CN1788732A - Use of kutkin I in preparing drug for treating hepatitis B, its formulation and preparation method - Google Patents
Use of kutkin I in preparing drug for treating hepatitis B, its formulation and preparation method Download PDFInfo
- Publication number
- CN1788732A CN1788732A CN 200410098646 CN200410098646A CN1788732A CN 1788732 A CN1788732 A CN 1788732A CN 200410098646 CN200410098646 CN 200410098646 CN 200410098646 A CN200410098646 A CN 200410098646A CN 1788732 A CN1788732 A CN 1788732A
- Authority
- CN
- China
- Prior art keywords
- kutkin
- group
- injection
- hepatitis
- preparation
- 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.)
- Granted
Links
- 239000003814 drug Substances 0.000 title claims abstract description 58
- 208000002672 hepatitis B Diseases 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- QSPOERJDZBVCJH-UHFFFAOYSA-N Kutkin Natural products COc1cc(ccc1OC2OC(CO)C(O)C(O)C2O)C(O)(OC)C(=O)OC=Cc3ccccc3 QSPOERJDZBVCJH-UHFFFAOYSA-N 0.000 title claims description 165
- XSIQHIDJSCQWBB-QHJBZRDQSA-N [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] 3-methoxy-4-[(E)-3-phenylprop-2-enoyl]oxybenzoate dihydrate Chemical compound O.O.COc1cc(ccc1OC(=O)\C=C\c1ccccc1)C(=O)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O XSIQHIDJSCQWBB-QHJBZRDQSA-N 0.000 title claims description 165
- 239000000203 mixture Substances 0.000 title claims description 7
- 229940079593 drug Drugs 0.000 title description 9
- 238000009472 formulation Methods 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 24
- 230000001154 acute effect Effects 0.000 claims abstract description 9
- 208000000419 Chronic Hepatitis B Diseases 0.000 claims abstract description 6
- 206010059193 Acute hepatitis B Diseases 0.000 claims abstract description 3
- 208000037628 acute hepatitis B virus infection Diseases 0.000 claims abstract description 3
- 239000007924 injection Substances 0.000 claims description 104
- 238000002347 injection Methods 0.000 claims description 104
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000011347 resin Substances 0.000 claims description 11
- 229920005989 resin Polymers 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000741 silica gel Substances 0.000 claims description 10
- 229910002027 silica gel Inorganic materials 0.000 claims description 10
- 229960001866 silicon dioxide Drugs 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 8
- 230000002829 reductive effect Effects 0.000 claims description 8
- -1 patch Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- 239000006228 supernatant Substances 0.000 claims description 7
- 210000003462 vein Anatomy 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 239000003480 eluent Substances 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 238000007689 inspection Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- 238000001179 sorption measurement Methods 0.000 claims description 4
- 241001483116 Neopicrorhiza scrophulariiflora Species 0.000 claims description 3
- 239000000284 extract Substances 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 238000005325 percolation Methods 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- 238000010298 pulverizing process Methods 0.000 claims description 3
- JLBJTVDPSNHSKJ-UHFFFAOYSA-N 4-Methylstyrene Chemical compound CC1=CC=C(C=C)C=C1 JLBJTVDPSNHSKJ-UHFFFAOYSA-N 0.000 claims description 2
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims description 2
- 241001470703 Picrorhiza kurrooa Species 0.000 claims description 2
- MPMBRWOOISTHJV-UHFFFAOYSA-N but-1-enylbenzene Chemical compound CCC=CC1=CC=CC=C1 MPMBRWOOISTHJV-UHFFFAOYSA-N 0.000 claims description 2
- 230000001055 chewing effect Effects 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 238000011049 filling Methods 0.000 claims description 2
- 229930182470 glycoside Natural products 0.000 claims description 2
- 150000002338 glycosides Chemical class 0.000 claims description 2
- 210000003205 muscle Anatomy 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 238000007920 subcutaneous administration Methods 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 210000003708 urethra Anatomy 0.000 claims description 2
- 210000001215 vagina Anatomy 0.000 claims description 2
- 210000004185 liver Anatomy 0.000 abstract description 34
- 230000000694 effects Effects 0.000 abstract description 24
- 206010023126 Jaundice Diseases 0.000 abstract description 13
- 210000000232 gallbladder Anatomy 0.000 abstract description 9
- XZGPUOQGERGURE-LUVHZPKESA-N [(2r,3s,4s,5r,6s)-6-[[(1as,1bs,2s,5ar,6s,6as)-6-hydroxy-1a-(hydroxymethyl)-2,5a,6,6a-tetrahydro-1bh-oxireno[5,6]cyclopenta[1,3-c]pyran-2-yl]oxy]-3,4,5-trihydroxyoxan-2-yl]methyl (e)-3-phenylprop-2-enoate Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H](O)[C@@H]1O)O)O[C@@H]1OC=C[C@H]2[C@H](O)[C@@H]3O[C@@]3([C@@H]12)CO)OC(=O)\C=C\C1=CC=CC=C1 XZGPUOQGERGURE-LUVHZPKESA-N 0.000 abstract description 6
- SCIGYBYAZUFDLA-YRWPAIAPSA-N globularin Natural products OC[C@H]1O[C@@H](O[C@@H]2OC=C[C@H]3[C@H](O)[C@@H]4O[C@]4(COC(=O)C=Cc5ccccc5)[C@@H]23)[C@H](O)[C@@H](O)[C@@H]1O SCIGYBYAZUFDLA-YRWPAIAPSA-N 0.000 abstract description 6
- KEUKDVIGAVVGLF-RUYHYXBRSA-N picroside I Natural products OC[C@]12O[C@H]1[C@@H]3O[C@@H](O[C@@H]4O[C@H](COC(=O)C=Cc5ccccc5)[C@@H](O)[C@H](O)[C@H]4O)C=C[C@@H]3[C@H]2O KEUKDVIGAVVGLF-RUYHYXBRSA-N 0.000 abstract description 6
- 238000005516 engineering process Methods 0.000 abstract description 5
- 230000036039 immunity Effects 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 5
- 230000001737 promoting effect Effects 0.000 abstract description 5
- 230000001105 regulatory effect Effects 0.000 abstract description 2
- 241001662043 Icterus Species 0.000 abstract 1
- 102000003929 Transaminases Human genes 0.000 abstract 1
- 108090000340 Transaminases Proteins 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 231100001231 less toxic Toxicity 0.000 abstract 1
- 230000004526 pharmaceutical effect Effects 0.000 abstract 1
- 241000700159 Rattus Species 0.000 description 26
- 239000012567 medical material Substances 0.000 description 26
- 210000002966 serum Anatomy 0.000 description 23
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 14
- 231100000012 chronic liver injury Toxicity 0.000 description 14
- 241000272522 Anas Species 0.000 description 13
- 241000699666 Mus <mouse, genus> Species 0.000 description 13
- 238000002474 experimental method Methods 0.000 description 13
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 11
- 230000001225 therapeutic effect Effects 0.000 description 11
- 238000012360 testing method Methods 0.000 description 10
- 206010067125 Liver injury Diseases 0.000 description 9
- 210000000941 bile Anatomy 0.000 description 9
- 229920002527 Glycogen Polymers 0.000 description 8
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 8
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical group C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- SPPIIOPGDLITJE-VLQRKCJKSA-N diazanium;(2s,3s,4s,5r,6s)-6-[[(3s,4ar,6ar,6bs,8as,11s,12ar,14ar,14bs)-11-carboxylato-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1h-picen-3-yl]oxy]-5-[(2r,3r,4s,5s,6s)-6-carboxy-3,4,5-trihydroxyoxan-2-yl]oxy-3,4-dihy Chemical group N.N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O SPPIIOPGDLITJE-VLQRKCJKSA-N 0.000 description 8
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 8
- 229940096919 glycogen Drugs 0.000 description 8
- 229960002591 hydroxyproline Drugs 0.000 description 8
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 8
- 210000000056 organ Anatomy 0.000 description 8
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 8
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical group ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 7
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 229960004756 ethanol Drugs 0.000 description 7
- 229960001627 lamivudine Drugs 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 108010006464 Hemolysin Proteins Proteins 0.000 description 6
- 108010050904 Interferons Proteins 0.000 description 6
- 102000014150 Interferons Human genes 0.000 description 6
- 239000003228 hemolysin Substances 0.000 description 6
- 231100000234 hepatic damage Toxicity 0.000 description 6
- 230000008818 liver damage Effects 0.000 description 6
- 239000000825 pharmaceutical preparation Substances 0.000 description 6
- 230000003285 pharmacodynamic effect Effects 0.000 description 6
- 210000000952 spleen Anatomy 0.000 description 6
- 231100000331 toxic Toxicity 0.000 description 6
- 230000002588 toxic effect Effects 0.000 description 6
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 5
- 241000700721 Hepatitis B virus Species 0.000 description 5
- 206010037660 Pyrexia Diseases 0.000 description 5
- 231100000753 hepatic injury Toxicity 0.000 description 5
- 229940079322 interferon Drugs 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 230000000242 pagocytic effect Effects 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- JBDOSUUXMYMWQH-UHFFFAOYSA-N 1-naphthyl isothiocyanate Chemical compound C1=CC=C2C(N=C=S)=CC=CC2=C1 JBDOSUUXMYMWQH-UHFFFAOYSA-N 0.000 description 4
- 241000272525 Anas platyrhynchos Species 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 238000008050 Total Bilirubin Reagent Methods 0.000 description 4
- 230000005856 abnormality Effects 0.000 description 4
- 239000000427 antigen Substances 0.000 description 4
- 102000036639 antigens Human genes 0.000 description 4
- 108091007433 antigens Proteins 0.000 description 4
- 230000001989 choleretic effect Effects 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 208000006454 hepatitis Diseases 0.000 description 4
- 230000036737 immune function Effects 0.000 description 4
- 231100001252 long-term toxicity Toxicity 0.000 description 4
- 210000002540 macrophage Anatomy 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
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 231100001274 therapeutic index Toxicity 0.000 description 4
- 210000001835 viscera Anatomy 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropanol Chemical compound CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 241000411851 herbal medicine Species 0.000 description 3
- 235000008216 herbs Nutrition 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 150000008145 iridoid glycosides Chemical class 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 229950009195 phenylpropanol Drugs 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 231100000820 toxicity test Toxicity 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-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
- 241000725618 Duck hepatitis B virus Species 0.000 description 2
- 241000201295 Euphrasia Species 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- 238000012449 Kunming mouse Methods 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
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 206010057249 Phagocytosis Diseases 0.000 description 2
- 101710098398 Probable alanine aminotransferase, mitochondrial Proteins 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 208000031320 Teratogenesis Diseases 0.000 description 2
- 102000007501 Thymosin Human genes 0.000 description 2
- 108010046075 Thymosin Proteins 0.000 description 2
