CN117357544A - 石榴素在制备黄嘌呤氧化酶抑制剂中的应用 - Google Patents
石榴素在制备黄嘌呤氧化酶抑制剂中的应用 Download PDFInfo
- Publication number
- CN117357544A CN117357544A CN202311448430.5A CN202311448430A CN117357544A CN 117357544 A CN117357544 A CN 117357544A CN 202311448430 A CN202311448430 A CN 202311448430A CN 117357544 A CN117357544 A CN 117357544A
- Authority
- CN
- China
- Prior art keywords
- pomegranate
- xanthine oxidase
- preparation
- uric acid
- hyperuricemia
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003064 xanthine oxidase inhibitor Substances 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims description 12
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 title 1
- 235000014360 Punica granatum Nutrition 0.000 claims abstract description 44
- 108010093894 Xanthine oxidase Proteins 0.000 claims abstract description 21
- 102100033220 Xanthine oxidase Human genes 0.000 claims abstract description 21
- 230000000694 effects Effects 0.000 claims abstract description 16
- 201000001431 Hyperuricemia Diseases 0.000 claims abstract description 14
- 241000219991 Lythraceae Species 0.000 claims abstract 5
- 150000001875 compounds Chemical class 0.000 claims description 7
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 abstract description 21
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 abstract description 21
- 229940116269 uric acid Drugs 0.000 abstract description 21
- 230000002401 inhibitory effect Effects 0.000 abstract description 12
- 210000002966 serum Anatomy 0.000 abstract description 8
- 238000010172 mouse model Methods 0.000 abstract description 6
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 238000000338 in vitro Methods 0.000 abstract 1
- 244000294611 Punica granatum Species 0.000 description 39
- 239000000243 solution Substances 0.000 description 11
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000008363 phosphate buffer Substances 0.000 description 9
- 239000007924 injection Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- -1 ribose phosphates Chemical class 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 229940075420 xanthine Drugs 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000013268 sustained release Methods 0.000 description 4
- 239000012730 sustained-release form Substances 0.000 description 4
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 3
- 244000119298 Emblica officinalis Species 0.000 description 3
- 235000015489 Emblica officinalis Nutrition 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- 229960003459 allopurinol Drugs 0.000 description 3
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- RYYCJUAHISIHTL-UHFFFAOYSA-N 5-azaorotic acid Chemical compound OC(=O)C1=NC(=O)NC(=O)N1 RYYCJUAHISIHTL-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 229920002307 Dextran Polymers 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
