CN104644554B - A kind of Etomidate pharmaceutical composition and preparation method thereof - Google Patents
A kind of Etomidate pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN104644554B CN104644554B CN201510096942.9A CN201510096942A CN104644554B CN 104644554 B CN104644554 B CN 104644554B CN 201510096942 A CN201510096942 A CN 201510096942A CN 104644554 B CN104644554 B CN 104644554B
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- oil
- injection
- etomidate
- phosphatide
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- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 title claims abstract description 52
- 229960001690 etomidate Drugs 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000008215 water for injection Substances 0.000 claims abstract description 29
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims abstract description 25
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims abstract description 24
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims abstract description 24
- 238000002347 injection Methods 0.000 claims abstract description 19
- 239000007924 injection Substances 0.000 claims abstract description 19
- 239000003921 oil Substances 0.000 claims description 39
- 235000019198 oils Nutrition 0.000 claims description 39
- 210000003022 colostrum Anatomy 0.000 claims description 36
- 235000021277 colostrum Nutrition 0.000 claims description 36
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 27
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 15
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 15
- 235000011187 glycerol Nutrition 0.000 claims description 15
- 239000003549 soybean oil Substances 0.000 claims description 14
- 235000012424 soybean oil Nutrition 0.000 claims description 14
- 210000000481 breast Anatomy 0.000 claims description 13
- 230000001954 sterilising effect Effects 0.000 claims description 13
- 239000000839 emulsion Substances 0.000 claims description 12
- -1 lauric acid Ester Chemical class 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 150000002148 esters Chemical group 0.000 claims description 6
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000004006 olive oil Substances 0.000 claims description 4
- 235000008390 olive oil Nutrition 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 239000003002 pH adjusting agent Substances 0.000 claims description 3
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 235000019485 Safflower oil Nutrition 0.000 claims description 2
- 239000004359 castor oil Substances 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- 239000003240 coconut oil Substances 0.000 claims description 2
- 235000019864 coconut oil Nutrition 0.000 claims description 2
- 235000012343 cottonseed oil Nutrition 0.000 claims description 2
- 239000002385 cottonseed oil Substances 0.000 claims description 2
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 2
- 229940093471 ethyl oleate Drugs 0.000 claims description 2
- 235000021323 fish oil Nutrition 0.000 claims description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 235000005713 safflower oil Nutrition 0.000 claims description 2
- 239000003813 safflower oil Substances 0.000 claims description 2
- WECGLUPZRHILCT-GSNKCQISSA-N 1-linoleoyl-sn-glycerol Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC[C@@H](O)CO WECGLUPZRHILCT-GSNKCQISSA-N 0.000 claims 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims 1
- 239000005639 Lauric acid Substances 0.000 claims 1
- JCABVIFDXFFRMT-DIPNUNPCSA-N [(2r)-1-[ethoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] octadec-9-enoate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC)OC(=O)CCCCCCCC=CCCCCCCCC JCABVIFDXFFRMT-DIPNUNPCSA-N 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims 1
- 230000003750 conditioning effect Effects 0.000 claims 1
- 239000008103 glucose Substances 0.000 claims 1
- 235000001727 glucose Nutrition 0.000 claims 1
- POULHZVOKOAJMA-UHFFFAOYSA-N methyl undecanoic acid Natural products CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims 1
- 239000012071 phase Substances 0.000 description 25
- 239000002245 particle Substances 0.000 description 22
- 239000008346 aqueous phase Substances 0.000 description 20
- 235000013336 milk Nutrition 0.000 description 11
- 239000008267 milk Substances 0.000 description 11
- 210000004080 milk Anatomy 0.000 description 11
- 238000013019 agitation Methods 0.000 description 10
- 230000004087 circulation Effects 0.000 description 10
- 229940046926 etomidate injection Drugs 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 238000000265 homogenisation Methods 0.000 description 10
- 229940090044 injection Drugs 0.000 description 10
- 238000009413 insulation Methods 0.000 description 10
- 239000012982 microporous membrane Substances 0.000 description 10
- 238000012545 processing Methods 0.000 description 10
- 238000004659 sterilization and disinfection Methods 0.000 description 10
