CN104922065B - Stable flurbiprofen axetil pharmaceutical composition - Google Patents
Stable flurbiprofen axetil pharmaceutical composition Download PDFInfo
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- CN104922065B CN104922065B CN201510319464.3A CN201510319464A CN104922065B CN 104922065 B CN104922065 B CN 104922065B CN 201510319464 A CN201510319464 A CN 201510319464A CN 104922065 B CN104922065 B CN 104922065B
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- Prior art keywords
- phosphatidyl
- flurbiprofen axetil
- oil
- pharmaceutical composition
- choline
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- ALIVXCSEERJYHU-UHFFFAOYSA-N Flurbiprofen axetil Chemical compound FC1=CC(C(C)C(=O)OC(OC(C)=O)C)=CC=C1C1=CC=CC=C1 ALIVXCSEERJYHU-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 229950005941 flurbiprofen axetil Drugs 0.000 title claims abstract description 50
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 23
- 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 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000008215 water for injection Substances 0.000 claims abstract description 27
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims abstract description 26
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims abstract description 26
- 238000002347 injection Methods 0.000 claims abstract description 11
- 239000007924 injection Substances 0.000 claims abstract description 11
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 39
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 33
- 239000003921 oil Substances 0.000 claims description 31
- 235000019198 oils Nutrition 0.000 claims description 31
- 235000011187 glycerol Nutrition 0.000 claims description 21
- -1 phosphatidyl Glycerine Chemical compound 0.000 claims description 21
- 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 17
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 17
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 238000003786 synthesis reaction Methods 0.000 claims description 13
- 239000003549 soybean oil Substances 0.000 claims description 11
- 235000012424 soybean oil Nutrition 0.000 claims description 11
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 8
- 150000002148 esters Chemical group 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 244000056139 Brassica cretica Species 0.000 claims description 6
- 235000003351 Brassica cretica Nutrition 0.000 claims description 6
- 235000003343 Brassica rupestris Nutrition 0.000 claims description 6
- 235000010460 mustard Nutrition 0.000 claims description 6
- 239000004006 olive oil Substances 0.000 claims description 6
- 235000008390 olive oil Nutrition 0.000 claims description 6
- 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 claims description 5
- 229960001231 choline Drugs 0.000 claims description 5
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 5
- 125000001095 phosphatidyl group Chemical group 0.000 claims description 5
- 150000008105 phosphatidylcholines Chemical class 0.000 claims description 5
- 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 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 101001000212 Rattus norvegicus Decorin Proteins 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims 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 claims description 4
- 239000003002 pH adjusting agent Substances 0.000 claims description 4
- 229940067605 phosphatidylethanolamines Drugs 0.000 claims description 4
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 claims description 4
- BIABMEZBCHDPBV-UHFFFAOYSA-N dipalmitoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-UHFFFAOYSA-N 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
- 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 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
- 240000002943 Elettaria cardamomum Species 0.000 claims description 2
- 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 description 2
- 244000068988 Glycine max Species 0.000 claims description 2
- 235000010469 Glycine max Nutrition 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 235000019485 Safflower oil Nutrition 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 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 description 2
- 235000005300 cardamomo Nutrition 0.000 claims description 2
- 239000004359 castor oil Substances 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- 239000003795 chemical substances by application Substances 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
- 210000002969 egg yolk Anatomy 0.000 claims description 2
- 235000019441 ethanol Nutrition 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
- 239000008103 glucose Substances 0.000 claims description 2
- 235000001727 glucose 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
- 235000013372 meat 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
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000011574 phosphorus Substances 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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- 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 claims 1
- 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 claims 1
- UFBKGZAKEXPJNY-UHFFFAOYSA-N C(CCCCCCCCCCC)(=O)[P] Chemical compound C(CCCCCCCCCCC)(=O)[P] UFBKGZAKEXPJNY-UHFFFAOYSA-N 0.000 claims 1
