로 체중이 감소하고 케톤증 (Ketonacidosis)이 되기 쉽다. 인슐린 투여로 치료가 가능하고 급성 형태가 많으며, 여아에게 발생빈도가 높고 성인보다 어린이에게 주로 나타난다. 인슐린 비의존형 당뇨병 (Type II. Noninsulin dependent diabetes mellitus NIDDM)은 40세 이후에 발병하는 성인형 당뇨병 (adult onset diabetes)이라고도 하며, 운동부족과 비만, 과식, 스트레스 등으로 인하여 근육이나 지방조직 등 말초조직에서 인슐린에 대한 감수성이 둔화되어 당대사의 장애가 4~5년의 이상 오랜 기간 지속되어 발병하게 된다. 제 2형 당뇨병은 식사요법과 운동요법으로 체중을 줄이면 50~80%는 치유가 되며, 인슐린을 투여하지 않아도 생명에는 지장이 없을 정도이므로 인슐린 비의존형 당뇨병이라고 한다. 이 외에 영양실조 관련 당뇨병 (제 3형 당뇨병)이 있으며, 이것은 제 3세계, 특히 열대지방에서 나타나는 젊은이 당뇨병으로 유아기에 영양실조의 병력을 가진 경우에 나타나는 당뇨병으로, 앞서 두 형태의 당뇨병과 약간 다른 모습을 보여, 세계보건기구는 이를 독립된 형으로 분리하였다.Diabetes can be roughly divided into two types. Insulin dependent diabetes mellitus (IDDM) accounts for about 10% of diabetic patients, and appears to be hereditary because it usually occurs in younger people under 20 years of age. It is called juvenile onset diavetes. This type of diabetes is caused by certain human lymphocyte antigen (HLA) and viral infections, which break down the β-cells in the Isle of Hanlanges, resulting in no insulin secretion. In general, weight loss and ketonacidosis are apt to occur. It is possible to treat with insulin administration, has many acute forms, has a high incidence in girls, and appears mainly in children. Type II.Non-insulin dependent diabetes mellitus NIDDM is also called adult onset diabetes, which develops after age 40. Peripheral tissues such as muscles and adipose tissue due to lack of exercise, obesity, overeating and stress, etc. Insulin sensitivity is slowed down, causing the metabolic disorders to persist for longer than four to five years. Type 2 diabetes mellitus diet and exercise therapy to lose weight by 50 to 80% of the healing, and without the insulin dose is not enough to hinder the life of non-insulin-dependent diabetes mellitus is called. In addition, there is malnutrition-related diabetes (type 3 diabetes), a younger diabetes that occurs in the third world, especially in the tropics, which occurs when a person has a history of malnutrition in infancy. In appearance, the World Health Organization separated it into an independent form.
당뇨병은 그 자체보다는 합병증이 더 위험하기 때문에, 오늘날 당뇨병 치료에 있어서 가장 큰 목표는 당뇨성 합병증의 유발이나 진행을 억제하는데 있다. 합병증은 당뇨병이 오래 지속되어 나타나는 현상으로 보통 10~15년을 경과한 후에 생기는 만성 합병증이 주이며, 그 대표적인 만성 합병증으로 당뇨성 망막증, 당뇨성 신증, 당뇨성 신경증 등이 있다. 당뇨성 신경증은 당뇨병으로 인해 신경계에 장애가 오는 것으로 말초신경의 장애, 건반사의 소실, 운동신경의 마비, 자율신경 장애 등으로 발바닥이 저릿저릿하고, 화끈거리고, 통증이 심하며, 성기능의 장애가 오고, 뇨나 대변을 가리지 못하는 증상을 가져오기도 한다. 당뇨성 신증은 미세혈관 합병증의 하나로 신 사구체 모세혈관의 경화성 병변에 의해 일어나는 것으로 특별한 증상이 없어도 소변검사를 통해 단백질이 나타나면 신증이 있음을 예측할 수 있다. 혈압의 상승은 당뇨병 신증을 악화시키는 요인으로도 작용하는데 보통 10~15년 이상 당뇨병을 앓은 사람들의 약 5 % 정도가 당뇨성 신증이 온다. 당뇨성 망막증은 미세혈관의 합병증 중의 하나로 당뇨병 환자에게 실명을 가져오는 심각한 합병증이다. 최근에 당뇨병 조절과 합병증과의 관계연구에 의하면 인슐린 치료를 강화시켜 혈당이 정상화되면 당뇨성 합병증 발생을 크게 감소시킬 수 있는 것으로 나타났다.Since diabetes is more dangerous than complications per se, the biggest goal in the treatment of diabetes today is to inhibit the development or progression of diabetic complications. Complications are long-standing symptoms of diabetes and chronic complications usually occur after 10 to 15 years. The most common chronic complications are diabetic retinopathy, diabetic nephropathy, and diabetic neurosis. Diabetic neuropathy is a disorder of the nervous system due to diabetes, which is caused by disorders of the peripheral nerves, loss of the keyboard, paralysis of motor nerves, autonomic nerve disorders, etc., resulting in tingling, burning, painful, and sexual dysfunction. It can also cause your stool to go away. Diabetic nephropathy is a microvascular complication caused by sclerotic lesions of renal glomerular capillaries. Even if there is no specific symptom, urine tests can predict nephropathy. An increase in blood pressure also acts to exacerbate diabetic nephropathy, usually about 5% of people who have had diabetes for more than 10 to 15 years. Diabetic retinopathy is a microvascular complication that is a serious complication that causes blindness in diabetics. Recent studies on the relationship between diabetes control and complications have shown that intensifying insulin therapy can significantly reduce the incidence of diabetic complications.
당뇨병에 있어서 고혈당이 합병증을 유발시키는 기전으로 폴리올 대사계(polyol pathway)의 이상, 체내에서 고혈당과 단백질의 결합, 산화적 스트레스, myoinositol의 감소와 Na+, K+-ATPase활성의 감소 등이 발표되었다.The mechanisms by which hyperglycemia causes complications in diabetes have been reported, such as abnormalities of the polyol pathway, binding of hyperglycemia and proteins in the body, oxidative stress, reduction of myoinositol and reduction of Na + and K + -ATPase activity.
그 중 폴리올 대사계(polyol pathway)는 포도당 대사경로의 하나로, 이는 포도당이 솔비톨을 거쳐 과당으로 변환되는 경로로 두 개의 반응계로 구성되며, 2종의 효소가 관여하는 것으로 알려져 있다(Gabbay K. H. and O'Sullivan J. B., Diabetes, 17, pp239, 1968; Dvornik D. et al., Science, 182, pp1146, 1973). 포도당은 에너지원으로 이용되는 중요한 물질로서 정상인의 경우 세포 내에 흡수된 후에 대부분은 헥소키나아제에 의하여 글루코오스-6-포스페이트로 되어 해당계에서 대사되고, 불과 몇 % 만이 폴리올 대사계를 거쳐 대사된다. 그러나 당뇨병에 의해 고혈당 상태가 되면 세포내의 포도당 흡수가 인슐린에 의존하지 않는 조직에서 포도당의 세포막투과는 세포 밖의 포도당 농도에 의존하므로 수정체, 망막, 각막, 말초신경, 혈관, 신사구체, 적혈구 등과 같은 인슐린 비의존성 조직의 세포내 포도당 농도는 상승하게 되고, 이들 세포내에 다량 존재하는 폴리올 대사계의 필수효소인 알도즈 환원효소(Aldose reductase)에 의하여 포도당의 대사가 항진되어 솔비톨이 과잉생성 된다. 그 결과 솔비톨이 축적되는 부위에 따라 발병 증상이 나타나는데, 당뇨성 백내장, 당뇨성 망막증, 당뇨성 각막증, 당뇨성 신경증, 당뇨성 신증 등의 당뇨성 합병증을 일으키게 된다. 알도즈 환원효소를 촉매하는 포도당이 솔비톨로 되는 환원반응은 그 평형에서 역반응이 일어나지 않으며, 솔비톨 탈수소효소(sorbitol dehydrogenase)의 활성이 알도즈 환원효소의 활성보다 낮기 때문에 솔비톨에서 과당으로의 변환량이 아주 적으므로 결과적으로 폴리올 대사계의 항진은 솔비톨을 축적시키게 된다. 당알콜인 솔비톨은 극성이 높아 세포막 외로 확산이 어렵기 때문에 솔비톨이 세포내에 축적되며, 이로 인해 세포내 삼투압을 상승시켜, 수정체내로 수분유입을 촉진하여 세포의 팽화를 일으킨다. 이 팽화는 수정체 섬유세포의 투과성을 항진하고, Na+, Cl의 유입과 K+, 아미노산, 펩티드, ATP, myo-inositol 등의 유출을 일으킨다. Na+이나 K+ 등의 전해질의 평형파괴에 의해 삼투압이 더 증가하게 되고, 세포의 팽화를 촉진하여 세포막은 정상을 유지할 수 없게 된다. 그와 동시에 세포내 단백질변성이 증가되어 수정체가 혼탁하게 되는데, 이와 같이 수정체가 혼탁해져 나타나는 백내장 증상을 당뇨성 합병증 진행과정의 한 지표로 사용한다.Among them, the polyol pathway is one of the glucose metabolism pathways, which is a pathway in which glucose is converted into fructose via sorbitol and is composed of two reaction systems, and two enzymes are known to be involved (Gabbay KH and O). Sullivan JB, Diabetes, 17, pp 239, 1968; Dvornik D. et al., Science, 182, pp 1146, 1973). Glucose is an important substance used as an energy source. After being absorbed into cells in normal people, most of them are metabolized in the corresponding system by hexokinase to glucose-6-phosphate, and only a few% are metabolized through the polyol metabolism. In diabetic hyperglycemia, however, cell membrane permeation of glucose depends on extracellular glucose concentrations in tissues where glucose uptake does not depend on insulin. Therefore, insulin such as lens, retina, cornea, peripheral nerve, blood vessels, renal glomeruli, and red blood cells Intracellular glucose concentration of non-dependent tissues is increased and glucose metabolism is enhanced by aldose reductase, an essential enzyme of polyol metabolism system, which is present in large amounts in these cells, resulting in excessive production of sorbitol. As a result, the onset symptoms appear according to the accumulation site of sorbitol, which causes diabetic complications such as cataract, diabetic retinopathy, diabetic keratosis, diabetic neurosis and diabetic nephropathy. Reduction reaction of glucose to sorbitol catalyzing aldose reductase does not occur in the equilibrium reaction, and the conversion of sorbitol to fructose is very high because the activity of sorbitol dehydrogenase is lower than that of aldose reductase. As a result, hyperolation of the polyol metabolic system will accumulate sorbitol. Since sorbitol, a sugar alcohol, has high polarity and is difficult to diffuse out of the cell membrane, sorbitol accumulates in the cell, thereby increasing intracellular osmotic pressure, thereby promoting water inflow into the lens and causing cell swelling. This swelling enhances the permeability of lens fibroblasts and causes influx of Na +, Cl and outflow of K +, amino acids, peptides, ATP, myo-inositol, and the like. Osmotic pressure is further increased by the equilibrium destruction of electrolytes such as Na + and K +, and the cell membrane is unable to maintain its normality by promoting swelling of cells. At the same time, intracellular protein denaturation increases and the lens becomes cloudy. Cataract symptoms, which appear to be clouded in the lens, are used as an indicator of the progress of diabetic complications.
따라서 솔비톨을 생성하는 효소인 알도즈 환원효소를 억제하게 되면, 솔비톨의 생성을 억제하는 물질이 당뇨성 백내장의 발병을 억제하는 것이 가능하다고 알려져 있다. 실제로, 많은 보고에 의하면, 인 비트로(in vitro) 실험에서 알도즈 환원효소를 억제하는 성분이 당뇨성 백내장의 실험모델인 galactosemic rats에서 백내장의 형성을 억제하는 것으로 밝혀졌다. Okuda 등 (Okuda J. et al., Chem. Pharm. Bull., 33, pp2990, 1985)은 알도즈 환원효소에 대한 억제 활성을 가지는 1-[(p-bromo-phenyl)-sulfonyl]hydantoin이 galactosemic rats에서의 백내장 형성을 억제하는 것을 보고하였고, 알도즈 환원효소 억제활성을 가지는 플라보노이드 성분이 당뇨성 백내장 생성억제와 관련성이 있다는 보고도 있다 (Varma S. D. and Kinoshit J. H., Biochem. Pharmacol., 25, pp2505, 1976; Parmar N. S. and Ghosh M. N., Exp. Eye. Res., 29, pp229, 1979). 또한, Shin 등 (Shin K. H. et al., Kor. J. Pharmacogn., 25, pp41, 1994)은 흰쥐 수정체로부터 제조한 알도즈 환원효소를 이용한 실험에서 황금에 함유된 플라보노이드 성분이 이 효소활성을 억제하며 동시에 galactosemic rats의 백내장 형성을 억제하는 것으로 보고하였으며, Aida 등 (Aida K. et al., Planta Med., 53, pp121, 1987)은 오랫동안 일본에서 당뇨성 신경증 치료에 사용되었던 한방약에 대하여 이들 추출물이 인 비트로 실험에서 알도즈 환원효소의 활성을 억제함을 보고하였고, 그 성분인 이소리퀴리티젠닌(Iso-liquiritigenin)이 알도즈 환원효소에 대한 강력한 억제활성을 가짐을 보고하였다 (Aida K. et al., Planta Med., 56, pp254, 1989).Therefore, it is known that by inhibiting aldose reductase, an enzyme that produces sorbitol, a substance that inhibits the production of sorbitol can suppress the development of diabetic cataract. Indeed, many reports have shown that in vitro experiments inhibit the formation of aldose reductase in galactosemic rats, an experimental model of diabetic cataracts. Okuda et al. (Okuda J. et al., Chem. Pharm. Bull., 33, pp2990, 1985) reported that galactosemic 1-[(p-bromo-phenyl) -sulfonyl] hydantoin with inhibitory activity against aldose reductase It has been reported to inhibit cataract formation in rats and that flavonoids with aldose reductase inhibitory activity have been associated with diabetic cataract suppression (Varma SD and Kinoshit JH, Biochem. Pharmacol., 25, pp2505). , 1976; Parmar NS and Ghosh MN, Exp.Eye.Res., 29, pp 229, 1979). In addition, Shin et al. (Shin KH et al., Kor. J. Pharmacogn., 25, pp41, 1994) reported that the flavonoids contained in gold inhibited the enzyme activity in experiments using aldose reductase prepared from rat lens. And at the same time reported to inhibit cataract formation in galactosemic rats. Aida et al. (Aida K. et al., Planta Med., 53, pp121, 1987) described these extracts for herbal medicines that have long been used to treat diabetic neurosis in Japan. In vitro experiments showed that the activity of aldose reductase was inhibited, and its component, iso-liquiritigenin, had a strong inhibitory activity against aldose reductase (Aida K. et. al., Planta Med., 56, pp 254, 1989).
