CN102309441B - Silymarin medicinal composition wrapper and preparation method thereof - Google Patents
Silymarin medicinal composition wrapper and preparation method thereof Download PDFInfo
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- CN102309441B CN102309441B CN201010222910.6A CN201010222910A CN102309441B CN 102309441 B CN102309441 B CN 102309441B CN 201010222910 A CN201010222910 A CN 201010222910A CN 102309441 B CN102309441 B CN 102309441B
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- silybin
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- 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 190
- 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 165
- 238000002360 preparation method Methods 0.000 title claims abstract description 83
- 239000000203 mixture Substances 0.000 title claims abstract description 55
- 229960004245 silymarin Drugs 0.000 title claims abstract description 23
- 235000017700 silymarin Nutrition 0.000 title claims abstract description 23
- 239000000243 solution Substances 0.000 claims abstract description 68
- 239000002904 solvent Substances 0.000 claims abstract description 68
- 229940090044 injection Drugs 0.000 claims abstract description 57
- 238000002347 injection Methods 0.000 claims abstract description 57
- 239000007924 injection Substances 0.000 claims abstract description 57
- 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 claims abstract description 56
- 239000012155 injection solvent Substances 0.000 claims abstract description 39
- 239000003814 drug Substances 0.000 claims abstract description 37
- 229940093181 glucose injection Drugs 0.000 claims abstract description 31
- 235000014899 silybin Nutrition 0.000 claims description 141
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 129
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 100
- 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 claims description 90
- VLGROHBNWZUINI-UHFFFAOYSA-N Silybin Natural products COc1cc(ccc1O)C2OC3C=C(C=CC3OC2CO)C4Oc5cc(O)cc(O)c5C(=O)C4O VLGROHBNWZUINI-UHFFFAOYSA-N 0.000 claims description 88
- 229940043175 silybin Drugs 0.000 claims description 88
- 239000003978 infusion fluid Substances 0.000 claims description 86
- 230000001954 sterilising effect Effects 0.000 claims description 80
- 229950000628 silibinin Drugs 0.000 claims description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 44
- 239000008215 water for injection Substances 0.000 claims description 43
- 150000003904 phospholipids Chemical class 0.000 claims description 34
- 239000000787 lecithin Substances 0.000 claims description 32
- 235000010445 lecithin Nutrition 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 26
- 102000002322 Egg Proteins Human genes 0.000 claims description 14
- 108010000912 Egg Proteins Proteins 0.000 claims description 14
- 241000287828 Gallus gallus Species 0.000 claims description 14
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 14
- 210000004681 ovum Anatomy 0.000 claims description 14
- 239000000470 constituent Substances 0.000 claims description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- 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 11
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 11
- 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 11
- 229960003511 macrogol Drugs 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 11
- 229940083466 soybean lecithin Drugs 0.000 claims description 11
- 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 10
- 229940067606 lecithin Drugs 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 9
- 238000004806 packaging method and process Methods 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 claims description 9
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 8
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 7
- 229940099352 cholate Drugs 0.000 claims description 7
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 7
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 claims description 6
- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 claims description 6
- 229960004756 ethanol Drugs 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 238000002390 rotary evaporation Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- FKJIJBSJQSMPTI-CAOXKPNISA-M sodium;(4r)-4-[(5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-3,7,12-trioxo-1,2,4,5,6,8,9,11,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl]pentanoate Chemical compound [Na+].C1CC(=O)C[C@H]2CC(=O)[C@H]3[C@@H]4CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]4(C)C(=O)C[C@@H]3[C@]21C FKJIJBSJQSMPTI-CAOXKPNISA-M 0.000 claims description 5
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 4
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 claims description 3
- 229960001091 chenodeoxycholic acid Drugs 0.000 claims description 3
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 claims description 2
- 239000008103 glucose Substances 0.000 abstract description 25
- 230000000694 effects Effects 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 88
- 229910052757 nitrogen Inorganic materials 0.000 description 44
- 238000007789 sealing Methods 0.000 description 44
- 238000001914 filtration Methods 0.000 description 39
- 239000012982 microporous membrane Substances 0.000 description 35
- 238000010521 absorption reaction Methods 0.000 description 22
- 244000068988 Glycine max Species 0.000 description 17
- 235000010469 Glycine max Nutrition 0.000 description 17
- 238000004659 sterilization and disinfection Methods 0.000 description 7
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 5
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000007812 deficiency Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000012856 packing Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000004576 sand Substances 0.000 description 3
- FDQAOULAVFHKBX-KMRPREKFSA-N (+)-Isosilybin A Natural products C1=C(O)C(OC)=CC([C@@H]2[C@H](OC3=CC(=CC=C3O2)[C@@H]2[C@@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 FDQAOULAVFHKBX-KMRPREKFSA-N 0.000 description 2
- FDQAOULAVFHKBX-HKTJVKLFSA-N (2r,3r)-3,5,7-trihydroxy-2-[(2r,3r)-2-(4-hydroxy-3-methoxyphenyl)-3-(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(=CC=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 FDQAOULAVFHKBX-HKTJVKLFSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- KDMGQPNVTKUNHV-UHFFFAOYSA-N Isosilybin Natural products C1=C(O)C(OC)=CC=C1C1C(CO)OC2=CC=C(C3C(C(=O)C4=C(O)C=C(O)C=C4O3)O)C=C2O1 KDMGQPNVTKUNHV-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 210000000941 bile Anatomy 0.000 description 2
- OKTJSMMVPCPJKN-YPZZEJLDSA-N carbon-10 atom Chemical class [10C] OKTJSMMVPCPJKN-YPZZEJLDSA-N 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 231100000753 hepatic injury Toxicity 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 239000008176 lyophilized powder Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000008347 soybean phospholipid Substances 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
- MSTDXOZUKAQDRL-UHFFFAOYSA-N 4-Chromanone Chemical compound C1=CC=C2C(=O)CCOC2=C1 MSTDXOZUKAQDRL-UHFFFAOYSA-N 0.000 description 1
- 208000022309 Alcoholic Liver disease Diseases 0.000 description 1
- 102000001381 Arachidonate 5-Lipoxygenase Human genes 0.000 description 1
- 108010093579 Arachidonate 5-lipoxygenase Proteins 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
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 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
- 244000272459 Silybum marianum Species 0.000 description 1
- 235000010841 Silybum marianum Nutrition 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000003035 anti-peroxidant effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- -1 dimyristoyl phosphatidyl cholines Chemical class 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 235000008384 feverfew Nutrition 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 235000003969 glutathione Nutrition 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 230000002443 hepatoprotective effect Effects 0.000 description 1
- 231100000334 hepatotoxic Toxicity 0.000 description 1
- 230000003082 hepatotoxic effect Effects 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 235000014593 oils and fats Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002633 protecting effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the field of medicines, and relates to a silymarin composition wrapper which is high in stability and obvious in curative effect and a preparation method thereof. The medicinal composition wrapper comprises a silymarin injection solution and an injection solvent which are loaded in respective containers to be combined and packaged. Before the silymarin composition wrapper is used clinically, the solvent and the silymarin solution are mixed uniformly and are diluted in 5 percent glucose or 10 percent glucose injection solution to be instilled, so the preparation process of the silymarin injection is simplified, the preparation cost is reduced, and the silymarin injection can be produced simply on a large scale.
