TW202333742A - Liquid pharmaceutical composition containing fosaprepitant, preparation method and application - Google Patents
Liquid pharmaceutical composition containing fosaprepitant, preparation method and application Download PDFInfo
- Publication number
- TW202333742A TW202333742A TW111141271A TW111141271A TW202333742A TW 202333742 A TW202333742 A TW 202333742A TW 111141271 A TW111141271 A TW 111141271A TW 111141271 A TW111141271 A TW 111141271A TW 202333742 A TW202333742 A TW 202333742A
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- TW
- Taiwan
- Prior art keywords
- fosaprepitant
- pharmaceutical composition
- liquid pharmaceutical
- acid
- transparency
- Prior art date
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- 229960002891 fosaprepitant Drugs 0.000 title claims abstract description 63
- 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 63
- 239000007788 liquid Substances 0.000 title claims abstract description 43
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000003381 stabilizer Substances 0.000 claims abstract description 16
- 239000008186 active pharmaceutical agent Substances 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000002738 chelating agent Substances 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 48
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 24
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 24
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 24
- 239000005642 Oleic acid Substances 0.000 claims description 24
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 24
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 24
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 24
- 229910019142 PO4 Inorganic materials 0.000 claims description 16
- 239000010452 phosphate Substances 0.000 claims description 16
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 16
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 15
- 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 13
- 239000004480 active ingredient Substances 0.000 claims description 13
- 229940044880 fosaprepitant dimeglumine Drugs 0.000 claims description 12
- VRQHBYGYXDWZDL-OOZCZQCLSA-N fosaprepitant dimeglumine Chemical compound 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
- 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 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 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 11
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 claims description 10
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group 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
- 229940095064 tartrate Drugs 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 7
- 229920000089 Cyclic olefin copolymer Polymers 0.000 claims description 6
- 238000011068 loading method Methods 0.000 claims description 6
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 5
- 239000011975 tartaric acid Substances 0.000 claims description 5
- 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
- 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
- 239000005022 packaging material Substances 0.000 claims description 4
- 239000004033 plastic Substances 0.000 claims description 4
- 229920003023 plastic Polymers 0.000 claims description 4
- -1 polypropylene Polymers 0.000 claims description 4
- 229940044551 receptor antagonist Drugs 0.000 claims description 4
- 239000002464 receptor antagonist Substances 0.000 claims description 4
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 4
- 239000004713 Cyclic olefin copolymer Substances 0.000 claims description 3
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 claims description 3
- 239000004698 Polyethylene Substances 0.000 claims description 3
- 239000004743 Polypropylene Substances 0.000 claims description 3
- 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 3
- 229920000915 polyvinyl chloride Polymers 0.000 claims description 3
- 239000004800 polyvinyl chloride Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 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
- 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 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
- 229960003194 meglumine Drugs 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
- 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
- 239000002253 acid Substances 0.000 claims 1
- 239000003002 pH adjusting agent Substances 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 14
- 238000009472 formulation Methods 0.000 abstract description 6
- 238000011109 contamination Methods 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000000034 method Methods 0.000 abstract description 3
- 230000000813 microbial effect Effects 0.000 abstract description 2
- 230000029219 regulation of pH Effects 0.000 abstract 1
- 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 39
- 229960001372 aprepitant Drugs 0.000 description 39
- 239000000243 solution Substances 0.000 description 17
- 238000001556 precipitation Methods 0.000 description 16
- 239000000047 product Substances 0.000 description 11
- 239000012535 impurity Substances 0.000 description 10
- 239000000872 buffer Substances 0.000 description 8
- 239000012895 dilution Substances 0.000 description 8
- 238000010790 dilution Methods 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 238000004108 freeze drying Methods 0.000 description 5
- 206010047700 Vomiting Diseases 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 229960004106 citric acid Drugs 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 238000005057 refrigeration Methods 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 239000012470 diluted sample Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 238000010606 normalization Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 101000831616 Homo sapiens Protachykinin-1 Proteins 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 102100024304 Protachykinin-1 Human genes 0.000 description 2
- 102100037346 Substance-P receptor Human genes 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229940108890 emend Drugs 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 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
- 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 2
- 230000008673 vomiting Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 1
- 229920004439 Aclar® Polymers 0.000 description 1
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- 229940121891 Dopamine receptor antagonist Drugs 0.000 description 1
- 101500027611 Homo sapiens Substance P Proteins 0.000 description 1
- 206010054996 Infusion site reaction Diseases 0.000 description 1
- 206010022095 Injection Site reaction Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 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
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- UUAGAQFQZIEFAH-UHFFFAOYSA-N chlorotrifluoroethylene Chemical group FC(F)=C(F)Cl UUAGAQFQZIEFAH-UHFFFAOYSA-N 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000095 emetic effect Effects 0.000 description 1
- 238000002474 experimental method 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
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo 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
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 229960005343 ondansetron Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient 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
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000005023 polychlorotrifluoroethylene (PCTFE) polymer Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 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
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- 229940076279 serotonin Drugs 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 1
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- UIVFDCIXTSJXBB-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C[C]2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CN=C21 UIVFDCIXTSJXBB-ITGUQSILSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—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)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本發明涉及一種含福沙匹坦的液體藥物組合物、其製備方法及用途。The invention relates to a liquid pharmaceutical composition containing fosaprepitant, its preparation method and use.
