WO2022111647A1 - Formulation combination containing freeze-dried formulation and reconstituted solvent, preparation method and application thereof - Google Patents
Formulation combination containing freeze-dried formulation and reconstituted solvent, preparation method and application thereof Download PDFInfo
- Publication number
- WO2022111647A1 WO2022111647A1 PCT/CN2021/133660 CN2021133660W WO2022111647A1 WO 2022111647 A1 WO2022111647 A1 WO 2022111647A1 CN 2021133660 W CN2021133660 W CN 2021133660W WO 2022111647 A1 WO2022111647 A1 WO 2022111647A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- freeze
- solvent composition
- water
- reconstituted
- raw material
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 177
- 239000002904 solvent Substances 0.000 title claims abstract description 104
- 238000009472 formulation Methods 0.000 title claims abstract description 91
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 72
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 62
- 229940125904 compound 1 Drugs 0.000 claims description 50
- 239000002994 raw material Substances 0.000 claims description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- 239000000243 solution Substances 0.000 claims description 37
- 239000004094 surface-active agent Substances 0.000 claims description 31
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 28
- 229920001223 polyethylene glycol Polymers 0.000 claims description 25
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 24
- 239000002202 Polyethylene glycol Substances 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 239000008215 water for injection Substances 0.000 claims description 22
- 239000000463 material Substances 0.000 claims description 20
- 239000006184 cosolvent Substances 0.000 claims description 19
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 14
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 12
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 11
- ULQISTXYYBZJSJ-UHFFFAOYSA-N 12-hydroxyoctadecanoic acid Chemical compound CCCCCCC(O)CCCCCCCCCCC(O)=O ULQISTXYYBZJSJ-UHFFFAOYSA-N 0.000 claims description 11
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 11
- -1 polyethylene Polymers 0.000 claims description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- KIHBGTRZFAVZRV-UHFFFAOYSA-N 2-Hydroxyoctadecanoic acid Natural products CCCCCCCCCCCCCCCCC(O)C(O)=O KIHBGTRZFAVZRV-UHFFFAOYSA-N 0.000 claims description 8
- DRNXELHHXZJHPN-OCLAHLCRSA-N alpha-D-GlcNS(6S)-(1->4)-beta-D-GlcA-(1->4)-alpha-D-GlcNS(3S,6S)-(1->4)-beta-D-GlcA(2S)-(1->4)-alpha-D-GlcNS(6S)-(1->4)-beta-D-GlcA(2S)-(1->4)-alpha-D-GlcNS(6S)-(1->4)-beta-D-GlcA-O-pNp Chemical group O[C@H]1[C@H](O)[C@@H](NS(O)(=O)=O)[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O[C@@H]3[C@@H](COS(O)(=O)=O)O[C@H](O[C@H]4[C@H](O)[C@@H](OS(O)(=O)=O)[C@H](O[C@H]5[C@H](O)[C@@H](NS(O)(=O)=O)[C@@H](O[C@H]6[C@H](O)[C@@H](OS(O)(=O)=O)[C@H](O[C@H]7[C@H](O)[C@@H](NS(O)(=O)=O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)C(Oc9ccc(cc9)[N+]([O-])=O)O[C@@H]8C(O)=O)O[C@@H]7COS(O)(=O)=O)O[C@@H]6C(O)=O)O[C@@H]5COS(O)(=O)=O)O[C@@H]4C(O)=O)[C@H](NS(O)(=O)=O)[C@H]3OS(O)(=O)=O)O[C@@H]2C(O)=O)O[C@@H]1COS(O)(=O)=O DRNXELHHXZJHPN-OCLAHLCRSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000004359 castor oil Substances 0.000 claims description 7
- 235000019438 castor oil Nutrition 0.000 claims description 7
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 7
- 239000004698 Polyethylene Substances 0.000 claims description 6
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 6
- 229940072106 hydroxystearate Drugs 0.000 claims description 6
- 229920000573 polyethylene Polymers 0.000 claims description 6
- 229920000642 polymer Polymers 0.000 claims description 6
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 5
- SHBUUTHKGIVMJT-UHFFFAOYSA-N Hydroxystearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OO SHBUUTHKGIVMJT-UHFFFAOYSA-N 0.000 claims description 5
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 5
- 229920001577 copolymer Polymers 0.000 claims description 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 5
- 229920000053 polysorbate 80 Polymers 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-Hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 239000004475 Arginine Substances 0.000 claims description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- 229920001304 Solutol HS 15 Polymers 0.000 claims description 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 4
- 239000008367 deionised water Substances 0.000 claims description 4
- 229910021641 deionized water Inorganic materials 0.000 claims description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical group [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 4
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 4
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 4
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- 229920000136 polysorbate Polymers 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000008213 purified water Substances 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- 239000001509 sodium citrate Substances 0.000 claims description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 4
