CN100594898C - Pharmaceutical composition of Silybin and preparation method thereof - Google Patents
Pharmaceutical composition of Silybin and preparation method thereof Download PDFInfo
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- CN100594898C CN100594898C CN200510016032A CN200510016032A CN100594898C CN 100594898 C CN100594898 C CN 100594898C CN 200510016032 A CN200510016032 A CN 200510016032A CN 200510016032 A CN200510016032 A CN 200510016032A CN 100594898 C CN100594898 C CN 100594898C
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- silibinin
- phospholipid
- preparation
- pharmaceutical composition
- fluidizer
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- SEBFKMXJBCUCAI-UHFFFAOYSA-N NSC 227190 Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC=C(C=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-UHFFFAOYSA-N 0.000 title claims abstract description 66
- SEBFKMXJBCUCAI-HKTJVKLFSA-N silibinin Chemical group C1=C(O)C(OC)=CC([C@@H]2[C@H](OC3=CC=C(C=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-HKTJVKLFSA-N 0.000 title claims abstract description 66
- 235000014899 silybin Nutrition 0.000 title claims abstract description 65
- 238000002360 preparation method Methods 0.000 title claims description 36
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 25
- FDQAOULAVFHKBX-UHFFFAOYSA-N Isosilybin A Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC(=CC=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 FDQAOULAVFHKBX-UHFFFAOYSA-N 0.000 title abstract description 4
- VLGROHBNWZUINI-UHFFFAOYSA-N Silybin Natural products COc1cc(ccc1O)C2OC3C=C(C=CC3OC2CO)C4Oc5cc(O)cc(O)c5C(=O)C4O VLGROHBNWZUINI-UHFFFAOYSA-N 0.000 title abstract description 4
- 229940043175 silybin Drugs 0.000 title abstract description 4
- 229950000628 silibinin Drugs 0.000 claims description 61
- 150000003904 phospholipids Chemical class 0.000 claims description 26
- 238000001035 drying Methods 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- 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 claims description 9
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 9
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 9
- 238000005469 granulation Methods 0.000 claims description 9
- 230000003179 granulation Effects 0.000 claims description 9
- 239000008101 lactose Substances 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 8
- 238000005352 clarification Methods 0.000 claims description 8
- 235000010445 lecithin Nutrition 0.000 claims description 8
- 239000000787 lecithin Substances 0.000 claims description 8
- 229940067606 lecithin Drugs 0.000 claims description 8
- 239000007921 spray Substances 0.000 claims description 8
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 7
- 239000008347 soybean phospholipid Substances 0.000 claims description 7
- 239000002671 adjuvant Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000000945 filler Substances 0.000 claims description 6
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 2
- 239000002775 capsule Substances 0.000 abstract description 22
- 239000003814 drug Substances 0.000 abstract description 16
- 238000000034 method Methods 0.000 abstract description 13
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- -1 phosphatidy lcholine compound Chemical class 0.000 abstract description 4
- 239000000047 product Substances 0.000 description 13
- 238000011049 filling Methods 0.000 description 12
- 238000004090 dissolution Methods 0.000 description 11
- 206010013786 Dry skin Diseases 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000012856 packing Methods 0.000 description 6
- 239000007788 liquid Substances 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
- 210000000170 cell membrane Anatomy 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000011978 dissolution method Methods 0.000 description 2
- 150000002327 glycerophospholipids Chemical class 0.000 description 2
- 235000019359 magnesium stearate Nutrition 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
- 239000003921 oil Substances 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 230000007096 poisonous effect Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- LRYZPFWEZHSTHD-HEFFAWAOSA-O 2-[[(e,2s,3r)-2-formamido-3-hydroxyoctadec-4-enoxy]-hydroxyphosphoryl]oxyethyl-trimethylazanium Chemical class CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](NC=O)COP(O)(=O)OCC[N+](C)(C)C LRYZPFWEZHSTHD-HEFFAWAOSA-O 0.000 description 1