本發明要求享有於2021年11月2日向中國國家知識產權局提交的,專利申請號為202111286261.0,名稱為「含福沙匹坦的液體藥物組合物、其製備方法及應用」的先申請案的優先權權益。所述先申請案的全文通過引用的方式結合於本發明中。The present invention claims the benefit of the prior application submitted to the State Intellectual Property Office of China on November 2, 2021, with the patent application number 202111286261.0 and titled "Liquid pharmaceutical composition containing fosaprepitant, preparation method and application thereof" Priority interests. The entire text of the prior application is incorporated into the present application by reference.
噁心和嘔吐(CINV)是癌症化療期間或癌症化療後常見的不良反應,該綜合症會對患者的功能狀態和生活品質產生重大影響,並且患者可能因為CINV而推遲化療計畫,有時候甚至拒絕治療。致吐反應可能是急性的(化療後24h內),或延遲的(化療後24h後)。急性致吐和延遲性致吐的潛在機制被認為是不同的。目前的療法包括5-羥色胺HT3受體拮抗劑,例如昂丹司瓊、托烷司瓊和格拉司瓊,以及多巴胺受體拮抗劑胃複安。這些化合物對急性CINV有足夠的作用,但是對延遲性CINV無作用。Nausea and vomiting (CINV) is a common adverse reaction during or after cancer chemotherapy. This syndrome can have a significant impact on patients' functional status and quality of life, and patients may delay or sometimes even refuse chemotherapy plans because of CINV. treatment. The emetogenic reaction may be acute (within 24 hours after chemotherapy) or delayed (after 24 hours after chemotherapy). The mechanisms underlying acute and delayed emesis are thought to be different. Current treatments include serotonin HT3 receptor antagonists such as ondansetron, tropisetron, and granisetron, and the dopamine receptor antagonist metoclopramide. These compounds are sufficiently effective against acute CINV but not against delayed CINV.
福沙匹坦二甲葡胺(Fosaprepitant dimeglumine)是默沙東公司(Merck Sharp&Dohme Corp)上市的用於注射的活性藥物成分。福沙匹坦(Fosaprepitant)為阿瑞匹坦(aprepitant)的水溶性磷酸化前藥,其在靜脈注射(IV)給藥後在體內迅速轉化為阿瑞匹坦。阿瑞匹坦是一種人類物質P神經激肽1(NK1)受體的拮抗劑。因此,福沙匹坦的藥理學活性和止吐效果反映其母體化合物阿瑞匹坦的那些藥理活性和止吐效果。Fosaprepitant dimeglumine is an active pharmaceutical ingredient for injection marketed by Merck Sharp & Dohme Corp. Fosaprepitant is a water-soluble phosphorylated prodrug of aprepitant, which is rapidly converted to aprepitant in the body after intravenous (IV) administration. Aprepitant is a human substance P neurokinin 1 (NK1) receptor antagonist. Therefore, the pharmacological activities and antiemetic effects of fosaprepitant mirror those of its parent compound, aprepitant.
由於在水性環境及高溫條件下,福沙匹坦(或其鹽)會水解成不溶於水的阿瑞匹坦,即使在固態下,如在冷凍乾燥製劑中,當水分控制不好時,福沙匹坦仍可水解降解,從而形成阿瑞匹坦。因此,為了防止在產品保存期限內潛在的福沙匹坦的水解降解形成的阿瑞匹坦而導致的結晶和沉澱,注射用福沙匹坦雙葡甲胺的配方中含有聚山梨酯80,作為阿瑞匹坦的增溶劑;且水分控制十分苛刻。Because in aqueous environments and high temperatures, fosaprepitant (or its salts) will be hydrolyzed into water-insoluble aprepitant, even in the solid state, such as in freeze-dried preparations, when the moisture control is not good, fosaprepitant will Saprepitant can still be hydrolytically degraded to form aprepitant. Therefore, in order to prevent potential hydrolytic degradation of fosaprepitant to form aprepitant during the shelf life of the product, resulting in crystallization and precipitation, the formulation of fosaprepitant dimeglumine for injection contains polysorbate 80, As a solubilizer of aprepitant; and the moisture control is very strict.
然而,聚山梨酯80(非離子表面活性劑,常作為低溶解度產品的增溶劑)會引起各種不良反應,包括嚴重的輸注部位反應和潛在的威脅生命的過敏反應;乳糖作為冷凍乾燥保護劑,輔料中可能的蛋白殘留會導致過敏,風險較高;冷凍乾燥品的水分控制苛刻,導致冷凍乾燥技術困難,且能耗較大。However, polysorbate 80 (a nonionic surfactant often used as a solubilizer for low-solubility products) can cause a variety of adverse reactions, including severe infusion site reactions and potentially life-threatening allergic reactions; lactose, as a freeze-drying protectant, Possible protein residues in excipients can lead to allergies, which poses a higher risk; freeze-dried products require strict moisture control, which makes freeze-drying technically difficult and consumes a lot of energy.