- 201000005569 Gout Diseases 0.000 description 2
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 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
- 240000009200 Macaranga tanarius Species 0.000 description 2
- 235000000487 Macaranga tanarius Nutrition 0.000 description 2
- DPBVYZVSXAZMAY-UHFFFAOYSA-N Macaranganin Natural products OC1=C(O)C(O)=CC(C(=O)OC2C(C3OC(=O)C4=CC(O)=C(O)C(O)=C4C4=C(O)C(O)=C(O)C=C4C(=O)OCC(C3OC(=O)C=3C=C(O)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(O)C(O)=C(O)C=2)=C1 DPBVYZVSXAZMAY-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241000745988 Phyllostachys Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- INAAWUYFPBBBCN-UHFFFAOYSA-N Punicafolin Natural products Oc1cc(cc(O)c1O)C(=O)OC2OC3COC(=O)c4c(O)c(O)c(O)c(O)c4c5c(O)c(O)c(O)c(O)c5C(=O)OC(C3OC(=O)c6cc(O)c(O)c(O)c6)C2OC(=O)c7cc(O)c(O)c(O)c7 INAAWUYFPBBBCN-UHFFFAOYSA-N 0.000 description 2
- 229920001264 Punicafolin Polymers 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 239000007938 effervescent tablet Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000002662 enteric coated tablet Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000007941 film coated tablet Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000007902 hard capsule Substances 0.000 description 2
- FVYXIJYOAGAUQK-UHFFFAOYSA-N honokiol Chemical compound C1=C(CC=C)C(O)=CC=C1C1=CC(CC=C)=CC=C1O FVYXIJYOAGAUQK-UHFFFAOYSA-N 0.000 description 2
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000008176 lyophilized powder Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 230000006961 mixed inhibition Effects 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 229950000193 oteracil Drugs 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- DPBVYZVSXAZMAY-UUUCSUBKSA-N punicafolin Chemical compound OC1=C(O)C(O)=CC(C(=O)O[C@H]2[C@@H]([C@H]3OC(=O)C4=CC(O)=C(O)C(O)=C4C4=C(O)C(O)=C(O)C=C4C(=O)OC[C@H]([C@H]3OC(=O)C=3C=C(O)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(O)C(O)=C(O)C=2)=C1 DPBVYZVSXAZMAY-UUUCSUBKSA-N 0.000 description 2
- 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 2
- 239000011780 sodium chloride Substances 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000006190 sub-lingual tablet Substances 0.000 description 2
- 239000007940 sugar coated tablet Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- 241000208140 Acer Species 0.000 description 1
- 240000004731 Acer pseudoplatanus Species 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000221377 Auricularia Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241001313087 Carpinus laxiflora Species 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010073508 Drug reaction with eosinophilia and systemic symptoms Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 244000192024 Euphorbia helioscopia Species 0.000 description 1