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 description 1
- VAJVDSVGBWFCLW-UHFFFAOYSA-N 3-Phenyl-1-propanol Chemical compound OCCCC1=CC=CC=C1 VAJVDSVGBWFCLW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000008964 Chemical and Drug Induced Liver Injury Diseases 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 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
- 206010072268 Drug-induced liver injury Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- UQOFGTXDASPNLL-XHNCKOQMSA-N Muscarine Chemical compound C[C@@H]1O[C@H](C[N+](C)(C)C)C[C@H]1O UQOFGTXDASPNLL-XHNCKOQMSA-N 0.000 description 1
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropyl alcohol Natural products CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 description 1
- ZONYXWQDUYMKFB-UHFFFAOYSA-N SJ000286395 Natural products O1C2=CC=CC=C2C(=O)CC1C1=CC=CC=C1 ZONYXWQDUYMKFB-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000320380 Silybum Species 0.000 description 1
- 244000272459 Silybum marianum Species 0.000 description 1
- 235000010841 Silybum marianum Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- LRCFXGAMWKDGLA-UHFFFAOYSA-N dioxosilane;hydrate Chemical compound O.O=[Si]=O LRCFXGAMWKDGLA-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000594 drug induced liver disease Toxicity 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004665 fatty acids Chemical group 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 229930003949 flavanone Natural products 0.000 description 1
- 150000002208 flavanones Chemical class 0.000 description 1
- 235000011981 flavanones Nutrition 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- LBEZAAAVJBINPH-UHFFFAOYSA-N mucronatine Natural products CN1C(OC)=NC(N)=C2N=CN=C21 LBEZAAAVJBINPH-UHFFFAOYSA-N 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 229940042880 natural phospholipid Drugs 0.000 description 1
- 235000014593 oils and fats Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 229940067626 phosphatidylinositols Drugs 0.000 description 1
- 150000004291 polyenes Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 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
- 238000000926 separation method Methods 0.000 description 1
- 229960004029 silicic acid Drugs 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 229960004245 silymarin Drugs 0.000 description 1
- 235000017700 silymarin Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- BCJMNZRQJAVDLD-FXGRWVCYSA-N usaramine Chemical compound O1C(=O)C(=C/C)/C[C@@H](C)[C@](O)(CO)C(=O)OCC2=CCN3[C@H]2[C@H]1CC3 BCJMNZRQJAVDLD-FXGRWVCYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a silybin and phosphatidy lcholine compound which is prepared into capsules with high dissolving degree. The invention also provides a process for preparing the silybin and phosphatidy lcholine compound and its capsule medicament, the preparing process is characterized by simple manufacturing method, high yield and fitting for mass production.
Description
Technical field
The present invention relates to medicinal composition, preparation and preparation method thereof field, particularly silibinin drug complex, preparation and preparation method thereof.
Technical background
20th century 60-80 age end, with H.wagner is West Germany pharmacy man its effective ingredient of extraction separation from Compositae Silybum plant Herba Silybi mariani (Silybum marianum) fruit of representative, be referred to as silymarin, be a class novel have a substituent flavone compound of C-9, i.e. the flavanolignan's class that forms with the plain analog derivative condensation of the pure and mild phenylpropyl alcohol of flavanone.(Silybin silibinin) is one of the main component of Herba Silybi mariani to silibinin.Through pharmacology and toxicological study, show that it has significant protection and stablizes liver plasma membrane, promote hepatocyte to recover, improve the effect of liver function.To various poisonous substances, the hepatic injury that causes as carbon tetrachloride, thioacetamide, muscarine, phallodine, mucronatine etc. all has protection therapeutical effect in various degree.Can be used for acute, chronic hepatitis, early stage liver cirrhosis, fatty liver, toxic or drug-induced liver disease.
