KR20180072632A - Pharmaceutical composition having angiogenesis inhibition activity comprising extract of Rubus coreanus Miquel - Google Patents
Pharmaceutical composition having angiogenesis inhibition activity comprising extract of Rubus coreanus Miquel Download PDFInfo
- Publication number
- KR20180072632A KR20180072632A KR1020180069602A KR20180069602A KR20180072632A KR 20180072632 A KR20180072632 A KR 20180072632A KR 1020180069602 A KR1020180069602 A KR 1020180069602A KR 20180069602 A KR20180069602 A KR 20180069602A KR 20180072632 A KR20180072632 A KR 20180072632A
- Authority
- KR
- South Korea
- Prior art keywords
- vegf
- inhibits
- vascular endothelial
- angiogenesis
- extract
- Prior art date
Links
- 239000000284 extract Substances 0.000 title claims abstract description 73
- 230000033115 angiogenesis Effects 0.000 title claims abstract description 37
- 230000000694 effects Effects 0.000 title claims abstract description 28
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 13
- 241001618264 Rubus coreanus Species 0.000 title claims abstract description 10
- 230000005764 inhibitory process Effects 0.000 title abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 65
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 claims abstract description 39
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims abstract description 38
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims abstract description 38
- 210000003556 vascular endothelial cell Anatomy 0.000 claims abstract description 18
- 239000004480 active ingredient Substances 0.000 claims abstract description 12
- 208000017442 Retinal disease Diseases 0.000 claims abstract description 10
- 206010038923 Retinopathy Diseases 0.000 claims abstract description 10
- 230000026731 phosphorylation Effects 0.000 claims abstract description 6
- 238000006366 phosphorylation reaction Methods 0.000 claims abstract description 6
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 claims abstract 3
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 claims abstract 3
- 239000000203 mixture Substances 0.000 claims description 29
- 230000002401 inhibitory effect Effects 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 15
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 12
- 241001092459 Rubus Species 0.000 claims description 10
- 235000017848 Rubus fruticosus Nutrition 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 241000894006 Bacteria Species 0.000 claims description 6
- 108091008605 VEGF receptors Proteins 0.000 claims description 5
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 claims description 5
- 230000010261 cell growth Effects 0.000 claims description 3
- 230000010595 endothelial cell migration Effects 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims 1
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 claims 1
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 48
- 201000011510 cancer Diseases 0.000 abstract description 41
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 15
- 208000010412 Glaucoma Diseases 0.000 abstract description 4
- 230000005012 migration Effects 0.000 abstract description 4
- 238000013508 migration Methods 0.000 abstract description 4
- 230000035755 proliferation Effects 0.000 abstract description 4
- 210000001367 artery Anatomy 0.000 abstract description 2
- 208000030533 eye disease Diseases 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 44
- 238000011282 treatment Methods 0.000 description 16
- 235000013305 food Nutrition 0.000 description 15
- 210000004204 blood vessel Anatomy 0.000 description 14
- 239000003814 drug Substances 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 206010029113 Neovascularisation Diseases 0.000 description 11
- 239000000306 component Substances 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 10
- 238000011161 development Methods 0.000 description 9
- 230000018109 developmental process Effects 0.000 description 9
- 230000036541 health Effects 0.000 description 9
- 210000001525 retina Anatomy 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 239000002246 antineoplastic agent Substances 0.000 description 8
- 210000002889 endothelial cell Anatomy 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 239000004037 angiogenesis inhibitor Substances 0.000 description 7
- 230000001093 anti-cancer Effects 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 239000002870 angiogenesis inducing agent Substances 0.000 description 6
- 229940041181 antineoplastic drug Drugs 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 235000013376 functional food Nutrition 0.000 description 6
- 239000008187 granular material Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 206010027476 Metastases Diseases 0.000 description 5
- 206010038934 Retinopathy proliferative Diseases 0.000 description 5
- 210000000709 aorta Anatomy 0.000 description 5
- 230000003833 cell viability Effects 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 108010082117 matrigel Proteins 0.000 description 5
- 230000009401 metastasis Effects 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 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 4
- 229930006000 Sucrose Natural products 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 150000001720 carbohydrates Chemical class 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229930014626 natural product Natural products 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000003765 sweetening agent Substances 0.000 description 4
- 201000004569 Blindness Diseases 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 3
- 230000009400 cancer invasion Effects 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 230000012292 cell migration Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 208000003120 Angiofibroma Diseases 0.000 description 2
- 102400000068 Angiostatin Human genes 0.000 description 2
- 108010079709 Angiostatins Proteins 0.000 description 2
- 208000020084 Bone disease Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 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 2
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 2
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 description 2
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 2
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 2
- 206010016654 Fibrosis Diseases 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
- 206010018498 Goitre Diseases 0.000 description 2
- 208000003807 Graves Disease Diseases 0.000 description 2
- 208000015023 Graves' disease Diseases 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 206010060820 Joint injury Diseases 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
- 229930195725 Mannitol Natural products 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- -1 PDGF Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 206010037649 Pyogenic granuloma Diseases 0.000 description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 244000299461 Theobroma cacao Species 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- 206010064996 Ulcerative keratitis Diseases 0.000 description 2
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 2
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 2
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 2
- 208000000260 Warts Diseases 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 208000002223 abdominal aortic aneurysm Diseases 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000001772 anti-angiogenic effect Effects 0.000 description 2
- 208000007474 aortic aneurysm Diseases 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 201000007717 corneal ulcer Diseases 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 230000003412 degenerative effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 201000011066 hemangioma Diseases 0.000 description 2
- 235000003642 hunger Nutrition 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 201000001371 inclusion conjunctivitis Diseases 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000000411 inducer Substances 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 208000002780 macular degeneration Diseases 0.000 description 2
- 210000001161 mammalian embryo Anatomy 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 201000003142 neovascular glaucoma Diseases 0.000 description 2
- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 231100000957 no side effect Toxicity 0.000 description 2
- 239000012457 nonaqueous media Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000006785 proliferative vitreoretinopathy Effects 0.000 description 2
- 201000001474 proteinuria Diseases 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 230000002207 retinal effect Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000009759 skin aging Effects 0.000 description 2
- 201000010153 skin papilloma Diseases 0.000 description 2
- 230000037351 starvation Effects 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000004083 survival effect Effects 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
- 206010044325 trachoma Diseases 0.000 description 2
- 230000000472 traumatic effect Effects 0.000 description 2
- 230000006444 vascular growth Effects 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
- 229940088594 vitamin Drugs 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- PFTAWBLQPZVEMU-DZGCQCFKSA-N (+)-catechin Chemical compound C1([C@H]2OC3=CC(O)=CC(O)=C3C[C@@H]2O)=CC=C(O)C(O)=C1 PFTAWBLQPZVEMU-DZGCQCFKSA-N 0.000 description 1
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-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
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 102100022987 Angiogenin Human genes 0.000 description 1
- 206010053555 Arthritis bacterial Diseases 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 238000009020 BCA Protein Assay Kit Methods 0.000 description 1
- 241000255789 Bombyx mori Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101150093802 CXCL1 gene Proteins 0.000 description 1
- 101100381481 Caenorhabditis elegans baz-2 gene Proteins 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 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 1
- 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 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 102400001047 Endostatin Human genes 0.000 description 1
- 108010079505 Endostatins Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 239000004606 Fillers/Extenders Substances 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
- 208000032843 Hemorrhage Diseases 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
- 241000282412 Homo Species 0.000 description 1
- 101000582950 Homo sapiens Platelet factor 4 Proteins 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 208000004575 Infectious Arthritis Diseases 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 238000000134 MTT assay Methods 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
- 108010047660 Mitochondrial intermediate peptidase Proteins 0.000 description 1
- 206010061323 Optic neuropathy Diseases 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 101710098940 Pro-epidermal growth factor Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- 101100372762 Rattus norvegicus Flt1 gene Proteins 0.000 description 1
- 206010038848 Retinal detachment Diseases 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 235000011034 Rubus glaucus Nutrition 0.000 description 1
- 244000235659 Rubus idaeus Species 0.000 description 1
- 235000009122 Rubus idaeus Nutrition 0.000 description 1
- 244000228451 Stevia rebaudiana Species 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- 102000013537 Thymidine Phosphorylase Human genes 0.000 description 1
- 108700023160 Thymidine phosphorylases Proteins 0.000 description 1
- 102000009618 Transforming Growth Factors Human genes 0.000 description 1
- 108010009583 Transforming Growth Factors Proteins 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 206010064390 Tumour invasion Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 102000016663 Vascular Endothelial Growth Factor Receptor-3 Human genes 0.000 description 1
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 1
- 102100039037 Vascular endothelial growth factor A Human genes 0.000 description 1
- 208000034698 Vitreous haemorrhage Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000013334 alcoholic beverage Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 108010072788 angiogenin Proteins 0.000 description 1
- 230000007152 anther development Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003125 aqueous solvent Substances 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
- 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 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
- 229960000397 bevacizumab Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000012503 blood component Substances 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 210000001043 capillary endothelial cell Anatomy 0.000 description 1
- 235000014171 carbonated beverage Nutrition 0.000 description 1
- ADRVNXBAWSRFAJ-UHFFFAOYSA-N catechin Natural products OC1Cc2cc(O)cc(O)c2OC1c3ccc(O)c(O)c3 ADRVNXBAWSRFAJ-UHFFFAOYSA-N 0.000 description 1
- 235000005487 catechin Nutrition 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229950001002 cianidanol Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000011254 conventional chemotherapy Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- HHEAADYXPMHMCT-UHFFFAOYSA-N dpph Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC([N+]([O-])=O)=C1[N]N(C=1C=CC=CC=1)C1=CC=CC=C1 HHEAADYXPMHMCT-UHFFFAOYSA-N 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-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
- 230000029142 excretion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 210000000416 exudates and transudate Anatomy 0.000 description 1
- 230000004438 eyesight Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 238000005858 glycosidation reaction Methods 0.000 description 1
- 239000003966 growth inhibitor Substances 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 235000001497 healthy food Nutrition 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 230000000409 histolytic effect Effects 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 235000015243 ice cream Nutrition 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002700 inhibitory effect on cancer Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- VMPHSYLJUKZBJJ-UHFFFAOYSA-N lauric acid triglyceride Natural products CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC VMPHSYLJUKZBJJ-UHFFFAOYSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 238000010232 migration assay Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 208000001491 myopia Diseases 0.000 description 1
- 230000004379 myopia Effects 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 235000012149 noodles Nutrition 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 206010030875 ophthalmoplegia Diseases 0.000 description 1
- 208000020911 optic nerve disease Diseases 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 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
- 229940049954 penicillin Drugs 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 235000013550 pizza Nutrition 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 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 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000004264 retinal detachment Effects 0.000 description 1
- 201000005404 rubella Diseases 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
- 235000013580 sausages 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
- 230000007017 scission Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 201000001223 septic arthritis Diseases 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 235000011888 snacks Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 235000020712 soy bean extract Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000005167 vascular cell Anatomy 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000007998 vessel formation Effects 0.000 description 1
- 230000004304 visual acuity Effects 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Images
Classifications
-
- 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
- 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
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
-
- 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
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Botany (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Biotechnology (AREA)
- Alternative & Traditional Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medical Informatics (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Description
본 발명은 복분자(Rubus coreanus Miquel) 수추출물을 유효성분으로 함유하는 신생혈관형성 억제 활성을 갖는 약학적 조성물에 관한 것이다.
