KR20200015030A - Pharmaceutical composition comprising the extraction of spent mushroom substrate for lentinus edodes as an effective component for prevention or treatment of thrombosis and health functional food comprising the same - Google Patents
Pharmaceutical composition comprising the extraction of spent mushroom substrate for lentinus edodes as an effective component for prevention or treatment of thrombosis and health functional food comprising the same Download PDFInfo
- Publication number
- KR20200015030A KR20200015030A KR1020180090288A KR20180090288A KR20200015030A KR 20200015030 A KR20200015030 A KR 20200015030A KR 1020180090288 A KR1020180090288 A KR 1020180090288A KR 20180090288 A KR20180090288 A KR 20180090288A KR 20200015030 A KR20200015030 A KR 20200015030A
- Authority
- KR
- South Korea
- Prior art keywords
- sms
- extract
- thrombosis
- shiitake
- pharmaceutical composition
- Prior art date
Links
- 240000000599 Lentinula edodes Species 0.000 title claims abstract description 118
- 235000001674 Agaricus brunnescens Nutrition 0.000 title claims abstract description 42
- 208000007536 Thrombosis Diseases 0.000 title claims abstract description 34
- 235000001715 Lentinula edodes Nutrition 0.000 title claims abstract description 32
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 22
- 230000036541 health Effects 0.000 title claims abstract description 21
- 235000013376 functional food Nutrition 0.000 title claims abstract description 17
- 230000002265 prevention Effects 0.000 title claims abstract description 16
- 239000000758 substrate Substances 0.000 title claims abstract description 6
- 238000000605 extraction Methods 0.000 title description 7
- 238000003306 harvesting Methods 0.000 claims abstract description 120
- 239000000284 extract Substances 0.000 claims abstract description 118
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 54
- 239000004480 active ingredient Substances 0.000 claims abstract description 33
- 239000002038 ethyl acetate fraction Substances 0.000 claims abstract description 22
- 239000002034 butanolic fraction Substances 0.000 claims abstract description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- LIKMAJRDDDTEIG-UHFFFAOYSA-N 1-hexene Chemical compound CCCCC=C LIKMAJRDDDTEIG-UHFFFAOYSA-N 0.000 claims description 13
- 230000002785 anti-thrombosis Effects 0.000 abstract description 25
- 239000000843 powder Substances 0.000 abstract description 21
- 230000005764 inhibitory process Effects 0.000 abstract description 20
- 230000023555 blood coagulation Effects 0.000 abstract description 19
- 230000000694 effects Effects 0.000 abstract description 17
- 239000003960 organic solvent Substances 0.000 abstract description 15
- 108010039209 Blood Coagulation Factors Proteins 0.000 abstract description 13
- 102000015081 Blood Coagulation Factors Human genes 0.000 abstract description 13
- 239000003114 blood coagulation factor Substances 0.000 abstract description 13
- 235000013305 food Nutrition 0.000 abstract description 12
- 210000003743 erythrocyte Anatomy 0.000 abstract description 11
- 230000002949 hemolytic effect Effects 0.000 abstract description 11
- 108090000790 Enzymes Proteins 0.000 abstract description 8
- 102000004190 Enzymes Human genes 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 8
- 239000006227 byproduct Substances 0.000 abstract description 7
- 230000003389 potentiating effect Effects 0.000 abstract description 7
- 229940019700 blood coagulation factors Drugs 0.000 abstract description 6
- 230000017531 blood circulation Effects 0.000 abstract description 5
- 239000003826 tablet Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 208000016988 Hemorrhagic Stroke Diseases 0.000 abstract description 3
- 208000032382 Ischaemic stroke Diseases 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 208000020658 intracerebral hemorrhage Diseases 0.000 abstract description 3
- 239000006187 pill Substances 0.000 abstract description 3
- 230000017570 negative regulation of blood coagulation Effects 0.000 abstract description 2
- 238000012258 culturing Methods 0.000 abstract 1
- 210000002381 plasma Anatomy 0.000 abstract 1
- 239000002609 medium Substances 0.000 description 54
- 230000001954 sterilising effect Effects 0.000 description 27
- 238000004659 sterilization and disinfection Methods 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 230000002401 inhibitory effect Effects 0.000 description 19
- 108090000190 Thrombin Proteins 0.000 description 18
- 229960004072 thrombin Drugs 0.000 description 18
- 238000004458 analytical method Methods 0.000 description 17
- 239000000523 sample Substances 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 13
- 238000004519 manufacturing process Methods 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 10
- 229960001138 acetylsalicylic acid Drugs 0.000 description 10
- 239000003146 anticoagulant agent Substances 0.000 description 10
- 239000000306 component Substances 0.000 description 10
- 235000000346 sugar Nutrition 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 108010094028 Prothrombin Proteins 0.000 description 7
- 102100027378 Prothrombin Human genes 0.000 description 7
- -1 and the like Substances 0.000 description 7
- 229940039716 prothrombin Drugs 0.000 description 7
- 239000002699 waste material Substances 0.000 description 7
- 102000009123 Fibrin Human genes 0.000 description 6
- 108010073385 Fibrin Proteins 0.000 description 6
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- 235000013361 beverage Nutrition 0.000 description 6
- 230000015271 coagulation Effects 0.000 description 6
- 238000005345 coagulation Methods 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 229950003499 fibrin Drugs 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 230000014508 negative regulation of coagulation Effects 0.000 description 6
- 229920001282 polysaccharide Polymers 0.000 description 6
- 239000005017 polysaccharide Substances 0.000 description 6
- 150000004804 polysaccharides Chemical class 0.000 description 6
- 150000001720 carbohydrates Chemical class 0.000 description 5
- 235000014633 carbohydrates Nutrition 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000006872 improvement Effects 0.000 description 5
- 238000011081 inoculation Methods 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 230000001766 physiological effect Effects 0.000 description 5
- 238000007711 solidification Methods 0.000 description 5
- 230000008023 solidification Effects 0.000 description 5
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 206010018910 Haemolysis Diseases 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000000855 fermentation Methods 0.000 description 4
- 230000004151 fermentation Effects 0.000 description 4
- 230000008588 hemolysis Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 235000015097 nutrients Nutrition 0.000 description 4
- 235000016709 nutrition Nutrition 0.000 description 4
- 150000008442 polyphenolic compounds Chemical class 0.000 description 4
- 235000013824 polyphenols Nutrition 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 208000018522 Gastrointestinal disease Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 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 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 206010047249 Venous thrombosis Diseases 0.000 description 3
- 229940127219 anticoagulant drug Drugs 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 235000015872 dietary supplement Nutrition 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229930003935 flavonoid Natural products 0.000 description 3
- 150000002215 flavonoids Chemical class 0.000 description 3
- 235000017173 flavonoids Nutrition 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 238000013379 physicochemical characterization Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 235000013616 tea Nutrition 0.000 description 3
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 235000019750 Crude protein Nutrition 0.000 description 2
- 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 2
- 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 2
- 206010051055 Deep vein thrombosis Diseases 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 239000004386 Erythritol Substances 0.000 description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 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 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 244000294411 Mirabilis expansa Species 0.000 description 2
- 235000015429 Mirabilis expansa Nutrition 0.000 description 2
- 240000007594 Oryza sativa Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- 241000286209 Phasianidae Species 0.000 description 2
- 240000001462 Pleurotus ostreatus Species 0.000 description 2
- 235000001603 Pleurotus ostreatus Nutrition 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 244000269722 Thea sinensis Species 0.000 description 2
- 108010000499 Thromboplastin Proteins 0.000 description 2
- 102000002262 Thromboplastin Human genes 0.000 description 2
- 239000013504 Triton X-100 Substances 0.000 description 2
- 229920004890 Triton X-100 Polymers 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 229960004676 antithrombotic agent Drugs 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 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 2
- 230000036772 blood pressure Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 2
- 235000019414 erythritol Nutrition 0.000 description 2
- 229940009714 erythritol Drugs 0.000 description 2
- 235000013373 food additive Nutrition 0.000 description 2
- 239000002778 food additive Substances 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 235000015203 fruit juice Nutrition 0.000 description 2
- 239000000446 fuel Substances 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
- 229960001031 glucose Drugs 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 235000013402 health food Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 244000144972 livestock Species 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- 235000013536 miso Nutrition 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 229960002920 sorbitol Drugs 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 230000002537 thrombolytic effect Effects 0.000 description 2
- 208000019553 vascular disease Diseases 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 239000002023 wood Substances 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 1
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 description 1
- FYGDTMLNYKFZSV-URKRLVJHSA-N (2s,3r,4s,5s,6r)-2-[(2r,4r,5r,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5r,6s)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1[C@@H](CO)O[C@@H](OC2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-URKRLVJHSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- GOLORTLGFDVFDW-UHFFFAOYSA-N 3-(1h-benzimidazol-2-yl)-7-(diethylamino)chromen-2-one Chemical compound C1=CC=C2NC(C3=CC4=CC=C(C=C4OC3=O)N(CC)CC)=NC2=C1 GOLORTLGFDVFDW-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 241000222518 Agaricus Species 0.000 description 1
- 206010003178 Arterial thrombosis Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- 229920002498 Beta-glucan Polymers 0.000 description 1
- JMGZEFIQIZZSBH-UHFFFAOYSA-N Bioquercetin Natural products CC1OC(OCC(O)C2OC(OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5)C(O)C2O)C(O)C(O)C1O JMGZEFIQIZZSBH-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 240000004160 Capsicum annuum Species 0.000 description 1
- 235000008534 Capsicum annuum var annuum Nutrition 0.000 description 1
- 235000007862 Capsicum baccatum Nutrition 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 108010059892 Cellulase Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008138 Cerebral venous thrombosis Diseases 0.000 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 102100023804 Coagulation factor VII Human genes 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- 239000001512 FEMA 4601 Substances 0.000 description 1
- 108010014172 Factor V Proteins 0.000 description 1
- 108010023321 Factor VII Proteins 0.000 description 1
- 108010071289 Factor XIII Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 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 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 241000237858 Gastropoda Species 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010027304 Menopausal symptoms Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 206010034719 Personality change Diseases 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 206010035148 Plague Diseases 0.000 description 1
- 244000252132 Pleurotus eryngii Species 0.000 description 1
- 235000001681 Pleurotus eryngii Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000206607 Porphyra umbilicalis Species 0.000 description 1
- 201000009454 Portal vein thrombosis Diseases 0.000 description 1
- 206010037437 Pulmonary thrombosis Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- HELXLJCILKEWJH-SEAGSNCFSA-N Rebaudioside A Natural products O=C(O[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1)[C@@]1(C)[C@@H]2[C@](C)([C@H]3[C@@]4(CC(=C)[C@@](O[C@H]5[C@H](O[C@H]6[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O6)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O6)[C@H](O)[C@@H](CO)O5)(C4)CC3)CC2)CCC1 HELXLJCILKEWJH-SEAGSNCFSA-N 0.000 description 1
- 206010056293 Renal vein occlusion Diseases 0.000 description 1
- 244000228451 Stevia rebaudiana Species 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229920001284 acidic polysaccharide Polymers 0.000 description 1
- 150000004805 acidic polysaccharides Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 230000002965 anti-thrombogenic effect Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000021328 arterial occlusion Diseases 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 108010047754 beta-Glucosidase Proteins 0.000 description 1
- 102000006995 beta-Glucosidase Human genes 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose 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-QUYVBRFLSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000003130 blood coagulation factor inhibitor Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000001728 capsicum frutescens Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 235000014171 carbonated beverage Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 229940106157 cellulase Drugs 0.000 description 1
- 201000005667 central retinal vein occlusion Diseases 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000002361 compost Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000004452 decreased vision Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- HELXLJCILKEWJH-UHFFFAOYSA-N entered according to Sigma 01432 Natural products C1CC2C3(C)CCCC(C)(C(=O)OC4C(C(O)C(O)C(CO)O4)O)C3CCC2(C2)CC(=C)C21OC(C1OC2C(C(O)C(O)C(CO)O2)O)OC(CO)C(O)C1OC1OC(CO)C(O)C(O)C1O HELXLJCILKEWJH-UHFFFAOYSA-N 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 1
- IVTMALDHFAHOGL-UHFFFAOYSA-N eriodictyol 7-O-rutinoside Natural products OC1C(O)C(O)C(C)OC1OCC1C(O)C(O)C(O)C(OC=2C=C3C(C(C(O)=C(O3)C=3C=C(O)C(O)=CC=3)=O)=C(O)C=2)O1 IVTMALDHFAHOGL-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 229940012413 factor vii Drugs 0.000 description 1
- 229940012444 factor xiii Drugs 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 239000010440 gypsum Substances 0.000 description 1
- 229910052602 gypsum Inorganic materials 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000000185 intracerebroventricular administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012533 medium component Substances 0.000 description 1
- 239000013028 medium composition Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 208000035824 paresthesia Diseases 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- LCLHHZYHLXDRQG-ZNKJPWOQSA-N pectic acid Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)O[C@H](C(O)=O)[C@@H]1OC1[C@H](O)[C@@H](O)[C@@H](OC2[C@@H]([C@@H](O)[C@@H](O)[C@H](O2)C(O)=O)O)[C@@H](C(O)=O)O1 LCLHHZYHLXDRQG-ZNKJPWOQSA-N 0.000 description 1
- 229940116257 pepper extract Drugs 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- OQUKIQWCVTZJAF-UHFFFAOYSA-N phenol;sulfuric acid Chemical compound OS(O)(=O)=O.OC1=CC=CC=C1 OQUKIQWCVTZJAF-UHFFFAOYSA-N 0.000 description 1
- 230000008635 plant growth Effects 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- FDRQPMVGJOQVTL-UHFFFAOYSA-N quercetin rutinoside Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 FDRQPMVGJOQVTL-UHFFFAOYSA-N 0.000 description 1
- 235000019203 rebaudioside A Nutrition 0.000 description 1
- 208000004644 retinal vein occlusion Diseases 0.000 description 1
- IKGXIBQEEMLURG-BKUODXTLSA-N rutin Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@@H]1OC[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-BKUODXTLSA-N 0.000 description 1
- ALABRVAAKCSLSC-UHFFFAOYSA-N rutin Natural products CC1OC(OCC2OC(O)C(O)C(O)C2O)C(O)C(O)C1OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5 ALABRVAAKCSLSC-UHFFFAOYSA-N 0.000 description 1
- 235000005493 rutin Nutrition 0.000 description 1
- 229960004555 rutoside Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 235000015067 sauces Nutrition 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960004793 sucrose Drugs 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
- 230000001629 suppression Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960003766 thrombin (human) Drugs 0.000 description 1
- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 201000005665 thrombophilia Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
Images
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
- A61K36/06—Fungi, e.g. yeasts
- A61K36/07—Basidiomycota, e.g. Cryptococcus
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- 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
- A23V2250/00—Food ingredients
- A23V2250/20—Natural extracts
- A23V2250/208—Fungi extracts
-
- 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
- A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Mycology (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Chemical & Material Sciences (AREA)
- Botany (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Hematology (AREA)
- Medical Informatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Alternative & Traditional Medicine (AREA)
- Biotechnology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Medicines Containing Plant Substances (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
Description
본 발명은 표고버섯 (Lentinus edodes) 재배 시 부산물로 발생하는, 수확 후 배지 (spent mushroom substrate, SMS)의 추출물을 유효성분으로 함유하는 혈전증(thrombosis)의 예방 또는 치료용 약학적 조성물 및 건강 기능 식품에 관한 것으로서, 보다 구체적으로는, 표고버섯 인공 재배용 배지에 표고버섯 종균을 접종 및 배양하여 표고버섯을 수확한 이후의 남은 폐배지의 열수 추출물 및 이의 에틸아세테이트 분획물, 부탄올 분획물 및 순차적 유기용매 분획 후의 물 잔류물을 유효성분으로 하는 강력한 혈액 응고 저해를 통한 혈전증의 예방 또는 치료/개선용 약학적 조성물 및 건강 기능 식품에 관한 것이다.The present invention is a pharmaceutical composition and health functional food for preventing or treating thrombosis (thrombosis) containing as an active ingredient the extract of the mushroom (spent mushroom substrate, SMS) generated as a by-product when cultivated shiitake mushroom ( Lentinus edodes ) More specifically, after inoculating and cultivating shiitake mushroom seedlings in a culture medium for shiitake mushroom cultivation, the hydrothermal extract of the remaining waste medium and the ethyl acetate fraction, butanol fraction and sequential organic solvent fractions after harvesting the shiitake mushroom A pharmaceutical composition for the prevention or treatment / improvement of thrombosis through strong blood coagulation inhibition using water residue as an active ingredient, and a health functional food.