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- 229920002307 Dextran Polymers 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 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 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 229960003194 meglumine Drugs 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- 229940114072 12-hydroxystearic acid Drugs 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 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 2
- 239000004471 Glycine Substances 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-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
- 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 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 claims description 2
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 claims description 2
- 229920002582 Polyethylene Glycol 600 Polymers 0.000 claims description 2
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 2
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 2
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 claims description 2
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 claims description 2
- 239000007983 Tris buffer Substances 0.000 claims description 2
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- IJCWFDPJFXGQBN-RYNSOKOISA-N [(2R)-2-[(2R,3R,4S)-4-hydroxy-3-octadecanoyloxyoxolan-2-yl]-2-octadecanoyloxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCCCCCCCCCCCC IJCWFDPJFXGQBN-RYNSOKOISA-N 0.000 claims description 2
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- 239000003708 ampul Substances 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 125000005587 carbonate group Chemical group 0.000 claims description 2
- 239000011521 glass Substances 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
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 2
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 239000002736 nonionic surfactant Substances 0.000 claims description 2
- 229960000502 poloxamer Drugs 0.000 claims description 2
- 229920001983 poloxamer Polymers 0.000 claims description 2
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 claims description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 2
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 claims description 2
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 claims description 2
- 235000011067 sorbitan monolaureate Nutrition 0.000 claims description 2
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- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 229920002675 Polyoxyl Polymers 0.000 claims 3
- 150000002148 esters Chemical class 0.000 claims 3
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
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- 238000002347 injection Methods 0.000 abstract description 15
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- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 abstract description 4
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 102100026596 Bcl-2-like protein 1 Human genes 0.000 abstract description 2
- 239000000546 pharmaceutical excipient Substances 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract 1
- 230000003204 osmotic effect Effects 0.000 description 13
- 239000000843 powder Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 8
- 238000004108 freeze drying Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 4
- 101000656751 Haloarcula marismortui (strain ATCC 43049 / DSM 3752 / JCM 8966 / VKM B-1809) 30S ribosomal protein S24e Proteins 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
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- 229940122035 Bcl-XL inhibitor Drugs 0.000 description 2
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- 238000010790 dilution Methods 0.000 description 2
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Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention relates to a formulation combination containing a freeze-dried formulation and a reconstituted solvent, preparation method and application thereof.
- Compound 1 or its pharmaceutically acceptable salt is a potential Bcl-2 and/or Bcl-xL inhibitor (see WO2014113413) .
- the compound can effectively induce apoptosis of cancer cells, and has an action mechanism that is highly consistent with targeting Bcl-2 and Bcl-xL.
- the compound can treat various cancers. Currently, we are conducting two phase I dose escalation trials of this compound in patients with advanced cancer in the United States and Australia and a simultaneous phase I dose escalation/expansion trial (as a monotherapy) for SCLC patients in China.
- compound 1 dissolves very poorly in acidic or near-neutral solutions, and the dissolution is greatly improved under alkaline conditions, but it is unstable under alkaline conditions. It is very challenging to explore the prescription of industrialized injection formulation.
- the present invention provides a formulation combination containing a freeze-dried formulation and a reconstituted solvent (vehicle) , preparation method and application thereof.
- the formulation combination comprises a freeze-dried powder containing Compound 1 or its pharmaceutically acceptable salt thereof and a reconstitution solvent.