또한, 당뇨병에서 합병증을 유발시키는 기전으로 폴리올 대사계(polyol pathway)의 이상 이외에 혈중의 과량의 당과 단백질과의 결합에 의한 단백질 당화반응(glycation)이 있다. 단백질 당화는 단백질의 아미노기와 당의 카르보닐기 사이의 반응에 의해 초기화되고, 가역적인 쉬프 염기(Schiff base)를 생성한다. 이 반응은 수 시간에 걸쳐서 이루어지며, 불안정한 구조로 형성된 쉬프 염기(Schiff base)는 더 안정한 구조인 케토아민(ketoamine) 혹은 아마도리 생성물(Amadori product)로 재배열하게 된다. 아마도리 생성물(Amadori product)의 형성은 수일간에 걸쳐서 생성되며, 생성물은 비가역적이다. 당이 결합된 단백질은 더 많은 결합을 하여 3-deoxyglucosones (3-DG)와 같은 디카보닐(dicarbonyl) 중간 생성물을 형성하고, 이를 최종당화산물 (Advanced Glycation Endproducts: 이하 간단하게 ‘AGEs’라 함)라 부른다. 생성된 AGEs는 복합체로서 단백질과 교차결합을 하고, 갈변화와 형광을 생성한다. 수많은 AGEs는 조직에서 검출되는데 크게 세 가지로 분류될 수 있다.In addition, as a mechanism for causing complications in diabetes, besides the polyol pathway, there is a protein glycation reaction due to the binding of excess sugar and protein in the blood. Protein glycosylation is initiated by the reaction between the amino group of the protein and the carbonyl group of the sugar, producing a reversible Schiff base. This reaction takes several hours, and the Schiff base, which is formed with an unstable structure, is rearranged to a more stable structure, ketoamine or Amadori product. Formation of the Amadori product occurs over several days and the product is irreversible. Sugar-bound proteins bind more to form dicarbonyl intermediates such as 3-deoxyglucosones (3-DG), which are referred to as Advanced Glycation Endproducts (hereinafter simply referred to as 'AGEs'). It is called. The resulting AGEs are complexes that crosslink with proteins, producing browning and fluorescence. Numerous AGEs are detected in tissues and can be classified into three categories.
첫째, 형광성을 띠며, 교차 결합된 AGEs로 펜트시다인(Pentosidine)과 crossline이 있다. 펜트시다인(Pentosidine)은 라이신과 아르기닌 잔기 사이에 교차결합을 형성하고, 당뇨가 유발되면 그 농도는 증가한다(McCance D. R. et al., J. Clin. Invest., 91, pp2470-2478, 1993). Crossline은 당뇨 쥐의 신장에서 처음으로 발견되었으며, 인 비트로(in vitro)와 인 비보(in vivo)에서 형성될 수 있다. First, it is fluorescent and cross-linked AGEs, such as pentosidine and crossline. Pentosidine forms a crosslink between lysine and arginine residues and increases in concentration when diabetes is induced (McCance DR et al., J. Clin. Invest., 91, pp 2470-2478, 1993). . Crossline was first discovered in the kidneys of diabetic rats and can be formed in vitro and in vivo.
둘째, 비형광성이며, 교차 결합된 AGEs로 imidazolium dilysine과 교차결합된 것과 alkyl formyl glycosyl pyrrole (AFGP) 교차결합된 것, 그리고 arginine-lysine imidazole (ALI)이 교차결합된 것이 있다. Imidazolium dilysine이 교차결합된 것은 glyoxal lysine dimer (GOLD) 혹은 methylglyoxal lysine dimer (MOLD)로 알려져 있으며, glyoxal 유도체와 lysine 잔기 사이의 반응에 의해 형성된다 (Frye E. B. et al., J. Biol. Chem., 273, pp18714-18716, 1998). Arginine-lysine imidazole (ALI)는 내부세포와 교차 결합한다(Al-Abed Y. and Bucala R., Bioconjugate Chem., 11, pp39-45, 2000).Second, non-fluorescent, cross-linked AGEs are cross-linked with imidazolium dilysine, cross-linked alkyl formyl glycosyl pyrrole (AFGP), and cross-linked arginine-lysine imidazole (ALI). Crosslinking of imidazolium dilysine is known as glyoxal lysine dimer (GOLD) or methylglyoxal lysine dimer (MOLD) and is formed by the reaction between glyoxal derivatives and lysine residues (Frye EB et al., J. Biol. Chem., 273, pp18714-18716, 1998). Arginine-lysine imidazole (ALI) cross-links with internal cells (Al-Abed Y. and Bucala R., Bioconjugate Chem., 11, pp 39-45, 2000).
세 번째, 교차결합이 없는 AGEs로 pyrraline과 N-carboxy methyllysine (CML)이 있다. Pyrraline은 교차결합이 없는 AGEs이며, 인간의 피부, 혈장, 뇌의 plaque에서 발견되며, CML은 단백질 존재 하에 다중불포화 지방산의 금속촉매에 의한 산화과정에서 아마도리 생성물(Amadori product)의 산화적 분해에 의해 형성된다. 그것은 AGEs의 주요 성분 중 하나이며, 그것의 농도는 당뇨병 환자 피부의 콜라겐에서 정상인 경우보다 두 배 증가하였다(Dyer D. G. et al., J. Clin. Invest., 91, pp2463-2469, 1993). 당뇨 합병증 발병에서 AGEs의 다른 작용은 아직 완전히 명확하게는 밝혀지지 않았다. 예를 들어 혈청에서 CML의 농도는 망막증이 있는 당뇨병 환자의 경우 증가하나 신증을 가진 환자에서는 증가하지 않았다. Pentosidine의 농도는 두 개의 군에서 모두 증가하는 것으로 나타났다.Third, non-crosslinking AGEs include pyrraline and N-carboxy methyllysine (CML). Pyrraline are cross-linked AGEs and are found in human skin, plasma and brain plaques, and CML is involved in the oxidative degradation of Amadori products during oxidation by metal catalysts of polyunsaturated fatty acids in the presence of proteins. Is formed by. It is one of the major components of AGEs, and its concentration has doubled in normal collagen in diabetic skin (Dyer D. G. et al., J. Clin. Invest., 91, pp 2463-2469, 1993). Other actions of AGEs in the development of diabetic complications are not yet fully clear. For example, the concentration of CML in serum was increased in diabetic patients with retinopathy but not in patients with nephropathy. Pentosidine levels were increased in both groups.
다만, 증가된 당화 반응과 축적된 조직 AGEs는 효소의 활성을 변화시키고, 리간드 결합을 감소시키며, 면역성을 변화시킬 수 있기 때문에 당뇨 합병증과 관련이 있다고 보고되었다(Vlassara H. and Dalace M. R., J. Intern. Med., 251, pp87-101, 2002). 이와 관련하여 최근 연구에서 당뇨병 환자에서 ACE-면역 복합체를 형성하는 혈청 AGEs의 작용에 대한 자동 항체가 존재함을 보고하였고, 그것은 아테롬성동백경화증에 중요한 역할을 한다. 당화 반응(Glycation)으로 유도된 유리 라디칼은 단백질 분해와 핵산과 지질에 산화를 야기시킬 수 있다. 또한 AGEs는 인지질에서도 형성될 수 있는데, 포스파티딜에탄올아민(phosphatidylethanolamine)과 포스파티딜세린(phosphatidylserine) 잔기와 같은 인지질에서 포도당과 아미노산 사이에 직접적인 반응에 의해서 지질 과산화를 유도할 수 있다고 알려져 있다(Vlassara H., Annal. Med., 28, pp419-426, 1996).However, increased glycosylation and accumulated tissue AGEs have been reported to be associated with diabetes complications because they can alter enzyme activity, decrease ligand binding, and alter immunity (Vlassara H. and Dalace MR, J. Intern. Med., 251, pp 87-101, 2002). In this regard, a recent study reported the existence of an automated antibody against the action of serum AGEs forming the ACE-immune complex in diabetic patients, which plays an important role in atherosclerosis. Free radicals induced by glycation can cause proteolysis and oxidation of nucleic acids and lipids. AGEs can also form in phospholipids, which are known to induce lipid peroxidation by direct reactions between glucose and amino acids in phospholipids such as phosphatidylethanolamine and phosphatidylserine residues (Vlassara H., Annal.Med., 28, pp 419-426, 1996).
당뇨병 환자에서 치료의 목적은 식이 조절에 의해 고혈당증을 감소시키는 것이다. 그러나 식이 조절은 어렵기 때문에 약리학적인 효과를 가진 화합물을 사용하여 고혈당을 저하시키고, 고혈당으로 인한 AGEs 생성을 감소시킬 수 있다. 많은 화합물들이 항 당화(glycation) 활성에 대해 연구되고 있으며, 알려진 당화 생성 억제제로는 아스피린, 아미노구아니딘, 펜아실티아졸리움 브로마이드(phenacylthiazolium bromide)와 항산화제 등이 있다. 당뇨병 환자의 경우 당화 반응과 AGEs의 생성은 자연적으로 발생하기 때문에 이것을 억제하는 억제제는 긴 반감기를 가져야 하고, 장기간 투여했을 때 독성을 나타내지 않아야 한다.The goal of treatment in diabetic patients is to reduce hyperglycemia by dietary control. However, because dietary control is difficult, compounds with pharmacological effects can be used to lower hyperglycemia and reduce the production of AGEs due to hyperglycemia. Many compounds have been studied for antiglycation activity, and known glycation inhibitors include aspirin, aminoguanidine, phenacylthiazolium bromide and antioxidants. In diabetic patients, glycation and the production of AGEs occur naturally, so inhibitors that inhibit them should have long half-lives and should not be toxic when administered for long periods.
당뇨성 합병증의 병태는 다양하며, 고혈당에 의한 것으로서 말초신경장애, 망막증, 신증, 백내장, 각막증 등이 있으며, 그 기전으로 폴리올 대사계(polyol pathway) 이상과 혈중의 과량의 당과 단백질의 결합을 들 수 있다. 폴리올 대사계(polyol pathway)는 포도당 대사경로의 하나로 포도당은 알도즈 환원효소에 의하여 솔비톨로 전환된다. 정상상태에서의 알도즈 환원효소는 포도당에 대한 기질친화성은 매우 낮아 솔비톨을 거의 생성하지 않지만, 당뇨병 상태에서는 수정체, 말초신경, 망막과 같은 인슐린 비감수성의 조직에서의 포도당 농도가 상승하면 위의 경로에 의하여 대량의 솔비톨을 생성하게 되며, 이러한 각 조직에서의 솔비톨 축적이 당뇨성 백내장, 말초신경장애, 당뇨성 망막증 등의 원인으로 알려져 있다. 또한 당뇨병의 고혈당 상태에서 당의 카보닐기와 단백질의 아미노기가 결합하여 AGEs를 생성하게 되고, 이것은 체내에 축적되어 당뇨성 망막증, 신증, 백내장, 아테롬성동맥경화와 같은 당뇨 합병증을 유발하게 된다. 그리하여 백내장 등의 당뇨성 합병증 예방 및 치료제로서 알도즈 환원효소 및 최종당화산물 생성 억제제가 주목을 받고 있으며, 이들 몇몇 억제제가 동물실험 및 임상시험에서 당뇨성 합병증을 개선함이 보고되는 등 합성물질 뿐만 아니라 천연물질로부터 알도즈 환원효소 및 최종당화산물 생성 억제성분을 규명하려는 활발한 연구가 이루어지고 있다.Diabetic complications vary and are caused by hyperglycemia, including peripheral neuropathy, retinopathy, nephropathy, cataracts, and corneal disease.The mechanisms are polyol pathway abnormalities and excess blood sugar and protein binding. Can be mentioned. The polyol pathway is one of the glucose metabolic pathways and glucose is converted to sorbitol by aldose reductase. Aldose reductase at steady state is very low in substrate affinity for glucose and rarely produces sorbitol, but in diabetic state, the glucose pathway in elevated insulin-insensitive tissues such as the lens, peripheral nerve, and retina increases. By generating a large amount of sorbitol, the accumulation of sorbitol in each of these tissues is known as the cause of diabetic cataracts, peripheral neuropathy, diabetic retinopathy. In the hyperglycemic state of diabetes, the carbonyl group of sugar and amino group of protein are combined to produce AGEs, which accumulate in the body and cause diabetic complications such as diabetic retinopathy, nephropathy, cataract and atherosclerosis. Thus, aldose reductase and final glycation inhibitors are attracting attention as agents for the prevention and treatment of diabetic complications such as cataracts, and some of these inhibitors have been reported to improve diabetic complications in animal and clinical trials. Rather, active studies have been conducted to identify aldose reductase and final glycation end product inhibitors from natural substances.
한편, 매생이 (Capsosiphon fulvescens)는 녹조류의 갈파래과에 속하고 전세계에 광범위하게 분포하며 한국에서는 남서해안지대를 따라서 자라며, 3월에서 4월경에 채집한다. 이러한 매생이는 전통적으로 특유의 향미와 부드러운 질감으로 오랫동안 기능성 식품으로 사용되어 왔으며 위장질환을 치료하거나 숙취제거에도 이용하여 왔다. 현재까지 매생이와 관련하여 항산화, 항종양, 항암, 면역증강효과, 골다공증 예방효과, 피부자극 완화효과, 멜라닌 색소 침착 억제효과, 숙취 완화 효과 및 간 보호 효과 등의 생리활성이 알려져 있으나, 다당류를 제외하고는 그 화학적 성분에 대하여서는 알려져 있지 않다.Meanwhile, prostitution ( Capsosiphon fulvescens ) belongs to the green algae of green algae and is widely distributed all over the world. It grows along the southwest coast in Korea and is collected from March to April. These falcons have traditionally been used as functional foods for a long time with their unique flavor and soft texture, and have been used to treat gastrointestinal diseases or to remove hangovers. Until now, physiological activities such as antioxidant, anti-tumor, anti-cancer, immune enhancing effect, osteoporosis prevention effect, skin irritation relieving effect, melanin pigmentation inhibitory effect, hangover relieving effect and liver protection effect have been known. The chemical composition is unknown.
이에 본 발명자들은 매생이를 이용한 기능성 약제학적 또는 식품학적 소재를 연구하던 중, 매생이 추출물 또는 이들로부터 분리된 화합물(capsofulvesin A, capsofulvesin B, chalinasterol)이 알도즈 환원효소 억제 활성을 가질 뿐만 아니라, 최종당화생성물(AGEs) 억제 활성을 가짐에 따라 당뇨성 합병증의 예방, 개선 또는 치료에 유용함을 확인함으로써 본 발명을 완성하였다. The inventors of the present invention, while studying the functional pharmaceutical or food material using the maeseng, the extracts or the compounds isolated from them (capsofulvesin A, capsofulvesin B, chalinasterol) not only have the aldose reductase inhibitory activity, but also the final glycosylation The present invention was completed by confirming that the products (AGEs) have an inhibitory activity and are useful for the prevention, improvement or treatment of diabetic complications.
따라서 본 발명의 목적은 매생이 추출물을 유효성분으로 포함하는 당뇨성 합병증 예방 또는 치료용 약제학적 조성물을 제공하는 것이다.Therefore, it is an object of the present invention to provide a pharmaceutical composition for preventing or treating diabetic complications, which comprises extract as an active ingredient.
또한 본 발명의 다른 목적은 매생이 추출물로부터 분리된 화합물 또는 이의 약제학적으로 허용 가능한 염을 유효성분으로 포함하는 당뇨성 합병증 예방 또는 치료용 약제학적 조성물을 제공하는 것이다.It is another object of the present invention to provide a pharmaceutical composition for preventing or treating diabetic complications, which comprises a compound or a pharmaceutically acceptable salt thereof isolated from an extract persimmon.
본 발명의 또 다른 목적은 매생이 추출물 또는 이로부터 분리된 화합물을 유효성분으로 포함하는 당뇨성 합병증의 예방 또는 개선용 건강기능식품을 제공하는 것이다.Still another object of the present invention is to provide a dietary supplement for preventing or improving diabetic complications, which comprises extracts or compounds isolated from it, as an active ingredient.
상기와 같은 본 발명의 목적을 달성하기 위해서, 본 발명은 매생이 추출물을 유효성분으로 포함하는 당뇨성 합병증 예방 또는 치료용 약제학적 조성물을 제공한다.In order to achieve the object of the present invention as described above, the present invention provides a pharmaceutical composition for the prevention or treatment of diabetic complications including the extract as an active ingredient.
본 발명의 일실시예에 있어서, 상기 추출물은 매생이 조추출물 또는 매생이 비극성용매 가용 추출물일 수 있다.In one embodiment of the present invention, the extract may be a crude extract of a falcon or a non-polar solvent soluble extract.