目前公開的專利文獻,基本都是福沙匹坦的冷凍乾燥技術。但冷凍乾燥技術費時、耗能,成本較大,本產品對水分的控制十分嚴苛;且在臨床上使用時,需要先進行複溶,增加了操作,會有染菌的風險。The currently published patent documents are basically freeze-drying technology for fosaprepitant. However, freeze-drying technology is time-consuming, energy-consuming, and costly. This product has very strict moisture control; and when used clinically, it needs to be reconstituted first, which increases the operation and risks bacterial contamination.
因此,尋找物理及化學穩定性好、製備技術簡單、適合於工業化生產的福沙匹坦劑型,是目前急需解決的技術問題。Therefore, finding a fosaprepitant dosage form with good physical and chemical stability, simple preparation technology, and suitable for industrial production is an urgent technical problem that needs to be solved.
本發明提供了一種含福沙匹坦的液體藥物組合物,其包含:藥物活性成分、螯合劑、穩定劑和pH調節劑,所述的藥物活性成分為福沙匹坦、其藥學上可接受的鹽、水合物或溶劑合物;所述的含福沙匹坦的液體藥物組合物不含聚山梨酯80和乳糖。The invention provides a liquid pharmaceutical composition containing fosaprepitant, which contains: a pharmaceutical active ingredient, a chelating agent, a stabilizer and a pH regulator. The pharmaceutical active ingredient is fosaprepitant, which is pharmaceutically acceptable. salt, hydrate or solvate; the fosaprepitant-containing liquid pharmaceutical composition does not contain polysorbate 80 and lactose.
根據本發明的實施方案,所述的福沙匹坦藥學上可接受的鹽較佳為福沙匹坦雙葡甲銨鹽。According to an embodiment of the present invention, the pharmaceutically acceptable salt of fosaprepitant is preferably fosaprepitant dimegglumine salt.
根據本發明的實施方案,所述的藥物活性成分的載藥量為1 mg/ml~400 mg/ml,進一步較佳為3 mg/ml~200 mg/ml,所述的載藥量是指福沙匹坦的重量與含福沙匹坦的液體藥物組合物體積的比值。According to the embodiment of the present invention, the drug loading capacity of the active pharmaceutical ingredient is 1 mg/ml~400 mg/ml, and more preferably 3 mg/ml~200 mg/ml. The drug loading capacity refers to The ratio of the weight of fosaprepitant to the volume of the liquid pharmaceutical composition containing fosaprepitant.
根據本發明的實施方案,所述的螯合劑選自檸檬酸、酒石酸、葡萄糖酸和乙二胺四乙酸或其藥學上可接受的鹽中的一種或多種;在一種實施例中,所述螯合劑為乙二胺四乙酸二鈉。較佳地,所述的螯合劑與所述的藥物活性成分的重量比為1:8~1:56(w/w),例如1:50、1:45、1:40、1:30,所述藥物活性成分的重量以福沙匹坦的重量計。According to an embodiment of the present invention, the chelating agent is selected from one or more of citric acid, tartaric acid, gluconic acid and ethylenediaminetetraacetic acid or pharmaceutically acceptable salts thereof; in one embodiment, the chelating agent The mixture is disodium ethylenediaminetetraacetate. Preferably, the weight ratio of the chelating agent to the active pharmaceutical ingredient is 1:8~1:56 (w/w), such as 1:50, 1:45, 1:40, 1:30, The weight of the active pharmaceutical ingredient is based on the weight of fosaprepitant.
根據本發明的實施方案,所述的穩定劑選自油酸、油酸鈉、醋酸鹽、碳酸鹽、磷酸鹽、檸檬酸鹽、酒石酸鹽和硼酸鹽中的一種或多種,較佳為油酸、油酸鈉和磷酸鹽中的一種或多種。According to an embodiment of the present invention, the stabilizer is selected from one or more of oleic acid, sodium oleate, acetate, carbonate, phosphate, citrate, tartrate and borate, preferably oleic acid , one or more of sodium oleate and phosphate.
在一些實施方案中,所述的穩定劑選自油酸和/或油酸鈉。In some embodiments, the stabilizer is selected from oleic acid and/or sodium oleate.
在一些實施方案中,所述的穩定劑選自醋酸鹽、碳酸鹽、磷酸鹽、檸檬酸鹽、酒石酸鹽和硼酸鹽中的一種或多種,較佳為磷酸鹽。In some embodiments, the stabilizer is selected from one or more of acetate, carbonate, phosphate, citrate, tartrate and borate, preferably phosphate.
在一些實施方案中,所述的穩定劑選自油酸與磷酸鹽的混合物,或者油酸鈉與磷酸鹽的混合物。In some embodiments, the stabilizer is selected from a mixture of oleic acid and phosphate, or a mixture of sodium oleate and phosphate.
在一些實施方案,所述磷酸鹽可以選自磷酸氫二鈉、磷酸二氫鈉中的一種或兩種,較佳為磷酸氫二鈉。In some embodiments, the phosphate can be selected from one or two of disodium hydrogen phosphate and sodium dihydrogen phosphate, preferably disodium hydrogen phosphate.
根據本發明的實施方案,所述的pH調節劑選自鹽酸、硫酸、磷酸、谷胺酸、天門冬胺酸、氫氧化鈉、胺丁三醇、精胺酸、賴胺酸、組胺酸、葡甲胺中的一種或多種。According to an embodiment of the present invention, the pH regulator is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, glutamic acid, aspartic acid, sodium hydroxide, tromethamine, arginine, lysine, and histidine. , one or more of meglumine.
