CN1679542A - Frozen powder injection of silybin and its preparing method - Google Patents
Frozen powder injection of silybin and its preparing method Download PDFInfo
- Publication number
- CN1679542A CN1679542A CN 200410023873 CN200410023873A CN1679542A CN 1679542 A CN1679542 A CN 1679542A CN 200410023873 CN200410023873 CN 200410023873 CN 200410023873 A CN200410023873 A CN 200410023873A CN 1679542 A CN1679542 A CN 1679542A
- Authority
- CN
- China
- Prior art keywords
- silibinin
- phase
- salt
- dried powder
- freeze
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 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 97
- SEBFKMXJBCUCAI-HKTJVKLFSA-N silibinin Chemical compound 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 97
- 235000014899 silybin Nutrition 0.000 title claims abstract description 94
- 239000000843 powder Substances 0.000 title claims abstract description 40
- 238000002347 injection Methods 0.000 title claims abstract description 17
- 239000007924 injection Substances 0.000 title claims abstract description 17
- 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 claims description 53
- 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 claims description 53
- 229940043175 silybin Drugs 0.000 title claims description 53
- 238000000034 method Methods 0.000 title claims description 10
- 229950000628 silibinin Drugs 0.000 claims abstract description 41
- 239000002904 solvent Substances 0.000 claims abstract description 13
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 41
- 229960003194 meglumine Drugs 0.000 claims description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- 238000002360 preparation method Methods 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 23
- -1 silibinin inorganic base salts Chemical class 0.000 claims description 23
- 239000000243 solution Substances 0.000 claims description 18
- 238000004108 freeze drying Methods 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 15
- 238000012856 packing Methods 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- 239000012982 microporous membrane Substances 0.000 claims description 10
- 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 claims description 6
- 229930195725 Mannitol Natural products 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000000594 mannitol Substances 0.000 claims description 6
- 235000010355 mannitol Nutrition 0.000 claims description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- 239000004475 Arginine Substances 0.000 claims description 5
- 150000001447 alkali salts Chemical class 0.000 claims description 5
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 5
- 238000011082 depyrogenation Methods 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 5
- 238000007710 freezing Methods 0.000 claims description 5
- 230000008014 freezing Effects 0.000 claims description 5
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 5
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 5
- 230000001954 sterilising effect Effects 0.000 claims description 5
- 238000004659 sterilization and disinfection Methods 0.000 claims description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000003963 antioxidant agent Substances 0.000 claims description 4
- 230000003078 antioxidant effect Effects 0.000 claims description 4
- 235000006708 antioxidants Nutrition 0.000 claims description 4
- 230000000536 complexating effect Effects 0.000 claims description 4
- 229910021645 metal ion Inorganic materials 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 4
- 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 3
- 239000008101 lactose Substances 0.000 claims description 3
- 235000010265 sodium sulphite Nutrition 0.000 claims description 3
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 229920000858 Cyclodextrin Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 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 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 2
- 229930003268 Vitamin C Natural products 0.000 claims description 2
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims description 2
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 2
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 2
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 2
- 239000008176 lyophilized powder Substances 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-M lysinate Chemical compound NCCCCC(N)C([O-])=O KDXKERNSBIXSRK-UHFFFAOYSA-M 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 claims description 2
- 235000019154 vitamin C Nutrition 0.000 claims description 2
- 239000011718 vitamin C Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 abstract description 2
- 150000001413 amino acids Chemical class 0.000 abstract 1
- 159000000011 group IA salts Chemical class 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 12
- 239000003814 drug Substances 0.000 description 10
- 101710098398 Probable alanine aminotransferase, mitochondrial Proteins 0.000 description 9
- 238000005303 weighing Methods 0.000 description 9
- 241000700159 Rattus Species 0.000 description 7