인체 구성 성분으로 혈액은 산소, 영양분, 노폐물의 운반 기능과 완충 작용, 체온 유지, 삼투압 조절 및 이온 평형 유지, 수분 일정 유지, 액성 조절 작용, 혈압의 유지 및 조절, 생체 방어 등 다양한 중요 기능들을 가지고 있다. 정상적인 혈액 순환은 체내에서의 혈액 응고 반응계와 혈전 용해 반응계가 상호 보완적으로 조절되면서 혈액 순환을 용이하게 하며, 이들 중 혈액 응고 반응계의 기작은 혈관벽에 혈소판이 점착, 응집하여 혈소판 혈전을 형성한 후, 혈액 응고계가 활성화되어 혈소판 응집괴를 중심으로 피브린 혈전이 형성되는 것으로 보고되어 있다. 혈전성 질환은 혈액 내의 혈소판과 혈장의 응고, 섬유소 분해, 응고 억제 과정의 조절과 균형이 여러 가지 요인으로 인하여 비정상적인 경우에 나타나며, 과도하게 생성된 혈전은 혈관을 막고 혈액 흐름을 방해하여 뇌경색, 뇌졸중, 심근 경색 등 다양한 뇌·심혈관계 질환을 야기하게 된다. As a constituent of human body, blood has various important functions such as transporting and buffering oxygen, nutrients, and wastes, maintaining body temperature, controlling osmotic pressure and ion balance, keeping moisture constant, controlling liquid, maintaining and controlling blood pressure, and defending the body. have. Normal blood circulation facilitates blood circulation as the blood coagulation reaction system and the thrombolytic reaction system in the body complement each other, and among them, the mechanism of the blood coagulation reaction system forms platelet thrombus by adhering and agglomerating platelets to blood vessel walls. In addition, it has been reported that the blood coagulation system is activated to form fibrin clots around platelet aggregates. Thrombotic disease occurs in abnormal cases due to various factors, such as the coagulation of platelets and plasma in the blood, fibrin breakdown, and the control and balance of coagulation inhibition processes. Excessive thrombus blocks blood vessels and impedes blood flow, leading to cerebral infarction and stroke. And myocardial infarction.
한편, 피브린 혈전의 생성은 수 많은 혈액 응고 인자들의 여러 단계 반응을 거쳐 피브린 응고에 관여하는 트롬빈이 활성화되어, 최종적으로 피브리노겐으로부터 피브린 단량체를 생성하게 하며, 피브린 단량체들은 칼슘에 의해 중합되어, 혈소판과 내피세포에 결합하게 되며 XIII 인자에 의해 교차 결합된 피브린 폴리머를 형성하면서 영구적인 혈전을 생성하게 된다. 또한, 트롬빈은 혈소판, V 인자, VII 인자들을 활성화시켜 혈액 응고 반응을 촉진시키는 등 혈전 생성에 중추적 역할을 하게 된다. 따라서, 트롬빈의 활성 저해 물질은 과다한 혈액 응고 이상으로 발생하는 다양한 혈전성 질환에 매우 유용한 예방 및 치료제로 사용될 수 있다. 한편, 내인성 혈전 생성 경로에는 XII 인자, XI 인자, IX 인자, X 인자의 순차적 활성화에 이은 프로트롬빈의 활성화가 최종적으로 트롬빈을 활성화하는 것으로 알려져 혈액 응고 인자의 특이적 저해 역시 중요한 혈전성 질환 치료제의 개발 타겟이 되고 있다. 현재까지 혈전성 질환의 예방과 치료에 헤파린, 쿠마린, 아스피린, 유로키네이즈 등의 다양한 항응고제, 항혈소판제, 혈전용해제 등이 사용되고 있으나, 이들은 가격이 매우 높을 뿐 아니라, 출혈성 부작용과 위장 장해 및 과민 반응 등으로 그 사용이 한정되고 있는 실정이다. On the other hand, the generation of fibrin thrombi undergoes a multi-step reaction of numerous blood coagulation factors, which activates thrombin, which is involved in fibrin coagulation, and finally generates fibrin monomers from fibrinogen, which are polymerized by calcium, It binds to endothelial cells and creates permanent thrombus, forming fibrin polymers cross-linked by factor XIII. In addition, thrombin plays a pivotal role in thrombus generation by activating platelets, factor V and factor VII to promote blood coagulation. Therefore, thrombin's activity inhibitory substance can be used as a prophylactic and therapeutic agent which is very useful for various thrombotic diseases caused by excessive blood clotting. Meanwhile, in the endogenous thrombus generation pathway, sequential activation of XII, XI, IX and X factors is followed by the activation of prothrombin, which is known to activate thrombin. It is targeted. Until now, various anticoagulants, antiplatelets, thrombolytics such as heparin, coumarin, aspirin, urokinase, etc. have been used for the prevention and treatment of thrombotic diseases, but they are very expensive, and hemorrhagic side effects, gastrointestinal disorders and hypersensitivity reactions Its use is limited to such circumstances.
표고버섯은 담자균강 주름버섯목 느타리과 잣버섯속에 속하는 식용 버섯으로 버섯 중 비타민 C의 함량이 가장 많으며, 각종 아미노산과 에르고스테롤 (ergosterol)을 다량 함유하고 있다. 건강 기능성 측면에서 항암, 폐질환 및 위장 질환 예방, 바이러스에 대한 면역 증강, 항체 생성 촉진, 혈압 강하, 동맥경화 예방, 혈중 지질 농도 조절 기능, 당뇨 억제 효과 등이 알려져 있다. Shiitake mushroom is a edible mushroom belonging to the genus Pleurotus eryngii and pine nuts, which have the highest content of vitamin C and contain a large amount of various amino acids and ergosterol. In terms of health function, anti-cancer, lung disease and gastrointestinal disease prevention, virus immunity enhancement, antibody production promotion, blood pressure lowering, arteriosclerosis prevention, blood lipid concentration control function, diabetes suppression effect and the like are known.
표고버섯과 관련된 특허로는 대한민국 등록특허 제10-1839507호 [표고버섯과 표고버섯 발효물이 함유된 양념 창난 젓갈 제조방법], 제10-1830763호 [표고버섯 추출물을 포함하는 쌀된장의 제조방법 및 이로부터 제조된 쌀된장], 제10-1823460호 [표고버섯분말을 이용한 반건조 우럭의 제조방법], 제10-1759312호 [표고버섯가루의 제조방법, 표고버섯가루를 이용한 영양바의 제조방법 및 이에 의해 제조된 영양바], 제10-1673573호 [표고버섯차의 제조방법 및 이로 제조된 표고버섯차]가 개시되어 있으며, 대한민국 공개특허 제10-2004-0038957호 [표고버섯분말을 함유한 김(laver) 제조를 주제로 한 식품]이 공개되어 있다. 현재까지 알려진 대부분의 특허는 표고버섯 재배법 및 표고버섯을 이용한 다양한 식품 제조에 대한 것으로, 표고버섯의 유용 생리 활성에 대한 특허는 매우 제한되어 있는 실정이다.Patents related to shiitake mushrooms include Korean Registered Patent No. 10-1839507 [Method for preparing seasoned salted fish sauce containing shiitake mushroom and shiitake mushroom fermentation], No. 10-1830763 [Manufacturing method of rice miso including shiitake mushroom extract] And rice miso prepared therefrom, No. 10-1823460 [Method for preparing semi-dried urok using shiitake mushroom powder], No. 10-1759312 [Method for preparing shiitake mushroom powder, preparation of nutrition bar using shiitake mushroom powder] Method and nutrition bar prepared thereby, No. 10-1673573 [Preparation method of shiitake mushroom tea and shiitake mushroom tea prepared therefrom], Korean Patent Publication No. 10-2004-0038957 Foods based on the manufacture of laver containing. Most of the patents known to date are for cultivating shiitake mushrooms and preparing various foods using shiitake mushrooms, and patents on useful physiological activities of shiitake mushrooms are very limited.
또한, 표고버섯의 유용 생리 활성 관련 특허로는 대한민국 등록특허 제10-1487742호 [표고버섯과 천마 추출물을 포함하는 항산화 효능을 갖는 식품 조성물], 제10-1806808호 [표고버섯 균사체를 이용하여 발효시킨 적하수오 발효물을 유효성분으로 함유하는 여성 갱년기 증상의 예방, 개선 또는 치료용 조성물], 제10-1611947호 [혈관 질환 예방 및 개선용 건강 식품 조성물 및 그 제조방법], 제10-1266528호 [표고버섯 균사체 배양물에서 추출된 다당체를 유효성분으로 함유하는 보습 및/또는 미백용 화장료 조성물]이 개시되어 있으며, 공개특허 제10-2017-0036912호 [표고버섯 추출물을 유효성분으로 함유하는 아토피 및 접촉성 피부염 예방 및 개선용 조성물], 공개특허 제10-2003-0056753호 [표고버섯 균사체, 아가리쿠스 균사체, 수용성 키토산을 함유하는 비만 조절용 건강 식품 조성물], 제10-2008-0110212호 [표고버섯 열수 추출물을 이용한 골길이 성장에 도움을 주는 조성물]이 공개되어 있다. 특히, 혈전증과 관련한 상기 대한민국 등록특허 제10-1611947호는 희렴, 하수오, 석창포, 원지, 표고버섯, 꽃송이버섯을 유효성분으로 포함하는 것을 특징으로 하는 [혈관 질환 예방 및 개선용 건강 식품 조성물 및 그 제조방법]이 개시되어 있으나, 약재 희렴을 주성분으로 하고 있어 현재까지 표고버섯 유래의 강력한 혈액 응고 저해를 통한 안전하면서도 실제적 이용 가능한 항혈전 조성물은 알려진 바 없는 실정이다.In addition, patents related to useful physiological activity of shiitake mushrooms are registered in Korean Patent No. 10-1487742 [Food composition having antioxidant efficacy including shiitake mushroom and cheonma extract], No. 10-1806808 [Fermentation using shiitake mushroom mycelium] A composition for the prevention, improvement or treatment of women's menopausal symptoms containing the prepared dropwise fermentation product as an active ingredient], No. 10-1611947 [Health food composition for preventing and improving vascular disease and preparation method thereof], No. 10-1266528 [Moisturizing and / or whitening cosmetic composition containing a polysaccharide extracted from shiitake mushroom mycelium culture as an active ingredient] is disclosed, and atopy containing shiitake mushroom extract as an active ingredient. And composition for preventing and improving contact dermatitis], Patent Publication No. 10-2003-0056753 [Health for the control of obesity containing shiitake mycelium, Agaricus mycelium, water-soluble chitosan Product composition], the No. 10-2008-0110212 [composition to aid in bone growth using the mushroom hot-water extract; this is disclosed. In particular, the Republic of Korea Patent No. 10-1611947 associated with thrombosis [Health food composition for preventing and improving vascular disease and its characteristics, characterized in that it comprises Happiness, Sewao, Seokchangpo, Wonji, Shiitake, Blossom mushroom as an active ingredient [Method of manufacture] is disclosed, but the anti-thrombotic composition that is safe and practically available through the inhibition of potent blood coagulation derived from shiitake mushroom has been known as a main ingredient of medicinal herb.
한편, 국내 식용버섯의 년간 총 생산량은 2013년 173,354 톤에서 2017 년 162,292 톤으로 보고되어 있으며, 2017 년의 경우 느타리버섯이 58,784 톤, 새송이 버섯이 48,588 톤, 팽이버섯이 38,092 톤, 양송이 버섯이 10,173 톤이 생산되었으며, 표고버섯 생산량은 25,000 톤으로 추정되고 있다 (농림축산식품부, 2016. 특용작물 생산실적). 이러한 버섯 재배는 천연 배지에서 점차 특정의 인공 배지를 사용하는 방식으로 변화되고 있다. 버섯의 인공 재배 및 생산량이 증가하면서, SMS의 배출도 급속도로 증가되고 있다. 일반적으로 버섯 1 kg 생산에 버섯 배지가 5 kg이 소비되는 것을 감안할 때, 국내 SMS는 년간 200만 톤 이상이 배출되는 것으로 추정된다. 특히 표고버섯의 경우, 다양한 나무의 톱밥 배지를 사용하는데, 2015 년 중국에서 수입된 톱밥 배지는 36,285 톤으로 2012 년 11,825 톤이었던 수입량과 비교하면 3 년만에 2 배 이상 증가하였다 (관세청 수출입통계; 주간조선, 2016. 4. 11).Meanwhile, the annual total production of domestic edible mushrooms is reported from 173,354 tons in 2013 to 162,292 tons in 2017.In 2017, 58,784 tons of oyster mushrooms, 48,588 tons of mushrooms of mushrooms, 38,092 tons of mushrooms of mushrooms, and 10,173 of mushrooms of mushrooms Tons were produced, and shiitake mushroom production is estimated at 25,000 tons (Ministry for Food, Agriculture, Forestry and Livestock, 2016. Production of specialty crops). Such mushroom cultivation is gradually changing in a natural medium using a specific artificial medium. As the artificial cultivation and production of mushrooms increases, the emissions of SMS are also rapidly increasing. Given that 5 kg of mushroom medium is typically consumed to produce 1 kg of mushrooms, domestic SMS is estimated to emit more than 2 million tons per year. Especially for shiitake mushrooms, various wood sawdust badges are used.In 2015, sawdust badges imported from China were 36,285 tons, more than doubled in three years compared to 11,825 tons in 2012 (KCS import and export statistics; weekly Shipbuilding, April 11, 2016).