- 239000003995 emulsifying agent Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 125000001095 phosphatidyl group Chemical group 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 101001000212 Rattus norvegicus Decorin Proteins 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 229960001231 choline Drugs 0.000 description 4
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 4
- FVJZSBGHRPJMMA-UHFFFAOYSA-N distearoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000002960 lipid emulsion Substances 0.000 description 4
- 230000003204 osmotic effect Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 244000056139 Brassica cretica Species 0.000 description 3
- 235000003351 Brassica cretica Nutrition 0.000 description 3
- 235000003343 Brassica rupestris Nutrition 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 235000010460 mustard Nutrition 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 description 2
- FVXDQWZBHIXIEJ-LNDKUQBDSA-N 1,2-di-[(9Z,12Z)-octadecadienoyl]-sn-glycero-3-phosphocholine Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC FVXDQWZBHIXIEJ-LNDKUQBDSA-N 0.000 description 2
- DSNRWDQKZIEDDB-SQYFZQSCSA-N 1,2-dioleoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC DSNRWDQKZIEDDB-SQYFZQSCSA-N 0.000 description 2
- 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 description 2
- TXLHNFOLHRXMAU-UHFFFAOYSA-N 2-(4-benzylphenoxy)-n,n-diethylethanamine;hydron;chloride Chemical compound Cl.C1=CC(OCCN(CC)CC)=CC=C1CC1=CC=CC=C1 TXLHNFOLHRXMAU-UHFFFAOYSA-N 0.000 description 2
- BPHQZTVXXXJVHI-UHFFFAOYSA-N dimyristoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCC BPHQZTVXXXJVHI-UHFFFAOYSA-N 0.000 description 2
- BIABMEZBCHDPBV-UHFFFAOYSA-N dipalmitoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-UHFFFAOYSA-N 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000004816 latex Substances 0.000 description 2
- 229920000126 latex Polymers 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229940067605 phosphatidylethanolamines Drugs 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- 241000894007 species Species 0.000 description 2
- MWRBNPKJOOWZPW-GPADLTIESA-N 1,2-di-[(9E)-octadecenoyl]-sn-glycero-3-phosphoethanolamine Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C\CCCCCCCC MWRBNPKJOOWZPW-GPADLTIESA-N 0.000 description 1
- MLKLDGSYMHFAOC-AREMUKBSSA-N 1,2-dicapryl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCC MLKLDGSYMHFAOC-AREMUKBSSA-N 0.000 description 1
- 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 description 1
- ZLGYVWRJIZPQMM-HHHXNRCGSA-N 2-azaniumylethyl [(2r)-2,3-di(dodecanoyloxy)propyl] phosphate Chemical compound CCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCC ZLGYVWRJIZPQMM-HHHXNRCGSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004254 Ammonium phosphate Substances 0.000 description 1
- OKUSWAGOKUGEDX-UHFFFAOYSA-N C(CCC)Br(CCCC)(CCCC)CCCC Chemical compound C(CCC)Br(CCCC)(CCCC)CCCC OKUSWAGOKUGEDX-UHFFFAOYSA-N 0.000 description 1
- NPUKDXXFDDZOKR-UHFFFAOYSA-N CCOC(c1cnc[n]1C(C)c1ccccc1)=O Chemical compound CCOC(c1cnc[n]1C(C)c1ccccc1)=O NPUKDXXFDDZOKR-UHFFFAOYSA-N 0.000 description 1
- 244000270834 Myristica fragrans Species 0.000 description 1
- 235000009421 Myristica fragrans Nutrition 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 241000220287 Sedum rubrotinctum Species 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- JLPULHDHAOZNQI-JLOPVYAASA-N [(2r)-3-hexadecanoyloxy-2-[(9e,12e)-octadeca-9,12-dienoyl]oxypropyl] 2-(trimethylazaniumyl)ethyl phosphate 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-JLOPVYAASA-N 0.000 description 1
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 1
- 235000019289 ammonium phosphates Nutrition 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 229940074046 glyceryl laurate Drugs 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- CBFCDTFDPHXCNY-UHFFFAOYSA-N octyldodecane Natural products CCCCCCCCCCCCCCCCCCCC CBFCDTFDPHXCNY-UHFFFAOYSA-N 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 229920002946 poly[2-(methacryloxy)ethyl phosphorylcholine] polymer Polymers 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
Abstract
The present invention relates to a kind of Etomidate pharmaceutical composition, contain Etomidate, oil for injection, phosphatide and water for injection, Etomidate parts by weight are 1, and the parts by weight of oil for injection are 50~100, the parts by weight of phosphatide are 3~9, and the parts by weight of water for injection are 250~1000.Phosphatidylcholine content is more than or equal to 75% (w/w) in described phosphatide, and phosphatidylethanolamine content is less than or equal to 15% (w/w).The Etomidate pharmaceutical composition of the present invention has higher stability.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, and in particular to a kind of Etomidate pharmaceutical composition and preparation method thereof.