- 235000011121 sodium hydroxide Nutrition 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- JMZOMFYRADAWOG-UHFFFAOYSA-N methyl 7-methoxy-4-(7-methoxy-5-methoxycarbonyl-1,3-benzodioxol-4-yl)-1,3-benzodioxole-5-carboxylate Chemical compound COC(=O)C1=CC(OC)=C2OCOC2=C1C1=C2OCOC2=C(OC)C=C1C(=O)OC JMZOMFYRADAWOG-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 208000006454 hepatitis Diseases 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229960004245 silymarin Drugs 0.000 description 3
- 235000017700 silymarin Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 208000007788 Acute Liver Failure Diseases 0.000 description 2
- 206010000804 Acute hepatic failure Diseases 0.000 description 2
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 2
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 2
- 206010008909 Chronic Hepatitis Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 238000010241 blood sampling Methods 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000007919 dispersible tablet Substances 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 231100000753 hepatic injury Toxicity 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 210000004279 orbit Anatomy 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- SEBFKMXJBCUCAI-WAABAYLZSA-N (2r,3r)-3,5,7-trihydroxy-2-[(2s,3s)-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-2,3-dihydrochromen-4-one Chemical compound 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-WAABAYLZSA-N 0.000 description 1
- 208000008964 Chemical and Drug Induced Liver Injury Diseases 0.000 description 1
- 235000008495 Chrysanthemum leucanthemum Nutrition 0.000 description 1
- 244000192528 Chrysanthemum parthenium Species 0.000 description 1
- 235000000604 Chrysanthemum parthenium Nutrition 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 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
- 210000001015 abdomen Anatomy 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 231100000354 acute hepatitis Toxicity 0.000 description 1
- 231100000836 acute liver failure Toxicity 0.000 description 1
- 102000011759 adducin Human genes 0.000 description 1
- 108010076723 adducin Proteins 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 235000008384 feverfew Nutrition 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 231100000748 severe hepatic injury Toxicity 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 239000000126 substance Substances 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
- 210000003462 vein Anatomy 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
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A freeze-dried powder injection of silibinin salt features that it contains silibinin salt which may be the inorganic or organic alkaline salt of silibinin or its salt of amino acid, the pH regulator and/or solubilizer.
Description
Technical field
The present invention relates to a kind of is effective ingredient with silibinin salt, and clinical freeze-dried powder that is used for the treatment of acute and chronic hepatitis and preparation method thereof relates to freeze-dried powder of the organic alkali salt of silibinin, inorganic base salts or alkaline amino acid salt and preparation method thereof particularly.
Background technology
Herba Silybi mariani is a feverfew, originates in southern Europe and north African, the hepatic disease that is used for the treatment of among the people.Nineteen sixty-eight Wagner etc. therefrom extracts a kind of flavone compound, called after silymarin (Silymarin), the main component that has now proved silymarin is silibinin (Silybin), its chemical name is: 2-(2,3-Dihydro-2-(4-hydroxy-3-methoxyphenyl)-3-(hydroxymethyl)-1,4-benzodioxin-6-yl)-2,3-dihydro-3,5,7-trihydroxy-4H-1-benzopyran-4-one, the clinical acute hepatitis that is used for, chronic hepatitis, first cirrhosis, fatty liver, toxic hepatitis (as taking prejudicial medicine of hepatocyte or frequent heavy drinking) protects the liver.Modern pharmacology studies show that silibinin has clear and definite protective effect to multiple hepatic injury.The silibinin salt of listing is for being silybin meglumine at present, and English name: Silybin Meglumine, its active component still are silibinin, but the dissolubility in water is far longer than silibinin.Existing kind is silybin meglumine tablets (national drug standards [WS-1001-(HD-0926)-2002]) on the silybin meglumine market, in addition, publication number be CN 1418637 A patent report a kind of " treatment hepatitis silybin meglumine dispersible tablet and preparation method thereof ".
Silibinin is water insoluble, and oral administration biaavailability is lower, is generally 20%～30%, and individual variation is bigger.Silybin meglumine is a weak acid and weak base salt, and water solublity is better, but still can separate out silibinin under acid condition.Separate out under one's belt after the silybin meglumine oral application, still can influence the absorption of silibinin.Can play therapeutical effect though take in a large number, can cause certain untoward reaction to take place,, also cause the waste of drug resource as the upper abdomen discomfort etc.In addition to some emergency and severe disease patients in when treatment, the speed that oral administration absorbs is slower, often delay treatment opportunity, causes unnecessary loss to the patient.The silybin meglumine dispersible tablet of silybin meglumine tablets in the national drug standards and patent report is oral administration, all has above-mentioned shortcoming.