인공 배지를 사용하는 경우, 버섯 재배에는 20~25 %의 영양 성분이 소요된다고 알려져 있으며 (Williams et al, 2001. Biores Technol. 79:227-230.; Bae et al, 2006. J Anim Sci & Technol Kor. 48:237-246). 따라서, SMS에는 상당량의 영양성분이 잔존하게 된다. 또한, SMS에는 이미 버섯 균사체가 대량 배양된 상태이므로 버섯 자실체 및 균사체로부터 유래하는 β-glucosidase, cellulase 등의 다양한 효소와 식물 생육 촉진 유효성분, 항균 물질, 병 저항성 유도체 등의 다양한 생리 활성을 가진 이차대사산물이 포함되어 있는 것으로 알려져 있다 (Hautzel and Anke., 1990, Z Naturforsch. 45: 1093-1098; Lim et al., 2012. Mycobiology. 41: 160-166; Parada et al., 2012 Crop Protection 30: 443-450; Suess, 2006, Agriculture and Lands. pp. 1-101). 따라서, SMS는 영양적으로나 생리 활성적으로 우수한 소재로 사용될 수 있다. 그러나, 현재까지 SMS를 이용한 고부가가치 기능성 소재로의 개발 연구는 매우 제한된 실정으로 SMS의 효율적인 재이용에 대한 연구에 관심이 집중되고 있다. If artificial media are used, mushroom cultivation is known to require 20-25% of nutrients (Williams et al, 2001. Biores Technol. 79: 227-230 .; Bae et al, 2006. J Anim Sci & Technol Kor. 48: 237-246). Therefore, a considerable amount of nutrients remain in the SMS. In addition, since SMS is already cultured in mushroom mycelium, a variety of enzymes such as β-glucosidase and cellulase derived from mushroom fruiting bodies and mycelium, and various physiological activities such as plant growth promoting active ingredients, antibacterial substances, disease resistant derivatives, etc. Metabolites are known to be included (Hautzel and Anke., 1990, Z Naturforsch. 45: 1093-1098; Lim et al., 2012. Mycobiology. 41: 160-166; Parada et al., 2012 Crop Protection 30 : 443-450; Suess, 2006, Agriculture and Lands.pp. 1-101). Therefore, SMS can be used as a nutritionally and bioactively superior material. However, until now, research into the development of high value-added functional materials using SMS has been very limited, and attention has been focused on research on efficient reuse of SMS.
국내의 경우, SMS의 일부는 사료용으로 사용되기도 하였으며 (정종천 외, 2012. J. Mushroom Sci. Prod. 10: 174-178), 버섯 재배에 10~30 % 첨가하여 인공배지로 재이용 (이남길 외, 2015. J. Mushrooms, 13: 310-313)되기도 하였으나, 인공 배지에 톱밥 함량이 높은 경우, 사료나 버섯 재배에 재이용되지 못하고 거의 퇴비로 사용되고 있는 실정이다. 최근, 외국에서는 SMS의 다양한 미생물 및 효소를 이용하여 축사 폐기물을 효율적으로 정화하고자 하는 연구가 활발히 진행되고 있어 (Luo X 등, 2018, Bioresour. Technol. 250: 611-620; Meng L 등, 2018. Bioresour. Technol. 253: 197-203; Meng X 등, 2018. Bioresour. Technol. 251: 22-30), 향후 SMS는 새로운 환경정화제로 사용 가능성이 제시되고 있다. In Korea, some of the SMS has been used for feed (Jung Jong-cheon et al., 2012. J. Mushroom Sci. Prod. 10: 174-178), and it is reused as artificial medium by adding 10-30% to mushroom cultivation (Namgil et al., 2015. J. Mushrooms, 13: 310-313) However, if the artificial medium has a high sawdust content, it is not used for feed or mushroom cultivation and is almost used as compost. Recently, studies have been actively conducted to efficiently purify livestock waste using various microorganisms and enzymes of SMS (Luo X et al., 2018, Bioresour. Technol. 250: 611-620; Meng L et al., 2018. Bioresour.Technol. 253: 197-203; Meng X et al., 2018.Bioresour.Technol. 251: 22-30), future SMS is suggested as a new environmental purifier.
SMS의 유용 물질 함량은, 버섯 접종 전의 배지 조성 및 배양 버섯의 종류 및 상태에 의해 달라지게 된다. 현재까지 대부분의 연구는 팽이버섯 SMS에 집중되어 있었으나 (정종천 외, 2012. J. Mushroom Sci. Prod. 10: 174-178), 최근에는 노루궁뎅이버섯의 SMS (이상엽, 2015, The Korean Journal of Mycology 43: 185-190) 및 표고 톱밥 배지의 베타-글루칸 함량에 대해서도 연구되고 있다 (박영애, 2016. 한국균학회지, 44: 296-299). 현재까지 SMS의 알려진 유용 생리 활성으로는 큰느타리버섯, 표고버섯, 노루궁뎅이버섯의 SMS의 실온에서의 물 추출물의 고추 생육 촉진 및 역병 억제 효과 (곽아민 외, 2015. J. Mushrooms, 13: 16-20; Kang DS 외, 2017. Plant Pathology J. 33: 264-275) 및 느타리버섯 SMS의 물 추출물의 항염증 효과가 알려져 있다 (Rivero-Perez N. 등, 2016. Indian J Pharmacol. 48: 141-144). 또한, SMS의 주요 활성 성분으로는 수용성 고분자 다당류 (polysaccharide)가 주로 보고되어 있으며, 최근 표고버섯 SMS에서 항산화 활성의 고분자 다당류가 보고된 바 있으며 (Zhu H 등, 2018, Int. J. Biol. Macromol. 112: 976-978), 암세포 생육 억제 활성의 산성 다당류 (Zhang Y 등, 2017. Int. J. Med. Mushrooms. 19: 395-403) 및 항균 활성의 다당류도 확인되어 있다 (Zhu H, 2012, Int. J. Biol. Macromol. 50: 840-843). 그러나, 현재까지 표고버섯 SMS에서 강력한 항혈전 활성이 보고된 바는 없다. The useful substance content of the SMS will depend on the medium composition before the mushroom inoculation and the type and condition of the cultured mushrooms. To date, most of the research has been focused on top mushroom SMS (Jung Mushroom, et al., 2012. J. Mushroom Sci. Prod. 10: 174-178), but recently, SMS of snail mushroom (Lee Sang-yeop, 2015, The Korean Journal of Mycology 43: 185-190) and beta-glucan content of shiitake sawdust medium (Young-Ae Park, 2016. Korean Journal of Mycology, 44: 296-299). To date, the known useful physiological activities of SMS include the growth of pepper extract, shiitake mushroom, and locust mushroom in water, at room temperature, to promote the growth of red pepper and inhibit the plague (Kwak Amin et al., 2015. J. Mushrooms, 13: 16 -20; Kang DS et al., 2017. Plant Pathology J. 33: 264-275) and anti-inflammatory effects of water extracts of Oyster mushroom SMS are known (Rivero-Perez N. et al., 2016. Indian J Pharmacol. 48: 141 -144). In addition, water soluble polymer polysaccharide (polysaccharide) has been mainly reported as the main active ingredient of SMS, and recently, an antioxidant active polymer polysaccharide has been reported in shiitake mushroom SMS (Zhu H et al., 2018, Int. J. Biol. 112: 976-978), acidic polysaccharides that inhibit cancer cell growth (Zhang Y et al., 2017. Int. J. Med. Mushrooms. 19: 395-403) and antimicrobial polysaccharides (Zhu H, 2012). , Int. J. Biol.Macromol. 50: 840-843). However, no strong antithrombotic activity has been reported in shiitake SMS.
또한, 최근까지 SMS 관련 특허는 모두 SMS를 이용한 연료용 팰릿 제조 (대한민국 등록특허 제10-1728233호, 버섯 재배 후의 폐배지 또는 폐목재를 활용한 연료용 펠릿 제조방법), 사료 제조 (대한민국 공개특허 제10-2014-0066036호, 버섯 폐배지를 이용한 사료 및 이의 제조방법), 및 당화용 효소 제조 (대한민국 등록특허 제10-1458628호, 버섯 폐배지로부터 당화효소를 제조하는 방법)에 대한 것으로 표고버섯 SMS의 강력한 항혈전 활성에 대해서 알려진 바 없다. In addition, until recently, all of the SMS-related patents were manufactured for fuel pellets using SMS (Korean Patent No. 10-1728233, a method for producing pellets for fuel using waste medium or waste wood after mushroom cultivation), and feed production (Korea Patent Publication) No. 10-2014-0066036, feed using a mushroom waste medium and its manufacturing method), and the preparation of glycosylation enzyme (Korean Patent No. 10-1458628, a method for producing a glycosylase from mushroom waste medium) The potent antithrombotic activity of mushroom SMS is unknown.
본 발명은 상기와 같은 종래 기술의 문제점을 해결하기 위하여 안출된 것으로서, 본 발명에서 해결하고자 하는 과제는 표고버섯 인공 재배시 부산물로 발생하는 SMS의 추출물을 유효성분으로 함유하는 혈전증의 예방 또는 치료용 약학적 조성물 및 건강 기능 식품을 제공하고자 하는 것이다.The present invention has been made to solve the problems of the prior art as described above, the problem to be solved in the present invention is for the prevention or treatment of thrombosis containing the extract of SMS generated as a by-product during shiitake artificial cultivation as an active ingredient It is to provide a pharmaceutical composition and dietary supplement.
상기와 같은 과제를 해결하기 위하여, 본 발명은 표고버섯 (Lentinus edodes) 수확 후 배지 (Spent Mushroom Substrate, SMS) 추출물을 유효성분으로 함유하는 혈전증의 예방 또는 치료용 약학적 조성물을 제공한다.In order to solve the above problems, the present invention provides a pharmaceutical composition for preventing or treating thrombosis containing Lentinus edodes (Spent Mushroom Substrate, SMS) after harvest as an active ingredient.
상기 추출물은 열수 추출물인 것이 바람직하다.The extract is preferably a hot water extract.
상기 추출물은 열수 추출물을 헥센, 에틸아세테이트 및 부탄올로 순차적으로 분획하여 수득되는 에틸아세테이트 분획물, 부탄올 분획물 및 물 잔류물로 이루어지는 군으로부터 1 종 이상 선택되는 것이 바람직하다.The extract is preferably selected from the group consisting of ethyl acetate fraction, butanol fraction and water residue obtained by sequentially fractionating hot water extract with hexene, ethyl acetate and butanol.
또한, 본 발명은 표고버섯 (Lentinus edodes) 수확 후 배지 (Spent Mushroom Substrate, SMS) 추출물을 유효성분으로 함유하는 혈전증의 예방 또는 개선용 건강 기능 식품을 제공한다.The present invention also provides a dietary supplement for the prevention or improvement of thrombosis containing Lentinus edodes (Spent Mushroom Substrate, SMS) after harvest as an active ingredient.
상기 추출물은 열수 추출물인 것이 바람직하다.The extract is preferably a hot water extract.
상기 추출물은 열수 추출물을 헥센, 에틸아세테이트 및 부탄올로 순차적으로 분획하여 수득되는 에틸아세테이트 분획물, 부탄올 분획물 및 물 잔류물로 이루어지는 군으로부터 1 종 이상 선택되는 것이 바람직하다.The extract is preferably selected from the group consisting of ethyl acetate fraction, butanol fraction and water residue obtained by sequentially fractionating hot water extract with hexene, ethyl acetate and butanol.
본 발명의 혈전증의 예방 또는 치료용 약학적 조성물 및 건강 기능 식품의 유효성분으로서의 표고버섯 인공 재배시 부산물로 발생하는 SMS의 추출물은 혈전 생성 관련 효소의 저해 및 혈액 응고 인자의 저해에 의한 강력한 항혈전 활성을 나타냄과 동시에, 인간 적혈구에 대한 용혈 활성을 전혀 나타내지 않고, 열 안정성이 우수하고, pH 2의 산성 조건 및 혈장 내에서도 혈액 응고 인자 저해 및 혈전 생성 관련 효소 저해 효과의 손실이 나타나지 않으므로, 혈행 개선을 통해 허혈성 뇌졸중 및 출혈성 뇌졸중과 같은 혈전증의 예방 및 치료용으로 사용할 수 있을 것으로 기대되며, 상기 유효성분은 추출액, 분말, 환, 정 등의 다양한 형태로 가공되어 상시 복용이 가능한 형태로 조제할 수 있는 뛰어난 효과가 있으므로 제약 산업 및 식품 산업상 매우 유용한 발명인 것이다.Extract of SMS generated as a by-product during the artificial cultivation of shiitake mushroom as an active ingredient of the pharmaceutical composition for preventing or treating thrombosis of the present invention and a health functional food is a potent antithrombosis caused by inhibition of enzymes related to blood clotting and inhibition of blood coagulation factors At the same time, it exhibits no hemolytic activity against human erythrocytes, excellent thermal stability, and no loss of blood coagulation factor inhibition and thrombus formation related enzyme inhibitory effects even in acidic conditions and plasma at pH 2, thereby improving blood circulation. Through it is expected to be used for the prevention and treatment of thrombosis, such as ischemic stroke and hemorrhagic stroke, the active ingredient is processed into various forms such as extract, powder, pills, tablets can be prepared in a form that can be taken at all times Its outstanding effect makes it very useful for the pharmaceutical and food industries It is a person.
도 1은 좌측으로부터 우측 방향으로 실험에 사용한 표고버섯 재배용 살균 배지, 살균 배지에 표고버섯 종균을 접종 및 배양하여 표고버섯을 1 회 수확한 이후의 SMS, 3 회 수확한 이후의 SMS, 및 수확한 표고버섯의 사진도이다.
도 2는 좌측으로부터 우측 방향으로 실험에 사용한 표고버섯 재배용 살균 배지, 살균 배지에 표고버섯 종균을 접종 및 배양하여 표고버섯을 1 회 수확한 이후의 SMS, 3 회 수확한 이후의 SMS, 및 수확한 표고버섯 각각의 열수 추출물을 나타낸 사진도이다. 1 is a sterilization medium for shiitake mushroom cultivation used in the experiment from left to right, inoculation and incubation of shiitake spawn seedlings in sterilization medium, SMS after harvesting shiitake mushrooms once, SMS after harvesting 3 times, and harvesting A photograph of shiitake mushrooms.