본 발명의 일실시예에 있어서, 상기 매생이 조추출물은 물, 에탄올, 메탄올, 부탄올 또는 이들의 혼합용매를 이용하여 추출한 추출물일 수 있다.In one embodiment of the present invention, the crude extract may be an extract extracted using water, ethanol, methanol, butanol or a mixed solvent thereof.
본 발명의 일실시예에 있어서, 상기 매생이 비극성용매 가용 추출물은 디클로로메탄, 클로로포름, 에틸아세테이트, 부탄올 또는 이들의 혼합용매를 이용하여 추출한 추출물일 수 있다.In one embodiment of the present invention, the medicinal non-polar solvent soluble extract may be an extract extracted using dichloromethane, chloroform, ethyl acetate, butanol or a mixed solvent thereof.
본 발명의 일실시예에 있어서, 상기 조성물은 알도즈 환원효소 억제 활성 및 최종당화생성물 억제 활성을 통해 당뇨성 합병증 치료 효과를 가질 수 있다.In one embodiment of the present invention, the composition may have a therapeutic effect on diabetic complications through aldose reductase inhibitory activity and final glycation product inhibitory activity.
본 발명의 일실시예에 있어서, 상기 당뇨성 합병증은 당뇨성 망막병증, 당뇨성 녹내장, 당뇨성 백내장, 당뇨성 신증 및 당뇨성 신경병증으로 이루어진 군으로부터 선택될 수 있다.In one embodiment of the present invention, the diabetic complications may be selected from the group consisting of diabetic retinopathy, diabetic glaucoma, diabetic cataract, diabetic nephropathy and diabetic neuropathy.
또한, 본 발명은 카프소플베신 A(capsofulvesin A), 카프소플베신 B(capsofulvesin B) 및 카리나스테롤(chalinasterol)로 이루어진 군으로부터 선택되는 어느 하나의 화합물 또는 이의 약제학적으로 허용 가능한 염을 유효성분으로 포함하는 당뇨성 합병증 예방 또는 치료용 약제학적 조성물을 제공한다.In addition, the present invention is any one compound selected from the group consisting of capsofulvesin A, capsofulvesin B and carinasterol or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a pharmaceutical composition for preventing or treating diabetic complications comprising.
본 발명의 일실시예에 있어서, 상기 화합물은 매생이 추출물로부터 분리될 수 있다.In one embodiment of the invention, the compound may be isolated from the extract every single life.
본 발명의 일실시예에 있어서, 상기 화합물은 건조된 매생이 분말에 메탄올을 넣어 환류냉각추출한 후 여과하여 매생이 조추출물을 수득하는 단계; 수득한 매생이 조추출물에 디클로로메탄을 가하여 혼합 후 분획하여 매생이 디클로로메탄 가용 추출물을 수득하는 단계; 수득한 매생이 디클로로메탄 가용 추출물을 전개용매로서 디클로로메탄과 메탄올의 혼합용매를 사용하여 칼럼 크로마토그래피를 수행하여 분획하는 단계; 및 상기 분획물에 다시 디클로로메탄과 메탄올의 혼합용매를 가하여 칼럼 크로마토그래피를 수행하는 단계를 포함하는 과정을 통하여 제조될 수 있다.In one embodiment of the present invention, the compound is a step of drying refrigeration extract methanol extract refrigeration cooling and then filtered to obtain the crude extract crude extract; Dichloromethane obtained by adding dichloromethane to the crude extract obtained by mixing and fractionation to obtain a soluble extract of dichloromethane; Fractionating dichloromethane soluble extract obtained by performing column chromatography using a mixed solvent of dichloromethane and methanol as a developing solvent; And adding a mixed solvent of dichloromethane and methanol to the fraction again to perform column chromatography.
본 발명의 일실시예에 있어서, 상기 조성물은 알도즈 환원효소 억제 활성을 통해 당뇨성 합병증 치료 효과를 가지는 것을 특징으로 하는 당뇨성 합병증 예방 또는 치료용 조성물일 수 있다.In one embodiment of the present invention, the composition may be a composition for preventing or treating diabetic complications, characterized in that it has a therapeutic effect of diabetic complications through aldose reductase inhibitory activity.
본 발명의 일실시예에 있어서, 상기 당뇨성 합병증은 당뇨성 망막병증, 당뇨성 녹내장, 당뇨성 백내장, 당뇨성 신증 및 당뇨성 신경병증으로 이루어진 군으로부터 선택될 수 있다.In one embodiment of the present invention, the diabetic complications may be selected from the group consisting of diabetic retinopathy, diabetic glaucoma, diabetic cataract, diabetic nephropathy and diabetic neuropathy.
또한, 본 발명은 매생이 추출물 또는 이로부터 분리된 카프소플베신 A(capsofulvesin A), 카프소플베신 B(capsofulvesin B) 및 카리나스테롤(chalinasterol)로 이루어진 군으로부터 선택되는 어느 하나의 화합물을 유효성분으로 포함하는 당뇨성 합병증의 예방 또는 개선용 건강기능식품을 제공한다.In addition, the present invention includes any one compound selected from the group consisting of capsofulvesin A (capsofulvesin A), capsofulvesin B (carsosterol) and carinasterol isolated from the extract every day To provide a dietary supplement for the prevention or improvement of diabetic complications.
본 발명의 일실시예에 있어서, 상기 매생이 추출물은 매생이 조추출물 또는 매생이 비극성용매 가용 추출물일 수 있다.In one embodiment of the present invention, the extract of the falconus may be a crude extract of the falcon or the non-polar solvent soluble extract.
본 발명의 일실시예에 있어서, 상기 당뇨성 합병증은 당뇨성 망막병증, 당뇨성 녹내장, 당뇨성 백내장, 당뇨성 신증 및 당뇨성 신경병증으로 이루어진 군으로부터 선택될 수 있다.In one embodiment of the present invention, the diabetic complications may be selected from the group consisting of diabetic retinopathy, diabetic glaucoma, diabetic cataract, diabetic nephropathy and diabetic neuropathy.
본 발명의 일실시예에 있어서, 상기 식품은 음료류, 육류, 초코렛, 식품류, 과자류, 피자, 라면, 기타 면류, 껌류, 사탕류, 아이스크림류, 알코올 음료류, 비타민 복합제 및 건강보조식품류로 이루어진 군으로부터 선택될 수 있다.In one embodiment of the present invention, the food is selected from the group consisting of beverage, meat, chocolate, foods, confectionery, pizza, ram noodles, gums, candy, ice cream, alcoholic beverages, .
본 발명의 매생이 추출물 또는 이로부터 분리된 화합물(capsofulvesin A, capsofulvesin B, chalinasterol)은 알도즈 환원효소 억제 활성이 뛰어날 뿐만 아니라, 최종당화생성물 억제 활성이 우수하다. 따라서 본 발명의 매생이 추출물 또는 이로부터 분리된 화합물은 당뇨성 합병증을 예방 또는 치료할 수 있는 물질로서 약리학적 조성물과 같은 의약품은 물론이고, 건강기능식품 등으로 활용할 수 있어 식품산업 및 의약산업에 응용될 경우 그 가치가 매우 높을 것으로 기대된다. 특히 본 발명의 매생이 추출물 또는 이로부터 분리된 화합물은 천연물로부터 유래된 물질로서, 세포독성 없이 안정성을 가지므로, 이를 유효성분으로 포함하는 본 발명의 조성물은 장기적 사용에도 안전한 이점을 가진다.The extracts or the compounds isolated from them (capsofulvesin A, capsofulvesin B, chalinasterol) of the present invention not only have an excellent aldose reductase inhibitory activity, but also have an excellent inhibitory activity on the final glycation product. Therefore, the extracts or the compounds isolated from the falcons of the present invention can be used as foods and pharmaceutical industries as well as pharmaceuticals, such as pharmacological compositions, as well as health functional foods as a substance that can prevent or treat diabetic complications. The value is expected to be very high. In particular, the extracts or the compounds isolated therefrom of the present invention is a material derived from natural products, and because they have stability without cytotoxicity, the composition of the present invention comprising them as an active ingredient has a safe advantage even for long-term use.
본 발명은 매생이 추출물의 당뇨성 합병증 예방 또는 치료의 신규 용도에 관한 것으로서, 매생이 추출물을 유효성분으로 포함하는 당뇨성 합병증 예방 또는 치료용 약제학적 조성물을 제공함에 그 특징이 있다.The present invention relates to a novel use of the prophylactic or diabetic complications of the extract of Maesan, which is characterized by providing a pharmaceutical composition for the prevention or treatment of diabetic complications comprising the extract as an active ingredient.
본 발명의‘매생이(Capsosiphon fulvescens)’는 녹조류의 갈파래과에 속하고 전세계에 광범위하게 분포하며 한국에서는 남서해안지대를 따라서 자라며, 3월에서 4월경에 채집한다. 이러한 매생이는 전통적으로 특유의 향미와 부드러운 질감으로 오랫동안 기능성 식품으로 사용되어 왔으며 위장질환을 치료하거나 숙취제거에도 이용하여 왔다. Capsosiphon of the present invention fulvescens ) belongs to the green algae of green algae and is widely distributed all over the world. It grows along the southwest coast in Korea and is collected around March to April. These falcons have traditionally been used as functional foods for a long time with their unique flavor and soft texture, and have been used to treat gastrointestinal diseases or to remove hangovers.
현재까지 매생이와 관련하여 항산화, 항종양, 항암, 면역증강효과, 골다공증 예방효과, 피부자극 완화효과, 멜라닌 색소 침착 억제효과, 숙취 완화 효과 및 간 보호 효과 등의 생리활성이 알려져 있으나, 다당류를 제외하고는 그 화학적 성분에 대하여서는 알려져 있지 않다.Until now, physiological activities such as antioxidant, anti-tumor, anti-cancer, immune enhancing effect, osteoporosis prevention effect, skin irritation relieving effect, melanin pigmentation inhibitory effect, hangover relieving effect and liver protection effect have been known. The chemical composition is unknown.
본 발명자들은 상기와 같은 특징을 갖는 매생이 추출물 또는 이들로부터 분리된 화합물(capsofulvesin A, capsofulvesin B, chalinasterol)이 알도즈 환원효소 억제 활성을 가질 뿐만 아니라, 최종당화생성물(AGEs) 억제 활성을 가짐을 확인함으로써, 이를 통해 당뇨성 합병증을 예방 또는 치료할 수 있는 물질로서 약리학적 조성물과 같은 의약품은 물론이고, 건강기능식품 등으로 활용할 수 있다는 사실을 최초로 규명하였다.The present inventors confirmed that the extracts or the compounds isolated from them (capsofulvesin A, capsofulvesin B, chalinasterol) having the above characteristics not only have aldose reductase inhibitory activity, but also have a final glycosylation product (AGEs) inhibitory activity. By doing so, it was first identified that a substance capable of preventing or treating diabetic complications could be used as a pharmacological composition, as well as a health functional food.
본 발명의 하기 실험예 1에서는, 매생이 조추출물 및 각 용매 분획물의 랫드 렌즈 알도즈 환원효소 (RLAR) 억제활성을 살펴본 결과, 매생이 조추출물 및 각 용매 분획물이 모두 알도즈 환원효소 억제활성을 가지는 것을 확인할 수 있었으며, 특히 매생이 에틸아세테이트 가용성 분획물이 IC50(μg/ml) 값이 20.61±0.36로 나타나, 가장 효과가 좋은 것을 알 수 있었다.In Experimental Example 1 of the present invention, as a result of looking at the rat lens aldose reductase (RLAR) inhibitory activity of the crude extract and each solvent fraction, it was found that the crude extract and each solvent fraction had both aldose reductase inhibitory activity In particular, the ethyl acetate soluble fraction was found to be 20.61 ± 0.36 of the ethyl acetate soluble fraction, which was the most effective.
또한 본 발명의 하기 실험예 3에서는, 매생이 조추출물 및 각 용매 분획물의 최종당화산물 생성 억제 활성을 살펴본 결과, 본 발명의 매생이 조추출물 및 각 용매 분획물이 모두 최종당화생성물 억제활성을 가지는 것을 확인할 수 있었으며, 특히 매생이 부탄올 가용성 분획물이 IC50(μg/ml) 값이 96.65±0.26로 나타나, 가장 효과가 좋은 것으로 나타났다.In addition, in Experimental Example 3 of the present invention, as a result of looking at the activity of inhibiting the production of the final glycosylated product of the crude extract and each solvent fraction, it can be confirmed that the crude extract and each solvent fraction of the present invention all have the final glycation inhibitory activity In particular, butanol soluble fraction showed the best effect, with IC50 (μg / ml) value of 96.65 ± 0.26.
이와 같은 결과를 통해, 본 발명자들은 매생이 추출물이 알도즈 환원효소 억제 활성이 뛰어날 뿐만 아니라, 최종당화생성물 억제 활성이 우수하다는 사실을 실험적으로 입증하였다.Through these results, the present inventors have experimentally proved that the extract of the falciparum is not only excellent in the aldose reductase inhibitory activity, but also excellent in the final glycation product inhibitory activity.
그러므로 매생이 추출물을 유효성분으로 포함하는 본 발명의 조성물은 당뇨성 합병증을 효과적으로 예방 또는 치료할 수 있다.Therefore, the composition of the present invention containing the extract as an active ingredient can effectively prevent or treat diabetic complications.
본 발명에 따른 매생이 추출물은 당업계에 공지된 추출 및 분리하는 방법을 사용하여 천연으로부터 추출 및 분리하여 수득한 것을 사용할 수 있으며, 본 발명에서 정의된‘추출물’은 적절한 용매를 이용하여 매생이로부터 추출한 것이며, 예를 들어, 매생이의 조추출물, 극성용매 가용 추출물 또는 비극성용매 가용 추출물을 모두 포함한다. 바람직하게는 건조된 매생이의 조추출물 또는 비극성용매 가용 추출물일 수 있다.According to the present invention can be used for extracting and extracting from the natural using the extract and separation method known in the art, 'extract' as defined in the present invention is extracted from the maestro using a suitable solvent For example, it includes all crude extracts of falcons, polar solvent soluble extracts or nonpolar solvent soluble extracts. Preferably, it may be a crude extract of dried pericarp or a nonpolar solvent soluble extract.
상기 매생이로부터 추출물을 추출하기 위한 적절한 용매로는 약제학적으로 허용되는 유기용매라면 어느 것을 사용해도 무방하며, 물 또는 유기용매를 사용할 수 있으며, 이에 제한되지는 않으나, 예를 들어, 정제수, 메탄올(methanol), 에탄올(ethanol), 프로판올(propanol), 이소프로판올(isopropanol), 부탄올(butanol) 등을 포함하는 탄소수 1 내지 4의 알코올, 아세톤(acetone), 에테르(ether), 벤젠(benzene), 클로로포름(chloroform), 에틸아세테이트(ethyl acetate), 메틸렌클로라이드(methylene chloride), 헥산(hexane) 및 시클로헥산(cyclohexane) 등의 각종 용매를 단독으로 혹은 혼합하여 사용할 수 있다.As a suitable solvent for extracting the extract from the falconus, any pharmaceutically acceptable organic solvent may be used, and water or an organic solvent may be used, but is not limited thereto. For example, purified water, methanol ( alcohols having 1 to 4 carbon atoms, acetone, ether, benzene, chloroform (including methanol, ethanol, propanol, isopropanol, butanol, etc.) Various solvents such as chloroform, ethyl acetate, methylene chloride, hexane and cyclohexane may be used alone or in combination.
본 발명의 일 실시예에서, 본 발명의 매생이 추출물이 매생이 조추출물인 경우 물, 에탄올, 메탄올, 부탄올 또는 이들의 혼합용매를 이용하여 추출할 수 있다.In one embodiment of the present invention, when the extract of the falsity of the present invention is a crude extract of the essence can be extracted using water, ethanol, methanol, butanol or a mixed solvent thereof.