- 235000012043 Euphorbia helioscopia Nutrition 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- 241001149162 Mallotus japonicus Species 0.000 description 1
- 244000110369 Mallotus repandus Species 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 241000284913 Micranthes melanocentra Species 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000007413 Nigella arvensis Nutrition 0.000 description 1
- 244000090896 Nigella sativa Species 0.000 description 1
- 235000016698 Nigella sativa Nutrition 0.000 description 1
- 244000108404 Nuphar japonicum Species 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 244000038594 Phyllanthus urinaria Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 241001647091 Saxifraga granulata Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 239000000469 ethanolic extract Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229960005101 febuxostat Drugs 0.000 description 1
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 208000016839 purine metabolism disease Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- NALYUPYCMXELRP-TVLONEIMSA-N tercatain Natural products O=C(O[C@@H]1[C@H](O)[C@H]2[C@@H](OC(=O)c3cc(O)c(O)c(O)c3)[C@@H](O1)COC(=O)c1c(c(O)c(O)c(O)c1)-c1c(O)c(O)c(O)cc1C(=O)O2)c1cc(O)c(O)c(O)c1 NALYUPYCMXELRP-TVLONEIMSA-N 0.000 description 1
- RHYYKHORHGKJES-FEUHLQPKSA-N tercatain Chemical compound O([C@H]1[C@@H]([C@H]2OCC3=C(C(=C(O)C(O)=C3)O)C3=C(O)C(O)=C(O)C=C3C(=O)OC[C@H]([C@H]2OC(=O)C=2C=C(O)C(O)=C(O)C=2)O1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 RHYYKHORHGKJES-FEUHLQPKSA-N 0.000 description 1
- 108010060026 terminin Proteins 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
-
- 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)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Biotechnology (AREA)
- Pain & Pain Management (AREA)
- Molecular Biology (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Alternative & Traditional Medicine (AREA)
- Rheumatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了石榴素在制备黄嘌呤氧化酶抑制剂中的应用。经体外试验证实，石榴素对黄嘌呤氧化酶活性有明显抑制作用；经实验性高尿酸血症小鼠模型试验证实，石榴素显著降低模型小鼠血清尿酸水平，可用于制备黄嘌呤氧化酶抑制剂，用于制备抑制黄嘌呤氧化酶活性治疗高尿酸血症的产品。
Description
技术领域
本发明属于医药领域，涉及石榴素在制备黄嘌呤氧化酶抑制剂中的应用。
背景技术
高尿酸血症是嘌呤代谢障碍所致的慢性代谢性疾病，是引发痛风的重要生化基础。高尿酸血症与心血管疾病、慢性肾脏病及代谢综合征，如糖尿病、肥胖等密切相关，是一种严重影响公共健康的疾病。
人体内尿酸的来源有内源性和外源性之分，外源性尿酸来源于食物，占体内尿酸来源的20％；内源性尿酸源于体内氨基酸、磷酸核糖及其他小分子合成和核酸分解代谢，占体内尿酸来源的80％。尿酸生成过多是高尿酸血症的一个主要发病原因。黄嘌呤氧化酶作为尿酸生成关键酶是降低尿酸药物的作用靶点。黄嘌呤氧化酶广泛分布于人体心、肺、肝等组织细胞浆内，能催化黄嘌呤和次黄嘌呤的氧化生成尿酸，并产生过氧化物自由基，尿酸浓度过高会导致高尿酸血症，并可引起痛风发作。别嘌呤醇和非布索坦是在临床上使用的黄嘌呤氧化酶抑制剂，但皮肤过敏、肝炎、超敏反应综合征等不良反应在一定程度上限制了其使用。
为筛选黄嘌呤氧化酶抑制剂，本案发明人构建了以黄嘌呤为底物，HPLC法测定尿酸生成量的黄嘌呤氧化酶抑制活性评价体系，从毒副作用小的天然产物中寻找黄嘌呤氧化酶抑制剂，发现了高活性化合物石榴叶素。