Because silibinin is insoluble in water and common organic solvents, oral absorption is poor, and its bioavailability is lower, thereby has influenced its clinical efficacy.For improving its bioavailability, the pharmacy worker has done a large amount of work both at home and abroad.The measure that improves the insoluble drug absorption generally has superfine grinding, salify, adds cosolvent etc.Adopt in recent years and make cyclodextrin clathrate, solid dispersion, the synthetic phospholipid complex is made methods such as different dosage form, studies show that, dissolution and bioavailability improve greatly.
From the solid preparation angle, phosphatide complexes is a kind of comparatively special solid dispersion, he has fixed fusing point, be that a kind of its chemical nature is more stable, the molecular compound (complex) that is different from medicine and phospholipid, this compounds is difference with the difference of phospholipid kind and medicine phospholipid ratio, phospholipid molecule can with the drug molecule combination of different numbers.Complex spectroscopy feature is inferred, stronger interaction has partly taken place in the polar group of medicine and phospholipid, suppressed freely rotating of strand in the molecule, and two length fatty acids chains of phospholipid do not participate in compound reaction, can move freely, the polarity of having wrapped up phospholipid partly forms a lipophilic surface, and it is stronger fat-soluble that complex is shown.It has changed the physicochemical property of medicine, makes the fat-soluble increase of medicine, and water solublity reduces.Promote drug molecule to combine and promote to absorb the raising bioavailability of medicament with cell membrane.
(SLC complex preparation technology relatively for Xu Jianwen etc., China's biochemical drug magazine-2002 year 5 phases, 245-246) a kind of SLC complex and preparation method thereof is disclosed, this complex is made up of silibinin and lecithin, and preparation method is as follows: take by weighing silibinin 43g, dissolve among the ethanol 1350ml, get red clear liquid, add lecithin 68g, heated and stirred all is dissolved to clear and bright until lecithin, about 5-6min, take back the stream device, 55 ℃ of reaction 1h tear reflux open, the evaporation and concentration while vibrating, immediately among the impouring normal hexane 3150ml, the solution upper strata is yellow turbid liquid when treating that liquid volume is evaporated to 270ml, and lower floor is a red oil, get red oil, vacuum drying gets red dry thing 30g, and yield is 27%.This method complicated operation, productive rate is low, has been suitable for poisonous and hazardous solvent, does not possess industrial application value, and does not disclose the method for making the preparation that is fit to clinical practice.
Summary of the invention
The technical problem that is solved
The invention provides a kind of Pharmaceutical composition of silibinin, and make preparation, said preparation dissolution height, be suitable for oral, and convenient clinical use; The present invention also provides Pharmaceutical composition of this silibinin and preparation method thereof, and this preparation method technology is simple, productive rate is high, is suitable for large-scale production, and can satisfy the requirement of GSP (GMP).
Technical scheme
A kind of Pharmaceutical composition of silibinin comprises silibinin, phospholipid and adjuvant, and wherein the weight sum of silibinin and phospholipid accounts for the 10-60% of composition total weight, and the ratio of the weight of silibinin and phospholipid is 1: 1-40.
The Pharmaceutical composition of this silibinin, phospholipid has wherein changed the physicochemical property of medicine, makes the fat-soluble increase of medicine, promotes drug molecule to combine with cell membrane and promote to absorb the raising bioavailability of medicament.The above-mentioned percentage range of the combination of these components and each component determines that by a large amount of tests combinations thereof and percentage range make the Pharmaceutical composition of silibinin of the present invention have good dissolution, its bioavailability height.
In the Pharmaceutical composition of above-mentioned silibinin, the weight sum preferable range of silibinin and phospholipid is the 30-50% that accounts for composition total weight, most preferably 40%.The ratio of the weight of silibinin and phospholipid is preferably 1: 1.5-4, most preferably 7: 13.
Used phospholipid can be any phospholipid in the Pharmaceutical composition of silibinin of the present invention, for example phosphoglyceride and sphingomyelins, phosphoglyceride such as phosphatidylcholine (claim not only lecithin), PHOSPHATIDYL ETHANOLAMINE (but also claiming cephalin), Phosphatidylserine, phosphatidyl glycerol, phosphatidylinositols, polyene phosphatidylcholine, cuorin etc., phospholipid can be synthetic or natural phospholipid, for example egg yolk lecithin and soybean phospholipid etc. are preferably based on the soybean phospholipid or the lecithin of phosphatidylcholine.