본 발명의 또 다른 실시예에서, 본 발명의 매생이 추출물이 매생이 비극성용매 가용 추출물인 경우 디클로로메탄, 클로로포름, 에틸아세테이트, 부탄올 또는 이들의 혼합용매를 이용하여 추출할 수 있다.In another embodiment of the present invention, if the extract of the falsity of the present invention is a non-polar solvent soluble extract can be extracted using dichloromethane, chloroform, ethyl acetate, butanol or a mixed solvent thereof.
추출 방법으로는 열수추출법, 냉침추출법, 환류냉각추출법, 용매추출법, 수증기증류법, 초음파추출법, 용출법, 압착법 등의 방법 중 어느 하나를 선택하여 사용할 수 있다. 또한, 목적하는 추출물은 추가로 통상의 분획 공정을 수행할 수도 있으며, 통상의 정제 방법을 이용하여 정제될 수도 있다. 본 발명의 매생이 추출물의 제조방법에는 제한이 없으며, 공지되어 있는 어떠한 방법도 이용될 수 있다.As the extraction method, any one of the methods such as hot water extraction method, cold extraction method, reflux cooling extraction method, solvent extraction method, steam distillation method, ultrasonic extraction method, elution method and compression method can be selected and used. In addition, the desired extract may be further subjected to a conventional fractionation process or may be purified using a conventional purification method. There is no limitation on the preparation method of the falsity extract of the present invention, any known method may be used.
예를 들면, 본 발명의 조성물에 포함되는 매생이 추출물은 상기한 열수 추출 또는 용매 추출법으로 추출된 1차 추출물을, 감압 증류 및 동결 건조 또는 분무 건조 등과 같은 추가적인 과정에 의해 분말 상태로 제조할 수 있다. 또한 상기 1차 추출물을 실리카겔 컬럼 크로마토그래피(silica gel column chromatography), 박층 크로마토그래피(thin layer chromatography), 고성능 액체 크로마토그래피(high performance liquid chromatography) 등과 같은 다양한 크로마토그래피를 이용하여 추가로 정제된 분획을 얻을 수도 있다.For example, the medicinal herb extract included in the composition of the present invention may be prepared in a powder state by additional processes such as distillation under reduced pressure and freeze drying or spray drying, which are extracted by the hydrothermal extraction or solvent extraction. . Further, the primary extract can be further purified by using various chromatographies such as silica gel column chromatography, thin layer chromatography, high performance liquid chromatography and the like, You can get it.
따라서 본 발명에 있어서 매생이 추출물은 추출, 분획 또는 정제의 각 단계에서 얻어지는 모든 추출액, 분획 및 정제물, 그들의 희석액, 농축액 또는 건조물을 모두 포함하는 개념이다.Therefore, in the present invention, the maesengyi extract is a concept that includes all the extracts, fractions and purified products obtained in each step of extraction, fractions or purification, their dilutions, concentrates or dried products.
본 발명의 일실시예에 따른 매생이 추출물을 제조하는 방법을 조금 더 구체적으로 살펴보면 다음과 같다.Looking more specifically at the method for producing an extract of Maesung according to an embodiment of the present invention.
먼저, 본 발명의 매생이 조추출물은 건조된 매생이를 분쇄하여 분말화한 후, 상기 분말에 메탄올을 첨가하여 3회 반복하여 환류냉각추출하고 여지로 감압 여과한 다음, 이러한 여과 추출물을 진공에서 증발시켜 건조된 파우더로 제조하는 과정을 거쳐 매생이 추출물을 수득할 수 있다.First, the crude extracts of the falsary saplings of the present invention are pulverized by drying the dried medicinal saplings, and then, methanol is added to the powder, and the mixture is reflux-cooled three times, filtered under reduced pressure, and the filtrate is evaporated under vacuum. Through the process of manufacturing the dried powder may be obtained extract perilla.
또한, 본 발명의 매생이 비극성용매 가용 추출물은 상기 매생이 조추출물 추출과정에서 얻은 수가용성 분획물에 비극성용매를 첨가하여 다시 수가용성 분획물 및 비극성용매 가용 분획물을 얻어, 이 중 비극성용매 가용 분획물을 건조하는 과정을 통하여 매생이 비극성용매 가용 추출물을 수득할 수 있다.In addition, the falsified non-polar solvent soluble extract of the present invention is obtained by adding the non-polar solvent to the water-soluble fraction obtained during the crude extract extraction process to obtain the water-soluble fraction and the soluble fraction of the non-polar solvent, the process of drying the soluble fraction of the non-polar solvent Through this can be obtained a non-polar solvent soluble extract.
본 발명의 조성물은 상기 매생이 추출물을 유효성분으로 포함하는 약제학적 조성물로서 이러한 유효성분 이외에 약제학적으로 적합하고 생리학적으로 허용되는 보조제를 사용하여 제조될 수 있으며, 상기 보조제로는 부형제, 붕해제, 감미제, 결합제, 피복제, 팽창제, 윤활제, 활택제 또는 향미제 등을 사용할 수 있다.The composition of the present invention can be prepared using a pharmaceutically acceptable and physiologically acceptable adjuvant in addition to such an active ingredient as a pharmaceutical composition comprising the extract as an active ingredient, the adjuvant, excipients, disintegrants, Sweetening agents, binders, coatings, expanding agents, lubricants, lubricants, or flavoring agents may be used.
상기 약제학적 조성물은 투여를 위해서 상기 기재한 유효성분 이외에 추가로 약제학적으로 허용 가능한 담체를 1종 이상 포함하여 약제학적 조성물로 바람직하게 제제화할 수 있다.The pharmaceutical composition may be formulated into a pharmaceutical composition containing at least one pharmaceutically acceptable carrier in addition to the above-described active ingredients for administration.
상기 약제학적 조성물의 제제 형태는 과립제, 산제, 정제, 피복정, 캡슐제, 좌제, 액제, 시럽, 즙, 현탁제, 유제, 점적제 또는 주사 가능한 액제 등이 될 수 있다. 예를 들어, 정제 또는 캡슐제의 형태로의 제제화를 위해, 유효 성분은 에탄올, 글리세롤, 물 등과 같은 경구, 무독성의 약제학적으로 허용 가능한 불활성 담체와 결합될 수 있다. 또한, 원하거나 필요한 경우, 적합한 결합제, 윤활제, 붕해제 및 발색제 또한 혼합물로 포함될 수 있다. 적합한 결합제는 이에 제한되는 것은 아니나, 녹말, 젤라틴, 글루코스 또는 베타-락토오스와 같은 천연 당, 옥수수 감미제, 아카시아, 트래커캔스 또는 소듐올레이트와 같은 천연 및 합성 검, 소듐 스테아레이트, 마그네슘 스테아레이트, 소듐 벤조에이트, 소듐 아세테이트, 소듐 클로라이드 등을 포함한다. 붕해제는 이에 제한되는 것은 아니나, 녹말, 메틸 셀룰로스, 아가, 벤토니트, 잔탄 검 등을 포함한다. 액상 용액으로 제제화되는 조성물에 있어서 허용 가능한 약제학적 담체로는, 멸균 및 생체에 적합한 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사용액, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 더 나아가 해당분야의 적절한 방법으로 Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화 할 수 있다.The pharmaceutical composition may be in the form of granules, powders, tablets, coated tablets, capsules, suppositories, liquids, syrups, juices, suspensions, emulsions, drops or injectable solutions. For example, for formulation into tablets or capsules, the active ingredient may be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Also, if desired or necessary, suitable binders, lubricants, disintegrants and coloring agents may also be included as a mixture. Suitable binders include but are not limited to natural and synthetic gums such as starch, gelatin, glucose or beta-lactose, corn sweeteners, acacia, trackercance or sodium oleate, sodium stearate, magnesium stearate, sodium Benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Acceptable pharmaceutical carriers for compositions that are formulated into a liquid solution include sterile water and sterile water suitable for the living body such as saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, One or more of these components may be mixed and used. If necessary, other conventional additives such as an antioxidant, a buffer, and a bacteriostatic agent may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Further, it can be suitably formulated according to each disease or ingredient, using the method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA as an appropriate method in the field.
본 발명의 일실시예에 있어서, 본 발명의 매생이 추출물은 조성물에 10 내지 1000μg/ml의 농도로 포함될 수 있으며, 또한 본 발명의 매생이 추출물은 조성물 총 중량에 대하여 0.1 ~ 95중량%로 포함될 수 있다.In one embodiment of the present invention, the perennial extract of the present invention may be included in the composition in a concentration of 10 to 1000μg / ml, and also the perennial extract of the present invention may be included in 0.1 to 95% by weight relative to the total weight of the composition. .
본 발명의 약제학적 조성물이 치료효과를 나타낼 수 있는 당뇨성 합병증으로는, 당뇨성 망막병증, 당뇨성 녹내장, 당뇨성 백내장, 당뇨성 신증 및 당뇨성 신경병증 등을 들 수 있되, 이에 한정되는 것은 아니다.
Examples of diabetic complications in which the pharmaceutical composition of the present invention may have a therapeutic effect include diabetic retinopathy, diabetic glaucoma, diabetic cataract, diabetic nephropathy, and diabetic neuropathy, but are not limited thereto. no.
또한, 본 발명은 하기 화학식 1 내지 3 중 어느 하나의 화합물 또는 이의 약제학적으로 허용 가능한 염을 유효성분으로 포함하는 당뇨성 합병증 예방 또는 치료용 약제학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing or treating diabetic complications comprising the compound of any one of the following Chemical Formulas 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 ‘카프소플베신 A(capsofulvesin A)’는 당지질의 일종으로 (2S)-1-O-(6z,9z,12z,15z-octadecatetraenoyl)-2-O-(4z,7z,10z,13z-hexadecatetraenoyl)-3-O-β-D-galacatopyranosyl glycerol로 나타낼 수 있으며, 분자식은 C43H66O10이다(화학식 1 참조).'Capsofulvesin A' of the present invention is a kind of glycolipid (2S) -1-O- (6z, 9z, 12z, 15z-octadecatetraenoyl) -2-O- (4z, 7z, 10z, 13z -hexadecatetraenoyl) -3-O-β-D-galacatopyranosyl glycerol, the molecular formula is C 43 H 66 O 10 (see Formula 1).
본 발명의 ‘카프소플베신 B(capsofulvesin B)’는 당지질의 일종으로 (2S)-l-O-(9z,12z,15z-octadecatrienoyl)-2-O-(7z,10z,13z-hexadecatrienoyl)-3-O-β-D-galactopyranosyl glycerol로 나타낼 수 있으며, 분자식은 C43H70O10이다(화학식 2 참조).Capsofulvesin B of the present invention is a type of glycolipid (2S) -lO- (9z, 12z, 15z-octadecatrienoyl) -2-O- (7z, 10z, 13z-hexadecatrienoyl) -3- O-β-D-galactopyranosyl glycerol, the molecular formula is C 43 H 70 O 10 (see Formula 2).
본 발명의 ‘카리나스테롤(chalinasterol)’은 Ostreasterol; 24-methylene-Cholesterol; 24-methylencholesterol 등으로 나타낼 수 있으며, 분자식은 C28H46O이다(화학식 3 참조).Carinasterol of the present invention is Ostreasterol; 24-methylene-Cholesterol; 24-methylencholesterol and the like, the molecular formula is C 28 H 46 O (see Formula 3).
본 발명에 따른 상기 화학식 1 내지 3의 화합물은 당업계에 공지된 추출 및 분리하는 방법을 사용하여 천연으로부터 추출 및 분리하여 수득할 수 있으며, 본 발명의 일 구체예에서는 매생이 추출물로부터 분리된 것일 수 있다.Compounds of Formulas 1 to 3 according to the present invention may be obtained by extraction and separation from nature using extraction and separation methods known in the art, in one embodiment of the present invention may be one that is isolated from the extract have.
본 발명에 따른 상기 화합물은 염, 바람직하게는 약학적으로 허용 가능한 염의 형태로 사용될 수 있는데, 상기 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의하여 형성된 산 부가염이 바람직하며, 상기 유리산으로는 유기산과 무기산을 사용할 수 있다. 상기 유기산은 이에 제한되는 것은 아니나, 구연산, 초산, 젖산, 주석산, 말레인산, 푸마르산, 포름산, 프로피온산, 옥살산, 트리플로오로아세트산, 벤조산, 글루콘산, 메타술폰산, 글리콜산, 숙신산, 4-톨루엔술폰산, 글루탐산 및 아스파르트산을 포함한다. 또한 상기 무기산은 이에 제한되는 것은 아니나, 염산, 브롬산, 황산 및 인산을 포함한다.The compound according to the present invention may be used in the form of a salt, preferably a pharmaceutically acceptable salt, wherein the salt is preferably an acid addition salt formed by a pharmaceutically acceptable free acid. Organic acids and inorganic acids can be used as the free acid. The organic acids include, but are not limited to, citric, acetic, lactic, tartaric, maleic, fumaric, formic, propionic, oxalic, trifluroacetic, benzoic, gluconic, methosulfonic, glycolic, succinic, Glutamic acid and aspartic acid. The inorganic acid includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid, and phosphoric acid.
또한, 본 발명에 따른 화합물(capsofulvesin A, capsofulvesin B, chalinasterol)은 천연으로부터 분리되거나 또는 당업계에 공지된 화학적 합성법으로 제조하여 사용할 수 있으며, 시중에서 판매되는 것을 사용할 수도 있다.In addition, the compounds according to the present invention (capsofulvesin A, capsofulvesin B, chalinasterol) may be isolated from nature or prepared by chemical synthesis known in the art, and may be commercially available.
본 발명의 화합물(capsofulvesin A, capsofulvesin B, chalinasterol)을 천연으로부터 분리할 경우, 종래의 물질을 추출 및 분리하는 방법을 사용하여 상기 화합물을 함유하고 있는 모든 종류의 식물로부터 수득할 수 있는데, 즉, 적절한 용매를 사용하여 식물(예, 매생이)의 추출물을 수득한 다음, 본 발명이 속하는 기술분야의 당업자에게 알려진 정제 방법을 이용하여 상기 추출물로부터 화합물을 정제할 수 있다. When the compound of the present invention (capsofulvesin A, capsofulvesin B, chalinasterol) is separated from nature, it can be obtained from all kinds of plants containing the compound by using a method of extracting and separating conventional substances, that is, Extracts of plants (eg, falcons) can be obtained using appropriate solvents and then the compounds can be purified from the extracts using purification methods known to those skilled in the art.
또한, 상기 추출을 위한 적절한 용매로는 물 또는 유기용매를 사용할 수 있으며, 바람직하게는 정제수, 메탄올(methanol), 에탄올(ethanol), 프로판올(propanol), 이소프로판올(isopropanol), 부탄올(butanol), 아세톤(acetone), 에테르(ether), 벤젠(benzene), 클로로포름(chloroform), 에틸아세테이트(ethyl acetate), 메틸렌클로라이드(methylene chloride), 헥산(hexane) 및 시클로헥산(cyclohexane) 등의 각종 용매를 단독으로 혹은 혼합하여 사용할 수 있다.Examples of suitable solvents for the extraction include water or an organic solvent. Preferred examples of the solvent include purified water, methanol, ethanol, propanol, isopropanol, butanol, acetone it is possible to use various solvents such as acetone, ether, benzene, chloroform, ethyl acetate, methylene chloride, hexane and cyclohexane, Or may be used in combination.