- the freeze-dried powder has good stability and the screened reconstitution solvent prescription can reconstitute the freeze-dried powder. After dissolution, the solution meets the requirements of pH, clarity, osmotic pressure, etc of injection, is suitable for clinical application.
- the structure of compound 1 is as follows:
- the present invention provides a formulation combination, which comprises: a freeze-dried formulation and a reconstituted solvent composition,
- freeze-dried formulation is obtained by lyophilizing a lyophilized solution comprising the following raw material components according to conventional lyophilization methods in the art: compound 1 or its pharmaceutically acceptable salt, freeze-dried skeleton material, co-solvent (auxiliary solvent) , water, and optionally pH regulator,
- the reconstituted solvent composition includes the following components by mass volume percentage (w/v) : 10%-15%polyethylene glycol, 3%-10%surfactant, 2%-20%monohydric alcohol containing 1-4 carbon atoms, pH regulator, water, and the pH of the reconstituted solvent is 9-12.
- the freeze-dried skeleton material in the raw material components of the freeze-dried formulation, can be a conventional freeze-dried skeleton material in the field, such as: one or more of glucose, sucrose, xylitol, sorbitol, mannitol, dextran, polyethylene glycol, lactose, raffinose, arginine, glycine, histidine, and trehalose; preferably trehalose, more preferably ⁇ , ⁇ -trehalose.
- the co-solvent in the raw material components of the freeze-dried formulation, can be a monohydric alcohol containing 1-4 carbon atoms, such as one or more of methanol, ethanol, propanol and tert-butanol, preferably tert-butanol.
- the water in the raw material components of the freeze-dried formulation, is deionized water, purified water, water for injection or sterile water for injection, for example, water for injection or sterile water for injection.
- the pH regulator in the raw material components of the freeze-dried formulation, can be selected from the group consisting of hydroxide, phosphate, dihydrogen phosphate, citrate, tartrate, arginine, carbonate, bicarbonate, acetate, meglumine, borate, Tris and HCl; for example selected from the group consisting of sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, sodium citrate, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, sodium acetate and HCl; another example is NaOH and/or HCl, another example is 10N NaOH and/or 5N HCl.
- the mass parts of the freeze-dried skeleton material are: for example 4-20 parts, preferably 10-20 parts, more preferably 16 parts.
- the mass parts of the co-solvent in the raw material components of the freeze-dried formulation, based on 1 mass part of compound 1, can be the conventional mass part in this type of freeze-dried formulation in the art, for example, 60-120 parts, preferably 80-100 parts, more preferably 90-92 parts (for example, 91.5 parts) .
- the mass parts of the water in the raw material components of the freeze-dried formulation, based on 1 mass part of compound 1, and the mass parts of the water can be conventional mass parts in this type of freeze-dried formulation in the art, for example: 60-120 parts, preferably 80-100 parts, more preferably 90-92 parts (for example, 91.5 parts) .
- the freeze-dried formulation is obtained by lyophilizing a lyophilized solution containing the following raw material components by mass part according to a conventional freeze-drying method in the art: 1 mass part of compound 1, 4-20 mass parts of freeze-dried skeleton material, 60 -120 mass parts of co-solvent (auxiliary solvent) and 60-120 mass parts of water, and optionally an appropriate amount of pH regulator.
- the freeze-dried formulation is obtained by lyophilizing a lyophilized solution containing the following raw material components by mass part according to a conventional freeze-drying method in the art: 1 part of compound 1, 10-20 parts of freeze-dried skeleton material, 80 -100 parts of co-solvent (auxiliary solvent) and 80-100 parts of water, and optionally an appropriate amount of pH regulator.
- the freeze-dried formulation is obtained by lyophilizing a lyophilized solution containing the following raw material components by mass part according to conventional freeze-drying methods in the art: 1 part of compound 1, 16 parts of freeze-dried skeleton material, 90-92 parts of co-solvent (auxiliary solvent) and 90-92 parts of water, optionally may also contain an appropriate amount of pH regulator.