- 208000031971 Yin Deficiency Diseases 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 229960003205 adefovir dipivoxil Drugs 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 210000001557 animal structure Anatomy 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- 210000005252 bulbus oculi Anatomy 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 229940124447 delivery agent Drugs 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- 230000007365 immunoregulation Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 230000003907 kidney function Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000003908 liver function Effects 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000002398 materia medica Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 230000003505 mutagenic effect Effects 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 230000008782 phagocytosis Effects 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000003252 repetitive effect Effects 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000003439 teratogenic agent Substances 0.000 description 2
- LCJVIYPJPCBWKS-NXPQJCNCSA-N thymosin Chemical compound SC[C@@H](N)C(=O)N[C@H](CO)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CO)C(=O)N[C@H](CO)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@H]([C@H](C)O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@H](CCC(O)=O)C(O)=O LCJVIYPJPCBWKS-NXPQJCNCSA-N 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 1
- UZEAHFLEZWXHCE-UHFFFAOYSA-N 3-iodo-2-methylaniline Chemical class CC1=C(N)C=CC=C1I UZEAHFLEZWXHCE-UHFFFAOYSA-N 0.000 description 1
- 244000296912 Ageratum conyzoides Species 0.000 description 1
- 235000004405 Ageratum conyzoides Nutrition 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 235000016535 Capraria biflora Nutrition 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000031404 Chromosome Aberrations Diseases 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 244000111489 Gardenia augusta Species 0.000 description 1
- 235000018958 Gardenia augusta Nutrition 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 235000017309 Hypericum perforatum Nutrition 0.000 description 1
- UBORTCNDUKBEOP-UHFFFAOYSA-N L-xanthosine Natural products OC1C(O)C(CO)OC1N1C(NC(=O)NC2=O)=C2N=C1 UBORTCNDUKBEOP-UHFFFAOYSA-N 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 206010074268 Reproductive toxicity Diseases 0.000 description 1
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- UBORTCNDUKBEOP-HAVMAKPUSA-N Xanthosine Natural products O[C@@H]1[C@H](O)[C@H](CO)O[C@H]1N1C(NC(=O)NC2=O)=C2N=C1 UBORTCNDUKBEOP-HAVMAKPUSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 231100000354 acute hepatitis Toxicity 0.000 description 1
- 231100000439 acute liver injury Toxicity 0.000 description 1
- 229960001997 adefovir Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000274 adsorptive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000035603 choleresis Effects 0.000 description 1
- 231100000005 chromosome aberration Toxicity 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 210000001953 common bile duct Anatomy 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000002650 habitual effect Effects 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000003118 histopathologic effect Effects 0.000 description 1
- 229940056582 human hair preparation Drugs 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 229930182489 iridoid glycoside Natural products 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229960001614 levamisole Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- JMZOMFYRADAWOG-UHFFFAOYSA-N methyl 7-methoxy-4-(7-methoxy-5-methoxycarbonyl-1,3-benzodioxol-4-yl)-1,3-benzodioxole-5-carboxylate Chemical group COC(=O)C1=CC(OC)=C2OCOC2=C1C1=C2OCOC2=C(OC)C=C1C(=O)OC JMZOMFYRADAWOG-UHFFFAOYSA-N 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 231100000299 mutagenicity Toxicity 0.000 description 1
- 230000007886 mutagenicity Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 108010092851 peginterferon alfa-2b Proteins 0.000 description 1
- 229930182487 phenolic glycoside Chemical class 0.000 description 1
- 150000007950 phenolic glycosides Chemical class 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 208000037920 primary disease Diseases 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000003014 reinforcing effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000007696 reproductive toxicity Effects 0.000 description 1
- 231100000372 reproductive toxicity Toxicity 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000011435 rock Substances 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
- 238000012216 screening Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 231100000378 teratogenic Toxicity 0.000 description 1
- 230000003390 teratogenic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000002562 urinalysis Methods 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- UBORTCNDUKBEOP-UUOKFMHZSA-N xanthosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(NC(=O)NC2=O)=C2N=C1 UBORTCNDUKBEOP-UUOKFMHZSA-N 0.000 description 1
- 239000008865 yin zhi huang Substances 0.000 description 1
Abstract
The present invention belongs to the field of new medicine technology, and is especially the application of picroside I in preparing medicine for treating hepatitis B. Picroside I has less toxic side effect and determined pharmaceutical effect. It has the effects of protecting liver, lowering transaminase, promoting the function of gallbladder, eliminating icterus, regulating immunity and resisting HBV, and thus possesses high curative effect on acute and chronic hepatitis B. The present invention also provides the preparation process of picroside I and its hepatitis B treating preparation forms. The picroside I preparing process of the present invention has low cost and simple operation and is suitable for industrial production.
Description
Technical field
The invention belongs to new Chinese medicine research and development field,, and provide the preparation method of kutkin I and the pharmaceutical preparation of treatment hepatitis B thereof in particular to the application of kutkin I in preparation treatment hepatitis B medicament.
Background technology
As everyone knows, China is a hepatitis B diseases big country.At present, the whole world estimates at the medicine that is used for the treatment of viral hepatitis more than 600 kinds, but does not still have gratifying medicine so far.The World Health Organization (WHO) West Pacific region eternal honor chairman doctor Han Xiangtai represent, current the most frequently used treatment hepatitis B medicament is cell interferon (Cytokine Interferon) and nucleoside analog (Nucleoside Analogues).Cell interferon commonly used comprises interferon-' alpha ', and interferon must be injected every day, and side effect is more, comprise flu symptom, myalgia, depression and diarrhoea etc. such as headache and fever occur, whether medication also depends on liver function, if liver function is badly damaged, then is not suitable for using interferon.Another kind of cell interferon Peg-intron is also bringing into use.Nucleoside analog as for commonly used then comprises lamivudine (Lamivudine) and adefovirdipivoxil (Adefovir).Lamivudine is used as the treatment chronic hepatitis B, belongs to oral drugs, and few side effects suppresses viral usefulness height, drug resistance can occur but take for a long time, produces the virus of mutation.The adefovirdipivoxil toxic and side effects is few, and this medicine also is used to suppress the research of HIV (human immunodeficiency virus), but discovers that large dose oral administration can influence renal function, and renal function bad person should not use.Use cell interferon and one of shortcoming of examining the beanstalk analog, be that all life-time service can cause serious adverse.Part regulate immune medicine for example thymosin (Thymosin) also be found therapeutic efficiency, but be not widely used as treating hepatitis B at present because detailed therapeutic efficiency is clear not as good as other medicines, price is also quite expensive.
Up to the present, there is not a kind of medicine absolute utility to be arranged for suppressing hepatitis B.Doctor Han Xiangtai thinks, treats in future on the method for hepatitis B, and Chinese herbal medicine can be taken on an important role.World Health Organization (WHO) also with the treatment by Chinese herbs hepatitis B as newly leading future, and wish with the therapy as future blending the east and the west.Therefore people focus on sight on the Chinese herbal treatment hepatitis B gradually.
The habitual always in the past Chinese herbal treatment hepatitis B of the traditional Chinese medical science is used treatment by Chinese herbs hepatitis and has been experienced secular practice, has also accumulated rich experience.Chinese herbal treatment hepatitis B price is cheap, curative effect is reliable and side effect is little, more and more becomes the main medicine of China's treatment hepatitis B.The treatment by Chinese herbs of hepatitis B comprises following several method: (1) liver heat removing dampness removing promotes that jaundice disappears; (2) blood circulation promoting and blood stasis dispelling improves liver microcirculation; (3) QI and blood regulating is transferred the general immunity function; (4) tonifying speen and tonifying kidney improves the clinical symptoms of hepatitis; (5) YIN nourishing, QI invigorating are treated various complication.But Chinese herbal medicine all is being short of science data aspect effectiveness for the treatment of hepatitis B and the safety.For this reason, press for to numerous hepatitis B disease patients provides pharmacological action clear and definite drug effect height, the medicine of the treatment hepatitis B that toxic and side effects is low.
The Chinese medicine Rhizoma Picrorhizae is former calls its " Great Cold " for Tang Materia Medica, " main hectic fever due to YIN-deficiency consumptive fever, the spleen reinforcing gallbladder makes eye bright "." Newly Revised Canon of Materia Medica " say " main hectic fever due to YIN-deficiency consumptive fever, the tonifying liver gallbladder makes eye bright ... thick the intestines and stomach "." Kaibao Bencao " calls its " bitter in the mouth, flat, nontoxic ".In " the thunder fire is boiled in water for a while, then dress with soy, vinegar, etc. pharmacy and separated ", it is returned through " going into liver, gallbladder, stomach three warps ".Miao Xiyong " Bencao Jingshu " say " Rhizoma Picrorhizae, kind remove damp and hot ... all are damp and hot, pathogenic heat, the cloudy latent heat institute that divides is sick all, there's no one who doesn't or isn't eliminates." " medicine justice " say: " Rhizoma Picrorhizae is solely gone into blood system and heat clearing away." " wet fire knot is poly-, non-this disease institute that can not go directly for " book on Chinese herbal medicine justice " speech." Rhizoma Picrorhizae kind remove damp and hot, removing food stagnancy poly-, the tonifying liver gallbladder can be removed the damp and hot pathogenic factor of chronic hepatitis B, protects the liver gallbladder helping except that the epidemic disease poison, for thorough treatment primary disease provides foundation.
