CN102652744A - Modified injection containing 13 compound vitamins and preparation method thereof - Google Patents
Modified injection containing 13 compound vitamins and preparation method thereof Download PDFInfo
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- CN102652744A CN102652744A CN2011100480151A CN201110048015A CN102652744A CN 102652744 A CN102652744 A CN 102652744A CN 2011100480151 A CN2011100480151 A CN 2011100480151A CN 201110048015 A CN201110048015 A CN 201110048015A CN 102652744 A CN102652744 A CN 102652744A
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- vitamin
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- 229940088594 vitamin Drugs 0.000 title claims abstract description 71
- 229930003231 vitamin Natural products 0.000 title claims abstract description 71
- 235000013343 vitamin Nutrition 0.000 title claims abstract description 71
- 239000011782 vitamin Substances 0.000 title claims abstract description 71
- 238000002347 injection Methods 0.000 title claims abstract description 67
- 239000007924 injection Substances 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 title abstract 2
- -1 compound vitamin Chemical class 0.000 claims abstract description 33
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 129
- 238000003756 stirring Methods 0.000 claims description 92
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 90
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 87
- 239000000243 solution Substances 0.000 claims description 85
- 239000008215 water for injection Substances 0.000 claims description 85
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 68
- 239000003708 ampul Substances 0.000 claims description 67
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 66
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 60
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 46
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 46
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 45
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 45
- 230000001954 sterilising effect Effects 0.000 claims description 44
- 235000019156 vitamin B Nutrition 0.000 claims description 43
- 239000011720 vitamin B Substances 0.000 claims description 43
- 229930003270 Vitamin B Natural products 0.000 claims description 41
- 238000004659 sterilization and disinfection Methods 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 36
- 229920000053 polysorbate 80 Polymers 0.000 claims description 36
- 239000008346 aqueous phase Substances 0.000 claims description 34
- 239000012071 phase Substances 0.000 claims description 34
- 238000005303 weighing Methods 0.000 claims description 34
- 229910052757 nitrogen Inorganic materials 0.000 claims description 33
- 238000001914 filtration Methods 0.000 claims description 30
- 239000003795 chemical substances by application Substances 0.000 claims description 29
- 235000004866 D-panthenol Nutrition 0.000 claims description 23
- 239000011703 D-panthenol Substances 0.000 claims description 23
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 claims description 23
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 23
- 229960002685 biotin Drugs 0.000 claims description 23
- 235000020958 biotin Nutrition 0.000 claims description 23
- 239000011616 biotin Substances 0.000 claims description 23
- 229960003949 dexpanthenol Drugs 0.000 claims description 23
- 229960000304 folic acid Drugs 0.000 claims description 23
- 235000019152 folic acid Nutrition 0.000 claims description 23
- 239000011724 folic acid Substances 0.000 claims description 23
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 22
- 229930003268 Vitamin C Natural products 0.000 claims description 22
- 239000011718 vitamin C Substances 0.000 claims description 22
- 235000019154 vitamin C Nutrition 0.000 claims description 22
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 20
- 239000004322 Butylated hydroxytoluene Substances 0.000 claims description 19
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 19
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 19
- 229940095259 butylated hydroxytoluene Drugs 0.000 claims description 19
- 230000001105 regulatory effect Effects 0.000 claims description 19
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 claims description 18
- FVTCRASFADXXNN-SCRDCRAPSA-N flavin mononucleotide Chemical compound OP(=O)(O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O FVTCRASFADXXNN-SCRDCRAPSA-N 0.000 claims description 18
- 229950001574 riboflavin phosphate Drugs 0.000 claims description 18
- 230000008901 benefit Effects 0.000 claims description 17
- 238000005261 decarburization Methods 0.000 claims description 17
- 239000012528 membrane Substances 0.000 claims description 17
- 239000012982 microporous membrane Substances 0.000 claims description 17
- 238000007789 sealing Methods 0.000 claims description 17
- 238000001179 sorption measurement Methods 0.000 claims description 17
- RBCOYOYDYNXAFA-UHFFFAOYSA-L (5-hydroxy-4,6-dimethylpyridin-3-yl)methyl phosphate Chemical compound CC1=NC=C(COP([O-])([O-])=O)C(C)=C1O RBCOYOYDYNXAFA-UHFFFAOYSA-L 0.000 claims description 16
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 15
- HZAXFHJVJLSVMW-UHFFFAOYSA-N monoethanolamine hydrochloride Natural products NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 15
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- 239000001509 sodium citrate Substances 0.000 claims description 14
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 14
- 239000004255 Butylated hydroxyanisole Substances 0.000 claims description 11
- 229940043253 butylated hydroxyanisole Drugs 0.000 claims description 11
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 11
- 229930003427 Vitamin E Natural products 0.000 claims description 10
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 10
- 239000011709 vitamin E Substances 0.000 claims description 10
- 235000019165 vitamin E Nutrition 0.000 claims description 10
- 229940046009 vitamin E Drugs 0.000 claims description 10
- VYGQUTWHTHXGQB-UHFFFAOYSA-N Retinol hexadecanoate Natural products CCCCCCCCCCCCCCCC(=O)OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-UHFFFAOYSA-N 0.000 claims description 9
- 235000019172 retinyl palmitate Nutrition 0.000 claims description 9
- 229940108325 retinyl palmitate Drugs 0.000 claims description 9
- 239000011769 retinyl palmitate Substances 0.000 claims description 9
- 239000003381 stabilizer Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 claims description 6
- 229960002477 riboflavin Drugs 0.000 claims description 6
- 235000019192 riboflavin Nutrition 0.000 claims description 6
- 239000002151 riboflavin Substances 0.000 claims description 6
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 claims description 6
- 229930003448 Vitamin K Natural products 0.000 claims description 5
- 239000011772 phylloquinone Substances 0.000 claims description 5
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 claims description 5
- 235000019168 vitamin K Nutrition 0.000 claims description 5
- 239000011712 vitamin K Substances 0.000 claims description 5
- 150000003721 vitamin K derivatives Chemical class 0.000 claims description 5
- 229940046010 vitamin k Drugs 0.000 claims description 5
- 229930003316 Vitamin D Natural products 0.000 claims description 4
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims description 4
- FDJOLVPMNUYSCM-UVKKECPRSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2,7, Chemical compound [Co+3].N#[C-].C1([C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)[N-]\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O FDJOLVPMNUYSCM-UVKKECPRSA-L 0.000 claims description 4
- JZRWCGZRTZMZEH-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 claims description 4
- 235000019166 vitamin D Nutrition 0.000 claims description 4
- 239000011710 vitamin D Substances 0.000 claims description 4
- 150000003710 vitamin D derivatives Chemical class 0.000 claims description 4
- 229940046008 vitamin d Drugs 0.000 claims description 4
- MBWXNTAXLNYFJB-LKUDQCMESA-N phylloquinone Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CCCC(C)CCCC(C)CCCC(C)C)=C(C)C(=O)C2=C1 MBWXNTAXLNYFJB-LKUDQCMESA-N 0.000 claims description 2
- 239000003963 antioxidant agent Substances 0.000 abstract description 12
- 239000002904 solvent Substances 0.000 abstract description 7
- 238000004321 preservation Methods 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 2
- 230000001186 cumulative effect Effects 0.000 description 13
- 230000003078 antioxidant effect Effects 0.000 description 11
- 235000006708 antioxidants Nutrition 0.000 description 11
- 239000002671 adjuvant Substances 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 230000003381 solubilizing effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 2
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 2
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 2
- 229940046001 vitamin b complex Drugs 0.000 description 2
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- 208000000412 Avitaminosis Diseases 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- 108020005199 Dehydrogenases Proteins 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 208000005232 Glossitis Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010021135 Hypovitaminosis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 1
- XJLXINKUBYWONI-NNYOXOHSSA-N NADP zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-NNYOXOHSSA-N 0.000 description 1
- 206010029400 Nicotinic acid deficiency Diseases 0.000 description 1
- 208000002141 Pellagra Diseases 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930003451 Vitamin B1 Natural products 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- LXNHXLLTXMVWPM-UHFFFAOYSA-N Vitamin B6 Natural products CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 235000002201 avitaminosis Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000003752 improving hair Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229950006238 nadide Drugs 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 235000019190 thiamine hydrochloride Nutrition 0.000 description 1
- 239000011747 thiamine hydrochloride Substances 0.000 description 1
- 229960000344 thiamine hydrochloride Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000010374 vitamin B1 Nutrition 0.000 description 1
- 239000011691 vitamin B1 Substances 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019158 vitamin B6 Nutrition 0.000 description 1
- 239000011726 vitamin B6 Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- 208000030401 vitamin deficiency disease Diseases 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses a modified injection containing 13 compound vitamins and a preparation method thereof, and relates to the field of medicinal preparations. In order to solve the problems of poor stability and rigorous preservation conditions of similar injections in the prior art, the invention discloses a compound vitamin injection which is separatedly loaded in two ampoules, and comprises 4 fat-soluble vitamins and 9 water-soluble vitamins in total; meanwhile solubilizers, antioxidants and preparation technology of the compound vitamin injection are also modified. The compound vitamin injection prepared by the invention has significantly improved stability, and can be preserved for 18 months at room temperature.