Description
Technical field
The present invention relates to medical art, is a kind of pharmaceutical composition and preparation method thereof, is specifically related to a kind of Silymarin medicinal composition wrapper and preparation method.
Background technology
Silibinin, medicine is called: silymarin, silybin, Silybin, Silymarin, LEGALON.Silibinin is the effective ingredient extracted from the seed of feverfew Herba Silybi mariani [Silybum marianum (L) Genrtn], it is a kind of polyhydroxy benzenes base chromanone, it still has another kind of isomer, be called Isosilybin (Isosillbinin, Isosilybin).Pharmacological research finds; silibinin has obvious the liver protecting effect; active oxygen in the present purged body of its acting body, to anti peroxidation of lipid, suppress the generation of nitric oxide (NO), suppress 5-lipoxygenase activity, antagonism glutathion (GsH) emptying; and protect the pharmacological effects such as liver plasma membrane, the reparation of promotion hepatocyte, regeneration, immunomodulating, anti-hepatic fibrosis, to all kinds hepatic injury that the hepatotoxic agent such as carbon tetrachloride, muscarine causes, there is obvious protective effect in addition.Therefore, silibinin has become one of widely used hepatic clinically, for various hepatopathy as chronic hepatopathy, virus hepatitis, liver cirrhosis, fatty liver, alcoholic liver damage, and the treatment of other poisoning metabolic hepatic injurys etc.
The various silibinin preparations that early clinic uses, mostly are oral formulations, but due to its water-soluble and oils and fats hardly, bioavailability is low, absorbtivity is unstable, greatly reduces clinical efficacy.In order to improve curative effect, meglumine salt and the phosphatide complexes oral formulations of silibinin go on the market in succession, although curative effect makes moderate progress, bioavailability is not significantly improved.
In order to significantly improve silibinin bioavailability in vivo; ejection preparation can be prepared into use; owing to being direct intravenously administrable; bioavailability can reach absolutely; significantly improve the liver-protective effect of silibinin; for the time that both can shorten treatment patient, also a saving the cost for the treatment of.At present, the numerous researchs about Silybinin injection are prepared into meglumine salt, then make lyophilized powder, carry out administration after using the water for injection of front meta-alkalescence (pH > 9.0) or aqueous megiumine solution to dissolve.Owing to there is the deficiency of following two aspects, limit its Clinical practice.First, the meglumine salt pH value of water solution of meta-alkalescence is bigger than normal, pH > 9.0, and the normal pH of blood of human body is 7.35-7.45, many untoward reaction can be brought to medication patient, silibinin extremely unstable in meta-alkalescence solution in addition, in preparation preparation and Clinical practice process, content can decline, thus affects therapeutic effect; Secondly; complicated preparation technology causes many difficulties to large-scale production; the preparation of silybin-N-methylglucamine brings the loss of the residual of organic solvent and medicine, and the preparation process of meglumine salt lyophilized powder is very long and complicated, significantly increases the preparation cost of injection.
For above-mentioned many deficiencies, the invention provides a kind of stable, eutherapeutic Silybinin injection and its preparation technology.
Summary of the invention
The object of the invention is the deficiency solving existing silibinin preparation, provides the Silymarin medicinal composition wrapper that a kind of good stability, toxic and side effects are little, evident in efficacy.
Silibinin drug compositions packing material of the present invention, packed by silybin infusion solution and injection solvent two kinds of solution combination and form, two kinds of medicaments independently load in a reservoir, and assembly packaging together.Should particularly point out, assembly packaging thing described herein, not mind which kind of material is packaging be, as long as this kind of material is suitable as pharmaceutical packing; Do not mind how pharmaceutical composition wires up by packing material in which way, as long as this packaging can be applicable to each self-enclosed respectively for silybin infusion solution and injection solvent two kinds of solution yet.Two kinds of medicaments described herein independently load in a reservoir, refer to that two kinds of solution are each self-enclosed, do not link up mutually, and might not two kinds of containers necessarily spatially mutually isolated, such as, two kinds of containers can directly be linked together mutually, or can there be pipeline centre, use the former two each self-enclosed, the pipeline between can opening during use, make the two communicate.In a word, this description just gives implements part way of the present invention, to any change or the amendment of embodiment of the present invention, only otherwise depart from spirit of the present invention, all thinks and is included in scope of the present invention.
Wherein, silybin infusion solution of the present invention, consists of the following composition:
Constituent content (grams per milliliter)
Active constituents of medicine 0.01-10.0%,
Phosphatidase 0 .1-30.0%,
Solvent for injection A surplus;
Wherein,
Active constituents of medicine is selected from: silibinin or silybin-phospholipid complex;
Phospholipid is selected from: one or more in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, distearoyl phosphatidylcholine, dipalmitoyl phosphatidyl choline and dimyristoyl phosphatidyl choline, preferably soya lecithin and/or Ovum Gallus domesticus Flavus lecithin;
Solvent for injection A is selected from: one or more in Macrogol 200, Liquid Macrogol, PEG400, Macrogol 600, glycerol, propylene glycol and dehydrated alcohol, one or more in preferred propylene glycol, dehydrated alcohol and PEG400.
Preferably, silybin infusion solution of the present invention, consists of the following composition:
Constituent content (grams per milliliter)
Active constituents of medicine 0.1-5.0%;
Phosphatidase 2 .0-25%;
Solvent for injection A surplus.
Preferred, silybin infusion solution of the present invention, consists of the following composition:
Constituent content (grams per milliliter)
Silibinin 0.3%
Soybean lecithin 10%
Propylene glycol surplus.
Wherein, injection solvent of the present invention, consists of the following composition:
Constituent content (grams per milliliter)
Cholate 0.1-20.0%,
Solvent for injection B surplus.
Wherein,
Cholate is selected from one or more in sodium cholate, NaTDC, NaGC, Glycodeoxrycholic acid, sodium ursodexoxycholate, SODIUM CHENODIOL, sodium taurocholate and sodium dehydrocholate, is preferably: sodium cholate and/or NaTDC;
Solvent for injection B is selected from: propylene glycol and/or water for injection, preferred water for injection.