Rhizoma Picrorhizae is a goatweed Rhizoma Picrorhizae Picrorhiza scrophulariifloraPennell dry rhizome, be herbaceos perennial, grow on the rock of extremely frigid zones and in the mound, perhaps the area without shade of shallow soil layer, be distributed in western Sichuan, northwestern Yunnan Province, southern Tibet.It is documented, contain iridoid glycosides, cucurbitacine, phenolic glycoside class in the Rhizoma Picrorhizae, also contain a spot of aromatic acid and D-mannitol in addition, wherein kutkin I (Picroside I) belongs to the iridoid glycoside compounds.The preparation method of relevant kutkin I and the application in the medicine of preparation treatment hepatitis B thereof yet there are no report.
The inventor adopts Traditional Chinese medical theory and modern science achievement to combine, adopt advanced extraction separation purification technique, from Chinese medicine Rhizoma Picrorhizae medical material, extract the effective ingredient kutkin I of its treatment hepatitis B, make its content surpass 90%, and kutkin I and corresponding pharmaceutical preparation thereof have been carried out the pharmacodynamics of treatment hepatitis B, pharmacological toxicology is learned research, found that this monomer pharmacological action is clear, has the inhibition hepatitis B replication, the liver protecting and ALT lowering, promoting the function of the gallbladder to alleviate jaundice, effects such as immunomodulating, toxic and side effects is extremely low, safe to use, can be the new Chinese medicine that vast hepatitis B patient provides a kind of high-efficiency low-toxicity.
Summary of the invention
The object of the present invention is to provide a kind of medical application of kutkin I, particularly, is the application in preparation treatment hepatitis B medicament.
Another object of the present invention is to provide the preparation method of kutkin I and the pharmaceutical dosage form of treatment hepatitis B thereof.
The present invention further provides the Chinese medicine composition that is used for the treatment of hepatitis B that contains kutkin I.
Kutkin I (Picroside I) belongs to the iridoid glycoside compounds.This chemical compound is white unformed powder, soluble in water and methanol, fusing point 100-102 ℃.Molecular formula is C
24H
28O
11, structural formula is as follows:
The invention provides the preparation method of kutkin I with industrial value.Its isolation and purification method is quick, simple, practical, and production cost is lower, and suitability for industrialized production is highly advantageous to.
The method of kutkin I extraction provided by the invention, separation, purification is as follows:
(1) extracts: dry rhizome or its pulverizing product of getting Rhizoma Picrorhizae (Picrorhiza scrophulariiflora Pennell) and India's Rhizoma Picrorhizae (Picrorhiza kurroa Royle ex Benth), water, ethanol, acetone equal solvent or its two kinds, the extraction of multiple mixed solvent, extracting solution is being evaporated to dried (or organic solvent-free) below 70 ℃, add water to suitable volume, the centrifugal precipitation of removing gets supernatant;
(2) separate: supernatant is by the good adsorption column of conventional treatment, and water and Different concentrations of alcohol eluting are respectively collected and contained the thin layer inspection and know the eluent that kutkin I is arranged, and concentrating under reduced pressure, vacuum drying below 70 ℃ are pulverized, the kutkin I crude product;
(3) purification: with kutkin I crude product anhydrous alcohol solution, filter, filtrate is admixed silica gel, water-bath volatilizes solvent, loads on the silicagel column top, with the two mixed solvent eluting of ethyl acetate, acetone or its, collect effluent, drying under reduced pressure, pulverize the kutkin I sample.
Used Rhizoma Picrorhizae medical material can be the medical material of pure natural in the said extracted process, also can be the medical material of artificial propagation.The Rhizoma Picrorhizae medical material of employing artificial growth can guarantee the steady sources of medical material, and is quality controllable, and can reduce production costs.
Used Rhizoma Picrorhizae medical material can be ground into the granularity of 10～30 order sizes in the said extracted process, can help the extraction of effective ingredient.
Used solvent can be water, ethanol, acetone in the said extracted process, both can use separately, also can merge with two or more solvent and use.The extracting method that adopts can use backflow, percolation or apparatus,Soxhlet's to extract.
The filler of used filling adsorption column can be the resin of nonpolar or low pole in the above-mentioned separation process, as styrene type (comprising methyl styrene type, ethyl styrene type), acrylonitrile type resin etc., specifically can adopt D-101 type, ZTC type, AB-8 type etc.
Optimal conditions in said extracted, separation, the purge process can pass through L
9(3
4) orthogonal table carries out the quadrature screening experiment, is index with the content and the rate of transform of kutkin I, filters out optimum experimental condition.
Kutkin I content is more than 95% in the kutkin I sample that makes according to the method described above, and the rate of transform is more than 55%.The extraction result is stable, and good reproducibility can be used for large-scale production.
Kutkin I of the present invention during disease, can use separately when being used for the treatment of hepatitis B, and the form of pharmaceutical composition that also can be by containing kutkin I is used.
Pharmaceutical composition provided by the invention can be by method known in the art preparation, and can be by administrations such as oral, Sublingual, percutaneous, muscle or subcutaneous, mucocutaneous, urethra, vagina or veins.
The invention provides with the kutkin I is active component, is used for the treatment of the pharmaceutical preparation and the related dose forms of hepatitis B.This pharmaceutical preparation is to be the effective active composition with above-mentioned kutkin I, and has comprised acceptable other adjuvant components on the pharmaceutics, and wherein said kutkin I content surpasses 90%, preferably is higher than 95%.Pharmaceutical preparation of the present invention comprises oral agents and non-intestinal drug delivery agent, and wherein oral agents comprises capsule, oral liquid, chewing agent, pill, tablet, granule etc., and non-intestinal drug delivery agent comprises injection dosage form and freeze-dried powder injection type etc.Pharmaceutical preparation of the present invention also comprises local administration preparation, comprises cream, ointment, patch, spray etc.Dosage form of the present invention is not limited to this.
Available auxiliary type agent can be conventional fillers such as starch, dextrin or cyclodextrin, sucrose, stearate when the preparation oral formulations.Can prepare by methods such as aseptic spray drying, low-temperature vacuum drying, lyophilizations at the preparation lyophilized injectable powder.Each preparation later stage preparation technology and equipment all belong to the routine techniques of pharmaceutical field, the present invention does not limit this, so will not describe in detail at this.
Creativeness of the present invention is to have by serial experiment proof kutkin I the effect of obvious treatment hepatitis B.In order to prove that kutkin I has therapeutical effect to hepatitis B, comprise therapeutical effect acute, chronic hepatitis B, kutkin I and related dose forms that the inventor uses the above method to make, adopted different animal models, carried out a large amount of zooperies by oral and injecting pathway, experimental result shows: (1) causes the liver of Rats with Acute Liver Injury and mice that tangible prevention protection and therapeutical effect are arranged to carbon tetrachloride, D-amido galactose and acetaminophen; (2) cause the liver of chronic hepatic injury rat that tangible prevention protection and therapeutical effect are arranged to autoallergic and carbon tetrachloride; (3) can obviously increase bilirubin direct content in the normal rat bile, tangible choleretic effect is promptly arranged; (4) can increase how bilirubin direct (TBIL), glutamate pyruvate transaminase (ALT) content in ester (ANIT) the icterogenicity hepatic injury mice serum of isothiocyanic acid-1-, promptly how ester causes mice jaundice liver damage that the obvious treatment effect is arranged to isothiocyanic acid-1-; (5) can obviously increase normal mouse macrophage phagocytic index, non-specific immunity is had tangible potentiation; (6) can obviously be increased in the normal mouse immune organ weight, promote the generation of hemolysin, have the effect that strengthens humoral immune function; (7) the duck hepatitis B there is the obvious treatment effect; (8) can obviously reduce hepatitis B virus surface antigen and the antigenic content of e in the 2.2.15 cell culture supernatant.
Main pharmacodynamics experimental technique of the present invention and result are as follows:
Test an injection kutkin I and D-Gal is caused the therapeutical effect of chmice acute hepatic injury
Observe the injection kutkin I causes the chmice acute hepatic injury to D-Gal (D-Galn) protective effect by the variation that detects mice serum ALT, AST.Get Kunming mouse by body weight be divided at random blank group, model control group, diammonium glycyrrhizinate group (50mg/kg), injection Rhizoma Picrorhizae sweet-I little (5mg/kg), in (10mg/kg), big (15mg/kg) three dosage groups, except that the blank group, all the other D-Gals of respectively organizing equal lumbar injection 1000mg/kg cause the chmice acute hepatic injury, each administration group 1h after modeling, 11h and 21h press 0.1mL/10g volume intravenous administration, behind the modeling 22h, pluck eyeball and get blood survey Serum ALT, AST value, and calculate the liver coefficient.The results are shown in following table.
It is little that table 1 injection kutkin I causes acute liver damage to D-Gal
The influence of Mus Serum ALT, AST (x ± s)
| Group | Dosage (mg/kg) | n | ALT(U/L) | AST(U/L) |
| Dosage group in the blank group model matched group diammonium glycyrrhizinate group injection kutkin I small dose group | - - 50 5 10 | 12 12 12 12 12 | 49.65±16.58 427.42±198.78△△△ 189.31±100.99** 253.94±103.23* 231.25±145.44* | 128.42±36.55 499.34±331.53△△△ 279.61±109.70* 321.86±103.22 280.86±56.21* |
| Heavy dose of group | 15 | 12 | 200.87±100.97** | 249.67±78.42* |
Annotate: compare * P＜0.05, * * P＜0.01 with model control group; Compare △ △ △ P＜0.001 with the blank group.
Table 2 injection kutkin I causes acute liver damage to D-Gal
The influence of mouse liver coefficient (x ± s)
| Group | Dosage (mg/kg) | n | Liver coefficient (%) |
| The heavy dose of group of dosage group in the blank group model control group diammonium glycyrrhizinate group injection kutkin I small dose group | - - 50 5 10 15 | 12 12 12 12 12 12 | 4.76±0.38 5.21±0.53△ 5.47±0.45 5.13±0.33 5.02±0.61 4.77±0.53 |
Annotate: compare △ P＜0.05 with the blank group.
Above-mentioned experimental result shows: the injection kutkin I is little, in, big three dosage groups compare with model control group, ALT, AST value all have remarkable reduction (P＜0.05 or P＜0.01).