The present invention relates to Rubus coreanus Miquel ) water extract as an active ingredient. The present invention also relates to a pharmaceutical composition having an activity of inhibiting angiogenesis.
사망원인 1위인 암에 대한 항암치료는 수술요법, 화학요법(chemotherapy), 방사선요법이 있다. 그동안 암을 극복하기 위한 많은 노력으로 예전에 비해 암환자의 생존기간이 많이 연장되었으나, 전통적인 항암치료는 부작용과 고통으로 인하여 많은 경우 원활한 치료효과를 기대할 수 없어 암은 여전히 두려움의 대상이 되고 있다. 그러므로 최근에는 정상세포에는 피해를 덜 줄 수 있는 새로운 연구 방법들이 시도되고 있는데, 면역요법, 유전자치료, 내성억제, 신생혈관억제제, 화학적 암예방제 등 생물학적 요법제에 대한 연구가 활발히 진행되고 있으며, 특히 부작용이 적은 천연물(natural products)로부터 새로운 항암물질을 개발하려는 연구가 다양한 분야에서 활발히 진행되고 있다. Chemotherapy, chemotherapy, and radiation therapy are the first cancer treatments for cancer. Although cancer survival has been prolonged by many efforts to overcome cancer, conventional cancer therapy is still a source of fear because it can not be expected to have a smooth therapeutic effect in many cases due to side effects and pain. Recently, new research methods that can lessen damage to normal cells have been attempted. Research on biological therapeutic agents such as immunotherapy, gene therapy, resistance inhibition, neovascularization inhibitor, and chemical cancer prevention have been actively carried out. Studies to develop new anticancer substances from natural products with low side effects are actively being carried out in various fields.
최근 개발된 표적항암제로 인하여 암환자들이 새로운 희망을 갖게 됐다. 표적항암제는 암세포에만 선택적으로 작용하고 정상세포에는 영향을 미치지 않는 새로운 개념의 항암제로서, 암세포의 생성 및 증식에 관여하는 신호전달경로를 억제하는 신호전달 억제제(Signal transduction inhibitor), 암세포가 일정한 크기이상의 성장을 하기 위해 필요로 하는 새로운 혈관형성을 차단하는 신생혈관형성 억제제(Angiogenesis inhibitor), 암세포의 예정된 세포사멸을 유도하여 세포증식을 차단하는 새로운 세포사멸 유도제(Apoptosis inducer) 등에서 가장 활발한 연구가 이루어지고 있다. 한편, 암은 매우 복잡한 경로로 발전하기 때문에 표적인자만을 선택적으로 억제하여서는 효율적인 암세포의 성장을 막을 수 없기 때문에, 최근에는 더 많은 경로를 차단하는 보다 우수한 효능을 갖는 새로운 다중표적항암제(Multi targeted anticancer agents) 개발이 다양하게 이루어지고 있다. 특히, 핵심적인 발암 경로의 차단과 암세포의 신생혈관생성을 동시에 차단하여 기존 항암제에 실패한 암환자에서도 우수한 효능을 갖고 부작용을 줄일 수 있는 다중표적항암제 개발이 활발히 진행되고 있다. 이러한 항암제 개발을 위해 미국은 National Cancer Institute (NCI)를 설립하여 천연물로부터의 항암 대량검색법을 개발하고 세계각지로부터 다양한 천연자원을 수집하여 항암검색을 실시해 오고 있다. 특히 일본은 신생혈관형성 억제제의 개발 및 발견에 투자하여 현재에는 그동안 개발한 여러 약제가 신생혈관형성에 관여하는 질병에 대한 효과를 보기위해 임상실험을 수행하고 있다. 국내에 있어서도 80년대부터 천연물로부터 유용한 항암물질을 개발하려는 많은 노력이 진행되었으나 아직 초보적인 단계이다. 오늘날 물질특허를 비롯한 지적소유권의 보호가 강력히 요구되는 세계적인 추세 속에서 국내 천연자원으로부터의 약리활성 물질의 개발에 관한 연구는 절실하다고 할 수 있으며, 선진국과 국제경쟁력을 높이기 위해서도 신규 약리활성 물질의 개발에 대한 자체기술력의 확보가 무엇보다도 중요하다고 할 수 있겠다.Recently developed cancer drugs have brought new hope to cancer patients. Target anticancer drug is a new concept of anticancer drug that selectively acts on cancer cells and does not affect normal cells. It is a signal transduction inhibitor that suppresses the signal transduction pathways involved in the production and proliferation of cancer cells, Angiogenesis inhibitor, which blocks the formation of new blood vessels required for growth, and apoptosis inducer, which blocks the cell proliferation by inducing predetermined cell apoptosis of cancer cells. have. On the other hand, since cancer develops into a very complicated pathway, selective inhibition of the target factors alone can not prevent the growth of cancer cells efficiently. Therefore, a new multi-targeted anticancer agents ) Has been developed variously. In particular, the development of a multi-target anticancer agent which can block the key cancer pathway and block the angiogenesis of the cancer cell simultaneously and thus can reduce side effects with excellent efficacy in cancer patients who have failed the conventional anticancer drugs is actively under development. To develop such anticancer drugs, the United States established the National Cancer Institute (NCI) to develop a large-scale anti-cancer screening method from natural products, and has collected various natural resources from all over the world and has conducted anti-cancer search. In particular, Japan has invested in the development and discovery of new angiogenesis inhibitors, and now, several drugs developed in the past have been conducting clinical trials to see the effects of angiogenesis-related diseases. In Korea, much efforts have been made to develop useful anti-cancer substances from natural products since the 80's, but it is still a rudimentary stage. Today, research on the development of pharmacologically active substances from domestic natural resources is desperate in the global trend where the protection of intellectual property including material patent is strongly demanded. In order to enhance international competitiveness with advanced countries, development of new pharmacologically active substances It is important to secure its own technology.
혈관신생(angiogenesis)이란 기존의 혈관으로부터 새로운 모세혈관이 만들어지는 것을 뜻한다. 정상적인 생리조건에서는 거의 일어나지 않는 엄격히 조절되는 현상이나 수정란 발생과정에서 배아가 발달될 때와 성인의 경우 상처가 치유될 때 그리고 여성의 생식주기에서 생식기계통의 변화 등에서 일어난다. 성인의 경우 모세혈관의 내피세포는 상대적으로 잘 분열하지 않으며 분열속도는 보통 수개월 내지 수년이다. 혈관신생은 여러 종류의 세포와 수용성 인자 및 세포외 기질(extracellular matrix) 성분과의 상호작용에 의한 복잡한 과정으로 일어나며 아직 그 작용기작은 완전히 규명되어 있지 않다. 신생혈관형성 억제제의 새로운 항암치료법으로서의 장점은 첫째, 신생혈관 작용(angiogenesis)은 원발성 혹은 전이성 종양에서 필수적이며, 암조직은 신생혈관에 의한 영양분과 산소 공급이 없으면 1~2 mm3 이상 성장 할 수 없다는 점이다(FolkmanJ,Semin Cancer Biol. 1992, 3:65-71). 신생혈관작용이 일어나는 동안 원발성(primary)암세포가 혈관내로 유입되어 다른 장소로 이동하여 전이(metastasis)암을 형성하게 된다. 따라서 신생혈관형성 억제제는 모든 고형성 종양(solid tumor)에서 공통적으로 사용될 수 있다는 가능성을 가진다. 둘째, 기존의 항암 화학요법은 암세포가 빠르게 성장하는 특징을 이용하여 치료하기 때문에 비교적 세포주기가 빠른 골수세포, 위장관계세포에 대해 독성을 나타내는 반면 신생혈관형성 억제제는 장기투여해도 비교적 적은 부작용을 나타낼 수 있다는 점이다. 뿐만 아니라 항암 화학요법은 형질이 변형된 암세포를 치료목표로 하기 때문에 새로운 내성을 나타낼 수 있지만, 신생혈관형성 억제제는 정상혈관세포가 치료의 대상이라는 점에서 내성을 나타낼 가능성이 적다. 셋째, 하나의 혈관세포는 수백 개의 암세포에 영양분과 산소를 공급하기 때문에 하나의 혈관세포의 억제를 통해서 많은 암세포를 억제하는 효과적인 치료 방법이 될 수 있다. 마지막으로 항암제 전달 방법에 있어서 기존의 항암 항암요법의 경우 항암제가 혈관 밖으로 유출되어 암세포에 영향을 나타내는 반면 혈관성장 억제제는 직접 혈관 내피세포에 접촉하여 작용하므로 약물 전달이 용이하다는 점이다. 동물실험에서 억제 효과를 나타내었던 항암제제들이 임상실험에서는 뚜렷한 효과를 나타내지 못한 경우가 많았다. 이는 암 조직마다 혈관내피세포의 발현형 차이와 각각의 종양 주위의 미세 환경과 서로 다른 혈관 성장인자들의 분포가 다르기 때문으로 생각된다. 따라서 혈관성장인자의 발현, 혈관내피세포의 다양성, 암 조직 주위의 미세 환경 등은 혈관성장 억제제를 통한 암의 치료에 중요한 영향을 미치게 된다. Angiogenesis refers to the creation of new capillaries from existing blood vessels. Strictly controlled phenomena that rarely occur under normal physiological conditions, such as when the embryo develops during the development of the embryo, in the case of wound healing in adults, and in changes in the genital system in the female reproductive cycle. In adults, capillary endothelial cells do not divide relatively well, and the rate of cleavage is usually from months to years. Angiogenesis is a complicated process by the interaction of various kinds of cells with water-soluble factors and extracellular matrix components, and their functional groups are not yet fully characterized. First, angiogenesis is essential in primary or metastatic tumors. Cancerous tissues can grow over 1 ~ 2 mm 3 without nutrients and oxygen supply by neovascularization. (Folkman J, Semin Cancer Biol. 1992, 3: 65-71). During neovascularization, primary cancer cells enter the blood vessels and migrate to other locations to form metastatic cancer. Therefore, neovascularization inhibitors have the potential to be commonly used in all solid tumors. Second, conventional chemotherapy treats cancer cells with rapid growth characteristics, so it is toxic to bone marrow cells and gastrointestinal cells, which have relatively high cell cycle, while neovascularization inhibitor has relatively few side effects It is possible. In addition, although chemotherapy with chemotherapy can be used as a therapeutic target for transformed cancer cells, new angiogenesis inhibitors are less likely to show tolerance in that normal vascular cells are treated. Third, because one blood vessel cell supplies nutrients and oxygen to hundreds of cancer cells, it can be an effective treatment for inhibiting many cancer cells through inhibition of one blood vessel cell. In the case of conventional anticancer chemotherapy, anticancer drugs flow out of blood vessels and affect cancer cells. However, blood vessel growth inhibitors directly contact vascular endothelial cells and thus drug delivery is easy. Anticancer drugs, which showed inhibitory effects in animal experiments, were not often effective in clinical trials. This is probably due to the difference in expression pattern of vascular endothelial cells and the distribution of different vascular growth factors in the microenvironment around each tumor. Therefore, expression of vascular growth factors, vascular endothelial cell diversity, and microenvironment surrounding cancer tissues have an important effect on the treatment of cancer through an angiostatic agent.