Description
Technical field
The invention belongs to technical field of medicine, particularly a kind of improved Compsoite vitamin injection and preparation method thereof.
Background technology
Vitamin (vitamin) is one type of trace organic substance that humans and animals must obtain from food for keeping normal physiological function; In people's bulk-growth, metabolism, growth course, play an important role; Being to keep the necessary type organic matter of human life activity, also is the important active substances that keeps health.Vitamin content in vivo seldom, and is but indispensable.Though the chemical constitution of various vitamin and character are different, they have following common ground: the first, vitamin is prevalent in the food; The second, the effect of vitamin mainly is the adjusting of participating in organism metabolism; Three, most vitamin, body can not synthesize or the synthetic quantity deficiency, can not satisfy the needs of body, must be often through extraneous acquisition; Four, human body is very little to the requirement of vitamin, but in case shortage will cause corresponding avitaminosis, health is caused damage.
Dissolubility according to vitamin can be divided into fatsoluble vitamin and water soluble vitamins with vitamin.Fatsoluble vitamin comprises vitamin A, vitamin D, vitamin E, vitamin K
1Four kinds, in food, exist jointly with lipid, when intestinal absorption, also absorb relevantly with lipid, it is low to drain efficient, thus during Excessive Intake, can accumulate in vivo, the generation illeffects, even poison.Water soluble vitamins comprises vitamin B complex, vitamin C (ascorbic acid) and choline.Wherein, vitamin B complex comprises vitamin B
1(thiamine hydrochloride), vitamin B
2(riboflavin), vitamin B
6(Pyridoxine Hydrochloride), vitamin B
12, nicotinic acid, pantothenic acid, folic acid, biotin.Nicotiamide is a water soluble vitamins, is nadide and coenzyme II ingredient, becomes the coenzyme of many dehydrogenases; Can influence eupnea and the metabolism of cell during shortage and cause pellagra; Be prone to absorb, be distributed to body tissue after the absorption, through liver metabolism; Only discharge from urine with original shape on a small quantity, be used for supplementing the nutrients and treating glossitis, dermatitis etc.Dexpanthenol is the vitamin(e) B group medicine, participates in metabolism; Have the metabolism that promotes human body protein, fat, saccharide, promote the growth of skin and mucomembranous cell, improve hair luster, improve immunity, effects such as antiinflammatory.
Because the particularity of vitamin character, the vitamins preparation of present domestic listing is many to be existed with the folk prescription form, and the small-volume injection of forming with water solublity and fatsoluble vitamin does not have the listing product at present as yet.13 kinds of Compsoite vitamin injections of external listing are the INFUVITADULT (Multiple Vitaminsfor Infusion) of hundred spies (Baxter) company.This product is two ampoule packings.Contain vitamin C, vitamin A palmitate, vitamin D in No. 1 ampoule of INFUVITADULT
3, vitamin B
1, vitamin B
2, Pyridoxine Hydrochloride, nicotiamide, Dexpanthenol, vitamin E, vitamin K, contain folic acid, biotin, vitamin B in No. 2 ampoules
12Contain 1.4% Tween 80 (having another name called polyoxyethylene sorbitan monoleate) in No. 1 ampoule, as solubilizing agent.This product adopts flowing steam sterilization, and (100 ℃, 30min), finished product is in 2-8 ℃ of preservation.One Chinese patent application CN101073580A discloses a kind of 13 kinds of Compsoite vitamin injections; No. 1 ampoule of the effective ingredient of its Compsoite vitamin injection first bottle and INFUVIT ADULT is identical; But its adjuvant contains solubilizing agent Tween 80 and propylene glycol simultaneously, antioxidant sodium sulfite and complexing of metal ion agent calcio-disodium edetate.Equally, the Compsoite vitamin injection that the technical scheme that CN101073580A put down in writing makes also adopt flowing steam sterilization (100 ℃, 30min).Sterilising conditions depends on the stability of injection, and injection is stable more, and its sterilising conditions that can tolerate is high more, otherwise, then low more.
Summary of the invention
13 kinds of Compsoite vitamin injection stability to existing in the above-mentioned prior art are not high, problems such as preservation condition harshness, and the present invention provides a kind of improved 13 kinds of Compsoite vitamin injections and preparation method thereof.
In order to realize the foregoing invention purpose, the technical scheme that the present invention adopts is following:
A kind of improved 13 kinds of Compsoite vitamin injections are divided in two ampoules, and the first ampoule injection contains: vitamin A palmitate, vitamin K
1, vitamin D
3, vitamin E, vitamin C, vitamin B
1, riboflavin sodium phosphate, Dexpanthenol, vitamin B
6, nicotiamide and pH regulator agent; The second ampoule injection contains: vitamin B
12, folic acid, biotin, stabilizing agent and pH regulator agent; It is characterized in that, contain in the first ampoule injection Tween 80 and propylene glycol or alcoholic acid any.
Through adjuvant to first ampoule, the especially selection of solubilizing agent, even do not add antioxidant, the stability of first ampoule also is significantly increased than prior art.