Figure 2 is a sterilization medium for shiitake mushroom cultivation used in the experiment from left to right, inoculation and incubation of shiitake spawn seedlings in the sterilization medium SMS after harvesting shiitake mushrooms once, SMS after three harvests, and harvested Photograph showing the hydrothermal extract of each shiitake mushroom.
이하, 본 발명을 상세하게 설명한다.EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.
본 발명의 발명자들은 표고버섯 SMS의 항혈전 효능을 검증하기 위하여, 표고버섯 재배를 위한 살균 배지(접종 이전의 새 배지), 살균 배지에 표고버섯 종균을 접종 및 배양하여 표고버섯을 1 회 수확한 이후의 SMS, 3 회 수확한 이후의 SMS, 및 수확한 표고버섯 각각의 건조분말을 준비하였다. 이후, 일정 방법으로 각각의 열수 추출물을 조제하고, 이들의 항혈전 활성을 평가한 결과, 표고버섯 분말 및 살균 배지에서는 나타나지 않는 강력한 혈액응고 저해활성을 1 회 수확 후 SMS 및 3 회 수확 후 SMS에서 확인하였으며, 이후 각각의 추출물로부터 에틸아세테이트 분획물, 부탄올 분획물 및 유기용매 분획 후의 물 잔류물을 항혈전 활성 성분으로 회수하였으며, 상기 추출물 및 분획물은 인간 적혈구에 대해 용혈 활성은 전혀 나타내지 않으면서도, 열 안정성과 산 안정성이 우수한 특징을 가짐을 확인함으로써 상기 추출물 및 분획물을 혈전증의 예방 또는 치료/개선용 약학적 조성물 및 건강 기능 식품으로 활용하고자 하였다. In order to verify the antithrombotic efficacy of shiitake mushroom SMS, the inventors of the present invention inoculated and cultured with shiitake mushroom seedlings in sterilization medium (new medium before inoculation) and sterilization medium for cultivation of shiitake mushrooms, and harvested shiitake mushrooms once. Thereafter, SMS, three crops after harvesting, and dried powder of each of the harvested shiitake mushrooms were prepared. Subsequently, the hydrothermal extracts were prepared by a constant method, and their antithrombotic activity was evaluated. As a result, the anti-coagulation inhibitory activity, which is not found in shiitake mushroom powder and sterilization medium, was found in SMS after one harvest and SMS after three harvests. After that, ethyl acetate fraction, butanol fraction and water residue after organic solvent fraction were recovered from each extract as an antithrombotic active ingredient, and the extract and fraction were thermally stable without showing any hemolytic activity against human erythrocytes. By confirming that the peracid stability has excellent characteristics, the extracts and fractions were intended to be utilized as pharmaceutical compositions and health functional foods for the prevention or treatment / improvement of thrombosis.
구체적으로, 본 발명자들은 건강기능성 효과가 우수하다고 알려진 표고버섯의 균사체 및 미성숙 자실체가 대량 배양된 후의 SMS에서 혈전증의 예방 또는 치료/개선용 약학적 조성물 및 건강 기능 식품을 개발하기 위하여, 살균 배지, 표고버섯 1 회 수확 후 SMS, 표고버섯 3 회 수확 후 SMS의 영양 성분 분석, 이화학적 특성 분석에 이어, 상기 시료들을 대상으로 열수 추출물을 각각 조제하고, 항혈전 활성을 평가하였으며, 이후 강력한 활성을 나타내는 1 회 및 3 회 수확 후 SMS 열수추출물들을 대상으로 각각 헥센, 에틸아세테이트 및 부탄올로 순차적 유기용매 분획하고, 마지막으로 분획 후 물 잔류물을 조제하였다. 각각의 추출물과 분획물들의 항혈전 활성을 인간 혈장과 인간 트롬빈에 대한 트롬빈 직접 저해 (Thrombin Time), 프로트롬빈 저해 (Prothrombin Time) 및 활성부분 트롬보플라스틴 타임 (activated Partial Thromboplastin Time: aPTT)을 평가한 결과, 표고버섯 1 회 및 3 회 수확한 이후의 SMS 열수 추출물 및 이의 에틸아세테이트 분획물, 부탄올 분획물 및 물 잔류물에서 강력한 혈액응고 저해활성을 확인하였다. 이러한 항혈전 활성은 임상에서 항혈전제로 사용되고 있는 아스피린을 능가하는 강력한 항혈전 활성이었다. 또한, 상기 표고버섯 인공재배 시의 수확 후 SMS 열수 추출물 및 활성 분획물들은 인간 적혈구에 대한 용혈 활성은 나타내지 않음을 확인하였다. Specifically, the present inventors, in order to develop a pharmaceutical composition for the prevention or treatment / improvement of thrombosis and health functional food in SMS after mass culture of mycelia and immature fruiting bodies of shiitake mushrooms known to have excellent health functional effects, After the harvest of shiitake mushrooms, SMS, and the nutritional analysis and physicochemical characterization of SMS after harvesting shiitake mushrooms 3 times, hydrothermal extracts were prepared for the samples, and antithrombotic activity was evaluated. After the 1st and 3rd harvests, the SMS hot water extracts were subjected to sequential organic solvent fractionation with hexene, ethyl acetate and butanol, respectively, and finally water residues were prepared after the fractionation. The antithrombotic activity of each extract and fractions was evaluated for Thrombin Time, Prothrombin Time and Activated Partial Thromboplastin Time (aPTT) against human plasma and human thrombin. As a result, strong anticoagulant activity was confirmed in SMS hydrothermal extract and ethyl acetate fraction, butanol fraction and water residue after 1 and 3 times of shiitake mushroom harvesting. This antithrombotic activity was a potent antithrombotic activity that surpassed aspirin, which is used in the clinic as an antithrombotic agent. In addition, the SMS hydrothermal extract and active fractions after harvesting during shiitake mushroom cultivation did not show hemolytic activity against human erythrocytes.
따라서, 본 발명은 표고버섯 수확 후 배지 추출물을 유효성분으로 함유하는 혈전증의 예방 또는 치료용 약학적 조성물을 제공한다.Accordingly, the present invention provides a pharmaceutical composition for preventing or treating thrombosis containing shiitake mushroom harvest as an active ingredient.
상기 추출물은 열수 추출물인 것이 바람직하다.The extract is preferably a hot water extract.
상기 추출물은 열수 추출물을 헥센, 에틸아세테이트 및 부탄올로 순차적으로 분획하여 수득되는 에틸아세테이트 분획물, 부탄올 분획물 및 물 잔류물로 이루어지는 군으로부터 1 종 이상 선택되는 것이 바람직하다.The extract is preferably selected from the group consisting of ethyl acetate fraction, butanol fraction and water residue obtained by sequentially fractionating hot water extract with hexene, ethyl acetate and butanol.
또한, 본 발명은 표고버섯 수확 후 배지 추출물을 유효성분으로 함유하는 혈전증의 예방 또는 개선용 건강 기능 식품을 제공한다.The present invention also provides a health functional food for preventing or improving thrombosis containing shiitake mushroom harvest as an active ingredient.
상기 추출물은 열수 추출물인 것이 바람직하다.The extract is preferably a hot water extract.
상기 추출물은 열수 추출물을 헥센, 에틸아세테이트 및 부탄올로 순차적으로 분획하여 수득되는 에틸아세테이트 분획물, 부탄올 분획물 및 물 잔류물로 이루어지는 군으로부터 1 종 이상 선택되는 것이 바람직하다.The extract is preferably selected from the group consisting of ethyl acetate fraction, butanol fraction and water residue obtained by sequentially fractionating hot water extract with hexene, ethyl acetate and butanol.
이하에서는, 본 발명의 표고버섯 인공재배 시의 수확 후 SMS 추출물 및 각 활성 분획 물질의 제조 방법 및 효능 실험 등을 보다 구체적으로 설명한다.Hereinafter, the method of producing and extracting the SMS extract and each active fraction material during the shiitake mushroom artificial cultivation of the present invention will be described in more detail.
본 발명은 표고버섯 인공 재배를 위한 살균 배지, 살균 배지에 표고버섯 종균을 접종 및 배양하여 표고버섯을 1 회 수확한 이후의 SMS, 3 회 수확한 이후의 SMS, 및 수확한 표고버섯의 각각의 분말을 준비하는 단계; 상기 4 종 시료로부터 추출물을 조제하는 단계; 상기 추출물의 항혈전 활성 평가 단계; 강력한 항혈전 활성을 나타내는 표고버섯 인공재배 시의 수확 후 SMS 추출물로부터 헥센, 에틸아세테이트 및 부탄올의 순차적 유기용매 분획물 조제 및 이후 얻어지는 물 잔류물의 조제 단계; 및 상기 분획물의 항혈전 활성 평가 단계 및 추출물과 활성 분획물의 활성 물질의 안정성 조사 단계를 포함한다.The present invention is a sterilization medium for artificial cultivation of shiitake mushrooms, inoculation and culture of shiitake mushroom seedlings in sterilization medium, SMS after harvesting shiitake mushrooms once, SMS after harvesting three times, and each of the harvested shiitake mushrooms Preparing a powder; Preparing an extract from the four samples; Evaluating the antithrombotic activity of the extract; Preparation of sequential organic solvent fractions of hexene, ethyl acetate and butanol from post-harvest SMS extracts during shiitake artificial cultivation exhibiting strong antithrombotic activity and subsequent water residues; And evaluating the antithrombotic activity of the fractions and investigating the stability of the active substances of the extracts and active fractions.
본 발명의 조성물에 포함되는 "표고버섯 인공재배 시의 수확 후 SMS 추출물"은 표고버섯을 접종 및 배양한 후 표고버섯을 1~3 회 수확한 이후의 폐기되는 SMS를 회수하여 분쇄하는 단계; 상기 분쇄된 SMS를 용매로 추출하는 단계 및 상기 추출액을 0.06 mm 이하의 여과망을 사용하여 여과하고, 이를 감압농축하는 단계에 의해 수득될 수 있다."SMS extract after harvesting shiitake mushroom cultivation" included in the composition of the present invention is a step of inoculating and cultivating shiitake mushrooms, and recovering and discarding the SMS that are discarded after harvesting shiitake mushrooms 1 to 3 times; Extracting the ground SMS with a solvent and filtering the extract using a filtering network of 0.06 mm or less, and concentrating it under reduced pressure.
본 발명에서 사용되는 용매는 물(냉수, 열수), 주정, 탄소수 1~4의 무수 또는 함수 저급 알코올(메탄올, 에탄올, 주정, 프로판올, 부탄올 등), 상기 저급알코올과 물과의 혼합용매 등을 이용할 수 있으며, 열수 추출이 가장 바람직하다.The solvent used in the present invention may be water (cold water, hot water), alcohol, anhydrous or hydrous lower alcohol having 1 to 4 carbon atoms (methanol, ethanol, alcohol, propanol, butanol, etc.), a mixed solvent of the lower alcohol and water, and the like. Hydrothermal extraction is most preferred.
상기 추출물, 바람직하게는 열수 추출물은 헥센, 에틸아세테이트 및 부탄올의 유기용매로 순차 또는 각각 분획하여 헥센 분획물, 에틸아세테이트 분획물, 부탄올 분획물 및 유기용매 분획 후의 물 잔류물을 추가적으로 수득할 수 있다.The extract, preferably hot water extract, may be sequentially or separately fractionated with an organic solvent of hexene, ethyl acetate and butanol to additionally obtain a water residue after hexene fraction, ethyl acetate fraction, butanol fraction and organic solvent fraction.
본 발명에서는, 표고버섯 재배용 살균 배지 추출물, 1 회 수확 후 SMS 추출물, 3 회 수확 후 SMS 추출물 및 표고버섯 건조분말의 추출물을 각각 5 mg/ml의 농도로 트롬빈 타임, 프로트롬빈 타임 및 에이피티 타임을 측정한 결과, 살균 배지 추출물 및 표고버섯 분말 추출물은 미약한 항혈전 활성을 나타낸 반면, 1 회 및 3 회 수확 후 SMS 추출물은 매우 강력한 트롬빈 저해 및 응고 인자 저해를 나타내었다. 상기 수확 후 SMS 추출물은 6 mg/ml 농도에서는 무첨가구에 비해 트롬빈 타임, 에에피티 타임을 모두 15 배 이상 연장시켜 매우 강력한 혈액 응고 저해 효과를 나타냄을 확인하였으며, 2.5 mg/ml 농도에서도 무첨가구에 비해 2.35~3.84 배 연장된 트롬빈 타임 및 2.95~3.46 배 연장된 에이피티 타임을 보였다. In the present invention, the sterilized medium extract for shiitake mushroom cultivation, the SMS extract after one harvest, the SMS extract after three harvests, and the extract of the shiitake mushroom dry powder at the concentration of 5 mg / ml, respectively, As a result, the bactericidal medium extract and shiitake powder extract showed weak antithrombotic activity, whereas after one and three harvests, the SMS extract showed very strong thrombin inhibition and coagulation factor inhibition. After the harvest, the SMS extract showed a very strong blood coagulation inhibitory effect by prolonging both thrombin time and epitaxial time by more than 15 times compared to the non-added group at 6 mg / ml concentration, even at 2.5 mg / ml concentration. The thrombin time was 2.35 ~ 3.84 times longer and the 2.95 ~ 3.46 times longer time.
상기 결과들로부터, 표고버섯 1 회 및 3 회 수확 후의 부산물인 1 회 및 3 회 수확 후 SMS 추출물의 유기용매 분획물 및 물 잔류물을 조제하였으며, 이들의 혈액응고 저해활성을 각각 평가한 결과, 1 회 수확 후 SMS 추출물의 에틸아세테이트 분획물 및 물 잔류물에서 매우 강력한 트롬빈 저해 및 응고 인자 저해를 확인하였으며, 3 회 수확 후 SMS 추출물의 에틸아세테이트 분획물, 부탄올 분획물 및 물 잔류물 모두에서 매우 강력한 트롬빈 저해 및 응고 인자 저해를 확인함으로서 표고버섯 수확 후의 SMS에는 다양한 용해도를 가진 다양한 항혈전 활성물질이 포함되어 있음을 확인하였다. 또한, 초기 살균 배지에서는 항혈전 활성이 미약하나, 1회 수확 후에서 3회 수확 후로 폐배지 상태가 될수록 강력한 항혈전 활성을 나타내므로, 이는 표고버섯 균사체, 자실체 및 배지 성분의 생물학적 전환 등의 복합적 변화에 의해 나타나는 활성 강화로 이해된다. From the above results, the organic solvent fractions and water residues of SMS extract after 1 and 3 harvests, which were by-products after 1 and 3 harvests of shiitake mushrooms, were prepared, and their blood coagulation inhibitory activity was evaluated. The strong thrombin inhibition and coagulation factor inhibition were confirmed in the ethyl acetate fraction and water residue of the SMS extract after the harvest, and the very strong thrombin inhibition in both the ethyl acetate fraction, butanol fraction and the water residue of the SMS extract after the third harvest. By confirming the inhibition of coagulation factor, it was confirmed that SMS after shiitake mushroom harvest contained various antithrombotic active substances with various solubilities. In addition, the anti-thrombotic activity is weak in the early sterilization medium, but as the lung medium after the first harvest after three harvests shows a strong antithrombotic activity, it is a complex such as biological conversion of shiitake mycelium, fruiting body and medium components It is understood as the enhancement of activity exhibited by the change.