In the Pharmaceutical composition of above-mentioned silibinin, adjuvant includes but not limited to filler, fluidizer and disintegrating agent, filler accounts for the 10-50% (w/w) of compositions, preferred 40% (w/w), fluidizer accounts for the 10-30% (w/w) of compositions, preferred 15% (w/w), disintegrating agent account for the 1-30% (w/w) of compositions, preferred 5% (w/w).Filler includes but not limited to maltose, microcrystalline Cellulose, glucose, lactose, sucrose, dextrin and starch etc., may be used alone, can also be used in combination, preferred lactose; Fluidizer includes but not limited to micropowder silica gel, Pulvis Talci, hydrated silica gel acid sodium, magnesium stearate etc., may be used alone, can also be used in combination the preferably talc powder; Disintegrating agent includes but not limited to microcrystalline Cellulose, magnesium stearate, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose etc., may be used alone, can also be used in combination, preferred carboxymethylstach sodium (CMS).
The present invention also provides the pharmaceutical combination preparation of above-mentioned silibinin, can be the oral formulations of any pharmaceutically acceptable, suitable clinical practice, as capsule or tablet, and preferred capsule preparations.
The present invention also provides the above-mentioned preparation method that contains the Pharmaceutical composition of silibinin:
1) gets an amount of silibinin and phospholipid;
2) add dehydrated alcohol, latter's volume (ml) is silibinin and phospholipid quality summation (g) 5-15 a times, and reflux makes the solution clarification;
3) be evaporated to the stiff shape;
4) add adjuvant, carry out the one-step palletizing drying, sieve and pulverize.
Wherein, step 2) volume (ml) that adds dehydrated alcohol in be preferably silibinin and phospholipid quality (g) summation 6-8 doubly, most preferably 6 times.
Wherein, the temperature of step 3) concentrating under reduced pressure is 40-80 ℃, and preferred 50-70 ℃, under said temperature, the liquid concurrent mixture rate of drying of silibinin-phospholipid can reach 60kg/ hour.
Wherein, the one-step palletizing drying of step 4) is the spray granulation drying, and temperature is 50-75 ℃, preferred 65 ℃.
Beneficial effect
The invention provides pharmaceutical composition that contains silibinin and preparation method thereof, this method has been used the solvent of nonhazardous, meets medicinal requirements; And the yield height of silibinin can reach 98%; Adopt the one-step palletizing dry technology, technological process is simple, and the production cycle shortens, can enhance productivity, and GMP compatible; Good product mobility, the dissolution height on average reaches 98.5%, the dissolution homogeneous.Solved the large-scale industrial production problem of the Pharmaceutical composition of silibinin.
The specific embodiment
Below further specify the present invention with embodiment, but therefore do not limit the present invention in the specific embodiment scope.
Dissolution method adopts dissolution method first method of two appendix XC of Pharmacopoeia of People's Republic of China version in 2005.
Embodiment 1
The preparation of silibinin
It is a certain amount of to get the silibinin seed, pulverizes and uses ethyl acetate extraction 20 hours in the rearmounted apparatus,Soxhlet's, and extracting solution is concentrated in rotary evaporator, reclaims solvent, gets pale brown color extractum, with the surperficial oils and fats of petroleum ether, gets paste silibinin crude product.Through defat, recrystallization, drying, get silibinin 350g again.
The preparation of silibinin Pharmaceutical composition
Silibinin 350g and soybean phospholipid 650g add the dehydrated alcohol of 6000ml, reflux makes the solution clarification, 60 ℃ are evaporated to the stiff shape, add lactose 1000g, Pulvis Talci 375g, carboxymethylstach sodium (CMS) 125g, 65 ℃ of spray granulation dryings, mistakes are sieved for No. 2, pulverize, get capsule filling, divide the capsule of packing into to make 10000 of finished products altogether.Make 3 batches of products altogether by above method, the capsule filling yield is respectively 97.0%, 97.2% and 97.2%, and dissolution is respectively 97.4%, 97.9% and 98.1%.