Conclusion: the injection kutkin I has the obvious treatment effect to the chmice acute hepatic injury that D-Gal brings out.
Test two injection kutkin Is to CCl
4Cause the prevention protective effect of rat chronic hepatic injury
Observe the injection kutkin I to CCl
4Cause the prevention protective effect of rat chronic hepatic injury.Get Wistar rat male and female half and half, according to body weight be divided at random blank group, model control group, diammonium glycyrrhizinate group (30mg/kg), injection kutkin I little (3.5mg/kg), in (7mg/kg) and big (10mg/kg) dosage group.The equal tail vein injection administration of each administration group, every day 1 time, 4 weeks of successive administration.After the administration 7 days, except that blank group rat, the equal subcutaneous injection 25%CCl of all the other each rats
4Peanut oil solution 2mL/kg 2 times weekly, in totally 3 weeks, causes the chronic hepatic injury model.24 hours abdominal aortic bloods after the last administration are measured Serum ALT, AST, TP, ALB, MDA, SOD, GSH content and hepatic glycogen, liver hydroxyproline.The results are shown in following table.
Table 3 injection kutkin I is to CCl
4Cause the rat chronic hepatic injury
The influence of serum AST, ALT (x ± s)
| Group | Dosage mg/kg | n | AST(U/L) | ALT(U/L) |
| The heavy dose of group of dosage group in the blank group model control group diammonium glycyrrhizinate group injection kutkin I small dose group | - - 30 3.5 7 10 | 12 12 12 14 14 14 | 135.22±37.10 700.73±154.75 △△△ 310.10±118.52 * 293.82±159.68 *** 183.42±87.72 *** 199.11±75.71 *** | 29.71±7.72 284.24±208.94 △△△ 123.84±111.60 * 103.40±49.39 ** 63.24±30.28 *** 62.82±25.09 *** |
Annotate: compare with model control group
*P＜0.05,
*P＜0.01,
* *P＜0.001; Compare with the blank group
△ △ △P＜0.001.
Table 4 injection kutkin I is to CCl
4Causing the rat chronic liver decreases
The influence of TP, ALB (x ± s)
| Group | Dosage (mg/kg) | n | TP(g/dl) | ALB(g/dl) |
| Blank group model matched group diammonium glycyrrhizinate group | - - 30 | 12 12 12 | 66.77±3.21 66.64±3.40 64.37±2.58 | 40.60±4.20 36.07±2.61 △△ 38.52±1.78 * |
| The heavy dose of group of dosage group in the injection kutkin I small dose group | 3.5 7 10 | 14 14 14 | 66.52±5.11 67.12±5.43 66.48±4.56 | 40.12±4.24 * 41.20±5.20 ** 44.74±3.76 *** |
Annotate: compare with model control group
*P＜0.05,
*P＜0.01,
* *P＜0.001; Compare with the blank group
△ △P＜0.01.
Table 5 injection kutkin I is to CCl
4Cause the glycogen of rat chronic hepatic injury
The influence of former and liver hydroxyproline (x ± s)
| Group | Dosage (mg/kg) | n | Hepatic glycogen (the mg/g liver is heavy) | Liver hydroxyproline (μ g/g) |
| The heavy dose of group of dosage group in the blank group model control group diammonium glycyrrhizinate group injection kutkin I small dose group | - - 30 3.5 7 10 | 12 12 12 14 14 14 | 9.72±1.17 4.78±2.85 △△△ 6.59±1.46 * 6.59±1.46 6.73±1.49 ** 7.41±1.84 ** | 191.2±51.1 553.3±112.5 △△△ 320.6±115.4 *** 519.71±156.62 339.7±119.4 ** 281.3±108.7 *** |
Annotate: compare with model control group
*P＜0.05,
*P＜0.01; Compare with the blank group
△ △ △P＜0.001.
Table 6 injection kutkin I is to CCl
4Cause in the rat chronic hepatic injury serum
The influence of MDA, SOD, GSH content (x ± s)
| Group | Dosage mg/kg | n | MDA (nmol/mL) | SOD (nU/mL) | GSH (mg/L) |
| Blank group model matched group | - - | 12 12 | 4.04±1.20 9.06±1.04 △△△ | 151.98±11.27 161.77±28.29 △ | 130.63±23.97 107.22±27.62 △ |
| The heavy dose of group of dosage group in the diammonium glycyrrhizinate group injection kutkin I small dose group | 30 3.5 7 10 | 12 14 14 14 | 6.82±1.48 *** 6.91±2.03 ** 6.80±1.40 *** 4.30±1.65 *** | 137.07±19.69 138.62±15.93 138.93±19.94 155.00±10.80 ** | 143.52±30.12 ** 122.57±22.30 137.81±19.49 ** 144.68±32.69 ** |
Annotate: compare with model control group
*P＜0.05,
*P＜0.01,
* *P＜0.001; Compare with the blank group
△P＜0.05,
△ △ △P＜0.001.
Above-mentioned experimental result shows: the injection kutkin I can obviously reduce Serum ALT, AST, MDA and liver hydroxyproline, and increased SOD, GSH, TP, ALB and glycogen initial value have significant difference (P＜0.05, P＜0.01 or P＜0.001).
Conclusion: the injection kutkin I is to CCl
4Cause the rat chronic hepatic injury tangible prevention protective effect is arranged.
Test three kutkin Is and carbon tetrachloride is caused the therapeutical effect of rat chronic hepatic injury
Observe the kutkin I oral administration causes the rat chronic hepatic injury to carbon tetrachloride therapeutical effect.Get the Wistar rat and adopt carbon tetrachloride (CCl
4) cause chronic hepatic injury after, be divided at random model control group, bifendate group (150mg/kg), kutkin I little (15mg/kg), in (30mg/kg), big (60mg/kg) dosage group, and set up blank group operation repetitive.Each organizes continuous gastric infusion, 4 weeks of successive administration.Blank group and model control group give the equal-volume normal saline.After the last administration 24 hours, carry out abdominal aortic blood after each treated animal anesthesia, separation of serum is surveyed Serum ALT, AST, TP, ALB value, and is got liver and do the pathological tissue inspection, mensuration liver hydroxyproline and liver glycogen content.The results are shown in following table.
Table 7 kutkin I is to the influence of chronic hepatic injury rat blood serum ALT, AST, A/G (x ± s)
| Group | Dosage | n | ALT | AST | A/G |
| mg/kg | (U/L) | (U/L) | |||
| The heavy dose of group of dosage group in the blank group model control group DDB group kutkin I small dose group | 150 15 30 60 | 12 18 14 14 14 14 | 40.85±6.35 562.52±85.64 △△△ 340.90±74.41 *** 468.25±74.80 ** 436.46±67.03 *** 389.25±86.24 *** | 149.17±20.51 843.78±28.46 △△△ 511.35±111.61 *** 768.12±117.13 742.39±108.63 * 583.88±129.37 *** | 1.1866±0.18 0.8876±0.21 △△△ 1.0962±0.15 ** 1.0361±0.24 1.0486±0.16 * 1.0860±0.20 * |
Annotate: compare with the blank group,
△ △ △P＜0.001; Compare with model control group,
*P＜0.05
*P＜0.01
* *P＜0.001.
Table 8 kutkin I is to chronic hepatic injury rats'liver glycogen, hydroxyproline content
And the influence of liver coefficient (x ± s)
| Group | Dosage (mg/kg) | n | Liver glycogen (mg/g) | Hydroxyproline (μ g/g) | Liver coefficient (%) |
| The heavy dose of group of dosage group in the blank group model control group DDB group kutkin I small dose group | 150 15 30 60 | 12 18 14 14 14 14 | 21.07±141 7.14±2.30 △△△ 14.53±3.87 *** 9.67±3.14 * 12.14±5.65 ** 14.12±4.69 *** | 8.42±4.65 19.74±7.55 △△ 12.03±9.59 * 13.90±8.40 * 13.37±8.66 * 11.52±5.30 ** | 2.682±0.25 5.859±1.34 △△△ 4.072±0.75 *** 4.982±1.12 4.671±1.5 * 3.721±1.74 *** |
Annotate: compare with the blank group,
△ △P＜0.01
△ △ △P＜0.001; Compare with model control group,
*P＜0.05
*P＜0.01
* *P＜0.001.
Above-mentioned experimental result shows: kutkin I is little, in, heavy dose of group and model control group relatively, ALT, liver hydroxyproline obviously reduce (P＜0.05), liver glycogen obviously raise (P＜0.05); In the kutkin I, heavy dose of group obviously reduces with model control group comparison AST, liver coefficient, A/G ratio obviously raise (P＜0.05).Pathological examination results points out each administration group and model control group relatively not to have significant difference.
Conclusion: kutkin I has the obvious treatment effect to rat chronic hepatic injury due to the carbon tetrachloride.
Test of the influence of four injection kutkin Is to normal macrophage phagocytosis of mice
Observe of the influence of injection kutkin I to normal macrophage phagocytosis of mice.Divide blank group, cyclophosphamide group (50mg/kg), levamisole group (30mg/kg), injection kutkin I small dose group (5mg/kg), middle dosage group (10mg/kg), heavy dose of group (15mg/kg) at random with the ICR mice, totally 6 groups, the cyclophosphamide group is pressed the 0.02mL/10g intraperitoneal injection every day, the levamisole group is pressed the 0.2mL/10g gastric infusion, each dosage group of injection kutkin I is all by 0.1mL/10g volume tail vein injection relative medicine, blank group tail vein injection equal-volume normal saline, once a day, continuous 7 days.24h after the last administration carries out carbon and cleans up experiment, calculates phagocytic index.Get Mouse Liver simultaneously and spleen is weighed, calculate organ coefficient.The results are shown in following table:
Table 9 injection kutkin I is to the influence of normal mouse macrophage phagocytic index (x ± s)
| Group | Dosage mg/kg | n | Phagocytic index |
| Blank group cyclophosphamide group levamisole group | - 50 30 | 14 14 14 | 0.0383±0.0069 0.0286±0.0114△ 0.0478±0.0069△△ |
| The heavy dose of group of dosage group in the injection kutkin I small dose group | 5 10 15 | 14 14 14 | 0.0431±0.0121 0.0456±0.0081△ 0.0470±0.0120△ |
Annotate: compare △ P＜0.05 △ △ P＜0.01 with the blank group
Table 10 injection kutkin I is to the influence of laboratory animal organ coefficient (x ± s)
| Group | Dosage mg/kg | n | Liver coefficient (%) | Spleen coefficient (%) |
| The heavy dose of group of dosage group in the blank group endoxan group levamisol group injection kutkin I small dose group | - 50 30 5 10 15 | 14 14 14 14 14 14 | 5.5087±0.4529 5.4878±0.6011 5.5092±0.4461 5.3290±0.2976 5.2614±0.5175 5.3466±0.3689 | 0.5031±0.0975 0.2210±0.0553△ 0.5165±0.0711 0.5348±0.3772 0.4874±0.0928 0.5027±0.0922 |
Annotate: compare △ △ △ P＜0.001 with the blank group
Above-mentioned experimental result shows: in the injection kutkin I, heavy dose of group and blank group relatively, phagocytic index all rises to some extent, learns by statistics to handle difference and all have significance (P＜0.05), organ coefficient does not then have significant change (P＞0.05).