- the freeze-dried formulation is obtained by lyophilizing a lyophilized solution containing the following raw material components by mass part according to a conventional freeze-drying method in the art: 1 part of compound 1, 16 parts of ⁇ , ⁇ -Trehalose, 91.5 parts of tert-butanol, 91.5 parts of water, an appropriate amount of pH regulator.
- the polyethylene glycol in the reconstitution solvent composition, is selected from polyethylene glycol PEG200-PEG1000, such as one or more of polyethylene glycol PEG200, PEG300, PEG400 and PEG600, preferably PEG400.
- the surfactant is selected from the group of nonionic surfactants consisting of: copolymer of hydroxystearic acid and polyvinyl alcohol and its analogs (such as 12-hydroxystearic acid-polyvinyl alcohol copolymer and its analogs) , the polymer of hydroxy-stearic acid and ⁇ -hydrogen- ⁇ -hydroxy poly (oxy-1, 2-ethane dimethyl) and its analogues (such as the polymer of 12-hydroxy-stearic acid and ⁇ -hydrogen- ⁇ -hydroxy poly (oxy-1, 2-ethane dimethyl) and its analogues) , polyethylene glycol-15-hydroxystearate and its analogs (such as polyethylene glycol-15 hydroxystearate and its analogs) , cholic acid, sodium cholate, Tween (for example, one or more of Tween 20, Tween 60 and Tween 80) , Span (for example, one or more of Span 20, Span 60
- the monohydric alcohol containing 1-4 carbon atoms is one or more of methanol, ethanol, propanol and tert-butanol, For example ethanol (anhydrous) and/or propanol.
- the pH regulator is selected from the group consisting of hydroxide, phosphate, dihydrogen phosphate, citrate, carbonate, bicarbonate and acetate; for example, selected from the group consisting of sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, sodium citrate, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate and sodium acetate; another example is sodium carbonate and/or sodium bicarbonate.
- the water in the reconstituted solvent composition, is deionized water, purified water, water for injection or sterile water for injection, for example, water for injection or sterile water for injection.
- the reconstituted solvent composition comprises 10%-15% (w/v) polyethylene glycol, preferably 11%-13% (w/v) polyethylene glycol.
- the reconstituted solvent composition comprises 3%-10% (w/v) surfactant, preferably 4%-8% (w/v) surfactant.
- the reconstituted solvent composition comprises 2%-20% (w/v) monohydric alcohol containing 1-4 carbon atoms, preferably 3%-10% (w/v) monohydric alcohol containing 1-4 carbon atoms; more preferably 3%-8% (w/v) monohydric alcohol containing 1-4 carbon atoms; more preferably 3%-6% (w/v) monohydric alcohol containing 1-4 carbon atoms or 4%-8% (w/v) monohydric alcohol containing 1-4 carbon atoms.
- the reconstituted solvent composition comprises an appropriate amount of pH regulator, and the pH of the reconstituted solvent composition is 9-12, preferably pH 10-12, and further preferably pH 11-12.
- the pH regulator when the pH regulator is carbonate, its mass-volume percentage is 0.10-0.15% (w/v) , preferably 0.12 % (w/v) .
- the reconstituted solvent composition comprises the following components by mass volume percentage (w/v) : 10%-15%polyethylene glycol, 3%- 10%Surfactant, 2%-8%monohydric alcohol containing 1-4 carbon atoms, pH regulator, water, the pH of the reconstituted solvent is 10-12.
- the reconstituted solvent composition comprises the following components by mass volume percentage (w/v) : 11%-13%polyethylene glycol, 4%-8%surfactant, 3%-6%monohydric alcohol containing 1-4 carbon atoms, pH regulator, water, the pH of the reconstituted solvent composition is 11-12,
- the reconstituted solvent composition comprises the following components by mass volume percentage (w/v) : 11%-13%polyethylene glycol, 4%-8%surfactant, 4%-8%monohydric alcohol containing 1-4 carbon atoms, pH regulator, water, and the pH of the reconstituted solvent composition is 9-10.
- the concentration is 10-13 mmol/L, preferably 11-13 mmol/L.
- the concentration is 60-70 mmol/L, preferably 65-70 mmol/L.