특히, 1 차 수확 후 SMS 추출물의 에틸아세테이트 분획물은 매우 강력한 트롬빈 저해, 프로트롬빈 저해 및 응고 인자 저해를 나타내었으며, 이는 아스피린보다 우수한 항혈전 활성으로 확인되었다. 따라서, 표고버섯 재배 시의 부산물로 발생하는 수확 후 SMS의 추출물 및 이의 활성 분획물은, 위장 장애와 같은 부작용 우려가 높은 아스피린을 대치할 수 있는 항응고제 (혈액 응고 저해제)로 개발 가능함을 확인하였다. In particular, the ethyl acetate fraction of the SMS extract after the first harvest showed very strong thrombin inhibition, prothrombin inhibition and coagulation factor inhibition, which was confirmed to be superior to aspirin in antithrombotic activity. Therefore, it was confirmed that the post-harvest SMS extract and its active fractions, which are generated as a by-product of shiitake mushroom cultivation, could be developed as anticoagulants (blood coagulation inhibitors) that can replace aspirin, which has high side effects such as gastrointestinal disorders.
한편, 조제된 표고버섯 재배용 살균 배지 추출물, 1 회 수확 후 SMS 추출물, 3 회 수확 후 SMS 추출물 및 표고버섯 건조분말의 추출물을 각각 0.25mg/ml의 농도로 하여 인간 혈소판에 대한 응집 저해 효과를 확인한 결과, 재배용 살균 배지 추출물에서 무첨가구에 비해 72.6 %의 혈소판 응집을 나타내었으며, 기타 추출물 시료들은 95.9~118.6 %의 응집도를 나타내었다. 대조구로 사용된 아스피린이 0.25 mg/ml 농도에서 24.9 %, 0.125 mg/ml 농도에서 85.9 %의 응집도를 나타내므로, 재배용 살균 배지 이외의 추출물 시료들은 혈소판 응집 저해 활성이 인정되지 않았다. On the other hand, the antimicrobial inhibitory effect on human platelets was confirmed by using a concentration of 0.25 mg / ml prepared sterilized culture medium for shiitake mushroom cultivation, SMS extract after one harvest, SMS extract after three harvests and shiitake mushroom dry powder. As a result, cultivated sterilized medium extract showed 72.6% platelet aggregation compared to no addition group, and the other extract samples showed 95.9 ~ 118.6% aggregation. Since aspirin used as a control showed a cohesiveness of 24.9% at a concentration of 0.25 mg / ml and 85.9% at a concentration of 0.125 mg / ml, the extract samples other than the culture sterilization medium did not recognize platelet aggregation inhibitory activity.
또한, 조제된 표고버섯 1 회 및 3 회 수확 후 SMS의 추출물의 유기용매 분획물 및 물 잔류물의 인간 혈소판 응집 저해를 확인한 결과, 1 회 수확 후 SMS 추출물의 에틸아세테이트 분획물 (0.25 mg/ml) 및 부탄올 분획물 (0.25 mg/ml)에서 55.1 % 및 76.5 %의 혈소판 응집능을 확인하였으며, 3 회 수확 후 SMS 추출물의 에틸아세테이트 분획물 (0.25 mg/ml)에서는 95.0 %의 혈소판 응집능을 확인하였다. 이와 같은 활성은 동일 농도의 아스피린보다는 낮은 응집 저해능이기는 하지만, 아스피린과 같은 부작용이 알려진 항혈전제를 대치할 수 있는 유용 발효 소재로서 혈소판 응집 저해제의 용도로서도 이용될 수 있음을 확인하였다. In addition, as a result of confirming inhibition of human platelet aggregation of organic solvent fraction and water residues of the extract of SMS after one and three harvests of prepared shiitake mushrooms, ethyl acetate fraction (0.25 mg / ml) and butanol of SMS extract after one harvest The platelet aggregation ability of 55.1% and 76.5% was confirmed in the fraction (0.25 mg / ml), and the platelet aggregation ability of 95.0% was confirmed in the ethyl acetate fraction (0.25 mg / ml) of SMS extract after three harvests. Although this activity has a lower aggregation inhibitory effect than the same concentration of aspirin, it was confirmed that side effects such as aspirin can be used as a platelet aggregation inhibitor as a useful fermentation material to replace the known anti-thrombotic agents.
본 발명의 표고버섯 인공 재배 시의 버섯 수확 후 SMS 추출물 및 이의 활성 분획물들은 감압건조 및 동결건조, 또는 분무건조 등과 같은 통상적인 분말화 과정을 거쳐 분말로 제조될 수 있다. 이들은 혈장 내의 다양한 분해효소에 분해되지 않으며, 100 ℃의 열처리와 pH 2의 인체 위 내의 pH에서도 활성을 유지한다.After the mushroom harvest during shiitake mushroom artificial cultivation of the present invention, the SMS extract and its active fractions may be prepared into powder through a conventional powdering process such as vacuum drying and freeze drying, or spray drying. They are not degraded by various degrading enzymes in plasma and remain active even at a heat treatment of 100 ° C. and pH in the human stomach at pH 2.
본 발명의 유효성분은 혈전증과 관련된 다양한 질환들의 예방 또는 치료용으로 사용될 수 있다. 상기 질환들은, 예를 들어, 동맥 혈전증으로서, 급성 심근 경색증, 가슴 통증, 호흡 곤란, 의식 소실, 허혈성 뇌졸중, 출혈성 뇌졸중, 두통, 운동 이상, 감각 이상, 성격 변화, 시력 저하, 간질 발작, 폐 혈전증, 심부정맥 혈전증, 하지 부종, 통증 및 급성 말초 동맥 폐쇄증 등을 들 수 있고, 정맥 혈전증으로서, 심부정맥 혈전증, 간문맥 혈전증, 급성 신장정맥 폐쇄증, 뇌 정맥동 혈전증 및 중심 망막정맥 폐쇄 등을 들 수 있다.The active ingredient of the present invention can be used for the prevention or treatment of various diseases associated with thrombosis. The diseases are, for example, arterial thrombosis, acute myocardial infarction, chest pain, shortness of breath, loss of consciousness, ischemic stroke, hemorrhagic stroke, headache, dyskinesia, paresthesia, personality changes, decreased vision, epileptic seizures, pulmonary thrombosis , Deep vein thrombosis, lower extremity edema, pain, and acute peripheral arterial obstruction. Examples of venous thrombosis include deep vein thrombosis, portal vein thrombosis, acute renal vein occlusion, cerebral venous thrombosis, and central retinal vein occlusion.
본 발명의 유효 성분을 포함하는 약학적 조성물은 각각의 사용 목적에 맞게 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁제, 에멀젼, 시럽, 에어로졸 등의 경구 제형, 멸균 주사용액의 주사제 등 다양한 형태로 제형화하여 사용할 수 있으며, 경구 투여하거나 정맥 내, 복강 내, 피하, 직장, 국소 투여 등을 포함한 다양한 경로를 통해 투여될 수 있다.The pharmaceutical composition comprising the active ingredient of the present invention may be prepared in accordance with conventional methods for the purpose of use, oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, and injectables of sterile injectable solutions. It may be formulated and used in various forms, and may be administered orally or through various routes including intravenous, intraperitoneal, subcutaneous, rectal, and topical administration.
이러한 약학적 조성물에는 추가적으로 담체, 부형제 또는 희석제 등이 더 포함될 수 있으며, 포함될 수 있는 적합한 담체, 부형제 또는 희석제의 예로는 락토오스, 덱스트로오스, 수크로오스, 솔비톨, 만니톨, 자일리톨, 에리쓰리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로스, 메틸 셀룰로스, 비정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 들 수 있다. 또한, 본 발명의 약학적 조성물은 충전제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 더 포함할 수도 있다.Such pharmaceutical compositions may further include carriers, excipients or diluents, and examples of suitable carriers, excipients or diluents that may be included include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, Starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, amorphous cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil Etc. can be mentioned. In addition, the pharmaceutical composition of the present invention may further include a filler, an anticoagulant, a lubricant, a humectant, a perfume, an emulsifier, a preservative, and the like.
바람직한 구체예로서, 경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 약학적 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로오스, 락토오스, 젤라틴 등을 혼합하여 제형화한다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 등과 같은 윤활제가 사용될 수도 있다.In a preferred embodiment, solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which solid preparations comprise at least one excipient such as starch, calcium carbonate, Sucrose, lactose, gelatin and the like are mixed and formulated. In addition to the simple excipients, lubricants such as magnesium stearate, talc and the like may also be used.
바람직한 구체예로서, 경구용 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 예시될 수 있으며, 흔히 사용되는 단순 희석제인 물, 액체 파라핀 이외에 여러 가지 부형제, 예를 들면, 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.As a preferred embodiment, oral liquid preparations may be exemplified by suspending agents, solvents, emulsions, syrups, and the like, and various excipients, for example, wetting agents, sweeteners, Fragrances, preservatives and the like.
바람직한 구체예로서, 비경구 투여를 위한 제제에는 멸균된 수용액제, 비수성용제, 현탁제, 유제, 동결건조제, 좌제 등을 예시할 수 있다. 비수성용제, 현탁제에는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 포함될 수 있다. 주사제에는 용해제, 등장화제, 현탁화제, 유화제, 안정화제, 방부제 등과 같은 종래의 첨가제가 포함될 수 있다.As a preferred embodiment, the preparation for parenteral administration may be sterile aqueous solution, non-aqueous solvent, suspension, emulsion, lyophilized, suppository and the like. Non-aqueous solvents and suspending agents may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like. Injectables may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives, and the like.
본 발명의 유효 성분은 약제학적으로 유효한 양으로 투여한다. 본 발명에서, "약제학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The active ingredient of the present invention is administered in a pharmaceutically effective amount. In the present invention, “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level means the type, severity, activity of the drug, Sensitivity to drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of drugs, and other factors well known in the medical arts. The pharmaceutical compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can achieve the maximum effect with a minimum amount without side effects, which can be readily determined by one skilled in the art.
바람직한 구체예로서, 본 발명의 약학적 조성물에서 유효성분의 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 ㎏ 당 1 내지 5,000 mg, 바람직하게는 100 내지 3,000 mg을 매일 또는 격일 투여하거나 1 일 1 내지 3 회로 나누어 투여할 수 있다. 그러나, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.In a preferred embodiment, the effective amount of the active ingredient in the pharmaceutical composition of the present invention may vary depending on the age, sex, and weight of the patient, and generally 1 to 5,000 mg, preferably 100 to 3,000 mg per kg body weight daily. Or every other day or divided into 1 to 3 times daily. However, since the dose may be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, etc., the above dosage does not limit the scope of the present invention by any method.
본 발명의 약학적 조성물은 다양한 경로를 통하여 대상에 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관 내 (intracerebroventricular) 주사에 의해 투여될 수 있다.The pharmaceutical composition of the present invention can be administered to a subject through various routes. All modes of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
본 발명에서 "투여"는 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 본 발명의 약학적 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 일반적인 모든 경로를 통하여 경구 또는 비경구 투여될 수 있다. 또한, 본 발명의 조성물은 유효성분을 표적 세포로 전달할 수 있는 임의의 장치를 이용해 투여될 수도 있다.As used herein, "administration" means providing a patient with any substance by any suitable method, wherein the route of administration of the pharmaceutical composition of the present invention is oral or parenteral via all common routes as long as the target tissue can be reached. Oral administration. In addition, the composition of the present invention may be administered using any device capable of delivering an active ingredient to a target cell.
본 발명에서 "대상"은, 특별히 한정되는 것은 아니지만, 예를 들어, 인간, 원숭이, 소, 말, 양, 돼지, 닭, 칠면조, 메추라기, 고양이, 개, 마우스, 쥐, 토끼 또는 기니아 피그를 포함하고, 바람직하게는 포유류, 보다 바람직하게는 인간을 의미한다."Subject" in the present invention is not particularly limited, but includes, for example, humans, monkeys, cattle, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits or guinea pigs. And preferably mammals, and more preferably humans.
또한, 본 발명의 건강 기능 식품은 혈전증의 예방 또는 개선에 효과적인 식품 및 음료 등에 다양하게 이용될 수 있다. 본 발명의 유효성분을 포함하는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있고, 분말, 과립, 정제, 캡슐 또는 음료인 형태로 사용할 수 있다.In addition, the health functional food of the present invention can be used in a variety of foods and beverages and the like effective in preventing or improving thrombosis. Examples of the food containing the active ingredient of the present invention include various foods, beverages, gums, teas, vitamin complexes, health supplements, and the like, and can be used in the form of powders, granules, tablets, capsules, or beverages. .
본 발명의 유효성분은 일반적으로 전체 식품 중량의 0.01 내지 15 중량%로 가할 수 있으며, 건강음료 조성물은 100 ml를 기준으로 0.02 내지 10 g, 바람직하게는 0.3 내지 1 g의 비율로 가할 수 있다.The active ingredient of the present invention can generally be added in 0.01 to 15% by weight of the total food weight, the health beverage composition may be added in a ratio of 0.02 to 10 g, preferably 0.3 to 1 g based on 100 ml.
본 발명의 건강 기능 식품은 지시된 비율로 필수 성분으로서 상기 화합물을 함유하는 것 외에 식품학적으로 허용 가능한 식품보조 첨가제, 예컨대, 천연 탄수화물 및 다양한 향미제 등을 추가 성분으로서 함유할 수 있다. In addition to containing the compound as an essential ingredient in the indicated proportions, the health functional food of the present invention may contain as food additives food additives such as natural carbohydrates and various flavoring agents.
상기 천연 탄수화물의 예로는 포도당, 과당 등의 단당류, 말토오스, 수크로오스 등의 이당류 및 덱스트린, 시클로덱스트린 등의 다당류와 같은 통상적인 당 및 자일리톨, 소르비톨, 에리쓰리톨 등의 당알코올이 있다. Examples of the natural carbohydrate include conventional sugars such as monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol.