Conclusion: the injection kutkin I has tangible potentiation to non-specific immunity.
Test of the influence of five injection kutkin Is to normal mouse humoral immune function
By observing the injection kutkin I, detect its influence to humoral immune function to the influence that the normal mouse hemolysin generates.ICR kind mice is divided into 6 groups at random by body weight, it is the blank group, levamisole (30mg/kg) group, cyclophosphamide group (20mg/kg) group, injection kutkin I little (5mg/kg), in (10mg/kg), big (15mg/kg) dosage group, wherein except that the levamisole group was pressed the 0.2mL/10g gastric infusion, each was organized all by 0.1mL/10g tail vein injection relative medicine, continuous 8 days.Administration second day, each organizes mouse peritoneal injection CRBC suspension 0.2mL, and continuous 7 days, 1h after the last immunity got blood and carries out hemolysin O D pH-value determination pH, got thymus, organ coefficient is weighed, calculated to spleen.The results are shown in following table.
Table 11 injection kutkin I is to the influence of normal mouse immune organ (x ± s)
| Group | Dosage mg/kg | n | Thymus coefficient (%) | Spleen coefficient (%) |
| The heavy dose of group of dosage group in the blank group endoxan group levamisol group injection kutkin I small dose group | 20 30 5 10 15 | 14 14 14 14 14 14 | 0.37±0.09 0.10±0.03△△△ 0.52±0.57 0.41±0.06 0.38±0.06 0.40±0.03 | 0.62±0.15 0.19±0.04△△△ 0.57±0.15 0.71±0.19 0.63±0.07 0.90±0.29△△ |
Annotate: compare △ △ P＜0.01, △ △ △ P＜0.001 with the blank group.
Table 12 injection kutkin I is to the influence of normal mouse hemolysin content (x ± s)
| Group | Dosage (mg/kg) | n | Hemolysin O D value |
| Blank group cyclophosphamide group | - 20 | 14 14 | 1.83±0.01 0.16±0.02△△△ |
| The heavy dose of group of dosage group in the levamisole group injection kutkin I small dose group | 30 5 10 15 | 14 14 14 14 | 1.84±0.02△ 1.88±0.12 2.04±0.32△ 1.86±0.01△△△ |
Annotate: compare △ P＜0.05 △ △ P＜0.01 △ △ △ P＜0.001 with the blank group
Above-mentioned experimental result shows: with the blank group relatively in the injection kutkin I, heavy dose of group hemolysin O D value all obviously raises, learning processing difference by statistics all has significance (P＜0.05, P＜0.001).Obviously raise with the heavy dose of group of blank group comparison injection kutkin I spleen coefficient, learning processing difference by statistics has highly significant (P＜0.01).
Conclusion: the injection kutkin I has the effect that strengthens the normal mouse humoral immune function.
Test the choleretic effect of six injection kutkin Is to normal rat
By observing of the influence of injection kutkin I, the choleretic effect of research injection kutkin I to bilirubin direct content in choleresis and the bile.Method is got 50 of Wistar male rats, body weight 220～240g, according to body weight be divided at random blank group, positive drug phenylpropanol soft gelatin capsule group (250mg/kg), injection kutkin I little (3.5mg/kg), in (7mg/kg) and big (10mg/kg) dosage group, totally 5 groups.Open the abdominal cavity behind the rat anesthesia, make common bile duct intubated and drained bile, collect the preceding 0h of medicine～0.5h bile, then respectively from sublingual vein administration 1mL/100g, collect 0h～0.5h after the administration, 0.5h～1.0h, 1.0h～1.5h, 1.5h～2.0h, 2.0h～2.5h, the bile flow of 2.5h～3.0h is also measured bilirubin direct content.The results are shown in following table.
Table 13 injection kutkin I is to the influence of rat bile flow (x ± s)
| Group | Dosage mg/kg | n | 0h～0.5h (mL) before the medicine | 1.0h～1.5h behind the medicine (mL) | 0.5h～1.0h behind the medicine (mL) | 1.0h～1.5h behind the medicine (mL) |
| The heavy dose of group of dosage group in the blank group positive controls injection kutkin I small dose group | - 250 3.5 7 10 | 10 10 10 10 10 | 0.31±0.10 0.32±0.08 0.30±0.08 0.32±0.10 0.33±0.09 | 0.31±0.10 0.40±0.05 △** 0.39±0.08 △* 0.43±0.13 * 0.43±0.10 △** | 0.25±0.06 0.43±0.06 △△*** 0.40±0.09 △*** 0.43±0.07 △*** 0.46±0.07 △△*** | 0.26±0.09 0.45±0.05 △△△*** 0.41±0.10 △** 0.46±0.06 △△*** 0.49±0.05 △△△*** |
| Group | Dosage mg/kg | n | 1.5h～2.0h behind the medicine (mL) | 2.0h～2.5h behind the medicine (mL) | 2.5h～3.0h behind the medicine (mL) |
| The heavy dose of group of dosage group in the blank group positive controls injection Hu xanthosine I small dose group | - 250 3.5 7 10 | 10 10 10 10 10 | 0.25±0.04 0.43±0.07 △*** 0.34±0.04 ** 0.45±0.08 △*** 0.45±0.06 △△*** | 0.23±0.06 0.40±0.09 △** 0.32±0.09 0.41±0.05 △*** 0.42±0.05 △*** | 0.23±0.05 0.32±0.09 0.33±0.05 * 0.36±0.07 ** 0.39±0.08 *** |
Annotate: compare * P＜0.05, * * P＜0.01, * * * P＜0.001 with the blank group; With comparison △ P＜0.05 before the self administration, △ △ P＜0.01, △ △ △ P＜0.001.
Table 14 injection kutkin I is to the influence of rat bile bilirubin direct (x ± s)
| Group | Dosage mg/kg | n | 0h～0.5h (μ mol/L) before the medicine | 0h～0.5h behind the medicine (μ mol/L) | 0.5h～1.0h behind the medicine (μ mol/L) | 1.01h～1.5h behind the medicine (μ mol/L) |
| Dosage group in the blank group phenylpropanol capsule and pill group injection kutkin I small dose group | - 250 3.5 7 | 10 10 10 10 | 75.75± 13.03 74.92± 16.07 77.44± 17.87 75.31± 17.20 | 77.43± 15.58 106.52± 17.05***△△△ 93.60± 21.59 106.47± 31.87*△ | 80.82± 15.83 125.65± 17.20***△△△ 111.02± 23.54**△△ 116.14± 29.45**△△△ | 81.57± 20.07 142.69± 13.95***△△△ 118.54± 24.24**△△△ 129.59± 28.17***△△△ |
| Heavy dose of group | 10 | 11 | 73.92± 16.25 | 101.77± 26.36*△△ | 126.93± 28.33***△△△ | 134.34± 27.50***△△△ |
| Group | Dosage mg/kg | n | 1.5h～2.0h behind the medicine (μ mol/L) | 2.0h～2.5h behind the medicine (μ mol/L) | 2.5h～3.0h behind the medicine (μ mol/L) |
| The heavy dose of group of dosage group in the blank group phenylpropanol capsule and pill group injection kutkin I small dose group | - 250 3.5 7 10 | 10 10 10 10 11 | 78.56± 16.09 115.12± 14.92***△△△ 115.59± 29.14**△△ 124.93± 24.57***△△△ 120.77± 26.49***△△△ | 72.54± 18.70 104.22± 15.07***△△△ 98.77± 23.36**△ 103.48± 23.51**△△ 112.42± 22.97***△△△ | 71.09± 14.72 100.80± 15.59***△△ 90.77± 15.29** 99.37± 24.37**△ 92.41± 18.65**△ |
Annotate: compare * P＜0.05, * * P＜0.01, * * * P＜0.001 with the blank group; With comparison △ P＜0.05 before the self administration, △ △ P＜0.01, △ △ △ P＜0.001.
Above-mentioned experimental result shows: each dosage group of injection kutkin I is compared with the blank group, and each time period bile flow all has rising in various degree, and can obviously increase the bilirubin direct content (P＜0.05, P＜0.01, P＜0.001) in the bile.
Conclusion: the injection kutkin I has tangible choleretic effect.
Test seven injection kutkin Is to isothiocyanic acid-1-how ester cause the therapeutical effect of mice jaundice liver damage
Observe the therapeutical effect of injection kutkin I by the variation that detects mice serum total bilirubin (TBIL), conjugated bilirubin (DBIL), glutamate pyruvate transaminase (ALT), glutamic oxaloacetic transaminase, GOT (AST) to the jaundice liver damage.Kunming mouse by body weight be divided at random blank group, model control group, positive mattress Cape jasmine Huang (200mg/kg), injection kutkin I little (5mg/kg), in totally 6 groups of (10mg/kg), big (15mg/kg) dosage groups, 12 every group.Except that the blank group, all the other each groups all gavage ANIT (100mg/kg) peanut oil solution by 0.1mL/10g and cause chmice acute jaundice model, and 6h, 24h, 47h are administered three times after the modeling.After the last administration 1 hour (be after the modeling 48 hours), each treated animal is plucked eyeball and is got blood, and centrifugal serum is surveyed TBIL, DBIL, ALT, AST.Get liver, the calculating organ coefficient of weighing.The results are shown in following table.
