CN102309441A - Silymarin medicinal composition wrapper and preparation method thereof - Google Patents
Silymarin medicinal composition wrapper and preparation method thereof Download PDFInfo
- Publication number
- CN102309441A CN102309441A CN2010102229106A CN201010222910A CN102309441A CN 102309441 A CN102309441 A CN 102309441A CN 2010102229106 A CN2010102229106 A CN 2010102229106A CN 201010222910 A CN201010222910 A CN 201010222910A CN 102309441 A CN102309441 A CN 102309441A
- Authority
- CN
- China
- Prior art keywords
- injection
- silybin
- solution
- solvent
- phospholipid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 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 229
- 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 206
- 238000002360 preparation method Methods 0.000 title claims abstract description 79
- 239000000203 mixture Substances 0.000 title abstract description 11
- 229960004245 silymarin Drugs 0.000 title abstract description 9
- 235000017700 silymarin Nutrition 0.000 title abstract description 9
- 238000002347 injection Methods 0.000 claims abstract description 203
- 239000007924 injection Substances 0.000 claims abstract description 203
- 229940090044 injection Drugs 0.000 claims abstract description 201
- 239000000243 solution Substances 0.000 claims abstract description 166
- 239000012155 injection solvent Substances 0.000 claims abstract description 81
- 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
- 239000003814 drug Substances 0.000 claims abstract description 34
- 229940093181 glucose injection Drugs 0.000 claims abstract description 31
- 239000002904 solvent Substances 0.000 claims abstract description 26
- 235000014899 silybin Nutrition 0.000 claims description 219
- 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 187
- 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 186
- 229940043175 silybin Drugs 0.000 claims description 186
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 129
- 230000001954 sterilising effect Effects 0.000 claims description 84
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 69
- 238000001914 filtration Methods 0.000 claims description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 50
- 239000008215 water for injection Substances 0.000 claims description 42
- 150000003904 phospholipids Chemical class 0.000 claims description 41
- 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 39
- 229940083466 soybean lecithin Drugs 0.000 claims description 39
- 229950000628 silibinin Drugs 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- -1 silibinin phospholipid Chemical class 0.000 claims description 28
- 238000010008 shearing Methods 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 26
- 229960003964 deoxycholic acid Drugs 0.000 claims description 21
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[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 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 claims description 21
- 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 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 12
- 238000004806 packaging method and process Methods 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 10
- 239000003833 bile salt Substances 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 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 8
- 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 7
- 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 7
- 229940067606 lecithin Drugs 0.000 claims description 7
- 239000000787 lecithin Substances 0.000 claims description 7
- 235000010445 lecithin Nutrition 0.000 claims description 7
- 238000012856 packing Methods 0.000 claims description 7
- 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 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
- 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 6
- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 claims description 6
- 210000002969 egg yolk Anatomy 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- 238000002390 rotary evaporation Methods 0.000 claims description 6
- VMSNAUAEKXEYGP-YEUHZSMFSA-M sodium glycodeoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 VMSNAUAEKXEYGP-YEUHZSMFSA-M 0.000 claims description 6
- WDFRNBJHDMUMBL-OICFXQLMSA-M sodium;(4r)-4-[(3r,5s,7r,8r,9s,10s,13r,14s,17r)-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoate 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)CC1 WDFRNBJHDMUMBL-OICFXQLMSA-M 0.000 claims description 6
- 229940068886 polyethylene glycol 300 Drugs 0.000 claims description 5
- 229960005150 glycerol Drugs 0.000 claims description 4
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 4
- OABYVIYXWMZFFJ-ZUHYDKSRSA-M sodium glycocholate 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)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 OABYVIYXWMZFFJ-ZUHYDKSRSA-M 0.000 claims description 4
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 3
- 229940113115 polyethylene glycol 200 Drugs 0.000 claims description 3
- 229940057847 polyethylene glycol 600 Drugs 0.000 claims description 3
- 229960004063 propylene glycol Drugs 0.000 claims description 2
- WDFRNBJHDMUMBL-FUXQPCDDSA-M sodium;(4r)-4-[(3r,5s,7s,8r,9s,10s,13r,14s,17r)-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoate 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)CC1 WDFRNBJHDMUMBL-FUXQPCDDSA-M 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims 1
- 239000008103 glucose Substances 0.000 abstract description 25
- 230000000694 effects Effects 0.000 abstract description 15
- 229940079593 drug Drugs 0.000 abstract description 5
- 230000002829 reductive effect Effects 0.000 abstract description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 88
- 238000011049 filling Methods 0.000 description 54
- 239000011521 glass Substances 0.000 description 46
- 229910052799 carbon Inorganic materials 0.000 description 45
- 238000007789 sealing Methods 0.000 description 45
- 229910052757 nitrogen Inorganic materials 0.000 description 44
- 238000005303 weighing Methods 0.000 description 44
- 238000011010 flushing procedure Methods 0.000 description 34
- 238000007796 conventional method Methods 0.000 description 33
- 238000004659 sterilization and disinfection Methods 0.000 description 32
- 239000012982 microporous membrane Substances 0.000 description 24
- 239000012528 membrane Substances 0.000 description 14
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 10
- 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 description 10
- 229910052708 sodium Inorganic materials 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 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 7
- 210000004185 liver Anatomy 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 239000005022 packaging material Substances 0.000 description 4
- 230000007547 defect Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000004576 sand Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 206010067125 Liver injury Diseases 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 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 2
- 239000012535 impurity Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 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 1
- 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 1
- 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
- 206010067484 Adverse reaction Diseases 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
- 241000208838 Asteraceae Species 0.000 description 1
- 208000008964 Chemical and Drug Induced Liver Injury Diseases 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 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 1
- 244000272459 Silybum marianum Species 0.000 description 1
- 235000010841 Silybum marianum Nutrition 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000001471 micro-filtration Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003551 muscarinic effect Effects 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
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 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 invention relates to the technical field of medicines, in particular to a pharmaceutical combination packaging material and a preparation method thereof, and specifically relates to a silybin pharmaceutical combination packaging material and a preparation method thereof.
Background
Silybin, alternative name of drug: silymarin, liver-benefiting, Silybin, Silymarin, LEGALON. Silibinin is an effective component extracted from seeds of Silybum marianum (L) Genrtn of Compositae, is a polyhydroxy benzene chromone, and has another isomer, called Isosilybin. Pharmacological research finds that silybin has an obvious liver protection effect, the effect is reflected in the pharmacological effects of eliminating active oxygen in vivo, resisting lipid peroxidation, inhibiting the generation of Nitric Oxide (NO), inhibiting the activity of 5-lipoxygenase, resisting the evacuation of glutathione (GsH), protecting liver cell membranes, promoting liver cell repair, regeneration, immunoregulation, resisting hepatic fibrosis and the like, and in addition, the silybin has an obvious protection effect on various types of liver injuries caused by liver toxicants such as carbon tetrachloride, muscarinic and the like. Therefore, clinically, silibinin becomes one of the widely used liver protection drugs, and is used for treating various liver diseases such as chronic liver disease, toxic hepatitis, liver cirrhosis, fatty liver, alcoholic liver damage, other toxic metabolic liver damage and the like.