- 235000021314 Palmitic acid Nutrition 0.000 claims 1
- 239000000284 extract Substances 0.000 claims 1
- 125000005456 glyceride group Chemical group 0.000 claims 1
- 239000004519 grease Substances 0.000 claims 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N n-hexadecanoic acid Natural products CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 229960002390 flurbiprofen Drugs 0.000 abstract description 19
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 abstract description 17
- 239000012535 impurity Substances 0.000 abstract description 10
- 239000000203 mixture Substances 0.000 abstract description 3
- 210000003022 colostrum Anatomy 0.000 description 36
- 235000021277 colostrum Nutrition 0.000 description 36
- 239000012071 phase Substances 0.000 description 25
- 239000008346 aqueous phase Substances 0.000 description 22
- 230000000052 comparative effect Effects 0.000 description 13
- 239000000839 emulsion Substances 0.000 description 13
- 210000000481 breast Anatomy 0.000 description 12
- 230000001954 sterilising effect Effects 0.000 description 12
- 238000004659 sterilization and disinfection Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 230000004087 circulation Effects 0.000 description 11
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 11
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 238000000265 homogenisation Methods 0.000 description 11
- 239000012982 microporous membrane Substances 0.000 description 11
- 239000007981 phosphate-citrate buffer Substances 0.000 description 11
- 239000002960 lipid emulsion Substances 0.000 description 10
- 239000002245 particle Substances 0.000 description 10
- 230000007062 hydrolysis Effects 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 239000004698 Polyethylene Substances 0.000 description 6
- 235000013336 milk Nutrition 0.000 description 6
- 239000008267 milk Substances 0.000 description 6
- 210000004080 milk Anatomy 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 230000006641 stabilisation Effects 0.000 description 4
- 238000011105 stabilization Methods 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical group CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-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
- 241000233788 Arecaceae Species 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 239000002585 base Substances 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
- 239000003814 drug Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 description 1
- 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
- TYAQXZHDAGZOEO-KXQOOQHDSA-N 1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCC TYAQXZHDAGZOEO-KXQOOQHDSA-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
- 206010067484 Adverse reaction Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000010513 Stupor 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
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229950003588 axetil Drugs 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 208000014446 corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome Diseases 0.000 description 1
- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 229940074046 glyceryl laurate Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000000917 hyperalgesic effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- 230000009854 mucosal lesion Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
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- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a stable flurbiprofen axetil pharmaceutical composition, which contains flurbiprofen axetil, phosphatidylcholine, phosphatidylethanolamine, oil for injection and water for injection; wherein the weight percentage of each component is as follows: 0.1-1% w/v of flurbiprofen axetil, 0.4-1.6% w/v of phosphatidylcholine, less than or equal to 0.18% w/v of phosphatidylethanolamine, and 10-30% w/v of oil for injection. The composition has improved stability, contains reduced levels of flurbiprofen as a hydrolyzed impurity, and has an extended shelf life of from 18 months to 24 months compared to commercially available products.
Description
Technical field
The present invention relates to a kind of Flurbiprofen axetil pharmaceutical composition of stabilization and preparation method thereof, and in particular to its effectively into
Divide the stability and its emulsion stability of flurbiprofen axetil.
Background technology
Flurbiprofen axetil is the pro-drug of Flurbiprofen, the analgesia available for Post operation and various cancers.Flurbiprofen
Ester injection is a kind of nonsteroidal targeted analgesics, and prostate is reduced by suppressing Cycloxygenase (COX) in spinal cord and periphery
The synthesis of element, reduce hyperalgesic state caused by operation wound.Fat emulsion formulation drug effect is stronger, works rapider, when continuing
Between it is longer, and be not easy to cause the adverse reactions such as mucosal lesion.It is used for Postoperative Analgesia After, and advantage is that no CNS inhibition is made
With not influenceing the revival in narcosis patient, can use immediately after surgery.Presently commercially available Flurbiprofen ester formulation only has
Florfenicol residues (trade name Furbiprofen axetil).