Table 15 injection kutkin I causes mice jaundice liver damage to ANIT
The influence of serum T BIL and DBIL (x ± s)
| Group | Dosage mg/kg | n | Serum T BIL (μ mol/l) | Serum DBIL (μ mol/l) |
| The heavy dose of group of dosage group in the blank group model control group anti-hepatitis-jaundice injection group injection kutkin I small dose group | - - 200 5 10 15 | 12 12 12 12 12 12 | 9.23±2.61 140.91±33.85 △△△ 100.20±14.37 ** 108.46±35.89 111.01±34.63 * 114.05±18.58 * | 7.43±2.57 98.65±29.51 △△△ 82.30±11.31 85.80±24.73 85.35±20.37 90.46±16.41 |
Annotate: compare with model control group
*P＜0.05,
*P＜0.01; Compare with the blank group
△ △ △P＜0.001.
Table 16 injection kutkin I causes mice jaundice liver damage to ANIT
The influence of Serum ALT and AST (x ± s)
| Group | Dosage mg/kg | n | Serum ALT (U/L) | Serum AST (U/L) |
| Blank group model matched group | - - | 12 12 | 46.83±13.99 887.65±243.47 △△△ | 143.25±37.56 871.16±119.45 △△△ |
| The heavy dose of group of dosage group in the Yinzhihuang Injection group injection kutkin I small dose group | 200 5 10 15 | 12 12 12 12 | 618.72±268.33 * 786.58±255.43 688.59±215.03 * 697.91±154.22 * | 742.56±166.10 * 832.58±147.15 807.50±207.15 767.23±149.16 |
Annotate: compare with model control group
*P＜0.05; Compare with the blank group
△ △ △P＜0.001.
Above-mentioned experimental result shows: in the injection kutkin I, heavy dose of group and model control group relatively, serum T BIL, ALT value all obviously reduce, and learn processing by statistics and have significant difference (P＜0.05).All the other each indexs and model control group compare, no significant difference (P＞0.05).
Conclusion: the injection kutkin I has the obvious treatment effect to mice jaundice liver damage.
Test of the influence of eight injection kutkin Is to the duck hepatitis B
Observe of the influence of injection kutkin I to DHB (DHBV).Experiment is established 6 groups, normal control group, model group, positive drug group (lamivudine 20mg/kg), injection kutkin I little (10mg/kg), in (20mg/kg), big (40mg/kg) dosage group, except that the normal control group, all the other each groups all adopt sheldrake hepatitis B model, intravenous route is adopted in administration, detects (T before the administration respectively
0), the 5th day (T after the administration
5), the 10th day (T
10) and drug withdrawal after the 3rd day (P
3) content of DHBV-DNA and preceding s surface antigen (DHBpresAg) during Sanguis Anas domestica is clear.Experiment repeats three batches.The results are shown in following table.
Table 17 injection kutkin I (HD-I) is to the influence of the clear DHBV-DNA content of Sanguis Anas domestica
| Batch | Group | Dosage mg/kg | Duck number | The clear DHBV-DNA average optical density value of Sanguis Anas domestica (± s) | |||
| T 0 | T 5 | T 10 | P 3 | ||||
| 1 | Model group 3TC HD-I (little) | 20 10 | 12 13 10 | 0.327±0.053 0.381±0.093 0.365±0.108 | 0.264±0.071 0.168±0.077***△△ 0.273±0.060** | 0.307±0.065 0.284±0.043*** 0.309±0.060 | 0.323±0.062 0.307±0.070** 0.319±0.046 |
| HD-I (in) HD-I (greatly) model group 3TC | 20 40 20 | 9 10 11 14 | 0.376±0.069 0.361±0.071 0.658±0.048 0.608±0.108 | 0.256±0.055** 0.208±0.055*** 0.673±0.075 0.229±0.120***△△△ | 0.314±0.054 0.231±0.064***△ 0.678±0.083 0.444±0.109***△△△ | 0.298±0.075** 0.189±0.052***△△△ 0.676±0.055 0.460±0.113***△△△ | |
| 2 | HD-I (little) HD-I (in) HD-I (greatly) model group 3TC | 10 20 40 20 | 12 13 14 10 13 | 0.609±0.071 0.640±0.090 0.641±0.056 0.303±0.077 0.304±0.144 | 0.588±0.093△ 0.465±0.070***△△△ 0.455±0.114***△△△ 0.286±0.078 0.162±0.037**△△△ | 0.399±0.082***△△△ 0.524±0.117***△△ 0.434±0.138***△△△ 0.293±0.056 0.211±0.052△△ | 0.478±0.123**△△△ 0.521±0.107***△△△ 0.299±0.133***△△△ 0.300±0.068 0.222±0.080△ |
| 3 | HD-I (little) HD-I (in) HD-I (greatly) | 10 20 40 | 12 11 11 | 0.308±0.059 0.269±0.134 0.378±0.138 | 0.308±0.070 0.214±0.153 0.328±0.138 | 0.334±0.063 0.205±0.022△△ 0.235±0.024**△△ | 0.293±0.109 0.167±0.056**△△ 0.235±0.069**△ |
Annotate: *: t check in pairs: administration group different time (T
5, T
10, P
3) (T before the clear DHBV-DNA average optical density value of Sanguis Anas domestica and the administration not
0) average optical density value relatively.*P＜0.05，**P＜0.01，***P＜0.001。
△: t check between group: administration group different time (T
0, T
5, T
10, P
3) clear DHBV-DNA average optical density value of Sanguis Anas domestica and model group (T
0, T
5, T
10, P
3) average optical density value relatively.△P＜0.05，△△P＜0.01，△△△P＜0.001
Table 19 injection kutkin I (HD-I) is to the influence of the clear DHBpresAg level of Sanguis Anas domestica
| Batch | Group | Dosage (mg/kg) | Duck number (only) | The clear DHBpresAg average optical density value of Sanguis Anas domestica (x ± s) | |||
| T 0 | T 5 | T 10 | P 3 | ||||
| Model group 3TC | 20 | 12 13 | 1.392±0.156 1.401±0.142 | 1.267±0.266 0.986±0.202***△△ | 1.326±0.148 1.207±0.058* | 1.341±0.191 1.190±0.125***△ | |
| 1 | HD-I (little) HD-I (in) HD-I (large-sized model group 3TC | 10 20 40 20 | 10 9 10 11 14 | 1.482±0.143 1.400±0.120 1.429±0.260 0.450±0.068 0.434±0.077 | 1.105±0.329*** 0.977±0.264**△ 1.111±0.421 0.391±0.072 0.400±0.093 | 1.196±0.263** 1.187±0.256* 1.101±0.441* 0.392±0.059 0.349±0.088** | 1.186±0.258*** 1.060±0.281**△ 1.061±0.425* 0.397±0.093 0.320±0.0.092***△ |
| 2 | HD-I (little) HD-I (in) HD-I (greatly) | 10 20 40 | 12 13 14 | 0.507±0.077 0.501±0.058 0.493±0.066 | 0.449±0.106 0.420±0.075* 0.435±0.059* | 0.448±0.129 0.392±0.044*** 0.369±0.060*** | 0.361±0.124** 0.396±0.079** 0.337±0.111*** |
| 3 | Model group 3TC HD-I (little) HD-I (in) | 20 10 20 | 10 13 12 11 | 0.741±0.079 0.687±0.184 0.764±0.056 0.727±0.050 | 0.732±0.093 0.485±0.194***△△ 0.597±0.156***△ 0.519±0.121***△△△ | 0.741±0.059 0.575±0.171**△△ 0.614±0.111***△△ 0.636±0.106*△ | 0.704±0.112 0.615±0.124* 0.607±0.116***△ 0.557±0.121***△△ |
| HD-I (greatly) | 40 | 11 | 0.748±0.103 | 0.598±0.198 | 0.575±0.202**△ | 0.549±0.191**△ |
Annotate: *: t check in pairs: administration different time (T
5, T
10, P
3) (T before the clear DHBpresAg OD of Sanguis Anas domestica value and the administration not
0) the OD value relatively.*P＜0.05，**P＜0.01，***P＜0.001。
△: t check between group: administration group different time (T0, T5, T10, P3) Sanguis Anas domestica clear DHBpresAg OD value and model group (T
0, T
5, T
10, P
3) the OD value relatively.△P＜0.05，△△P＜0.01，△△△P＜0.001。
Above-mentioned experimental result shows: to Sanguis Anas domestica clear in DHBV-DNA assay result be: in the three batches of experiments injection kutkin I little, in, before the 3rd day the clear DHBV-DNA average optical density value of Sanguis Anas domestica and the administration significance decline (P＜0.001 or P＜0.01) is arranged relatively after the 5th day, the 10th day and the drug withdrawal after the administration of heavy dose of group; The injection kutkin I is little, in, after the administration of heavy dose of group the 5th day, the 10th day with drug withdrawal after the 3rd day serum DHBV-DNA level respectively with corresponding model group administration after the 5th day, the 10th day with drug withdrawal after compared in the 3rd day and all to have significance to descend (P＜0.001 or P＜0.01 or P＜0.05), and have certain dose-effect relationship.To Sanguis Anas domestica clear in DHBpresAg assay result be: in the three batches of experiments injection kutkin I little, in, before the 3rd day Sanguis Anas domestica clear DHBpresAg OD value and the administration significance decline (P＜0.001 or P＜0.01 or P＜0.05) is arranged relatively after the 5th day, the 10th day and the drug withdrawal after the administration of heavy dose of group; The injection kutkin I is little, in, after the administration of heavy dose of group the 5th day, the 10th day with drug withdrawal after the 3rd day serum DHBpresAg level respectively with corresponding model group administration after the 5th day, the 10th day with drug withdrawal after compared in the 3rd day significance descend (P＜0.001 or P＜0.01 or P＜0.05) all arranged.
Conclusion: in the injection kutkin I body dhbv dna is had than the obvious suppression effect.