또한, 상기 식물(예, 매생이) 추출물로부터 상기 화합물(capsofulvesin A, capsofulvesin B, chalinasterol)의 분리 및 정제는 실리카겔(silica gel)이나 활성 알루미나(alumina)등의 각종 합성수지를 충진한 컬럼 크로마토그래피(column chromatography) 및 고속액체크로마토그래피(HPLC) 등을 단독으로 혹은 병행하여 사용할 수 있다. 그러나 유효성분의 추출 및 분리정제 방법은 반드시 상기한 방법에 한정되는 것은 아니다.In addition, the separation and purification of the compounds (capsofulvesin A, capsofulvesin B, chalinasterol) from the extract of the plant (eg, perennial) is performed by column chromatography filled with various synthetic resins such as silica gel or activated alumina. chromatography), high performance liquid chromatography (HPLC) and the like can be used alone or in combination. However, the method of extracting and separating and purifying the active ingredient is not necessarily limited to the above-mentioned method.
본 발명의 일실시예에 따르면, (a) 건조된 매생이 분말에 메탄올을 넣어 환류냉각추출한 후 여과하여 매생이 조추출물을 수득하는 단계; (b) 수득한 매생이 조추출물에 디클로로메탄을 가하여 혼합 후 분획하여 매생이 디클로로메탄 가용 추출물을 수득하는 단계; (c) 수득한 매생이 디클로로메탄 가용 추출물을 전개용매로서 디클로로메탄과 메탄올의 혼합용매를 사용하여 칼럼 크로마토그래피를 수행하여 분획하는 단계; 및 (d) 상기 분획물에 다시 디클로로메탄과 메탄올의 혼합용매를 가하여 칼럼 크로마토그래피를 수행하는 단계를 포함하는 과정을 통하여 본 발명의 상기 화합물(capsofulvesin A, capsofulvesin B, chalinasterol)을 분리할 수 있다.According to one embodiment of the present invention, (a) drying the refractory to methanol and reflux extraction by putting methanol in the powder to obtain the crude extract by the fibrils; (b) adding dichloromethane to the crude extract obtained by mixing dichloromethane and fractionating the mixture to obtain a dichloromethane soluble extract; (c) fractionating the obtained dichloromethane soluble extract by column chromatography using a mixed solvent of dichloromethane and methanol as a developing solvent; And (d) adding the mixed solvent of dichloromethane and methanol to the fraction again to perform column chromatography to separate the compounds of the present invention (capsofulvesin A, capsofulvesin B, chalinasterol).
한편, 현재까지 카프소플베신 A (capsofulvesin A), 카프소플베신 B (capsofulvesin B) 및 카리나스테롤 (chalinasterol)이 당뇨성 합병증 치료에 효과를 가진다는 내용에 대해서는 전혀 보고된 바가 없다.On the other hand, to date, capsofulvesin A (capsofulvesin A), capsofulvesin B (capsofulvesin B) and carinasterol (chalinasterol) has not been reported to have any effect on the treatment of diabetic complications.
본 발명자들은 매생이 추출물로부터 분리된 화합물인 카프소플베신 A (capsofulvesin A), 카프소플베신 B (capsofulvesin B) 및 카리나스테롤 (chalinasterol) 각각이 알도즈 환원효소 억제 활성을 가짐을 확인함으로써, 이를 통해 당뇨성 합병증을 예방 또는 치료할 수 있는 화합물로서 약리학적 조성물과 같은 의약품은 물론이고, 건강기능식품 등으로 활용할 수 있다는 사실을 최초로 규명하였다.The present inventors confirmed that each of capsofulvesin A, capsofulvesin B, and carinasterol, which are compounds isolated from the extract, has an aldose reductase inhibitory activity, thereby preventing diabetes. As a compound capable of preventing or treating sex complications, it has been found for the first time that it can be used as a health functional food as well as pharmaceuticals such as pharmacological compositions.
본 발명의 하기 실험예2에서는, 매생이 추출물에서 분리된 상기 화합물의 알도즈 환원효소 억제활성을 살펴본 결과, 카프소플베신 A (capsofulvesin A), 카프소플베신 B (capsofulvesin B) 및 카리나스테롤 (chalinasterol)은 IC50(μM) 값이 각각 52.53±2.82, 100.92±7.34, 345.27±8.68μM로 나타나 현저한 알도즈 환원효소 억제활성을 가지는 것을 확인함으로써, 상기 화합물의 효과를 실험적으로 입증하였다.In the following Experimental Example 2 of the present invention, as a result of examining the aldose reductase inhibitory activity of the compound isolated from the extract, the capsofulvesin A (capsofulvesin A), capsofulvesin B and carinasterol (chalinasterol) The IC50 (μM) values were 52.53 ± 2.82, 100.92 ± 7.34, and 345.27 ± 8.68μM, respectively, to confirm that they had significant aldose reductase inhibitory activity, thereby experimentally demonstrating the effect of the compound.
따라서 상기와 같은 특징을 갖는 화합물 또는 그의 염을 유효성분으로 포함하는 본 발명의 조성물은 알도즈 환원효소 억제활성을 통하여 당뇨성 합병증 예방 또는 치료에 유용하게 사용될 수 있다.Therefore, the composition of the present invention comprising a compound having the above characteristics or a salt thereof as an active ingredient can be usefully used for preventing or treating diabetic complications through aldose reductase inhibitory activity.
본 발명의 조성물로 예방 또는 치료할 수 있는 당뇨성 합병증으로는, 당뇨성 망막병증, 당뇨성 녹내장, 당뇨성 백내장, 당뇨성 신증 및 당뇨성 신경병증 등을 들 수 있되, 이에 한정되는 것은 아니다.Diabetic complications that can be prevented or treated with the composition of the present invention include, but are not limited to, diabetic retinopathy, diabetic glaucoma, diabetic cataract, diabetic nephropathy and diabetic neuropathy.
본 발명의 화합물(capsofulvesin A, capsofulvesin B, chalinasterol)을 유효성분으로 포함하는 약제학적 조성물은 상기 유효성분 이외에 약제학적으로 적합하고 생리학적으로 허용되는 보조제를 사용하여 제조될 수 있으며, 상기 보조제로는 부형제, 붕해제, 감미제, 결합제, 피복제, 팽창제, 윤활제, 활택제 또는 향미제 등을 사용할 수 있다.A pharmaceutical composition comprising the compound of the present invention (capsofulvesin A, capsofulvesin B, chalinasterol) as an active ingredient may be prepared using a pharmaceutically acceptable and physiologically acceptable adjuvant in addition to the active ingredient. Excipients, disintegrants, sweeteners, binders, coatings, swelling agents, lubricants, lubricants or flavoring agents and the like can be used.
상기 약제학적 조성물은 투여를 위해서 상기 기재한 유효성분 이외에 추가로 약제학적으로 허용 가능한 담체를 1종 이상 포함하여 약제학적 조성물로 바람직하게 제제화할 수 있다.
The pharmaceutical composition may be preferably formulated into a pharmaceutical composition including one or more pharmaceutically acceptable carriers in addition to the above-described active ingredient for administration.
또한, 본 발명은 당뇨성 합병증 예방 또는 치료용 의약의 제조를 위한 매생이 추출물 또는 매생이 추출물로부터 분리된 화합물(capsofulvesin A, capsofulvesin B, chalinasterol)을 유효성분으로 포함하는 조성물의 용도를 제공한다. 상기한 매생이 추출물 또는 매생이 추출물로부터 분리된 화합물(capsofulvesin A, capsofulvesin B, chalinasterol)을 유효성분으로 포함하는 본 발명의 조성물은 당뇨성 합병증의 예방 또는 치료용 의약의 제조를 위한 용도로 이용될 수 있다.
In another aspect, the present invention provides a use of a composition comprising a medicinal herb extract or a compound isolated from the medicinal extract (capsofulvesin A, capsofulvesin B, chalinasterol) as an active ingredient for the manufacture of a medicament for preventing or treating diabetic complications. The composition of the present invention comprising the above-mentioned syphilis extract or compound isolated from the extract (capsofulvesin A, capsofulvesin B, chalinasterol) as an active ingredient can be used for the manufacture of a medicament for the prevention or treatment of diabetic complications .
또한, 본 발명은 포유동물에게 매생이 추출물 또는 매생이 추출물로부터 분리된 화합물(capsofulvesin A, capsofulvesin B, chalinasterol)을 투여하는 것을 포함하는 당뇨성 합병증의 예방 또는 치료방법을 제공한다.The present invention also provides a method for preventing or treating diabetic complications comprising administering to a mammal a perennial extract or a compound isolated from a perennial extract (capsofulvesin A, capsofulvesin B, chalinasterol).
여기에서 사용된 용어 "포유동물"은 치료, 관찰 또는 실험의 대상인 포유동물을 말하며, 바람직하게는 인간을 말한다. The term "mammal " as used herein refers to a mammal that is the subject of treatment, observation or experimentation, preferably a human.
여기에서 사용된 용어 "치료상 유효량"은 연구자, 수의사, 의사 또는 기타 임상에 의해 생각되는 조직계, 동물 또는 인간에서 생물학적 또는 의학적 반응을 유도하는 유효 성분 또는 약제학적 조성물의 양을 의미하는 것으로, 이는 치료되는 질환 또는 장애의 증상의 완화를 유도하는 양을 포함한다. 본 발명의 유효 성분에 대한 치료상 유효 투여량 및 투여횟수는 원하는 효과에 따라 변화될 것임은 당업자에게 자명하다. 그러므로, 투여될 최적의 투여량은 당업자에 의해 쉽게 결정될 수 있으며, 질환의 종류, 질환의 중증도, 조성물에 함유된 유효성분 및 다른 성분의 함량, 제형의 종류, 및 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절될 수 있다. 본 발명의 치료방법에 있어서, 성인의 경우, 본 발명의 매생이 추출물 또는 매생이 추출물로부터 분리된 화합물(capsofulvesin A, capsofulvesin B, chalinasterol)을 1일 1회 내지 수회 투여시, 0.01㎎/kg~250㎎/kg의 용량으로 투여하는 것이 바람직하다.The term "therapeutically effective amount " as used herein refers to the amount of active ingredient or pharmaceutical composition that elicits a biological or medical response in a tissue system, animal or human, as contemplated by a researcher, veterinarian, The amount that induces the relief of the symptoms of the disease or disorder being treated. It will be apparent to those skilled in the art that the therapeutically effective dose and the number of administrations of the active ingredient of the present invention will vary depending on the desired effect. Thus, the optimal dosage to be administered can be readily determined by those skilled in the art and will vary with the nature of the disease, the severity of the disease, the amount of active and other ingredients contained in the composition, the type of formulation, and the age, The age, body weight, sex, diet, time of administration, route of administration and fraction of the composition, duration of treatment, concurrent medication, and the like. In the treatment method of the present invention, in the case of an adult, when the perennial extract of the present invention or the compound isolated from the extract (capsofulvesin A, capsofulvesin B, chalinasterol) is administered once to several times a day, 0.01 mg / kg to 250 mg Administration at a dose of / kg is preferred.
본 발명의 치료방법에서 본 발명의 매생이 추출물 또는 매생이 추출물로부터 분리된 화합물(capsofulvesin A, capsofulvesin B, chalinasterol)을 유효성분으로 포함하는 조성물은 경구, 직장, 정맥내, 동맥내, 복강내, 근육내, 흉골내, 경피, 국소, 안구내 또는 피내 경로를 통해 통상적인 방식으로 투여할 수 있다.
In the treatment method of the present invention, the composition comprising the extract of the falconus or the compound isolated from the extract (capsofulvesin A, capsofulvesin B, chalinasterol) as an active ingredient is oral, rectal, intravenous, intraarterial, intraperitoneal, intramuscular. Administration may be in conventional manner via the intrasternal, transdermal, topical, intraocular or intradermal route.
또한, 본 발명은 매생이 추출물 또는 이로부터 분리된 화합물(capsofulvesin A, capsofulvesin B, chalinasterol)을 유효성분으로 포함하는 당뇨성 합병증의 예방 또는 개선용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for the prevention or improvement of diabetic complications comprising the extract as a active ingredient (capsofulvesin A, capsofulvesin B, chalinasterol) as an active ingredient.
본 발명의 건강기능식품은 당뇨성 합병증의 예방 및 개선을 목적으로, 정제, 캅셀, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공할 수 있다.The health functional food of the present invention may be prepared and processed in the form of tablets, capsules, powders, granules, liquids, pills and the like for the purpose of preventing and improving diabetic complications.
본 발명에서 “건강기능식품”이라 함은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 말하며, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.In the present invention, the term " health functional food " refers to foods manufactured and processed using raw materials or ingredients having useful functions in accordance with Law No. 6727 on Health Functional Foods. Or to obtain a beneficial effect in health use such as physiological action.
본 발명의 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 식품 첨가물로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.The health functional food of the present invention may include a conventional food additive, and the suitability as a food additive, unless otherwise specified, in accordance with the General Regulations of the Food Additives and General Test Methods approved by the Food and Drug Administration, etc. Judging by the standards and standards.
상기 “식품 첨가물 공전”에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼슘, 니코틴산, 계피산 등의 화학적 합성물; 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물; L-글루타민산나트륨제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류 등을 들 수 있다.Examples of the items listed in the above-mentioned "food additives" include chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; Natural additives such as persimmon extract, licorice extract, crystalline cellulose, high color pigment and guar gum; L-glutamic acid sodium preparations, noodle-added alkalis, preservative preparations, tar coloring preparations and the like.
예를 들어, 정제 형태의 건강기능식품은 본 발명의 유효성분인 매생이 추출물 또는 이로부터 분리된 화합물(capsofulvesin A, capsofulvesin B, chalinasterol)을 부형제, 결합제, 붕해제 및 다른 첨가제와 혼합한 혼합물을 통상의 방법으로 과립화한 다음, 활택제 등을 넣어 압축성형하거나, 상기 혼합물을 직접 압축 성형할 수 있다. 또한 상기 정제 형태의 건강기능식품은 필요에 따라 교미제 등을 함유할 수도 있다.For example, in the form of dietary supplements, a mixture of a medicinal herb extract, an active ingredient of the present invention, or a compound isolated therefrom (capsofulvesin A, capsofulvesin B, chalinasterol) with an excipient, a binder, a disintegrant and other additives is usually used. After granulation by a method of the present invention, the lubricant may be added by compression molding or the mixture may be directly compression molded. In addition, the health functional food in the form of tablets may contain a mating agent and the like as necessary.
캅셀 형태의 건강기능식품 중 경질 캅셀제는 통상의 경질 캅셀에 본 발명의 유효성분인 매생이 추출물 또는 이로부터 분리된 화합물(capsofulvesin A, capsofulvesin B, chalinasterol)을 부형제 등의 첨가제와 혼합한 혼합물을 충진하여 제조할 수 있으며, 연질 캅셀제는 백운풀 추출물을 부형제 등의 첨가제와 혼합한 혼합물을 젤라틴과 같은 캅셀기제에 충진하여 제조할 수 있다. 상기 연질 캅셀제는 필요에 따라 글리세린 또는 소르비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다.Hard capsules among the health functional foods in the form of capsules are filled with a mixture of additives such as excipients or the like (capsofulvesin A, capsofulvesin B, chalinasterol), which is an active ingredient of the present invention, or a conventional hard capsule, in a conventional hard capsule The soft capsule may be prepared by filling a capsule base such as gelatin with a mixture of a dolomite extract and an additive such as an excipient. The soft capsule may contain a plasticizer such as glycerin or sorbitol, a coloring agent, a preservative and the like, if necessary.
환 형태의 건강기능식품은 본 발명의 유효성분인 매생이 추출물 또는 이로부터 분리된 화합물(capsofulvesin A, capsofulvesin B, chalinasterol)과 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 제피제로 제피할 수 있으며, 또는 전분, 탈크와 같은 물질로 표면을 코팅할 수도 있다.The health functional food in the form of a cyclic shape is formed by a known method of a mixture of an extract, or a compound (capsofulvesin A, capsofulvesin B, chalinasterol), an excipient, a binder, a disintegrant, and the like which is an active ingredient of the present invention. It can be prepared by the use, and, if necessary, can be coated with sucrose or other coating agent, or the surface can be coated with a material such as starch, talc.