Embodiment 2
The preparation of silibinin is with embodiment 1
The preparation of silibinin Pharmaceutical composition
Silibinin 350g and soybean phospholipid 350g add the dehydrated alcohol of 3500ml, reflux makes the solution clarification, 40 ℃ are evaporated to the stiff shape, add lactose 460g, Pulvis Talci 70g, carboxymethylstach sodium (CMS) 70g, 50 ℃ of spray granulation dryings, mistakes are sieved for No. 2, pulverize, get capsule filling, divide the capsule of packing into to make 10000 of finished products altogether.Make 3 batches of products altogether by above method, the capsule filling yield is respectively 97.5%, 97.3% and 97.2%, and dissolution is respectively 97.7%, 97.9% and 98.3%.
Embodiment 3
The preparation of silibinin is with embodiment 1
The preparation of silibinin Pharmaceutical composition
Silibinin 350g and lecithin 14000g add the dehydrated alcohol of 86100ml, reflux makes the solution clarification, 80 ℃ are evaporated to the stiff shape, add lactose 70000g, Pulvis Talci 40000g, carboxymethylstach sodium (CMS) 19150g, 50 ℃ of spray granulation dryings, mistakes are sieved for No. 2, pulverize, get capsule filling, divide the capsule of packing into to make 10000 of finished products altogether.Make 3 batches of products altogether by above method, the capsule filling yield is respectively 97.5%, 97.4% and 97.1%, and dissolution is respectively 97.8%, 98.0% and 98.5%.
Embodiment 4
The preparation of silibinin is with embodiment 1
The preparation of silibinin Pharmaceutical composition
Silibinin 350g and lecithin 1400g add the dehydrated alcohol of 20500ml, reflux makes the solution clarification, 50 ℃ are evaporated to the stiff shape, add lactose 600g, Pulvis Talci 300g, carboxymethylstach sodium (CMS) 350g, 65 ℃ of spray granulation dryings, mistakes are sieved for No. 2, pulverize, get capsule filling, divide the capsule of packing into to make 10000 of finished products altogether.Make 3 batches of products altogether by above method, the capsule filling yield is respectively 97.5%, 97.3% and 97.2%, and dissolution is respectively 97.8%, 97.9% and 98.3%.
Embodiment 5
The preparation of silibinin is with embodiment 1
The preparation of silibinin Pharmaceutical composition
Silibinin 350g and soybean phospholipid 650g add the dehydrated alcohol of 10500ml, reflux makes the solution clarification, 60 ℃ are evaporated to the stiff shape, add lactose 1000g, Pulvis Talci 375g, carboxymethylstach sodium (CMS) 125g, 75 ℃ of spray granulation dryings, mistakes are sieved for No. 2, pulverize, get capsule filling, divide the capsule of packing into to make 10000 of finished products altogether.Make 3 batches of products altogether by above method, the capsule filling yield is respectively 97.4%, 97.5% and 97.2%, and dissolution is respectively 97.9%, 98.2% and 98.3%.
Embodiment 6
The preparation of silibinin is with embodiment 1
The preparation of silibinin Pharmaceutical composition
Silibinin 350g and soybean phospholipid 650g add the dehydrated alcohol of 6000ml, reflux makes the solution clarification, 60 ℃ are evaporated to the stiff shape, add lactose 1000g, Pulvis Talci 375g, carboxymethylstach sodium (CMS) 125g, 65 ℃ of spray granulation dryings, mistakes are sieved for No. 2, pulverize, get capsule filling, divide the capsule of packing into to make 10000 of finished products altogether.Make 3 batches of products altogether by above method, the capsule filling yield is respectively 97.5%, 97.5% and 97.0%, and dissolution is respectively 97.5%, 98.0% and 98.1%.