But existing flurbiprofen axetil fat emulsion can be because process conditions, storage bar during preparing, storing
Part and influence its stability, national drug standards YBH15412004 require florfenicol residues in 0~20 DEG C of closed guarantor
Deposit, avoid freezing, the term of validity 18 months.Flurbiprofen axetil fat emulsion in high-temperature sterilization or placement process it is possible that
Particle diameter is unstable or even demulsifying phenomenon, so as to influence its stability and security；Meanwhile its main ingredient flurbiprofen axetil is esters
Compound, facile hydrolysis generates impurity Flurbiprofen during storage, so as to cause active constituent content to reduce, on impurity content
Rise, influence its validity and security.Various researchs have been carried out in order to improve the stability of flurbiprofen axetil fat emulsion.Example
Such as, patent CN102988291B improves its stability by changing preparation technology, and supplementary material mixed process is entered at normal temperatures
OK.Patent CN102188393B and CN104188905A are to solve the problems, such as the above by changing prescription, but from injection
From the aspect of the Clinical practice security of agent, although the species for increasing auxiliary material may improve the vitro stability of preparation, together
When also increase internal potential safety hazard.
In view of the foregoing, the present invention develops the good good flurbiprofen axetil of emulsion stability simultaneously of medicine stability
Pharmaceutical composition.
The content of the invention
The invention provides a kind of Flurbiprofen axetil pharmaceutical composition of stabilization with and preparation method thereof, be related to its effectively into
Divide the stability of flurbiprofen axetil and the stability of fat emulsion.
The invention provides a kind of Flurbiprofen axetil pharmaceutical composition of stabilization, containing flurbiprofen axetil, phosphatidyl choline,
Phosphatidyl-ethanolamine, oil for injection, the percentage of appearance again of water for injection, wherein each component are as follows：
The percentage of appearance again of above-mentioned Flurbiprofen axetil pharmaceutical composition, wherein phosphatidyl-ethanolamine is preferably 0.15%-
0.18%w/v.
Above-mentioned Flurbiprofen axetil pharmaceutical composition, the percentage of appearance again of phosphatidyl-ethanolamine are further preferably less than
0.15%w/v, and contain the phosphatidyl glycerol that appearance percentage is 0.02-0.2%w/v again.More preferably phosphatidyl-ethanolamine
0.06%~0.14%w/v, 0.05~0.1%w/v of phosphatidyl glycerol.
The phosphatidyl choline is the phosphatidyl choline and its salt of natural origin, such as the phosphorus extracted in soybean or yolk
Phosphatidylcholine and its salt, the phosphatidyl choline and its salt or their any combination of synthesis；The phosphatidyl choline choosing of the synthesis
From DSPC (DSPC), dioleyl phosphatidyl choline (DOPC), Dioctonoyl pnosphotidyl choline
(DPPC), L-Dimyristoylphosphatidylcholine (DMPC), DDPC DDPC, dilauroyl phosphatidyl courage
Alkali (DLPC), two mustard phosphatidyl cholines (DEPC), 1- stearyl -2- oleolyl phosphatidyl cholines (SOPC), 1- palms
Acyl group -2- oleolyl phosphatidyl cholines (POPC), 1- myristoyl -2- oleolyl phosphatidyl cholines (MOPC), 1- stearoyls
Base -2- palmityls phosphatidyl choline (SPPC), 1- stearyl -2- myristoyls phosphatidyl cholines (SMPC), 1- palms
Acyl group -2- stearoyl phosphatidyls choline (PSPC), 1- palmityl -2- myristoyls phosphatidyl cholines (PMPC), 1- meat
Cardamom acyl group -2- stearoyl phosphatidyls choline (MSPC), 1- myristoyl -2- palmityls phosphatidyl cholines (MPPC) or
It is combined.
The phosphatidyl glycerol be natural origin phosphatidyl glycerol and its salt, the phosphatidyl glycerol and its salt of synthesis or it
Any combination；The phosphatidyl glycerol of the synthesis is selected from DSPG (DSPG), dioleoyl phosphatide
Acyl glycerine (DOPG), DPPG (DPPG), DMPG (DMPG), 1- palmityls
Base -2- oleolyl phosphatidyls glycerine (POPG), two mustard acyl phosphatidyl glycerols (DEPG), PE (DLPG) or
It is combined.