Background technology
Etomidate [R (+) -1- (1- phenethyls) -1 hydrogen-imidazole-5] is that a kind of unique general anesthesia lures
Agent and sedative are led, its security is apparently higher than barbiturates.The therapeutic index of R type Etomidates is significantly higher than other whole bodies
Arcotic.Preclinical zooscopy displays that injection Etomidate only causes atomic weak hemodynamic responses and breathing to press down
System.Etomidate safety margin is big, rapid safety of regaining consciousness, and breathing is suppressed without obvious, to memoryless in art, cardiovascular system is steady
It is fixed, especially suitable for old, weak, blood volume be relatively low and patient with angiocardiopathy.
Mainly there are two kinds of formulations in the Etomidate of clinical practice：1. liquid drugs injection：Etomidate is dissolved in 35% propane diols
The parenteral solution being prepared；The osmotic concentration of liquid drugs injection is 464mOsm/L, significantly larger than physiology osmotic concentration；2. fat emulsion：
As import China " Eto-lipuro ", be Etomidate 20% in long chain fat emulsion, composition be Etomidate, soybean oil, in
Chain triglyceride, glycerine, lecithin, enuatrol, water for injection.The osmotic concentration of " Eto-lipuro " emulsion is 390mOsm/L, is approached
Physiology osmotic concentration scope.Therefore compared with liquid drugs injection, fat emulsion can substantially reduce the side effects such as injection pain and injury of blood vessel
Etomidate easily hydrolyzes, and produces and relies on miaow acid.Shown according to " Eto-lipuro " import registered standard, it relies on miaow acid
Content is higher, and using impurity external standard method, limit must not be 2%, and said preparation preserves below 25 DEG C, must not freeze, have
The effect phase is 2 years.
Patent CN103961314A discloses a kind of Etomidate fat emulsion of stabilization, and the latex pH is 4.5-7.0,
By adjusting latex pH to faintly acid, it is suppressed that the hydrolysis of Etomidate ester bond, reduce relevant material, will have in the term of validity
Close material and rely on miaow acid control 1%.
To those skilled in the art, the major way for controlling drug hydrolysis is exactly control ph, and emulsion is one
Kind thermodynamic unstable system, pH value affect the change of milk particle surface charge distribution, and regulation pH value simply causes milk particle steady
Qualitative decline.Therefore, in addition to control ph, it is necessary to asked using superior technique scheme to solve the hydrolysis of Etomidate
Topic.
The content of the invention
The present invention has found that the stability of Etomidate is influenceed by pH after being analyzed by lot of experiments outside, unexpectedly also by breast
The influence of constituent species and content in agent phosphatide.Therefore, the present invention solves by the species and proportioning of component in phosphatide
The problem of Etomidate stability, also, solve the problems, such as milk particle particle diameter increase.