Claims (6)
1. the Pharmaceutical composition of a silibinin, comprise silibinin, phospholipid and adjuvant, phospholipid wherein is based on the soybean phospholipid of phosphatidylcholine or lecithin, adjuvant is filler, fluidizer and disintegrating agent, filler wherein is a lactose, fluidizer is that Pulvis Talci and disintegrating agent are carboxymethyl starch sodium; Wherein the weight sum of silibinin and phospholipid accounts for 40% of composition total weight, and the ratio of the weight of silibinin and phospholipid is 7: 13, and filler, fluidizer and disintegrating agent account for 40%, 15% and 5% of composition total weight respectively.
2. the pharmaceutical combination preparation of a silibinin is incapsulated by the Pharmaceutical composition of the silibinin of claim 1 and to make.
3. the preparation method of the Pharmaceutical composition of the silibinin of claim 1 comprises the following steps:
1) gets silibinin and phospholipid;
2) add dehydrated alcohol, latter's volume is silibinin and phospholipid quality summation 5-15 a times, and wherein volume is in ml, and quality is in g, and reflux makes the solution clarification;
3) be evaporated to the stiff shape;
4) add adjuvant, carry out the one-step palletizing drying, sieve and pulverize.
4. the preparation method of the Pharmaceutical composition of the silibinin of claim 3, wherein the temperature of the concentrating under reduced pressure of step 3) is 40-80 ℃.
5. the preparation method of the Pharmaceutical composition of the silibinin of claim 3, wherein the one-step palletizing drying of step 4) is the spray granulation drying.
6. the preparation method of the Pharmaceutical composition of the silibinin of claim 3, wherein the exsiccant temperature of the granulation of step 4) is 50-75 ℃.
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| US10376490B2 (en) | 2015-03-23 | 2019-08-13 | Tasly Pharmaceutical Group Co., Ltd. | Pharmaceutical composition containing silybin |
| CN114146085A (en) * | 2021-12-02 | 2022-03-08 | 江苏海洋大学 | Preparation method of silybin-polyene phosphatidylcholine compound |
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| CN102772308B (en) * | 2012-08-14 | 2013-09-18 | 惠州市九惠制药股份有限公司 | Silymarin phospholipid compound, mask containing same and preparation method of same |
| CN103751799A (en) * | 2014-01-27 | 2014-04-30 | 江苏健佳药业有限公司 | Phospholipid complex of silybum marianum extract and preparation method for phospholipid complex |
| CN103751798A (en) * | 2014-01-27 | 2014-04-30 | 江苏健佳药业有限公司 | Silybin-phospholipid complex and preparation method thereof |
| CN103751785A (en) * | 2014-01-27 | 2014-04-30 | 江苏健佳药业有限公司 | Silymarin-phospholipid complex and preparation method thereof |
| CN105816422B (en) | 2015-01-05 | 2020-08-14 | 天士力医药集团股份有限公司 | Silibinin injection and preparation method thereof |
| CN105983018B (en) * | 2015-03-23 | 2022-06-03 | 天士力医药集团股份有限公司 | A pharmaceutical composition containing silibinin |
| CN105853374B (en) * | 2016-04-26 | 2018-06-26 | 江苏中兴药业有限公司 | A kind of preparation method of silybin-phospholipid complex |
| KR102394648B1 (en) * | 2019-03-25 | 2022-05-09 | (주)아모레퍼시픽 | Composition for enhancing bioavailability of silymarin |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US10376490B2 (en) | 2015-03-23 | 2019-08-13 | Tasly Pharmaceutical Group Co., Ltd. | Pharmaceutical composition containing silybin |
| CN114146085A (en) * | 2021-12-02 | 2022-03-08 | 江苏海洋大学 | Preparation method of silybin-polyene phosphatidylcholine compound |
| CN114146085B (en) * | 2021-12-02 | 2023-11-10 | 江苏海洋大学 | Preparation method of silybin-polyene phosphatidylcholine compound |
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