암조직에서 지금까지 밝혀진 일반적인 혈관신생 과정을 살펴보면, 먼저 혈관신생은 암세포에서 분비되는 혈관신생 유도인자(angiogenic factor)에 의해 시작된다. 이 유도인자는 혈관내피세포의 수용체와 결합하여 내피세포를 자극하게 되고 자극된 내피세포는 성장(proliferation), 침투(invasion), 이동(migration)과 분화(differentiation) 그리고 모세혈관형성 등 다양하고 복잡한 일련의 과정을 시작한다. 내피세포의 침투, 이동에는 조직 분해효소의 활성화 등이 필요하며 이는 암세포의 침투과정과 매우 유사하다. 혈관형성과정을 조절하는 많은 촉진인자와 억제인자들이 보고되었는데 그중에서도 VEGF는 혈관형성 촉진인자, 안지오스타틴(angiostatin)(O'Reilly MS, Holmgren L, Shing Y et al., Cell. 1994,21; 79:315-328)과 엔도스타틴(endostatin)(O'Reilly MS, Boehem T, Shing Y et al., Cell. 1997, 24; 88(2):277-285)은 혈관형성 억제인자로 가장 많이 알려져 있다. The general angiogenesis process that has been found so far in cancer tissues is as follows. First, angiogenesis is initiated by an angiogenic factor secreted from cancer cells. This inducer stimulates endothelial cells by binding to receptors of vascular endothelial cells, and stimulated endothelial cells have a variety of complex and complex processes including proliferation, invasion, migration and differentiation, and capillary formation Start a series of processes. The penetration and migration of endothelial cells require activation of histolytic enzymes, which is very similar to the penetration of cancer cells. VEGF is an angiostatin promoter, angiostatin (O'Reilly MS, Holmgren L, Shing Y et al., Cell. 1994,21; 79: 315-328) and endostatin (O'Reilly MS, Boehem T, Shing Y et al., Cells 1997, 24; 88 (2): 277-285) are the most known inhibitors of angiogenesis.
혈관내피세포 성장인자(vascular endothelial growth factor, VEGF)는 거의 모든 세포에서 분비되며, 종양의 침투성과 깊은 관계가 있다(Takahashi Y, Kitadai Y, Bucana CD et al., Cancer Res. 1995, 55(18):3964-3968). VEGF 수용체는 혈관 내피세포에 일반적으로 존재하지만 신경세포, 카포시 육종(Kaposi's sarcoma), 조혈모세포 등에서 발현되며, VEGFR-1(flt-1), VEGFR-2(Kdr/flk-1), VEGFR-3(flt-4) 등 3종류가 있다. VEGF가 결합되면 수용체 타이로신(tyrosine) 잔기의 인산화와 함께 수용체 이중화(dimerization)작용으로 신호가 전달된다. VEGFR-1은 내피세포의 이동, VEGFR-2는 내피세포의 성장과 혈액유출 효과에 관여한다. 직접적인 혈관형성인자 외에도 비특이적 인자들인 aFGF, bFGF, TGF, EGF, PDGF, 혈소판-유래 내피세포 성장인자(platelet-derived endothelial cell growth factor), 안지오제닌(angiogenin), IL-8, MIP, PF4, GRO 등이 혈관 형성에 관여한다(Moore BB, Arenberg DA, Addison CL et al., J Lab Clin Med. 1998, 132(2):97-103). 또한, VEGF의 발현 및 작용기전에 대한 연구와 함께 이를 조절하는 상위의 신호전달 과정을 저해함으로써 신생혈관형성을 억제할 수 있는 것에 대한 연구가 활발하다. 혈관 형성촉진인자의 활성을 감소시키는 VEGF 수용체에 대한 항체나 수용체 인산화 억제제는 대장암의 간 전이(metastasis)를 억제하는 효과를 나타내었으며, 이는 간에 형성된 암 조직의 혈관의 감소에 기인되었다(Shaheen RM, Davis DW, Liu W et al., Cancer Res. 1999, 59(21):5412-5416). 이외에도 혈관내피세포의 고사를 유도하는 기전, 혈관형성 촉진인자나 내피세포의 생존인자들을 조절하는 간접인자들의 작용 억제, 체내에 존재하는 신생혈관 억제제의 활성을 증가시키는 방법들에 대한 연구들이 활발히 진행되고 있다. Vascular Endothelial Growth Factor (VEGF) is secreted from almost all cells and is closely related to tumor invasion (Takahashi Y, Kitadai Y, Bucana CD et al., Cancer Res 1995, 55 (18 ): 3964-3968). VEGF receptors are generally found in vascular endothelial cells but are expressed in neurons, Kaposi's sarcoma, hematopoietic stem cells and the like, and VEGFR-1 (flt-1), VEGFR-2 (Kdr / flk- (flt-4). When VEGF is bound, signaling is carried out by receptor dimerization along with phosphorylation of the receptor tyrosine residues. VEGFR-1 is involved in endothelial cell migration, and VEGFR-2 is involved in endothelial cell growth and blood flow efficacy. In addition to direct angiogenic factors, non-specific factors such as aFGF, bFGF, TGF, EGF, PDGF, platelet-derived endothelial cell growth factor, angiogenin, IL-8, MIP, PF4, GRO, and the like are involved in angiogenesis (Moore BB, Arenberg DA, Addison CL et al., J Lab Clin Med 1998, 132 (2): 97-103). In addition, studies on the expression of VEGF and its inhibition of neuronal angiogenesis by inhibiting the signal transduction process that regulates this action and the action of the neuronal vasculature are actively studied. Antibody or receptor phosphorylation inhibitors to VEGF receptors that decrease the activity of angiogenesis promoting factors have been shown to inhibit metastasis of colorectal cancer, which is attributed to the reduction of blood vessels in the cancer tissue formed in the liver (Shaheen RM , Davis DW, Liu W et al., Cancer Res 1999, 59 (21): 5412-5416). In addition, studies on the mechanism of inducing apoptosis of vascular endothelial cells, the inhibition of the action of indirect factors controlling the survival factors of angiogenesis promoter or endothelial cells, and the methods of increasing the activity of neovascular inhibitors present in the body are actively conducted .
당뇨병성 망막증은 망막 저산소증 및 허혈로 인한 신생혈관 형성이 주된 원인이 되어 발병하는 질병으로, 여러 요인들이 관여하게 되는데, 특히 신생혈관형성인자이자 혈관투과성인자로 알려진 신생혈관형성인자(VEGF)가 가장 중요한 역할을 담당하고 있다. 아직까지 당뇨병성 망막증을 예방하거나 그 진행을 억제하는데 효과가 입증된 약물은 없으나 많은 망막증 발생기전 중 신생혈관형성에 관여하는 여러 성장인자에 대한 억제제 개발이 주목받고 있다. 최근에 아바스틴(Abastin, bevacizu Mab)과 같은 항신생혈관형성인자가 당뇨망막병증을 줄인다는 보고가 있다 (Avery R.L., 2006, Ophthalmology, 113:363-72; Spaide R.F., 2006, Retina, 26:275-8; Iturralde D., 2006, Retina, 26:279-84). 그러나 이 또한 부작용이 있어 지금은 부작용이 없는 천연물로부터 항신생혈관형성인자와 같은 물질을 개발하고자 많은 연구가 진행되고 있다.Diabetic retinopathy is a disease caused by retinal hypoxia and ischemia-induced neovascularization, and various factors are involved. Especially, neovascularization factor (VEGF), which is known as angiogenic factor and vascular permeability factor, It plays an important role. Although there is no drug that has been shown to prevent diabetic retinopathy or inhibit the progression of diabetic retinopathy, the development of inhibitors for various growth factors involved in angiogenesis in retinopathy has attracted attention. Recently, anti-angiogenic factors such as Abastin (bevacizu Mab) have been reported to reduce diabetic retinopathy (Avery RL, 2006, Ophthalmology, 113: 363-72; Spaide RF, 2006, Retina, 26: 275 -8; Iturralde D., 2006, Retina, 26: 279-84). However, many studies have been conducted to develop such substances as anti-angiogenic factors from natural products which have side effects and which have no side effects.