Silybin meglumine is when the preparation lyophilized preparation, at first need to be mixed with aqueous solution, and the aqueous solution of silybin meglumine at ambient temperature, promptly becomes turbid in 30 minutes, can't satisfy production to the needs of time, dried frozen aquatic products in this case can't use clinically.
This patent has proposed the method for three head it offs, and the one, add solubilizing agent, the 2nd, regulate pH value, the 3rd, not only add solubilizing agent but also regulate pH; Thereby guarantee solution clear in 4 hours of preparation, satisfied the requirement of producing, simultaneously, meet clinical instructions for use behind the lyophilized preparation compatibility normal saline the time; In addition, the process using that this patent relates to lyophilization, production process is finished under the temperature the end of than, and the vacuum tamponade, makes stability of drug improve greatly.This patent has not only creatively solved silibinin aqueous solution short time internal haze, the problem that can't produce lyophilized preparation, and the preparation lyophilized preparation possess remarkable advantages, accord with the demands of the market.
The invention provides and be suitable for suitability for industrialized production, steady quality, be convenient to that transportation stores and can quick-dissolving silybin meglumine lyophilized preparation.
Summary of the invention
The invention provides silibinin salt freeze-dried powder.Silibinin salt can be silibinin inorganic base salts, the organic alkali salt of silibinin or silibinin amino acid salts.The silibinin inorganic base salts is selected from: silibinin sodium salt, silibinin potassium salt, silibinin ammonium salt; The organic alkali salt of silibinin is selected from: silybin-N-methylglucamine, silibinin amine salt; The silibinin amino acid salts is selected from: silibinin arginine salt, silibinin lysinate.Silibinin salt is preferably silybin meglumine.
The present invention also provides the preparation method of preparation Herba Silybi mariani freeze-dried powder.
Herba Silybi mariani freeze-dried powder provided by the invention contains PH regulator, solubilizing agent or its group.The PH regulator is selected from one or more in sodium hydroxide, potassium hydroxide, meglumine, sodium carbonate, the potassium carbonate; Solubilizing agent is selected from one or more in 2-HP-, beta-schardinger dextrin-, sulfobutyl ether-beta-schardinger dextrin-, alpha-cyclodextrin, gamma-cyclodextrin, polyvinylpyrrolidone, the Polyethylene Glycol.When freeze-dried powder provided by the invention added water to the lyophilized powder equal-volume, its pH value of aqueous solution was 7-12, is preferably 9-11.Freeze-dried powder provided by the invention can also contain one or more in excipient, antioxidant, the complexing of metal ion agent.Excipient is selected from one or more in mannitol, sucrose, lactose, arginine, lysine, glycine, sorbitol, the low molecular dextran; Antioxidant is selected from one or more in sodium thiosulfate, sodium sulfite, thiourea, the vitamin C; The complexing of metal ion agent is selected from one or more among EDTA-4Na, EDTA-2Na, the EDTA.
The preparation method of freeze-dried powder provided by the invention is: preparation contains the aqueous solution of solubilizing agent in proportion; Silibinin salt places the aqueous solution of above-mentioned solubilizing agent in proportion, stirs to make dissolving; Regulating pH value with the pH regulator agent is 7-12; By requirement sterilization, the depyrogenation of injection, filtering with microporous membrane, packing; Lyophilization.Lyophilization divided for three phases; The first phase, the quick freezing phase; Speed cooling with per minute 1-10 ℃ drops to-30 to-50 ℃ until solution temperature, keeps 2-5 hour; The second phase, the distillation phase (removing Free water); Evacuation makes vacuum between 50-500 μ bas, and temperature was kept 5-20 hour between-30 to-10 ℃; The third phase, the redrying phase (removing bound water).Vacuum remains on 50-500 μ bas, and temperature remains on 0-50 ℃, and this process was kept 2 to 10 hours; The vacuum tamponade, promptly.
The preparation method of freeze-dried powder provided by the invention is: get silibinin salt in proportion and place aqueous solution, regulating pH value with the pH regulator agent is 10-12; By requirement sterilization, the depyrogenation of injection, filtering with microporous membrane, packing; Lyophilization.Lyophilization divided for three phases.The first phase, the quick freezing phase.Speed cooling with per minute 1-10 ℃ drops to-30 to-50 ℃ 2 until solution temperature, keeps 2-5 hour; The second phase, the distillation phase (removing Free water).Evacuation makes vacuum between 50-500 μ bas, and temperature was kept 5-20 hour between-30 to-10 ℃; The third phase, the redrying phase (removing bound water).Vacuum remains on 50-500 μ bas, and temperature remains on 0-50 ℃, and this process was kept 2 to 10 hours.