The phosphatidyl-ethanolamine be natural origin phosphatidyl-ethanolamine and its salt, the phosphatidyl-ethanolamine of synthesis and its
Salt or their any combination；The phosphatidyl-ethanolamine of the synthesis is selected from DSPE (DSPE), and two
Oleolyl phosphatidyl monoethanolamine (DOPE), DPPE (DPPE), two myristoyl phosphatidyl ethanols
Amine (DMPE), two mustard acyl phosphatidyl-ethanolamines (DEPE), two lauroyl phosphatidyl-ethanolamines (DLPE) or its combination.
In above-mentioned Flurbiprofen axetil pharmaceutical composition, the 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, second
Acylated monoglyceride, propane diols dibasic acid esters, glyceryl linoleate, polyethylene glycol glyceryl laurate ester or its combination；Preferably olive
Oil and medium chain triglyceride, both weight ratios are 1:1.
Above-mentioned Flurbiprofen axetil pharmaceutical composition, it is characterised in that be also selected from hydrogen comprising pH adjusting agent, the pH adjusting agent
Sodium oxide molybdena, hydrochloric acid, phosphoric acid, phosphate, citric acid, citrate, acetic acid, acetate or its combination.
Above-mentioned Flurbiprofen axetil pharmaceutical composition, it is characterised in that also comprising isotonic regulator, the isotonic regulator choosing
From glycerine, glucose, mannitol, propane diols or its combination.
The preparation method of above-mentioned Flurbiprofen axetil pharmaceutical composition, comprises the following steps：
(1) preparation of oil phase：Flurbiprofen axetil, phosphatidyl choline, phosphatidyl-ethanolamine, phosphatide are added into oil for injection
The stirring of acyl glycerine makes its dissolving, as oil phase；
(2) preparation of colostrum：Step (1) oil phase is added in the water for injection containing isotonic regulator, high speed shear point
Dissipate, form colostrum；
(3) it is high-pressure homogenising：Step (2) colostrum is high-pressure homogenising, obtains smart breast；
(4) filter, embedding, sterilize (F0>12), produce.
Flurbiprofen axetil fat emulsion prepared by the present invention is contrasted with commercially available flurbiprofen axetil fat emulsion, can
To obtain the more excellent flurbiprofen axetil Fat Emulsion of stability, reduce the degraded of flurbiprofen axetil, impurity Flurbiprofen
Content is lower, while can extend the shelf-life of flurbiprofen axetil fat emulsion, and 24 months were extended to from 18 months.
Embodiment
Comparative example 1
General step prepared by emulsion is described as follows：
(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 phosphatidyl choline, phosphatidyl-ethanolamine and flurbiprofen axetil, stirring is molten
Solution, as oil phase；
(3) under high speed shear, oil phase is added in 65 DEG C of aqueous phase, high speed shear speed 10000rpm, the time
10min, form colostrum；
(4) disodium hydrogen phosphate citrate buffer (disodium hydrogen phosphate and citric acid mol ratio 4：1) colostrum pH value 6.0 is adjusted
~6.5, add to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1000bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding；
(7) moist heat sterilization (F0>12), produce.
Comparative example 2
General step prepared by emulsion is described as follows：
(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 phosphatidyl choline, phosphatidyl-ethanolamine and flurbiprofen axetil, stirring is molten
Solution, as oil phase；
(3) under high speed shear, oil phase is added in 65 DEG C of aqueous phase, high speed shear speed 10000rpm, the time
10min, form colostrum；
(4) disodium hydrogen phosphate citrate buffer (disodium hydrogen phosphate and citric acid mol ratio 4：1) colostrum pH value 6.0 is adjusted
~6.5, add to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1000bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding；
(7) moist heat sterilization (F0>12), produce.