The early clinical use of various silybin preparations is mostly oral preparations, but because the silybin preparations are hardly dissolved in water and grease, the bioavailability is low, the absorption amount is unstable, and the clinical curative effect is greatly reduced. In order to improve the curative effect, the oral preparation of the compound of the meglumine salt and the phospholipid of the silibinin is sequentially marketed, and although the curative effect is improved, the bioavailability is not obviously improved.
In order to remarkably improve the bioavailability of the silybin in vivo, the silybin can be prepared into an injection preparation for use, the bioavailability can reach one hundred percent due to direct intravenous administration, the liver protection effect of the silybin is remarkably improved, the treatment time of a patient can be shortened, and the treatment cost is also saved. At present, many studies on silybin injection are to prepare it into meglumine salt, then prepare it into freeze-dried powder, and administer it after dissolving it with alkaline water for injection (pH > 9.0) or aqueous solution of meglumine before use. The clinical use of the medicine is limited due to the following two defects. Firstly, the pH value of the aqueous solution of the slightly alkaline meglumine salt is larger, the pH value is more than 9.0, the normal pH value of the blood of a human body is 7.35-7.45, a plurality of adverse reactions can be brought to a patient taking the medicine, and in addition, the silybin is extremely unstable in the slightly alkaline solution, and the content of the silybin can be reduced in the preparation and clinical use processes, so that the treatment effect is influenced; secondly, the complex preparation process causes a lot of difficulties for large-scale production, the preparation of the silybin meglumine salt brings about the residue of organic solvent and the loss of medicine, the preparation process of the meglumine salt freeze-dried powder is long and complex, and the preparation cost of the injection is obviously increased.
Aiming at the defects, the invention provides a stable silybin injection with good curative effect and a preparation process thereof.
Disclosure of Invention
The invention aims to overcome the defects of the existing silybin preparation and provides a silybin medicinal composition wrapper which has good stability, small toxic and side effects and remarkable curative effect.
The packing material of the silybin pharmaceutical composition is formed by packaging the silybin injection solution and the injection solvent in a combined way, and the two medicaments are respectively and independently loaded in a container and are packaged together in a combined way. It should be particularly noted that the combination package described herein is not limited to any material for packaging, as long as the material is suitable for use as a package for pharmaceutical products; the packaging material is not required to be any way to package the pharmaceutical composition, as long as the packaging material is suitable for respectively sealing the silybin injection solution and the injection solvent. The two medicaments are separately loaded in the containers, which means that the two solutions are respectively sealed and not communicated, but the two containers are not necessarily spatially isolated from each other, for example, the two containers may be directly connected to each other, or a pipeline may be arranged in the middle, the two containers are respectively sealed before use, and the pipeline between the two containers can be opened to communicate the two containers when in use. In general, this description is given for the sake of illustration only of some ways of carrying out the invention, and any variations or modifications of the embodiments of the invention are considered to be included in the scope of the invention, without departing from the spirit thereof.
The silybin injection solution disclosed by the invention comprises the following components:
component content (g/ml)
0.01 to 10.0 percent of active ingredients of the medicine,
0.1 to 30.0 percent of phospholipid,
the rest is solvent A for injection;
wherein,
the pharmaceutically active ingredient is selected from: silibinin or silibinin phospholipid complex;
the phospholipid is selected from: one or more of soybean lecithin, egg yolk lecithin, distearoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine and dimyristoyl phosphatidylcholine, preferably soybean lecithin and/or egg yolk lecithin;
the solvent A for injection is selected from: one or more of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, glycerol, propylene glycol and absolute ethyl alcohol, preferably one or more of propylene glycol, absolute ethyl alcohol and polyethylene glycol 400.
Preferably, the silybin injection solution disclosed by the invention consists of the following components:
component content (g/ml)
0.1-5.0% of active pharmaceutical ingredient;
2.0-25% of phospholipid;
the rest is solvent A for injection.
More preferably, the silybin injection solution provided by the invention comprises the following components:
component content (g/ml)
0.3 percent of silybin
10 percent of soybean lecithin
The balance of propylene glycol.
The injection solvent comprises the following components:
component content (g/ml)
0.1 to 20.0 percent of bile salt,
the rest is solvent B for injection.
Wherein,
the bile salt is selected from one or more of sodium cholate, sodium deoxycholate, sodium glycocholate, sodium glycodeoxycholate, sodium ursodeoxycholate, sodium chenodeoxycholate, sodium taurocholate and sodium dehydrocholate, preferably: sodium cholate and/or sodium deoxycholate;
the solvent B for injection is selected from: propylene glycol and/or water for injection, preferably water for injection.
Preferably, the injection solvent of the invention consists of the following components:
component content (g/ml)
5.0 to 15.0 percent of bile salt;
the rest is solvent B for injection.
More preferably, the injection solvent of the present invention comprises the following components:
component content (g/ml)
10% of sodium deoxycholate;
the rest is solvent B for injection.
In the silybin pharmaceutical composition wrapper, the volume ratio of the silybin injection solution to the injection solvent is 1: 99-99: 1, preferably 1: 9-9: 1.
The formulation of the other most preferred silybin pharmaceutical combination packages of the present invention is in the examples.
The silybin pharmaceutical composition wrapper of the invention can be used for intravenous administration after being uniformly mixed and diluted by diluent in clinical use, and the diluent can be any clinically available diluent, including but not limited to glucose injection, normal saline injection and the like, and preferably glucose injection. The amount of diluent used can be readily determined by the clinician in light of the prior art and his basic knowledge.
The silybin pharmaceutical composition package of the present invention may further comprise a diluent, and the diluent may be any clinically available diluent, including but not limited to glucose injection, physiological saline injection, etc., preferably glucose injection.
In the silybin pharmaceutical composition wrapper, the volume ratio of the silybin injection solution, the injection solvent and the diluent is 1-99: 1-99, preferably 1-9: 1-9.
The invention also aims to provide a preparation method of the silybin medicinal combination packing.
The preparation method of the silybin medicinal composition packing material comprises the following steps: preparing silybin injection solution and injection solvent respectively, and packaging together.