구체적으로, 복분자의 성분이나 생리활성에 대한 연구는 카테킨(catechin) 분리 및 DPPH에 대한 항산화(Hong BK, Kim JK, Kim H, Lee JW, Yu CH, Kim MJ, 2006. Proc. of Soc. Korean Med. Crop. Sci. 14:632-633), 페놀계 배당체 분리(Hur JM, Yang EJ, Choi SH, Song KS, 2006, J. Korean Soc. Appl. Biol. Chem. 49:149-152), 암세포 성장 억제 효과(Shin IC, Sa JH, Kim TW, Park KY, Jeong KJ, Lee TW, Han KS, Shim TH, Oh HS, 2005, Rep. Inst. Health & Environ. 16:39-45), 암세포에 대한 세포독성(Park KM, Yang MC, Lee KH, Kim KR, Choi SU, Lee KR, 2006, Arch. Pharm. Res. 29(12):1086-1090) 등이 있다. 복분자(Rubus coreanus Miquel)는 주로 산기슭에 자라고 주로 열매를 이용한다. Specifically, studies on the components and physiological activities of the bokbunja were performed by catechin separation and antioxidant treatment against DPPH (Hong BK, Kim JK, Kim H, Lee JW, Yu CH, Kim MJ, 2006. Proc. Of Soc. 49: 149-152), phenol-based glycosidation (Hur JM, Yang EJ, Choi SH, Song KS, 2006, J. Korean Soc. Appl. Biol. Inhibition of growth of cancer cells (Shin IC, Sa JH, Kim TW, Park KY, Jeong KJ, Lee TW, Han KS, Shim TH, Oh HS, 2005, Rep. Inst. (Park KM, Yang MC, Lee KH, Kim KR, Choi SU, Lee KR, 2006, Arch Pharm Res. 29 (12): 1086-1090). Rubus coreanus Miquel ) grows mainly at the foot of a mountain and mainly uses fruit.
한편, 한국특허등록 10-0616067호에는 복분자 추출물을 포함하는 항암 조성물이 개시되어 있으며, 보다 구체적으로 복분자로부터 열수, 유기용매로 추출한 추출물을 이용한 항암조성물이 개시되어 있다. 다만 상기 문헌에는 복분자 추출물이 암 세포에 대하여 증식 억제 효과를 나타내고, 암 세포의 DNA 합성을 억제하며, 암세포 사멸(apoptosis)을 유도할 수 있다는 점이 개시되어 있을 뿐 신생혈관형성을 억제할 수 있는 효과를 나타낼 수 있다는 점에 대하여 전혀 개시하고 있지 않다.On the other hand, Korean Patent Registration No. 10-0616067 discloses an anticancer composition comprising a bokbunja extract, and more specifically, an anticancer composition using an extract extracted from bokbunja with hot water and an organic solvent. However, the above-mentioned document discloses that the bokbunja extract exhibits a proliferation inhibitory effect on cancer cells, inhibits DNA synthesis of cancer cells, induces apoptosis, and can inhibit neovascularization Quot; can not be displayed at all.
즉, 현재까지 본 발명에 사용된 복분자 수추출물의 신생혈관형성 억제 효과 및 그 기전에 관한 보고는 없다. That is, there is no report on the inhibitory effect on the angiogenesis of the extract of the bacterium used in the present invention and its mechanism.
이에 본 발명자들은 복분자 수추출물의 신생혈관형성 억제 활성을 확인하고 본 발명을 완성하기에 이르렀다.
Accordingly, the present inventors have confirmed the activity of inhibiting angiogenesis of bokbunja water extract and completed the present invention.
본 발명의 목적은 복분자 수추출물을 유효성분으로 함유하는 신생혈관형성 억제 활성을 갖는 약학 조성물을 제공하는 것이다. It is an object of the present invention to provide a pharmaceutical composition having an activity of inhibiting angiogenesis, which comprises a brambled water extract as an active ingredient.
본 발명의 다른 목적은 복분자 수추출물을 유효성분으로 함유하는 신생혈관형성 억제 활성을 갖는 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition having an activity of inhibiting angiogenesis, which comprises a brambled water extract as an active ingredient.
본 발명의 다른 목적은 신생혈관형성 억제 활성을 나타내는 복분자 수추출물을 제조하는 방법을 제공하는 것이다.
Another object of the present invention is to provide a method for producing a bacterium water extract which exhibits an activity of inhibiting angiogenesis.
상기 목적을 달성하기 위해, 본 발명은 복분자 수추출물을 유효성분으로 함유하는 약학적 조성물을 제공함으로써, 상기 과제를 해결하였다.
In order to achieve the above object, the present invention solves the above-mentioned problems by providing a pharmaceutical composition containing an extract of brambled water as an active ingredient.
본 발명은 복분자 수추출물을 유효성분으로 함유하는 약학적 조성물에 관한 것으로서, 본 발명에 따른 복분자 수추출물은 신생혈관형성을 억제하는 효과를 나타낸다. 따라서 생체 내에서 신생혈관형성을 요구하는 비정상적으로 증식된 세포와 관련된 질환, 예를 들어 과도한 신생혈관 형성으로 인한 당뇨병성 망막증 치료제 또는 각종 종양 등의 치료제로서 매우 유용하여 신생혈관형성 억제용 약학 조성물, 식품 조성물로 사용될 수 있다.
The present invention relates to a pharmaceutical composition containing an extract of brambled water as an active ingredient, and the brambled water extract according to the present invention has an effect of inhibiting neovascularization. Therefore, it is very useful as a therapeutic agent for a disease associated with abnormally proliferated cells requiring neovascularization in vivo, for example, a therapeutic agent for diabetic retinopathy or various tumors due to excessive neovascularization, and is useful as a pharmaceutical composition for inhibiting angiogenesis, Can be used as a food composition.
도 1은 본 발명의 일 실시예로서 복분자 수추출물의 세포독성에 관한 실험으로써 MTT 분석방법의 결과를 도시한 도면이다.
도 2는 본 발명의 일 실시예로서 복분자 수추출물의 VEGF에 대한 세포신호전달에 관한 웨스턴 블롯(Western blot) 분석방법의 결과를 도시한 도면이다.
도 3은 본 발명의 일 실시예로서 복분자 수추출물의 세포증식 분석방법의 결과를 도시한 도면이다.
도 4는 본 발명의 일 실시예로서 복분자 수추출물의 세포이동 분석방법의 결과를 도시한 도면이다.
도 5는 본 발명의 일 실시예로서 복분자 수추출물의 혈관형성 분석방법의 결과를 도시한 도면이다.
도 6은 본 발명의 일 실시예로서 복분자 수추출물의 쥐 대동맥 발아(sprouting) 분석방법의 결과를 도시한 도면이다. FIG. 1 is a graph showing the results of an MTT assay as an experiment on cytotoxicity of an extract of bokromatic water as an embodiment of the present invention.
FIG. 2 is a graph showing the results of a Western blot analysis method for cell signal transduction to VEGF of a brambled water extract as an embodiment of the present invention.
FIG. 3 is a graph showing the results of a method for analyzing cell proliferation of a brambled water extract as an embodiment of the present invention.
FIG. 4 is a graph showing the results of a cell migration assay of a bactobacillus water extract as an example of the present invention.
FIG. 5 is a graph showing the results of the blood vessel formation analysis method of the brambled water extract as one embodiment of the present invention.
FIG. 6 is a graph showing the results of a method for analyzing rat aortic sprouting of brambled water extract as an embodiment of the present invention.
본 발명은 복분자 수추출물을 유효성분으로 함유하는 신생혈관형성 억제 활성을 갖는 약학적 조성물을 제공한다. The present invention provides a pharmaceutical composition having an activity of inhibiting angiogenesis, which comprises an extract of Rubus coreanus as an active ingredient.
본 발명의 일 양태에서, 상기 수추출물은 냉수 추출물일 수 있다. In one embodiment of the present invention, the water extract may be cold water extract.
본 발명의 일 양태에서, 상기 복분자는 건조된 복분자를 말한다.In one embodiment of the present invention, the brambles refer to dried brambles.
본 발명의 일 양태에서, 상기 수추출물은 복분자 2배 중량 이상의 냉수를 가하여 12시간 이상 추출할 수 있다.In one embodiment of the present invention, the water extract may be extracted for at least 12 hours by adding cold water at least twice the weight of the brambles.
본 발명의 일 양태에서, 상기 약학적 조성물은 당뇨병성 망막증, 신생혈관성 녹내장, 후수정체 섬유증식증, 증식성 유리체 망막병증, 미성숙 망막병증, 안과 염증, 각막 궤양, 원추 박막, 황반 변성, 쇼그렌 증후군, 근시 안과 종양, 각막이식 거부반응, 이상 창상 유합, 트라코마(trachoma), 골질환, 류머티스성 관절염(rheumatoid arthritis), 골관절염, 패혈증성 관절염, 혈관종(hemangiomas), 섬유성 혈관종(angiofibroma), 건선(psoriasis), 화농성 육아종(pyogenic granuloma), 단백뇨증, 복대동맥류 질환, 외상성 관절 손성에 따른 퇴행성 연골손실, 신경계 수초탈락 질환, 간경변, 신사구체 질환, 배태막의 미성숙 파열증, 염증성 장질환, 치근막 질환, 동맥경화증, 재협착증, 중추신경계의 염증질환, 알츠하이머 질환, 피부 노화, 갑상선 과증식, 그레이브스 병(Grave’s disease), 암 발생(cancer development), 암 침윤 및 암 전이(cancer metastasis)로 이루어진 그룹으로부터 선택되는 질환의 예방 또는 치료목적으로 활용될 수 있다.In one aspect of the present invention, the pharmaceutical composition is useful for the treatment of diabetic retinopathy, neovascular glaucoma, posterior capsular hyperplasia, proliferative vitreoretinopathy, immature retinopathy, ocular inflammation, corneal ulcer, cone diaphragm, macular degeneration, Sjogren's syndrome, Ophthalmoplegia, septic arthritis, hemangiomas, angiofibroma, psoriasis, psoriatic arthritis, ophthalmopathy, ophthalmopathy, ophthalmopathy, myopia ophthalmopathy, corneal transplant rejection, abnormal wound union, trachoma, bone disease, rheumatoid arthritis, ), Pyogenic granuloma, proteinuria, abdominal aortic aneurysm, degenerative cartilage loss due to traumatic joint injury, nervous system herniated warts disease, cirrhosis, gynecological diseases, immature platelets of inflammation, inflammatory bowel disease, Inflammatory diseases of the central nervous system, Alzheimer's disease, skin aging, thyroid hyperplasia, Grave's disease, cancerous foot (Cancer development), it can be used as prophylaxis or treatment of diseases selected from the group consisting of cancer invasion and metastasis (cancer metastasis).