Silybin meglumine lyophilized preparation involved in the present invention all complies with relevant regulations in the check of items such as content, pyrogen, antibacterial, pH value, clarity.
The specific embodiment
Embodiment 1:
Dosing: take by weighing silybin meglumine 500.00g, place container, add mannitol 100g, sodium sulfite 10g, EDTA-2Na0.5g adds water and makes dissolving in right amount, transfers pH to 10.5 with sodium hydroxide solution, adds water to 10000ml, stirs; Filtration, packing: adopt 0.22 μ filtering with microporous membrane, filtrate is by every 2.0ml packing; Lyophilization: the speed cooling with 5 ℃ of per minutes, be cooled to-40 ℃ until product, kept 3 hours; The beginning evacuation, control vacuum is at 100 ± 50 μ bas, and product temperature is controlled at-20 ℃, keeps 15 hours; Then, progressively be warming up to 20 ℃, control vacuum at 200 ± 50 μ bas, reach 20 ℃ 2 after, continued to keep 3 hours, the vacuum tamponade, promptly.
Embodiment 2:
Dosing: take by weighing 2-HP-100.00g, add water and make dissolving, take by weighing silybin meglumine 100.00g, place above-mentioned solution, stir; Add lactose 400g again, sodium thiosulfate 3.0g, EDTA-2Na0.5g stirs and makes dissolving, transfers pH to 9 with sodium hydroxide solution, adds water to 10000ml, stirs; Filtration, packing: adopt 0.22 μ filtering with microporous membrane, filtrate is by every 1.0ml packing; Lyophilization: the speed cooling with 5 ℃ of per minutes, be cooled to-40 ℃ until product, kept 3 hours; The beginning evacuation, control vacuum is at 100 ± 50 μ bas, and product temperature is controlled at-20 ℃, keeps 15 hours; Then, progressively be warming up to 20 ℃, control vacuum at 200 ± 50 μ bas, reach 20 ℃ 2 after, continued to keep 3 hours, the vacuum tamponade, promptly.
Embodiment 3:
Dosing: take by weighing 2-HP-50.00g, add water and make dissolving, take by weighing silybin meglumine 100.00g, place above-mentioned solution, stir; Add mannitol 400g again, sodium thiosulfate 5.0g, EDTA-2Na0.5g stirs and makes dissolving, transfers pH to 9.5 with sodium hydroxide solution, adds water to 10000ml, stirs; Filtration, packing: adopt 0.22 μ filtering with microporous membrane, filtrate is by every 2.0ml packing; Lyophilization: the speed cooling with 5 ℃ of per minutes, be cooled to-40 ℃ until product, kept 3 hours; The beginning evacuation, control vacuum is at 100 ± 50 μ bas, and product temperature is controlled at-20 ℃, keeps 15 hours; Then, progressively be warming up to 20 ℃, control vacuum at 200 ± 50 μ bas, reach 20 ℃ after, continued to keep 3 hours, the vacuum tamponade, promptly.
Embodiment 4:
Preparation silibinin sodium salt solution: take by weighing silibinin 24g, put in the reaction vessel, add 500ml water, adopt magnetic stirrer, slowly add sodium hydrate aqueous solution (1mol/L) 50ml while stirring, continue to be stirred to silibinin and dissolve fully; Dosing: take by weighing mannitol 40g, join in the top solution, stir and make dissolving, transfer pH to 10, add water to 1000ml, stir with sodium hydroxide solution; Filtration, packing: adopt 0.22 μ filtering with microporous membrane, filtrate is by every 2.0ml packing; Lyophilization: the speed cooling with 5 ℃ of per minutes, be cooled to-40 ℃ until product, kept 3 hours; The beginning evacuation, control vacuum is at 100 ± 50 μ bas, and product temperature is controlled at-20 ℃, keeps 15 hours; Then, progressively be warming up to 20 ℃, control vacuum at 200 ± 50 μ bas, reach 20 ℃ after, continued to keep 3 hours, the vacuum tamponade, promptly.