- the reconstituted solvent composition is composed of the following components by mass-volume percentage (w/v) : 11%polyethylene glycol 400, 8%Solutol HS-15, 6%absolute ethanol, 0.12%sodium carbonate, and the rest is water for injection.
- the mass-volume ratio of the compound 1 and the reconstituted solvent composition may be ⁇ 20 mg/mL; for example, 18 mg/mL, 16 mg/mL, 10 mg/mL, 8mg/mL, 6mg/mL.
- the reconstituted solvent composition is prepared by a preparation method including the following steps:
- freeze-dried formulation is prepared by a preparation method including the following steps:
- the present invention provides a reconstituted solvent composition for reconstitute freeze-dried formulation.
- the reconstituted solvent composition may be the reconstituted solvent composition described in any of the above-mentioned formulation combinations.
- the present invention provides a freeze-dried formulation of Compound 1, which may be the freeze-dried formulation described in any of the above-mentioned formulation combinations.
- the present invention also provides a medicine kit, which comprises: a medicinal container containing a freeze-dried formulation, and another medicinal container containing a reconstituted solvent composition, The definition of the freeze-dried formulation and the reconstituted solvent composition is as described in any of the formulation combinations described above.
- the medicinal container in the present invention can be an amber or colorless glass medicine bottle with an elastic stopper and a crimped aluminum lid, or any amber or colorless container suitable for immediate use systems.
- the medical container in the present invention includes, but is not limited to, an ampoule or a vial, preferably a vial.
- the reagents and raw materials used in the present invention are all commercially available.
- the positive and progressive effect of the present invention is that: the formulation combination of the present invention comprising the reconstituted solvent composition and the freeze-dried formulation which can be configured on-site to obtain a clinical formulation containing compound 1 or its pharmaceutically acceptable salt when apply.
- the reconstitution prescription finally screened by the present invention can meet the requirements of reconstitution time, osmotic pressure, reconstitution pH, clarity and the like.
- Figure 1 shows the clarity of the diluted solution (3.2mg/ml) in Example 4 at 2-8°C for 0 hours and 26 hours; at 0 hours, the left vial contained the dilute solution of freeze-dried powder , and the right vial contained 1#turbidity standard solution; at 26 hours, the left vial contained the liquid sample of the diluted solution of freeze-dried powder, the right vial contained the 1#turbidity standard solution.
- Compound 1 0.1 g, ⁇ , ⁇ -trehalose 1.6 g, tert-butanol 9.15 g, water for injection 9.15 g, 10N NaOH/5N HCl appropriate amount.
- Compound 1 0.1g, sucrose 2.0g, ethanol 10g, water for injection 10g, 10N NaOH/5N HCl appropriate amount.
- Compound 1 0.1 g, mannitol 1.5 g, tert-butanol 12.0 g, water for injection 12.0 g, 10N NaOH/5N HCl appropriate amount.
- Compound 1 0.1 g, dextran 0.8 g, tert-butanol 7.0 g, water for injection 7.0 g, 10N NaOH/5N HCl appropriate amount.
- Compound 1 0.1 g, glucose 1.3 g, tert-butanol 7.0 g, water for injection 7.0 g, 10N NaOH/5N HCl appropriate amount.
- Example 1-1 Take Example 1-1 as an example for preparation:
- Example 1-2 to Example 1-6 were prepared according to the method referring to Example 1-1.
- the pH of injection should equal to or similar to that of human blood.
- the general requirement for the pH of injection ranges from 4 to 9; therefore, the pH value of reconstituted solution is required less than 9, the osmotic pressure should be within 280-320 mOsm/kg, and also the injection should comply with the requirements for clarity of China Pharmacopoeia (taking 1#turbidity standard solution as a control solution) .
- the freeze-dried powders used in the following development tests are all the freeze-dried powders prepared in Example 1-1 (0.1g compound 1 per vial) , and the volume of reconstituted solvent is 10ml.
- the general operation for reconstitution is as follows: add 10ml of solvent to the freeze-dried product vial, observe the phenomenon and check the pH value. If it is clear, dilution will be conducted, the pH and osmotic pressure should be tested, and the experimental phenomena and results should be recorded.