Comparative example 3
General step prepared by emulsion is described as follows：
(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, phosphatidyl choline, phosphatidyl-ethanolamine, phosphatidyl glycerol and fluorine is added and compares Lip river
Fragrant ester, stirring and dissolving, as oil phase；
(3) under high speed shear, oil phase is added in 65 DEG C of aqueous phase, high speed shear speed 10000rpm, the time
10min, form colostrum；
(4) disodium hydrogen phosphate citrate buffer (disodium hydrogen phosphate and citric acid mol ratio 4：1) colostrum pH value 6.0 is adjusted
~6.5, add to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1000bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding；
(7) moist heat sterilization (F0>12), produce.
Comparative example 4
General step prepared by emulsion is described as follows：
(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 phosphatidyl choline, phosphatidyl glycerol and flurbiprofen axetil, stirring is molten
Solution, as oil phase；
(3) under high speed shear, oil phase is added in 65 DEG C of aqueous phase, high speed shear speed 10000rpm, the time
10min, form colostrum；
(4) disodium hydrogen phosphate citrate buffer (disodium hydrogen phosphate and citric acid mol ratio 4：1) colostrum pH value 6.0 is adjusted
~6.5, add to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1000bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding；
(7) moist heat sterilization (F0>12), produce.
Embodiment 1
General step prepared by emulsion is described as follows：
(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 phosphatidyl choline, phosphatidyl-ethanolamine and flurbiprofen axetil, stirring is molten
Solution, as oil phase；
(3) under high speed shear, oil phase is added in 65 DEG C of aqueous phase, high speed shear speed 10000rpm, the time
10min, form colostrum；
(4) disodium hydrogen phosphate citrate buffer (disodium hydrogen phosphate and citric acid mol ratio 4：1) colostrum pH value 6.0 is adjusted
~6.5, add to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1000bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding；
(7) moist heat sterilization (F0>12), produce.
Embodiment 2
General step prepared by emulsion is described as follows：
(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 phosphatidyl choline, phosphatidyl-ethanolamine and flurbiprofen axetil, stirring is molten
Solution, as oil phase；
(3) under high speed shear, oil phase is added in 65 DEG C of aqueous phase, high speed shear speed 10000rpm, the time
10min, form colostrum；
(4) disodium hydrogen phosphate citrate buffer (disodium hydrogen phosphate and citric acid mol ratio 4：1) colostrum pH value 6.0 is adjusted
~6.5, add to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1000bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding；
(7) moist heat sterilization (F0>12), produce.
Embodiment 3
General step prepared by emulsion is described as follows：
(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, phosphatidyl choline, phosphatidyl-ethanolamine, phosphatidyl glycerol and fluorine is added and compares Lip river
Fragrant ester, stirring and dissolving, as oil phase；
(3) under high speed shear, oil phase is added in 65 DEG C of aqueous phase, high speed shear speed 10000rpm, the time
10min, form colostrum；
(4) disodium hydrogen phosphate citrate buffer (disodium hydrogen phosphate and citric acid mol ratio 4：1) colostrum pH value 6.0 is adjusted
~6.5, add to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1000bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding；
(7) moist heat sterilization (F0>12), produce.
Embodiment 4
General step prepared by emulsion is described as follows：
(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 phosphatidyl choline, phosphatidyl glycerol and flurbiprofen axetil, stirring is molten
Solution, as oil phase；
(3) under high speed shear, oil phase is added in 65 DEG C of aqueous phase, high speed shear speed 10000rpm, the time
10min, form colostrum；
(4) disodium hydrogen phosphate citrate buffer (disodium hydrogen phosphate and citric acid mol ratio 4：1) colostrum pH value 6.0 is adjusted
~6.5, add to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1000bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding；
(7) moist heat sterilization (F0>12), produce.
Test case 1
0 day under the conditions of the sample of embodiment 1~4 and comparative example 1~4 is respectively placed in into 60 DEG C, 5 days, determine within 10 days
The content of milk particle particle diameter and hydrolysis impurity Flurbiprofen.