Embodiment 5:
Preparation silibinin arginine salt: take by weighing silibinin 4.8g, put in the reaction vessel, add 95% ethanol 100ml, adopt magnetic stirrer, slowly add simultaneously arginine aqueous solution (0.1mol/L) 120ml, suitably heating continues to be stirred to silibinin and dissolves fully, drying under reduced pressure gets the silibinin arginine.Dosing: take by weighing 2-HP-10g, add water 150ml and make dissolving.Get above-mentioned silibinin arginine and be added in this solution, add mannitol 10g again, sodium thiosulfate 0.1g transfers pH to 9.5 with sodium hydroxide solution, stirs and makes dissolving fully, adds water to 200ml, stirs; Filtration, packing: adopt 0.22 μ filtering with microporous membrane, filtrate is by every 1.0ml packing; Lyophilization: the speed cooling with 5 ℃ of per minutes, be cooled to-40 ℃ until product, kept 3 hours; The beginning evacuation, control vacuum is at 100 ± 50 μ bas, and product temperature is controlled at-20 ℃, keeps 15 hours; Then, progressively be warming up to 20 ℃, control vacuum at 200 ± 50 μ bas, reach 20 ℃ after, continued to keep 3 hours, the vacuum tamponade, promptly.
Test example 1: injection silybin meglumine lyophilized preparation and meglumine tablets effect are relatively
Experiment material:
Silybin meglumine freeze-dried powder (Silybin powder pin) is pressed embodiment 1 preparation, and 50mg/ props up, lot number: 20030911.Silybin meglumine tablets (Silybin sheet), Jiangsu Zhongxing Pharmaceutical Co., Ltd. produces, 50mg/ sheet, lot number: 20030803.Bifendate drop pill, Dezhou, Shandong Province pharmaceutical factory produces, 1.5mg/ ball, lot number: 030205.Glutamic oxaloacetic transaminase, GOT (GOT) is measured test kit, lot number: 20030501, and glutamate pyruvate transaminase (GPT) is measured test kit, lot number: 20030602, reitman-frankel method is measured, and Shanghai Rongsheng Bioisystech Co., Ltd produces.
Animal:
Kunming mouse, male, body weight 18 ~ 22g, Shandong Province's natural drug Engineering Technical Research Centre animal center provides, the quality certification number:
Experimental technique:
90 of mices are divided into 9 groups at random, 10 every group, are respectively normal group, model group, bifendate matched group, the high, medium and low dosage group of silybin meglumine tablets and the high, medium and low dosage group of silybin meglumine freeze-dried powder.
Bifendate drop pill and silybin meglumine tablets are made into the suspension of respective concentration with distilled water, and the silybin meglumine freeze-dried powder is made into respective concentration solution with the injection normal saline.Dosage 0.2ml/10g.
Normal group and model group mouse stomach are given distilled water, and each group of bifendate and silybin meglumine tablets is irritated the suspension that stomach gives relative medicine, and the silybin meglumine freeze-dried powder is respectively organized tail vein injection and given relative medicine, once a day, and successive administration 5 days.
After the administration in the 5th day, except that normal control group mice, each organizes the injection soybean oil solution that the equal lumbar injection of mice contains 0.1% carbon tetrachloride, 0.1ml/10g.Fasting immediately 16 hours, the eye socket blood sampling, separation of serum is measured GPT and GOT level.
Experimental result:
Table 1. silybin-N-methylglucamine tablet and lyophilized injectable powder are to CCl
4Cause the mouse liver injury protective effect relatively
| Group | Dosage (mg/kg) | ??GOT ??(U/L) | ????GPT ????(U/L) |
| Normal model DDB Silybin sheet Silybin sheet Silybin sheet Silybin powder pin Silybin powder pin Silybin powder pin | ????—— ????????—— ????????7.5 ????200 ????50 ????12.5 ????100 ????25 ????6.25 | ??11.8±4.9 ??115.2±61.8 ##??27.7±16.0 **??41.2±26.4 **??58.2±32.5 *??88.7±43.0 ??25.7±13.3 **??45.4±15.8 **??70.0±27.5 * | ????15.8±10.2 ????136.5-60.7 ##????28.3±15.9 **????46.3±22.4 **????72.2±33.0 **????107.5±38.9 ????29.7±18.7 **????60.6±33.1 **????90.3±30.6 * |
##, compare with normal group P＜0.01.