Preferably, injection solvent of the present invention, consists of the following composition:
Constituent content (grams per milliliter)
Cholate 5.0-15.0%;
Solvent for injection B surplus.
Preferred, injection solvent of the present invention, consists of the following composition:
Constituent content (grams per milliliter)
NaTDC 10%;
Solvent for injection B surplus.
In Silymarin medicinal composition wrapper of the present invention, silybin infusion solution is 1: 99 ~ 99: 1 with the volume ratio of injection solvent, preferably 1: 9 ~ 9: 1.
The formula of other most preferred Silymarin medicinal composition wrappers of the present invention in an embodiment.
Silymarin medicinal composition wrapper of the present invention, intravenously administrable is got final product by after both mix homogeneously diluted when Clinical practice, described diluent can be any useful clinically diluent, include but not limited to glucose injection, normal saline solution etc., preferred glucose injection.The amount clinician of diluent used can determine easily according to prior art and its ABC grasped.
Silymarin medicinal composition wrapper of the present invention, can also comprise diluent, and described diluent can be any useful clinically diluent, includes but not limited to glucose injection, normal saline solution etc., preferred glucose injection.
In Silymarin medicinal composition wrapper of the present invention, silybin infusion solution, injection solvent and the volume ratio of diluent are 1 ~ 99: 1 ~ 99: 1 ~ 99, preferably 1 ~ 9: 1 ~ 9: 1 ~ 9.
Another object of the present invention is the preparation method providing Silymarin medicinal composition wrapper of the present invention.
The preparation method of Silymarin medicinal composition wrapper of the present invention comprises: prepare silybin infusion solution and injection solvent respectively, packaging together.
Wherein, Silymarin medicinal composition wrapper of the present invention, when silybin infusion solution pharmaceutical active composition is silibinin, the preparation of described silybin infusion solution comprises the steps:
(1) by said ratio, active constituents of medicine, phospholipid are dissolved in appropriate solvent for injection A;
(2) in above-mentioned solution, add needle-use activated carbon adsorbing contaminant, filter, by filtrate subpackage, sterilizing.
Specifically, comprise the steps:
(1) by proportioning, active constituents of medicine, phospholipid are added in appropriate solvent for injection A, stir at 25-80 DEG C or shear and dissolve, be then settled to full dose with solvent for injection;
(2) 0.02%-3.5% (grams per milliliter) by amount of solution in above-mentioned solution adds needle-use activated carbon, adsorbs 20-70 minute, then filters, by filtrate subpackage, sterilizing at 30-75 DEG C.
If Silymarin medicinal composition wrapper of the present invention, if the active component of silybin infusion solution is silybin-phospholipid complex, then silybin-phospholipid complex can be bought from market, also can method conventionally prepare, or according to following formula, make by the following method:
The formula of silybin-phospholipid complex: silibinin: phospholipid=1: 0.5 ~ 1: 10, ratio is mass ratio;
Phospholipid in wherein said silybin-phospholipid complex is selected from one or more in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, distearoyl phosphatidylcholine, dipalmitoyl phosphatidyl choline and dimyristoyl phosphatidyl choline, preferably soya lecithin and/or Ovum Gallus domesticus Flavus lecithin.
The preparation method of silybin-phospholipid complex is specifically as follows: silibinin and phospholipid are joined in the dehydrated alcohol of 5 ~ 50 times amount, and 40 DEG C ~ 55 DEG C water-baths are dissolved, then rotary evaporation removing ethanol, and gained powder is the phosphatide complexes of silibinin.
Wherein, Silymarin medicinal composition wrapper of the present invention, the preparation of wherein said injection solvent comprises the steps:
(1) gallbladder salt is dissolved by said ratio solvent for injection B;
(2) in above-mentioned solution, add needle-use activated carbon adsorbing contaminant, filter, by filtrate subpackage, sterilizing.
Specifically, comprise the steps:
(1) by proportioning, cholate is added in appropriate solvent for injection B, stir at 25-80 DEG C or shear and dissolve, be then settled to full dose with solvent for injection B;
(2) 0.02%-3.5% (grams per milliliter) by amount of solution in above-mentioned solution adds needle-use activated carbon, adsorbs 20-70 minute, then filters, by filtrate subpackage, sterilizing at 30-75 DEG C.
Wherein, the sterilizing in injection solution of the present invention and solvent preparation process adopts the mode of high-temperature steam, flowing steam or microporous filter membrane to carry out, and preferred high-temperature steam carries out sterilizing, and wherein high temperature sterilize temperature is 100-121 DEG C, time 8-45 minute; The defecator used, includes but not limited to microporous filter membrane, sand stick, sintered filter funnel or bag type filter.
The present invention is most preferred flies the preparation method of Ji guest injection in an embodiment.
Silybinin injection of the present invention is compared with traditional oral formulations, significantly improve bioavailability, greatly improve hepatoprotective curative effect, compare existing silibinin frozen powder for injection preparation, there is higher safety and stability, extend the shelf-life of product, in addition, process for preparation of injection of the present invention is simple, and the prices of raw and semifnished materials are cheap, also significantly reduce the production cost of injection of the present invention.
Detailed description of the invention
The present invention further illustrates the present invention by following specific embodiment, but not as restriction of the present invention.
Embodiment 1, Silybinin injection of the present invention
1. the preparation of silybin infusion solution
Take 0.5 gram of silibinin, 15 grams of soybean lecithins add in appropriate propylene glycol, dissolve completely in 50 DEG C of down cuts (10000rpm) to medicine and phospholipid, then be settled to 150 milliliters with propylene glycol, add in needle-use activated carbon 2.5 grams to above-mentioned solution, adsorb 30 minutes in 40 DEG C, with filtering with microporous membrane, be sub-packed in vial by 1.5 mls/branch, routine fills nitrogen, sealing, with high-temp steam sterilizing pot 121 DEG C of sterilizings 15 minutes, obtain silybin infusion solution.
2. inject the preparation of solvent
Take in 35 grams of NaTDCs to appropriate water for injection, stir at 25 DEG C and make it to dissolve, then be settled to 350 milliliters with water for injection, add in needle-use activated carbon 3.5 grams to above-mentioned solution, 35 DEG C of absorption 30 minutes, with filtering with microporous membrane, be sub-packed in vial by 3.5 mls/branch, routine fills nitrogen, sealing, with high-temp steam sterilizing pot 121 DEG C of sterilizings 15 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 2, Silybinin injection of the present invention
1. the preparation of silybin infusion solution
Take 1 gram of silibinin, 20 grams of soybean lecithins add in appropriate propylene glycol, dissolve completely in 50 DEG C of down cuts (8000rpm) to medicine and phospholipid, then be settled to 150 milliliters with propylene glycol, add in needle-use activated carbon 6 grams to above-mentioned solution, adsorb 20 minutes in 60 DEG C, with filtering with microporous membrane, be sub-packed in vial by 1.5 mls/branch, routine fills nitrogen, sealing, with high-temp steam sterilizing pot 115 DEG C of sterilizings 18 minutes, obtain silybin infusion solution.