- the pH and clarity can meet the requirements of injection solution, but the osmotic pressure cannot meet the requirements of injection solution. Therefore, consider reducing the amount of PEG400 and surfactants and increasing the amount of ethanol.
- the 2-5-4 and 2-5-5 groups can meet the injection requirements in terms of clarity, pH after reconstitution, and osmotic pressure after dilution.
- the main component compound 1 has the highest solubility in PEG400.
- the concentration range of 13% (w/v) to 30% (w/v) of PEG 400 combining with other components can make the solution clarified after reconstitution, but PEG400 contributes more to the osmotic pressure of the diluted solution which need to be combined with other components for screening.
- 3 concentrations of 11% (w/v) , 13% (w/v) , 15% (w/v) are selected in this experiment
- Surfactant can be choosed from the solubilizing surfactant known in the art.
- HS-15 as a surfactant can reduce the amount of PEG400 and alkali in the reconstituted solvent. 3 concentrations of 4% (w/v) , 6% (w/v) , and 8% (w/v) were selected for screening,
- the optional surfactants are Tween 80 and Solutol HS15; Solutol HS15 was used in this prescription screening.
- the 4 components in the reconstituted solvent are screened based on multi-factor experiments.
- the prescription and experimental results that meet the requirements of the injection are as follows
- Preparation process Weigh the excipients according to the above prescription, add the prescription amount of PEG400, HS-15, absolute ethanol, add 30% (w/v) water for injection, mix well, add the prescription amount of sodium carbonate, stir to dissolve. Finally, add water for injection to make the volume constant, stir and mix well, and filter to obtain it.
- Step 1 Take 2 parts of 10mL reconstitution solvent respectively, then add 10ml reconstitution solvent to 1 vial of of freeze-dried powder prepared in Example 1-1 at room temperature, repeat the above operation, manually mix, record the reconstitution time of each vial, observe the appearance of the reconstituted solution of each vial and compare against with 1#turbidity standard solution, the results are shown in Figure 1.
- Step 2 Precisely pipette 18ml of the reconstituted solution, then dilute to 50ml with water for injection. Then take out 10ml of the diluted solution separately for non-HPLC testing; the remaining volume is used for HPLC testing.
- Stability study conditions Hold for 8 hours at 2-8°C and protected from light.
- Measurement indicators appearance, pH value, assay, related substances and osmotic pressure (only for 0h sample)
- Study time point 2-8°C, sampling and testing at 0h, 2h, 4h, 6h, and 8h respectively.
- the diluted solution can remain stable within 8 hours at 2-8°C.
- the stable time of the prepared injection solution is much longer than the administration time (including the time-consuming factors such as preparation time and injection administration time) , therefore safe administration can be achieved clinically.
Abstract
Provided herein is a formulation combination containing a freeze-dried formulation and a reconstituted solvent composition, preparation method and application thereof. A formulation combination comprising: a free-dried formulation containing compound (1) as an inhibitor of Bcl-2/Bcl-xL or its pharmaceutically acceptable salt and appropriate excipients, and a reconstitution solvent is also provided. The formulation combination is suitable for clinical injection and administration with the advantages of good stability and reconstitution effect.
Description
The present invention claims the priority of the PCT/CN2020/132297, filed on November 27, 2020, the contents of which are incorporated herein by its entirety.
The invention relates to a formulation combination containing a freeze-dried formulation and a reconstituted solvent, preparation method and application thereof.
Compound (3R) -1- (3- (4- (4- (4- (3- (2- (4-chlorophenyl) -1-isopropyl-4-methanesulfonyl-5-methyl-1H-pyrrol-3-yl) -5-fluorophenyl) piperazin-1-yl) -phenylaminosulfonyl) -2-trifluoromethanesulfonyl-anilino) -4-phenylthio-butyl) -Piperidine-4-carboxylic acid 3-phosphonopropyl ester (hereinafter referred to as compound 1) or its pharmaceutically acceptable salt is a kind of Bcl-2/Bcl-xL inhibitor. The structural formula is as follows:
Compound 1 or its pharmaceutically acceptable salt is a potential Bcl-2 and/or Bcl-xL inhibitor (see WO2014113413) . The compound can effectively induce apoptosis of cancer cells, and has an action mechanism that is highly consistent with targeting Bcl-2 and Bcl-xL. The compound can treat various cancers. Currently, we are conducting two phase I dose escalation trials of this compound in patients with advanced cancer in the United States and Australia and a simultaneous phase I dose escalation/expansion trial (as a monotherapy) for SCLC patients in China.
However, compound 1 dissolves very poorly in acidic or near-neutral solutions, and the dissolution is greatly improved under alkaline conditions, but it is unstable under alkaline conditions. It is very challenging to explore the prescription of industrialized injection formulation.
Summary of the invention
The present invention provides a formulation combination containing a freeze-dried formulation and a reconstituted solvent (vehicle) , preparation method and application thereof. The formulation combination comprises a freeze-dried powder containing Compound 1 or its pharmaceutically acceptable salt thereof and a reconstitution solvent. The freeze-dried powder has good stability and the screened reconstitution solvent prescription can reconstitute the freeze-dried powder. After dissolution, the solution meets the requirements of pH, clarity, osmotic pressure, etc of injection, is suitable for clinical application. The structure of compound 1 is as follows:
The present invention provides a formulation combination, which comprises: a freeze-dried formulation and a reconstituted solvent composition,
Wherein, the freeze-dried formulation is obtained by lyophilizing a lyophilized solution comprising the following raw material components according to conventional lyophilization methods in the art: compound 1 or its pharmaceutically acceptable salt, freeze-dried skeleton material, co-solvent (auxiliary solvent) , water, and optionally pH regulator,
The reconstituted solvent composition includes the following components by mass volume percentage (w/v) : 10%-15%polyethylene glycol, 3%-10%surfactant, 2%-20%monohydric alcohol containing 1-4 carbon atoms, pH regulator, water, and the pH of the reconstituted solvent is 9-12.
In some embodiments of the invention, in the raw material components of the freeze-dried formulation, the freeze-dried skeleton material (also called proppant, scaffold or lyoprotectant) can be a conventional freeze-dried skeleton material in the field, such as: one or more of glucose, sucrose, xylitol, sorbitol, mannitol, dextran, polyethylene glycol, lactose, raffinose, arginine, glycine, histidine, and trehalose; preferably trehalose, more preferably α, α-trehalose.
In some embodiments of the invention, in the raw material components of the freeze-dried formulation, the co-solvent can be a monohydric alcohol containing 1-4 carbon atoms, such as one or more of methanol, ethanol, propanol and tert-butanol, preferably tert-butanol.
In some embodiments of the invention, in the raw material components of the freeze-dried formulation, the water is deionized water, purified water, water for injection or sterile water for injection, for example, water for injection or sterile water for injection.
In some embodiments of the invention, in the raw material components of the freeze-dried formulation, the pH regulator can be selected from the group consisting of hydroxide, phosphate, dihydrogen phosphate, citrate, tartrate, arginine, carbonate, bicarbonate, acetate, meglumine, borate, Tris and HCl; for example selected from the group consisting of sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, sodium citrate, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, sodium acetate and HCl; another example is NaOH and/or HCl, another example is 10N NaOH and/or 5N HCl.
In some embodiments of the invention, in the raw material components of the freeze-dried formulation, based on 1 mass part of compound 1, the mass parts of the freeze-dried skeleton material are: for example 4-20 parts, preferably 10-20 parts, more preferably 16 parts.
In some embodiments of the invention, in the raw material components of the freeze-dried formulation, based on 1 mass part of compound 1, the mass parts of the co-solvent can be the conventional mass part in this type of freeze-dried formulation in the art, for example, 60-120 parts, preferably 80-100 parts, more preferably 90-92 parts (for example, 91.5 parts) .
In some embodiments of the invention, in the raw material components of the freeze-dried formulation, based on 1 mass part of compound 1, and the mass parts of the water can be conventional mass parts in this type of freeze-dried formulation in the art, for example: 60-120 parts, preferably 80-100 parts, more preferably 90-92 parts (for example, 91.5 parts) .