상기 향미제로는 타우마틴; 레바우디오시드 A 또는 글리시르히진과 같은 스테비아 등의 천연 향미제 및 사카린, 아스파르탐 등의 합성 향미제를 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 건강 기능 식품 100 ml 당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g을 사용한다. 상기 외에 본 발명의 건강 기능 식품은 여러 가지 영양제, 비타민, 광물, 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 건강 기능 식품은 천연 과일 주스 및 과일 주스 음료 및 야채 음료 등의 제조를 위한 과육을 함유할 수도 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 본 발명의 유효성분 100 중량부 당 0.01 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.As the flavoring agent, taumartin; Natural flavors such as stevia such as rebaudioside A or glycyrzin and synthetic flavors such as saccharin and aspartame can be used. The ratio of the natural carbohydrate is generally used from about 1 to 20 g, preferably from about 5 to 12 g per 100 ml of the health functional food of the present invention. In addition to the above, the health functional food of the present invention includes various nutrients, vitamins, minerals, synthetic flavors and natural flavoring agents, colorants and neutralizing agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloids Thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like. In addition, the health functional food of the present invention may contain flesh for preparing natural fruit juice, fruit juice beverage, vegetable beverage and the like. These components can be used independently or in combination. The proportion of such additives is generally selected from 0.01 to about 20 parts by weight per 100 parts by weight of the active ingredient of the present invention.
이하에서는 실시예를 통하여 본 발명을 더욱 상세하게 설명한다. 하기 실시예는 본 발명의 바람직한 일 구체예일 뿐이며, 본 발명의 권리범위가 하기 실시예의 범위로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. The following examples are only preferred embodiments of the present invention, and the scope of the present invention is not limited to the following examples.
[실시예]EXAMPLE
실시예 1: 표고버섯 재배용 살균 배지, 1 회 수확 후 SMS, 3 회 수확 후 SMS 및 표고버섯의 이화학적 특성 분석 및 색 분석 Example 1: Physicochemical Characterization and Color Analysis of Shiitake Mushroom Sterilization Medium, SMS after One Harvest, SMS and Shiitake Mushroom After Three Harvests
2017년 중국 금전시에 제조된 표고버섯 재배용 배지 (조성: 참나무 80 %, 밀기울 19 %, 식용석고 1 %)를 압착 밀봉하고, 이를 100 ℃에서 8 시간 살균하여 무균 배지를 조제한 다음, 표고버섯 종균 808을 접종하여 약 120 일간 배양실 배양하고, 다시 재배사에서 40 일간 23 ℃, 습도 70 % 조건에서 배양한 후 발생 작업을 하였다. 이후, 생성된 표고버섯을 1 회 수확 (1 주기 수확)한 이후 1 회 수확 후 SMS를 준비하였으며, 이후 표고버섯을 재발생하여 2 회 (2 주기 수확) 및 3 회 수확 (3 주기 수확)하였으며, 이후 남은 3 회 수확 후 SMS를 회수하였다 (도 1).Shiitake mushroom cultivation medium (composition: oak 80%, bran 19%, edible gypsum 1%) prepared in 2017 at the Chinese cash register was press-sealed and sterilized at 100 ℃ for 8 hours to prepare a sterile medium, 808 was inoculated and incubated in the culture room for about 120 days, and then incubated in a grower for 40 days at 23 ° C. and 70% humidity conditions, and then generated. Thereafter, the resulting shiitake mushrooms were harvested once (1 cycle harvest) and then SMS was prepared after 1 harvest. Then, the shiitake mushrooms were re-generated 2 times (2 cycles harvesting) and 3 times (3 cycles harvesting). SMS was recovered after the remaining three harvests (FIG. 1).
상기의 살균 배지, 1회 수확 후 SMS, 3 회 수확 후 SMS 및 수확한 표고버섯의 사진도는 도 1에 나타내었으며, 이의 조단백, 조탄수화물, 조지질, 회분 및 수분함량을 식품공전에 따라 측정하여 열량을 표 1에 나타내었다.The photographs of the sterilization medium, SMS after one harvest, SMS after three harvests, and harvested shiitake mushrooms are shown in FIG. 1, and the crude protein, carbohydrate, crude lipid, ash and moisture content thereof were measured according to food regulations. The calories are shown in Table 1.
[표 1] 살균 배지, 1 회 수확 후 SMS, 3 회 수확 후 SMS 및 표고버섯의 영양 성분 분석[Table 1] Nutritional analysis of sterilization medium, SMS after 1 harvest, SMS and shiitake mushroom after 3 harvests
수분함량은 초기 46.8 %에서 1 차 수확 후 52.6 %, 3 차 수확 후 54.0 %로 변화하였으며, 조단백은 살균 배지에서 3.1 %이었으나, 수확 후 SMS에서는 6.75~7.5 %로 2 배 이상 증가하였다. 회분 함량 역시 살균 배지에서는 6.55 %이었으나, 수확 후 SMS에서는 14.77~14.93 %로 급격히 증가하였다. 표고버섯의 회분 함량은 0.8 %를 나타내었다. 반면, 조지질 함량은 변화가 미미하였으며, 조탄수화물은 1 차 수확 후에는 43.3 %에서 25.7 %로 급격히 감소하였다가 3 차 수확 후에는 23.2 %를 나타내었다. 이는 1 차, 3 차 수확 후의 배지가 다량의 표고버섯 균사체 및 자실체를 함유하여 나타난 결과로 판단된다. Moisture content was changed from 46.8% at the beginning to 52.6% after the first harvest and 54.0% after the third harvest. The crude protein was 3.1% in the sterile medium, but increased more than twice from 6.75% to 7.5% in the SMS after harvesting. Ash content was also 6.55% in sterilization medium, but after harvest, it increased rapidly from 14.77 to 14.93% in SMS. Ash content of shiitake mushroom was 0.8%. On the other hand, crude lipid content was minimal and crude carbohydrates decreased rapidly from 43.3% to 25.7% after the first harvest and 23.2% after the third harvest. This is judged to be the result of the medium after primary and tertiary harvest containing a large amount of shiitake mycelium and fruiting body.
한편, 표고버섯 배지 및 표고버섯의 분쇄 후 각각의 시료의 색 분석 결과, 살균 배지는 상대적으로 낮은 명도, 적색도, 황색도를 나타내어 색차는 73.3을 나타내었으며, 1 회 수확 후 SMS 및 3 회 수확 후 SMS는 각각 46.3 및 44.75를 나타내어 유사한 명도, 적색도, 황색도를 나타내었다 (표 2). 이때, 색차 분석은 Hunter Color Difference meter (Super color SP-80 Colormeter, Tokyo Denshoku Co., Japan)를 이용하여 측정하였으며, 명도 (백색 100 ~ 0 검정색), 적색도 (적색 100 ~ -80 녹색), 황색도 (황색 70 ~ -80 검정색)를 측정하였다. 이때, 표준백판의 색도는 L값이 92.44, a값이 -0.06, b값이 1.35로 기준을 정하였으며, 시료 당 3 회 측정하여 평균값을 구하여 나타내었고, 색차(△E)는 다음의 식을 이용하여 계산하였다.On the other hand, as a result of the color analysis of each sample after grinding the shiitake mushroom medium and shiitake mushroom, the sterilization medium showed relatively low brightness, redness, yellowness, and the color difference was 73.3. Post SMS showed 46.3 and 44.75, respectively, showing similar brightness, redness and yellowness (Table 2). At this time, the color difference analysis was measured using a Hunter Color Difference meter (Super color SP-80 Colormeter, Tokyo Denshoku Co., Japan), brightness (white 100 ~ 0 black), redness (red 100 ~ -80 green), Yellowness (yellow 70-80 black) was measured. In this case, the chromaticity of the standard whiteboard was determined by L. value of 92.44, a value of -0.06, and b value of 1.35. The average value was obtained by measuring three times per sample, and the color difference (△ E) was expressed by the following equation. Calculated using.
[표 2] 살균 배지, 1 회 수확 후 SMS, 3 회 수확 후 SMS 및 표고버섯 분말의 색차 분석[Table 2] Color difference analysis of sterilization medium, SMS after one harvest, SMS and shiitake powder after three harvests
실시예 2: 살균 배지, 1 회 수확 후 SMS, 3 회 수확 후 SMS 및 표고버섯 열수 추출물 조제 및 이의 이화학적 특성 분석 Example 2: Preparation of sterile medium, SMS after one harvest, SMS and shiitake hot water extract after three harvests, and physicochemical characterization thereof
실시예 1에서 준비된 살균 배지, 1 회 수확 후 SMS, 3 회 수확 후 SMS, 표고버섯 건조 분말을 대상으로 열수 추출물을 조제하였다. 각각의 시료에 대해 10 배의 증류수를 가하고, 100 ℃에서 1 시간 추출한 후, 얻어진 추출물의 pH, brix 및 색차를 측정하였으며, 그 결과는 표 3에 나타내었다.A hydrothermal extract was prepared for the sterilization medium prepared in Example 1, SMS after one harvest, SMS after three harvests, and shiitake mushroom dry powder. 10 times of distilled water was added to each sample, and extracted at 100 ° C. for 1 hour, and then the pH, brix, and color difference of the obtained extract were measured, and the results are shown in Table 3.
[표 3] 살균 배지, 1 회 수확 후 SMS, 3 회 수확 후 SMS, 표고버섯 분말 열수 추출물의 이화학적 특성 [Table 3] Physicochemical Properties of Sterilized Medium, SMS after 1st Harvest, SMS after 3rd Harvest, Shiitake Powder Hydrothermal Extract
살균 배지의 초기 pH는 5.6이었으나, 1 회 및 3 회 수확 후 SMS의 경우, 4.6으로 감소되었다. 또한, 살균 배지의 초기 brix는 6.0에서 1 회 및 3 회 수확 후 SMS는 16.0과 20.0으로 증가되었으며, 산도 역시 초기 0에서 1 회 및 3 회 수확 후 SMS는 0.83, 1.40으로 증가하였다. 반면, 열수 추출물의 색 분석에서는 수확 횟수 증가에 따라 명도와 적색도의 감소 및 황색도의 증가가 나타났으며, 색차는 초기 살균 배지 76.8에서 3 차 수확 후 SMS에서는 78.2로 증가하였다. 즉, 표고버섯의 배양이 길어질수록 SMS는 산도 및 brix의 증가, 황색도의 증가가 두드러졌다 (도 2). The initial pH of the sterile medium was 5.6, but decreased to 4.6 for SMS after 1 and 3 harvests. In addition, the initial brix of the sterilization medium increased from 6.0 to 16.0 and 20.0 after 1 and 3 harvests, and the acidity also increased to 0.83 and 1.40 after 1 and 3 harvests. On the other hand, the color analysis of the hydrothermal extract showed that the lightness, redness and yellowness increased with increasing number of harvests, and the color difference increased from 76.8 in early sterilization medium to 78.2 in SMS after the third harvest. In other words, the longer the culture of shiitake mushrooms, the more noticeable the increase in acidity, brix, and yellowness of SMS were (Figure 2).
실시예 3: 살균 배지, 1 회 수확 후 SMS, 3 회 수확 후 SMS 및 표고버섯 열수 추출물의 성분 분석Example 3: Component analysis of sterilization medium, SMS after one harvest, SMS after three harvests, and shiitake hot water extract
실시예 2에서 제조된 열수 추출물을 필터링한 후, 감압 농축하여 분말로 제조하였으며, 각각의 추출 효율 및 추출물의 성분 분석 결과는 표 4에 나타내었다. 성분 분석으로 총 폴리페놀, 총 플라보노이드, 총당 및 환원당 함량을 측정하였다. 총 폴리페놀 함량은 추출 검액 400 μl에 50 μl의 Folin-ciocalteau, 100 μl의 Na2CO3 포화 용액을 넣고, 실온에서 1 시간 방치한 후 725 nm에서 흡광도를 측정하였다. 표준시약으로는 tannic acid를 사용하였다. 총 플라보노이드 함량은 각각의 시료를 18 시간 메탄올 교반 추출하고, 여과한 추출 검액 400 μl에 90 % diethylene glycol 4 ml를 첨가하고, 다시 1 N NaOH 40 μl를 넣고, 37 ℃에서 1 시간 반응 후 420 nm에서 흡광도를 측정하였다. 표준시약으로는 rutin을 사용하였다. 환원당은 DNS법으로, 총당은 phenol-sulfuric acid법을 이용하여 정량하였다. After filtering the hot water extract prepared in Example 2, and concentrated under reduced pressure to prepare a powder, the results of each extraction efficiency and component analysis of the extract is shown in Table 4. Component analysis determined total polyphenols, total flavonoids, total sugars and reducing sugars content. In the total polyphenol content, 50 μl of Folin-ciocalteau, 100 μl of Na 2 CO 3 saturated solution was added to 400 μl of the extraction sample solution, and the absorbance was measured at 725 nm after standing at room temperature for 1 hour. Tannic acid was used as the standard reagent. For the total flavonoid content, each sample was extracted by stirring for 18 hours with methanol, 4 ml of 90% diethylene glycol was added to 400 µl of the filtered extract sample, and 40 µl of 1 N NaOH was added again. Absorbance was measured at. Rutin was used as a standard reagent. Reducing sugar was determined by DNS method and total sugar was determined by phenol-sulfuric acid method.
[표 4] 살균 배지, 1 회 수확 후 SMS, 3 회 수확 후 SMS 및 표고버섯 열수 추출물의 성분 분석[Table 4] Component analysis of sterilized medium, SMS after one harvest, SMS and shiitake hot water extract after three harvests
표 4에 나타낸 바와 같이, 추출 효율은 살균 배지에서는 1 %로 매우 낮았으나, SMS는 5.1~9.2 %의 높은 수율을 보였으며, 1 차 수확 후 SMS (5.1 %)보다 3 차 수확 후 SMS (9.2 %)가 약 1.8 배 높은 추출 수율을 보였다. 표고버섯 건조 분말의 열수 추출물의 추출 효율은 34.7 %로 매우 높았다. 이는 표고버섯 재배가 진행될수록 살균 배지의 분해로 인한 가용성 성분의 증가 때문으로 판단된다. As shown in Table 4, the extraction efficiency was very low (1%) in the sterilization medium, but SMS showed a high yield of 5.1-9.2%, and SMS after the third harvest (9.2) was higher than SMS (5.1%) after the first harvest. %) Showed about 1.8 times higher extraction yield. The extraction efficiency of the hydrothermal extract of shiitake dry powder was very high as 34.7%. This is believed to be due to the increase in soluble components due to decomposition of the sterilization medium as the shiitake cultivation proceeds.
총 폴리페놀 분석 결과, 살균 배지는 20.5 mg/g을 나타내어 표고버섯보다 2.5 배 높은 함량을 보였으며, 1 차 및 3 차 수확 후 SMS의 경우 34.9~37.5 mg/g을 함유하여 살균 배지 및 수확된 표고버섯보다 월등히 높은 함량을 보였다. 이러한 패턴은 총 플라보노이드 함량 분석에서도 동일하게 나타났다 (표 4). 따라서, 1 차 및 3 차 수확 후 SMS는 버섯 재배용 살균 배지 및 수확한 표고버섯보다 우수한 생리 활성을 나타내리라 예측되었다. As a result of the total polyphenol analysis, the sterilization medium showed 20.5 mg / g, which was 2.5 times higher than shiitake mushroom, and after the first and the third harvest, SMS contained 34.9 ~ 37.5 mg / g. It was much higher than shiitake mushrooms. This pattern is the same in the analysis of total flavonoid content (Table 4). Therefore, after the first and third harvest, SMS was expected to show better physiological activity than mushroom sterilization medium and harvested shiitake mushrooms.