The invention provides a kind of Etomidate pharmaceutical composition, contain Etomidate, oil for injection, phosphatide and injection
Water, Etomidate parts by weight are 1, and the parts by weight of oil for injection are 50~100, and the parts by weight of phosphatide are 3~9, water for injection
Parts by weight are 250~1000.Phosphatidylcholine content is more than or equal to 75% (w/w) in described phosphatide, and phosphatidyl-ethanolamine contains
Amount is 10~15% (w/w) less than or equal to 15% (w/w), more preferably phosphatidylethanolamine content.
Also contain phosphatidyl glycerol in described phosphatide, its content is in 0.5~10% (w/w).
Phosphatidylcholine content is more than or equal to 75% (w/w) more preferably in phosphatide, and phosphatidyl glycerol content is 1~5%
(w/w), phosphatidylethanolamine content is less than or equal to 7% (w/w), much further preferably from without phosphatidyl-ethanolamine.
The phosphatide that described phosphatide extracts in yolk, above-mentioned phosphatidyl choline, phosphatidyl-ethanolamine and phosphatidyl are sweet
The content of oil is determined using HPLC methods.Above-mentioned content requirement, or described phosphorus are complied with by adjusting extraction and purification process
Fat can also use phosphatidyl choline, phosphatidyl-ethanolamine and the phosphatidyl glycerol of synthesis to be matched by above-mentioned content.
The phosphatidyl choline of the synthesis is selected from DSPC (DSPC), dioleyl phosphatidyl choline
(DOPC), Dioctonoyl pnosphotidyl choline (DPPC), L-Dimyristoylphosphatidylcholine (DMPC), didecyl acyl phospholipids acyl
Choline DDPC, DLPC (DLPC), two mustard phosphatidyl cholines (DEPC), 1- stearyls -2- oil
Phosphatidyl choline (SOPC), 1- palmityl -2- oleolyl phosphatidyl cholines (POPC), 1- myristoyl -2- oleoyls
Base phosphatidyl choline (MOPC), 1- stearyl -2- palmityls phosphatidyl cholines (SPPC), 1- stearyl -2- nutmegs
Phosphatidyl choline (SMPC), 1- palmityl -2- stearoyl phosphatidyls choline (PSPC), 1- palmityl -2- Pork and beans
Cool phosphatidyl choline (PMPC), 1- myristoyl -2- stearoyl phosphatidyls choline (MSPC), 1- myristoyls -
2- palmityls phosphatidyl choline (MPPC) or its combination.
The phosphatidyl-ethanolamine of the synthesis is selected from DSPE (DSPE), dioleoyl phosphatidyl
Monoethanolamine (DOPE), DPPE (DPPE), two myristoyl phosphatidyl-ethanolamines (DMPE), two mustard
Acyl phosphatidyl-ethanolamine (DEPE), two lauroyl phosphatidyl-ethanolamines (DLPE) or its combination.
The phosphatidyl glycerol of the synthesis is selected from DSPG (DSPG), DOPG
(DOPG), DPPG (DPPG), DMPG (DMPG), 1- palmityls -2-
Oleolyl phosphatidyl glycerine (POPG), two mustard acyl phosphatidyl glycerols (DEPG), PE (DLPG) or its group
Close.
Described oil for injection be selected from refined soybean oil, safflower oil, cottonseed oil, olive oil, coconut oil, castor oil, fish oil,
Medium chain mono, medium chain triglyceride dibasic acid esters, medium chain triglyceride, ethyl oleate, acetylated monoglyceride, propane diols dibasic acid esters, Asia
Olein, polyethylene glycol glyceryl laurate ester or its combination.
The Etomidate pharmaceutical composition, also comprising pH adjusting agent, the pH adjusting agent be selected from sodium hydroxide, hydrochloric acid,
Phosphoric acid, phosphate, citric acid, citrate, acetic acid, acetate or its combination.
The Etomidate pharmaceutical composition, also it is selected from glycerine, grape comprising isotonic regulator, the isotonic regulator
Sugar, mannitol, propane diols or its combination.