根據本發明的實施方案,所述的含福沙匹坦的液體藥物組合物pH值範圍為7.0~10.0,進一步較佳為7.5~9.5,比如為8.0、8.5、8.8、9.0。According to an embodiment of the present invention, the pH value of the fosaprepitant-containing liquid pharmaceutical composition ranges from 7.0 to 10.0, more preferably from 7.5 to 9.5, such as 8.0, 8.5, 8.8, and 9.0.
在一些實施方案中,所述的穩定劑的用量為0.5~20%(W/V),例如1~20%(W/V),比如1~10%(W/V),所述的用量是指穩定劑的重量(g)與含福沙匹坦的液體藥物組合物總體積(mL)的百分比;In some embodiments, the dosage of the stabilizer is 0.5~20% (W/V), such as 1~20% (W/V), such as 1~10% (W/V). It refers to the percentage of the weight of the stabilizer (g) to the total volume (mL) of the fosaprepitant-containing liquid pharmaceutical composition;
在一些實施方案中,當所述的穩定劑選自油酸和/或油酸鈉時,所述的油酸和/或油酸鈉的用量較佳為0.5~10%(W/V);在一些實施例中,所述的油酸和/或油酸鈉的用量為1~5%(W/V),比如為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 oleic acid and/or sodium oleate, the dosage of oleic acid and/or sodium oleate is preferably 0.5~10% (W/V); In some embodiments, the dosage of oleic acid and/or sodium oleate is 1~5% (W/V), such as 1.44% (W/V), 2% (W/V), 2.11% (W/V), 2.88% (W/V), 4.23% (W/V);
在一些實施方案中,當所述的穩定劑選自醋酸鹽、碳酸鹽、磷酸鹽、檸檬酸鹽、酒石酸鹽和硼酸鹽中的一種或多種時,所述的醋酸鹽、碳酸鹽、磷酸鹽、檸檬酸鹽、酒石酸鹽和硼酸鹽中的一種或多種的用量較佳為0.5~10%(W/V);在一些實施方案中,所述的醋酸鹽、碳酸鹽、磷酸鹽、檸檬酸鹽、酒石酸鹽和硼酸鹽中的一種或多種的用量為1~5%(W/V),比如為1.6%(W/V)、2%(W/V)、3%(W/V)、4%(W/V)。In some embodiments, when the stabilizer is selected from one or more of acetate, carbonate, phosphate, citrate, tartrate and borate, the acetate, carbonate, phosphate The dosage of one or more of citrate, tartrate and borate is preferably 0.5~10% (W/V); in some embodiments, the acetate, carbonate, phosphate, citric acid The dosage of one or more of salt, tartrate and borate is 1~5% (W/V), such as 1.6% (W/V), 2% (W/V), 3% (W/V) , 4% (W/V).
根據本發明的實施方案,所述的含福沙匹坦的液體藥物組合物可以選自以下配方中的任意一種:According to an embodiment of the present invention, the fosaprepitant-containing liquid pharmaceutical composition can be selected from any one of the following formulas:
配方1:12.265%(W/V)福沙匹坦雙葡甲胺、0.27%(W/V) EDTA-2Na、1.44%(W/V)油酸,並用0.1 M/1.0 M的NaOH調節pH,pH 8.5~9.5;Formula 1: 12.265% (W/V) fosaprepitant dimeglumine, 0.27% (W/V) EDTA-2Na, 1.44% (W/V) oleic acid, and adjust the pH with 0.1 M/1.0 M NaOH , pH 8.5~9.5;
配方2:12.265%(W/V)福沙匹坦雙葡甲胺、0.27%(W/V) EDTA-2Na、2.88%(W/V)油酸、3%(W/V)磷酸氫二鈉,並用1.0 M的NaOH調節pH,pH 8.0~9.5。Formula 2: 12.265% (W/V) fosaprepitant dimeglumine, 0.27% (W/V) EDTA-2Na, 2.88% (W/V) oleic acid, 3% (W/V) dihydrogen phosphate Sodium, and adjust the pH with 1.0 M NaOH to pH 8.0~9.5.
本發明還提供了所述的含福沙匹坦的液體藥物組合物在製備藥物製劑中的用途。The present invention also provides the use of the fosaprepitant-containing liquid pharmaceutical composition in preparing pharmaceutical preparations.
本發明還提供一種藥物製劑,含有上述含福沙匹坦的液體藥物組合物。The present invention also provides a pharmaceutical preparation containing the above-mentioned fosaprepitant-containing liquid pharmaceutical composition.
根據本發明的實施方案,所述的藥物製劑的給藥方式為非胃腸道給藥,比如為注射給藥。According to an embodiment of the present invention, the pharmaceutical preparation is administered parenterally, such as by injection.
根據本發明的實施方案,所述的藥物製劑可以為注射劑;臨床上可採用靜脈輸液。若採用靜脈輸液,則採用生理鹽水稀釋即可。所述的生理鹽水稀釋的倍數較佳為25倍~500倍,進一步較佳為50倍~125倍。According to the embodiment of the present invention, the pharmaceutical preparation can be an injection; clinically, intravenous infusion can be used. If intravenous infusion is used, dilute it with normal saline. The dilution ratio of the physiological saline is preferably 25 times to 500 times, and further preferably 50 times to 125 times.
根據本發明的實施方案,所述的藥物製劑可以包含包材,所述的包材可以為塑膠、硼矽玻璃或鍍膜硼矽玻璃。所述的塑膠選自PVC(聚氯乙烯)、PP(聚丙烯)、PE(聚乙烯)、COP(環烯烴聚合物)、COC(環烯烴共聚物)和阿克拉(Aclar,三氟氯乙烯共聚物和均聚物)中的一種或多種。According to an embodiment of the present invention, the pharmaceutical preparation may include a packaging material, and the packaging material may be plastic, borosilicate glass or coated borosilicate glass. The plastic is selected from PVC (polyvinyl chloride), PP (polypropylene), PE (polyethylene), COP (cyclic olefin polymer), COC (cyclic olefin copolymer) and Aclar (chlorotrifluoroethylene). One or more of copolymers and homopolymers).
根據本發明的實施方案,所述的藥物製劑用於治療NK-1受體引起的疾病,所述的NK-1受體引起的疾病包括但不限於嘔吐。According to an embodiment of the present invention, the pharmaceutical preparation is used to treat diseases caused by NK-1 receptors, including but not limited to vomiting.
本發明還提供了所述的含福沙匹坦的液體藥物組合物在製備NK-1受體拮抗劑中的用途。The invention also provides the use of the fosaprepitant-containing liquid pharmaceutical composition in the preparation of NK-1 receptor antagonists.
本發明還提供了一種治療NK-1受體引起的疾病的方法,其為給需要的患者服用有效劑量的所述的含福沙匹坦的液體藥物組合物或所述藥物製劑。所述的NK-1受體引起的疾病包括但不限於嘔吐。The present invention also provides a method for treating diseases caused by NK-1 receptors, which involves taking an effective dose of the fosaprepitant-containing liquid pharmaceutical composition or the pharmaceutical preparation to a patient in need. The diseases caused by the NK-1 receptor include but are not limited to vomiting.
本發明的有益效果在於:本發明的含福沙匹坦的液體藥物組合物,具有製備技術簡單,物理、化學穩定性好,臨床使用方便不需複溶,配製過程微生物污染風險低,適合於工業化生產等優點。The beneficial effects of the present invention are: the fosaprepitant-containing liquid pharmaceutical composition of the present invention has simple preparation technology, good physical and chemical stability, is convenient for clinical use and does not require reconstitution, has low risk of microbial contamination during the preparation process, and is suitable for Industrial production and other advantages.
解決了現有技術中福沙匹坦冷凍乾燥技術費時、耗能、成本較大、對水分的控制十分嚴苛、且在臨床上使用時需要先進行複溶、增加了操作,會有染菌的風險等缺陷。It solves the problem that the freeze-drying technology of fosaprepitant in the existing technology is time-consuming, energy-consuming, costly, has very strict moisture control, and needs to be reconstituted before clinical use, which increases the number of operations and may lead to bacterial contamination. Risks and other shortcomings.
術語定義與說明Definitions and explanations of terms
除非另有說明,本申請說明書和發明申請專利範圍中記載的術語定義,包括其作為實例的定義、示例性的定義、較佳的定義、實施例中具體的定義等,可以彼此之間任意組合和結合。這樣的組合和結合應當屬於本申請說明書記載的範圍內。Unless otherwise stated, the definitions of terms recorded in the specification and patent scope of this application, including their definitions as examples, exemplary definitions, preferred definitions, specific definitions in embodiments, etc., can be arbitrarily combined with each other. and combine. Such combinations and combinations should fall within the scope of the description of this application.
上述「%(W/V)」指的是該組分的重量(g)與含福沙匹坦的液體藥物組合物總體積(mL)的百分比。The above “% (W/V)” refers to the percentage of the weight (g) of the component to the total volume (mL) of the fosaprepitant-containing liquid pharmaceutical composition.
術語「治療有效量」是指足以實現預期應用(包括但不限於如下定義的疾病治療)的本發明藥物活性成分的量。治療有效量可以取決於以下因素而改變:預期應用(體外或者體內),或者所治療的受試者和疾病病症如受試者的重量和年齡、疾病病症的嚴重性和給藥方式等,其可以由所屬技術領域中具有通常知識者容易地確定。具體劑量將取決於以下因素而改變:所選擇的特定活性成分、所依據的給藥方案、是否與其它化合物組合給藥、給藥的時間安排、所給藥的組織和所承載的物理遞送系統。The term "therapeutically effective amount" refers to an amount of a pharmaceutically active ingredient of the present invention sufficient to achieve the intended use, including but not limited to the treatment of disease as defined below. The therapeutically effective amount may vary depending on factors such as the intended application (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 and the mode of administration, etc. It can be easily determined by a person with ordinary knowledge in the technical field. The specific dosage will vary depending on the specific active ingredient selected, the dosing regimen followed, whether administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system upon which it is administered. .
具體實施方式Detailed implementation
下文將結合具體實施例對本發明的技術方案做更進一步的詳細說明。應當理解,下列實施例僅為示例性地說明和解釋本發明,而不應被解釋為對本發明保護範圍的限制。凡基於本發明上述內容所實現的技術均涵蓋在本發明旨在保護的範圍內。The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following examples are only illustrative and explain the present invention and should not be construed as limiting the scope of the present invention. All technologies implemented based on the above contents of the present invention are covered by the scope of protection intended by the present invention.
除非另有說明,以下實施例中使用的原料和試劑均為市售商品,或者可以通過已知方法製備。下列實施例中未註明具體條件的實驗方法,按照常規方法和條件,或按照商品說明書選擇。Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. Experimental methods that do not indicate specific conditions in the following examples should be selected according to conventional methods and conditions, or according to product specifications.
實施例1Example 1
表1 實施例1的配方
此處描述用於形成配方1~3穩定的福沙匹坦組合物的示例性製備方法:加入配方量的EDTA-2Na、油酸、0.1 M氫氧化鈉溶液後,根據溶液溶解情況,加入1 M氫氧化鈉溶液,直至攪拌溶解後,再加入API(福沙匹坦雙葡甲胺),用1 M的NaOH/ 20%HCl稀釋液調節至目標pH值。製備所得的藥液採用0.45 µm濾芯預過濾,灌裝封口,得到終產品。An exemplary preparation method for forming a stable fosaprepitant composition in formulas 1 to 3 is described here: after adding the formula amount of EDTA-2Na, oleic acid, and 0.1 M sodium hydroxide solution, add 1 M sodium hydroxide solution until stirred and dissolved, then add API (fosaprepitant dimeglumine), and adjust to the target pH value with 1 M NaOH/20% HCl diluent. The prepared medicinal liquid is pre-filtered with a 0.45 µm filter element, filled and sealed to obtain the final product.
模擬穩定性樣品的穩定性:於60℃放置24 h,暫存2~8℃冰箱中。觀察冷藏前後穩定性樣品的外觀,冷藏後檢測有關物質。檢測結果如表2所示。Stability of simulated stability samples: placed at 60°C for 24 hours, and temporarily stored in a refrigerator at 2~8°C. Observe the appearance of the stability samples before and after refrigeration, and detect relevant substances after refrigeration. The test results are shown in Table 2.
模擬臨床稀釋的樣品穩定性:60℃放置24 h的樣品,採用0.9%氯化鈉稀釋液稀釋100倍,稀釋樣品放置2~8℃冰箱,分別在5 h、24 h取樣,0.45 µm PES濾頭過濾後暫存2~8℃冰箱中,觀察未過濾樣品的外觀,檢測過濾後藥液的含量。檢測結果如表3所示。Stability of simulated clinical dilution samples: samples stored at 60°C for 24 hours were diluted 100 times with 0.9% sodium chloride diluent. The diluted samples were placed in a refrigerator at 2~8°C, sampled at 5 hours and 24 hours, and filtered with 0.45 µm PES. After filtration, temporarily store it in a refrigerator at 2~8°C, observe the appearance of the unfiltered sample, and detect the content of the filtered liquid. The test results are shown in Table 3.
表2 實施例1中配方的檢測結果
結果顯示,配方1~3各條件下均澄清、透明,並無異物析出。有關物質中阿瑞匹坦(活性成分)含量雖有增長,但高溫和低溫條件下均無析出風險。The results show that formulas 1 to 3 are clear and transparent under each condition, and no foreign matter precipitates. Although the content of aprepitant (active ingredient) in the relevant substances has increased, there is no risk of precipitation under high or low temperature conditions.
表3 實施例1中稀釋後配方的檢測結果
結果顯示,配方1~3,60℃放置24 h的樣品,稀釋100倍後,放於2~8℃下24 h,樣品均澄清、透明,並無異物析出。且5 h和24 h的API含量基本一致,說明低溫條件下,也不會析出不溶性的阿瑞匹坦。The results show that for formulas 1 to 3, samples placed at 60°C for 24 hours were diluted 100 times and placed at 2 to 8°C for 24 hours. The samples were all clear and transparent, and no foreign matter precipitated. Moreover, the API content at 5 h and 24 h was basically the same, indicating that insoluble aprepitant would not precipitate under low temperature conditions.
實施例2Example 2
檢測不同用量的油酸對產品的穩定性的影響情況。Test the effect of different dosages of oleic acid on the stability of the product.
表4 實施例2的配方
此處描述用於形成配方4~9的福沙匹坦組合物的示例性製備方法:在配方量60~70%注射用水中,加入配方量的EDTA-2Na、油酸、API(福沙匹坦雙葡甲胺),攪拌均勻,加入1 M氫氧化鈉,攪拌至澄清溶液,檢測pH值;採用1 M NaOH / 20% HCl調節pH值至8.5±0.1,定容後檢測pH值。製備所得的藥液採用0.45 µm濾芯預過濾,灌裝封口,得到終產品。An exemplary preparation method of the fosaprepitant composition used to form formulas 4 to 9 is described here: in the formula amount of 60 to 70% water for injection, add the formula amount of EDTA-2Na, oleic acid, API (fosaprepitant Tansimeglumine), stir evenly, add 1 M sodium hydroxide, stir until the solution is clear, and check the pH value; use 1 M NaOH / 20% HCl to adjust the pH value to 8.5 ± 0.1, and check the pH value after diluting the volume. The prepared medicinal liquid is pre-filtered with a 0.45 µm filter element, filled and sealed to obtain the final product.
得到的樣品置於60℃穩定性考察,分別於0、4、8、24 h檢測有關物質。結果如表5。The obtained samples were placed at 60°C for stability investigation, and related substances were detected at 0, 4, 8, and 24 h respectively. The results are shown in Table 5.
表5 實施例2的配方穩定性結果
在以上配方中,2 ml裝量的配方中,當油酸用量為28.8 mg(1.44W/V%)時,阿瑞匹坦最大為8.07%,外觀澄清透明;4 ml裝量的配方中,油酸用量為28.8 mg(0.72 W/V%)時,阿瑞匹坦最大為9.24%,且放置後外觀上有沉澱析出。In the above formula, in the 2 ml formula, when the oleic acid dosage is 28.8 mg (1.44W/V%), the maximum aprepitant content is 8.07%, and the appearance is clear and transparent; in the 4 ml formula, When the dosage of oleic acid is 28.8 mg (0.72 W/V%), the maximum amount of aprepitant is 9.24%, and there is precipitation on the appearance after being placed.
由上述結果可知,油酸濃度越小,阿瑞匹坦含量越多,析出風險越大。It can be seen from the above results that the smaller the oleic acid concentration, the greater the aprepitant content, and the greater the risk of precipitation.
實施例3Example 3
檢測不同緩衝離子對產品穩定性的影響。具體配方如表6所示。Test the effect of different buffer ions on product stability. The specific formula is shown in Table 6.
表6 實施例3的配方
此處描述用於形成配方10~16的福沙匹坦組合物的示例性製備方法:在配方量60~70%注射用水中,加入配方量的EDTA-2Na、緩衝鹽,再加入API(福沙匹坦雙葡甲胺)溶解後,檢測pH值。採用1 M NaOH/ HCl調節pH值至10.0,定容後檢測pH值。製備所得的藥液採用0.45 µm濾芯預過濾,灌裝封口,得到終產品。An exemplary preparation method of the fosaprepitant composition used to form formulas 10 to 16 is described here: in the formula amount of 60 to 70% water for injection, add the formula amount of EDTA-2Na and buffer salt, and then add API (Fosaprepitant After sapitant and dimeglumine) is dissolved, check the pH value. Use 1 M NaOH/HCl to adjust the pH to 10.0, and then check the pH after diluting to volume. The prepared medicinal liquid is pre-filtered with a 0.45 µm filter element, filled and sealed to obtain the final product.
得到的產品置60℃檢測其穩定性,分別於0、24 h檢測有關物質。結果如表7所示。The obtained product was stored at 60°C to test its stability, and related substances were tested at 0 and 24 h respectively. The results are shown in Table 7.
表7 實施例3的配方穩定性檢測結果
在同pH值下,配方14—檸檬酸緩衝液、配方15—酒石酸緩衝液、配方16—硼酸緩衝液在60℃、0 h時的阿瑞匹坦含量較高(大部分配方在0 h的阿瑞匹坦含量基本為0.2~0.3%),特別是配方14,0 h阿瑞匹坦含量為0.99%,遠高於其它配方。At the same pH value, Formula 14—Citric Acid Buffer, Formula 15—Tartaric Acid Buffer, and Formula 16—Boric Acid Buffer have higher aprepitant content at 60°C and 0 h (most formulas at 0 h The aprepitant content is basically 0.2~0.3%), especially in formula 14, the aprepitant content at 0 h is 0.99%, which is much higher than other formulas.
60℃、24 h時,配方14—檸檬酸緩衝液和配方15—酒石酸緩衝液配方的阿瑞匹坦含量最高,超過4%。緩衝離子對中,阿瑞匹坦含量漲幅最慢的是配方11—磷酸鹽緩衝液體系,且阿瑞匹坦終含量最低,為3.32%。At 60°C and 24 h, the aprepitant content of Formula 14—Citric Acid Buffer and Formula 15—Tartaric Acid Buffer was the highest, exceeding 4%. Among the buffer ion pairs, the slowest increase in aprepitant content was found in Formula 11—phosphate buffer system, and the final aprepitant content was the lowest at 3.32%.
緩衝對為磷酸鹽體系時,阿瑞匹坦增加最少,體系最穩定。When the buffer pair is a phosphate system, aprepitant increases the least and the system is the most stable.
實施例4Example 4
表8 實施例4的配方
以上配方按照實施2中的製備方法製備,將得到的產品置於60℃檢測穩定性,分別於0、4、8、24 h檢測有關物質。結果如表9。The above formula was prepared according to the preparation method in Implementation 2. The obtained product was placed at 60°C to test the stability, and related substances were tested at 0, 4, 8, and 24 hours respectively. The results are shown in Table 9.
表9 實施例4的配方穩定性結果
由上述資料可知,單用油酸的配方(配方4),外觀澄清透明,物理穩定性好。聯用磷酸鹽後,穩定性進一步提升,阿瑞匹坦增長幅度降低明顯。說明磷酸根體系對產品的穩定性有一定穩定作用,濃度越大,體系越穩定。From the above data, it can be seen that the formula using oleic acid alone (formula 4) has a clear and transparent appearance and good physical stability. After combined with phosphate, the stability was further improved, and the growth rate of aprepitant was significantly reduced. It shows that the phosphate system has a certain stabilizing effect on the stability of the product. The greater the concentration, the more stable the system.
實施例5Example 5
表10 實施例5的配方
以上配方按照實施例2中的製備方法製備得到的產品倒置放於25 ℃和40 ℃高溫檢測穩定性。同時以上市製劑(商品名EMEND,持證商:MERCK SHARP & DOHME CORP.,生產廠商Patheon Manufacturing Services LLC,批號:T037941)作對比。數據如表11所示。The product prepared with the above formula according to the preparation method in Example 2 was placed upside down at high temperatures of 25°C and 40°C to detect stability. At the same time, the marketed preparation (trade name EMEND, licensee: MERCK SHARP & DOHME CORP., manufacturer Patheon Manufacturing Services LLC, batch number: T037941) was used for comparison. The data is shown in Table 11.
表11 實施例5的配方與上市製劑穩定性結果對比
配方21各時間點樣品外觀澄清透明,阿瑞匹坦雖有增長趨勢但並未析出,體系穩定。說明配方21的穩定性與上市製劑相當。The appearance of the samples of Formula 21 at each time point was clear and transparent. Although aprepitant showed an increasing trend, it did not precipitate, and the system was stable. It shows that the stability of Formula 21 is equivalent to that of the marketed preparation.
模擬臨床稀釋的樣品穩定性:採用上述40℃-10天的配方21樣品,用0.9%氯化鈉稀釋75倍,放置於25℃下,分別於0、4、8、24 h取樣,觀察稀釋樣品的外觀,檢測稀釋藥液的福沙匹坦含量、有關物質。Stability of simulated clinical dilution samples: Use the above 40℃-10 day formula 21 sample, dilute it 75 times with 0.9% sodium chloride, place it at 25℃, take samples at 0, 4, 8, and 24 hours, and observe the dilution The appearance of the sample was examined, and the fosaprepitant content and related substances of the diluted medicinal solution were detected.
表12 配方21穩定性40℃-10天樣品稀釋穩定性
稀釋液穩定性考察結果表明,API含量穩定,阿瑞匹坦基本保持不變,總雜質增長較小,稀釋液穩定性良好。The results of the stability investigation of the diluent showed that the API content was stable, aprepitant remained basically unchanged, the total impurities increased slightly, and the stability of the diluent was good.
實施例6Example 6
配方21置於高溫80℃放置4 h後,觀察外觀檢測有關物質。模擬臨床稀釋的樣品穩定性,用0.9%氯化鈉稀釋75倍,放置於25℃下,分別於0、14、24 h取樣,觀察稀釋樣品的外觀,檢測稀釋後藥液的有關物質。同時以上市製劑(商品名EMEND,持證商:MERCK SHARP & DOHME CORP.,生產廠商Patheon Manufacturing Services LLC,批號:T037941)作對比。After formula 21 was placed at high temperature of 80°C for 4 hours, the appearance was observed to detect related substances. To simulate the stability of clinically diluted samples, dilute them 75 times with 0.9% sodium chloride, place them at 25°C, and take samples at 0, 14, and 24 hours respectively. Observe the appearance of the diluted samples and detect related substances in the diluted liquid. At the same time, the marketed preparation (trade name EMEND, licensee: MERCK SHARP & DOHME CORP., manufacturer Patheon Manufacturing Services LLC, batch number: T037941) was used for comparison.
表13 配方21穩定性80℃-4 h樣品與上市製劑稀釋穩定性對比
結果顯示,配方21高溫80℃-4 h後阿瑞匹坦增加到5.68%,外觀仍澄清透明,總雜質與上市製劑相當;原液稀釋後25℃下放置24 h,外觀上無變化,阿瑞匹坦和其他雜質均無顯著變化,總雜質含量與上市製劑相當,表明穩定性良好。The results showed that after formula 21 was heated to 80°C for -4 hours, aprepitant increased to 5.68%, the appearance was still clear and transparent, and the total impurities were equivalent to the marketed preparation; after the original solution was diluted and placed at 25°C for 24 hours, there was no change in appearance. There were no significant changes in pitant and other impurities, and the total impurity content was comparable to that of the marketed formulation, indicating good stability.
本發明提供的含福沙匹坦的液體藥物組合物,製備技術簡單,活性成分阿瑞匹坦雖有增加,但物理和化學穩定性仍保持良好,且模擬臨床稀釋後的給藥樣品物理和化學穩定性均良好。The fosaprepitant-containing liquid pharmaceutical composition provided by the invention has simple preparation technology. Although the active ingredient aprepitant is increased, the physical and chemical stability is still good, and the physical and chemical stability of the administered sample after clinical dilution is simulated. Chemical stability is good.
以上,對本發明的實施方式進行了說明。但是,本發明不限定於上述實施方式。凡在本發明的精神和原則之內,所做的任何修改、等同替換、改進等,均應包含在本發明的保護範圍之內。The embodiments of the present invention have been described above. However, the present invention is not limited to the above-described embodiment. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.
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