2. inject the preparation of solvent
Take in 17.5 grams of NaTDCs to appropriate water for injection, stir at 25 DEG C and make it to dissolve, then be settled to 350 milliliters with water for injection, add in needle-use activated carbon 1.75 grams to above-mentioned solution, 45 DEG C of absorption 25 minutes, with filtering with microporous membrane, be sub-packed in vial by 3.5 mls/branch, routine fills nitrogen, sealing, with high-temp steam sterilizing pot 118 DEG C of sterilizings 18 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 3, Silybinin injection of the present invention
1. the preparation of silybin infusion solution
Take 1.5 grams of silibinin, 35 grams of Ovum Gallus domesticus Flavus lecithins add in appropriate propylene glycol, dissolve completely in 50 DEG C of down cuts (10000rpm) to medicine and phospholipid, then be settled to 300 milliliters with propylene glycol, add in needle-use activated carbon 10.5 grams to above-mentioned solution, adsorb 30 minutes in 53 DEG C, filter with bag type filter, be sub-packed in vial by 3 mls/branch, routine fills nitrogen, sealing, with high-temp steam sterilizing pot 115 DEG C of sterilizings 30 minutes, obtain silybin infusion solution.
2. inject the preparation of solvent
Take in 15 grams of NaTDCs to appropriate water for injection, stir at 35 DEG C and make it to dissolve, then be settled to 200 milliliters with water for injection, add in needle-use activated carbon 1.1 grams to above-mentioned solution, 55 DEG C of absorption 35 minutes, filter with bag type filter, be sub-packed in vial by 2 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 115 DEG C of sterilizings 30 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 4, Silybinin injection of the present invention
1. the preparation of silybin infusion solution
Taking 1.67 grams of silibinin, 10 grams of soybean lecithins and 13 grams of Ovum Gallus domesticus Flavus lecithins adds in appropriate propylene glycol, dissolve completely in 70 DEG C of down cuts (10000rpm) to medicine and phospholipid, then be settled to 200 milliliters with propylene glycol, add in needle-use activated carbon 4.7 grams to above-mentioned solution, adsorb 70 minutes in 30 DEG C, filter with sand stick, be sub-packed in vial by 2 mls/branch, routine rushes nitrogen, sealing, with 100 DEG C of flowing steam sterilizations 35 minutes, obtain silybin infusion solution.
2. inject the preparation of solvent
Take in 18 grams of NaTDCs to appropriate propylene glycol, stir at 40 DEG C and make it to dissolve, then be settled to 300 milliliters with propylene glycol, add in needle-use activated carbon 1.5 grams to above-mentioned solution, 30 DEG C of absorption 70 minutes, filter with sand stick, be sub-packed in vial by 3 mls/branch, routine rushes nitrogen, sealing, with 100 DEG C of flowing steam sterilizations 35 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 5, Silybinin injection of the present invention
1. the preparation of silybin infusion solution
Take 0.3 gram of silibinin, 6 grams of soybean lecithins add in appropriate dehydrated alcohol, dissolve completely in 50 DEG C of down cuts (10000rpm) to medicine and phospholipid, then be settled to 300 milliliters with dehydrated alcohol, add in needle-use activated carbon 5 grams to above-mentioned solution, adsorb 30 minutes in 60 DEG C, with filtering with microporous membrane, be sub-packed in vial by 3 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 121 DEG C of sterilizings 12 minutes, obtain silybin infusion solution.
2. inject the preparation of solvent
Take in 10 grams of sodium cholate to appropriate water for injection, stir at 50 DEG C and make it to dissolve, then be settled to 200 milliliters with water for injection, add in needle-use activated carbon 0.4 gram to above-mentioned solution, 60 DEG C of absorption 30 minutes, with filtering with microporous membrane, be sub-packed in vial by 2 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 121 DEG C of sterilizings 12 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 6, Silybinin injection of the present invention
1. the preparation of silybin infusion solution
Take 1.67 grams of silibinin, 0.75 gram of distearoyl phosphatidylcholine adds in 40 milliliters of propylene glycol, dissolve completely in 50 DEG C of down cuts (10000rpm) to medicine and phospholipid, then 50 milliliters are settled to dehydrated alcohol, add in needle-use activated carbon 0.1 gram to above-mentioned solution, adsorb 25 minutes in 45 DEG C, filter with bag type filter, be sub-packed in vial by 0.5 ml/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 118 DEG C of sterilizings 20 minutes, obtain silybin infusion solution.
2. inject the preparation of solvent
Take in 36 grams of sodium cholate to appropriate water for injection, stir at 50 DEG C and make it to dissolve, then be settled to 450 milliliters with water for injection, add in needle-use activated carbon 0.9 gram to above-mentioned solution, 45 DEG C of absorption 30 minutes, filter with bag type filter, be sub-packed in vial by 4.5 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 118 DEG C of sterilizings 20 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 7, Silybinin injection of the present invention
1. the preparation of silybin infusion solution
Taking 45 grams of silibinin, 82.5 grams of soybean lecithins and 52.5 grams of dipalmitoyl phosphatidyl choline adds in 150 milliliters of propylene glycol, dissolve completely in 70 DEG C of down cuts (10000rpm) to medicine and phospholipid, then 450 milliliters are settled to PEG400, add in needle-use activated carbon 0.09 gram to above-mentioned solution, adsorb 20 minutes in 60 DEG C, with filtering with microporous membrane, be sub-packed in vial by 4.5 mls/branch, routine rushes nitrogen, sealing, with 100 DEG C of flowing steam sterilizations 35 minutes, obtain silybin infusion solution.
2. inject the preparation of solvent
Take in 5 grams of NaGCs and 5 grams of sodium dehydrocholate to appropriate water for injection, stir at 65 DEG C and make it to dissolve, then be settled to 50 milliliters with water for injection, add in needle-use activated carbon 0.025 gram to above-mentioned solution, 35 DEG C of absorption 30 minutes, with filtering with microporous membrane, be sub-packed in vial by 0.5 ml/branch, routine rushes nitrogen, sealing, with 100 DEG C of flowing steam sterilizations 35 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 8, Silybinin injection of the present invention
1. the preparation of silybin infusion solution
Take 0.8 gram of silibinin, 20.7 grams of soybean lecithins add in appropriate propylene glycol, dissolve completely in 65 DEG C of down cuts (10000rpm) to medicine and phospholipid, then be settled to 200 milliliters with propylene glycol, add in needle-use activated carbon 6.7 grams to above-mentioned solution, adsorb 30 minutes in 60 DEG C, with filtering with microporous membrane, be sub-packed in vial by 2 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 121 DEG C of sterilizings 10 minutes, obtain silybin infusion solution.