Test nine injection kutkin Is to the inhibiting in vitro study of hepatitis B virus
Whether observation in vitro injection kutkin I is inhibited to hepatitis B virus (HBV).Detect the toxicity of injection kutkin I with mtt assay to the 2.2.15 cell; Detect the content that variable concentrations injection kutkin I acts on behind the 2.2.15 cell different time HBV related antigen-surface antigen (HBsAg) and e antigen (HBeAg) in the cells and supernatant, the half toxic concentration (TC of calculating medicine pair cell with the ELISA method
50) and to antigenic half-inhibition concentration (IC
50), with TC
50And IC
50Ratio (being therapeutic index) estimate the effectiveness and the safety of medicine, TI＞2 are safe and effective.The normal control group is set simultaneously, blank group, and positive drug lamivudine (3TC) group operation repetitive.The results are shown in following table.
Table 20 injection kutkin I is to the therapeutic index of HbsAg and HBsAg
| Medicine | TI to HBsAg | TI to HBsAg | ||||
| Batch | 1 | 2 | 3 | 1 | 2 | 3 |
| Injection kutkin I 3TC | 2.0 5.2 | 5.0 5.4 | 1.9 3.3 | 4.8 - | 5.2 1.7 | 4.5 - |
Annotate: criterion is: TI＞2 are for effective; 1≤TI≤2 are poisonous effective; TI＜1 is a toxic action.
The explanation of above-mentioned experimental result: the three batches of experiment injection kutkin Is are respectively 2.97 and 4.83 to the meansigma methods of HBsAg and HBeAg therapeutic index; The positive drug lamivudine is 4.83 to the therapeutic index of HBsAg, and HBeAg is not had inhibitory action.
Conclusion: the injection kutkin I is external to have the obvious suppression effect to HBV.
The pharmacodynamic experiment result shows that kutkin I not only has the liver protecting and ALT lowering, promoting the function of the gallbladder to alleviate jaundice and immunoregulation effect preferably, but also has significant anti-HBV effect.
In order to study the toxic action that kutkin I may exist body, estimate the drug safety that utilizes the Chinese medicine medicine that this monomer is prepared into, the inventor has carried out the general toxicity experiment and specific toxicity is tested.
One, general toxicity experiment
1. studies on acute toxicity
Experimental result shows the LD of the injection type intravenous administration of kutkin I to mice
50Value is 1040mg/kg, and intravenous administration is to the LD of rat
50Value is 171.4mg/kg, and intraperitoneal injection is to the LD of rat
50For the 552mg/kg medicine does not have obvious acute toxicity damage to the vital tissue of animal and internal organs.
2. long term toxicity research
(1) kutkin I injection type intraperitoneal injection is to the long term toxicity research of rat
Establish 4 groups altogether, be respectively solvent control group (equal-volume normal saline), the little 40mg/ (kgd) of kutkin I injection type, middle 150mg/ (kgd) and big three dosage groups of 300mg/ (kgd) are equivalent to 5 times, 21 times, 42 times of pharmacodynamics effective dose respectively.With general performance, body weight, food ration, hematology and serum biochemistry index, routine urinalysis, bone marrow classification, organ weights, organ coefficient before and after the animals administer serves as to detect index, and be aided with the pathological examination that animal is respectively organized internal organs, the toxicity situation of overall merit medicine.The result shows that the heavy dose of treated animal body weight gain of kutkin I injection type is slow, and all the other every indexs are all normal.In, every detection index of small dose group animal also shows no obvious abnormalities.The result of histopathologic examination shows that three dosage treated animals are respectively organized the internal organs no abnormality seen.Be safe dose in can thinking below the dosage.
(2) kutkin I injection type intravenous drip administration is to the long term toxicity research of Beagle
Establish 4 groups altogether, be respectively solvent control group (equal-volume normal saline), the little 20mg/ of kutkin I injection type (kgd), middle 77.46mg/ (kgd) and big three dosage groups of 150mg/ (kgd).Be equivalent to 10,40 and 70 times of pharmacodynamics effective dose respectively.Observation index is the same.The result shows that the every detection index of large, medium and small dosage treated animal is no abnormality seen also.The pathology detection results suggest, three each vital tissue internal organs Non Apparent Abnormalities of dosage treated animal.
Comprehensive above-mentioned two long term toxicity results of study, we think that injection kutkin I toxicity is lower, safety range is wide, considerably beyond the scope of pharmacodynamics effective dose.
Two, specific toxicity experiment
1. the mutagenic action of kutkin I research
Studied the potential in vitro and in vivo mutagenicity of kutkin I respectively by " Salmonella typhimurium back mutation experiment ", " experiment of Chinese hamster lung fibroblast (CHL) chromosomal aberration " and " mouse bone marrow cells is had a liking for the polychromatocyte micronucleus and formed experiment ".The result shows, no matter kutkin I in external still body, does not all have significantly direct or indirect mutagenic action.
2. the Study on Teratogenic of kutkin I
Observe kutkin I at rat sensitive period to teratogenic agent successive administration by the sensitive period to teratogenic agent reproductive toxicity test of kutkin I, but whether the teratogenesis fetal hair (Crinis Carbonisatus) is given birth to.The result shows that each dosage of kutkin I does not all have tangible teratogenesis.
In sum, the kutkin I toxic and side effects is less, pharmacological action is clear and definite, it not only has the liver protecting and ALT lowering, promoting the function of the gallbladder to alleviate jaundice and immunoregulation effect preferably, but also has significant anti-HBV effect, this is one of creative place of the present invention, is the not available characteristics of domestic like product.As injection, this drug effect is rapid, and acute hepatitis is had excellent curative in addition.As oral agents, its major advantage is less than toxicity such as Western medicine such as lamivudine, aciclovirs, should take for a long time.The above-mentioned kutkin I that experimental results show that is a kind of active compound that hepatitis B comprises the acute or chronic hepatitis B disease for the treatment of, and the pharmaceutical composition that contains kutkin I is the good medicine for the treatment of the hepatitis B disease simply.
Rhizoma Picrorhizae can adopt the method for artificial growth to breed at present, has guaranteed the steady sources of medical material, and is quality controllable, and a large amount of plantation can reduce production costs with exploitation.In view of China is hepatitis B big country, the medicine that kutkin I is developed to the treatment hepatitis B will have than wide market application prospect.
Specific embodiment
The present invention is further elaborated with following embodiment, but the present invention is not limited to the content that the following example comprises.
The preparation method of embodiment 1 kutkin I
Get Rhizoma Picrorhizae medical material 3000g (kutkin I content 3.19% in the medical material), be ground into the medicated powder of 10 mesh sieves.70% alcohol reflux with 12 times of medical material bulking values (v/w), it is 1.18～1.20 concentrated solution that the gained percolate is condensed into relative density at 60 ℃, the gained concentrated solution adds the entry dilution, centrifugal, the gained supernatant passes through D-101 macroporous adsorptive resins (resin path: high=1: 10 with the speed of 1.2L/Kg.h, resin demand is 2.5 times of medical material weight), after treating that medicinal liquid flows into resin fully, use the water of 20 times of medical material bulking values (v/w) successively, 32 times of medical material bulking values (v/w), 15% ethanol elution impurity, use 20 times of medical material bulking values (v/w), 25% ethanol elution kutkin I then, collect eluent, 60 ℃ of concentrating under reduced pressure, vacuum drying, pulverize, the reuse dehydrated alcohol dissolves medicated powder, filter, filtrate is admixed silica gel, and 60 ℃ of water-baths volatilize solvent, loads on (silica gel footpath: high=1: 10, silicagel column top, the silica gel consumption is 1 times of medical material weight), with 10 times of medical material bulking values (V/W) eluent ethyl acetate, collect effluent, 60 ℃ of drying under reduced pressure, pulverize kutkin I sample 56.85g, kutkin I content 95.24%, kutkin I weight 54.14g, the kutkin I rate of transform 56.57%.(annotate: the volume number of one hour effluent of " L/Kg.h " expression per kilogram medical material, down together.)
The preparation method of embodiment 2 kutkin Is
Get Rhizoma Picrorhizae medical material 84kg (kutkin I content 3.19% in the medical material), be ground into the medicated powder of 10 mesh sieves.70% ethanol speed percolation with 8 times of medical material bulking values (v/w), it is 1.18～1.20 concentrated solution that the gained percolate is condensed into relative density at 60 ℃, gained concentrated solution thin up, centrifugal, the gained supernatant is by ZTC type resin column, after treating that medicinal liquid flows into resin fully, use the water of 18 times of medical material bulking values (v/w) successively, 25 times of medical material bulking values (v/w), 15% ethanol elution impurity is used 25 times of medical material bulking values (v/w), 25% ethanol elution then, collect eluent, 60 ℃ of concentrating under reduced pressure, vacuum drying is pulverized, 1 times of medical material bulking value of reuse (v/w) dehydrated alcohol dissolves medicated powder, filter, filtrate is admixed silica gel, and 60 ℃ of water-baths volatilize solvent, load on the silicagel column top, with 10 times of medical material bulking values (V/W) acetone eluting, collect effluent, 60 ℃ of drying under reduced pressure, pulverize kutkin I sample 1.55kg, kutkin I content 95.30%, kutkin I weight 1.48kg, the kutkin I rate of transform 55.12%.
[embodiment 3] injection kutkin I preparation technology
Prescription: kutkin I 60.0g, make 1000.
Method for making: get kutkin I 60.0g, add the about 2800mL of water for injection, 65 ℃ of water-baths make dissolving, add total amount of preparation 2.0 ‰ active carbons (6.0g), stir half an hour, filter, add water to 3000mL on filter, continue with 0.45 μ m, 0.22 μ m microporous filter membrane classified filtering, filtrate quantitatively is sub-packed in the 10mL cillin bottle with every bottle of 3mL, lyophilization, recharge high-purity nitrogen, jump a queue, roll lid, packing, promptly.