The invention provides a kind of preparation method of Etomidate pharmaceutical composition, comprise the following steps：
(1) preparation of oil phase：Etomidate is added into oil for injection, phosphatide, stirring makes its dissolving, as oil phase；
(2) preparation of colostrum：Step (1) oil phase is added in water for injection, high speed shear is disperseed, and forms colostrum；
(3) it is high-pressure homogenising：Step (2) colostrum is high-pressure homogenising, obtains smart breast；
(4) embedding, sterilizing, is produced.
The present invention after substantial amounts of test data analyzer by having been surprisingly found that, except pH value, phosphatidyl-ethanolamine in phosphatide
Hydrolysis of the content to Etomidate also has large effect, and phosphatidylethanolamine content is too high, then hydrolysis increase；But phosphatidyl second
Alcohol amine content is too low (being less than 10%), can cause milk particle particle diameter increase in autoclaving process again.Further, by increasing phosphorus
The ratio of phosphatidyl glycerol, milk particle particle diameter increase in autoclaving process can be avoided, and be found surprisingly that, phosphatidyl glycerol energy
Preferably reduce the hydrolysis of Etomidate.
Etomidate pharmaceutical composition prepared by the present invention, particle diameter reduces without significant changes in sterilizing and placement process
Impurity relies on the amount of miaow acid, adds stability, reduces safety risks.
Specific embodiment
The present invention is described in further detail with reference to embodiment, so that those of ordinary skill in the art can be more clearly
Understand and implement the present invention.It is to be understood, however, that the present invention is not limited to these embodiments.Made for the present invention
What change, modification and equivalent substitution without departing from the spirit and scope of the present invention, all falls within the scope of the present invention.
Embodiment 1
Phosphatidylcholine content 75% in phosphatide, phosphatidylethanolamine content 18%, without phosphatidyl glycerol.
Processing step：
(1) water for injection is taken, is heated to 65 DEG C, glycerine dissolving is added, as aqueous phase；
(2) soybean oil is taken, is heated to 65 DEG C, adds phosphatide and Etomidate, stirring and dissolving, as oil phase；
(3) under high velocity agitation, oil phase is slowly injected in the aqueous phase of 65 DEG C of insulations, 10000rpm high speed shears 10min
Make to form uniform colostrum；
(4) colostrum pH value 7.4~7.6 is adjusted, is added to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1200bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding, Etomidate Injection is produced；
(7) high-temperature sterilization (F0 ＞=12).
Embodiment 2
Phosphatidylcholine content 75% in phosphatide, phosphatidylethanolamine content 15%, without phosphatidyl glycerol.
Processing step：
(1) water for injection is taken, is heated to 65 DEG C, glycerine dissolving is added, as aqueous phase；
(2) soybean oil is taken, is heated to 65 DEG C, adds emulsifying agent and Etomidate, stirring and dissolving, as oil phase；
(3) under high velocity agitation, oil phase is slowly injected in the aqueous phase of 65 DEG C of insulations, 10000rpm high speed shears 10min
Make to form uniform colostrum；
(4) colostrum pH value 7.4~7.6 is adjusted, is added to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1200bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding, Etomidate Injection is produced；
(7) high-temperature sterilization (F0 ＞=12).
Embodiment 3
Phosphatidylcholine content 75% in phosphatide, phosphatidylethanolamine content 10%, without phosphatidyl glycerol.
Processing step：
(1) water for injection is taken, is heated to 65 DEG C, glycerine dissolving is added, as aqueous phase；
(2) soybean oil is taken, is heated to 65 DEG C, adds emulsifying agent and Etomidate, stirring and dissolving, as oil phase；
(3) under high velocity agitation, oil phase is slowly injected in the aqueous phase of 65 DEG C of insulations, 10000rpm high speed shears 10min
Make to form uniform colostrum；
(4) colostrum pH value 7.4~7.6 is adjusted, is added to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1200bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding, Etomidate Injection is produced；
(7) high-temperature sterilization (F0 ＞=12).
Embodiment 4
Phosphatidylcholine content 75% in phosphatide, phosphatidylethanolamine content 7%, without phosphatidyl glycerol.