Certainly, in order further to improve the stability of the first ampoule injection, the present invention's first ampoule injection can further contain any or theys' of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) or Radix Gentianae acyl ethanolamine any mixture.Wherein BHA, BHT are fat-soluble antioxidant, and Radix Gentianae acyl ethanolamine is a water solublity antioxidant.
Said butylated hydroxyanisole consumption can be 0～0.005mg/ml, and said butylated hydroxytoluene consumption can be 0～0.02mg/ml, and said Radix Gentianae acyl ethanolamine consumption can be 0～0.04g/ml.
As preferably, the consumption of Tween 80 is that the consumption of 12～20mg/ml and propylene glycol is that 0.001～0.3g/ml or consumption of ethanol are 0.001～0.3ml/ml in the first ampoule injection of 13 kinds of Compsoite vitamin injections of the present invention.
As the stabilizing agent of the second ampoule injection, so long as pharmaceutically suitable stabilizing agent all can, the preferred propylene glycol of the present invention, wherein the consumption of propylene glycol is 0.001～0.3g/ml.
Preferred as further, the invention provides a kind of improved 13 kinds of Compsoite vitamin injections, it is characterized in that the said first ampoule injection is grouped into by following one-tenth: vitamin A palmitate 3300IU, vitamin K
10.15mg, vitamin D
3200IU, vitamin E 10IU, vitamin C 200mg, vitamin B
16mg, riboflavin sodium phosphate 5mg (in riboflavin 3.6mg), Dexpanthenol 15mg, vitamin B
66mg, nicotiamide 40mg, Tween 80 (consumption be 12～20mg/ml) and propylene glycol (consumption be 0.001～0.3g/ml) or ethanol (consumption is 0.001～0.3ml/ml), and pH value to 4～7 are regulated in the pH regulator agent; The said second ampoule injection is grouped into by following one-tenth: vitamin B
12(consumption is 0.001～0.3g/ml), and pH value to 4.5～7 are regulated in the pH regulator agent for 5 μ g, folic acid 6mg, biotin 60 μ g, propylene glycol.
As the pH regulator agent of the first ampoule injection, so long as pharmaceutically suitable pH regulator agent all can, the preferred sodium hydroxide of the present invention.As the pH regulator agent of the second ampoule injection, so long as pharmaceutically suitable pH regulator agent all can, any of preferably citric acid of the present invention or sodium citrate or their any mixture.
Among the present invention, the described consumption of each adjuvant is meant the content of corresponding adjuvant in corresponding injection.
The method for preparing of aforementioned 13 kinds of Compsoite vitamin injections comprises the steps:
(1) first ampoule: measure vitamin A palmitate, vitamin K by prescription
1, vitamin D
3, vitamin E places container, mix homogeneously adds the recipe quantity Tween 80 and continues to be mixed to evenly, must oil-phase solution, take by weighing vitamin C, vitamin B by recipe quantity
1, riboflavin sodium phosphate, Dexpanthenol, nicotiamide, vitamin B
6Place container, add the water for injection that is cooled to room temperature and be stirred to dissolving, regulate pH to 3～5 with the pH regulator agent; Add recipe quantity propylene glycol or ethanol, get aqueous phase solution, adding 0.03% (w/v) activated carbon adsorption with the filtering with microporous membrane of 0.22 μ m; Filter, oil-phase solution is slowly joined in the aqueous phase solution of quick stirring, pH to 4～7 are regulated in the pH regulator agent; Benefit adds to the full amount of water for injection, and filters, fills nitrogen, fill, sterilization;
(2) second ampoules: take by weighing recipe quantity folic acid, biotin, add the water for injection that is cooled to room temperature, stirring and dissolving under the nitrogen protection; It is miscible to add the stirring of recipe quantity stabilizing agent, and pH to 4.5～7 are transferred in the pH regulator agent, add the needle-use activated carbon of dense part long-pending 0.05% (W/V), stirring at normal temperature 15 minutes, and decarburization filters; Get the vitamin B of recipe quantity
12Add the water for injection dissolving that is cooled to room temperature on a small quantity, join in the aforementioned solution, replenish water for injection, stir, 0.22 μ m microporous filter membrane fine straining, fill, sealing by fusing, sterilization to full dose.
When containing above-mentioned antioxidant in first ampoule, the method for preparing of aforementioned 13 kinds of Compsoite vitamin injections of the present invention comprises the steps:
(1) first ampoule: measure vitamin A palmitate, vitamin K by prescription
1, vitamin D
3, vitamin E and butylated hydroxyanisole and/or butylated hydroxytoluene place container, heating-up temperature adds Tween 80 then and continues to be stirred to evenly to stirring, oil-phase solution, take by weighing vitamin C, vitamin B by recipe quantity
1, riboflavin sodium phosphate, Dexpanthenol, nicotiamide, vitamin B
6, Radix Gentianae acyl ethanolamine places container, adds the water for injection that is cooled to room temperature and is stirred to dissolving, regulates pH to 3～5 with the pH regulator agent; Add recipe quantity propylene glycol or ethanol, promptly get aqueous phase solution, adding 0.03% (w/v) activated carbon adsorption with the filtering with microporous membrane of 0.22 μ m; Filter, oil-phase solution is slowly joined in the aqueous phase solution of quick stirring, regulate pH to 4～7 with the pH regulator agent; Benefit adds to the full amount of water for injection, and filters, fills nitrogen, fill, sterilization;
(2) second ampoules: take by weighing recipe quantity folic acid, biotin, add the water for injection that is cooled to room temperature, stirring and dissolving under the nitrogen protection; It is miscible to add the stirring of recipe quantity stabilizing agent, and pH to 4.5～7 are transferred in the pH regulator agent, add the needle-use activated carbon of dense part long-pending 0.05% (W/V), stirring at normal temperature 15 minutes, and decarburization filters; Get the vitamin B of recipe quantity
12Add the water for injection dissolving that is cooled to room temperature on a small quantity, join in the aforementioned solution, replenish water for injection, stir, 0.22 μ m microporous filter membrane fine straining, fill, sealing by fusing, sterilization to full dose.
In the aforementioned method for preparing, the preferred sodium hydroxide of the first ampoule pH regulator agent, any of the second ampoule pH regulator agent preferably citric acid or sodium citrate or their any mixture.The step of aforementioned method for preparing (one), step (two) all are two independent processes, do not have operational order between them.
Do further detailed description with regard to technical scheme of the present invention at present.
The screening of solubilizing agent in (one) first ampoule
In order to reach identical or better solubilizing effect, the inventor finds after deliberation, Tween 80 and propylene glycol, and perhaps Tween 80 and ethanol can improve solubilizing effect jointly as solubilizing agent.The inventor investigates the content of Tween 80, and when the consumption of Tween 80 during less than 12mg/ml, injection sterilization back is prone to take place muddy, and Tween 80 is comparatively suitable at 12～20mg/ml.Further find,, when the propylene glycol consumption surpasses 0.3g/ml or amount of ethanol and surpasses 0.3ml/ml, occur crystallization easily after the injection sterilization when Tween 80 during in 12～20mg/ml scope through screening.Obtain through further screening, when the Tween 80 consumption was 12～20mg/ml, the propylene glycol consumption was 0.001～0.3g/ml; Or the Tween 80 consumption is when being 12～20mg/ml, and amount of ethanol 0.001～0.3ml/ml can improve the solubilizing effect of fatsoluble vitamin greatly.Most preferably, the Tween 80 consumption is 16mg/ml, and the propylene glycol consumption is 0.1g/ml; Or the Tween 80 consumption is 16mg/ml, and when amount of ethanol was 0.05ml/ml, solubilizing effect was best.