When the active pharmaceutical ingredient in the silybin injection solution is silybin, the preparation of the silybin injection solution comprises the following steps:
(1) dissolving the active ingredients and phospholipid in a proper amount of solvent A for injection according to the mixture ratio;
(2) adding needle activated carbon into the above solution to adsorb impurities, filtering, packaging the filtrate, and sterilizing.
Specifically, the method comprises the following steps:
(1) adding the active ingredients of the medicine and phospholipid into a proper amount of solvent A for injection according to the proportion, stirring or shearing the mixture to dissolve the active ingredients and the phospholipid at the temperature of between 25 and 80 ℃, and then fixing the volume to the full volume by using the solvent for injection;
(2) adding activated carbon for injection into the solution at 0.02-3.5% (g/ml) of the solution, adsorbing at 30-75 deg.C for 20-70 min, filtering, packaging the filtrate, and sterilizing.
If the silybin pharmaceutical combination wrapper of the invention is used, and if the active ingredient of the silybin injection solution is the silybin phospholipid complex, the silybin phospholipid complex can be purchased from the market, or prepared according to the prior art method, or prepared according to the following formula by the following method:
the formula of the silybin phospholipid complex comprises the following components: silybin and phospholipid in the mass ratio of 1: 0.5-1: 10;
the phospholipid in the silibinin phospholipid complex is selected from one or more of soybean lecithin, egg yolk lecithin, distearoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine and dimyristoyl phosphatidylcholine, and preferably soybean lecithin and/or egg yolk lecithin.
The preparation method of the silybin phospholipid complex specifically comprises the following steps: adding silybin and phospholipid into 5-50 times of absolute ethanol, dissolving in water bath at 40-55 ℃, and removing ethanol by rotary evaporation to obtain powder, namely the phospholipid complex of the silybin.
The silybin drug combination packing material provided by the invention comprises the following steps of:
(1) dissolving bile salt with solvent B for injection according to the above proportion;
(2) adding needle activated carbon into the above solution to adsorb impurities, filtering, packaging the filtrate, and sterilizing.
Specifically, the method comprises the following steps:
(1) adding bile salt into a proper amount of solvent B for injection according to a ratio, stirring or shearing for dissolving at 25-80 ℃, and then fixing the volume to the full volume by using the solvent B for injection;
(2) adding activated carbon for injection into the solution at 0.02-3.5% (g/ml) of the solution, adsorbing at 30-75 deg.C for 20-70 min, filtering, packaging the filtrate, and sterilizing.
Wherein, the sterilization in the preparation process of the injection solution and the solvent is carried out by adopting high-temperature steam, circulating steam or a microporous filter membrane, preferably high-temperature steam for sterilization, wherein the high-temperature sterilization temperature is 100 ℃ and 121 ℃, and the time is 8-45 minutes; the filtration devices used include, but are not limited to, microfiltration membranes, sand filter rods, sintered funnels, or bag filters.
The most preferred processes for the preparation of silybin injections according to the invention are given in the examples.
Compared with the traditional oral preparation, the silybin injection provided by the invention has the advantages that the bioavailability is obviously improved, the liver protection curative effect is greatly improved, the safety and the stability are higher, the quality guarantee period of the product is prolonged, in addition, the preparation process of the silybin injection provided by the invention is simple, the raw material price is low, and the production cost of the injection is also obviously reduced.
Detailed Description
The invention is further illustrated by the following specific examples, which are not to be construed as limiting the invention.
Example 1 Silibinin injection of the invention
1. Preparation of silybin injection solution
Weighing 0.5 g of silybin and 15g of soybean lecithin, adding the silybin and the soybean lecithin into a proper amount of propylene glycol, shearing at 50 ℃ (10000rpm) until the medicine and the phospholipid are completely dissolved, then fixing the volume to 150 ml by using the propylene glycol, adding 2.5 g of active carbon for injection into the solution, adsorbing for 30 minutes at 40 ℃, filtering by using a microporous membrane, filling into a glass bottle according to 1.5 ml/branch, filling nitrogen by a conventional method, sealing, and sterilizing for 15 minutes at 121 ℃ by using a high-temperature steam sterilization pot to obtain the silybin injection solution.
2. Preparation of injection solvent
Weighing 35 g of sodium deoxycholate into a proper amount of water for injection, stirring at 25 ℃ to dissolve the sodium deoxycholate, then using the water for injection to fix the volume to 350 ml, adding 3.5 g of active carbon for injection into the solution, adsorbing at 35 ℃ for 30 minutes, filtering by a microporous membrane, filling 3.5 ml/branch of the solution into a glass bottle, filling nitrogen in the glass bottle by a conventional method, sealing the glass bottle, and sterilizing by a high-temperature steam sterilization kettle at 121 ℃ for 15 minutes to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 2 Silibinin injection of the invention
1. Preparation of silybin injection solution
Weighing 1 g of silybin and 20 g of soybean lecithin, adding the silybin and the soybean lecithin into a proper amount of propylene glycol, shearing at 50 ℃ (8000rpm) until the medicine and the phospholipid are completely dissolved, then adding propylene glycol to a constant volume of 150 ml, adding 6 g of active carbon for injection into the solution, adsorbing at 60 ℃ for 20 minutes, filtering by using a microporous filter membrane, filling 1.5 ml/branch into a glass bottle, filling nitrogen conventionally, sealing, and sterilizing by using a high-temperature steam sterilization pot at 115 ℃ for 18 minutes to obtain the silybin injection solution.
2. Preparation of injection solvent
Weighing 17.5 g of sodium deoxycholate into a proper amount of water for injection, stirring at 25 ℃ to dissolve the sodium deoxycholate, then fixing the volume to 350 ml by using the water for injection, adding 1.75 g of active carbon for injection into the solution, adsorbing at 45 ℃ for 25 minutes, filtering by using a microporous filter membrane, filling 3.5 ml/branch of the solution into a glass bottle, filling nitrogen by a conventional method, sealing, and sterilizing by using a high-temperature steam sterilization pot at 118 ℃ for 18 minutes to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 3 Silibinin injection of the invention
1. Preparation of silybin injection solution
Weighing 1.5g of silybin and 35 g of egg yolk lecithin, adding the silybin and the egg yolk lecithin into a proper amount of propylene glycol, shearing at 50 ℃ (10000rpm) until the medicine and the phospholipid are completely dissolved, then using the propylene glycol to fix the volume to 300 ml, adding 10.5 g of active carbon for injection into the solution, adsorbing at 53 ℃ for 30 minutes, filtering by using a bag filter, filling 3 ml/branch into a glass bottle, filling nitrogen conventionally, sealing, and sterilizing at 115 ℃ for 30 minutes by using a high-temperature steam sterilization pot to obtain the silybin injection solution.