Processing step：
(1) water for injection is taken, is heated to 65 DEG C, glycerine dissolving is added, as aqueous phase；
(2) soybean oil is taken, is heated to 65 DEG C, adds emulsifying agent and Etomidate, stirring and dissolving, as oil phase；
(3) under high velocity agitation, oil phase is slowly injected in the aqueous phase of 65 DEG C of insulations, 10000rpm high speed shears 10min
Make to form uniform colostrum；
(4) colostrum pH value 7.4~7.6 is adjusted, is added to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1200bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding, Etomidate Injection is produced；
(7) high-temperature sterilization (F0 ＞=12).
Testing example 1
Influence factor experiment (60 DEG C) is carried out to the Etomidate fatty emulsion of above-mentioned preparation, relied on particle diameter, relevant material
Miaow acid is inspection target.
Measure about material uses high performance liquid chromatography, and chromatographic condition is as follows：Chromatographic column：C18 posts,
Intertsil ODS-2 (4.6 × 250mm, 5 μm)；Mobile phase：Acetonitrile -0.01mol/1 ammonium phosphate solutions (contain 1% tetrabutyl bromine
Change ammonium, pH6.5 ± 0.1 adjusted with phosphoric acid) (40: 60)；Detection wavelength：243nm；Flow velocity：1.0ml/min.
It is as shown in table 1 to influence result of the test：
The influence factor result of the test of table 1 compares
According to milk particle result, the particle diameter of embodiment 4 is substantially bigger than normal, and substantially increases after placing 10 days.Illustrate phosphatidyl second
During alcohol amine content 7%, it is difficult to control milk particle particle diameter, it is necessary to by phosphatidylethanolamine content control more than 10% (embodiment 3)
Product cut size can be controlled.
According to the result about material, by embodiment 1 to embodiment 4, as phosphatidylethanolamine content declines, relevant thing
Matter gradually reduces, and embodiment 1 is about content of material at 10 days close to 0.5%, hence it is evident that higher than embodiment 2-4, therefore, it is necessary to by phosphorus
The content of phosphatidyl-ethanolamine is controlled in 15% (embodiment 2) below in fat.
Embodiment 5
Phosphatidylcholine content 75% in phosphatide, phosphatidylethanolamine content 7%, phosphatidyl glycerol 1%.
Processing step：
(1) water for injection is taken, is heated to 65 DEG C, glycerine dissolving is added, as aqueous phase；
(2) soybean oil is taken, is heated to 65 DEG C, adds emulsifying agent and Etomidate, stirring and dissolving, as oil phase；
(3) under high velocity agitation, oil phase is slowly injected in the aqueous phase of 65 DEG C of insulations, 10000rpm high speed shears 10min
Make to form uniform colostrum；
(4) colostrum pH value 7.4~7.6 is adjusted, is added to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1200bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding, Etomidate Injection is produced；
(7) high-temperature sterilization (F0 ＞=12).
Embodiment 6
Matched using the DSPG (DSPG) of phosphatidyl choline (PC-98T) and synthesis, weight ratio
For 95: 5, without PE.
Processing step：
(1) water for injection is taken, is heated to 65 DEG C, glycerine dissolving is added, as aqueous phase；
(2) soybean oil is taken, is heated to 65 DEG C, adds emulsifying agent and Etomidate, stirring and dissolving, as oil phase；
(3) under high velocity agitation, oil phase is slowly injected in the aqueous phase of 65 DEG C of insulations, 10000rpm high speed shears 10min
Make to form uniform colostrum；
(4) colostrum pH value 7.4~7.6 is adjusted, is added to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1200bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding, Etomidate Injection is produced；
(7) high-temperature sterilization (F0 ＞=12).
Embodiment 7
Phosphatidylcholine content 80% in phosphatide, phosphatidylethanolamine content 5%, phosphatidyl glycerol 10%.
Processing step：
(1) water for injection is taken, is heated to 65 DEG C, glycerine dissolving is added, as aqueous phase；
(2) soybean oil is taken, is heated to 65 DEG C, adds emulsifying agent and Etomidate, stirring and dissolving, as oil phase；
(3) under high velocity agitation, oil phase is slowly injected in the aqueous phase of 65 DEG C of insulations, 10000rpm high speed shears 10min
Make to form uniform colostrum；
(4) colostrum pH value 7.4~7.6 is adjusted, is added to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1200bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding, Etomidate Injection is produced；
(7) high-temperature sterilization (F0 ＞=12).