한편, 총당의 경우 살균 배지에서 가장 높은 144.9 mg/g함량을 나타내었으며, 환원당의 경우에는 1 차 및 3 차 수확 후 SMS에서 가장 높은 53.4~54.0 mg/g함량을 보였다. 반면, 표고버섯 추출물에서는 다른 시료와 달리 매우 낮은 총당 (21.6 mg/g) 및 환원당 (19.7 mg/g) 함량을 보였다.Meanwhile, total sugar showed the highest content of 144.9 mg / g in the sterilization medium, and reducing sugar showed the highest content of 53.4-54.0 mg / g in the SMS after the first and third harvests. On the other hand, shiitake extract showed very low total sugar (21.6 mg / g) and reducing sugar (19.7 mg / g) content, unlike other samples.
실시예 4: 살균 배지, 1 회 수확 후 SMS, 3 회 수확 후 SMS 및 표고버섯 열수 추출물의 혈액응고 저해활성 Example 4: Blood coagulation inhibitory activity of sterilization medium, SMS after one harvest, SMS and shiitake mushroom hot water extract after three harvests
실시예 2에서 조제된 다양한 추출물을 대상으로 혈액응고 저해활성을 평가하여 그 결과를 표 5에 나타내었다. 이때, 혈액응고 저해활성의 평가 방법은 기존에 보고된 방법에 준해 평가하였으며 (Sohn et al., 2004. Kor. J. Pharmacogn 35. 52-61; Kwon et al., 2004. J. Life Science, 14. 509-513; 류 등 2010. J. Life Science, 20. 922-928), 트롬빈 타임, 프로트롬빈 타임과 에이피티 타임을 측정하였다. 혈장은 시판 control plasma (MD Pacific Technology Co., Ltd, Huayuan Industrial Area, China)를 사용하였으며, 트롬빈 타임, 프로트롬빈 타임과 에이피티 타임 측정법은 다음과 같은 과정으로 수행되었다.Blood coagulation inhibitory activity was evaluated for various extracts prepared in Example 2, and the results are shown in Table 5. At this time, the evaluation method of blood coagulation inhibitory activity was evaluated according to the previously reported method (Sohn et al., 2004. Kor. J. Pharmacogn 35. 52-61; Kwon et al., 2004. J. Life Science, 14. 509-513; Ryu et al. 2010. J. Life Science, 20. 922-928), thrombin time, prothrombin time and episode time. Plasma was used as a commercial control plasma (MD Pacific Technology Co., Ltd, Huayuan Industrial Area, China), and thrombin time, prothrombin time and episode time measurements were performed as follows.
트롬빈 타임 (Thrombin Time: TT)Thrombin Time (TT)
37 ℃에서 0.5 U 트롬빈 (Sigma Co., USA) 50 μl와 20 mM CaCl2 50 μl, 다양한 농도의 시료 추출액 10 μl를 Amelung coagulometer KC-1A (Japan)의 튜브에 혼합하여 2 분간 반응시킨 후, 혈장 100 μl를 첨가한 후 혈장이 응고될 때까지의 시간을 측정하였다. 대조로는 아스피린 (Sigma Co., USA)을 사용하였으며, 용매 대조구로는 시료 대신 DMSO를 사용하였다. DMSO의 경우 24.2 초의 응고시간을 나타내었다. 트롬빈 저해 효과는 3 회 이상 반복한 실험의 평균치로 나타내었으며, 트롬빈 저해활성은 시료 첨가시의 응고시간을 용매 대조구의 응고시간으로 나눈 값으로 나타내었다.50 μl of 0.5 U thrombin (Sigma Co., USA), 50 μl of 20 mM CaCl 2 , and 10 μl of various sample extracts were mixed in a tube of Amelung coagulometer KC-1A (Japan) and reacted for 2 minutes. After the addition of 100 μl of plasma, the time until the plasma coagulated was measured. Aspirin (Sigma Co., USA) was used as a control and DMSO was used instead of the sample as a solvent control. DMSO showed a solidification time of 24.2 seconds. The thrombin inhibitory effect was expressed as the average value of the experiment repeated three or more times, and the thrombin inhibitory activity was expressed as the coagulation time when the sample was added divided by the coagulation time of the solvent control.
프로트롬빈 타임 (Prothrombin Ttime : PT)Prothrombin Ttime (PT)
표준혈장 (MD Pacific Co., China) 70 μl와 다양한 농도의 시료액 10 μl를 Amelung coagulometer KC-1A (Japan)의 튜브에 첨가하여 37 ℃에서 3 분간 가온 후, 130 μl의 PT reagent를 첨가하고 혈장이 응고될 때까지의 시간을 3 회 반복한 실험의 평균치로 나타내었다. 대조로는 아스피린 (Sigma Co., USA)을 사용하였으며, 용매 대조구로는 시료 대신 DMSO를 사용하였다. DMSO의 경우 16.8 초의 응고시간을 나타내었다. 프로트롬빈 저해활성은 시료 첨가시의 응고시간을 용매 대조구의 응고시간으로 나눈 값으로 나타내었다.70 μl of standard plasma (MD Pacific Co., China) and 10 μl of sample solution of various concentrations were added to a tube of Amelung coagulometer KC-1A (Japan), warmed at 37 ° C. for 3 minutes, and then 130 μl of PT reagent was added. The time to plasma coagulation is expressed as the average of three repeated experiments. Aspirin (Sigma Co., USA) was used as a control and DMSO was used instead of the sample as a solvent control. DMSO had a solidification time of 16.8 seconds. The prothrombin inhibitory activity was expressed by the solidification time of sample addition divided by the solidification time of the solvent control.
aPTT (activated Partial Thromboplastin Time) aPTT (activated Partial Thromboplastin Time)
혈장 100 μl와 다양한 농도의 시료 추출액 10 μl를 Amelung coagulometer KC-1A (Japan)의 튜브에 첨가하여 37 ℃에서 3 분간 가온한 후, 50 μl의 aPTT reagent (Sigma, ALEXINTM)를 첨가하고, 다시 37 ℃에서 3 분간 배양하였다. 이후, 50 μl CaCl2 (35 mM)을 첨가한 후, 혈장이 응고될 때까지의 시간을 측정하였다. 용매 대조구로는 시료 대신 DMSO를 사용하였으며, 이 경우 42.2 초의 응고시간을 나타내었다. aPTT의 결과는 3 회 반복한 실험의 평균치로 나타내었으며, 혈액응고인자 저해활성은 시료 첨가시의 aPTT를 용매 대조구의 aPTT로 나눈 값으로 나타내었다.100 μl of plasma and 10 μl of various concentrations of the sample extract were added to a tube of Amelung coagulometer KC-1A (Japan), warmed at 37 ° C. for 3 minutes, and then 50 μl of aPTT reagent (Sigma, ALEXIN TM ) was added again. Incubated at 37 ° C. for 3 minutes. Thereafter, 50 μl CaCl 2 (35 mM) was added and the time until the plasma coagulated was measured. DMSO was used as a solvent control instead of the sample, in which case it showed a solidification time of 42.2 seconds. The results of aPTT were shown as the average value of three repeated experiments, and the coagulation factor inhibitory activity was expressed as aPTT at the time of sample addition divided by aPTT of the solvent control.
[표 5] 살균 배지, 1 회 수확 후 SMS, 3 회 수확 후 SMS, 수확 표고버섯 분말 열수 추출물의 혈액응고 저해활성[Table 5] Blood coagulation inhibitory activity of sterilized medium, SMS after 1 time harvest, SMS after 3 times harvest, hydrothermal extract of shiitake mushroom powder
표 5에 나타낸 바와 같이, 대조구로 사용된 아스피린의 경우, 5 mg/ml 농도에서 TT, PT 및 aPTT를 모두 무첨가구에 비해 15 배 이상 연장시켰으며, 1.5 mg/ml농도에서도 TT, PT 및 aPTT를 각각 1.55 배, 1.39 배 및 1.46 배 연장시켜 혈액응고를 효율적으로 저해함을 확인하였다. 한편, 살균 배지 및 표고버섯 추출물의 경우 5 mg/ml 농도에서 TT, PT 및 aPTT를 각각 무첨가구에 비해 1.05 배, 1.51 배, 1.25 배와 1.07 배, 0.93 배, 1.10 배 증가시켜 약한 트롬빈, 프로트롬빈 및 혈액응고인자 저해를 보였다. 그러나, 1 차 및 3 차 수확 후 SMS 추출물의 경우, 5 mg/ml 농도에서 TT, PT 및 aPTT를 각각 무첨가구에 비해 15 배 이상, 1.76 배, 4.97 배와 15 배 이상, 1.05 배, 13 배 증가시켜 우수한 항응고 활성을 나타내었다. 특히, 수확 후 SMS 추출물들은 6 mg/ml 이상의 농도에서는 강력한 트롬빈 및 혈액응고인자 저해를 보여 TT 및 aPTT를 무첨가구에 비해 모두 15 배 이상 연장시켰다 (표 5). 기존의 표고버섯의 내인성 혈액응고인자 저해 (aPTT)에 의한 항혈전 활성이 보고된 바 있으나 (Kang DS 등, 2017. Plant Pathol. J. 33, 264-275), 표고버섯 수확 후 SMS에서의 강력한 항혈전 활성은 현재까지 알려진 바 없으며, 이러한 활성은 살균 배지에서의 표고버섯 균사체 성장에 의해 새롭게 생성된 물질에 기인한 것으로 판단된다. 상기 결과는 표고버섯 SMS가 신규의 항혈전 소재로 개발 가능함을 제시하고 있다.As shown in Table 5, in the case of aspirin used as a control, TT, PT and aPTT were all extended by 15 times or more at 5 mg / ml compared with no addition, and TT, PT and aPTT even at 1.5 mg / ml. Was increased by 1.55 times, 1.39 times, and 1.46 times, respectively, to effectively inhibit blood coagulation. On the other hand, in the case of sterilized medium and shiitake extract, TT, PT and aPTT were increased by 1.05 times, 1.51 times, 1.25 times and 1.07 times, 0.93 times and 1.10 times, respectively, at 5 mg / ml. And blood coagulation factor inhibition. However, for SMS extracts after primary and tertiary harvest, TT, PT and aPTT were at least 15 times, 1.76 times, 4.97 times and 15 times higher, 1.05 times, and 13 times higher than the non-added at 5 mg / ml concentration, respectively. Increased to show good anticoagulant activity. In particular, post-harvest SMS extracts showed potent thrombin and coagulation factor inhibition at concentrations above 6 mg / ml, extending both TT and aPTT by more than 15-fold compared to no additions (Table 5). Although antithrombotic activity has been reported due to the inhibition of endogenous coagulation factor (aPTT) of shiitake mushrooms (Kang DS et al., 2017. Plant Pathol. J. 33, 264-275) Antithrombotic activity has not been known to date, and this activity is believed to be due to a substance newly produced by shiitake mycelium growth in sterile medium. The results suggest that shiitake SMS can be developed as a novel antithrombogenic material.
실시예 5: 1 회 수확 후 SMS 및 3 회 수확 후 SMS 열수 추출물의 순차적 유기용매 분획물의 조제 및 성분 분석Example 5 Preparation and Component Analysis of Sequential Organic Solvent Fractions of SMS After One Harvest and SMS Hydrothermal Extract After Three Harvests
실시예 2에서 조제된 1 회 수확 후 SMS와 3 회 수확 후 SMS 열수 추출물의 활성 성분을 확인하기 위해, 각각의 추출물을 대상으로 헥센, 에틸아세테이트, 부탄올을 이용하여 순차적 유기용매 분획을 수행하였으며, 최종적으로 물 잔류물을 회수하였다. 각각의 회수된 분획물의 성분 분석은 실시예 3과 동일한 방법으로 성분을 분석하였으며, 그 결과는 표 6에 나타내었다. In order to confirm the active ingredients of the SMS after the first harvest and the SMS hot water extract after the third harvest prepared in Example 2, each extract was subjected to sequential organic solvent fractions using hexene, ethyl acetate, butanol, Finally water residue was recovered. Component analysis of each recovered fraction was analyzed in the same manner as in Example 3, the results are shown in Table 6.
[표 6] 1 회 수확 후 SMS와 3 회 수확 후 SMS 열수 추출물의 순차적 유기용매 분획물의 조제 및 성분 분석[Table 6] Preparation and Component Analysis of Sequential Organic Solvent Fractions of SMS After One Harvest and SMS Hot Water Extract After Three Harvests
표 6에 나타낸 바와 같이, 1 회 및 3 회 수확 후 SMS의 추출물은 유기용매 분획 이후 대부분이 물 잔류물로 이행되어 열수 추출물은 수용성 성분을 상당량 함유하고 있음을 알 수 있었다. 1 회 수확 후 SMS 추출물의 에틸아세테이트 분획물은 5.7 %, 부탄올 분획물은 24.3 %를 차지하였으며, 3 회 수확 후 SMS 추출물의 에틸아세테이트 분획물은 8.1 %, 부탄올 분획물은 17.3 %를 차지하였다. 즉, 1 회 및 3 회 수확 후 SMS 100 g으로부터 에틸아세테이트 분획물은 각각 0.29 g 및 0.75 g을, 부탄올 분획물은 각각 1.24 g 및 1.58 g을 회수할 수 있었다. 한편, 1 회 및 3 회 수확 후 SMS의 헥센 분획물은 각각 0.2 % 및 0.1 %로 매우 낮았으므로 향후의 항혈전 활성 평가에는 제외하였다. As shown in Table 6, the SMS extract after one and three times the harvest was mostly transferred to the water residue after the organic solvent fraction, it can be seen that the hot water extract contains a significant amount of water-soluble components. After one harvest, the ethyl acetate fraction of SMS extract accounted for 5.7%, butanol fraction of 24.3%. After three harvests, the ethyl acetate fraction of SMS extract accounted for 8.1% and butanol fraction of 17.3%. That is, the ethyl acetate fractions were 0.29 g and 0.75 g, and the butanol fractions 1.24 g and 1.58 g, respectively. On the other hand, the hexene fraction of SMS after 1 and 3 harvests was very low, 0.2% and 0.1%, respectively, and thus was excluded from future antithrombotic activity evaluation.