2. inject the preparation of solvent
Take in 30 grams of NaTDCs to appropriate water for injection, stir at 35 DEG C and make it to dissolve, then be settled to 300 milliliters with water for injection, add in needle-use activated carbon 10.5 grams to above-mentioned solution, 35 DEG C of absorption 30 minutes, with filtering with microporous membrane, be sub-packed in vial by 3 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 121 DEG C of sterilizings 10 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 9, Silybinin injection of the present invention
1. the preparation of silybin infusion solution
Taking 0.03 gram of silibinin, 0.6 gram of dimyristoyl phosphatidyl choline and 0.4 gram of soybean lecithin adds in 200 milliliters of propylene glycol, dissolve completely in 45 DEG C of down cuts (10000rpm) to medicine and phospholipid, then 300 milliliters are settled to glycerol, add in needle-use activated carbon 0.5 gram to above-mentioned solution, adsorb 30 minutes in 40 DEG C, with filtering with microporous membrane, be sub-packed in vial by 3 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 121 DEG C of sterilizings 15 minutes, obtain silybin infusion solution.
2. inject the preparation of solvent
Take in 0.1 gram of Glycodeoxrycholic acid and 0.1 gram of sodium dehydrocholate to appropriate water for injection, stir at 25 DEG C and make it to dissolve, then be settled to 200 milliliters with water for injection, add in needle-use activated carbon 1 gram to above-mentioned solution, 35 DEG C of absorption 30 minutes, with filtering with microporous membrane, be sub-packed in vial by 2 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 121 DEG C of sterilizings 15 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 10, Silybinin injection of the present invention
1. the preparation of silybin infusion solution
Take 0.85 gram of silibinin, 40 grams of soybean lecithins add in appropriate propylene glycol, dissolve completely in 80 DEG C of down cuts (10000rpm) to medicine and phospholipid, then be settled to 150 milliliters with propylene glycol, add in needle-use activated carbon 5.7 grams to above-mentioned solution, adsorb 30 minutes in 75 DEG C, filtering active carbon is crossed with sintered filter funnel, degerming with 0.22 μm of filtering with microporous membrane, be sub-packed in vial by 1.5 mls/branch, routine rushes nitrogen, sealing, obtains silybin infusion solution.
2. inject the preparation of solvent
Take in 70 grams of NaTDCs to appropriate water for injection, stir at 80 DEG C and make it to dissolve, then be settled to 350 milliliters with water for injection, add in needle-use activated carbon 10.5 grams to above-mentioned solution, 75 DEG C of absorption 30 minutes, filtering active carbon is crossed with sintered filter funnel, degerming with 0.22 μm of filtering with microporous membrane, be sub-packed in vial by 3.5 mls/branch, routine rushes nitrogen, sealing, obtains injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 11, Silybinin injection of the present invention
1. the preparation of silybin infusion solution
Taking 7.5 grams of silibinin, 27.5 grams of soybean lecithins and 5 grams of Ovum Gallus domesticus Flavus lecithins adds in appropriate propylene glycol, dissolve completely in 50 DEG C of down cuts (10000rpm) to medicine and phospholipid, then 150 milliliters are settled to propylene glycol, add in needle-use activated carbon 4 grams to above-mentioned solution, adsorb 30 minutes in 40 DEG C, with filtering with microporous membrane, be sub-packed in vial by 1.5 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 118 DEG C of sterilizings 15 minutes, obtain silybin infusion solution.
2. inject the preparation of solvent
Take in 43.8 grams of NaTDCs and 8.7 grams of sodium cholate to appropriate water for injection, stir at 25 DEG C and make it to dissolve, then be settled to 350 milliliters with water for injection, add in needle-use activated carbon 2.3 grams to above-mentioned solution, 35 DEG C of absorption 30 minutes, with filtering with microporous membrane, be sub-packed in vial by 3.5 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 118 DEG C of sterilizings 15 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 12, Silybinin injection of the present invention
1. the preparation of silybin infusion solution
Take 0.73 gram of silibinin, 5 grams of Ovum Gallus domesticus Flavus lecithins add in 70 milliliters of propylene glycol, dissolve completely in 50 DEG C of down cuts (10000rpm) to medicine and phospholipid, then be settled to 150 milliliters with dehydrated alcohol, add in needle-use activated carbon 3.5 grams to above-mentioned solution, adsorb 30 minutes in 40 DEG C, with filtering with microporous membrane, be sub-packed in vial by 1.5 mls/branch, routine rushes nitrogen, sealing, with 100 DEG C of flowing steam sterilizations 45 minutes, obtain silybin infusion solution.
2. inject the preparation of solvent
Take in 17.5 grams of Bile Saltses and 7 grams of sodium ursodexoxycholates to appropriate water for injection; stir at 25 DEG C and make it to dissolve; then be settled to 350 milliliters with water for injection, add in needle-use activated carbon 10.5 grams to above-mentioned solution, 35 DEG C of absorption 30 minutes; with filtering with microporous membrane; be sub-packed in vial by 3.5 mls/branch, routine rushes nitrogen, sealing; with 100 DEG C of flowing steam sterilizations 45 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 13, Silybinin injection of the present invention
1. the preparation of silybin infusion solution
Take 3.51 grams of silibinin, 10 grams of soybean lecithins add in 100 milliliters of propylene glycol, dissolve completely in 65 DEG C of down cuts (10000rpm) to medicine and phospholipid, then be settled to 200 milliliters with Macrogol 200, add in needle-use activated carbon 3.3 grams to above-mentioned solution, adsorb 30 minutes in 40 DEG C, filter with bag type filter, be sub-packed in vial by 2 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 121 DEG C of sterilizings 15 minutes, obtain silybin infusion solution.