Embodiment 8
Phosphatidylcholine content 75% in phosphatide, phosphatidylethanolamine content 10%, phosphatidyl glycerol 0.5%.
Processing step：
(1) water for injection is taken, is heated to 65 DEG C, glycerine dissolving is added, as aqueous phase；
(2) soybean oil is taken, is heated to 65 DEG C, adds emulsifying agent and Etomidate, stirring and dissolving, as oil phase；
(3) under high velocity agitation, oil phase is slowly injected in the aqueous phase of 65 DEG C of insulations, 10000rpm high speed shears 10min
Make to form uniform colostrum；
(4) colostrum pH value 7.4~7.6 is adjusted, is added to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1200bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding, Etomidate Injection is produced；
(7) high-temperature sterilization (F0 ＞=12).
Testing example 2
Determine the content of milk particle and support miaow acid under the conditions of influence factor of embodiment 5~8.
The influence factor result of the test of table 2 compares (60 DEG C)
Embodiment 5 compared with Example 4, adds the PG of 1% content, and as a result milk particle particle diameter has obtained good control.
PE is free of in embodiment 6, relies on miaow acid control below 0.1%.
Embodiment 7 has not only controlled the increase of particle diameter, and relies on miaow acid also to obtain good control.
Embodiment 8 compared with Example 3, adds the PG of 0.5% content, and as a result milk particle particle diameter only became from 0 day to 10 days
Change 5nm (embodiment 3 changed about 15nm from 0 day to 5 days), rely on the increase of miaow acid to be also significantly lower than embodiment 3.
As a result showing, PG not only contributes to control the particle diameter of milk particle, and for relying on the growth of miaow acid also to have well
Inhibitory action.
Embodiment 9
Phosphatidylcholine content 80% in phosphatide, phosphatidylethanolamine content 12.5%, without PG.
Processing step：
(1) water for injection is taken, is heated to 65 DEG C, glycerine dissolving is added, as aqueous phase；
(2) soybean oil and medium chain triglyceride are taken, is heated to 65 DEG C, emulsifying agent and Etomidate is added, stirring and dissolving, makees
For oil phase；
(3) under high velocity agitation, oil phase is slowly injected in the aqueous phase of 65 DEG C of insulations, 10000rpm high speed shears 10min
Make to form uniform colostrum；
(4) colostrum pH value 7.0 is adjusted, is added to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1200bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding, Etomidate Injection is produced；
(7) high-temperature sterilization (F0 ＞=12).
Embodiment 10
Phosphatidylcholine content 80% in phosphatide, phosphatidylethanolamine content 12.5%, without PG.
Processing step：
(1) water for injection is taken, is heated to 65 DEG C, glycerine dissolving is added, as aqueous phase；
(2) soybean oil and medium chain triglyceride are taken, is heated to 65 DEG C, emulsifying agent and Etomidate is added, stirring and dissolving, makees
For oil phase；
(3) under high velocity agitation, oil phase is slowly injected in the aqueous phase of 65 DEG C of insulations, 10000rpm high speed shears 10min
Make to form uniform colostrum；
(4) colostrum pH value 7.0 is adjusted, is added to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1200bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding, Etomidate Injection is produced；
(7) high-temperature sterilization (F0 ＞=12).
Testing example 3
The sample of embodiment 9 and 10 is placed into long-term stable experiment (25 DEG C), period sampling measuring, measurement result simultaneously
It is as shown in the table.
As a result show, the relevant material of embodiment 10 is significantly lower than embodiment 9.Illustrate in the control about material, olive
The effect of olive oil is better than soybean oil.