It is as shown in table 1 to influence result of the test：
Table 1
It is can be found that according to comparative example 1-2 and embodiment 1-2 test result：The content of hydrolysis impurity Flurbiprofen is with PE
Increase and be in increased trend, when PE holds percentage and is more than 0.18%w/v again, the increase of Flurbiprofen content becomes apparent
(increased to 1.81%) when being 0.91%, 10 days during 1 Flurbiprofen content of comparative example 0 day, therefore PE is held to percentage control again
In below 0.18%w/v, the content of hydrolysis impurity Flurbiprofen can be effectively reduced.Can according to the test result of average grain diameter
To find, when PE, which holds percentage, is less than 0.15%w/v again, the average grain diameter of milk particle is more than 300nm (comparative example 2, average grain diameter
It is 348.5nm at 0 day, is 356.7nm at 30 days).According to hydrolysis impurity and the testing result of average grain diameter, PE holds percentage again
Preferably 0.15-0.18%w/v.
According to comparative example 3 and the average grain diameter of embodiment 3 and Flurbiprofen testing result, 0.02% can will be defined under PG
w/v；According to comparative example 4 and embodiment 4 it can be found that with the increase of PG amounts, stablizing effect does not increase and average grain diameter is omited
There is increase, therefore 0.2%w/v will be defined on PG.
Test case 2
By comparative example 1, embodiment 2, the sample obtained by embodiment 3 is placed 24 months under the conditions of 18 DEG C, determination sample
The content of average grain diameter and hydrolysis impurity Flurbiprofen at 0,3,6,9,12,18,24 month, as a result as shown in table 2.
Table 2
It can be obtained by the result of table 2, at 24 months, the flurbiprofen axetil Fat Emulsion obtained by embodiment 2 and embodiment 3 was being put
Particle diameter is stable during putting, and the content of hydrolysis impurity Flurbiprofen is significantly lower than comparative example 1.
Embodiment 5
General step prepared by emulsion is described as follows：
(1) water for injection is taken, is heated to 65 DEG C, glycerine dissolving is added, as aqueous phase；
(2) olive oil is taken, is heated to 65 DEG C, adds phosphatidyl choline, DSPE and flurbiprofen axetil, stirring and dissolving, as
Oil phase；
(3) under high speed shear, oil phase is added in 65 DEG C of aqueous phase, high speed shear speed 10000rpm, the time
10min, form colostrum；
(4) disodium hydrogen phosphate citrate buffer (disodium hydrogen phosphate and citric acid mol ratio 4：1) colostrum pH value 6.0 is adjusted
~6.5, add to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1000bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding；
(7) moist heat sterilization (F0>12), produce.
After tested, Flurbiprofen content is 0.15%, and the average grain diameter of milk particle is 315.7nm.
Embodiment 6
General step prepared by emulsion is described as follows：
(1) water for injection is taken, is heated to 65 DEG C, glycerine dissolving is added, as aqueous phase；
(2) olive oil and medium chain triglyceride are taken, is heated to 65 DEG C, phosphatidyl choline, DSPE, DSPG and fluorine is added and compares Lip river
Fragrant ester, stirring and dissolving, as oil phase；
(3) under high speed shear, oil phase is added in 65 DEG C of aqueous phase, high speed shear speed 10000rpm, the time
10min, form colostrum；
(4) disodium hydrogen phosphate citrate buffer (disodium hydrogen phosphate and citric acid mol ratio 4：1) colostrum pH value 6.0 is adjusted
~6.5, add to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1000bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding；
(7) moist heat sterilization (F0>12), produce.
After tested, Flurbiprofen content is 0.18%, and the average grain diameter of milk particle is 220.8nm.