*, P＜0.05;
*, compare with model group P＜0.01.
Experimental result shows that therapeutic effect still obviously was better than the gastric infusion group when silybin meglumine drug administration by injection reduced by one times at dosage.
Test example 2: injection silybin meglumine lyophilized preparation and its tablet are to rat fulminant hepatic failure therapeutical effect comparative experiments material: silybin meglumine freeze-dried powder (Silybin powder pin), and press embodiment 1 and prepare, 50mg/ props up, lot number: 20030911.Silybin meglumine tablets (Silybin sheet), Jiangsu Zhongxing Pharmaceutical Co., Ltd. produces, 50mg/ sheet, lot number: 20030803.Bifendate drop pill, Dezhou, Shandong Province pharmaceutical factory produces, 1.5mg/ ball, lot number: 030205.Glutamic oxaloacetic transaminase, GOT (GOT) is measured test kit, lot number: 20030501, and glutamate pyruvate transaminase (GPT) is measured test kit, lot number: 20030602, reitman-frankel method is measured, and Shanghai Rongsheng Bioisystech Co., Ltd produces.Thioacetamide (TAA), the Sigma product.Animal: the Wistar rat, male, body weight 150 ~ 180g, Shandong Province's natural drug Engineering Technical Research Centre animal center provides, the quality certification number:
Experimental technique:
60 of rats, be divided into 5 groups at random, every group 10, be respectively normal group, model group, silybin meglumine tablets height (100mg/kg), low (25mg/kg) dosage group and silybin meglumine freeze-dried powder height (50mg/kg), low (12.5mg/kg) dosage group.
Bifendate drop pill and silybin meglumine tablets are made into the suspension of respective concentration with distilled water, and the silybin meglumine freeze-dried powder is made into respective concentration solution with the injection normal saline.Dosage 0.2ml/10g.
Model group and administration group rat skin lower injection TAA 600mg/kg 2 times, 24 hours at interval, normal rats was given the equivalent normal saline, after last gives TAA, gives relative medicine immediately, silybin meglumine tablets agent gastric infusion, freeze dried powder tail intravenously administrable.After 6 hours, each organizes the blood sampling of rat eye socket, and separation of serum is measured GPT and GOT level.
Experimental result:
Table 2. silybin-N-methylglucamine tablet and lyophilized injectable powder compare the protective effect that TAA causes rats'liver depletion
| Group | Dosage (mg/kg) | ??GOT ??(U/L) | ??GPT ??(U/L) |
| Normal model Silybin sheet Silybin sheet Silybin powder pin Silybin powder pin | ????—— ????????—— ????????100 ????25 ????50 ????12.5 | ??4.6±3.6 ??409.0±66.8 ##??365.9±56.9 ??377.3±64.5 ??292.3±68.2 *??339.7±64.5 * | ??4.6±3.6 ??500.1±134.9 ##??444.9±106.4 ??487.8±113.9 ??330.7±95.9 **??387.6±87.9 * |
##, compare with normal group P＜0.01.
*, P＜0.05;
*, compare with model group P＜0.01.
The result shows (seeing Table 2), and each dosage group of silybin meglumine freeze dried powder causes GOT after the rat acute liver failure and GPT to TAA and raises certain protective action is arranged, and the silybin meglumine tablets agent is not showing therapeutical effect under the high dose more yet.Illustrate that the silybin-N-methylglucamine drug administration by injection is better than oral administration to the therapeutic effect of acute severe liver injury.
Claims (10)
1. silibinin salt freeze-dried powder is characterised in that and contains PH regulator, solubilizing agent or its combination.
2. freeze-dried powder according to claim 1, silibinin salt can be silibinin inorganic base salts, the organic alkali salt of silibinin or silibinin amino acid salts; The silibinin inorganic base salts is selected from: silibinin sodium salt, silibinin potassium salt, silibinin ammonium salt; The organic alkali salt of silibinin is selected from: silybin-N-methylglucamine, silibinin amine salt; The silibinin amino acid salts is selected from: silibinin arginine salt, silibinin lysinate.
3. freeze-dried powder according to claim 2, silibinin salt is preferably silybin meglumine.