2. inject the preparation of solvent
Take in 40.5 grams of sodium ursodexoxycholates to appropriate water for injection, stir at 45 DEG C and make it to dissolve, then be settled to 300 milliliters with water for injection, add in needle-use activated carbon 6 grams to above-mentioned solution, 35 DEG C of absorption 30 minutes, with filtering with microporous membrane, be sub-packed in vial by 3 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 121 DEG C of sterilizings 15 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 14, Silybinin injection of the present invention
1. the preparation of silybin infusion solution
Taking 2.1 grams of silibinin, 17 grams of soybean lecithins and 27 grams of dipalmitoyl phosphatidyl choline adds in 140 milliliters of propylene glycol, dissolve completely in 40 DEG C of down cuts (10000rpm) to medicine and phospholipid, then 400 milliliters are settled to Macrogol 600, add in needle-use activated carbon 10 grams to above-mentioned solution, adsorb 30 minutes in 40 DEG C, filter with bag type filter, be sub-packed in vial by 4 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 118 DEG C of sterilizings 15 minutes, obtain silybin infusion solution.
2. inject the preparation of solvent
Take in 9 grams of Bile Saltses to appropriate water for injection; stir at 55 DEG C and make it to dissolve; then be settled to 100 milliliters with water for injection, add in needle-use activated carbon 1.5 grams to above-mentioned solution, 35 DEG C of absorption 30 minutes; filter with bag type filter; be sub-packed in vial by 1 ml/branch, routine rushes nitrogen, sealing; with high-temp steam sterilizing pot 118 DEG C of sterilizings 15 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 15, Silybinin injection of the present invention
1. the preparation of silybin infusion solution
Take 1 gram of silibinin, 14 grams of soybean lecithins add in appropriate propylene glycol, dissolve completely in 60 DEG C of down cuts (8000rpm) to medicine and phospholipid, then be settled to 150 milliliters with propylene glycol, add in needle-use activated carbon 4.5 grams to above-mentioned solution, adsorb 30 minutes in 40 DEG C, with filtering with microporous membrane, be sub-packed in vial by 1.5 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 121 DEG C of sterilizings 15 minutes, obtain silybin infusion solution.
2. inject the preparation of solvent
Take in 42 grams of SODIUM CHENODIOLs to appropriate water for injection, stir at 35 DEG C and make it to dissolve, then be settled to 350 milliliters with water for injection, add in needle-use activated carbon 2.6 grams to above-mentioned solution, 35 DEG C of absorption 30 minutes, with filtering with microporous membrane, be sub-packed in vial by 2 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 121 DEG C of sterilizings 15 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 16, Silybinin injection of the present invention
1. the preparation of silybin infusion solution
Taking 1.2 grams of silibinin, 12 grams of dimyristoyl phosphatidyl cholines and 16 grams of lecithin adds in 190 milliliters of dehydrated alcohol, dissolve completely in 50 DEG C of down cuts (10000rpm) to medicine and phospholipid, then 300 milliliters are settled to propylene glycol, add in needle-use activated carbon 10 grams to above-mentioned solution, adsorb 30 minutes in 40 DEG C, with filtering with microporous membrane, be sub-packed in vial by 3 mls/branch, routine rushes nitrogen, sealing, with 100 DEG C of flowing steam sterilizations 35 minutes, obtain silybin infusion solution.
2. inject the preparation of solvent
Take in 9 grams of sodium ursodexoxycholates and 10 grams of Glycodeoxrycholic acids to appropriate water for injection, stir at 45 DEG C and make it to dissolve, then be settled to 200 milliliters with water for injection, add in needle-use activated carbon 2.1 grams to above-mentioned solution, 35 DEG C of absorption 30 minutes, with filtering with microporous membrane, be sub-packed in vial by 2 mls/branch, routine rushes nitrogen, sealing, with flowing steam 100 DEG C of sterilizings 35 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 17, Silybinin injection of the present invention
1. the preparation of silybin infusion solution
Take 0.45 gram of silibinin, 45 grams of soybean lecithins add in appropriate propylene glycol, dissolve completely in 80 DEG C of down cuts (10000rpm) to medicine and phospholipid, then be settled to 150 milliliters with propylene glycol, add in needle-use activated carbon 0.03 gram to above-mentioned solution, adsorb 30 minutes in 75 DEG C, filtering active carbon is crossed with sintered filter funnel, degerming with 0.22 μm of filtering with microporous membrane, be sub-packed in vial by 1.5 mls/branch, routine rushes nitrogen, sealing, obtains silybin infusion solution.
2. inject the preparation of solvent
Take in 2.6 grams of sodium cholate to 170 milliliter propylene glycol, stir at 25 DEG C and make it to dissolve, then be settled to 350 milliliters with water for injection, add in needle-use activated carbon 1.75 grams to above-mentioned solution, 35 DEG C of absorption 30 minutes, filtering active carbon is crossed with sintered filter funnel, degerming with 0.22 μm of filtering with microporous membrane, be sub-packed in vial by 3.5 mls/branch, routine rushes nitrogen, sealing, obtains injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 18, Silybinin injection of the present invention
1. the preparation of silybin-phospholipid complex
Joined by silibinin 4g and soybean lecithin 4.8g in 168 milliliters of dehydrated alcohol, 40 DEG C of water-baths are dissolved, then rotary evaporation removing ethanol, and gained powder is the phosphatide complexes of silibinin.
2. the preparation of silybin infusion solution
Take 1.87 grams of silybin-phospholipid complexes, 22.7 grams of soybean lecithins add in appropriate propylene glycol, dissolve completely in 50 DEG C of down cuts (10000rpm) to medicine and phospholipid, then 200 milliliters are settled to propylene glycol, add in needle-use activated carbon 3.3 grams to above-mentioned solution, adsorb 30 minutes in 50 DEG C, with filtering with microporous membrane, be sub-packed in vial by 0.5 ml/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 115 DEG C of sterilizings 20 minutes, obtain silybin infusion solution.
3. inject the preparation of solvent
Take in 36 grams of sodium ursodexoxycholates and 15 grams of Bile Salts to 100 milliliter propylene glycol; stir at 25 DEG C and make it to dissolve; then be settled to 300 milliliters with water for injection, add in needle-use activated carbon 9 grams to above-mentioned solution, 35 DEG C of absorption 30 minutes; with filtering with microporous membrane; be sub-packed in vial by 4.5 mls/branch, routine rushes nitrogen, sealing; with high-temp steam sterilizing pot 115 DEG C of sterilizings 20 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 19, Silybinin injection of the present invention
1. the preparation of silybin-phospholipid complex
Joined by silibinin 3g and soybean lecithin 3.8g in 100 milliliters of dehydrated alcohol, 40 DEG C of water-baths are dissolved, then rotary evaporation removing ethanol, and gained powder is the phosphatide complexes of silibinin.
2. the preparation of silybin infusion solution
Taking 2 grams of silybin-phospholipid complexes, 30 grams of soybean lecithins and 20 grams of Ovum Gallus domesticus Flavus lecithins adds in 100 milliliters of propylene glycol, dissolve completely in 55 DEG C of down cuts (8000rpm) to medicine and phospholipid, then 300 are settled to Liquid Macrogol) milliliter, add in needle-use activated carbon 5 grams to above-mentioned solution, adsorb 30 minutes in 40 DEG C, with filtering with microporous membrane, be sub-packed in vial by 4.5 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 115 DEG C of sterilizings 25 minutes, obtain silybin infusion solution.