Surprisingly, when above-mentioned selection is made in solubilizing agent, can not contain antioxidant in the dosage form prescription in first ampoule, and 13 kinds of Compsoite vitamin injection stability that obtain in view of the above obviously are superior to 13 kinds of Compsoite vitamin injections of the prior art.
(2) selection of antioxidant
In order further to improve the stability of the first ampoule injection, also can add suitable antioxidant in the dosage form prescription of first ampoule.Discover that when adding any or theys' any mixture of butylated hydroxyanisole, butylated hydroxytoluene or Radix Gentianae acyl ethanolamine in first ampoule, each item index of the first ampoule injection that obtains all further improves.Preferably, the butylated hydroxyanisole consumption is that 0～0.005mg/ml, butylated hydroxytoluene consumption are that 0～0.02mg/ml, Radix Gentianae acyl ethanolamine consumption are 0～0.04g/ml.
Through inventor's above-mentioned research, 13 kinds of Compsoite vitamin injections that the present invention obtains have following beneficial effect:
(1) do not use antioxidant, 13 kinds of Compsoite vitamin injection safeties that obtain and stability significantly improve than prior art.
(2) improved 13 kinds of Compsoite vitamin injections (no matter whether adding antioxidant) of obtaining of the present invention all can adopt remaining probabilistic method sterilization, and its condition is 115～121 ℃, and sterilization time is 30～12min; Optimum sterilising conditions is 115 ℃, 30min or 121 ℃, and 8min, the F0 value reaches 8-12.Improved 13 kinds of Compsoite vitamin injections of the present invention (no matter whether adding antioxidant) all can be preserved 18 months down in room temperature (10～30 ℃).Therefore, compared to prior art, 13 kinds of Compsoite vitamin injection stability that the present invention obtains are significantly improved.
The specific embodiment
Below in conjunction with the specific embodiment foregoing invention content of the present invention is done further to describe in detail.
But should this be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.Not breaking away under the above-mentioned technological thought situation of the present invention, according to ordinary skill knowledge and customary means, make various replacements and change, all should comprise within the scope of the invention.
Embodiment 1
First ampoule:
By prescription measure fatsoluble vitamin and BHA, BHT places container, mixes, add Tween 80 then and continue to be stirred to evenly, oil phase.Take by weighing vitamin C, vitamin B by recipe quantity
1, riboflavin sodium phosphate, Dexpanthenol, nicotiamide, vitamin B
6, Radix Gentianae acyl ethanolamine, add the water for injection that is cooled to room temperature and be stirred to dissolving, regulate pH to 4.0～4.5 with NaOH, add the recipe quantity propylene glycol, promptly get aqueous phase solution, adding 0.03% (w/v) activated carbon adsorption, filtration with the filtering with microporous membrane of 0.22 μ m.Oil-phase solution is slowly joined in the aqueous phase solution of quick stirring, the NaOH solution with 50% is regulated pH to 4.0～4.5, and benefit adds to the full amount of water for injection, and filters, fills nitrogen, fill, and 121 ℃, the 8min sterilization.
Second ampoule:
Take by weighing recipe quantity folic acid, biotin, add the water for injection that is cooled to room temperature of dosing amount cumulative volume 50%, stirring and dissolving under the nitrogen protection; It is miscible to add the stirring of recipe quantity propylene glycol, transfers pH to 4.5～4.6 with citric acid, adds the needle-use activated carbon of dense part long-pending 0.05% (W/V), stirring at normal temperature 15 minutes, and decarburization filters; Get the vitamin B of recipe quantity
12Add the water for injection dissolving that has been cooled to room temperature on a small quantity, join in the aforementioned solution, replenish water for injection, stir, 0.22 μ m microporous filter membrane fine straining, fill, sealing by fusing, 121 ℃, 8min sterilization to full dose.
Embodiment 2
First ampoule:
By prescription measure fatsoluble vitamin and BHA, BHT places container, mixes, add Tween 80 then and continue to be stirred to evenly, oil phase, take by weighing vitamin C, vitamin B by recipe quantity
1, riboflavin sodium phosphate, Dexpanthenol, nicotiamide, vitamin B
6, Radix Gentianae acyl ethanolamine, add the water for injection that is cooled to room temperature and be stirred to dissolving, regulate pH to 4.9～5.0 with NaOH, add the recipe quantity propylene glycol; Filtering with microporous membrane with 0.22 μ m promptly gets aqueous phase solution, adds 0.03% (w/v) activated carbon adsorption, filters; Oil-phase solution is slowly joined in the aqueous phase solution of quick stirring, the NaOH solution with 50% is regulated pH to 6～7, and benefit adds to the full amount of water for injection; Filter, fill nitrogen, fill, 115 ℃, the 30min sterilization.
Second ampoule:
Take by weighing recipe quantity folic acid, biotin, add the water for injection that is cooled to room temperature of dosing amount cumulative volume 50%, stirring and dissolving under the nitrogen protection; It is miscible to add the stirring of recipe quantity propylene glycol, transfers pH to 5.5～6.0 with citric acid, adds the needle-use activated carbon of dense part long-pending 0.05% (W/V), stirring at normal temperature 15 minutes, and decarburization filters; Get the vitamin B of recipe quantity
12Add the water for injection dissolving that has been cooled to room temperature on a small quantity, join in the aforementioned solution, replenish water for injection, stir, 0.22 μ m microporous filter membrane fine straining, fill, sealing by fusing, 115 ℃, 30min sterilization to full dose.
Embodiment 3
First ampoule:
By prescription measure fatsoluble vitamin and BHA, BHT places container, stirs, add Tween 80 then and continue to be stirred to evenly, oil phase.Take by weighing vitamin C, vitamin B by recipe quantity
1, riboflavin sodium phosphate, Dexpanthenol, nicotiamide, vitamin B
6, Radix Gentianae acyl ethanolamine, add the water for injection that is cooled to room temperature and be stirred to dissolving, regulate pH to 4.9～5.0 with NaOH, add the recipe quantity propylene glycol, promptly get aqueous phase solution, adding 0.03% (w/v) activated carbon adsorption, filtration with the filtering with microporous membrane of 0.22 μ m.Oil-phase solution is slowly joined in the aqueous phase solution of quick stirring, the NaOH solution with 50% is regulated pH to 5.5～6, and benefit adds to the full amount of water for injection; Filter, fill nitrogen, fill, 121 ℃, the 8min sterilization; This batch product is carried out stability keep sample (under 25 ℃ of temperature), the result sees table 1:
Table 1
Second ampoule:
Take by weighing recipe quantity folic acid, biotin, add the water for injection that is cooled to room temperature of dosing amount cumulative volume 50%, stirring and dissolving under the nitrogen protection; It is miscible to add the stirring of recipe quantity propylene glycol, transfers pH to 5.5～6.0 with citric acid and sodium citrate, adds the needle-use activated carbon of dense part long-pending 0.05% (W/V), stirring at normal temperature 15 minutes, and decarburization filters; Get the vitamin B of recipe quantity
12Add the water for injection dissolving that has been cooled to room temperature on a small quantity, join in the aforementioned solution, replenish water for injection, stir, 0.22 μ m microporous filter membrane fine straining, fill, sealing by fusing, 121 ℃, 8min sterilization to full dose.