Claims (9)
1. a kind of Etomidate fatty emulsion, contain Etomidate, oil for injection, phosphatide and water for injection, it is characterised in that rely on
Miaow ester parts by weight are 1, and the parts by weight of oil for injection are 50~100, and the parts by weight of phosphatide are 3~9, and the parts by weight of water for injection are
250~1000, phosphatidylcholine content is more than or equal to 75%w/w in the phosphatide, and phosphatidylethanolamine content is 10%~
15%w/w.
2. Etomidate fatty emulsion according to claim 1, in the phosphatide containing phosphatidyl glycerol content be 0.5~
10%w/w.
3. a kind of Etomidate fatty emulsion, contain Etomidate, oil for injection, phosphatide and water for injection, it is characterised in that rely on
Miaow ester parts by weight are 1, and the parts by weight of oil for injection are 50~100, and the parts by weight of phosphatide are 3~9, and the parts by weight of water for injection are
250~1000, phosphatidylcholine content is more than or equal to 75%w/w in the phosphatide, and phosphatidylethanolamine content is less than or equal to 7%
W/w, the content of phosphatidyl glycerol is 1~5%w/w.
4. Etomidate fatty emulsion according to claim 3, it is characterised in that phosphatidyl ethanol is free of in the phosphatide
Amine.
5. the Etomidate fatty emulsion according to claim 1 or 3, it is characterised in that also adjusted comprising pH adjusting agent, the pH
Save agent and be selected from sodium hydroxide, hydrochloric acid, phosphoric acid, phosphate, citric acid, citrate, acetic acid, acetate or its combination.
6. the Etomidate fatty emulsion according to claim 1 or 3, it is characterised in that described etc. also comprising isotonic regulator
Ooze conditioning agent and be selected from glycerine, glucose, mannitol, propane diols or its combination.
7. according to any described Etomidate fatty emulsions of claim 1-4, it is characterised in that described oil for injection is selected from essence
Soybean oil processed, safflower oil, cottonseed oil, olive oil, coconut oil, castor oil, fish oil, medium chain mono, medium chain triglyceride dibasic acid esters, in
Chain triglyceride, ethyl oleate, acetylated monoglyceride, propane diols dibasic acid esters, glyceryl linoleate, polyethylene glycol lauric acid
Ester or its combination.
8. Etomidate fatty emulsion according to claim 7, it is characterised in that described oil for injection be selected from olive oil and
Medium chain triglyceride, both weight ratios are 1: 1.
9. the preparation method of Etomidate fatty emulsion described in a kind of claim 6, it comprises the following steps：
(1) preparation of oil phase：Etomidate is added into oil for injection, phosphatide, stirring makes its dissolving, as oil phase；
(2) preparation of colostrum：Step (1) oil phase is added and contained in isotonic regulator water for injection, high speed shear is disperseed, and is formed
Colostrum；
(3) it is high-pressure homogenising：Step (2) colostrum is high-pressure homogenising, obtains smart breast；
(4) filter, embedding, sterilizing, produce.
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| CN104887629A (en) * | 2015-06-09 | 2015-09-09 | 北京蓝丹医药科技有限公司 | Stable propanidid fat emulsion |
| CN104922065B (en) * | 2015-06-11 | 2018-01-02 | 北京蓝丹医药科技有限公司 | Stable flurbiprofen axetil pharmaceutical composition |
| CN105055310B (en) * | 2015-08-30 | 2018-03-09 | 四川百利药业有限责任公司 | A kind of injection Etomidate composition and preparation method thereof |
| CN105663042A (en) * | 2016-02-03 | 2016-06-15 | 北京蓝丹医药科技有限公司 | Stable narcotic drug fat emulsion and preparation method thereof |
| CN110045034B (en) * | 2019-04-30 | 2022-02-08 | 江苏东南纳米材料有限公司 | Method for determining content of erucyl phosphatidylcholine by high performance liquid chromatography |
| CN111419797B (en) * | 2020-05-25 | 2021-03-16 | 武汉大安制药有限公司 | Etomidate injection preparation and preparation method thereof |
| CN114668720A (en) * | 2020-12-24 | 2022-06-28 | 远大生命科学(武汉)有限公司 | Etomidate emulsion injection and preparation method thereof |
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