2. Preparation of injection solvent
Weighing 15g of sodium deoxycholate into a proper amount of water for injection, stirring at 35 ℃ to dissolve the sodium deoxycholate, then using the water for injection to fix the volume to 200 ml, adding 1.1 g of active carbon for injection into the solution, adsorbing at 55 ℃ for 35 minutes, filtering by using a bag filter, filling 2 ml/branch into a glass bottle, flushing nitrogen conventionally, sealing, and sterilizing by using a high-temperature steam sterilization pot at 115 ℃ for 30 minutes to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 4 Silibinin injection of the invention
1. Preparation of silybin injection solution
Weighing 1.67 g of silybin, 10 g of soybean lecithin and 13 g of yolk lecithin, adding the materials into a proper amount of propylene glycol, shearing at 70 ℃ (10000rpm) until the materials and the phospholipids are completely dissolved, then using the propylene glycol to fix the volume to 200 ml, adding 4.7 g of active carbon for injection into the solution, adsorbing at 30 ℃ for 70 minutes, filtering by using a sand filter stick, filling the solution into glass bottles according to 2 ml/piece, flushing nitrogen by a conventional method, sealing the bottles, and sterilizing by using circulating steam at 100 ℃ for 35 minutes to obtain the silybin injection solution.
2. Preparation of injection solvent
Weighing 18 g of sodium deoxycholate into a proper amount of propylene glycol, stirring at 40 ℃ to dissolve the sodium deoxycholate, then using the propylene glycol to fix the volume to 300 ml, adding 1.5g of active carbon for injection into the solution, adsorbing at 30 ℃ for 70 minutes, filtering by using a sand filter stick, filling 3 ml/piece of the solution into a glass bottle, filling nitrogen by a conventional method, sealing, and sterilizing by using 100 ℃ circulating steam for 35 minutes to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 5 Silibinin injection of the invention
1. Preparation of silybin injection solution
Weighing 0.3 g of silybin and 6 g of soybean lecithin, adding the silybin and the soybean lecithin into a proper amount of absolute ethyl alcohol, shearing at 50 ℃ (10000rpm) until the medicine and the phospholipid are completely dissolved, then using the absolute ethyl alcohol to fix the volume to 300 ml, adding 5g of active carbon for injection into the solution, adsorbing at 60 ℃ for 30 minutes, filtering by using a microporous membrane, filling 3 ml/branch into a glass bottle, flushing nitrogen by a conventional method, sealing, and sterilizing by using a high-temperature steam sterilization pot at 121 ℃ for 12 minutes to obtain the silybin injection solution.
2. Preparation of injection solvent
Weighing 10 g of sodium cholate into a proper amount of water for injection, stirring at 50 ℃ to dissolve the sodium cholate, then fixing the volume to 200 ml by using the water for injection, adding 0.4 g of active carbon for injection into the solution, adsorbing at 60 ℃ for 30 minutes, filtering by using a microporous membrane, filling 2 ml/piece of the solution into a glass bottle, flushing nitrogen by a conventional method, sealing, and sterilizing by using a high-temperature steam sterilization pot at 121 ℃ for 12 minutes to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 6 Silibinin injection of the invention
1. Preparation of silybin injection solution
Weighing 1.67 g of silybin and 0.75 g of distearoyl phosphatidylcholine, adding into 40 ml of propylene glycol, shearing at 50 ℃ (10000rpm) until the medicine and the phospholipid are completely dissolved, then using absolute ethyl alcohol to fix the volume to 50 ml, adding 0.1 g of active carbon for injection into the solution, adsorbing at 45 ℃ for 25 minutes, filtering by using a bag filter, filling into a glass bottle according to 0.5 ml/branch, flushing nitrogen conventionally, sealing, and sterilizing by using a high-temperature steam sterilization pot at 118 ℃ for 20 minutes to obtain the silybin injection solution.
2. Preparation of injection solvent
Weighing 36 g of sodium cholate into a proper amount of water for injection, stirring at 50 ℃ to dissolve the sodium cholate, then fixing the volume to 450 ml by using the water for injection, adding 0.9 g of active carbon for injection into the solution, adsorbing at 45 ℃ for 30 minutes, filtering by using a capsule filter, filling 4.5 ml/piece of the active carbon into a glass bottle, flushing nitrogen by a conventional method, sealing, and sterilizing by using a high-temperature steam sterilizing pot at 118 ℃ for 20 minutes to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 7 Silibinin injection of the invention
1. Preparation of silybin injection solution
Weighing 45 g of silybin, 82.5 g of soybean lecithin and 52.5 g of dipalmitoyl phosphatidylcholine, adding into 150 ml of propylene glycol, shearing at 70 ℃ (10000rpm) until the medicine and the phospholipids are completely dissolved, then using polyethylene glycol 400 to fix the volume to 450 ml, adding 0.09 g of active carbon for injection into the solution, adsorbing at 60 ℃ for 20 minutes, filtering by using a microporous membrane, filling into a glass bottle according to 4.5 ml/branch, flushing nitrogen conventionally, sealing, and sterilizing by using 100 ℃ circulating steam for 35 minutes to obtain the silybin injection solution.
2. Preparation of injection solvent
Weighing 5g of sodium glycocholate and 5g of sodium dehydrocholate into a proper amount of water for injection, stirring at 65 ℃ to dissolve the sodium glycocholate, then fixing the volume to 50 ml with the water for injection, adding 0.025 g of active carbon for injection into the solution, adsorbing at 35 ℃ for 30 minutes, filtering by a microporous filter membrane, filling into a glass bottle according to 0.5 ml/branch, flushing nitrogen by a conventional method, sealing, and sterilizing by 100 ℃ circulating steam for 35 minutes to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 8 Silibinin injection of the invention
1. Preparation of silybin injection solution
Weighing 0.8 g of silybin and 20.7 g of soybean lecithin, adding the silybin and the soybean lecithin into a proper amount of propylene glycol, shearing at 65 ℃ (10000rpm) until the medicine and the phospholipid are completely dissolved, then fixing the volume to 200 ml by using the propylene glycol, adding 6.7 g of active carbon for injection into the solution, adsorbing for 30 minutes at 60 ℃, filtering by using a microporous membrane, filling into a glass bottle according to 2 ml/branch, flushing nitrogen by a conventional method, sealing, and sterilizing for 10 minutes at 121 ℃ by using a high-temperature steam sterilization pot to obtain the silybin injection solution.