Embodiment 4
First ampoule:
Measure fatsoluble vitamin and butylated hydroxytoluene (BHT) places container by prescription, mix, add Tween 80 then and continue to be stirred to evenly, oil phase.Take by weighing vitamin C, vitamin B by recipe quantity
1, riboflavin sodium phosphate, Dexpanthenol, nicotiamide, vitamin B
6, add the water for injection that is cooled to room temperature and be stirred to dissolving, regulate pH to 4.0～4.1 with NaOH, add the recipe quantity propylene glycol, promptly get aqueous phase solution, adding 0.03% (w/v) activated carbon adsorption, filtration with the filtering with microporous membrane of 0.22 μ m.Oil-phase solution is slowly joined in the aqueous phase solution of quick stirring, the NaOH solution with 50% is regulated pH to 4.0～4.1, and benefit adds to the full amount of water for injection, and filters, fills nitrogen, fill, and 115 ℃, the 30min sterilization.
Second ampoule:
Take by weighing recipe quantity folic acid, biotin, add the water for injection that is cooled to room temperature of dosing amount cumulative volume 50%, stirring and dissolving under the nitrogen protection; It is miscible to add the stirring of recipe quantity propylene glycol, transfers pH to 4.5～4.6 with citric acid and sodium citrate, adds the needle-use activated carbon of dense part long-pending 0.05% (W/V), stirring at normal temperature 15 minutes, and decarburization filters; Get the vitamin B of recipe quantity
12Add the water for injection dissolving that has been cooled to room temperature on a small quantity, join in the aforementioned solution, replenish water for injection, stir, 0.22 μ m microporous filter membrane fine straining, fill, sealing by fusing, 115 ℃, 30min sterilization to full dose.
Embodiment 5
First ampoule:
Measure fatsoluble vitamin and butylated hydroxyanisole (BHA) places container by prescription, mix, add Tween 80 then and continue to be stirred to evenly, oil phase.Taking by weighing vitamin C, vitamin B1, riboflavin sodium phosphate, Dexpanthenol, nicotiamide, vitamin B6 by recipe quantity adds the water for injection that is cooled to room temperature and is stirred to dissolving; Regulate pH to 4.0～4.5 with NaOH; Add the recipe quantity propylene glycol; Filtering with microporous membrane with 0.22 μ m promptly gets aqueous phase solution, adds 0.03% (w/v) activated carbon adsorption, filters.Oil-phase solution is slowly joined in the aqueous phase solution of quick stirring, the NaOH solution with 50% is regulated pH to 5.0～5.5, and benefit adds to the full amount of water for injection, and filters, fills nitrogen, fill, and 115 ℃, the 30min sterilization.
Second ampoule:
Take by weighing recipe quantity folic acid, biotin, add the water for injection that is cooled to room temperature of dosing amount cumulative volume 50%, stirring and dissolving under the nitrogen protection; It is miscible to add the stirring of recipe quantity propylene glycol, transfers pH to 4.5～5.0 with citric acid and sodium citrate, adds the needle-use activated carbon of dense part long-pending 0.05% (W/V), stirring at normal temperature 15 minutes, and decarburization filters; Get the vitamin B of recipe quantity
12Add the water for injection dissolving that has been cooled to room temperature on a small quantity, join in the aforementioned solution, replenish water for injection, stir, 0.22 μ m microporous filter membrane fine straining, fill, sealing by fusing, 115 ℃, 30min sterilization to full dose.
Embodiment 6
First ampoule:
Measure fatsoluble vitamin by prescription and place container, stir, add Tween 80 then and continue to be stirred to evenly, get oil phase.Take by weighing vitamin C, vitamin B by recipe quantity
1, riboflavin sodium phosphate, Dexpanthenol, nicotiamide, vitamin B
6, add the water for injection that is cooled to room temperature and be stirred to dissolving, regulate pH to 4.5～5.0 with NaOH, add the recipe quantity propylene glycol, promptly get aqueous phase solution, adding 0.03% (w/v) activated carbon adsorption, filtration with the filtering with microporous membrane of 0.22 μ m.Oil-phase solution is slowly joined in the aqueous phase solution of quick stirring, the NaOH solution with 50% is regulated pH to 6.5～7.0, and benefit adds to the full amount of water for injection, and filters, fills nitrogen, fill, and 121 ℃, the 8min sterilization.
Second ampoule:
Take by weighing recipe quantity folic acid, biotin, add the water for injection that is cooled to room temperature of dosing amount cumulative volume 50%, stirring and dissolving under the nitrogen protection; It is miscible to add the stirring of recipe quantity propylene glycol, transfers pH to 5.5～6.0 with citric acid and sodium citrate, adds the needle-use activated carbon of dense part long-pending 0.05% (W/V), stirring at normal temperature 15 minutes, and decarburization filters; Get the vitamin B of recipe quantity
12Add the water for injection dissolving that has been cooled to room temperature on a small quantity, join in the aforementioned solution, replenish water for injection, stir, 0.22 μ m microporous filter membrane fine straining, fill, sealing by fusing, 121 ℃, 8min sterilization to full dose.
Embodiment 7
First ampoule:
Measure fatsoluble vitamin by prescription and place container, mix, add Tween 80 then and continue to be stirred to evenly, get oil phase.Take by weighing vitamin C, vitamin B by recipe quantity
1, riboflavin sodium phosphate, Dexpanthenol, nicotiamide, vitamin B
6Place container, add the water for injection that is cooled to room temperature and be stirred to dissolving, regulate pH to 4.0～4.5, add recipe quantity ethanol, promptly get aqueous phase solution, adding 0.03% (w/v) activated carbon adsorption, filtration with the filtering with microporous membrane of 0.22 μ m with NaOH.Oil-phase solution is slowly joined in the aqueous phase solution of quick stirring, the NaOH solution with 50% is regulated pH to 4.5～5.0, and benefit adds to the full amount of water for injection, and filters, fills nitrogen, fill, and 121 ℃, the 8min sterilization.