石榴素，又名1,2,4-O-三没食子酰基-3,6-六羟基二苯基-β-D-葡萄糖，英文名称punicafolin，主要存在于石榴Punica granatum、血桐Macaranga tanarius、叶下珠Phyllanthus urinaria、滇橄榄Phyllanthus emblica、黑蕊虎耳草Saxifragamelanocentra、余甘子Phyllanthus emblica、疏花鹅耳枥Carpinus laxiflora、野梧桐Mallotus japonicus、泽漆Euphorbia helioscopia、石岩枫Mallotus repandus、日本荷根Nuphar japonicum等植物中。具有驱虫作用、抑制透明质酸酶和抗氧化作用、抗丙型肝炎病毒作用和抑制HT1080纤维肉瘤细胞的侵袭作用。
但未见石榴素抑制黄嘌呤氧化酶活性作用和抗高尿酸血症作用的公开记载。
发明内容
本案发明人以抗高尿酸血症主要靶点寻找活性化合物。在对植物花资源黄嘌呤氧化酶抑制活性筛选的过程中，发现石榴花70％乙醇提取物对黄嘌呤氧化酶活性有显著地抑制作用。采用黄嘌呤氧化酶抑制活性指标指导下的导向分离模式发现石榴花提取物抗高尿酸血症活性化合物，从有效部位中分离鉴定了异柯里拉京，英文名称isocorilagin、榄仁素，英文名称tercatain和石榴素，英文名称punicafolin，均首次从石榴花中分离鉴定。
异柯里拉京是如下结构式的化合物：
榄仁素是如下结构式的化合物：
石榴素是如下结构式的化合物：
发现石榴素对黄嘌呤氧化酶活性半数抑制浓度IC50值为(3.98±0.04)μM，榄仁素对黄嘌呤氧化酶活性半数抑制浓度IC50值为(14.27±0.24)μM，异柯里拉京在100μM浓度下对黄嘌呤氧化酶活性抑制率为(50.04±0.24)％。石榴素显著降低高尿酸血症小鼠模型小鼠血清尿酸水平，因而完成了本发明。
本发明目的是提供石榴素在制备黄嘌呤氧化酶抑制剂中的应用。
石榴素抑制黄嘌呤氧化酶活性，可在制备黄嘌呤氧化酶抑制剂中应用，通过抑制黄嘌呤氧化酶活性，抑制催化黄嘌呤和次黄嘌呤的氧化生成尿酸，可在制备抑制黄嘌呤氧化酶活性治疗高尿酸血症产品中应用。
本发明的石榴素在制备黄嘌呤氧化酶抑制剂中的应用优点为作用机制明确，石榴素可从石榴、血桐、叶下珠、滇橄榄、黑蕊虎耳草、余甘子、疏花鹅耳枥、野梧桐、泽漆、石岩枫、日本荷根等植物中分离，毒副作用小。
本发明还提供用本发明所述的石榴素以及可接受的载体或赋形剂制备的制剂产品。这些制剂产品选自以下剂型：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、泡腾片剂、舌下片剂、胶囊剂、硬胶囊剂、软胶囊剂、微囊剂、微球剂、颗粒剂、丸剂、滴丸剂、散剂、膏剂、口服液、混悬剂、溶液剂、气雾剂、注射剂，注射乳剂、冻干粉针，还可以根据需要制备成缓释或控释制剂产品。
本发明的含有所述石榴素的制剂产品，在制备制剂产品时可加入可接受的载体，所述可接受的载体来自：抗氧剂、鏊合剂、表面活性剂、填充剂、崩解剂、湿润剂、溶剂、缓释材料、肠溶材料、pH调节剂、矫味剂、色素等，常用载体如：甘露糖醇、右旋糖苷、乳糖、葡萄糖、山梨醇、木糖醇、注射用水、注射用乙醇、氯化钠、硅衍生物、纤维素、纤维素衍生物、明胶、聚乙烯吡咯烷酮、甘油、吐温80、琼脂、碳酸钙、聚乙二醇、环糊精、磷脂类材料、滑石粉、硬脂酸镁、硬脂酸钙等。
以下通过具体实施例对本发明作进一步的说明，并非对本发明的限定，依照本领域公知的现有技术，本发明的实施方式并不限于具体实施例。
具体实施方式
实施例1
石榴素对黄嘌呤氧化酶抑制作用半数抑制浓度IC50测定
HPLC测定方法：Diamonsil ODS色谱柱(250mm×4.6mm，5μm)；流动相：100mmol/L磷酸二氢钠溶液(pH＝3.5)；检测波长：290nm；流速：1.0mL/min。
测定体系：不同浓度石榴素溶液(含0.25％DMSO的0.07mol/L磷酸盐缓冲液)200μL加入0.07mol/L磷酸盐缓冲液140μL，黄嘌呤氧化酶溶液120μL(0.02unit/mL，0.07mol/L磷酸盐缓冲液)，25℃保温15min，加入黄嘌呤溶液240μL(300μmol/L，0.07mol/L磷酸盐缓冲液)，25℃保温15min，加入1mol/L盐酸100μL终止反应。空白对照测定，石榴素溶液用含1％DMSO的0.07mol/L磷酸盐缓冲液代替。HPLC法测定尿酸生成量，每组浓度平行三次，计算抑制率。以石榴素浓度为横坐标，石榴素对黄嘌呤氧化酶抑制率为纵坐标绘制IC50曲线，通过SPSS统计学软件计算出石榴素的IC50为(3.98±0.04)μM；临床治疗药物别嘌呤醇的IC50为(1.63±0.05)μM。
实施例2
石榴素对黄嘌呤氧化酶抑制作用类型测定
HPLC测定方法：Diamonsil ODS色谱柱(250mm×4.6mm，5μm)；流动相：100mmol/L磷酸二氢钠溶液(pH＝3.5)；检测波长：290nm；流速：1.0mL/min。
测定体系：不同浓度石榴素溶液(含0.25％DMSO的0.07mol/L磷酸盐缓冲液)200μL，加入0.07mol/L磷酸盐缓冲液140μL，加入黄嘌呤溶液240μL(100μmol/L、50μmol/L、37.5μmol/L、25μmol/L，0.07mol/L磷酸盐缓冲液)，黄嘌呤氧化酶溶液120μL(0.05unit/mL，0.07mol/L磷酸盐缓冲液)，25℃保温1min，加入1mol/L盐酸100μL终止反应。HPLC法测定尿酸生成量，每组浓度平行三次，按Lineweaver-Burk双倒数图法确定抑制作用类型。不同浓度石榴素Lineweaver-Burk双倒数直线均相交于第二象限，表示石榴素的抑制类型为混合型抑制；不同浓度临床治疗药物别嘌呤醇Lineweaver-Burk双倒数直线均相交于Y轴，表示别嘌呤醇的抑制类型为竞争性抑制。
实施例3
石榴素对实验性高尿酸血症模型小鼠血清尿酸水平的影响
小鼠随机分为6组，每组20只，分别为正常对照组(生理盐水10mL/Kg)、模型对照组(氧嗪酸钾250mg/Kg)，石榴素高剂量组(氧嗪酸钾250mg/Kg+石榴素20mg/Kg)，石榴素中剂量组(氧嗪酸钾250mg/Kg+石榴素10mg/Kg)，石榴素低剂量组(氧嗪酸钾250mg/Kg+石榴素5mg/Kg)，别嘌呤醇对照组(氧嗪酸钾250mg/Kg+别嘌呤5mg/Kg)。每天AM9:00分别灌胃给予模型对照组和各给药组氧嗪酸钾，1小时后各给药组分别灌胃给药，给药周期7天，正常对照组和模型对照组灌胃给予等量生理盐水。在第7天给药1小时后，小鼠眼球后静脉丛取血(取血前1血小时禁食)，在10000×g条件下离心5分钟，取血清。采用磷钨酸还原法测定血清尿酸水平。结果见表1。