상기 본 발명의 약학적 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 약학적으로 허용 가능한 담체를 포함하는 상기 조성물은 경구 또는 비경구의 여러 가지 제형일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스 또는 락토오스, 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용될 수 있다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁용제로는 프로필렌 글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween)61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.The pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier. The composition comprising a pharmaceutically acceptable carrier can be of various oral or parenteral formulations. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin, . In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used. have. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used as the non-aqueous solvent and suspension agent. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.
상기 약학적 조성물은 정제, 환제, 산제, 과립제, 캡슐제, 현탁제, 내용액제, 유제, 시럽제, 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제 및 좌제로 이루어진 군으로부터 선택되는 어느 하나의 제형을 가질 수 있다.The pharmaceutical composition may be in the form of tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations and suppositories It can have one formulation.
상기 본 발명의 조성물은 약학적으로 유효한 양으로 투여한다. The composition of the present invention is administered in a pharmaceutically effective amount.
본 발명에서 용어 "약학적으로 유효한 양”은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 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. 그러나 바람직한 효과를 위해서, 본 발명의 추출물은 1일 1 내지 200 mg/kg으로, 바람직하게는 10 내지 100 mg/kg으로 투여될 수 있다.The term "pharmaceutically effective amount " as used herein means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will vary depending on the species and severity, age, sex, , The sensitivity to the drug, the time of administration, the route of administration and the rate of excretion, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. 1 to 200 mg / kg, preferably 10 to 100 mg / kg per day.
본 발명의 조성물은 개별 치료제로 투여하거나 신생혈관형성 억제 효과를 나타내는 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다.The composition of the present invention may be administered in the form of an individual therapeutic agent or in combination with another therapeutic agent exhibiting an effect of inhibiting angiogenesis, and may be administered sequentially or simultaneously with a conventional therapeutic agent. And can be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without adverse effect, and can be easily determined by those skilled in the art.
본 발명에서 용어, "개체”란 신생혈관형성 억제 활성을 통해 예방 또는 치료할 수 있는 질환이 이미 발병되었거나, 발병될 수 있는 인간을 포함한 모든 동물을 의미하고 본 발명의 추출물을 포함하는 조성물을 개체에게 투여함으로써, 상기 질환을 효과적으로 예방 및 치료할 수 있다. As used herein, the term "individual " means all animals, including humans, who have already developed or are capable of developing a disease that can be prevented or treated through the inhibition of neovascularization, and the composition comprising the extract of the present invention may be administered to a subject The above diseases can be effectively prevented and treated.
상기 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 본 발명의 조성물은 목적하는 바에 따라 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 비내 투여, 폐내 투여, 직장내 투여될 수 있으나, 이에 제한되지는 않는다. 또한 상기 조성물은 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수 있다.The route of administration of the composition may be administered via any conventional route so long as it can reach the target tissue. The composition of the present invention may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, orally, intranasally, intrapulmonarily, or rectally, though it is not intended to be limited thereto. The composition may also be administered by any device capable of transferring the active agent to the target cell.
본 발명은 복분자 수추출물을 유효성분으로 함유하는 신생혈관형성 억제 활성을 갖는 식품 조성물을 제공한다. The present invention provides a food composition having an activity of inhibiting angiogenesis, comprising an extract of brambled water as an active ingredient.
본 발명의 일 양태에서, 복분자의 수추출물을 유효성분으로 함유하는 신생혈관형성 억제 활성을 갖는 식품 조성물을 제공한다. In one aspect of the present invention, there is provided a food composition having an activity of inhibiting angiogenesis, which comprises an extract of water of bokbunja as an active ingredient.
본 발명의 일 양태에서, 상기 복분자는 건조된 복분자를 말한다.In one embodiment of the present invention, the brambles refer to dried brambles.
본 발명의 일 양태에서, 상기 추출물은 복분자 2배 중량 이상의 냉수를 가하여 12시간 이상 추출할 수 있다.In one embodiment of the present invention, the extract can be extracted for at least 12 hours by adding cold water at least twice the weight of the brambles.
본 발명의 일 양태에서, 상기 식품 조성물은 당뇨병성 망막증, 신생혈관성 녹내장, 후수정체 섬유증식증, 증식성 유리체 망막병증, 미성숙 망막병증, 안과 염증, 각막 궤양, 원추 박막, 황반 변성, 쇼그렌 증후군, 근시 안과 종양, 각막이식 거부반응, 이상 창상 유합, 트라코마(trachoma), 골질환, 류머티스성 관절염(rheumatoid arthritis), 골관절염, 패혈증성 관절염, 혈관종(hemangiomas), 섬유성 혈관종(angiofibroma), 건선(psoriasis), 화농성 육아종(pyogenic granuloma), 단백뇨증, 복대동맥류 질환, 외상성 관절 손성에 따른 퇴행성 연골손실, 신경계 수초탈락 질환, 간경변, 신사구체 질환, 배태막의 미성숙 파열증, 염증성 장질환, 치근막 질환, 동맥경화증, 재협착증, 중추신경계의 염증질환, 알츠하이머 질환, 피부 노화, 갑상선 과증식, 그레이브스 병(Grave’s disease), 암 발생(cancer development), 암 침윤 및 암 전이(cancer metastasis)로 이루어진 그룹으로부터 선택되는 질환의 예방 또는 완화 목적으로 활용될 수 있다.In one aspect of the invention, the food composition is selected from the group consisting of diabetic retinopathy, neovascular glaucoma, posterior capsular hyperplasia, proliferative vitreoretinopathy, immature retinopathy, ocular inflammation, corneal ulcer, cone diaphragm, macular degeneration, Sjogren's syndrome, Ophthalmopathy, hemangiomas, angiofibroma, psoriasis, ophthalmopathy, ophthalmic tumor, corneal transplant rejection, abnormal wounds, trachoma, bone disease, rheumatoid arthritis, osteoarthritis, , Pyogenic granuloma, proteinuria, abdominal aortic aneurysm disease, degenerative cartilage loss due to traumatic joint injury, nervous system herniated warts disease, cirrhosis, gynecological diseases, immature platelets of germinal membranes, inflammatory bowel disease, , Restenosis, inflammatory diseases of the central nervous system, Alzheimer's disease, skin aging, thyroid hyperplasia, Grave's disease, cancer (c anther development, cancer invasion, and cancer metastasis. < Desc /
본 발명에 따른 식품은, 복분자 수추출물, 보다 구체적으로는 냉수 추출물을 포함하되, 적절한 식품보조첨가제가 포함될 수 있다.The food according to the present invention may include a raspberry extract, more specifically a cold water extract, and may include suitable food supplementary additives.
본 발명의 일 양태에서, 상기 식품은 건강기능식품일 수 있다.In one aspect of the invention, the food may be a health functional food.
본 발명에서 용어 "식품보조첨가제”란 식품에 보조적으로 첨가될 수 있는 구성요소를 의미하며, 각 제형의 건강기능식품을 제조하는데 첨가되는 것으로서 당업자가 적절히 선택하여 사용할 수 있다. 식품보조첨가제의 예로는 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등이 포함되지만, 상기 예들에 의해 본 발명의 식품보조첨가제의 종류가 제한되는 것은. 아니다.The term "food-aid additive " in the present invention means a component which can be added to foods in a supplementary manner, and it can be appropriately selected and used by those skilled in the art as being added to produce health functional foods of each formulation. A coloring agent and a filler, a pectic acid and a salt thereof, an alginic acid and a salt thereof, an organic acid, a protective colloid thickener, a pH adjuster, a stabilizer, a stabilizer and a stabilizer such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, A preservative, a glycerin, an alcohol, a carbonating agent used in a carbonated drink, etc. However, the types of the food-aid additives of the present invention are not limited by the above examples.
본 발명에서 용어 "건강기능식품”이란 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 정제, 캅셀, 분말, 과립, 액상 및 환 등의 형태로 제조 및 가공한 식품을 말한다. 여기서 기능성이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 건강기능식품은 당업계에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조 시에는 당업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, 본 발명의 건강기능식품은 신생혈관형성 억제 효과를 증진시키기 위한 보조제로 섭취가 가능하다. The term "health functional food " in the present invention refers to a food prepared and processed in the form of tablets, capsules, powders, granules, liquids and rings by using raw materials and components having useful functions in the human body. The health functional food of the present invention can be prepared by a method commonly used in the art, and the health functional food of the present invention can be manufactured by the method Unlike general medicines, there is an advantage that there are no side effects that may occur when a drug is taken for a long time by using a food as a raw material, and the portability In addition, the health functional food of the present invention can be ingested as an adjuvant for enhancing the effect of inhibiting angiogenesis.