Second ampoule:
Take by weighing recipe quantity folic acid, biotin, add the water for injection that is cooled to room temperature of dosing amount cumulative volume 50%, stirring and dissolving under the nitrogen protection; It is miscible to add the stirring of recipe quantity propylene glycol, transfers pH to 5.5～6.0 with citric acid and sodium citrate, adds the needle-use activated carbon of dense part long-pending 0.05% (W/V), stirring at normal temperature 15 minutes, and decarburization filters; The vitamin B12 of getting recipe quantity adds the water for injection dissolving that has been cooled to room temperature on a small quantity, joins in the aforementioned solution, replenishes water for injection to full dose; Stir 0.22 μ m microporous filter membrane fine straining, fill; Sealing by fusing, 121 ℃, the 8min sterilization; This batch product is carried out stability keep sample (under 25 ℃), the result sees table 2:
Table 2
Embodiment 8
First ampoule:
Measure fatsoluble vitamin and butylated hydroxyanisole (BHA) places container by prescription, stir, add Tween 80 then and continue to be stirred to evenly, oil phase.Take by weighing vitamin C, vitamin B by recipe quantity
1, riboflavin sodium phosphate, Dexpanthenol, nicotiamide, vitamin B
6, Radix Gentianae acyl ethanolamine, add the water for injection that is cooled to room temperature and be stirred to dissolving, regulate pH to 4.0～4.5 with NaOH, add recipe quantity ethanol, promptly get aqueous phase solution, adding 0.03% (w/v) activated carbon adsorption, filtration with the filtering with microporous membrane of 0.22 μ m.Oil-phase solution is slowly joined in the aqueous phase solution of quick stirring, the NaOH solution with 50% is regulated pH to 4.0～4.5 benefits and is added to the full amount of water for injection, and filters, fills nitrogen, fill, and 121 ℃, the 8min sterilization.
Second ampoule:
Take by weighing recipe quantity folic acid, biotin, add the water for injection that is cooled to room temperature of dosing amount cumulative volume 50%, stirring and dissolving under the nitrogen protection; It is miscible to add the stirring of recipe quantity propylene glycol, transfers pH to 4.5～4.6 with citric acid and sodium citrate, adds the needle-use activated carbon of dense part long-pending 0.05% (W/V), stirring at normal temperature 15 minutes, and decarburization filters; Get the vitamin B of recipe quantity
12Add the water for injection dissolving that has been cooled to room temperature on a small quantity, join in the aforementioned solution, replenish water for injection, stir, 0.22 μ m microporous filter membrane fine straining, fill, sealing by fusing, 121 ℃, 8min sterilization to full dose.
Embodiment 9
First ampoule:
Measure fatsoluble vitamin, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) by prescription and place container, stir, add Tween 80 then and continue to be stirred to evenly, get oil phase.Take by weighing vitamin C, vitamin B by recipe quantity
1, riboflavin, Dexpanthenol, nicotiamide, vitamin B
6, add the water for injection that is cooled to room temperature and be stirred to dissolving, regulate pH to 4.0～5.0 with NaOH, add recipe quantity ethanol, promptly get aqueous phase solution, adding 0.03% (w/v) activated carbon adsorption, filtration with the filtering with microporous membrane of 0.22 μ m.Oil-phase solution is slowly joined in the aqueous phase solution of quick stirring, the NaOH solution with 50% is regulated pH to 6.5～7, and benefit adds to the full amount of water for injection, and filters, fills nitrogen, fill, and 115 ℃, the 30min sterilization.
Second ampoule:
Take by weighing recipe quantity folic acid, biotin, add the water for injection that is cooled to room temperature of dosing amount cumulative volume 50%, stirring and dissolving under the nitrogen protection; It is miscible to add the stirring of recipe quantity propylene glycol, transfers pH to 6.5～7 with sodium citrate, adds the needle-use activated carbon of dense part long-pending 0.05% (W/V), stirring at normal temperature 15 minutes, and decarburization filters; Get the vitamin B of recipe quantity
12Add the water for injection dissolving that has been cooled to room temperature on a small quantity, add in the above-mentioned solution, replenish water for injection, stir, 0.22 μ m microporous filter membrane fine straining, fill, sealing by fusing, 115 ℃, 30min sterilization to full dose.
Embodiment 10
First ampoule:
Measure fatsoluble vitamin and butylated hydroxytoluene (BHT) places container by prescription, mix, add Tween 80 then and continue to be stirred to evenly, oil phase.Take by weighing vitamin C, vitamin B by recipe quantity
1, riboflavin sodium phosphate, Dexpanthenol, nicotiamide, vitamin B
6, Radix Gentianae acyl ethanolamine, add the water for injection that is cooled to room temperature and be stirred to dissolving, regulate pH to 4.0～4.5 with NaOH, add the recipe quantity propylene glycol, promptly get aqueous phase solution, adding 0.03% (w/v) activated carbon adsorption, filtration with the filtering with microporous membrane of 0.22 μ m.Oil-phase solution is slowly joined in the aqueous phase solution of quick stirring, the NaOH solution with 50% is regulated pH to 5.0～5.5, and benefit adds to the full amount of water for injection, and filters, fills nitrogen, fill, and 121 ℃, the 8min sterilization.
Second ampoule:
Take by weighing recipe quantity folic acid, biotin, add the water for injection that is cooled to room temperature of dosing amount cumulative volume 50%, stirring and dissolving under the nitrogen protection; It is miscible to add the stirring of recipe quantity propylene glycol, transfers pH to 4.5～5.0 with citric acid and sodium citrate, adds the needle-use activated carbon of dense part long-pending 0.05% (W/V), stirring at normal temperature 15 minutes, and decarburization filters; Get the vitamin B of recipe quantity
12Add the water for injection dissolving that has been cooled to room temperature on a small quantity, join in the aforementioned solution, replenish water for injection, stir, 0.22 μ m microporous filter membrane fine straining, fill, sealing by fusing, 115 ℃, 30min sterilization to full dose.
Embodiment 11
First ampoule:
Measure fatsoluble vitamin by prescription and place container, stir, add Tween 80 then and continue to be stirred to evenly, get oil phase.Take by weighing vitamin C, vitamin B by recipe quantity
1, riboflavin, Dexpanthenol, nicotiamide, vitamin B
6, Radix Gentianae acyl ethanolamine, add the water for injection that is cooled to room temperature and be stirred to dissolving, regulate pH to 4.0～5.0 with NaOH, add recipe quantity ethanol, promptly get aqueous phase solution, adding 0.03% (w/v) activated carbon adsorption, filtration with the filtering with microporous membrane of 0.22 μ m.Oil-phase solution is slowly joined in the aqueous phase solution of quick stirring, the NaOH solution with 50% is regulated pH to 6.0～7.0, and benefit adds to the full amount of water for injection, and filters, fills nitrogen, fill, and 121 ℃, the 8min sterilization.
Second ampoule:
Take by weighing recipe quantity folic acid, biotin, add the water for injection that is cooled to room temperature of dosing amount cumulative volume 50%, stirring and dissolving under the nitrogen protection; It is miscible to add the stirring of recipe quantity propylene glycol, transfers pH to 6.5～7 with citric acid and sodium citrate, adds the needle-use activated carbon of dense part long-pending 0.05% (W/V), stirring at normal temperature 15 minutes, and decarburization filters; Get the vitamin B of recipe quantity
12Add the water for injection dissolving that has been cooled to room temperature on a small quantity, join in the aforementioned solution, replenish water for injection, stir, 0.22 μ m microporous filter membrane fine straining, fill, sealing by fusing, 121 ℃, 8min sterilization to full dose.