2. Preparation of injection solvent
Weighing 30 g of sodium deoxycholate into a proper amount of water for injection, stirring at 35 ℃ to dissolve the sodium deoxycholate, then using the water for injection to fix the volume to 300 ml, adding 10.5 g of active carbon for injection into the solution, adsorbing at 35 ℃ for 30 minutes, filtering by using a microporous membrane, filling 3 ml/branch of the solution into a glass bottle, flushing nitrogen by a conventional method, sealing, and sterilizing by using a high-temperature steam sterilization pot at 121 ℃ for 10 minutes to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 9 Silibinin injection of the invention
1. Preparation of silybin injection solution
Weighing 0.03 g of silybin, 0.6 g of dimyristoyl phosphatidylcholine and 0.4 g of soybean lecithin, adding into 200 ml of propylene glycol, shearing at 45 ℃ (10000rpm) until the medicine and the phospholipid are completely dissolved, then fixing the volume to 300 ml by using glycerol, adding 0.5 g of active carbon for injection into the solution, adsorbing at 40 ℃ for 30 minutes, filtering by using a microporous membrane, filling into glass bottles according to the ratio of 3 ml/branch, flushing nitrogen conventionally, sealing, and sterilizing by using a high-temperature steam sterilization pot at 121 ℃ for 15 minutes to obtain the silybin injection solution.
2. Preparation of injection solvent
Weighing 0.1 g of sodium glycodeoxycholate and 0.1 g of sodium dehydrocholate into a proper amount of water for injection, stirring at 25 ℃ to dissolve the sodium glycodeoxycholate and the sodium dehydrocholate, then fixing the volume to 200 ml with the water for injection, adding 1 g of activated carbon for injection into the solution, adsorbing at 35 ℃ for 30 minutes, filtering with a microporous membrane, filling into a glass bottle according to the volume of 2 ml per branch, flushing nitrogen conventionally, sealing, and sterilizing with a high-temperature steam sterilization pot at 121 ℃ for 15 minutes to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 10 Silibinin injection of the invention
1. Preparation of silybin injection solution
Weighing 0.85 g of silybin and 40 g of soybean lecithin, adding the silybin and the soybean lecithin into a proper amount of propylene glycol, shearing at 80 ℃ (10000rpm) until the medicine and the phospholipid are completely dissolved, then fixing the volume to 150 ml by using the propylene glycol, adding 5.7 g of active carbon for injection into the solution, adsorbing for 30 minutes at 75 ℃, filtering the active carbon by using a vertical melting funnel, filtering the active carbon, filtering and sterilizing by using a 0.22 mu m microporous filter membrane, filling 1.5 ml/branch of the solution into a glass bottle, flushing nitrogen conventionally, and sealing to obtain the silybin injection solution.
2. Preparation of injection solvent
Weighing 70 g of sodium deoxycholate into a proper amount of water for injection, stirring at 80 ℃ to dissolve the sodium deoxycholate, then using the water for injection to fix the volume to 350 ml, adding 10.5 g of active carbon for injection into the solution, adsorbing at 75 ℃ for 30 minutes, filtering the active carbon by a vertical melting funnel, filtering and sterilizing by a 0.22 mu m microporous filter membrane, filling 3.5 ml/branch of the solution into a glass bottle, flushing nitrogen by a conventional method, and sealing to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 11 Silibinin injection of the invention
1. Preparation of silybin injection solution
Weighing 7.5 g of silybin, 27.5 g of soybean lecithin and 5g of yolk lecithin, adding the materials into a proper amount of propylene glycol, shearing at 50 ℃ (10000rpm) until the materials and the phospholipids are completely dissolved, then using the propylene glycol to fix the volume to 150 ml, adding 4g of active carbon for injection into the solution, adsorbing at 40 ℃ for 30 minutes, filtering by using a microporous membrane, filling 1.5 ml/branch into a glass bottle, flushing nitrogen by a conventional method, sealing, and sterilizing by using a high-temperature steam sterilization pot at 118 ℃ for 15 minutes to obtain the silybin injection solution.
2. Preparation of injection solvent
Weighing 43.8 g of sodium deoxycholate and 8.7 g of sodium cholate into a proper amount of water for injection, stirring at 25 ℃ to dissolve the sodium deoxycholate and the sodium cholate, then using the water for injection to fix the volume to 350 ml, adding 2.3 g of active carbon for injection into the solution, adsorbing at 35 ℃ for 30 minutes, filtering by using a microporous membrane, filling into a glass bottle according to the volume of 3.5 ml per branch, flushing nitrogen by a conventional method, sealing, and sterilizing by using a high-temperature steam sterilization pot at 118 ℃ for 15 minutes to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 12 Silibinin injection of the invention
1. Preparation of silybin injection solution
Weighing 0.73 g of silybin and 5g of egg yolk lecithin, adding the silybin and the egg yolk lecithin into 70 ml of propylene glycol, shearing at 50 ℃ (10000rpm) until the medicine and the phospholipid are completely dissolved, then using absolute ethyl alcohol to fix the volume to 150 ml, adding 3.5 g of active carbon for injection into the solution, adsorbing for 30 minutes at 40 ℃, filtering by using a microporous membrane, filling into a glass bottle according to 1.5 ml/branch, flushing nitrogen by a conventional method, sealing, and sterilizing for 45 minutes by using 100 ℃ circulating steam to obtain the silybin injection solution.
2. Preparation of injection solvent
Weighing 17.5 g of sodium taurocholate and 7 g of sodium ursodesoxycholate into a proper amount of water for injection, stirring at 25 ℃ to dissolve the sodium taurocholate and the sodium ursodesoxycholate, then fixing the volume to 350 ml by using the water for injection, adding 10.5 g of active carbon for injection into the solution, adsorbing at 35 ℃ for 30 minutes, filtering by using a microporous membrane, filling into a glass bottle according to the volume of 3.5 ml/branch, flushing nitrogen by a conventional method, sealing, and sterilizing by using 100 ℃ circulating steam for 45 minutes to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 13 Silibinin injection of the invention
1. Preparation of silybin injection solution
Weighing 3.51 g of silybin and 10 g of soybean lecithin, adding the silybin and the soybean lecithin into 100 ml of propylene glycol, shearing at 65 ℃ (10000rpm) until the medicine and the phospholipid are completely dissolved, then using polyethylene glycol 200 to fix the volume to 200 ml, adding 3.3 g of activated carbon for injection into the solution, adsorbing at 40 ℃ for 30 minutes, filtering by using a bag filter, filling 2 ml/branch into a glass bottle, flushing nitrogen by a conventional method, sealing, and sterilizing by using a high-temperature steam sterilization pot at 121 ℃ for 15 minutes to obtain the silybin injection solution.
2. Preparation of injection solvent
Weighing 40.5 g of sodium ursodesoxycholate into a proper amount of water for injection, stirring at 45 ℃ to dissolve the sodium ursodesoxycholate, then fixing the volume to 300 ml with the water for injection, adding 6 g of active carbon for injection into the solution, adsorbing at 35 ℃ for 30 minutes, filtering with a microporous membrane, filling 3 ml/branch of the solution into a glass bottle, flushing nitrogen conventionally, sealing, and sterilizing with a high-temperature steam sterilizer at 121 ℃ for 15 minutes to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 14 Silibinin injection of the invention
1. Preparation of silybin injection solution
Weighing 2.1 g of silybin, 17 g of soybean lecithin and 27 g of dipalmitoyl phosphatidylcholine, adding into 140 ml of propylene glycol, shearing at 40 ℃ (10000rpm) until the medicine and the phospholipids are completely dissolved, then using polyethylene glycol 600 to fix the volume to 400 ml, adding 10 g of active carbon for injection into the solution, adsorbing at 40 ℃ for 30 minutes, filtering by using a bag filter, filling into glass bottles according to 4 ml/branch, flushing nitrogen by a conventional method, sealing, and sterilizing by using a high-temperature steam sterilization pot at 118 ℃ for 15 minutes to obtain the silybin injection solution.
2. Preparation of injection solvent
Weighing 9 g of sodium taurocholate into a proper amount of water for injection, stirring at 55 ℃ to dissolve the sodium taurocholate, then fixing the volume to 100 ml with the water for injection, adding 1.5g of active carbon for injection into the solution, adsorbing at 35 ℃ for 30 minutes, filtering by using a bag filter, filling 1 ml/branch into a glass bottle, flushing nitrogen conventionally, sealing, and sterilizing by using a high-temperature steam sterilization pot at 118 ℃ for 15 minutes to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 15 Silibinin injection of the invention
1. Preparation of silybin injection solution
Weighing 1 g of silybin and 14 g of soybean lecithin, adding the silybin and the soybean lecithin into a proper amount of propylene glycol, shearing at 60 ℃ (8000rpm) until the medicine and the phospholipid are completely dissolved, then adding propylene glycol to a constant volume of 150 ml, adding 4.5 g of active carbon for injection into the solution, adsorbing at 40 ℃ for 30 minutes, filtering by using a microporous membrane, filling into a glass bottle according to the volume of 1.5 ml per minute, flushing nitrogen by a conventional method, sealing, and sterilizing by using a high-temperature steam sterilization pot at 121 ℃ for 15 minutes to obtain the silybin injection solution.
2. Preparation of injection solvent
Weighing 42 g of sodium chenodeoxycholate into a proper amount of water for injection, stirring at 35 ℃ to dissolve the sodium chenodeoxycholate, then fixing the volume to 350 ml by using the water for injection, adding 2.6 g of activated carbon for injection into the solution, adsorbing at 35 ℃ for 30 minutes, filtering by using a microporous membrane, filling 2 ml/piece of the solution into a glass bottle, flushing nitrogen by a conventional method, sealing, and sterilizing by using a high-temperature steam sterilization pot at 121 ℃ for 15 minutes to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 16 Silibinin injection of the invention
1. Preparation of silybin injection solution
Weighing 1.2 g of silybin, 12 g of dimyristoyl phosphatidylcholine and 16 g of lecithin, adding into 190 ml of absolute ethanol, shearing at 50 ℃ (10000rpm) until the medicine and the phospholipid are completely dissolved, then using propylene glycol to fix the volume to 300 ml, adding 10 g of active carbon for injection into the solution, adsorbing at 40 ℃ for 30 minutes, filtering by using a microporous membrane, filling into glass bottles according to 3 ml/branch, flushing nitrogen by a conventional method, sealing, and sterilizing by using circulating steam at 100 ℃ for 35 minutes to obtain the silybin injection solution.
2. Preparation of injection solvent
Weighing 9 g of sodium ursodesoxycholate and 10 g of sodium glycodeoxycholate into a proper amount of water for injection, stirring at 45 ℃ to dissolve the sodium ursodesoxycholate and the sodium glycodeoxycholate, then using the water for injection to fix the volume to 200 ml, adding 2.1 g of active carbon for injection into the solution, adsorbing at 35 ℃ for 30 minutes, filtering by using a microporous membrane, filling 2 ml/branch of the solution into a glass bottle, filling nitrogen by a conventional method, sealing, and sterilizing by using circulating steam at 100 ℃ for 35 minutes to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 17 Silibinin injection of the invention
1. Preparation of silybin injection solution
Weighing 0.45 g of silybin and 45 g of soybean lecithin, adding the silybin and the soybean lecithin into a proper amount of propylene glycol, shearing at 80 ℃ (10000rpm) until the medicine and the phospholipid are completely dissolved, then fixing the volume to 150 ml by using the propylene glycol, adding 0.03 g of active carbon for injection into the solution, adsorbing for 30 minutes at 75 ℃, filtering the active carbon by using a vertical melting funnel, filtering and sterilizing by using a 0.22 mu m microporous filter membrane, filling 1.5 ml/branch of the solution into a glass bottle, filling nitrogen by a conventional method, and sealing to obtain the silybin injection solution.
2. Preparation of injection solvent
Weighing 2.6 g of sodium cholate into 170 ml of propylene glycol, stirring at 25 ℃ to dissolve the sodium cholate, then using injection water to fix the volume to 350 ml, adding 1.75 g of active carbon for injection into the solution, adsorbing at 35 ℃ for 30 minutes, filtering the active carbon by a vertical melting funnel, filtering the active carbon by a 0.22 mu m microporous filter membrane for sterilization, filling the solution into a glass bottle according to 3.5 ml/branch, flushing nitrogen by a conventional method, and sealing to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 18 Silibinin injection of the invention
1. Preparation of silybin phospholipid complex
Adding 4g of silybin and 4.8g of soybean lecithin into 168 ml of absolute ethyl alcohol, dissolving in a water bath at 40 ℃, and then removing the ethyl alcohol by rotary evaporation to obtain powder, namely the phospholipid compound of the silybin.
2. Preparation of silybin injection solution
Weighing 1.87 g of silybin phospholipid complex and 22.7 g of soybean lecithin, adding into a proper amount of propylene glycol, shearing at 50 ℃ (10000rpm) until the medicine and the phospholipid are completely dissolved, then fixing the volume to 200 ml with the propylene glycol, adding 3.3 g of activated carbon for injection into the solution, adsorbing at 50 ℃ for 30 minutes, filtering with a microporous filter membrane, filling into a glass bottle according to 0.5 ml/branch, flushing nitrogen by a conventional method, sealing, and sterilizing with a high-temperature steam sterilization pot at 115 ℃ for 20 minutes to obtain the silybin injection solution.
3. Preparation of injection solvent
Weighing 36 g of sodium ursodesoxycholate and 15g of sodium taurocholate into 100 ml of propylene glycol, stirring at 25 ℃ to dissolve the sodium ursodesoxycholate and the sodium taurocholate, then using water for injection to fix the volume to 300 ml, adding 9 g of active carbon for injection into the solution, adsorbing at 35 ℃ for 30 minutes, filtering by using a microporous filter membrane, filling 4.5 ml/branch into a glass bottle, filling nitrogen by a conventional method, sealing, and sterilizing by using a high-temperature steam sterilization pot at 115 ℃ for 20 minutes to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 19 Silibinin injection of the invention
1. Preparation of silybin phospholipid complex
Adding 3g of silybin and 3.8g of soybean lecithin into 100 ml of absolute ethyl alcohol, dissolving in a water bath at 40 ℃, and then removing the ethyl alcohol by rotary evaporation to obtain powder, namely the phospholipid compound of the silybin.
2. Preparation of silybin injection solution
Weighing 2g of silybin phospholipid complex, 30 g of soybean lecithin and 20 g of yolk lecithin, adding the silybin phospholipid complex, the soybean lecithin and the yolk lecithin into 100 ml of propylene glycol, shearing at 55 ℃ (8000rpm) until the medicine and the phospholipid are completely dissolved, then using polyethylene glycol 300 to fix the volume to 300) ml, adding 5g of activated carbon for injection into the solution, adsorbing at 40 ℃ for 30 minutes, filtering with a microporous membrane, filling into glass bottles according to 4.5 ml/branch, flushing nitrogen by a conventional method, sealing, and sterilizing with a high-temperature steam sterilization pot at 115 ℃ for 25 minutes to obtain the silybin injection solution.
3. Preparation of injection solvent
Weighing 12 g of sodium cholate and 10 g of sodium dehydrocholate into a proper amount of water for injection, stirring at 25 ℃ to dissolve the sodium cholate and the sodium dehydrocholate, then fixing the volume to 200 ml by using the water for injection, adding 3g of active carbon for injection into the solution, adsorbing for 30 minutes at 35 ℃, filtering by using a microporous filter membrane, filling into a glass bottle according to 0.5 ml/branch, flushing nitrogen by a conventional method, sealing, and sterilizing for 25 minutes at 115 ℃ by using a high-temperature steam sterilizing pot to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 20 Silibinin injection of the invention
1. Preparation of silybin phospholipid complex
Adding 2g of silybin, 15g of soybean lecithin and 5g of egg yolk lecithin into 255 ml of absolute ethanol, dissolving in a water bath at 40 ℃, and then removing the ethanol by rotary evaporation to obtain powder, namely the phospholipid compound of the silybin.
2. Preparation of silybin injection solution
Weighing 5g of silybin phospholipid complex and 42 g of soybean lecithin, adding the silybin phospholipid complex and 42 g of soybean lecithin into 100 ml of propylene glycol, shearing at 70 ℃ until the medicine and the phospholipid are completely dissolved, then using glycerol to fix the volume to 150 ml, adding 2g of active carbon for injection into the solution, adsorbing at 50 ℃ for 30 minutes, filtering by using a microporous membrane, filling into a glass bottle according to the volume of 1.5 ml per branch, flushing nitrogen by a conventional method, sealing, and sterilizing by using a high-temperature steam sterilization pot at 118 ℃ for 20 minutes to obtain the silybin injection solution.
3. Preparation of injection solvent
Weighing 43.7 g of sodium deoxycholate into 150 ml of propylene glycol, stirring at 45 ℃ to dissolve the sodium deoxycholate, then using water for injection to fix the volume to 350 ml, adding 12.25 g of active carbon for injection into the solution, adsorbing at 35 ℃ for 30 minutes, filtering by using a microporous membrane, filling 3.5 ml/branch of the solution into a glass bottle, flushing nitrogen by a conventional method, sealing, and sterilizing by using a high-temperature steam sterilization pot at 118 ℃ for 20 minutes to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 21 Silibinin injection of the invention
1. Preparation of silybin phospholipid complex
Adding 3g of silybin and 1.5g of egg yolk lecithin into 100 ml of absolute ethyl alcohol, dissolving in a water bath at 40 ℃, and then removing the ethyl alcohol by rotary evaporation to obtain powder, namely the phospholipid compound of the silybin.
2. Preparation of silybin injection solution
Weighing 1.8 g of silybin phospholipid complex, 24 g of soybean lecithin and 5g of distearoyl phosphatidylcholine, adding into 100 ml of propylene glycol, shearing at 55 ℃ (8000rpm) until the medicine and the phospholipids are completely dissolved, then using polyethylene glycol 300 to fix the volume to 300 ml, adding 4.5 g of active carbon for injection into the solution, adsorbing at 40 ℃ for 30 minutes, filtering by using a microporous membrane, filling into a glass bottle according to 3 ml/branch, filling nitrogen by a conventional method, sealing, and sterilizing by using a high-temperature steam sterilization pot at 115 ℃ for 25 minutes to obtain the silybin injection solution.
3. Preparation of injection solvent
Weighing 12 g of sodium cholate and 9 g of sodium chenodeoxycholate into a proper amount of water for injection, stirring at 25 ℃ to dissolve the sodium cholate and the sodium chenodeoxycholate, then fixing the volume to 200 ml by using the water for injection, adding 2.9 g of activated carbon for injection into the solution, adsorbing at 35 ℃ for 30 minutes, filtering by using a microporous filter membrane, filling 2 ml/piece of the solution into a glass bottle, flushing nitrogen by a conventional method, sealing, and sterilizing at 115 ℃ for 25 minutes by using a high-temperature steam sterilizing pot to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Example 22 Silibinin injection of the invention
1. Preparation of silybin injection solution
Weighing 2.67 g of commercially available silybin phospholipid complex, 26.7 g of soybean lecithin and 8g of distearoyl phosphatidylcholine, adding into 200 ml of propylene glycol, shearing at 55 ℃ (8000rpm) until the medicine and the phospholipids are completely dissolved, then using polyethylene glycol 300 to fix the volume to 400 ml, adding 4.67 g of active carbon for injection into the solution, adsorbing at 40 ℃ for 30 minutes, filtering by using a microporous membrane, filling into glass bottles according to 4 ml/branch, flushing nitrogen conventionally, sealing, and sterilizing by using a high-temperature steam sterilization pot at 115 ℃ for 25 minutes to obtain the silybin injection solution.
2. Preparation of injection solvent
Weighing 10 g of sodium ursodesoxycholate into a proper amount of water for injection, stirring at 25 ℃ to dissolve the sodium ursodesoxycholate, then fixing the volume to 100 ml by using the water for injection, adding 1.3 g of active carbon for injection into the solution, adsorbing at 35 ℃ for 30 minutes, filtering by using a microporous membrane, filling 1 ml/branch of the solution into a glass bottle, flushing nitrogen by a conventional method, sealing, and sterilizing by using a high-temperature steam sterilization pot at 115 ℃ for 25 minutes to obtain the injection solvent.