表1石榴素对实验性高尿酸血症模型小鼠血清尿酸水平的影响
同正常对照组比较：##P<0.01
同模型对照组比较：*P<0.05，**P<0.01
同正常对照组比较，模型对照组大鼠血清尿酸水平明显增高。别嘌呤醇5mg/Kg组、石榴素10mg/Kg和20mg/Kg组同模型组比较，显著降低模型小鼠血清尿酸水平。
实施例4
石榴素用可接受的载体或赋形剂制备的药物制剂产品。这些制剂选产品自以下剂型：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、泡腾片剂、舌下片剂、胶囊剂、硬胶囊剂、软胶囊剂、微囊剂、微球剂、颗粒剂、丸剂、滴丸剂、散剂、膏剂、口服液、混悬剂、溶液剂、气雾剂、注射剂，注射乳剂、冻干粉针，还可以根据需要制备成缓释或控释制剂产品，在制备制剂产品时可加入可接受的载体，所述可接受的载体来自：抗氧剂、鏊合剂、表面活性剂、填充剂、崩解剂、湿润剂、溶剂、缓释材料、肠溶材料、pH调节剂、矫味剂、色素等，常用载体如：甘露糖醇、右旋糖苷、乳糖、葡萄糖、山梨醇、木糖醇、注射用水、注射用乙醇、氯化钠、硅衍生物、纤维素、纤维素衍生物、明胶、聚乙烯吡咯烷酮、甘油、吐温80、琼脂、碳酸钙、聚乙二醇、环糊精、磷脂类材料、滑石粉、硬脂酸镁、硬脂酸钙。上述制备工艺均为本领域常规操作，在此不加赘述。
Claims (2)
1.石榴素在黄嘌呤氧化酶抑制剂中的应用，其特征在于，所述石榴素是如下结构式的化合物：
2.根据权利要求1所述的应用，其特征在于，用于制备抑制黄嘌呤氧化酶活性治疗高尿酸血症产品中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311448430.5A CN117357544A (zh) | 2023-11-02 | 2023-11-02 | 石榴素在制备黄嘌呤氧化酶抑制剂中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311448430.5A CN117357544A (zh) | 2023-11-02 | 2023-11-02 | 石榴素在制备黄嘌呤氧化酶抑制剂中的应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117357544A true CN117357544A (zh) | 2024-01-09 |
Family
ID=89400244
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311448430.5A Pending CN117357544A (zh) | 2023-11-02 | 2023-11-02 | 石榴素在制备黄嘌呤氧化酶抑制剂中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117357544A (zh) |
-
2023
- 2023-11-02 CN CN202311448430.5A patent/CN117357544A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI795462B (zh) | 光安定性及溶出性優異的醫藥製劑 | |
| CN103845317B (zh) | 恩他卡朋在预防或治疗肥胖等代谢综合征中的应用 | |
| KR20100132521A (ko) | 영양분의 흡수를 증가시키는데 효과적인 약학적 조성물 및 복령 추출물 | |
| WO2020253835A1 (zh) | 含有硝酸盐和维生素的组合物、其制备方法、制剂及其用途 | |
| CN111821310A (zh) | 一种瑞德西韦制剂及其适应症 | |
| CN109310700A (zh) | 使用曲匹地尔治疗锥体外系综合征 | |
| WO2008001494A1 (fr) | Agent pharmaceutique destiné à la prévention de la fatigue et/ou à la récupération en cas de fatigue | |
| CN107613978B (zh) | Mek抑制剂的药物组合物及其制备方法 | |
| HK1244224A1 (zh) | Mek抑制劑的藥物組合物及其製備方法 | |
| CN117357544A (zh) | 石榴素在制备黄嘌呤氧化酶抑制剂中的应用 | |
| CN114917345A (zh) | 靶向soat1蛋白的化合物在制备预防和/或治疗肝癌药物中的应用 | |
| CN112592328A (zh) | 草豆蔻中二芳基庚烷-查尔酮聚合物及其药物组合物与应用 | |
| CN102697772A (zh) | 一种治疗痛风的药物组合物及其应用 | |
| WO2015112724A1 (en) | Naca for the treatment of chronic or acute cognitive dysfunction | |
| JPH07330593A (ja) | 疲労改善剤 | |
| CN113304139B (zh) | Viniferifuran在制备黄嘌呤氧化酶抑制药物中的应用 | |
| KR20190046675A (ko) | 간질환 예방 또는 치료용 의약 조성물 | |
| CN108714143B (zh) | 一种含有非布司他的片剂及其制备方法 | |
| CA3179278A1 (en) | Compositions and methods of treatment with glutathione | |
| CN111803499B (zh) | 一种治疗抗痛风、抗高尿酸血症的药物组合物ⅱ | |
| CN110974823A (zh) | 一种含有托吡司特的复方控释制剂 | |
| CN104721205B (zh) | 决明酮苷在制备黄嘌呤氧化酶抑制剂中的应用 | |
| CN1880301B (zh) | 硫普罗宁赖氨酸及其制备方法和用途 | |
| CN112494509A (zh) | 一种防治阿尔茨海默症的组合物及应用 | |
| CN113304138B (zh) | Vitisinol D在制备黄嘌呤氧化酶抑制药物中的应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |