CN117693347A - Liquid pharmaceutical composition containing fosaprepitant, preparation method and application thereof - Google Patents
Liquid pharmaceutical composition containing fosaprepitant, preparation method and application thereof Download PDFInfo
- Publication number
- CN117693347A CN117693347A CN202280047203.9A CN202280047203A CN117693347A CN 117693347 A CN117693347 A CN 117693347A CN 202280047203 A CN202280047203 A CN 202280047203A CN 117693347 A CN117693347 A CN 117693347A
- Authority
- CN
- China
- Prior art keywords
- fosaprepitant
- pharmaceutical composition
- liquid pharmaceutical
- liquid
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960002891 fosaprepitant Drugs 0.000 title claims abstract description 69
- BARDROPHSZEBKC-OITMNORJSA-N fosaprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NC(=O)N(P(O)(O)=O)N1 BARDROPHSZEBKC-OITMNORJSA-N 0.000 title claims abstract description 61
- 239000007788 liquid Substances 0.000 title claims abstract description 45
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000000203 mixture Substances 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 21
- 239000004480 active ingredient Substances 0.000 claims abstract description 18
- 239000003381 stabilizer Substances 0.000 claims abstract description 16
- 239000002738 chelating agent Substances 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims abstract description 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 5
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 5
- 229940068968 polysorbate 80 Drugs 0.000 claims abstract description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 4
- 239000008101 lactose Substances 0.000 claims abstract description 4
- 239000012453 solvate Substances 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 23
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 23
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 23
- 239000005642 Oleic acid Substances 0.000 claims description 23
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 23
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 23
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 23
- 229910019142 PO4 Inorganic materials 0.000 claims description 16
- 239000010452 phosphate Substances 0.000 claims description 16
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 14
- VRQHBYGYXDWZDL-OOZCZQCLSA-N fosaprepitant dimeglumine Chemical group CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NN(P(O)(O)=O)C(=O)N1 VRQHBYGYXDWZDL-OOZCZQCLSA-N 0.000 claims description 12
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 12
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 10
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 10
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 claims description 10
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 8
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 8
- 229940095064 tartrate Drugs 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 6
- 238000011068 loading method Methods 0.000 claims description 6
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 claims description 5
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 5
- -1 polypropylene Polymers 0.000 claims description 5
- 229920000089 Cyclic olefin copolymer Polymers 0.000 claims description 4
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 4
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000005388 borosilicate glass Substances 0.000 claims description 4
- 229960003194 meglumine Drugs 0.000 claims description 4
- 239000004033 plastic Substances 0.000 claims description 4
- 229920003023 plastic Polymers 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- 229920004439 Aclar® Polymers 0.000 claims description 3
- 239000004698 Polyethylene Substances 0.000 claims description 3
- 239000004743 Polypropylene Substances 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 239000005023 polychlorotrifluoroethylene (PCTFE) polymer Substances 0.000 claims description 3
- 229920000915 polyvinyl chloride Polymers 0.000 claims description 3
- 239000004800 polyvinyl chloride Substances 0.000 claims description 3
- 229940044551 receptor antagonist Drugs 0.000 claims description 3
- 239000002464 receptor antagonist Substances 0.000 claims description 3
- 239000004475 Arginine Substances 0.000 claims description 2
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 239000000174 gluconic acid Substances 0.000 claims description 2
- 235000012208 gluconic acid Nutrition 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 2
- 235000011007 phosphoric acid Nutrition 0.000 claims description 2
- 229920000573 polyethylene Polymers 0.000 claims description 2
- 229920001155 polypropylene Polymers 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 2
- 229960000281 trometamol Drugs 0.000 claims description 2
- 239000005022 packaging material Substances 0.000 claims 2
- 239000004713 Cyclic olefin copolymer Substances 0.000 claims 1
- 229960003121 arginine Drugs 0.000 claims 1
- 229960005261 aspartic acid Drugs 0.000 claims 1
- 229960002989 glutamic acid Drugs 0.000 claims 1
- 229960002885 histidine Drugs 0.000 claims 1
- 229960000443 hydrochloric acid Drugs 0.000 claims 1
- 229960003646 lysine Drugs 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- 229960004838 phosphoric acid Drugs 0.000 claims 1
- 229940083608 sodium hydroxide Drugs 0.000 claims 1
- 229940032330 sulfuric acid Drugs 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 12
- 238000004090 dissolution Methods 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000000813 microbial effect Effects 0.000 abstract description 2
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 35
- 229960001372 aprepitant Drugs 0.000 description 35
- 238000000034 method Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- 238000009472 formulation Methods 0.000 description 9
- 238000010606 normalization Methods 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000872 buffer Substances 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 239000012470 diluted sample Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 102100037346 Substance-P receptor Human genes 0.000 description 3
- 206010047700 Vomiting Diseases 0.000 description 3
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- 239000007853 buffer solution Substances 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
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- 229920001577 copolymer Polymers 0.000 description 2
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- 230000000694 effects Effects 0.000 description 2
- 229940108890 emend Drugs 0.000 description 2
- 239000002895 emetic Substances 0.000 description 2
- 229940044880 fosaprepitant dimeglumine Drugs 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 238000005057 refrigeration Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 1
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- 101000831616 Homo sapiens Protachykinin-1 Proteins 0.000 description 1
- 101500027611 Homo sapiens Substance P Proteins 0.000 description 1
- 206010054996 Infusion site reaction Diseases 0.000 description 1
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- 102100024304 Protachykinin-1 Human genes 0.000 description 1
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- 239000004327 boric acid Substances 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
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- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 description 1
- 229960003727 granisetron Drugs 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
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- 238000011835 investigation Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 229960005343 ondansetron Drugs 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000012898 sample dilution Substances 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
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- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A liquid pharmaceutical composition containing fosaprepitant, and its preparation method and application are provided. A liquid pharmaceutical composition comprising fosaprepitant, comprising: the pharmaceutical composition comprises a pharmaceutical active ingredient, a chelating agent, a stabilizer and a pH regulator, wherein the pharmaceutical active ingredient is fosaprepitant, pharmaceutically acceptable salt, hydrate or solvate thereof; the liquid medicine composition containing fosaprepitant does not contain polysorbate 80 and lactose. The liquid medicine composition containing fosaprepitant has the advantages of simple preparation process, good physical and chemical stability, convenient clinical use, no need of re-dissolution, low risk of microbial pollution in the preparation process, suitability for industrial production and the like.
Description
The application claims the priority benefit of the prior application of the patent application No. 202111286261.0 entitled "liquid pharmaceutical composition containing fosaprepitant, its preparation method and application" filed by 2021, 11 and 2 to China national intellectual property agency. The entirety of the prior application is incorporated by reference into this application.
The invention relates to a liquid pharmaceutical composition containing fosaprepitant, a preparation method and application thereof.
Nausea and Vomiting (CINV) are common adverse reactions during or after cancer chemotherapy, which can have a significant impact on the functional state and quality of life of the patient, and patients may delay the chemotherapy regimen due to CINV, sometimes even refusing treatment. Emetic responses may be acute (within 24 hours after chemotherapy), or delayed (24 hours after chemotherapy). The underlying mechanisms of acute and delayed emetics are believed to be different. Current therapies include 5-hydroxytryptamine HT3 receptor antagonists such as ondansetron, tropisetron, and granisetron, and dopamine receptor antagonists metoclopramide. These compounds have sufficient effect on acute CINV but have no effect on delayed CINV.
Fosaprepitant dimeglumine (Fosaprepitant dimeglumine) is an active pharmaceutical ingredient marketed by the company moxadong (Merck Sharp & Dohme Corp) for injection. Fosaprepitant (Fosaprepitant) is a water-soluble phosphorylated prodrug of aprepitant (aprepitant) that rapidly converts to aprepitant in vivo following Intravenous (IV) administration. Aprepitant is an antagonist of the human substance P neurokinin 1 (NK 1) receptor. Thus, the pharmacological activity and anti-emetic effect of fosaprepitant reflect those of the parent compound aprepitant.
Because fosaprepitant (or a salt thereof) is hydrolyzed into water-insoluble aprepitant under the conditions of aqueous environment and high temperature, fosaprepitant can be hydrolyzed and degraded even in a solid state, such as in a freeze-dried preparation, when the water content is not well controlled, thereby forming aprepitant. Therefore, in order to prevent crystallization and precipitation caused by aprepitant formed by potential hydrolytic degradation of the fosaprepitant during the shelf life of the product, the prescription of the fosaprepitant meglumine for injection contains polysorbate 80 as a solubilizer of the aprepitant; and the moisture control is very harsh.
However, polysorbate 80 (a nonionic surfactant, often as a solubilizing agent for low solubility products) can cause various adverse reactions, including serious infusion site reactions and potentially life-threatening allergic reactions; lactose is used as a freeze-drying protective agent, and possible protein residues in auxiliary materials can cause allergy and have high risk; the freeze-dried product has strict moisture control, so that the freeze-drying process is difficult and the energy consumption is high.
The currently published patent documents are basically freeze-drying processes of fosaprepitant. But the freeze-drying process is time-consuming, energy-consuming and relatively high in cost, and the product is very harsh in controlling the moisture; and when in clinical use, the re-dissolution is needed, the operation is increased, and the risk of bacteria infection is increased.
Therefore, searching for the fosaprepitant formulation which has good physical and chemical stability, simple preparation process and suitability for industrial production is a technical problem which needs to be solved urgently at present.
Disclosure of Invention
The invention provides a liquid pharmaceutical composition containing fosaprepitant, which comprises the following components: the pharmaceutical composition comprises a pharmaceutical active ingredient, a chelating agent, a stabilizer and a pH regulator, wherein the pharmaceutical active ingredient is fosaprepitant, pharmaceutically acceptable salt, hydrate or solvate thereof; the liquid medicine composition containing fosaprepitant does not contain polysorbate 80 and lactose.
According to an embodiment of the present invention, the pharmaceutically acceptable salt of fosaprepitant is preferably fosaprepitant meglumine salt.
According to the embodiment of the invention, the drug loading of the active pharmaceutical ingredient is 1mg/ml to 400mg/ml, more preferably 3mg/ml to 200mg/ml, and the drug loading refers to the ratio of the mass of fosaprepitant to the volume of the liquid pharmaceutical composition containing fosaprepitant.
According to an embodiment of the invention, the chelating agent is selected from one or more of citric acid, tartaric acid, gluconic acid and ethylenediamine tetraacetic acid or pharmaceutically acceptable salts thereof; in one embodiment, the chelating agent is disodium edetate. Preferably, the mass ratio of the chelating agent to the pharmaceutically active ingredient is 1:8 to 1:56 (w/w), for example 1:50, 1:45, 1:40, 1:30, the mass of the pharmaceutically active ingredient being calculated as fosaprepitant.
According to an embodiment of the invention, the stabilizer is selected from one or more of oleic acid, sodium oleate, acetate, carbonate, phosphate, citrate, tartrate and borate, preferably one or more of oleic acid, sodium oleate and phosphate.
In some embodiments, the stabilizer is selected from oleic acid and/or sodium oleate.
In some embodiments, the stabilizer is selected from one or more of acetate, carbonate, phosphate, citrate, tartrate and borate, preferably phosphate.
In some embodiments, the stabilizer is selected from a mixture of oleic acid and phosphate, or a mixture of sodium oleate and phosphate.
In some embodiments, the phosphate may be selected from one or both of disodium hydrogen phosphate, sodium dihydrogen phosphate, preferably disodium hydrogen phosphate.
According to an embodiment of the present invention, the pH adjuster is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, glutamic acid, aspartic acid, sodium hydroxide, tromethamine, arginine, lysine, histidine, meglumine.
According to an embodiment of the present invention, the liquid pharmaceutical composition comprising fosaprepitant has a pH in the range of 7.0 to 10.0, more preferably 7.5 to 9.5, such as 8.0, 8.5, 8.8, 9.0.
In some embodiments, the stabilizer is used in an amount of 0.5 to 20% (W/V), for example 1 to 20% (W/V), such as 1 to 10% (W/V), by mass of stabilizer (g) to total volume (mL) of the liquid pharmaceutical composition comprising fosaprepitant;
in some embodiments, when the stabilizer is selected from oleic acid and/or sodium oleate, the oleic acid and/or sodium oleate is preferably used in an amount of 0.5 to 10% (W/V); in some embodiments, the oleic acid and/or sodium oleate is used in an amount of 1 to 5% (W/V), such as 1.44% (W/V), 2% (W/V), 2.11% (W/V), 2.88% (W/V), 4.23% (W/V);
in some embodiments, when the stabilizer is selected from one or more of acetate, carbonate, phosphate, citrate, tartrate and borate, the amount of one or more of acetate, carbonate, phosphate, citrate, tartrate and borate is preferably 0.5 to 10% (W/V); in some embodiments, one or more of acetate, carbonate, phosphate, citrate, tartrate and borate is used in an amount of 1 to 5% (W/V), such as 1.6% (W/V), 2% (W/V), 3% (W/V), 4% (W/V).
According to an embodiment of the present invention, the fosaprepitant liquid pharmaceutical composition may be selected from any one of the following formulations:
formula 1:12.265% (W/V) fosaprepitant meglumine, 0.27% (W/V) EDTA-2Na, 1.44% (W/V) oleic acid, and pH adjusted with 0.1M/1.0M NaOH to pH 8.5-9.5.
Formula 2:12.265% (W/V) fosaprepitant meglumine, 0.27% (W/V) EDTA-2Na, 2.88% (W/V) oleic acid, 3% (W/V) disodium hydrogen phosphate, and pH adjusted by 1.0M NaOH to pH 8.0-9.5.
The invention also provides application of the liquid medicine composition containing fosaprepitant in preparing a medicine preparation.
The invention also provides a pharmaceutical preparation, which contains the liquid pharmaceutical composition containing fosaprepitant.
According to an embodiment of the invention, the pharmaceutical formulation is administered parenterally, for example by injection.
According to an embodiment of the present invention, the pharmaceutical formulation may be an injection; intravenous infusion can be used clinically. If intravenous transfusion is adopted, physiological saline is adopted for dilution. The dilution factor of the physiological saline is preferably 25 to 500 times, more preferably 50 to 125 times.
According to an embodiment of the present invention, the pharmaceutical formulation may comprise a coating material, which may be plastic, borosilicate glass or coated borosilicate glass. The plastic is selected from one or more of PVC (polyvinyl chloride), PP (polypropylene), PE (polyethylene), COP (cycloolefin polymer), COC (cycloolefin copolymer) and Aclar (Aclar, chlorotrifluoroethylene copolymer and homopolymer).
According to an embodiment of the present invention, the pharmaceutical formulation is used for the treatment of diseases caused by NK-1 receptors, including but not limited to emesis.
The invention also provides application of the liquid medicine composition containing fosaprepitant in preparation of NK-1 receptor antagonists.
The present invention also provides a method of treating diseases caused by NK-1 receptor by administering to a patient in need thereof an effective dose of said liquid pharmaceutical composition containing fosaprepitant or said pharmaceutical formulation. The NK-1 receptor induced diseases include, but are not limited to emesis.
The invention has the beneficial effects that: the liquid medicine composition containing fosaprepitant has the advantages of simple preparation process, good physical and chemical stability, convenient clinical use, no re-dissolution, low risk of microbial pollution in the preparation process, suitability for industrial production and the like.
Solves the defects that the freeze-drying process of fosaprepitant in the prior art is time-consuming, energy-consuming, high in cost, very strict in control of moisture, and needs to be re-dissolved firstly when in clinical use, increases the operation, has the risk of bacteria infection and the like.
Definition and description of terms
Unless otherwise indicated, the definitions of terms set forth in the specification and claims of this application, including as examples, exemplary definitions, preferred definitions, specific definitions in the examples, and the like, may be arbitrarily combined and combined with each other. Such combinations and combinations are intended to be within the scope of the present description.
The above "% (W/V)" refers to the percentage of the mass (g) of the component to the total volume (mL) of the liquid pharmaceutical composition containing fosaprepitant.
The term "therapeutically effective amount" refers to an amount of the pharmaceutically active ingredient of the present invention sufficient to achieve the intended use, including but not limited to the treatment of a disease as defined below. The therapeutically effective amount may vary depending on the following factors: the intended use (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, the manner of administration, and the like, can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the particular active ingredient selected, the regimen based on, whether to administer the compound in combination with other compounds, the timing of administration, the organization of administration, and the physical delivery system carried.
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1
Table 1 prescriptions for example 1
| Name of the name | Prescription 1 | Prescription 2 | Prescription 3 |
| Fusapitant meglumine mg | 245.3 | 245.3 | 245.3 |
| EDTA-2Na mg | 5.4 | 5.4 | 5.4 |
| Oleic acid mg | 28.8 | 28.8 | 28.8 |
| 0.1mol/LNaOH ml | 1 | 1 | 1 |
| PH regulator | qs pH 8.79 | qs pH 9.00 | qs pH 9.29 |
| Constant volume to ml | 2 | 2 | 2 |
Exemplary methods of preparation for forming the stable fosaprepitant compositions of formulas 1-3 are described herein: after adding the prescribed amount of EDTA-2Na, oleic acid and 0.1M sodium hydroxide solution, 1M sodium hydroxide solution is added according to the dissolution condition of the solution until the solution is stirred and dissolved, then API (fosaprepitant meglumine) is added, and the solution is adjusted to the target pH value by using 1M NaOH/20% HCl diluent. The prepared liquid medicine is prefiltered by a 0.45 mu m filter element, and is filled and sealed to obtain the final product.
Stability of simulation stability lofting: placing at 60 ℃ for 24 hours, and temporarily storing in a refrigerator at 2-8 ℃. The appearance of the stable samples before and after refrigeration was observed and the related substances were detected after refrigeration. The test results are shown in Table 2.
Sample stability simulating clinical dilution: placing a sample at 60 ℃ for 24 hours, diluting the sample by 100 times by using 0.9% sodium chloride diluent, placing the diluted sample in a refrigerator at 2-8 ℃, sampling for 5 hours and 24 hours respectively, temporarily storing the sample in the refrigerator at 2-8 ℃ after filtering by a 0.45 mu m PES filter head, observing the appearance of the unfiltered sample, and detecting the content of the filtered liquid medicine. The test results are shown in Table 3.
Table 2 test results of the prescription in example 1
* Aprepitant results were calculated as area normalization.
The results showed that the formulations 1 to 3 were clear and transparent under all conditions, and no foreign matter was deposited. There is an increase in aprepitant (active ingredient) content in the relevant materials, but there is no risk of precipitation under both high and low temperature conditions.
TABLE 3 detection results of the diluted prescriptions in example 1
The results show that the samples with the prescriptions of 1-3 and placed at 60 ℃ for 24 hours are clear and transparent and have no foreign matters precipitated after being diluted by 100 times and placed at 2-8 ℃ for 24 hours. And the API contents of 5h and 24h are basically consistent, which shows that insoluble aprepitant can not be precipitated under the low-temperature condition.
Example 2
And (5) examining the influence of different dosages of oleic acid on the stability of the product.
Table 4 prescription of example 2
Exemplary methods of preparing fosaprepitant compositions for forming prescriptions 4-9 are described herein: adding EDTA-2Na, oleic acid and API (fosaprepitant meglumine) with the prescription amount into water for injection with the prescription amount of 60-70%, uniformly stirring, adding 1M sodium hydroxide, stirring to clear solution, and detecting the pH value; the pH value is regulated to 8.5+/-0.1 by adopting 1M NaOH/20% HCl, and the pH value is detected after the constant volume. The prepared liquid medicine is prefiltered by a 0.45 mu m filter element, and is filled and sealed to obtain the final product.
The obtained samples are subjected to stability inspection at 60 ℃ and related substances are detected at 0, 4, 8 and 24 hours respectively. The results are shown in Table 5.
Table 5 prescription stability results for example 2
* Aprepitant results were calculated as area normalization.
In the above prescription, when the oleic acid dosage is 28.8mg (1.44W/V%) in the prescription with 2ml of the filling quantity, the aprepitant is 8.07% at maximum, and the appearance is clear and transparent; in the formulation with a 4ml charge, the amount of oleic acid was 28.8mg (0.72W/V%) and aprepitant was 9.24% at maximum, and a precipitate was found to be apparent after leaving.
From the above results, it was found that the smaller the oleic acid concentration, the larger the aprepitant content and the larger the risk of precipitation.
Example 3
And (5) examining the influence of different buffer ions on the stability of the product. The specific prescription is shown in table 6.
Table 6 prescriptions for example 3
Exemplary methods of preparing fosaprepitant compositions for forming prescriptions 10-16 are described herein: EDTA-2Na and buffer salt with the prescribed amount are added into water for injection with the prescribed amount of 60-70%, and then API (fosaprepitant meglumine) is added for dissolution, and then the pH value is detected. The pH value is regulated to 10.0 by adopting 1M NaOH/HCl, and the pH value is detected after the constant volume. The prepared liquid medicine is prefiltered by a 0.45 mu m filter element, and is filled and sealed to obtain the final product.
The stability of the obtained product is inspected at 60 ℃, and related substances are detected at 0h and 24h respectively. The results are shown in Table 7.
TABLE 7 prescription stability test results for example 3
* Aprepitant results were calculated as area normalization.
The aprepitant content of the prescription 14-citric acid buffer solution, the prescription 15-tartaric acid buffer solution and the prescription 16-boric acid buffer solution at 60 ℃ and 0h is higher (the aprepitant content of most prescriptions at 0h is basically 0.2-0.3%), and particularly the aprepitant content of the prescription 14,0h is 0.99% which is far higher than that of other prescriptions.
At 60 ℃ for 24 hours, the aprepitant content of the prescription 14-citric acid buffer and the prescription 15-tartaric acid buffer is highest and exceeds 4%. In the buffer ion pair, the highest fluctuation of aprepitant content is the 11-phosphate buffer system, and the lowest final aprepitant content is 3.32%.
When the buffer pair is a phosphate system, aprepitant increases least, and the system is most stable.
Example 4
Table 8 prescriptions for example 4
The above formula is prepared according to the preparation method in the embodiment 2, and the obtained product is placed at 60 ℃ to examine stability, and related substances are detected at 0, 4, 8 and 24 hours respectively. The results are shown in Table 9.
Table 9 prescription stability results for example 4
* Aprepitant results were calculated as area normalization.
From the above data, the oleic acid alone (formula 4) was clear and transparent in appearance and good in physical stability. After phosphate is combined, the stability is further improved, and the increase amplitude of aprepitant is obviously reduced. The phosphate radical system has a certain stabilizing effect on the stability of the product, and the higher the concentration is, the more stable the system is.
Example 5
Table 10 prescription of example 5
| Name of the name | Prescription 21 |
| Fusapitant meglumine mg | 245.3 |
| EDTA-2Na mg | 5.4 |
| Disodium hydrogen phosphate mg | 60 |
| Oleic acid mg | 57.6 |
| PH regulator | Adjusting pH to 8.5 |
| Constant volume to ml | 2 |
The product prepared by the preparation method in the embodiment 2 is placed at the high temperature of 25 ℃ and 40 ℃ to examine the stability. Meanwhile, commercial preparations (trade name EMEND, underwriter: MERCK SHARP & DOHME CORP., manufacturer Patheon Manufacturing Services LLC, lot number: T037941) were compared. The data are shown in Table 11.
Table 11 comparison of the stability results of the formulations of example 5 with those of the commercial formulations
* Aprepitant is an active ingredient, calculated by area normalization, and does not incorporate total miscellaneous calculation.
The sample in the formula 21 has clear and transparent appearance, aprepitant has a growing trend but is not precipitated, and the system is stable. Indicating that the stability of formulation 21 is comparable to the commercial formulation.
Sample stability simulating clinical dilution: the prescription 21 sample of 40-10 days is adopted, diluted 75 times by 0.9% sodium chloride, placed at 25 ℃ and sampled at 0, 4, 8 and 24 hours respectively, the appearance of the diluted sample is observed, and the fosaprepitant content and related substances of the diluted liquid medicine are detected.
Table 12 prescription 21 stability 40-10 day sample dilution stability
* Aprepitant is an active ingredient, calculated by area normalization, and does not incorporate total miscellaneous calculation.
The stability investigation result of the diluent shows that the API content is stable, the aprepitant basically remains unchanged, the total impurity growth is small, and the stability of the diluent is good.
Example 6
After the prescription 21 was left at a high temperature of 80℃for 4 hours, the substances of interest were observed for appearance. Simulating the stability of a clinically diluted sample, diluting by 75 times with 0.9% sodium chloride, placing at 25 ℃ for sampling at 0, 14 and 24 hours respectively, observing the appearance of the diluted sample, and detecting related substances of the diluted liquid medicine. Meanwhile, commercial preparations (trade name EMEND, underwriter: MERCK SHARP & DOHME CORP., manufacturer Patheon Manufacturing Services LLC, lot number: T037941) were compared.
Table 13 comparison of stability of prescription 21 sample at 80-4 h and dilution stability of commercial formulation
* Aprepitant is an active ingredient, calculated by area normalization, and does not incorporate total miscellaneous calculation.
The result shows that aprepitant increases to 5.68% after prescription 21 is heated for 80-4 h, the appearance is still clear and transparent, and the total impurities are equivalent to those of the existing preparation; the stock solution is placed for 24 hours at 25 ℃ after dilution, the appearance is unchanged, aprepitant and other impurities are not changed remarkably, and the total impurity level is equivalent to that of a market preparation, thus showing good stability.
The liquid medicine composition containing fosaprepitant provided by the invention has the advantages that the preparation process is simple, the physical and chemical stability of the active ingredient aprepitant is still good although the active ingredient aprepitant is increased, and the physical and chemical stability of a simulated clinical diluted administration sample is good.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
- A liquid pharmaceutical composition comprising fosaprepitant, characterized in that it comprises: the pharmaceutical composition comprises a pharmaceutical active ingredient, a chelating agent, a stabilizer and a pH regulator, wherein the pharmaceutical active ingredient is fosaprepitant, pharmaceutically acceptable salt, hydrate or solvate thereof; the liquid medicine composition containing fosaprepitant does not contain polysorbate 80 and lactose.
- The liquid pharmaceutical composition comprising fosaprepitant of claim 1, wherein: the pharmaceutically acceptable salt of fosaprepitant is fosaprepitant meglumine salt;and/or the number of the groups of groups,the drug loading rate of the active pharmaceutical ingredients is 1 mg/ml-400 mg/ml, and the drug loading rate refers to the ratio of the mass of fosaprepitant to the volume of the liquid pharmaceutical composition containing fosaprepitant;preferably, the drug loading rate of the active pharmaceutical ingredient is 3 mg/ml-200 mg/ml, and the drug loading rate refers to the ratio of the mass of fosaprepitant to the volume of the liquid pharmaceutical composition containing fosaprepitant.
- Liquid pharmaceutical composition comprising fosaprepitant according to claim 1 or 2, characterized in that: the chelating agent is one or more selected from citric acid, tartaric acid, gluconic acid and ethylenediamine tetraacetic acid or pharmaceutically acceptable salts thereof;and/or the number of the groups of groups,the weight ratio of the chelating agent to the pharmaceutical active ingredient is 1:8-1:56, and the mass of the pharmaceutical active ingredient is calculated by the mass of fosaprepitant.
- A liquid pharmaceutical composition comprising fosaprepitant according to any one of claims 1-3, characterized in that: the stabilizer is one or more selected from acetate, carbonate, phosphate, citrate, tartrate, borate, oleic acid and sodium oleate;preferably, the pH regulator is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, glutamic acid, aspartic acid, sodium hydroxide, tromethamine, arginine, lysine, histidine and meglumine.
- A liquid pharmaceutical composition comprising fosaprepitant according to any one of claims 1-4, characterized in that: the pH value of the liquid composition containing fosaprepitant ranges from 7.0 to 10.0, and is preferably 7.5 to 9.5.
- A liquid pharmaceutical composition comprising fosaprepitant according to any one of claims 1-5, characterized in that: the amount of the stabilizer is 0.5-20% (W/V), such as 1-20% (W/V), and the amount refers to the percentage of the mass (g) of the stabilizer to the total volume (mL) of the fosaprepitant liquid pharmaceutical composition;when the stabilizer adopts oleic acid and/or sodium oleate, the dosage of the oleic acid and/or sodium oleate is preferably 0.5-10% (W/V); when the stabilizer is one or more of acetate, carbonate, phosphate, citrate, tartrate and borate, the amount of one or more of acetate, carbonate, phosphate, citrate, tartrate and borate is preferably 0.5 to 10% (W/V).
- Liquid pharmaceutical composition comprising fosaprepitant according to any one of claims 1-6, characterized in that: the fosaprepitant liquid pharmaceutical composition can be prepared from any one of the following components:formula 1:12.265% (W/V) fosaprepitant meglumine, 0.27% (W/V) EDTA-2Na, 1.44% (W/V) oleic acid, and adjusting pH with 0.1M/1.0M NaOH to pH 8.5-9.5;formula 2:12.265% (W/V) fosaprepitant meglumine, 0.27% (W/V) EDTA-2Na, 2.88% (W/V) oleic acid, 3% (W/V) disodium hydrogen phosphate, and pH adjusted by 1.0M NaOH to pH 8.0-9.5.
- Liquid pharmaceutical composition comprising fosaprepitant according to any one of claims 1 to 7, characterized in that: the liquid composition containing fosaprepitant is a liquid composition for parenteral administration.
- Use of a liquid pharmaceutical composition comprising fosaprepitant according to any one of claims 1-8 for the preparation of an NK-1 receptor antagonist.
- Use of a liquid pharmaceutical composition comprising fosaprepitant according to any one of claims 1-8 for the preparation of a pharmaceutical formulation; the pharmaceutical preparation can be injection;preferably, the pharmaceutical preparation comprises a packaging material, wherein the packaging material is plastic, borosilicate glass or coated borosilicate glass;preferably, the plastic is selected from one or more of polyvinyl chloride, polypropylene, polyethylene, cyclic olefin polymer, cyclic olefin copolymer, and aclar.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111286261 | 2021-11-02 | ||
| CN2021112862610 | 2021-11-02 | ||
| PCT/CN2022/128205 WO2023078171A1 (en) | 2021-11-02 | 2022-10-28 | Fosaprepitant-containing liquid pharmaceutical composition, preparation method therefor, and use thereof |
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| CN117693347A true CN117693347A (en) | 2024-03-12 |
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| CN202280047203.9A Pending CN117693347A (en) | 2021-11-02 | 2022-10-28 | Liquid pharmaceutical composition containing fosaprepitant, preparation method and application thereof |
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| CN (1) | CN117693347A (en) |
| TW (1) | TW202333742A (en) |
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| CN104042572B (en) * | 2013-03-12 | 2016-04-06 | 江苏奥赛康药业股份有限公司 | A kind of composition for injection containing fosaprepitant and preparation method thereof |
| CN104414980B (en) * | 2013-08-22 | 2017-03-29 | 成都苑东生物制药股份有限公司 | A kind of injection fosaprepitant dimeglumine compositionss and preparation method thereof |
| CN106943358B (en) * | 2016-01-06 | 2021-08-31 | 河南省肿瘤医院 | Fosaprepitant dimeglumine freeze-dried powder injection and preparation method thereof |
| US9974742B2 (en) * | 2016-02-01 | 2018-05-22 | Heron Therapeutics, Inc. | Emulsion formulations of an NK-1 receptor antagonist and uses thereof |
| US11065265B2 (en) * | 2018-05-18 | 2021-07-20 | Spes Pharmaceuticals Inc. | Compositions of fosaprepitant and methods of preparation |
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