과립 형태의 건강기능식품은 본 발명의 유효성분인 매생이 추출물 또는 이로부터 분리된 화합물(capsofulvesin A, capsofulvesin B, chalinasterol)과 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다.The health functional food in the form of granules is granulated by a known method of a mixture of an extract, or a compound (capsofulvesin A, capsofulvesin B, chalinasterol), an excipient, a binder, a disintegrant, etc., which is an active ingredient of the present invention. It can be prepared, and may contain a flavoring agent, a copper, etc. as necessary.
상기 건강기능식품은 음료류, 육류, 초코렛, 식품류, 과자류, 피자, 라면, 기타 면류, 껌류, 사탕류, 아이스크림류, 알코올 음료류, 비타민 복합제 및 건강보조식품류 등일 수 있다.
The health functional food may be a beverage, a meat, a chocolate, a food, a confectionery, a pizza, a ramen, a noodle, a gum, a candy, an ice cream, an alcoholic beverage, a vitamin complex and a health supplement food.
이하, 실시예를 통하여 본 발명을 보다 상세히 설명하고자 한다. 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for further illustrating the present invention, and the scope of the present invention is not limited to these examples.
<< 실시예Example 1> 1>
매생이Mysterious 조추출물의Crude extract 제조 Produce
본 발명에 사용한 매생이는 전남 완도에서 채집하여 사용하였다. 건조 매생이는 마쇄하였으며, 이렇게 마쇄된 매생이 분말 0.87 ㎏을 메탄올 10 ℓ에 넣고 70 ℃에서 일정시간 간격 (12h, 6h, 3h)으로 3회 반복하여 환류냉각추출한 후 여지 (와트만사, 미국)로 감압 여과한 다음, 여과 추출물은 진공회전농축기로 40 ℃에서 메탄올을 제거한 후 추출된 잔사로서 매생이 조추출물 52.0 g을 수득하였다. 이 중 1.0 g을 취하여 알도즈 환원효소 억제활성 검색을 위한 시료로 사용하였다.
The falcons used in the present invention were collected and used in Wando, Jeonnam. The dried falcon was crushed, and the crushed falcon was mixed with 0.87 kg of powder in 10 l of methanol and reflux-cooled at 70 ° C. three times at regular intervals (12h, 6h, 3h), and then depressurized to room (Watman, USA). After filtration, the filtrate extract removed methanol at 40 ° C. with a vacuum rotary concentrator, and then obtained 52.0 g of crude extract as a residue. 1.0 g of this was used as a sample for screening the aldose reductase inhibitory activity.
<< 실시예Example 2> 2>
매생이Mysterious 디클로로메탄 가용 추출물의 제조 Preparation of Dichloromethane Soluble Extract
상기 실시예 1에서 얻은 수가용성 분획물 2 ℓ에 디클로로메탄 2 ℓ를 가하여 혼합한 후 3~4차례 분획하여 수가용성 분획물 2 ℓ 및 디클로로메탄 가용성 분획물 2 ℓ를 얻은 후, 이 디클로로메탄 가용성 분획물을 건조하여 디클로로메탄 가용 추출물 8.70 g을 수득하여 시료로 사용하였으며, 이 중 0.5 g을 취하여 알도즈 환원효소 억제활성 검색을 위한 시료로 사용하였다.
2 L of dichloromethane was added to 2 L of the water-soluble fraction obtained in Example 1, mixed, and then fractionated three to four times to obtain 2 L of the water-soluble fraction and 2 L of the dichloromethane-soluble fraction. The dichloromethane-soluble fraction was dried. 8.70 g of dichloromethane soluble extract was obtained and used as a sample, and 0.5 g of the sample was used as a sample for screening aldose reductase inhibitory activity.
<< 실시예Example 3> 3>
매생이Mysterious 에틸아세테이트 가용 추출물의 제조 Preparation of ethyl acetate soluble extract
상기 실시예 2에서 얻은 수가용성 분획물 2 ℓ에 에틸아세테이트 2 ℓ를 가하여 혼합한 후 3~4차례 분획하여 수가용성 분획물 2 ℓ 및 에틸아세테이트 가용성 분획물 2 ℓ를 얻은 후, 이 에틸 아세테이트 분획물을 건조하여 에틸 아세테이트 가용 추출물 0.70 g을 수득하여 시료로 사용하였으며, 이 중 0.1 g을 취하여 알도즈 환원효소 억제활성 검색을 위한 시료로 사용하였다.
2 L of ethyl acetate was added to 2 L of the water-soluble fraction obtained in Example 2, followed by mixing three to four times to obtain 2 L of the water-soluble fraction and 2 L of the ethyl acetate-soluble fraction, which was then dried. 0.70 g of ethyl acetate soluble extract was obtained and used as a sample, 0.1 g of which was used as a sample for searching for aldose reductase inhibitory activity.
<< 실시예Example 4> 4>
매생이Mysterious n- n- 부탄올Butanol 가용 추출물의 제조 Preparation of Soluble Extracts
상기 실시예 3에서 얻은 수가용성 분획층 2 ℓ에 부탄올 2 ℓ를 가하여 혼합한 후 3~4차례 분획하여 수가용성 분획물 2 ℓ 및 부탄올 가용성 분획물 2 ℓ를 얻은 후, 수가용성 분획물 및 n-부탄올 가용성 분획물을 건조하여 수가용 추출물 및 n-부탄올 가용 추출물 4.77 g을 수득하여 시료로 사용하였으며, 이 중 0.1 g을 취하여 알도즈 환원효소 억제활성 검색을 위한 시료로 사용하였다.
2 L of butanol was added to 2 L of the water-soluble fraction obtained in Example 3, followed by mixing 3-4 times to obtain 2 L of water-soluble fraction and 2 L of butanol-soluble fraction, followed by water-soluble fraction and n-butanol-soluble. The fractions were dried to obtain 4.77 g of soluble extract and 4.77 g of n-butanol soluble extract, and 0.1 g of the extract was used as a sample for searching for aldose reductase inhibitory activity.
<< 실시예Example 5> 5>
본 발명의 The 당지질Glycolipid ( ( glycolipidglycolipid )과 )and 카리나스테롤Carinasterol ( ( chalinasterolchalinasterol )의 화합물의 분리Isolation of Compounds
상기 실시예 2를 통해 수득한 매생이 디클로로메탄 가용 추출물 8.0g을 전개용매로서 디클로로메탄 : 메탄올의 100:1 → 1:1의 혼합용매를 사용하여 칼럼 크로마토그래피를 수행하였다. 고정상으로는 키에셀 겔 60 (Kiesel gel 60, 230-400 매쉬)을 사용하여 시간당 1000 ㎖씩 분획을 수행하여 18개의 하부 분획물 (CF01~CF18)로 나누었다. CF09 (0.87 g)을 디클로로메탄 : 메탄올의 100:1 → 1:1의 혼합용매를 키에셀 겔 칼럼 크로마토그래피를 수행하여 화합물 1을 분리하였으며, CF11 (0.6 g)을 디클로로메탄 : 메탄올의 40:1 → 1:1의 혼합용매를 키에셀 겔 칼럼 크로마토그래피와 메탄올로 세파덱스 LH-20 (st. Louis, MO, 시그마 사)으로 정제하여 화합물 2, 3을 분리하였다.8.0 g of the lysed dichloromethane soluble extract obtained in Example 2 was subjected to column chromatography using a mixed solvent of dichloromethane: methanol 100: 1 → 1: 1 as a developing solvent. The stationary phase was divided into 18 lower fractions (CF01-CF18) by fractionation by 1000 ml per hour using Kiesel gel 60 (Kiesel gel 60, 230-400 mesh). CF09 (0.87 g) was mixed with dichloromethane: methanol in a mixed solvent of 100: 1 → 1: 1 and subjected to Kissel gel column chromatography to separate compound 1, and CF11 (0.6 g) was added to dichloromethane: methanol at 40: A mixed solvent of 1 → 1: 1 was purified by Kiesel gel column chromatography and methanol using Sephadex LH-20 (st. Louis, MO, Sigma) to separate compounds 2 and 3.
분리한 각각의 화합물을 NMR 및 MS 등과 같은 각종 분석기기로 분석한 결과는 하기와 같다.
The separated compounds were analyzed by various analyzers such as NMR and MS, and the results are as follows.
(1) 화합물 1 : 카프소플베신 A (capsofulvesin A)(1) Compound 1: capsofulvesin A
물질의 성상: 노란색의 오일Appearance of substance: Yellow oil
물질의 분자식: C43H66O10 Molecular formula of substance: C 43 H 66 O 10
(2S)-1-O-(6z,9z,12z,15z-octadecatetraenoyl)-2-O-(4z,7z,10z,13z-hexadecatetraenoyl)-3-O-β-D-galacatopyranosylglycerol (1): [α] -31.3 (c 0.1, MeOH); UV (MeOH) λmax(logε) 205 (4.21), 235 (3.76) nm; IR(KBr) νmax 3424 (O-H), 3012 (H-C=C), 1737 (C=O), 1638 (C=C), 1079(C-O)cm-1; FABMS m/z 765 [M+Na]+, 563 [M+H-galactose]+, 495 [M+H-R1]+, 467 [M+H-R2]+, 333 [M+H-R1-galactose]+, 305 [M+H-R2-galactose]+; HRFABMS m/z 765.4547 (calcd. for C43H66O10Na, 765.4544); 1H NMR (CDCl3, 400MHz) δ 4.21 (1H, dd, J=12.0,6.8Hz, H-1a), 4.40 (1H, dd, J=12.0,2.8Hz, H-1b), 5.29 (1H, m, H-2), 3.70 (1H, dd, J=10.4,5.8Hz, H-3a), 3.93 (1H, dd, J=10.4,5.8Hz, H-3b), 5.28-5.46 (16H, H-4′′, 5′′, 7′′, 8′′, 10′′, 11′′, 13′′, 14′′, 6′, 7′, 9′, 10′, 12′, 13′, 15′, 16′), 2.81-2.84 (12H, H2-6′′, 9′′, 12′′, 8′, 11′, 14′), 2.41 (4H, br s, H2-2′′,3′′), 2.36 (2H, t, J=7.6Hz, H2-2′), 2.05-2.10 (6H, H2-15′′, 17′, 5′), 1.66 (2H, q, J=7.6Hz, H2-3′), 1.43 (2H, q, J=7.6Hz, H2-4′), 0.97 (6H, t,J=7.6Hz, H3-16′′, H3-18′), 4.26 (1H, d, J=7.2Hz, H-1′′′), 3.63 (1H, dd, J=10.2, 7.2Hz, H-2′′′), 3.53 (1H, dd, J=10.2, 3.5Hz, H-3′′′), 4.04 (1H, dd, J=3.5, 1.5Hz, H-4′′′), 3.65 (1H, t, J=6.3Hz, H-5′′′), 3.80 (1H, dd, J=10.2, 6.3 Hz, H-6′′′a), 3.63 (1H, dd, J=10.2, 6.3 Hz, H-6′′′b); 13CNMR (CDCl3, 100MHz)δ 63.1 (C-1), 71.2 (C-2), 68.2 (C-3), 173.8 (C-1′′), 172.9 (C-1′), 129.8a,128.8a,128.5a,128.1a,128.0a,127.8a,127.3,132.3(C-4′′, 5′′, 7′′, 8′′, 10′′, 11′′, 13′′, 14′′), 129.5a,128.3a,128.1a,128.0a,127.9a,127.8a,127.1,131.3, (C-6′, 7′, 9′, 10′, 12′, 13′, 15′, 16′), 34.2 (C-2′′, 2′), 22.8 (C-3′′), 24.6 (C-3′), 29.3 (C-4′), 27.0 (C-5′), 25.8 (C-6′′, 9′′, 12′′, 8′, 11′, 14′), 20.7 (C-15′′, 17′), 14.5 (C-16′′, 18′), 104.2 (C-1′′′), 70.6 (C-2′′′), 73.6 (C-3′′′), 68.9 (C-4′′′), 74.7 (C-5′′′), 61.4 (C-6′′′).
(2S) -1-O- (6z, 9z, 12z, 15z-octadecatetraenoyl) -2-O- (4z, 7z, 10z, 13z-hexadecatetraenoyl) -3-O-β-D-galacatopyranosylglycerol (1): [ α] -31.3 (c 0.1, MeOH); UV (MeOH) λ max (log ε) 205 (4.21), 235 (3.76) nm; IR (KBr) ν max 3424 (OH), 3012 (HC = C), 1737 (C = O), 1638 (C = C), 1079 (CO) cm-1; FABMS m / z 765 [M + Na] +, 563 [M + H-galactose] +, 495 [M + H-R1] +, 467 [M + H-R2] +, 333 [M + H-R1- galactose] +, 305 [M + H-R2-galactose] +; HRFABMS m / z 765.4547 (calcd. For C 43 H 66 O 10 Na, 765.4544); 1 H NMR (CDCl 3, 400 MHz) δ 4.21 (1H, dd, J = 12.0,6.8 Hz, H-1a), 4.40 (1H, dd, J = 12.0,2.8 Hz, H-1b), 5.29 (1H, m, H-2), 3.70 (1H, dd, J = 10.4,5.8 Hz, H-3a), 3.93 (1H, dd, J = 10.4,5.8 Hz, H-3b), 5.28-5.46 (16H, H-4 ′ ′, 5 ′ ′, 7 ′ ′, 8 ′ ′, 10 ′ ′, 11 ′ ′, 13 ′ ′, 14 ′ ′, 6 ′, 7 ′, 9 ′, 10 ′, 12 ′, 13 ′, 15 ′, 16 ′), 2.81-2.84 (12H, H2-6 ′ ′, 9 ′ ′, 12 ′ ′, 8 ′, 11 ′, 14 ′), 2.41 (4H, br s, H2-2 ′ ′, 3 ′ ′, 2.36 (2H, t, J = 7.6 Hz, H2-2 ′), 2.05-2.10 (6H, H2-15 ′ ′, 17 ′, 5 ′), 1.66 (2H, q, J = 7.6 Hz , H2-3 ′), 1.43 (2H, q, J = 7.6 Hz, H2-4 ′), 0.97 (6H, t, J = 7.6 Hz, H3-16 ′ ′, H3-18 ′), 4.26 (1H , d, J = 7.2 Hz, H-1 ′ ′ ′, 3.63 (1H, dd, J = 10.2, 7.2 Hz, H-2 ′ ′ ′), 3.53 (1H, dd, J = 10.2, 3.5 Hz, H-3 ′ ′ ′, 4.04 (1H, dd, J = 3.5, 1.5 Hz, H-4 ′ ′ ′), 3.65 (1H, t, J = 6.3 Hz, H-5 ′ ′ ′), 3.80 ( 1H, dd, J = 10.2, 6.3 Hz, H-6''a), 3.63 (1H, dd, J = 10.2, 6.3 Hz, H-6''b); 13 CNMR (CDCl 3, 100 MHz) δ 63.1 (C-1), 71.2 (C-2), 68.2 (C-3), 173.8 (C-1 ′ ′), 172.9 (C-1 ′), 129.8a, 128.8a , 128.5a, 128.1a, 128.0a, 127.8a, 127.3,132.3 (C-4 '′, 5 ′ ′, 7 ′ ′, 8 ′ ′, 10 ′ ′, 11 ′ ′, 13 ′ ′, 14 ′ ′ ), 129.5a, 128.3a, 128.1a, 128.0a, 127.9a, 127.8a, 127.1,131.3, (C-6 ', 7', 9 ', 10', 12 ', 13', 15 ', 16' ), 34.2 (C-2 ′ ′, 2 ′), 22.8 (C-3 ′ ′), 24.6 (C-3 ′), 29.3 (C-4 ′), 27.0 (C-5 ′), 25.8 (C -6 '′, 9 ′ ′, 12 ′ ′, 8 ′, 11 ′, 14 ′), 20.7 (C-15 ′ ′, 17 ′), 14.5 (C-16 ′ ′, 18 ′), 104.2 (C -1 ′ ′ ′, 70.6 (C-2 ′ ′ ′), 73.6 (C-3 ′ ′ ′), 68.9 (C-4 ′ ′ ′), 74.7 (C-5 ′ ′ ′), 61.4 (C -6 ''.