Embodiment 7
General step prepared by emulsion is described as follows：
(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, adds phosphatidyl choline, phosphatidyl-ethanolamine, phosphatide
Acyl glycerine and flurbiprofen axetil, stirring and dissolving, as oil phase；
(3) under high speed shear, oil phase is added in 65 DEG C of aqueous phase, high speed shear speed 10000rpm, the time
10min, form colostrum；
(4) disodium hydrogen phosphate citrate buffer (disodium hydrogen phosphate and citric acid mol ratio 4：1) colostrum pH value 6.0 is adjusted
~6.5, add to the full amount of water for injection；
(5) colostrum is transferred in high pressure homogenizer and emulsified, homogenization pressure 1000bar, 3 circulations；
(6) filter：By smart breast through 0.45 μm of filtering with microporous membrane, embedding；
(7) moist heat sterilization (F0>12), produce.
After tested, Flurbiprofen content is 0.30%, and the average grain diameter of milk particle is 239.8nm.
Sample obtained by embodiment 5-7 shows that its milk particle particle diameter is stable through study on the stability result, and Flurbiprofen content is obvious
Less than the Flurbiprofen in the sample of same period comparative example 1.
Claims (10)
1. a kind of Flurbiprofen axetil pharmaceutical composition, contain flurbiprofen axetil, phosphatidyl choline, phosphatidyl-ethanolamine, injection
Oil, water for injection；The percentage of appearance again of wherein each component is as follows：
2. a kind of Flurbiprofen axetil pharmaceutical composition, contain flurbiprofen axetil, phosphatidyl choline, phosphatidyl-ethanolamine, phosphatidyl
Glycerine, oil for injection, water for injection；The percentage of appearance again of wherein each component is as follows：
3. Flurbiprofen axetil pharmaceutical composition according to claim 2, it is characterised in that appearance hundred again of phosphatidyl-ethanolamine
Divide 0.06~0.14%w/v of ratio, it is 0.05-0.1%w/v that phosphatidyl glycerol holds percentage again.
4. Flurbiprofen axetil pharmaceutical composition according to claim 1 or 2, it is characterised in that described phosphatidyl choline
For the phosphatidyl choline and its salt of natural origin, the phosphatidyl choline and its salt or their any combination of synthesis；It is described natural
The phosphatidyl choline that the phosphatidyl choline in source extracts in soybean or yolk, the phosphatidyl choline of the synthesis are selected from two
Stearoyl phosphatidyl choline, dioleyl phosphatidyl choline, Dioctonoyl pnosphotidyl choline, two myristoyl phosphatidyls
Choline, DDPC DDPC, DLPC, two mustard phosphatidyl cholines, 1- stearoyls
Base -2- oleolyl phosphatidyl cholines, 1- palmityl -2- oleolyl phosphatidyl cholines, 1- myristoyl -2- oleolyl phosphatidyls
Phatidylcholine, 1- stearyl -2- palmityl phosphatidyl cholines, 1- stearyl -2- myristoyl phosphatidyl cholines, 1- palm fibres
Palmitic acid acyl group -2- stearoyl phosphatidyl choline, 1- palmityl -2- myristoyl phosphatidyl cholines, 1- myristoyls -2-
Stearoyl phosphatidyl choline, 1- myristoyls -2- palmityls phosphatidyl choline or its combination.
5. Flurbiprofen axetil pharmaceutical composition according to claim 1 or 2, it is characterised in that described phosphatidyl ethanol
Amine be natural origin phosphatidyl-ethanolamine and its salt, the phosphatidyl-ethanolamine and its salt or their any combination of synthesis；Institute
The phosphatidyl-ethanolamine for stating synthesis is selected from DSPE, DOPE, two palmityls
Base phosphatidyl-ethanolamine, two myristoyl phosphatidyl-ethanolamines, two mustard acyl phosphatidyl-ethanolamines, two lauroyl phosphatidyl ethanols
Amine or its combination.