각각의 분획물의 총 폴리페놀 함량 분석 결과, 1 회 수확 후 SMS의 헥센 분획물이 가장 높은 54.8 mg/g을 나타내었으며, 에틸아세테이트 분획물 > 부탄올 분획물 > 물 잔류물 순으로 나타났다. 그러나, 3 회 수확 후 SMS의 경우, 에틸아세테이트 분획물이 가장 높은 95.4 mg/g을 나타내었으며, 물 잔류물 > 부탄올 분획물 > 헥센 분획물 순으로 나타났다. 이러한 결과는 1 회 수확 후 SMS 추출물과 3 회 수확 후 SMS 추출물의 성분이 상이함을 의미하고 있다. As a result of analysis of the total polyphenol content of each fraction, the hexene fraction of SMS showed the highest 54.8 mg / g after one harvest, followed by ethyl acetate fraction> butanol fraction> water residue. However, after 3 harvests, the ethyl acetate fraction showed the highest 95.4 mg / g, followed by water residue> butanol fraction> hexene fraction. These results indicate that the SMS extract after one harvest and the SMS extract after three harvests are different.
실시예 6: 1 회 수확 후 SMS와 3 회 수확 후 SMS 열수 추출물의 순차적 유기용매 분획물의 혈액응고 저해활성 Example 6 Blood Coagulation Inhibitory Activity of Sequential Organic Solvent Fractions of SMS After One Harvest and SMS Hot Water Extract After Three Harvests
실시예 5에서 얻어진 다양한 분획물들을 대상으로 항응고 활성을 실시예 4의 방법과 동일하게 평가하였다. 표 7에 나타낸 바와 같이, 1 회 수확 후 SMS 추출물의 에틸아세테이트 분획물 및 물 잔류물은 강력한 항응고 활성을 나타내었으며, 3 회 수확 후 SMS 추출물의 에틸아세테이트 분획물, 부탄올 분획물 및 물 잔류물은 모두에서 강력한 항응고 활성을 나타내었다. The anticoagulant activity of the various fractions obtained in Example 5 was evaluated in the same manner as in Example 4. As shown in Table 7, the ethyl acetate fraction and water residue of SMS extract after one harvest showed strong anticoagulant activity, and the ethyl acetate fraction, butanol fraction and water residue of SMS extract after three harvests It exhibited strong anticoagulant activity.
[표 7] 1 회 수확 후 SMS와 3 회 수확 후 SMS 열수 추출물의 순차적 유기용매 분획물의 혈액응고 저해활성[Table 7] Blood clotting inhibitory activity of sequential organic solvent fractions of SMS after one harvest and SMS hot water extract after three harvests
실시예 7: 1 회 수확 후 SMS와 3 회 수확 후 SMS 열수 추출물 및 이의 활성 분획물의 인간 적혈구 용혈 활성Example 7: Human red blood cell hemolysis activity of SMS after one harvest and SMS hydrothermal extract and three times after harvest
표고버섯은 오랫동안 식용과 약용으로 사용되어 왔으며, 표고버섯 수확 후 SMS는 사료로 사용되어 왔다. 본 발명에서는 SMS 추출물 및 이들의 활성 분획물의 급성 독성을 평가하기 위해 인간 적혈구 용혈 활성 시험을 하였으며, 그 결과는 표 8에 나타내었다. 이때, 용혈 활성은 기존의 보고 (정인창, 손호용, 2014년, Korean J. Microbiol. Biotechnol. 42: 285-292)에 준해 평가하였으며, 간단하게는 PBS로 3 회 수세한 인간 적혈구 100 μl를 96-well microplate에 가하고, 다양한 농도의 시료용액 100 μl를 가한 다음 37 ℃에서 30 분간 반응시켰으며, 이후, 반응액을 10 분간 원심분리 (1,500 rpm)하여 상등액 100 μl를 새로운 microtiter plate로 옮긴 후 용혈에 따른 헤모글로빈 유출 정도를 414 nm에서 측정하였다. 시료의 용매 대조구로는 DMSO (2 %)를 사용하였으며, 적혈구 용혈을 위한 실험 대조구로는 Triton X-100 (1 mg/ml)를 사용하였다. 용혈 활성은 다음의 수식을 이용하여 계산하였다.Shiitake mushrooms have been used for edible and medicinal purposes for a long time, and SMS has been used as feed after harvesting shiitake mushrooms. In the present invention, the human erythrocyte hemolytic activity test was performed to evaluate the acute toxicity of the SMS extract and their active fractions, and the results are shown in Table 8. At this time, hemolytic activity was evaluated according to the existing report (Jeong In Chang, Son Ho Yong, 2014, Korean J. Microbiol. Biotechnol. 42: 285-292), and simply, 100 μl of human red blood cells washed three times with PBS was 96- 100 μl of various sample solutions were added to the well microplate, and then reacted at 37 ° C. for 30 minutes. Then, the reaction solution was centrifuged for 10 minutes (1,500 rpm) to transfer 100 μl of the supernatant to a new microtiter plate. The degree of hemoglobin outflow was measured at 414 nm. DMSO (2%) was used as a solvent control of the sample, and Triton X-100 (1 mg / ml) was used as an experimental control for red blood cell hemolysis. Hemolytic activity was calculated using the following formula.
[표 8] 1 회 수확 후 SMS와 3 회 수확 후 SMS 열수 추출물 및 이의 활성 분획물의 인간 적혈구 용혈 활성[Table 8] Human red blood cell hemolysis activity of SMS hydrothermal extract and its active fractions after SMS and 3 times after harvest
먼저, 대조구로 사용된 DMSO와 물은 적혈구 용혈 활성이 없었으며, triton X-100은 1 mg/ml 농도에서 적혈구를 100 % 용혈시킴을 확인하였다. 한편, 1 회와 3 회 수확 후 SMS 추출물 및 이의 활성 분획물들은 1 mg/ml에서도 용혈 활성은 전혀 나타나지 않았다. 용혈 활성이 있다고 알려진 항암제인 엠포테라신 B는 0.00625 mg/ml 농도에서 55.5 %, 0.05 mg/ml 농도에서 93.7 %의 용혈활성을 나타냄을 고려할 때, 표고버섯 수확 후 SMS 추출물 및 이의 활성 분획물들은 용혈 활성이 없는 것으로 판단된다. First, DMSO and water used as a control did not have erythrocyte hemolytic activity, triton X-100 was confirmed that 100% hemolysis of red blood cells at a concentration of 1 mg / ml. On the other hand, SMS extract and its active fractions after 1 and 3 times harvesting did not show any hemolytic activity even at 1 mg / ml. Considering that the anticancer drug known as hemolytic activity, empoterasin B, exhibited 55.5% hemolytic activity at 0.00625 mg / ml and 93.7% at 0.05 mg / ml, the SMS extract and its active fractions after harvesting shiitake mushrooms It is judged that there is no activity.
실시예 8: 1 회 수확 후 SMS와 3 회 수확 후 SMS 열수 추출물 및 이의 활성 분획물의 혈장, 산 및 열 안정성 평가 Example 8 Evaluation of Plasma, Acid and Thermal Stability of SMS After One Harvest and SMS Hydrothermal Extract and Three After Harvest
상기 실시예 2 및 실시예 5에서 얻어진 표고버섯 1 회 수확 후 SMS, 3 회 수확 후 SMS 추출물 및 이의 활성 분획물을 대상으로 항혈전 활성에 대한 혈장 안정성, 열 안정성 및 산 안정성을 확인하였다. 상기 시료들은 100 ℃에서 1 시간 열 처리, pH 2 (0.01 M HCl)에서의 1 시간 처리, 혈장에서 1 시간 처리시에도 혈액 응고 저해 활성의 심각한 감소가 나타나지 않아 높은 안정성을 나타내었다. 따라서, 상기의 추출물 및 활성 분획물들은 소화 흡수 과정 및 식품 제조 과정 중, 우수한 항혈전 활성을 유지할 것으로 예상된다.Plasma stability, thermal stability and acid stability against antithrombotic activity of the shiitake mushrooms obtained in Examples 2 and 5 after harvesting SMS, SMS extracts after harvesting three times, and active fractions thereof were confirmed. The samples did not show a significant decrease in blood coagulation inhibitory activity even after 1 hour heat treatment at 100 ° C., 1 hour treatment at pH 2 (0.01 M HCl), and 1 hour treatment in plasma, indicating high stability. Therefore, the extracts and active fractions above are expected to maintain excellent antithrombotic activity during digestive absorption and food preparation.
Claims (4)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020180090288A KR102128625B1 (en) | 2018-08-02 | 2018-08-02 | Pharmaceutical composition comprising the extraction of spent mushroom substrate for lentinus edodes as an effective component for prevention or treatment of thrombosis and health functional food comprising the same |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020180090288A KR102128625B1 (en) | 2018-08-02 | 2018-08-02 | Pharmaceutical composition comprising the extraction of spent mushroom substrate for lentinus edodes as an effective component for prevention or treatment of thrombosis and health functional food comprising the same |
Publications (2)
Publication Number | Publication Date |
---|---|
KR20200015030A true KR20200015030A (en) | 2020-02-12 |
KR102128625B1 KR102128625B1 (en) | 2020-07-01 |
Family
ID=69569902
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020180090288A KR102128625B1 (en) | 2018-08-02 | 2018-08-02 | Pharmaceutical composition comprising the extraction of spent mushroom substrate for lentinus edodes as an effective component for prevention or treatment of thrombosis and health functional food comprising the same |
Country Status (1)
Country | Link |
---|---|
KR (1) | KR102128625B1 (en) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101078306B1 (en) * | 2009-04-17 | 2011-10-31 | (주)에이치케이바이오텍 | Fibrinolytic Composition Having Culture Of Bacillus Subtilis Natto And Mushroom Fungi |
KR20140066036A (en) * | 2012-11-22 | 2014-05-30 | 경남과학기술대학교 산학협력단 | Feed using spent mushroom substrate and preparation method thereof |
KR101458628B1 (en) * | 2012-05-30 | 2014-11-12 | 한경대학교 산학협력단 | Method for producing saccharogenic amylases from spent mushroom substrates |
KR101611947B1 (en) | 2015-06-11 | 2016-04-12 | 정재경 | Functional food composition for preventing and treating blood vessel disease and producing method thefeof |
KR101728233B1 (en) * | 2015-09-23 | 2017-05-11 | 농업회사법인 포천버섯개발주식회사 | A method for manufacturing pellets for fuel using dis-used badges or logs after cultivation of mushrooms |
KR20180059622A (en) * | 2016-11-25 | 2018-06-05 | 한경대학교 산학협력단 | COMPOSITION FOR PREVENTING PLANT PATHOGENS COMPRISING EXTRACT FROM SPENT SUBSTRATE OF Lentinula edodes AND METHOD FOR PREPARING THE SAME |
-
2018
- 2018-08-02 KR KR1020180090288A patent/KR102128625B1/en active IP Right Grant
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101078306B1 (en) * | 2009-04-17 | 2011-10-31 | (주)에이치케이바이오텍 | Fibrinolytic Composition Having Culture Of Bacillus Subtilis Natto And Mushroom Fungi |
KR101458628B1 (en) * | 2012-05-30 | 2014-11-12 | 한경대학교 산학협력단 | Method for producing saccharogenic amylases from spent mushroom substrates |
KR20140066036A (en) * | 2012-11-22 | 2014-05-30 | 경남과학기술대학교 산학협력단 | Feed using spent mushroom substrate and preparation method thereof |
KR101611947B1 (en) | 2015-06-11 | 2016-04-12 | 정재경 | Functional food composition for preventing and treating blood vessel disease and producing method thefeof |
KR101728233B1 (en) * | 2015-09-23 | 2017-05-11 | 농업회사법인 포천버섯개발주식회사 | A method for manufacturing pellets for fuel using dis-used badges or logs after cultivation of mushrooms |
KR20180059622A (en) * | 2016-11-25 | 2018-06-05 | 한경대학교 산학협력단 | COMPOSITION FOR PREVENTING PLANT PATHOGENS COMPRISING EXTRACT FROM SPENT SUBSTRATE OF Lentinula edodes AND METHOD FOR PREPARING THE SAME |
Also Published As
Publication number | Publication date |
---|---|
KR102128625B1 (en) | 2020-07-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR101854658B1 (en) | Pharmaceutical composition comprising the extracts of teleogryllus emma as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR101845160B1 (en) | Pharmaceutical composition comprising the extraction of salicornia spp. seed as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR102176092B1 (en) | Pharmaceutical composition comprising the extract of acorn pollen as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR102158674B1 (en) | Pharmaceutical composition comprising the extract of darae pollen as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR102013312B1 (en) | Pharmaceutical composition comprising the extract of apios americana medikus as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR101883181B1 (en) | Pharmaceutical composition comprising the extraction of moringa oleifera root as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR102128625B1 (en) | Pharmaceutical composition comprising the extraction of spent mushroom substrate for lentinus edodes as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR102318970B1 (en) | Pharmaceutical composition comprising the extract of prune as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR102013288B1 (en) | Pharmaceutical composition comprising the extracts from stem of actinidia arguta as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR101217713B1 (en) | Methods for fermentative production of fibrinolytic enzyme from Auricularia auricula-judae and uses thereof | |
KR20210056858A (en) | Pharmaceutical composition comprising the extract of black soldier fly as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
US20240131098A1 (en) | Pharmaceutical composition and health functional food containing extract of fruiting body of ganoderma lucidum as active ingredient for prevention or treatment of thrombosis | |
KR20240048690A (en) | Pharmaceutical composition comprising the extract of ganoderma gibbosum fruiting body as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR102216221B1 (en) | Pharmaceutical composition comprising the extract of pine pollen as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR20240048685A (en) | Pharmaceutical composition comprising the extract of songhwa mushroom fruiting body as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR102453875B1 (en) | Pharmaceutical composition comprising the extract of rose flower as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR101479816B1 (en) | Pharmaceutical composition comprising the extract of phellinus linteus as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR102120490B1 (en) | Pharmaceutical composition for prevention or treatment of thrombosis comprising the ethylacetate fraction of shiitake mushroom extract as an effective component and health functional food comprising the same | |
KR101945733B1 (en) | Pharmaceutical composition comprising the ethanol extracts of yunnongchamssal as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR102092960B1 (en) | Pharmaceutical composition comprising ethylacetate fraction fractionated from ethanol extract of abeliophyllum distichum stem as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR20100096442A (en) | Methods for fermentative production of fibrinolytic enzyme from auricularia auricula-judae and uses thereof | |
KR20240018095A (en) | Pharmaceutical composition comprising the extract of lycium chinensis as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR20220048892A (en) | Pharmaceutical composition comprising the extract of glehnia littoralis as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR101800372B1 (en) | Pharmaceutical composition comprising the extraction of unripe korean peaches as an effective component for prevention or treatment of thrombosis and health functional food comprising the same | |
KR101710263B1 (en) | Pharmaceutical composition comprising the extract of hovenia dulcis as an effective component for prevention or treatment of thrombosis and health functional food comprising the same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A201 | Request for examination | ||
E902 | Notification of reason for refusal | ||
E701 | Decision to grant or registration of patent right | ||
GRNT | Written decision to grant |