4. according to the arbitrary described freeze-dried powder of claim 1-3, the PH regulator is selected from one or more in sodium hydroxide, potassium hydroxide, meglumine, sodium carbonate, the potassium carbonate; Solubilizing agent is selected from one or more in 2-HP-, beta-schardinger dextrin-, sulfobutyl ether-beta-schardinger dextrin-, alpha-cyclodextrin, gamma-cyclodextrin, polyvinylpyrrolidone, the Polyethylene Glycol.
5. according to the arbitrary described freeze-dried powder of claim 1-3, be characterised in that its pH value of aqueous solution is 7-12 when adding water to freeze-dried powder with the lyophilized powder equal-volume.
6. according to the described freeze-dried powder of claim 1-3, it can also contain in excipient, antioxidant, the complexing of metal ion agent one or more.
7. freeze-dried powder according to claim 6, excipient is selected from one or more in mannitol, sucrose, lactose, arginine, lysine, glycine, sorbitol, the low molecular dextran; Antioxidant is selected from one or more in sodium thiosulfate, sodium sulfite, thiourea, the vitamin C; The complexing of metal ion agent is selected from one or more among EDTA-4Na, EDTA-2Na, the EDTA.
8. the preparation method of the arbitrary described freeze-dried powder of claim 1-7, form by following steps:
(1) prepares the aqueous solution that contains solubilizing agent in proportion;
(2) get the aqueous solution that silibinin salt places above-mentioned solubilizing agent in proportion, stir and make dissolving;
(3) regulating pH value with the pH regulator agent is 7-12;
(4) by requirement sterilization, the depyrogenation of injection, filtering with microporous membrane, packing;
(5) lyophilization.Lyophilization divided for three phases.The first phase, the quick freezing phase.Speed cooling with per minute 1-10 ℃ drops to-30 to-50 ℃ until solution temperature, keeps 2-5 hour; The second phase, the distillation phase (removing Free water).Evacuation makes vacuum between 50-500 μ bas, and temperature was kept 5-20 hour between-30 to-10 ℃; The third phase, the redrying phase (removing bound water).Vacuum remains on 50-500 μ bas, and temperature remains on 0-50 ℃, and this process was kept 2 to 10 hours.
(6) vacuum tamponade, promptly.
9. according to the preparation method of the arbitrary described silibinin salt lyophilized preparation of claim 1-7, be characterised in that:
(1) get silibinin salt in proportion and place aqueous solution, regulating pH value with the pH regulator agent is 10-12;
(2) by requirement sterilization, the depyrogenation of injection, filtering with microporous membrane, packing;
(3) lyophilization.Lyophilization divided for three phases.The first phase, the quick freezing phase.Speed cooling with per minute 1-10 ℃ drops to-30 to-50 ℃ until solution temperature, keeps 2-5 hour; The second phase, the distillation phase (removing Free water).Evacuation makes vacuum between 50-500 μ bas, and temperature was kept 5-20 hour between-30 to-10 ℃; The third phase, the redrying phase (removing bound water).Vacuum remains on 50-500 μ bas, and temperature remains on 0-50 ℃, and this process was kept 2 to 10 hours.
10. the preparation method of the arbitrary described freeze-dried powder of claim 1-7, form by following steps:
(1) prepares the aqueous solution that contains solubilizing agent in proportion;
(2) get the aqueous solution that silibinin salt places above-mentioned solubilizing agent in proportion, stir and make dissolving;
(3) by requirement sterilization, the depyrogenation of injection, filtering with microporous membrane, packing;
(4) lyophilization.Lyophilization divided for three phases.The first phase, the quick freezing phase.Speed cooling with per minute 1-10 ℃ drops to-30 to-50 ℃ until solution temperature, keeps 2-5 hour; The second phase, the distillation phase (removing Free water).Evacuation makes vacuum between 50-500 μ bas, and temperature was kept 5-20 hour between-30 to-10 ℃; The third phase, the redrying phase (removing bound water).Vacuum remains on 50-500 μ bas, and temperature remains on 0-50 ℃, and this process was kept 2 to 10 hours.
(5) vacuum tamponade, promptly.
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| CN101244041B (en) * | 2007-02-13 | 2011-04-06 | 广州安健实业发展有限公司 | Medicament for preventing and treating acute liver damnification and preparation thereof |
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