(2) 화합물 2 : 카프소플베신 B (capsofulvesin B)(2) Compound 2: Capsofulvesin B
물질의 성상: 노란색 오일Appearance of substance: Yellow oil
물질의 분자식: C43H70O10 Molecular formula of substance: C 43 H 70 O 10
(2S)-l-O-(9z,12z,15z-octadecatrienoyl)-2-O-(7z,10z,13z-hexadecatrienoyl)-3-O-β-D-galactopyranosyl glycerol (2): [a] -35.0 (c 0.1, MeOH); UV (MeOH) max (log e) 206 (4.22), 236 (3.76) nm; IR (KBr) max 3423 (O-H), 3012 (H-C=C), 1740 (C=O), 1638 (C=C), 1071 (C-O) cm-1; FABMS m/z 769 [M+Na]+, 567 [M+H-galactose]+, 497 [M+H-R1]+, 469[M+H-R2]+,335 [M+H-R1-galactose]+, 307 [M+H-R2-galactose]+; HRFABMS m/z 769.4867 (calcd. for C43H70O10Na, 769.4872); 1H NMR (CDCl3, 400MHz) d 4.21 (1H, dd, J=12.0,6.8Hz, H-1a), 4.40 (1H, dd, J=12.0,2.8Hz, H-1b), 5.30 (1H, m, H-2), 3.71 (1H, dd, J=10.4,5.8Hz, H-3a), 3.94 (1H, dd, J=10.4,5.8Hz, H-3b), 5.28-5.43 (12H, H-7'', 8'', 10'', 11'', 13'', 14'', 9', 10', 12', 13', 15', 16'), 2.79-2.82 (8H, H2-9'',12'',11',14'), 2.35 (4H, t, J=7.6Hz,H2-2'',2'), 1.65 (2H, q, J=7.6Hz,H2-3''), 1.63 (2H, q, J=7.6Hz,H2-3'), 2.03-2.11 (8H, m, H2-15'', 6'', 8' 17'), 1.26 (8H, br s, H2-4'-H2-7'), 0.98 (6H, t,J=7.6Hz,H3-16'', 18'), 4.26 (1H, d, J=7.2Hz, H-1'''), 3.63 (1H, dd, J=10.2,7.2Hz, H-2'''), 3.53 (1H, dd, J=10.2,3.5Hz, H-3'''), 4.04 (1H, dd, J=3.5,1.5Hz, H-4'''), 3.65 (1H, t, J=6.3Hz, H-5'''), 3.80 (1H, dd, J=10.2,6.3Hz, H-6'''a), 3.63 (1H, dd, J=10.2,6.3Hz, H-6'''b); 13CNMR(CDCl3, 100MHz) d 63.1 (C-1), 71.3 (C-2), 68.3 (C-3), d 173.0 (C-1'), 174.0 (C-1''), 130.4a,128.6a,128.1a,127.9a,127.3,132.2(C-7'', 8'', 10'', 11'', 13'', 14''), 130.0a,128.6a,128.1a,128.0a,127.3, 132.2, (C-9', 10', 12', 13', 15', 16'), 34.3 (C-2'', 2'), 25.0 (C-3'', 3'), 29.3 (C-5''), 27.2 (C-6''), 25.8 (C-9'', 12'', 11', 14'), 20.7 (C-15'', 17'), 14.5 (C-16'', 18'), 104.3 (C-1'''), 70.6 (C-2'''), 73.7 (C-3'''), 68.9 (C-4'''), 74.8 (C-5'''), 61.5 (C-6''').
(2S) -lO- (9z, 12z, 15z-octadecatrienoyl) -2-O- (7z, 10z, 13z-hexadecatrienoyl) -3-O-β-D-galactopyranosyl glycerol (2): [a] -35.0 ( c 0.1, MeOH); UV (MeOH) max (log e) 206 (4.22), 236 (3.76) nm; IR (KBr) max 3423 (OH), 3012 (HC = C), 1740 (C = O), 1638 (C = C), 1071 (CO) cm-1; FABMS m / z 769 [M + Na] +, 567 [M + H-galactose] +, 497 [M + H-R1] +, 469 [M + H-R2] +, 335 [M + H-R1- galactose] +, 307 [M + H-R2-galactose] +; HRFABMS m / z 769.4867 (calcd. For C 43 H 70 O 10 Na, 769.4872); 1 H NMR (CDCl 3, 400 MHz) d 4.21 (1H, dd, J = 12.0,6.8 Hz, H-1a), 4.40 (1H, dd, J = 12.0,2.8 Hz, H-1b), 5.30 (1H, m, H-2), 3.71 (1H, dd, J = 10.4,5.8 Hz, H-3a), 3.94 (1H, dd, J = 10.4,5.8 Hz, H-3b), 5.28-5.43 (12H, H-7 '', 8 '', 10 '', 11 '', 13 '', 14 '', 9 ', 10', 12 ', 13', 15 ', 16'), 2.79-2.82 (8H, H2- 9 '', 12 '', 11 ', 14'), 2.35 (4H, t, J = 7.6Hz, H2-2 '', 2 '), 1.65 (2H, q, J = 7.6Hz, H2-3 ''), 1.63 (2H, q, J = 7.6 Hz, H2-3 '), 2.03-2.11 (8H, m, H2-15'',6'',8' 17 '), 1.26 (8H, br s, H2-4'-H2-7 '), 0.98 (6H, t, J = 7.6 Hz, H3-16``, 18'), 4.26 (1H, d, J = 7.2 Hz, H-1 '''), 3.63 (1H, dd, J = 10.2,7.2 Hz, H-2'''), 3.53 (1H, dd, J = 10.2,3.5 Hz, H-3 '''), 4.04 (1H, dd , J = 3.5,1.5Hz, H-4 '''), 3.65 (1H, t, J = 6.3Hz, H-5'''), 3.80 (1H, dd, J = 10.2,6.3Hz, H- 6 '''a), 3.63 (1H, dd, J = 10.2,6.3 Hz, H-6'''b); 13 CNMR (CDCl 3, 100 MHz) d 63.1 (C-1), 71.3 (C-2), 68.3 (C-3), d 173.0 (C-1 '), 174.0 (C-1''), 130.4a, 128.6 a, 128.1a, 127.9a, 127.3,132.2 (C-7``, 8 '', 10 '', 11 '', 13 '', 14 ''), 130.0a, 128.6a, 128.1a, 128.0a , 127.3, 132.2, (C-9 ', 10', 12 ', 13', 15 ', 16'), 34.3 (C-2``, 2 '), 25.0 (C-3'',3') , 29.3 (C-5``), 27.2 (C-6 ''), 25.8 (C-9 '', 12 '', 11 ', 14'), 20.7 (C-15 '', 17 '), 14.5 (C-16``, 18 '), 104.3 (C-1'''), 70.6 (C-2 '''), 73.7 (C-3'''), 68.9 (C-4 ''' ), 74.8 (C-5 '''), 61.5 (C-6''').
(3) 화합물 3 : 카리나스테롤 (chalinasterol)(3) Compound 3: carlinasterol
물질의 성상: 무정형 분말. Form of material: amorphous powder.
물질의 분자식: C28H46OMolecular Formula of Material: C 28 H 46 O
Chalinasterol - 1H NMR (CDC13, 400MHz) d: 0.65 (3H, s, H-18), 0.87 (3H, s, H-19), 1.24 (3H, d, J=7.0Hz, H-21), 1.57 (6H, m, H-26, H-27), 3.52 (3r-H), 5.32 (1H, m, H-5), 5.34 (2H, s, H-28); 13C NMR (CDCI3, 100MHz) d: 34.29 (C-I), 29.76 (C-2), 73.36 (C-3), 38.59 (C-4), 146.96 (C-5), 126.42 (C-6), 32.17 (C-7), 35.74 (C-8), 53.69 (C-9), 35.77 (C-10), 20.99 (C-11), 28.59 (C-12), 41.98 (C-13), 55.92 (C-14), 24.17 (C-15), 40.11 (C-16), 50.03 (C-17), 12.03 (C-18), 12.21 (C-19), 34.29 (C-20), 19.53 (C-21), 37.15 (C-22), 22.33 (C-23), 144.64 (C-24), 29.76 (C-25), 20.99 (C-26), 22.27 (C-27), 123.45 (C-28).
Chalinasterol-1 H NMR (CDC13, 400 MHz) d: 0.65 (3H, s, H-18), 0.87 (3H, s, H-19), 1.24 (3H, d, J = 7.0 Hz, H-21), 1.57 (6H, m, H-26, H-27), 3.52 (3r-H), 5.32 (1H, m, H-5), 5.34 (2H, s, H-28); 13 C NMR (CDCI3, 100 MHz) d: 34.29 (CI), 29.76 (C-2), 73.36 (C-3), 38.59 (C-4), 146.96 (C-5), 126.42 (C-6), 32.17 (C-7), 35.74 (C-8), 53.69 (C-9), 35.77 (C-10), 20.99 (C-11), 28.59 (C-12), 41.98 (C-13), 55.92 ( C-14), 24.17 (C-15), 40.11 (C-16), 50.03 (C-17), 12.03 (C-18), 12.21 (C-19), 34.29 (C-20), 19.53 (C -21), 37.15 (C-22), 22.33 (C-23), 144.64 (C-24), 29.76 (C-25), 20.99 (C-26), 22.27 (C-27), 123.45 (C- 28).
<< 실험예Experimental Example 1> 1>
매생이Mysterious 조추출물Crude extract 및 각 용매 And each solvent 분획물의Fraction 랫드Rat 렌즈 lens 알도즈Aldoz 환원효소 ( Reducing enzyme RLARRLAR ) 억제활성) Inhibitory activity
매생이 조추출물 및 각 용매 분획물의 랫드 렌즈 알도즈 환원효소 억제활성을 측정하기 위한 효소원의 조제는 Hayman and Kinoshite (Hayman S. and Kinoshite I. H., J. Biol. Chem., 240, pp877-882, 1965)가 사용한 방법을 수정하여 실시하였다.Preparation of enzyme source for measuring rat extract aldose reductase inhibitory activity of crude extracts and each solvent fractions of the falciparum hayman and Kinoshite (Hayman S. and Kinoshite IH, J. Biol. Chem., 240, pp877-882, 1965 The method used was modified.
흰쥐의 안구에서 수정체를 적출하고, 그 습중량에 따라 일정량 (수정체 1개당 sodium phosphate buffer (pH 6.2) 0.5 ml 첨가)의 sodium phosphate buffer (pH 6.2)를 가하여 homogenization하였다. 이를 4℃에서 10,000 g로 20분간 원심 분리한 후, 그 상등액을 취하여 효소원으로 사용하였다. 1.5 ml 석영 큐벳에 potassium phosphate buffer (pH 7.0) 621 μl, 효소 90 μl, 조효소인 NADPH (1.6 mM) 90 μl, DMSO에 녹인 측정시료 9 μl를 넣고, 마지막으로 기질인 DL-glyceraldehyde (50 mM)을 90 μl을 넣어 총 반응액이 900 μl가 되도록 하여 340 nm에서 4분간 spectrophotometer를 측정하여 NADPH의 흡광도 감소율을 측정하였다. 대조군은 시료 대신에 DMSO를 첨가하여 측정하고, 양성 대조군은 퀘르세틴 (quercetin: Sigma, St. Louis, MO, USA)을 이용하여 농도별로 측정하였다. 랫드 렌즈 알도즈 환원효소 억제활성 실험 % 는 하기의 수학식 1로 구하였고, 선회귀방정식을 사용하여 통계처리 하였다.
The lens was extracted from the eye of the rat, and homogenization was performed by adding sodium phosphate buffer (pH 6.2) of a certain amount (addition of 0.5 ml of sodium phosphate buffer (pH 6.2) per lens) according to the wet weight. After centrifugation at 10,000 g for 20 minutes at 4 ℃, the supernatant was taken and used as the enzyme source. Into a 1.5 ml quartz cuvette, add 621 μl potassium phosphate buffer (pH 7.0), 90 μl enzyme, 90 μl coenzyme NADPH (1.6 mM), 9 μl sample dissolved in DMSO, and finally DL-glyceraldehyde (50 mM) 90 μl was added so that the total reaction solution was 900 μl, and the absorbance reduction rate of NADPH was measured by measuring a spectrophotometer at 340 nm for 4 minutes. The control group was measured by adding DMSO instead of the sample, and the positive control group was measured by concentration using quercetin (quercetin: Sigma, St. Louis, MO, USA). % Of rat lens aldose reductase inhibitory activity was calculated by Equation 1 below and statistically processed using a regression equation.
<수학식 1>&Quot; (1) "
% 억제율 = 1-(시료의 흡광도-대조군의 흡광도)/표준흡광도×100
% Inhibition = 1- (absorbance of sample-absorbance of control) / standard absorbance × 100
그 결과, 상기 표 1에서 나타낸 바와 같이, 매생이 조추출물 및 각 용매 분획물이 모두 알도즈 환원효소 억제활성을 가지는 것을 확인할 수 있었으며, 특히 매생이 에틸아세테이트 가용성 분획물이 IC50 값이 20.61±0.36로 나타나, 가장 효과가 좋은 것으로 나타났다.
As a result, as shown in Table 1 above, it was confirmed that the crude extract and each solvent fraction had aldose reductase inhibitory activity, and the ethylacetate soluble fraction of the medium was shown to have an IC50 value of 20.61 ± 0.36. The effect was found to be good.
<< 실험예Experimental Example 2> 2>
매생이Mysterious 추출물에서 분리된 Isolated from the extract 카프소플베신Capsofplevecin A ( A ( capsofulvesincapsofulvesin A), A), 카프소플베신Capsofplevecin B ( B ( capsofulvesincapsofulvesin B) 및 B) and 카리나스테롤Carinasterol ( ( chalinasterolchalinasterol ) 화합물의 ) Of the compound 랫드Rat 렌즈 lens 알도즈Aldoz 환원효소 ( Reducing enzyme RLARRLAR ) 억제활성) Inhibitory activity
상기 실시예 5에서 수득된 3가지 당지질(glycolipid)의 화합물 카프소플베신 A (capsofulvesin A)와 카프소플베신 B (capsofulvesin B)과 카리나스테롤 (chalinasterol)의 랫드 렌즈 알도즈 환원효소에 대한 억제활성을 상기 실험예 1과 같은 방법으로 실시하여, 그 결과를 하기 표 2에 나타내었다.
The inhibitory activity of the capsulfolevesin A, capsofulvesin B, and carinasterol on the rat lens aldose reductase of the three glycolipids obtained in Example 5 was obtained. It carried out by the same method as Experimental Example 1, the results are shown in Table 2 below.
상기 표 2에 나타낸 바와 같이, 카프소플베신 A (capsofulvesin A), 카프소플베신 B (capsofulvesin B) 및 카리나스테롤 (chalinasterol)은 IC50 값이 각각 52.53±2.82, 100.92±7.34, 345.27±8.68μM로 나타나 현저한 알도즈 환원효소 억제활성을 가지는 것을 확인할 수 있었다.