유효 성분의 혼합양은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품의 제조 시에 본 발명에 따른 복분자 수추출물은 원료 조성물 중 1 ~ 10 중량%, 바람직하게는 5 ~ 10중량%의 양으로 첨가된다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하로도 사용될 수 있다.The amount of the active ingredient to be mixed can be suitably determined according to the intended use (prevention, health or therapeutic treatment). Generally, the brambled water extract according to the present invention is added in an amount of 1 to 10% by weight, preferably 5 to 10% by weight, of the raw material composition when the food is prepared. However, in the case of long-term ingestion intended for health and hygiene purposes or for the purpose of controlling health, the amount can also be used in the above-mentioned range.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강식품을 모두 포함한다.There is no particular limitation on the kind of the food. Examples of the food to which the above substance can be added include dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, Alcoholic beverages, and vitamin complexes, all of which include healthy foods in a conventional sense.
본 발명의 건강식품에는 통상의 식품과 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유될 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토스, 수크로스와 같은 디사카라이드 및 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드, 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 당 일반적으로 약 0.01 ~ 0.04 g, 바람직하게는 약 0.02 ~ 0.03 g 이다.
The health food of the present invention may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary foods. The above-mentioned natural carbohydrates are sugar saccharides such as monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and xylitol, sorbitol and erythritol. As the sweetening agent, natural sweetening agents such as tau Martin and stevia extract, synthetic sweetening agents such as saccharine and aspartame, and the like can be used. The ratio of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 of the composition of the present invention.
적용예Application example 1: 과다한 신생혈관형성으로 인한 당뇨병성 망막증 치료 1: Treatment of diabetic retinopathy due to excessive neovascularization
당뇨병에 의한 실명은 25세 이후에 발생하는 실명의 가장 흔한 원인이 된다. 당뇨병환자들에게서 흔히 나타나는 눈의 질환으로는 결막염, 백내장, 녹내장, 안근마비, 시신경병증 등 눈의 다양한 조직에 합병증이 발생하지만 실명의 가장 중요한 원인은 역시 망막병증이다. 망막병증의 유병률은 당뇨병을 앓은 유병기간과 밀접한 관계가 있다. 제 1형 당뇨병환자의 경우 유병기간 5년 이하에서 약 15%, 15년 이상에서 95%이상에서 망막병증이 발생하고, 제 2형 당뇨병환자의 경우 유병기간 5년 이하에서 약 30%, 15년 이상에서 약 80%에서 망막병증이 발생한다. 이외에도 만성 고혈당증, 고혈압, 임신, 사춘기, 신장질환, 고지혈증 등이 망막병증의 발생과 진행에 영향을 끼친다. 당뇨망막병증은 망막의 병변이 망막내부에 국한되어 있는 비증식성 망막병증과 망막으로부터 신생혈관조직이 유리체강 내부로 자라 들어가는 증식성 망막병증으로 구분된다. 초기에는 가벼운 정맥 확장과 혈관벽이 탄력을 잃으면서 꽈리처럼 부풀어 오르는 미세혈관류가 발생하고, 좀더 진행하면 혈관 투과성이 증가하면서 혈액 성분이 빠져나와서 망막이 붓고, 출혈이나 삼출물이 생긴다. 모세혈관이 막히면 혈액순환이안 되는 부위가 늘어나고 망막내부에서 신생혈관이 자라나기 시작한다. 이러한 변화들이 망막의 중심부를 침범하게 되면 시력이 저하된다. 좀 더 진행하면 망막이나 시신경 유두, 홍채 등에 신생혈관이 자라나게 되는 증식성 망막병증으로 발전되고, 갑작스런 유리체 출혈이나 견인 망막박리를 초래하여 심각한 시력 저하를 초래한다. 초기내지 중기의 변화들이 중심부 망막을 침범하지 않는 경우 전혀 시력이 저하되지 않고 말기까지 진행되어 발견되는 경우가 있다. 따라서 본 발명의 복분자 수추출물의 신생혈관형성 억제 효과는 당뇨병성 망막증의 치료에 효과적이다.
Blindness due to diabetes is the most common cause of blindness that occurs after
적용예Application example 2: 종양(암) 2: tumor (cancer)
종양은 암세포가 그들의 조직덩어리에 작은 혈관을 증식시키는 능력이 강화될 때에만 발생한다. 암세포는 신생혈관 형성(Angiogenesis)을 촉진하거나 또는 모세혈관(capillaries)을 형성하는 혈관 내피세포(endothelial cells)를 증식하는 요소, 즉 혈관내피세포 성장인자(VEGF)를 분비함으로써 작은 혈관을 증식시키는 능력을 강화한다. 만일 이들 신생혈관 형성(Angiogenesis)요소들이 억제되거나 차단된다면, 종양은 산소와 영양부족 상태가 되며, 암세포가 만들어낸 독성물질 속에서 괴사하게 된다. 종양덩어리로부터 떨어져 나온 암세포는 만일 신생혈관 형성(Angiogenesis)을 유도하는 요소의 분비능력을 상실하거나 신생혈관 형성을 막으면 다른 기관에 전이 될 수 없다. 따라서 본 발명의 복분자 수추출물의 신생혈관형성 억제 효과는 암세포의 성장과 전이를 막아 암 치료에 효과적이다.
Tumors occur only when the ability of cancer cells to grow small blood vessels in their tissue mass is enhanced. Cancer cells have the ability to proliferate small blood vessels by secreting vascular endothelial cell growth factor (VEGF), an element that promotes angiogenesis or proliferates endothelial cells that form capillaries, . If these new angiogenesis factors are suppressed or blocked, the tumor becomes oxygenated and undernourished and becomes necrotic in the toxic material produced by cancer cells. Cancer cells detached from tumor masses can not be transferred to other organs if they lose the ability to secrete elements that lead to angiogenesis or block angiogenesis. Therefore, the inhibitory effect of the bacterium water extract of the present invention on angiogenesis is effective in cancer treatment by preventing growth and metastasis of cancer cells.
이하, 본 발명에 따르는 실시예 및 본 발명에 따르지 않는 비교예를 통하여 본 발명을 보다 상세히 설명하나, 본 발명의 범위가 하기 제시된 실시예에 의해 제한되는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to Examples of the present invention and Comparative Examples which are not based on the present invention, but the scope of the present invention is not limited by the following Examples.
실시예Example
1：복분자 1: bokbunja
수추출물의Water extract
제조 Produce
*복분자 중량대비 2배 중량의 냉수를 가하고 12시간 동안 추출 후 여과하고 동결 건조하여 복분자 수추출물을 수득하였다.
* Two times the weight of cold water was added to the weight of the bokbunja, and the mixture was extracted for 12 hours, filtered and lyophilized to obtain a bokbunja water extract.
실시예Example 2：복분자 2: bokbunja 수추출물의Water extract 제조 Produce
복분자 중량대비 3배 중량의 냉수를 가하고 12시간 동안 추출 후 여과하고 동결 건조하여 복분자 수추출물을 수득하였다.
Three times the weight of cold water was added to the weight of the bokbunja, the mixture was extracted for 12 hours, filtered and lyophilized to obtain a bokbunja water extract.
실시예Example 3：복분자 3: bokbunja 수추출물의Water extract 제조 Produce
복분자 중량대비 4배 중량의 냉수를 가하고 12시간 동안 추출 후 여과하고 동결 건조하여 복분자 수추출물을 수득하였다.
Four times the weight of cold water was added to the weight of the bokbunja, the mixture was extracted for 12 hours, filtered and lyophilized to obtain a bokbunja water extract.
실시예Example 4：복분자 추출물( 4: Rubus coreanus extract ( RCMERCME )의 제조)
복분자 중량대비 5배 중량의 냉수를 가하고 12시간 동안 추출 후 여과하고 동결 건조하여 복분자 수추출물을 수득하였다.
Five times the weight of cold water was added to the weight of the bokbunja, the mixture was extracted for 12 hours, filtered and lyophilized to obtain a bokbunja water extract.
실험예Experimental Example 1：복분자 1: bokbunja 수추출물의Water extract 세포독성 실험 Cytotoxicity experiment
실시예 1에서 얻어진 복분자 추출물(RCME)이 인간 탯줄정맥혈관내피세포에 독성이 있는지를 MTT 세포 생존능력 분석방법으로 조사하였다. The ability of the bacterium extract (RCME) obtained in Example 1 to be toxic to human umbilical vein endothelial cells was examined by MTT cell viability assay.
이를 위해 먼저, 혈관내피세포(HUVECs)를 20% FBS(Hyclone), 헤파린(5 unit/ml), bFGF(3 ng/ml), 100 unit/ml 페니실린, 100 μg/ml 스트렙토마이신을 첨가한 M199 배지에 접종하고 37℃, 5% CO2 배양기에서 배양하였다. 모든 실험에서 세포의 생존율은 95% 이상으로 유지시켰다. For this purpose, HUVECs were first treated with M199 supplemented with 20% FBS (Hyclone), heparin (5 units / ml), bFGF (3 ng / ml), 100 units / ml penicillin, 100 μg / ml streptomycin And cultured in a 5% CO 2 incubator at 37 ° C. Cell viability was maintained above 95% in all experiments.
상기에서 배양된 HUVECs 세포를 5× 104 cells/well의 농도로 12 웰 플레이트에 분주하고, 37℃, 5% CO2 배양기에서 24시간 동안 배양하였다. 상기 세포에 복분자 수추출물(1, 5, 10, 25, 50, 100 μg/ml)을 다양한 농도로 각 웰에 처리한 후, 37℃, 5% CO2 배양기에서 24시간 동안 배양하였다. The HUVECs cells cultured as described above were dispensed into 12-well plates at a concentration of 5 × 10 4 cells / well and cultured in a 5% CO 2 incubator at 37 ° C. for 24 hours. The cells were treated with various concentrations of bovine fluid (1, 5, 10, 25, 50, 100 μg / ml) at various concentrations and cultured in a 5% CO 2 incubator at 37 ° C for 24 hours.
배양이 완료된 후, 배지가 있는 상태에서 각 웰에 5 mg/ml의 MTT 시약을 100㎕의 농도로 첨가하고 배양기에서 4시간 배양하였다. 4시간 후, 배양액을 제거하고 각 웰에 DMSO(dimethyl sulfoxide)를 150 ㎕씩 첨가하고, 스펙트로포토미터(spectrophotometer)를 사용하여 595 nm에서 흡광도를 측정함으로써 세포생존능력을 분석하였다. After completion of the cultivation, 100 μl of 5 mg / ml MTT reagent was added to each well in the presence of the medium and cultured in an incubator for 4 hours. After 4 hours, the culture solution was removed, and 150 쨉 l of DMSO (dimethyl sulfoxide) was added to each well. Cell viability was analyzed by measuring the absorbance at 595 nm using a spectrophotometer.