6. Flurbiprofen axetil pharmaceutical composition according to claim 2, it is characterised in that described phosphatidyl glycerol is day
Phosphatidyl glycerol and its salt, the phosphatidyl glycerol of synthesis and its salt or their any combination in right source；The phosphorus of the synthesis
Phosphatidyl glycerol is selected from DSPG, DOPG, DPPG, two meat
Cardamom acyl group phosphatidyl glycerol, 1- palmityl -2- oleolyl phosphatidyl glycerine, two mustard acyl phosphatidyl glycerols, two lauroyl phosphorus
Phosphatidyl glycerol or its combination.
7. Flurbiprofen axetil pharmaceutical composition according to claim 1 or 2, it is characterised in that described injection grease separation
Autofining soybean oil, safflower oil, cottonseed oil, olive oil, coconut oil, castor oil, fish oil, medium chain mono, medium chain triglyceride are double
Ester, medium chain triglyceride, ethyl oleate, acetylated monoglyceride, propane diols dibasic acid esters, glyceryl linoleate, polyethylene glycol bay
Acid glyceride or its combination.
8. Flurbiprofen axetil pharmaceutical composition according to claim 7, it is characterised in that described oil for injection is olive
Oil and medium chain triglyceride, both weight ratios are 1:1.
9. Flurbiprofen axetil pharmaceutical composition according to claim 1 or 2, it is characterised in that also comprising pH adjusting agent, institute
State pH adjusting agent and be selected from sodium hydroxide, hydrochloric acid, phosphoric acid, phosphate, citric acid, citrate, acetic acid, acetate or its combination.
10. Flurbiprofen axetil pharmaceutical composition according to claim 1 or 2, it is characterised in that also comprising isotonic regulation
Agent, the isotonic regulator are selected from glycerine, glucose, mannitol, propane diols or its combination.
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| CN108619088A (en) * | 2017-03-24 | 2018-10-09 | 北京普德康利医药科技发展有限公司 | A kind of florfenicol residues |
| CN109985005A (en) * | 2017-12-29 | 2019-07-09 | 北京普德康利医药科技发展有限公司 | Flurbiprofen axetil Fat Emulsion and preparation method thereof |
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| CN104490779A (en) * | 2014-12-26 | 2015-04-08 | 北京蓝丹医药科技有限公司 | Flurbiprofen axetil fat emulsion injection |
| CN104644554A (en) * | 2015-03-05 | 2015-05-27 | 北京蓝丹医药科技有限公司 | Etomidate pharmaceutical composition and preparation method thereof |
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| CN103393631B (en) * | 2013-08-22 | 2015-04-08 | 北京蓝丹医药科技有限公司 | Flurbiprofen axetil pharmaceutical composition |
| CN104434798A (en) * | 2014-12-18 | 2015-03-25 | 北京蓝丹医药科技有限公司 | Flurbiprofen axetil pharmaceutical composition for relieving fever |
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| CN104490779A (en) * | 2014-12-26 | 2015-04-08 | 北京蓝丹医药科技有限公司 | Flurbiprofen axetil fat emulsion injection |
| CN104644554A (en) * | 2015-03-05 | 2015-05-27 | 北京蓝丹医药科技有限公司 | Etomidate pharmaceutical composition and preparation method thereof |
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Effective date of registration: 20210426 Address after: 226123 No.18, Qinghua Road, Sanchang street, Haimen District, Nantong City, Jiangsu Province Patentee after: Jiangsu Huiju Pharmaceutical Co.,Ltd. Address before: 101111 Beijing city Daxing District Branch Street No. 88 Yizhuang biomedical park, building 1508 room Patentee before: BEIJING PUDEKANGLI PHARMACEUTICAL TECHNOLOGY DEVELOPMENT Co.,Ltd. |
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| TR01 | Transfer of patent right | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 226123 No.18, Qinghua Road, Sanchang street, Haimen District, Nantong City, Jiangsu Province Patentee after: Jiangsu Huiju Pharmaceutical Co.,Ltd. Address before: 226123 No.18, Qinghua Road, Sanchang street, Haimen District, Nantong City, Jiangsu Province Patentee before: Jiangsu Huiju Pharmaceutical Co.,Ltd. |
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| CP01 | Change in the name or title of a patent holder |