In clinical application, one silybin injection solution and one injection solvent are mixed uniformly and then diluted into 5% glucose or 10% glucose injection for instillation.
Test for stability of drug
This test compares the stability of the formulations of the present invention with the conventional formulations in glucose solution.
Test samples: the preparation of the invention was taken as the sample in example 1; the common sample is meglumine salt of silybin, and is prepared by referring to the bracket literature (silybin powder injection quality standard and safety evaluation research, Harbin university of commerce college, Vol.23, No. 1, pages 15-18 of 2007). The glucose solution is 5% glucose injection.
Chromatographic conditions are as follows: liquid phase conditions: agilent 1100 liquid chromatogram, Agilent G1314A VWD detector, Agilent G1311A quaternary pump, Agilent G1314A VWD detector, Agilent LC1100 chromatogram data workstation, the analytical column is Diamonsil C18 analytical column (5 mu, 4.6mm multiplied by 250mm), methanol-2% glacial acetic acid (55: 45) is mobile phase, the flow rate is 1.0 ml/min, the detection wavelength is 288nm, the sample injection amount is 20 mu l, and the external standard method is used for peak area quantification.
The test method comprises the following steps: the sample in example 1 and the common sample are diluted in 5% glucose injection according to 80 mug/ml, the content of 0h is 100%, and the samples are injected for 0h, 2h, 4h and 6h, and the content change is compared.
The results of the tests are shown in the following table.
The tests prove that the preparation of the invention is more stable than the meglumine salt of silybin in the glucose injection, and has more research and development prospects.
Experiments prove that the silybin injection with other contents can achieve the effects of the experimental examples.
Claims (10)
1. A silybin pharmaceutical composition packing material is characterized in that the silybin pharmaceutical composition packing material comprises a silybin injection solution and an injection solvent which are respectively loaded in respective containers and packed together in a combined way,
the silybin injection solution comprises the following components in percentage by weight/volume:
0.01 to 10.0 percent of active ingredients of the medicine,
0.1 to 30.0 percent of phospholipid,
the rest is solvent A for injection;
wherein the pharmaceutically active ingredient is selected from: silibinin or silibinin phospholipid complex;
the phospholipid is selected from: one or more of soybean lecithin, yolk lecithin, distearoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine and dimyristoyl phosphatidylcholine;
the solvent A for injection is selected from: one or more of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, glycerol, propylene glycol and absolute ethyl alcohol;
wherein, the injection solvent comprises the following components by weight/volume percentage:
0.1 to 20.0 percent of bile salt,
the rest is solvent B for injection;
wherein the bile salt is selected from: one or more of sodium cholate, sodium deoxycholate, sodium glycocholate, sodium glycodeoxycholate, sodium ursodeoxycholate, sodium chenodeoxycholate, sodium taurocholate and sodium dehydrocholate;
the solvent B for injection is selected from: propylene glycol and/or water for injection.
2. The pharmaceutical combination package according to claim 1, wherein the silibinin injection solution consists of the following components in weight/volume percentage:
0.1-5.0% of active pharmaceutical ingredient;
2.0-25% of phospholipid;
the rest of solvent for injection.
3. The pharmaceutical combination package according to claim 2, wherein the silibinin injection solution consists of the following components in weight/volume percentage:
0.3 percent of silybin;
10% of soybean lecithin;
the balance of propylene glycol.
4. The pharmaceutical combination package of any one of claims 1-3, wherein the injection vehicle is comprised of the following weight/volume percentages of ingredients:
5.0 to 15.0 percent of bile salt;
the rest of solvent for injection.
5. The pharmaceutical combination package of claim 4, wherein the injection vehicle comprises the following components in weight/volume percent:
10% of sodium deoxycholate;
the rest of solvent for injection.
6. A pharmaceutical combination package according to any one of claims 1-3, further comprising a diluent.
7. The pharmaceutical composition package according to claim 6, wherein the diluent is a glucose injection solution.
8. The method for preparing any one of the pharmaceutical combination wrappers of claims 1-7, comprising preparing a silybin injection solution and an injection vehicle separately, and packaging together, wherein when the pharmaceutically active ingredient in the silybin injection solution is silybin, the preparing of the silybin injection solution comprises the following steps:
(1) adding silybin and phospholipid into a proper amount of solvent A for injection according to a ratio, stirring or shearing for dissolving at 25-80 ℃, and then fixing the volume to the full volume by using the solvent A for injection;
(2) adding activated carbon for injection into the solution according to 0.02-3.5% of the solution, adsorbing at 30-75 deg.C for 20-70 min, filtering, packaging, and sterilizing.
9. The preparation method of any one of the pharmaceutical combination packages of claims 1-7, which comprises preparing a silybin injection solution and an injection solvent respectively, and packaging the silybin injection solution and the injection solvent together, wherein the preparation method of the injection solvent is characterized by comprising the following steps:
(1) adding bile salt into a proper amount of solvent B for injection according to a ratio, stirring or shearing for dissolving at 25-80 ℃, and then fixing the volume to the full volume by using the solvent B for injection;
(2) adding activated carbon for injection into the solution according to 0.02-3.5% of the solution, adsorbing at 30-75 deg.C for 20-70 min, filtering, packaging, and sterilizing.
10. The method for preparing any one of the pharmaceutical combination packages of claims 1-7, comprising preparing a silybin injection solution and an injection solvent separately, and packaging together, wherein when the pharmaceutically active ingredient in the silybin injection solution is a silybin phospholipid complex, the silybin phospholipid complex is formulated as follows:
the formula of the silybin phospholipid complex comprises the following components: silybin and phospholipid in the mass ratio of 1: 0.5-1: 10; wherein the phospholipid is selected from: one or more of soybean lecithin, yolk lecithin, distearoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine and dimyristoyl phosphatidylcholine;
is prepared by the following steps: adding silybin and phospholipid into 5-50 times of absolute ethanol, dissolving in water bath at 40-55 ℃, and removing ethanol by rotary evaporation to obtain powder, namely the phospholipid complex of the silybin.
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| 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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| CN112494452A (en) * | 2020-12-16 | 2021-03-16 | 福建瑞泰来医药科技有限公司 | Silibinin capsule and preparation method thereof |
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| US8877259B2 (en) | 2012-02-09 | 2014-11-04 | Mary Kay Inc. | Cosmetic formulation |
| 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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| CN102309441B (en) | 2015-07-22 |
| CN102958510B (en) | 2015-09-09 |
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