3. inject the preparation of solvent
Take in 12 grams of sodium cholate and sodium dehydrocholate 10 grams to appropriate water for injection, stir at 25 DEG C and make it to dissolve, then be settled to 200 milliliters with water for injection, add in needle-use activated carbon 3 grams to above-mentioned solution, 35 DEG C of absorption 30 minutes, with filtering with microporous membrane, be sub-packed in vial by 0.5 ml/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 115 DEG C of sterilizings 25 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 20, Silybinin injection of the present invention
1. the preparation of silybin-phospholipid complex
Join in 255 milliliters of dehydrated alcohol by silibinin 2g, a soybean lecithin 15g and 5 gram Ovum Gallus domesticus Flavus lecithin, 40 DEG C of water-baths are dissolved, then rotary evaporation removing ethanol, and gained powder is the phosphatide complexes of silibinin.
2. the preparation of silybin infusion solution
Take 5 grams of silybin-phospholipid complexes, 42 grams of soybean lecithins add in 100 milliliters of propylene glycol, dissolve completely in 70 DEG C of down cuts (8000rpm) to medicine and phospholipid, then be settled to 150 milliliters with glycerol, add in needle-use activated carbon 2 grams to above-mentioned solution, adsorb 30 minutes in 50 DEG C, with filtering with microporous membrane, be sub-packed in vial by 1.5 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 118 DEG C of sterilizings 20 minutes, obtain silybin infusion solution.
3. inject the preparation of solvent
Take in 43.7 grams of NaTDC to 150 milliliter propylene glycol, stir at 45 DEG C and make it to dissolve, then be settled to 350 milliliters with water for injection, add in needle-use activated carbon 12.25 grams to above-mentioned solution, 35 DEG C of absorption 30 minutes, with filtering with microporous membrane, be sub-packed in vial by 3.5 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 118 DEG C of sterilizings 20 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 21, Silybinin injection of the present invention
1. the preparation of silybin-phospholipid complex
Joined by silibinin 3g and Ovum Gallus domesticus Flavus lecithin 1.5g in 100 milliliters of dehydrated alcohol, 40 DEG C of water-baths are dissolved, then rotary evaporation removing ethanol, and gained powder is the phosphatide complexes of silibinin.
2. the preparation of silybin infusion solution
Taking 1.8 grams of silybin-phospholipid complexes, 24 grams of soybean lecithins and 5 grams of distearoyl phosphatidylcholine adds in 100 milliliters of propylene glycol, dissolve completely in 55 DEG C of down cuts (8000rpm) to medicine and phospholipid, then 300 milliliters are settled to Liquid Macrogol, add in needle-use activated carbon 4.5 grams to above-mentioned solution, adsorb 30 minutes in 40 DEG C, with filtering with microporous membrane, be sub-packed in vial by 3 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 115 DEG C of sterilizings 25 minutes, obtain silybin infusion solution.
3. inject the preparation of solvent
Take in 12 grams of sodium cholate and SODIUM CHENODIOL 9 grams to appropriate water for injection, stir at 25 DEG C and make it to dissolve, then be settled to 200 milliliters with water for injection, add in needle-use activated carbon 2.9 grams to above-mentioned solution, 35 DEG C of absorption 30 minutes, with filtering with microporous membrane, be sub-packed in vial by 2 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 115 DEG C of sterilizings 25 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Embodiment 22, Silybinin injection of the present invention
1. the preparation of silybin infusion solution
Taking the silybin-phospholipid complex bought in 2.67 grams of markets, 26.7 grams of soybean lecithins and 8 grams of distearoyl phosphatidylcholine adds in 200 milliliters of propylene glycol, dissolve completely in 55 DEG C of down cuts (8000rpm) to medicine and phospholipid, then 400 milliliters are settled to Liquid Macrogol, add in needle-use activated carbon 4.67 grams to above-mentioned solution, adsorb 30 minutes in 40 DEG C, with filtering with microporous membrane, be sub-packed in vial by 4 mls/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 115 DEG C of sterilizings 25 minutes, obtain silybin infusion solution.
2. inject the preparation of solvent
Take in 10 grams of sodium ursodexoxycholates to appropriate water for injection, stir at 25 DEG C and make it to dissolve, then be settled to 100 milliliters with water for injection, add in needle-use activated carbon 1.3 grams to above-mentioned solution, 35 DEG C of absorption 30 minutes, with filtering with microporous membrane, be sub-packed in vial by 1 ml/branch, routine rushes nitrogen, sealing, with high-temp steam sterilizing pot 115 DEG C of sterilizings 25 minutes, obtain injection solvent.
During Clinical practice, a silybin infusion solution is injected solvent mix homogeneously with one, be then diluted in 5% glucose or 10% glucose injection and instil.
Medicine stability test
This test preparation more of the present invention and the stability of ordinary preparation in glucose solution.
Test specimen: the sample in invention formulation Example 1; Common sample is the meglumine salt of silibinin, with reference to document preparation in bracket (silibinin powder pin quality standard and safety evaluatio research, Harbin University of Commerce's journal, the 23rd volume the 1st phase 15-18 page in 2007).Glucose solution is 5% glucose injection.
Chromatographic condition: liquid-phase condition: Agilent 1100 liquid chromatograph, Agilent G1314A VWD detector, AgilentG1311A type quaternary pump, Agilent G1314A VWD detector, Agilent LC1100 Data Processing in Chromatography Workstation, analytical column is Diamonsil C18 analytical column (5 μ, 4.6mm × 250mm), methanol-2% glacial acetic acid (55: 45) is mobile phase, flow velocity 1.0 milliliters/min, determined wavelength 288nm, sample size is 20 μ l, and external standard method is with peak area quantification.
Test method: the sample in embodiment 1 and common sample are diluted in 5% glucose injection by 80 μ g/ milliliters, with 0h content for 100%, in 0h, 2h, 4h, 6h sample introduction, compare the change of content.
Result of the test sees the following form.
More than test proof, in glucose injection, preparation of the present invention is stablized than the meglumine salt of silibinin, has more Prospect of R & D.
Confirmed by test, the Silybinin injection of other content of the present invention all can reach the effect described in this test example.