[embodiment 4] kutkin I tablet producing technology
Prescription: make 1000 altogether, each component and content are as follows:
Rhizoma Coptidis glycosides I 30g
Starch 180g
Microcrystalline Cellulose 60g
Lactose 30g
Magnesium stearate 1.5g
Method for making: get the kutkin I sample, wherein kutkin I content surpasses 90%, it is pulverized 80 mesh sieves, with mix homogeneously such as starch, microcrystalline Cellulose, lactose, with 8% starch slurry system soft material, drying, granulate adds magnesium stearate, mixing, tabletting, quality inspection, packing, promptly.
Claims (10)
1, the medical application of kutkin I is characterized in that the application in preparation treatment hepatitis B medicament.
2, purposes according to claim 1 is characterized in that the application of kutkin I in the acute and chronic hepatitis B medicament of preparation treatment.
3, medicine according to claim 1 is characterized in that containing the pharmaceutical composition that is used for the treatment of hepatitis B of Rhizoma Coptidis glycosides I.
4, pharmaceutical composition according to claim 3 is characterized in that said composition can be by administrations such as oral, Sublingual, percutaneous, muscle, subcutaneous, mucocutaneous, urethra, vagina, veins.
5, pharmaceutical composition according to claim 3, it is characterized in that said composition can exist with oral agents, injection and local administration preparation form, wherein oral agents comprises capsule, oral liquid, chewing agent, pill, tablet, granule etc., injection comprises injection dosage form and freeze-dried powder injection type etc., and local administration preparation comprises cream, ointment, patch, spray etc.
6, pharmaceutical composition according to claim 3 is characterized in that described kutkin I content surpasses 90%.
7,, it is characterized in that and can obtain by following method according to the described kutkin I of claim 1～6:
(1) extracts: dry rhizome or its pulverizing product of getting Rhizoma Picrorhizae (Picrorhiza scrophulariiflora Pennell) and India's Rhizoma Picrorhizae (Picrorhiza kurroa Royle ex Benth), water, ethanol, acetone equal solvent or its two kinds, the extraction of multiple mixed solvent, extracting solution be evaporated to below 70 ℃ dried, add water to suitable volume, the centrifugal precipitation of removing gets supernatant;
(2) separate: by the good adsorption column of conventional treatment, water and Different concentrations of alcohol eluting are respectively collected and are contained the thin layer inspection and know the eluent that kutkin I is arranged with the supernatant of gained, concentrating under reduced pressure, vacuum drying, pulverizing below 70 ℃, the kutkin I crude product;
(3) purification: with kutkin I crude product anhydrous alcohol solution, filter, filtrate is admixed silica gel, water-bath volatilizes solvent, loads on the silicagel column top, with the two mixed solvent eluting of ethyl acetate, acetone or its, collect effluent, drying under reduced pressure, pulverize the kutkin I sample.
8, preparation method according to claim 7 is characterized in that extracting method can use backflow, percolation or apparatus,Soxhlet's extracting method.
9, preparation method according to claim 7, the filler that it is characterized in that filling adsorption column used in the separation process can be the resin of nonpolar or low pole, as styrene type (comprising methyl styrene type, ethyl styrene type), acrylonitrile type resin etc.
10, preparation method according to claim 9 is characterized in that resin used in the separation process is D-101 type, ZTC type, AB-8 type.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100986464A CN100386087C (en) | 2004-12-15 | 2004-12-15 | Use of kutkin I in preparing drug for treating hepatitis B, its formulation and preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100986464A CN100386087C (en) | 2004-12-15 | 2004-12-15 | Use of kutkin I in preparing drug for treating hepatitis B, its formulation and preparation method |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2007101643215A Division CN101186627B (en) | 2004-12-15 | 2004-12-15 | Method for preparing picroside I |
| CNA2007101872816A Division CN101194911A (en) | 2004-12-15 | 2004-12-15 | Medicine composition for treating hepatitis B |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1788732A true CN1788732A (en) | 2006-06-21 |
| CN100386087C CN100386087C (en) | 2008-05-07 |
Family
ID=36786977
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100986464A Expired - Fee Related CN100386087C (en) | 2004-12-15 | 2004-12-15 | Use of kutkin I in preparing drug for treating hepatitis B, its formulation and preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100386087C (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102920831A (en) * | 2012-11-20 | 2013-02-13 | 济南康众医药科技开发有限公司 | Preparation method of rhizoma picrorhizae total saponins |
| CN104402950A (en) * | 2014-12-29 | 2015-03-11 | 济南东源生物医药技术有限公司 | Preparation method of kutkin I crystal |
| CN104693253A (en) * | 2015-03-30 | 2015-06-10 | 济南东源生物医药技术有限公司 | Industrial preparation method for high-purity 6'-O-trans-cinnamyl catalpol |
| CN112168834A (en) * | 2020-10-12 | 2021-01-05 | 上海中医药大学 | Application of picroside I in preparation of medicine for preventing and treating hepatic fibrosis |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5145955A (en) * | 1991-10-28 | 1992-09-08 | Council Of Scientific & Industrial Research | Process for the preparation and composition of a fraction containing picroside I and kutkoside |
| US6733800B1 (en) * | 1999-07-26 | 2004-05-11 | Ashok Rajgarhia | Synergistic composition for the treatment of liver and liver associated ailments and a process for preparing the same |
| CN1141101C (en) * | 2000-12-19 | 2004-03-10 | 吉林省力源药业股份有限公司 | Chinese medicine for treating hepatitis B and its preparing process |
| CN1458159A (en) * | 2002-05-15 | 2003-11-26 | 成都博瑞医药科技开发有限公司 | Process for preparing extract of picrorhiza iridoid glycoside |
-
2004
- 2004-12-15 CN CNB2004100986464A patent/CN100386087C/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102920831A (en) * | 2012-11-20 | 2013-02-13 | 济南康众医药科技开发有限公司 | Preparation method of rhizoma picrorhizae total saponins |
| CN102920831B (en) * | 2012-11-20 | 2014-07-23 | 济南康众医药科技开发有限公司 | Preparation method of rhizoma picrorhizae total saponins |
| CN104402950A (en) * | 2014-12-29 | 2015-03-11 | 济南东源生物医药技术有限公司 | Preparation method of kutkin I crystal |
| CN104402950B (en) * | 2014-12-29 | 2017-06-16 | 济南东源生物医药技术有限公司 | A kind of picroside Ⅰ crystallization preparation method |
| CN104693253A (en) * | 2015-03-30 | 2015-06-10 | 济南东源生物医药技术有限公司 | Industrial preparation method for high-purity 6'-O-trans-cinnamyl catalpol |
| CN112168834A (en) * | 2020-10-12 | 2021-01-05 | 上海中医药大学 | Application of picroside I in preparation of medicine for preventing and treating hepatic fibrosis |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100386087C (en) | 2008-05-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1977852B (en) | Medicinal composition containing stilbene total glycoside and its use for pharmaceutical treating hepatitis B | |
| CN101186627B (en) | Method for preparing picroside I | |
| CN1788732A (en) | Use of kutkin I in preparing drug for treating hepatitis B, its formulation and preparation method | |
| CN1478508A (en) | Chinese medicinal composition for treating fatty liver and its preparation method | |
| CN1739645A (en) | Infant Kechuanling Chinese medicine prepn for treating dyspneic cough and its prepn | |
| CN1116891C (en) | Hepatitis B treating medicine | |
| CN1506090A (en) | Rheum emodi wall extract and medicine composition with the extract as active component | |
| CN1931230A (en) | Isodon lophanthoides extract and its prepn process and application | |
| CN1682780A (en) | Medicine for treating uaemia and insufficiency of kidney-yang and kidney exhaustion and its preparing method | |
| CN100339090C (en) | Novel pomegranate leaf extract and medicinal use thereof | |
| CN1679658A (en) | Chinese medicine preparation for treating AIDS and process thereof | |
| CN101194911A (en) | Medicine composition for treating hepatitis B | |
| CN1730023A (en) | Hepatitis virus resistant Chinese medicinal formulation and method for preparing same | |
| CN1679693A (en) | Medicine for treating hepatopathy and preparation thereof | |
| CN1251745C (en) | Medicine for treating liver and biliary diseases and its preparing method | |
| CN1541691A (en) | Acute icterohepatitis treating Chinese traditional medicine and its preparation | |
| CN1111064C (en) | Hepatitis treating medicine and its production process | |
| CN1618430A (en) | Adefovir composite medicine for treating hepatitis B | |
| CN1543968A (en) | Drug prepared by mulberry bark extract | |
| CN1287834C (en) | Powder for treating coronary heart disease and angina pectoris and its preparing process | |
| CN1742798A (en) | Wuhaiyingliu preparation and new preparing method | |
| CN1251712C (en) | Chinese medicine composition for treating hepatitis and its preparing method | |
| CN1739732A (en) | Compound Chuanhuning prepn and its prepn process | |
| CN1718225A (en) | Compound traditional Chinese medicine for treating hepatic lesion, and its prepn. method | |
| CN1778308A (en) | Use of picrorrhiza glycoside II in preparation of medicine for treating hepatitis B |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| DD01 | Delivery of document by public notice |
Addressee: Zhou Yawei Document name: Notification to Pay the Fees |
|
| ASS | Succession or assignment of patent right |
Owner name: BEIDA SHIJIA TECHNOLOGY DEVELOPMENT CO., LTD. Free format text: FORMER OWNER: ZHOU YAWEI Effective date: 20150119 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 100080 HAIDIAN, BEIJING TO: 100084 HAIDIAN, BEIJING |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20150119 Address after: 100084 No. 123 North Main Street, Haidian District, Beijing, Zhongguancun Patentee after: Beida Shijia Technology Development Co.,Ltd. Address before: 100080 Beijing city Haidian District North Wei Xiu Yuan Building 1 room 106 17 Patentee before: Zhou Yawei |
|
| DD01 | Delivery of document by public notice |
Addressee: Zhou Yawei Document name: Notification of Passing Examination on Formalities |
|
| C56 | Change in the name or address of the patentee | ||
| CP02 | Change in the address of a patent holder |
Address after: 102206, 20 floor, No. 6, life road, Beijing, Changping District, 3 Patentee after: Beida Shijia Technology Development Co.,Ltd. Address before: 100084 No. 123 North Main Street, Haidian District, Beijing, Zhongguancun Patentee before: Beida Shijia Technology Development Co.,Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080507 |