Embodiment 12
First ampoule:
Measure fatsoluble vitamin by prescription and place container, stir, add Tween 80 then and continue to be stirred to evenly, get oil phase.Take by weighing vitamin C, vitamin B by recipe quantity
1, riboflavin, Dexpanthenol, nicotiamide, vitamin B
6, add the water for injection that is cooled to room temperature and be stirred to dissolving, regulate pH to 4.0～5.0 with NaOH, add recipe quantity ethanol, promptly get aqueous phase solution, adding 0.03% (w/v) activated carbon adsorption, filtration with the filtering with microporous membrane of 0.22 μ m.Oil-phase solution is slowly joined in the aqueous phase solution of quick stirring, the NaOH solution with 50% is regulated pH to 6.0～7.0, and benefit adds to the full amount of water for injection, and filters, fills nitrogen, fill, and 121 ℃, the 8min sterilization.
Second ampoule:
Take by weighing recipe quantity folic acid, biotin, add the water for injection that is cooled to room temperature of dosing amount cumulative volume 50%, stirring and dissolving under the nitrogen protection; It is miscible to add the stirring of recipe quantity propylene glycol, transfers pH to 6.5～7 with citric acid and sodium citrate, adds the needle-use activated carbon of dense part long-pending 0.05% (W/V), stirring at normal temperature 15 minutes, and decarburization filters; Get the vitamin B of recipe quantity
12Add the water for injection dissolving that has been cooled to room temperature on a small quantity, join in the aforementioned solution, replenish water for injection, stir, 0.22 μ m microporous filter membrane fine straining, fill, sealing by fusing, 121 ℃, 8min sterilization to full dose.
Embodiment 13
First ampoule:
Measure fatsoluble vitamin by prescription and place container, mix, add Tween 80 then and continue to be stirred to evenly, get oil phase.Take by weighing vitamin C, vitamin B by recipe quantity
1, riboflavin sodium phosphate, Dexpanthenol, nicotiamide, vitamin B
6, add the water for injection that is cooled to room temperature and be stirred to dissolving, regulate pH to 4.0～4.5 with NaOH, add the recipe quantity propylene glycol, promptly get aqueous phase solution, adding 0.03% (w/v) activated carbon adsorption, filtration with the filtering with microporous membrane of 0.22 μ m.Oil-phase solution is slowly joined in the aqueous phase solution of quick stirring, the NaOH solution with 50% is regulated pH to 5.0～5.5, and benefit adds to the full amount of water for injection, and filters, fills nitrogen, fill, and 121 ℃, the 8min sterilization.
Second ampoule:
Take by weighing recipe quantity folic acid, biotin, add the water for injection that is cooled to room temperature of dosing amount cumulative volume 50%, stirring and dissolving under the nitrogen protection; It is miscible to add the stirring of recipe quantity propylene glycol, transfers pH to 4.5～5.0 with citric acid and sodium citrate, adds the needle-use activated carbon of dense part long-pending 0.05% (W/V), stirring at normal temperature 15 minutes, and decarburization filters; Get the vitamin B of recipe quantity
12Add the water for injection dissolving that has been cooled to room temperature on a small quantity, join in the aforementioned solution, replenish water for injection, stir, 0.22 μ m microporous filter membrane fine straining, fill, sealing by fusing, 115 ℃, 30min sterilization to full dose.
13 kinds of Compsoite vitamin injections through technical scheme of the present invention obtains all can carry out 115-121 ℃ of sterilization, and can satisfy that each item index still meets the requirements after room temperature (10～30 ℃) is down preserved 18 months.
Claims (10)
1. improved 13 kinds of Compsoite vitamin injections are divided in two ampoules, and the first ampoule injection contains: vitamin A palmitate, vitamin K
1, vitamin D
3, vitamin E, vitamin C, vitamin B
1, riboflavin sodium phosphate, Dexpanthenol, vitamin B
6, nicotiamide and pH regulator agent;
The second ampoule injection contains: vitamin B
12, folic acid, biotin, stabilizing agent and pH regulator agent;
It is characterized in that, contain in Tween 80 and propylene glycol or the ethanol any in the first ampoule injection.
2. a kind of improved 13 kinds of Compsoite vitamin injections according to claim 1 is characterized in that, further contain any or theys' of butylated hydroxyanisole, butylated hydroxytoluene or Radix Gentianae acyl ethanolamine any mixture in the said first ampoule injection.
3. a kind of improved 13 kinds of Compsoite vitamin injections according to claim 2; It is characterized in that; Said butylated hydroxyanisole consumption is 0～0.005mg/ml, and said butylated hydroxytoluene consumption is 0～0.02mg/ml, and said Radix Gentianae acyl ethanolamine consumption is 0～0.04g/ml.
4. according to each described a kind of improved 13 kinds of Compsoite vitamin injections of claim 1-3; It is characterized in that; The consumption of Tween 80 is 12～20mg/ml described in the first ampoule injection; The consumption of said propylene glycol is 0.001～0.3g/ml, and said consumption of ethanol is 0.001～0.3ml/ml.
5. according to each described a kind of improved 13 kinds of Compsoite vitamin injections of claim 1-3, it is characterized in that the stabilizing agent of the said second ampoule injection is a propylene glycol, wherein the consumption of propylene glycol is 0.001～0.3g/ml.
6. a kind of improved 13 kinds of Compsoite vitamin injections according to claim 1 is characterized in that the said first ampoule injection is grouped into by following one-tenth: vitamin A palmitate 3300IU, vitamin K
10.15mg, vitamin D
3200IU, vitamin E 10IU, vitamin C 200mg, vitamin B
16mg, riboflavin sodium phosphate 5mg (in riboflavin 3.6mg), Dexpanthenol 15mg, vitamin B
66mg, nicotiamide 40mg, Tween 80 12～20mg/ml and propylene glycol 0.001～0.3g/ml or ethanol 0.001～0.3ml/ml, pH value to 4～7 are regulated in the pH regulator agent;
The said second ampoule injection is grouped into by following one-tenth: vitamin B
125 μ g, folic acid 0.6mg, biotin 60 μ g, propylene glycol 0.001～0.3g/ml, pH value to 4.5～7 are regulated in the pH regulator agent.
7. according to claim 1,2 or 6 each described a kind of improved 13 kinds of Compsoite vitamin injections; It is characterized in that; The consumption of Tween 80 is 16mg/ml described in the first ampoule injection, and the consumption of said propylene glycol is 0.1g/ml, and said consumption of ethanol is 0.05ml/ml.
8. according to claim 1,2 or 6 each described a kind of improved 13 kinds of Compsoite vitamin injections, it is characterized in that the pH regulator agent of the said first ampoule injection is a sodium hydroxide; The pH regulator agent of the described second ampoule injection is any or theys' of citric acid or sodium citrate a any mixture.