이때, 세포생존능력은 복분자 수추출물을 처리하지 않은 대조군의 세포생존능력을 100%로 하고 이에 대한 상대적인 값으로 나타내었다. At this time, the cell viability was expressed as a relative value with 100% of the cell viability of the control group not treated with the bokbunja water extract.
실험 결과, 복분자 수추출물의 처리 농도가 증가할수록 세포생존능력이 감소하는 것으로 나타났다 (도 1). As a result, the cell viability was decreased as the treatment concentration of the bokbunja extract increased (Fig. 1).
그래서 이하 모든 실험은 세포독성이 없는 농도에서 수행하였다.
Thus, all of the following experiments were performed at a concentration that is not cytotoxic.
실험예 2：복분자 수추출물의 VEGF 에 대한 세포신호전달( ERK , p38 , VEGF 수용체 인산화) 실험 Experimental Example 2: bokbunja can extract Cell signaling for VEGF (ERK, p38, VEGF receptor phosphorylation) experiments
혈관내피세포를 60 mm 플레이트에 분주한 후 다음날에 6시간 혈청기아(serum starvation)를 주었다. VEGF(20 ng/ml)를 처리하기 40분 전에 복분자 수추출물을 처리하였다. Vascular endothelial cells were plated on 60 mm plates and serum starvation was given for 6 hours on the next day. Brambone water extracts were treated 40 minutes before treatment with VEGF (20 ng / ml).
상기 VEGF(20 ng/ml)를 처리한 후 10분 뒤에 RIPA 버퍼[12mM EDTA, 137 mM NaCl, 20 mM Tris-HCl(pH 8.0), 1 mM Na3VO4(Sigma-Aldrich, USA) 10 mM NaF(Sigma), 1 mM PMSF(Sigma), 1% Triton X-100, 10% 글리세롤, 프로테아제 억제 칵테일(Roche,Germany)]를 이용하여 세포를 용해(lysis)하였다. After 10 minutes of the treatment with VEGF (20 ng / ml), 10 mM RIPA buffer (12 mM EDTA, 137 mM NaCl, 20 mM Tris-HCl (pH 8.0), 1 mM Na 3 VO 4 (Sigma-Aldrich, USA) Cells were lysed using NaF (Sigma), 1 mM PMSF (Sigma), 1% Triton X-100, 10% glycerol, protease inhibitory cocktail (Roche, Germany).
용해된 세포를 1.5 ml 튜브에 넣고 피펫팅한 다음, 얼음위에서 20분간 방치하였다. 이를 14,000 rpm에서 20분간 원심분리하여 상등액을 회수하여 단백질을 분리하였다. 분리한 단백질은 BCA 단백질 분석 키트(Pierce, Rockford, Illinois)를 사용하여 각각의 샘플 농도를 결정하고 전기영동(SDS-PAGE)하였다. The dissolved cells were placed in a 1.5 ml tube, pipetted, and left on ice for 20 minutes. The supernatant was recovered by centrifugation at 14,000 rpm for 20 minutes to separate proteins. Separated proteins were determined for each sample concentration using a BCA protein assay kit (Pierce, Rockford, Ill.) And electrophoresed (SDS-PAGE).
상기 분리된 단백질을 이용하여 웨스턴 블롯 분석을 수행하였다. 즉, 샘플의 전기영동이 끝나면 젤에서 폴리비닐리덴 플루오라이드 멤브레인(Polyvinylidene Fluoride membrane, Pall Corporation)으로 단백질을 트랜스퍼 한 후, 상기 멤브레인을 상온에서 2시간동안 3% BSA 용액(Amresco, USA)으로 블럭킹(blocking) 하고, 1차 항체를 처리하여 2시간 동안 상온에서 반응시켰다. 상기 1차 항체로는 세포사 관련 신호 기전들에 대한 항체인 항-ERK 항체, 항-p-ERK, 항-p38 항체, 항-p-p38 항체, 항-VEGF 수용체 항체, 항-p-VEGF 수용체 항체를 셀 시그날링 테크놀러지사(Cell Signaling Technology, Beverly, MA)로부터 구입하여 사용하였다. 일차 항체와의 반응이 완료되면 약 15분 동안 세척하고 다시 45분간 2차 항체를 처리하여 반응시켰다. Western blot analysis was performed using the separated proteins. After electrophoresis of the sample was completed, the protein was transferred from the gel to a polyvinylidene fluoride membrane (Pall Corporation), and the membrane was blocked with 3% BSA solution (Amresco, USA) at room temperature for 2 hours blocked, treated with primary antibody, and reacted at room temperature for 2 hours. The primary antibodies include anti-ERK antibody, anti-p-ERK, anti-p38 antibody, anti-p-p38 antibody, anti-VEGF receptor antibody, anti-p-VEGF receptor Antibodies were purchased from Cell Signaling Technology (Beverly, Mass.) And used. After completion of the reaction with the primary antibody, the cells were washed for about 15 minutes and reacted for 45 minutes with the secondary antibody.
반응 후 30분 이상 충분히 세척한 후 ECL 검출 키트(Santa Cruz Biotechnology)를 사용하여 밴드를 확인하였다. After the reaction was thoroughly washed for at least 30 minutes, the band was confirmed using an ECL detection kit (Santa Cruz Biotechnology).
실험 결과, VEGF에 의해 유도된 ERK, p38, VEGF 수용체의 인산화가 복분자 수추출물에 의해 저해되는 것을 볼 수 있다.(도 2)
Experimental results show that the phosphorylation of ERK, p38, and VEGF receptors induced by VEGF is inhibited by the water extract of brambles (Figure 2)
실험예Experimental Example 3 : 3: VEGFVEGF 에 의한 세포증식에 미치는 복분자 On the Cell Proliferation by 수추출물의Water extract 영향 실험 Influence experiment
상기 실험예 1과 동일한 방법으로 배양한 혈관 내피 세포를 4x104 cells/well의 농도로 12 웰 플레이트에 분주하였다. 6시간 정도의 혈청 기아(serum starvation)를 준 후, 복분자 수추출물을 전처리하고 VEGF(20 ng/ml)를 처리하였다. The vascular endothelial cells cultured in the same manner as in Experimental Example 1 were dispensed into a 12-well plate at a concentration of 4
처리한지 24시간 뒤에, 세포계수기를 이용하여 세포의 개수를 측정하였다.Twenty-four hours after the treatment, the number of cells was measured using a cell counter.
실험 결과, 복분자 수추출물이 VEGF에 의한 혈관 내피 세포의 증식을 억제하는 것으로 나타났다(도 3).
As a result of the experiment, it was shown that the extract of bokbunja extract inhibited VEGF-induced vascular endothelial cell proliferation (Fig. 3).
실험예Experimental Example 4 : 4 : VEGFVEGF 에 의한 세포이동에 미치는 복분자 On the cell migration by 수추출물의Water extract 영향 실험 Influence experiment
먼저 트렌스웰 인서트(transwell insert)의 아래 면을 젤라틴(gelatin)으로 코팅한 후 그 안에 1× 105 개의 혈관 내피 세포와 VEGF(20 ng/ml), 복분자 수추출물을 넣고 4시간 배양한 후에 배양이 끝나면 웰의 내면을 면봉 등으로 닦아서 이동하지 않은 세포들을 제거하였다. First, the lower surface of the transwell insert was coated with gelatin, and then 1 × 10 5 vascular endothelial cells, VEGF (20 ng / ml) and bokbunja water extract were added thereto, followed by incubation for 4 hours. At the end of the incubation, the inner surface of the well was wiped with a swab or the like to remove unmoved cells.
아래쪽으로 이동한 세포의 수는 헤마톡실린(hematoxylin)과 에오신(eosin)으로 염색하여 200배 현미경 시야에서 계수하여 처리하지 않은 군과 비교하였다. 처리하지 않은 대조군의 세포이동을 100%로 하고 이에 대한 상대적인 값으로 나타내었다.The number of cells that migrated downward was compared with the untreated group by staining with hematoxylin and eosin and counting in the 200x microscopic field. The cell migration of the untreated control group was defined as 100% and expressed as a relative value.
실험 결과, 복분자 수추출물이 VEGF에 의한 혈관 내피 세포의 이동을 억제하였다(도 4).
As a result of the experiment, the extract of bokbunja water inhibited the migration of vascular endothelial cells by VEGF (Fig. 4).
실험예 5: VEGF 에 의한 관형성(tube formation)에 미치는 복분자 수 추출물의 영향 실험
Experimental Example 5: Influence of the water content of bokbunja extract on tube formation by VEGF
*24 웰 플레이트에 마트리겔(matrigel)을 200 ㎕ 코팅한 후 37℃에서 30분간 배양하였다. 배양된 혈관내피세포를 2× 105 cells/well의 농도로 코팅된 24 웰 플레이트에 분주하였다. 세포의 분주 전 VEGF(20 ng/ml)와 복분자 수추출물을 처리하고, 분주 후 20시간 뒤에 현미경으로 관형성을 관찰하였다. 이 실험은 1% FBS M199 배지를 사용하여 수행하였다.200 μl of matrigel was coated on a 24-well plate and cultured at 37 ° C for 30 minutes. The cultured
실험결과, VEGF에 의해 유도되는 관형성이 복분자 수추출물에 의해 저해되는 것을 확인 할 수 있었다(도 5).
As a result of the experiment, it was confirmed that the tube formation induced by VEGF is inhibited by the brambled water extract (FIG. 5).