Claims (8)
1. a Silymarin medicinal composition wrapper, is characterized in that, comprise silybin infusion solution and injection solvent, both are loaded in respective container respectively, assembly packaging together,
Wherein, described silybin infusion solution, is grouped into by the one-tenth of following weight/volume percent:
Active constituents of medicine 0.1-5.0%;
Phosphatidase 2 .0-25%;
Solvent for injection A surplus;
Wherein, active constituents of medicine is selected from: silibinin or silybin-phospholipid complex, wherein, the phospholipid in described silybin-phospholipid complex is selected from one or more in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, distearoyl phosphatidylcholine, dipalmitoyl phosphatidyl choline and dimyristoyl phosphatidyl choline;
Phospholipid is selected from: one or more in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, distearoyl phosphatidylcholine, dipalmitoyl phosphatidyl choline and dimyristoyl phosphatidyl choline;
Solvent for injection A is selected from: one or more in Macrogol 200, Liquid Macrogol, PEG400, Macrogol 600, glycerol, propylene glycol and dehydrated alcohol;
Wherein, described injection solvent, is grouped into by the one-tenth of following weight/volume percent:
Cholate 5.0-15.0%,
Solvent for injection B surplus;
Wherein, cholate is selected from: one or more in sodium cholate, NaTDC, NaGC, Glycodeoxrycholic acid, sodium ursodexoxycholate, SODIUM CHENODIOL, sodium taurocholate and sodium dehydrocholate;
Solvent for injection B is selected from: propylene glycol and/or water for injection.
2. pharmaceutical composition according to claim 1, is characterized in that, described silybin infusion solution, is grouped into by the one-tenth of following weight/volume percent:
Silibinin 0.3%;
Soybean lecithin 10%;
Propylene glycol surplus.
3. pharmaceutical composition according to claim 1, is characterized in that, described injection solvent, is grouped into by the one-tenth of following weight/volume percent:
NaTDC 10%;
Solvent for injection surplus.
4. pharmaceutical composition according to claim 1 and 2, is characterized in that, also comprises diluent.
5. pharmaceutical composition according to claim 4, is characterized in that, described diluent is glucose injection.
6. the preparation method of the arbitrary pharmaceutical composition described in claim 1-5, comprise and prepare silybin infusion solution and injection solvent respectively, packaging together, it is characterized in that, when silybin infusion solution pharmaceutical active composition is silibinin, the preparation of described silybin infusion solution comprises the following steps:
(1) by proportioning, silibinin, phospholipid are added in appropriate solvent for injection A, stir at 25-80 DEG C or shear and dissolve, be then settled to full dose with solvent for injection A;
(2) 0.02%-3.5% by amount of solution in above-mentioned solution adds needle-use activated carbon, and addition is weight volumn concentration, adsorbs 20-70 minute, then filter at 30-75 DEG C, by filtrate subpackage, sterilizing.
7. the preparation method of the arbitrary pharmaceutical composition described in claim 1-5, comprises and prepares silybin infusion solution and injection solvent respectively, packaging together, it is characterized in that, the preparation method of wherein said injection solvent, is characterized in that, comprise the following steps:
(1) by proportioning, cholate is added in appropriate solvent for injection B, stir at 25-80 DEG C or shear and dissolve, be then settled to full dose with solvent for injection B;
(2) 0.02%-3.5% by amount of solution in above-mentioned solution adds needle-use activated carbon, and addition is weight volumn concentration, adsorbs 20-70 minute, then filter at 30-75 DEG C, by filtrate subpackage, sterilizing.
8. the preparation method of the arbitrary pharmaceutical composition described in claim 1-5, comprise and prepare silybin infusion solution and injection solvent respectively, packaging together, it is characterized in that, when silybin infusion solution pharmaceutical active composition is silybin-phospholipid complex, described silybin-phospholipid complex according to following formula:
The formula of silybin-phospholipid complex: silibinin: phospholipid=1:0.5 ~ 1:10, ratio is mass ratio; Wherein, described phospholipid is selected from: one or more in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, distearoyl phosphatidylcholine, dipalmitoyl phosphatidyl choline and dimyristoyl phosphatidyl choline;
Make by the following method: silibinin and phospholipid are joined in the dehydrated alcohol of 5 ~ 50 times amount, 40 DEG C ~ 55 DEG C water-baths are dissolved, then rotary evaporation removing ethanol, and gained powder is the phosphatide complexes of silibinin.
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| CN201010222910.6A CN102309441B (en) | 2010-07-09 | 2010-07-09 | Silymarin medicinal composition wrapper and preparation method thereof |
| CN201180029030.XA CN102958510B (en) | 2010-07-09 | 2011-07-08 | A kind of Silymarin medicinal composition wrapper and preparation method thereof |
| PCT/CN2011/076988 WO2012003804A1 (en) | 2010-07-09 | 2011-07-08 | Pharmaceutical composition of silybin and preparation method thereof |
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| NL2032689B1 (en) * | 2022-08-05 | 2023-04-12 | Moms Garden Gmbh | Milk thistle extract complex, preparation method thereof and use in protecting liver, whitening skin and aiding sleep |
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| US8877259B2 (en) | 2012-02-09 | 2014-11-04 | Mary Kay Inc. | Cosmetic formulation |
| CN105983014A (en) * | 2015-03-23 | 2016-10-05 | 天士力制药集团股份有限公司 | Medicine composition containing silibinin, VE and L-carnitine |
| CN112494452B (en) * | 2020-12-16 | 2023-01-06 | 福建瑞泰来医药科技有限公司 | Silibinin capsule and preparation method thereof |
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| NL2032689B1 (en) * | 2022-08-05 | 2023-04-12 | Moms Garden Gmbh | Milk thistle extract complex, preparation method thereof and use in protecting liver, whitening skin and aiding sleep |
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| CN102309441A (en) | 2012-01-11 |
| CN102958510B (en) | 2015-09-09 |
| WO2012003804A1 (en) | 2012-01-12 |
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Address after: 300410 Tianjin city Beichen District Huaihe road and road intersection Dingjiang tianzhijiao Park forensic Center for Intellectual Property Department Patentee after: Tasly Pharmaceutical Group Limited by Share Ltd Address before: 300410 Tianjin City Hedong District of Beichen Puji Road No. 2 city of the modern Chinese Medicine Patentee before: Tasly Pharmaceutical Group Co., Ltd. |
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Effective date of registration: 20191205 Address after: 300410 Tianjin City Hedong District of Beichen Puji Road No. 2 (city of the modern Chinese Medicine) Co-patentee after: Tianjin Tasly sants Pharmaceutical Co. Ltd. Patentee after: Tasly Pharmaceutical Group Limited by Share Ltd Address before: 300410 Tianjin city Beichen District Huaihe road and road intersection Dingjiang tianzhijiao Park forensic Center for Intellectual Property Department Patentee before: Tasly Pharmaceutical Group Limited by Share Ltd |