9. the method for preparing of the said a kind of improved 13 kinds of Compsoite vitamin injections of claim 1 is characterized in that, comprises the steps:
(1) first ampoule: measure vitamin A palmitate, vitamin K by prescription
1, vitamin D
3, vitamin E places container, mix homogeneously adds the recipe quantity Tween 80 and continues to be mixed to evenly, must oil-phase solution; Take by weighing vitamin C, vitamin B by recipe quantity
1, riboflavin sodium phosphate, Dexpanthenol, nicotiamide, vitamin B
6Place container, add the water for injection that is cooled to room temperature and be stirred to dissolving, regulate pH to 3～5, add recipe quantity propylene glycol or ethanol, get aqueous phase solution, add 0.03% (w/v) activated carbon adsorption, filtration with the filtering with microporous membrane of 0.22 μ m with the pH regulator agent; Oil-phase solution is slowly joined in the aqueous phase solution of quick stirring, pH to 4～7 are regulated in the pH regulator agent, and benefit adds to the full amount of water for injection, filtration, fill, sterilization;
(2) second ampoules: take by weighing recipe quantity folic acid, biotin, add the water for injection that is cooled to room temperature, stirring and dissolving under the nitrogen protection; It is miscible to add the stirring of recipe quantity stabilizing agent, and pH to 4.5～7 are transferred in the pH regulator agent, add the needle-use activated carbon of dense part long-pending 0.05% (W/V), stirring at normal temperature 15 minutes, and decarburization filters; Get the vitamin B of recipe quantity
12Add the water for injection dissolving that is cooled to room temperature on a small quantity, join in the aforementioned solution, replenish water for injection, stir, 0.22 μ m microporous filter membrane fine straining, fill, sealing by fusing, sterilization to full dose.
10. the method for preparing of the said a kind of improved 13 kinds of Compsoite vitamin injections of claim 2 is characterized in that, comprises the steps:
(1) first ampoule: measure vitamin A palmitate, vitamin K by prescription
1, vitamin D
3, vitamin E and butylated hydroxyanisole and/or butylated hydroxytoluene place container, mix homogeneously adds the recipe quantity Tween 80 then and continues to be mixed to evenly, oil-phase solution; Take by weighing vitamin C, vitamin B by recipe quantity
1, riboflavin sodium phosphate, Dexpanthenol, nicotiamide, vitamin B
6, Radix Gentianae acyl ethanolamine places container, adds the water for injection that is cooled to room temperature and is stirred to dissolving, regulates pH to 3～5 with the pH regulator agent; The propylene glycol or the ethanol that add recipe quantity; Filtering with microporous membrane with 0.22 μ m promptly gets aqueous phase solution, adds 0.03% (w/v) activated carbon adsorption, filters; Oil-phase solution is slowly joined in the aqueous phase solution of quick stirring, regulate pH to 4～7 with the pH regulator agent, benefit adds to the full amount of water for injection, and filters, fills nitrogen, fill, sterilization;
(2) second ampoules: take by weighing recipe quantity folic acid, biotin, add the water for injection that is cooled to room temperature, stirring and dissolving under the nitrogen protection; It is miscible to add the stirring of recipe quantity stabilizing agent, and pH to 4.5～7 are transferred in the pH regulator agent, add the needle-use activated carbon of dense part long-pending 0.05% (W/V), stirring at normal temperature 15 minutes, and decarburization filters; Get the vitamin B of recipe quantity
12Add the water for injection dissolving that is cooled to room temperature on a small quantity, join in the aforementioned solution, replenish water for injection, stir, 0.22 μ m microporous filter membrane fine straining, fill, sealing by fusing, sterilization to full dose.
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| CN201110048015.1A CN102652744B (en) | 2011-03-03 | 2011-03-03 | Modified injection containing 13 compound vitamins and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104224820A (en) * | 2014-09-19 | 2014-12-24 | 辽宁海思科制药有限公司 | Pharmaceutical composition containing 13 kinds of multivitamins and preparation method thereof |
| CN104415041A (en) * | 2013-08-23 | 2015-03-18 | 辽宁海思科制药有限公司 | Composite vitamin injection pharmaceutical composition containing 13 vitamins and preparation method thereof |
| CN108815178A (en) * | 2018-07-30 | 2018-11-16 | 济南康和医药科技有限公司 | One kind containing 13 kinds of Compsoite vitamin injections and its preparation process |
| CN114601846A (en) * | 2020-12-03 | 2022-06-10 | 河北科星药业有限公司 | Complex vitamin amino acid injection for livestock and preparation method and application thereof |
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| CN1843362A (en) * | 2006-04-30 | 2006-10-11 | 贵阳云岩西创药物科技开发有限公司 | Composite vitamin injection and its preparation method |
| CN1989975A (en) * | 2005-12-30 | 2007-07-04 | 成都博瑞医药科技开发有限公司 | Method for preparing composite injection of 12 vitamins |
| CN101073580A (en) * | 2007-06-22 | 2007-11-21 | 北京润德康医药技术有限公司 | Compsoite vitamin injection and its production |
| CN101181289A (en) * | 2007-11-28 | 2008-05-21 | 南京海陵中药制药工艺技术研究有限公司 | Injection of 13 kinds complex vitamin and preparing technique thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1989975A (en) * | 2005-12-30 | 2007-07-04 | 成都博瑞医药科技开发有限公司 | Method for preparing composite injection of 12 vitamins |
| CN1843362A (en) * | 2006-04-30 | 2006-10-11 | 贵阳云岩西创药物科技开发有限公司 | Composite vitamin injection and its preparation method |
| CN101073580A (en) * | 2007-06-22 | 2007-11-21 | 北京润德康医药技术有限公司 | Compsoite vitamin injection and its production |
| CN101181289A (en) * | 2007-11-28 | 2008-05-21 | 南京海陵中药制药工艺技术研究有限公司 | Injection of 13 kinds complex vitamin and preparing technique thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104415041A (en) * | 2013-08-23 | 2015-03-18 | 辽宁海思科制药有限公司 | Composite vitamin injection pharmaceutical composition containing 13 vitamins and preparation method thereof |
| CN104415041B (en) * | 2013-08-23 | 2019-03-12 | 辽宁海思科制药有限公司 | 13 kinds of Compsoite vitamin injection pharmaceutical compositions of one kind and preparation method thereof |
| CN104224820A (en) * | 2014-09-19 | 2014-12-24 | 辽宁海思科制药有限公司 | Pharmaceutical composition containing 13 kinds of multivitamins and preparation method thereof |
| CN108815178A (en) * | 2018-07-30 | 2018-11-16 | 济南康和医药科技有限公司 | One kind containing 13 kinds of Compsoite vitamin injections and its preparation process |
| CN114601846A (en) * | 2020-12-03 | 2022-06-10 | 河北科星药业有限公司 | Complex vitamin amino acid injection for livestock and preparation method and application thereof |
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| CN102652744B (en) | 2014-06-18 |
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Address after: The 856000 Tibet autonomous region in southern area of Zedang town Xiang Qu Road No. 8 Patentee after: HAISCO PHARMACEUTICAL Group Inc. Patentee after: SICHUAN HAISCO PHARMACEUTICAL Co.,Ltd. Patentee after: LIAONING HAISCO PHARMACEUTICAL Co.,Ltd. Address before: The 856000 Tibet autonomous region in southern area of Zedang town Xiang Qu Road No. 8 Patentee before: TIBET HAISCO PHARMACEUTICAL GROUP Co.,Ltd. Patentee before: SICHUAN HAISCO PHARMACEUTICAL Co.,Ltd. Patentee before: LIAONING HAISCO PHARMACEUTICAL Co.,Ltd. |
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