As shown in Table 2, capsofulvesin A, capsofulvesin B, and carinasterol exhibited IC50 values of 52.53 ± 2.82, 100.92 ± 7.34, and 345.27 ± 8.68μM, respectively. It was confirmed that it has a significant aldose reductase inhibitory activity.
<< 실험예Experimental Example 3> 3>
매생이Mysterious 조추출물Crude extract 및 각 용매 And each solvent 분획물의Fraction 최종당화산물The final glycation product 생성 억제 활성 측정 Measurement of inhibitory activity
매생이로부터 분리된 프레닐레이티드 플라보노이드 (prenylated flavonoids)의 최종당화산물 생성 억제 활성의 측정은 Vinson (Vinson J. A., J. Nutr. Biochem., 7, pp659-663, 1996)이 사용한 방법을 수정하여 실시하였다.Determination of final glycation end product production inhibitory activity of prenylated flavonoids isolated from the larvae was performed by modifying the method used by Vinson (Vinson JA, J. Nutr. Biochem., 7, pp659-663, 1996). It was.
AGE 반응 시약은 세균 증식을 막기 위해서 0.02% sodiumazide가 첨가된 50 mM sodium phosphate buffer (pH 7.4)에 10 mg/ml의 bovine serum albumin (Sigma, St. Louis, MO, USA)과 0.2 M fructose와 0.2 M glucose를 넣어 만든다. 시료는 10% DMSO에 녹인 후, AGE 반응 시약 950 μl에 반응시료 50 μl를 넣은 후, 37 ℃에서 7 일간 배양한다. 배양 후, 반응 생성물의 형광강도를 spectrofluorometric detector로 excitation과 emission 파장을 350 nm과 450 nm에서 측정한다. 최종당화산물 생성 억제활성 실험 % 는 하기의 수학식 2로 구하였고, 선회귀방정식을 사용하여 통계처리 하였다.
To prevent bacterial growth, AGE reaction reagents contained 10 mg / ml bovine serum albumin (Sigma, St. Louis, MO, USA) and 0.2 M fructose and 0.2 in 50 mM sodium phosphate buffer (pH 7.4) with 0.02% sodiumazide. M glucose is added. The sample was dissolved in 10% DMSO, 50 μl of the reaction sample was added to 950 μl of the AGE reaction reagent, and then incubated at 37 ° C. for 7 days. After incubation, the fluorescence intensity of the reaction product was measured with a spectrofluorometric detector at excitation and emission wavelengths of 350 nm and 450 nm. % Of the final glycation product inhibitory activity was calculated by Equation 2 below and statistically processed using a regression equation.
<수학식 2>&Quot; (2) "
% 억제율 = 1-(시료의 흡광도-대조군의 흡광도)/표준흡광도×100
% Inhibition = 1- (absorbance of sample-absorbance of control) / standard absorbance × 100
그 결과 상기 표 3에서 나타낸 바와 같이, 매생이 조추출물 및 각 용매 분획물이 모두 최종당화생성물 억제활성을 가지는 것을 확인할 수 있었으며, 특히 매생이 부탄올 가용성 분획물이 IC50 값이 96.65±0.26로 나타나, 가장 효과가 좋은 것으로 나타났다.
As a result, as shown in Table 3, it was confirmed that the crude extracts and each solvent fractions have the final glycation inhibitory activity, especially the butanol soluble fractions showed the IC50 value of 96.65 ± 0.26, the most effective Appeared.
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far I looked at the center of the preferred embodiment for the present invention. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.
AGEs: Advanced Glycation EndproductsAGEs: Advanced Glycation Endproducts
Claims (15)
상기 추출물은 매생이 조추출물 또는 매생이 비극성용매 가용 추출물인 것을 특징으로 하는 당뇨성 합병증 예방 또는 치료용 약제학적 조성물.The method of claim 1,
The extract is a pharmaceutical composition for the prevention or treatment of diabetic complications, characterized in that the extract is a crude extract or the soluble extract is a non-polar solvent.
상기 매생이 조추출물은 물, 에탄올, 메탄올, 부탄올 또는 이들의 혼합용매를 이용하여 추출한 것을 특징으로 하는 당뇨성 합병증 예방 또는 치료용 약제학적 조성물.3. The method of claim 2,
The crude extract of the maeseng is a pharmaceutical composition for preventing or treating diabetic complications, characterized in that extracted using water, ethanol, methanol, butanol or a mixed solvent thereof.
상기 매생이 비극성용매 가용 추출물은 디클로로메탄, 클로로포름, 에틸아세테이트, 부탄올 또는 이들의 혼합용매를 이용하여 추출한 것을 특징으로 하는 당뇨성 합병증 예방 또는 치료용 약제학적 조성물.3. The method of claim 2,
The medicinal extract of the bipolar non-solvent solvent is a pharmaceutical composition for preventing or treating diabetic complications, characterized in that extracted using dichloromethane, chloroform, ethyl acetate, butanol or a mixed solvent thereof.
상기 조성물은 알도즈 환원효소 억제 활성 및 최종당화생성물 억제 활성을 통해 당뇨성 합병증 치료 효과를 가지는 것을 특징으로 하는 당뇨성 합병증 예방 또는 치료용 약제학적 조성물.The method of claim 1,
The composition is a pharmaceutical composition for preventing or treating diabetic complications, characterized in that it has a therapeutic effect of diabetic complications through aldose reductase inhibitory activity and final glycation product inhibitory activity.
상기 당뇨성 합병증은 당뇨성 망막병증, 당뇨성 녹내장, 당뇨성 백내장, 당뇨성 신증 및 당뇨성 신경병증으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 당뇨성 합병증 예방 또는 치료용 약제학적 조성물.The method according to any one of claims 1 to 5,
The diabetic complication is a diabetic retinopathy, diabetic glaucoma, diabetic cataract, diabetic nephropathy and diabetic neuropathy, pharmaceutical composition for preventing or treating diabetic complications, characterized in that selected from the group.
.A pharmaceutical composition for preventing or treating diabetic complications comprising the compound of any one of Formulas 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient;
.
상기 화합물은 매생이 추출물로부터 분리된 것을 특징으로 하는 당뇨성 합병증 예방 또는 치료용 약제학적 조성물. The method of claim 7, wherein
The compound is a pharmaceutical composition for the prevention or treatment of diabetic complications, characterized in that the perennial is separated from the extract.
상기 화합물은 건조된 매생이 분말에 메탄올을 넣어 환류냉각추출한 후 여과하여 매생이 조추출물을 수득하는 단계; 수득한 매생이 조추출물에 디클로로메탄을 가하여 혼합 후 분획하여 매생이 디클로로메탄 가용 추출물을 수득하는 단계; 수득한 매생이 디클로로메탄 가용 추출물을 전개용매로서 디클로로메탄과 메탄올의 혼합용매를 사용하여 칼럼 크로마토그래피를 수행하여 분획하는 단계; 및 상기 분획물에 다시 디클로로메탄과 메탄올의 혼합용매를 가하여 칼럼 크로마토그래피를 수행하는 단계를 포함하는 과정을 통하여 제조되는 것을 특징으로 하는 당뇨성 합병증 예방 또는 치료용 약제학적 조성물.The method of claim 7, wherein
Wherein the compound is dried and dried methanol extract reflux cooling by putting methanol in the powder and filtered to obtain a crude extract crude life; Dichloromethane obtained by adding dichloromethane to the crude extract obtained by mixing and fractionation to obtain a soluble extract of dichloromethane; Fractionating dichloromethane soluble extract obtained by performing column chromatography using a mixed solvent of dichloromethane and methanol as a developing solvent; And adding a mixed solvent of dichloromethane and methanol to the fraction again to carry out column chromatography to prepare a pharmaceutical composition for preventing or treating diabetic complications.
상기 조성물은 알도즈 환원효소 억제 활성을 통해 당뇨성 합병증 치료 효과를 가지는 것을 특징으로 하는 당뇨성 합병증 예방 또는 치료용 약제학적 조성물.The method of claim 7, wherein
The composition is a pharmaceutical composition for preventing or treating diabetic complications, characterized in that it has a therapeutic effect of diabetic complications through aldose reductase inhibitory activity.
상기 당뇨성 합병증은 당뇨성 망막병증, 당뇨성 녹내장, 당뇨성 백내장, 당뇨성 신증 및 당뇨성 신경병증으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 당뇨성 합병증 예방 또는 치료용 약제학적 조성물.11. The method according to any one of claims 7 to 10,
The diabetic complication is a diabetic retinopathy, diabetic glaucoma, diabetic cataract, diabetic nephropathy and diabetic neuropathy, pharmaceutical composition for preventing or treating diabetic complications, characterized in that selected from the group.
상기 매생이 추출물은 매생이 조추출물 또는 매생이 비극성용매 가용 추출물인 것을 특징으로 하는 당뇨성 합병증의 예방 또는 개선용 건강기능식품.The method of claim 12,
The extract of the falconus is a health functional food for the prevention or improvement of diabetic complications, characterized in that the medicinal extract of the falcon or soluble extract is a nonpolar solvent.
상기 당뇨성 합병증은 당뇨성 망막병증, 당뇨성 녹내장, 당뇨성 백내장, 당뇨성 신증 및 당뇨성 신경병증으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 당뇨성 합병증의 예방 또는 개선용 건강기능식품.The method of claim 12,
The diabetic complications are diabetic retinopathy, diabetic glaucoma, diabetic cataract, diabetic nephropathy and diabetic neuropathy health functional food for preventing or improving diabetic complications, characterized in that selected from the group.
상기 식품은 음료류, 육류, 초코렛, 식품류, 과자류, 피자, 라면, 기타 면류, 껌류, 사탕류, 아이스크림류, 알코올 음료류, 비타민 복합제 및 건강보조식품류로 이루어진 군으로부터 선택되는 것을 특징으로 하는 당뇨성 합병증의 예방 또는 개선용 건강기능식품.15. The method according to any one of claims 12 to 14,
The food is a diabetic complication, characterized in that selected from the group consisting of beverages, meat, chocolate, food, confectionery, pizza, ramen, other noodles, gum, candy, ice cream, alcoholic beverages, vitamin complexes and dietary supplements Health functional food for prevention or improvement.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020120063862A KR20130140448A (en) | 2012-06-14 | 2012-06-14 | Pharmaceutical compositions for prevention or treatment of diabetic complications comprising an extract of capsosiphon fulvescens or the compounds isolated from thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020120063862A KR20130140448A (en) | 2012-06-14 | 2012-06-14 | Pharmaceutical compositions for prevention or treatment of diabetic complications comprising an extract of capsosiphon fulvescens or the compounds isolated from thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
KR20130140448A true KR20130140448A (en) | 2013-12-24 |
Family
ID=49985061
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020120063862A KR20130140448A (en) | 2012-06-14 | 2012-06-14 | Pharmaceutical compositions for prevention or treatment of diabetic complications comprising an extract of capsosiphon fulvescens or the compounds isolated from thereof |
Country Status (1)
Country | Link |
---|---|
KR (1) | KR20130140448A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20180019495A (en) * | 2016-08-16 | 2018-02-26 | 전남대학교산학협력단 | Pharmaceutical Composition for Improving, Protecting or Treating Alcoholic Liver Disease comprising Capsosiphon fulvescens Extract as Active Ingredient |
KR102156720B1 (en) * | 2020-04-16 | 2020-09-16 | 주식회사 씨웰 | Manufacturing method for active materials of anti-complement from seaweed fulvescens and active materials of anti-complement from seaweed fulvescens manufactured by the same |
CN115634240A (en) * | 2022-09-29 | 2023-01-24 | 西藏大学 | Luteolin green algae hydrogel preparation and preparation method and application thereof |
-
2012
- 2012-06-14 KR KR1020120063862A patent/KR20130140448A/en not_active Application Discontinuation
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20180019495A (en) * | 2016-08-16 | 2018-02-26 | 전남대학교산학협력단 | Pharmaceutical Composition for Improving, Protecting or Treating Alcoholic Liver Disease comprising Capsosiphon fulvescens Extract as Active Ingredient |
KR102156720B1 (en) * | 2020-04-16 | 2020-09-16 | 주식회사 씨웰 | Manufacturing method for active materials of anti-complement from seaweed fulvescens and active materials of anti-complement from seaweed fulvescens manufactured by the same |
CN115634240A (en) * | 2022-09-29 | 2023-01-24 | 西藏大学 | Luteolin green algae hydrogel preparation and preparation method and application thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Jagtap et al. | Artocarpus: A review of its traditional uses, phytochemistry and pharmacology | |
KR20090084439A (en) | A composition comprising extract of sophora flavescens or prenylated flavonoids compounds isolated therefrom preventing or treating diabetic complication | |
KR101793153B1 (en) | Compositions for the prevention or treatment of metabolic syndrome or antioxidant containing extracts of black soybean leaves, flavonol glycosides as an active ingredient | |
CA2830639A1 (en) | Use of compounds isolated from morus bark | |
KR100989093B1 (en) | Composition Comprising the Extracts of Branch of Lindera obtusiloba for Prevention and Treatment of Cardiovascular Diseases | |
KR101682697B1 (en) | Compositions for prevention or treatment of diabetic complications comprising extract of Aucuba japonica | |
KR101427784B1 (en) | An anti-diabetes composition comprising Ginseng Radix and mulberry tree extract as effective ingredients | |
KR20090094614A (en) | An extract of Nelumbo nucifera's leaves for preventing or treating diabetic complication | |
KR100948332B1 (en) | Composition Comprising the Extracts of Lysimachia clethroides for Prevention and Treatment of Cardiovascular Diseases | |
KR20130140448A (en) | Pharmaceutical compositions for prevention or treatment of diabetic complications comprising an extract of capsosiphon fulvescens or the compounds isolated from thereof | |
KR100926454B1 (en) | The composition comprising the extracts, fractions and the isolated compounds of Rhus verniciflua for prevention and treatment of diabetic complications | |
KR20110055771A (en) | Composition comprising extract of cirsium japonicum or compounds isolated therefrom for preventing or treating diabetes and diabetic complications | |
KR20140025914A (en) | Pharmaceutical compositions for prevention or treatment of diabetic complications comprising fucoxanthin | |
KR101469201B1 (en) | A COMPOSITION COMPRISING EXTRACT OF Laminaria japonica OR PORPYRIN-RELATED COMPOUNDS ISOLATED THEREFROM PREVENTING OR TREATING DIABETIC COMPLICATION | |
KR100839185B1 (en) | Composition comprising plantamajoside for treating or preventing diabete and diabetic complication | |
KR101681980B1 (en) | Compositions for prevention or treatment of diabetic complications comprising extract of Colona auricaulata | |
KR101469961B1 (en) | Method for separating porpyrin-related compounds from laminaria japonica for use in the prevention or treatment of diabetic complication | |
KR100814368B1 (en) | Composition comprising chebulic acid for treating or preventing diabete and diabetic complication | |
KR100908038B1 (en) | Gompi extract for preventing or treating diabetic complications | |
KR101219185B1 (en) | Novel biphenyl compound or pharmaceutically acceptable salt thereof, preparation method thereof and pharmaceutical composition for preventing or treating complications of diabetes mellitus | |
KR102025572B1 (en) | Composition for preventing, ameliorating or treating metabolic diseases comprising mixture of Diospyros lotus leaf and grape fruit stem extract as effective component | |
KR20150115973A (en) | Composition for treating diabete and diabete-induced complication containing an extract from Aster sphathulifolius | |
KR20150084405A (en) | Composition for Prevention and Treatment of Cardiovascular Diseases | |
KR20080092664A (en) | Composition comprising chebulic acid for treating or preventing diabete and diabetic complication | |
KR20100128668A (en) | An composition for preventing or improving diabete comprising an extract of rhus chinensis |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A201 | Request for examination | ||
E902 | Notification of reason for refusal | ||
E902 | Notification of reason for refusal | ||
E601 | Decision to refuse application |