실험예 6: VEGF 에 의한 쥐 대동맥 발아(sprouting)에 미치는 복분자 수추출물의 영향 실험
EXPERIMENTAL EXAMPLE 6 Effect of Extract of Rubella Extract on Sprouting of Rat Aorta by VEGF
*24 웰 플레이트에 120 ㎕ 마트리겔(matrigel)을 코팅하고 37℃에서 30분간 배양하였다. 7 주령된 SD 레트의 대동맥을 적출하고 PBS로 혈관을 깨끗이 씻은 후, 대동맥 주위에 붙어있는 가는 혈관을 모두 떼어내었다. 피와 가는 혈관이 제거된 대동맥을 1 mm 정도의 두께로 자른 다음 마트리겔(matrigel)이 코팅된 24 웰 플레이트 위에 올려놓고 그 위에 다시 한번 50 ㎕ 마트리겔(matrigel)을 넣어서 37℃에서 30분간 배양하였다. 마트리겔(matrigel)로 둘러싸여 굳어진 동맥위에 VEGF(20 ng/ml)와 복분자 수추출물이 들어있는 배지를 넣었다. 일주일후 현미경으로 발아(sprouting) 개수를 관찰하였다. * A 24-well plate was coated with 120 쨉 l matrigel and incubated at 37 째 C for 30 minutes. The aorta of the 7-week-old SDLET was removed and the blood vessels were cleaned with PBS, and all the thin blood vessels attached to the aorta were removed. The blood and blood vessels were removed and the aorta was cut to a thickness of 1 mm and placed on a 24-well plate coated with matrigel. Then, 50 쨉 l matrigel was added to the plate and incubated at 37 째 C for 30 minutes Respectively. A medium containing VEGF (20 ng / ml) and brambone water extract was placed on the hardened artery surrounded by matrigel. After one week, the number of sprouting was observed under a microscope.
실험 결과, 복분자 수추출물이 VEGF에 의한 쥐 대동맥의 발아(sprouting)를 억제하는 것으로 나타났다(도 6).
Experimental results showed that the water extract of Rubus coreans inhibited sprouting of the rat aorta by VEGF (FIG. 6).
<< 제조예Manufacturing example >>
제조예 1. 산제의 제조Production Example 1. Preparation of powder
상기 성분들을 분말화하여 혼합한 후 기밀포에 충진하여 산제를 제조한다.
The above components are powdered and mixed, and filled in an airtight container to prepare a powder.
제조예 2. 정제의 제조Production Example 2. Preparation of tablets
통상의 정제의 제조방법에 따라 상기 성분들을 혼합한 후 이를 타정하여 정제를 제조한다.
The tablets are prepared by mixing the above components according to a conventional method for producing tablets and then tableting them.
제조예 3. 캅셀제의 제조Preparation Example 3. Preparation of capsules
통상의 캅셀제의 제조방법에 따라 상기 성분들을 혼합한 후 젤라틴 캡슐에 충진하여 캅셀제를 제조한다.
The above components are mixed according to a conventional method for preparing a capsule, and then filled in a gelatin capsule to prepare a capsule.
제조예 4. 과립제의 제조Production Example 4. Preparation of Granules
상기 성분들을 혼합한 후 30% 에탄올 100mL를 첨가하여 60℃에서 건조시켜 과립을 형성한 후 포에 충진하여 과립제를 제조한다.
After mixing the above components, 100 mL of 30% ethanol is added and the mixture is dried at 60 ° C to form granules, which are filled in a capsule to prepare granules.
제조예 5. 환제의 제조Production Example 5. Preparation of a pellet
상기 성분들을 혼합한 후 통상의 환제의 제조방법에 따라 1환 당 4g이 되도록 제조한다. After mixing the above components, the mixture is prepared to be 4 g per one ring according to a conventional method for producing a pellet.
제조예 6. 주사제의 제조Production Example 6. Preparation of injection
통상의 주사제 제조방법에 따라 1 앰플당 3mL가 되도록 상기 성분을 혼합하여 제조한다.
The above components are mixed and prepared so as to have a volume of 3 mL per ampoule according to a usual injection preparation method.
제조예 7. 액제의 제조Production Example 7. Production of liquid agent
통상의 액제 제조방법에 따라 정제수에 상기 성분을 용해시키고, 적절한 향을 가한 다음 병에 충진하여 멸균시켜 제조한다.
Dissolving the above components in purified water according to a usual liquid preparation method, adding an appropriate fragrance, filling the bottle and sterilizing it.
Claims (4)
Rubus coreanus Miquel ) as an active ingredient and inhibits vascular endothelial cell growth by vascular endothelial growth factor (VEGF), inhibits vascular endothelial cell migration, inhibits tube formation, Wherein the compound inhibits sprouting and thereby exhibits an activity of inhibiting angiogenesis.
상기 복분자는 건조된 복분자인 것을 특징으로 하는 당뇨병성 망막증 예방 또는 치료용 약학적 조성물.
The method according to claim 1,
The pharmaceutical composition for preventing or treating diabetic retinopathy according to claim 1, wherein the brambles are dried brambles.
상기 복분자 냉수 추출물은 혈관내피세포증식인자(vascular endothelial growth factor, VEGF)에 의한 ERK(extracellular signal regulated kinase), p38 또는 VEGF 수용체의 인산화를 억제하여 신생혈관형성 억제 활성을 나타내는 것을 특징으로 하는 당뇨병성 망막증 예방 또는 치료용 약학적 조성물.
The method according to claim 1,
Wherein the bacterium cold water extract inhibits angiogenesis-inhibiting activity by inhibiting ERK (extracellular signal regulated kinase), p38 or VEGF receptor phosphorylation by vascular endothelial growth factor (VEGF) A pharmaceutical composition for preventing or treating retinopathy.
Rubus coreanus Miquel ) as an active ingredient and inhibits vascular endothelial cell growth by vascular endothelial growth factor (VEGF), inhibits vascular endothelial cell migration, inhibits tube formation, The composition for improving diabetic retinopathy is characterized in that it inhibits sprouting and thus exhibits an activity of inhibiting angiogenesis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020180069602A KR20180072632A (en) | 2018-06-18 | 2018-06-18 | Pharmaceutical composition having angiogenesis inhibition activity comprising extract of Rubus coreanus Miquel |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020180069602A KR20180072632A (en) | 2018-06-18 | 2018-06-18 | Pharmaceutical composition having angiogenesis inhibition activity comprising extract of Rubus coreanus Miquel |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020170108179A Division KR20170101868A (en) | 2017-08-25 | 2017-08-25 | Pharmaceutical composition having angiogenesis inhibition activity comprising extract of Rubus coreanus Miquel |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20180072632A true KR20180072632A (en) | 2018-06-29 |
Family
ID=62780894
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020180069602A KR20180072632A (en) | 2018-06-18 | 2018-06-18 | Pharmaceutical composition having angiogenesis inhibition activity comprising extract of Rubus coreanus Miquel |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR20180072632A (en) |
-
2018
- 2018-06-18 KR KR1020180069602A patent/KR20180072632A/en active Application Filing
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9649351B2 (en) | Anti-angiogenic agents and anti-obesity substances applied with anti-angiogenesis from natural products | |
| US10517913B2 (en) | Composition for prevention, alleviation, or treatment of peripheral neuropathy comprising Lithospermi Radix extract as an effective component | |
| CN101057674B (en) | Composition for preventing and curing diabetes | |
| KR100733913B1 (en) | Agent for the protection of brain cell and Agent for the prevention or treatment of cerebral infarction and stroke comprising anthocyanin | |
| KR101341195B1 (en) | Composition for Prevention or Treatment of Breast Cancer Comprising Genipin | |
| KR20100004466A (en) | A pharmaceutical composition having angiogenesis inhibition activity | |
| KR101481709B1 (en) | Composition for preventing or treating erectile dysfunction comprising Sac-1004 compound | |
| KR101579820B1 (en) | Pharmaceutical compositions for the treatment of cancer metastasis or inhibition of metastasis containing Quassia undulata extracts as active fractions | |
| KR20190070844A (en) | A composition comprising the compounds isolated from an extract of Allium sativum L. for treating and preventing muscle-related disorder | |
| KR102556464B1 (en) | Composition for inhibiting proliferation of tumor comprising Oenothera Radix extract as effective component | |
| KR101720610B1 (en) | The pharmaceutical composition Inula helenium hexane fractions thereof or compound isolated from the fraction comprising inhibitory activity of STAT for prevention or treatment of breast cancer | |
| KR20180072632A (en) | Pharmaceutical composition having angiogenesis inhibition activity comprising extract of Rubus coreanus Miquel | |
| KR20170101868A (en) | Pharmaceutical composition having angiogenesis inhibition activity comprising extract of Rubus coreanus Miquel | |
| KR20160129809A (en) | Pharmaceutical composition having angiogenesis inhibition activity comprising cold water based extract of Cinnamomum cassia | |
| KR20160102933A (en) | Pharmaceutical composition having angiogenesis inhibition activity comprising extract of Rubus coreanus Miquel | |
| KR101717057B1 (en) | Compositions for Preventing or Treating Lung Cancer Diseases | |
| KR20160002068A (en) | Pharmaceutical composition having angiogenesis inhibition activity comprising cold water based extract of Cinnamomum cassia | |
| KR20150104794A (en) | Pharmaceutical composition having angiogenesis inhibition activity comprising extract of Rubus coreanus Miquel | |
| KR20160118405A (en) | Pharmaceutical composition having angiogenesis inhibition activity comprising extract of Coptis japonica Makino | |
| KR20170097499A (en) | Composition for preventing, improviong or treating disease caused by side effect of anticancer agent comprising Phragmites communis Trin extract as effective component | |
| KR20170126844A (en) | Pharmaceutical composition having angiogenesis inhibition activity comprising cold water based extract of Cinnamomum cassia | |
| KR101881142B1 (en) | Composition for preventing, improving or treating disease caused by side effect of anticancer agent comprising Cistanchis Herba extract as effective component | |
| KR102640481B1 (en) | Composition for inhibiting proliferation of tumor comprising Salvia plebeia extract as effective component | |
| KR102672575B1 (en) | Composition comprising herbal mixture extract for inhibiting anti-cancer drug resistance | |
| JP5985062B2 (en) | A composition for preventing or treating cancer comprising an extract of a fruit, leaf, or stem of Altocalus artilis, or a fraction thereof as an active ingredient |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A107 | Divisional application of patent |