Preferably, the freeze-dried formulation is obtained by lyophilizing a lyophilized solution containing the following raw material components by mass part according to a conventional freeze-drying method in the art: 1 mass part of compound 1, 4-20 mass parts of freeze-dried skeleton material, 60 -120 mass parts of co-solvent (auxiliary solvent) and 60-120 mass parts of water, and optionally an appropriate amount of pH regulator.
Preferably, the freeze-dried formulation is obtained by lyophilizing a lyophilized solution containing the following raw material components by mass part according to a conventional freeze-drying method in the art: 1 part of compound 1, 10-20 parts of freeze-dried skeleton material, 80 -100 parts of co-solvent (auxiliary solvent) and 80-100 parts of water, and optionally an appropriate amount of pH regulator.
Preferably, the freeze-dried formulation is obtained by lyophilizing a lyophilized solution containing the following raw material components by mass part according to conventional freeze-drying methods in the art: 1 part of compound 1, 16 parts of freeze-dried skeleton material, 90-92 parts of co-solvent (auxiliary solvent) and 90-92 parts of water, optionally may also contain an appropriate amount of pH regulator.
In some embodiments of the invention, the freeze-dried formulation is obtained by lyophilizing a lyophilized solution containing the following raw material components by mass part according to a conventional freeze-drying method in the art: 1 part of compound 1, 16 parts of α, α-Trehalose, 91.5 parts of tert-butanol, 91.5 parts of water, an appropriate amount of pH regulator.
In some embodiments of the invention, in the reconstitution solvent composition, the polyethylene glycol is selected from polyethylene glycol PEG200-PEG1000, such as one or more of polyethylene glycol PEG200, PEG300, PEG400 and PEG600, preferably PEG400.
In some embodiments of the invention, in the reconstituted solvent composition, the surfactant is selected from the group of nonionic surfactants consisting of: copolymer of hydroxystearic acid and polyvinyl alcohol and its analogs (such as 12-hydroxystearic acid-polyvinyl alcohol copolymer and its analogs) , the polymer of hydroxy-stearic acid and α-hydrogen-Ω-hydroxy poly (oxy-1, 2-ethane dimethyl) and its analogues (such as the polymer of 12-hydroxy-stearic acid and α-hydrogen-Ω-hydroxy poly (oxy-1, 2-ethane dimethyl) and its analogues) , polyethylene glycol-15-hydroxystearate and its analogs (such as polyethylene glycol-15 hydroxystearate
and its analogs) , cholic acid, sodium cholate, Tween (for example, one or more of Tween 20, Tween 60 and Tween 80) , Span (for example, one or more of Span 20, Span 60, and Span 65) , poloxamer, and castor oil polyoxyester; for example, one or more of Tween 80,
and castor oil polyoxyester (35) (or ELP or polyoxyethylene 35 castor oil) , another example is
HS-15 (HS-15 for short) .
In some embodiments of the invention, in the reconstituted solvent composition, the monohydric alcohol containing 1-4 carbon atoms is one or more of methanol, ethanol, propanol and tert-butanol, For example ethanol (anhydrous) and/or propanol.
In some embodiments of the invention, in the reconstituted solvent composition, the pH regulator is selected from the group consisting of hydroxide, phosphate, dihydrogen phosphate, citrate, carbonate, bicarbonate and acetate; for example, selected from the group consisting of sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, sodium citrate, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate and sodium acetate; another example is sodium carbonate and/or sodium bicarbonate.
In some embodiments of the invention, in the reconstituted solvent composition, the water is deionized water, purified water, water for injection or sterile water for injection, for example, water for injection or sterile water for injection.
In some embodiments of the invention, the reconstituted solvent composition comprises 10%-15% (w/v) polyethylene glycol, preferably 11%-13% (w/v) polyethylene glycol.
In some embodiments of the invention, the reconstituted solvent composition comprises 3%-10% (w/v) surfactant, preferably 4%-8% (w/v) surfactant.
In some embodiments of the invention, the reconstituted solvent composition comprises 2%-20% (w/v) monohydric alcohol containing 1-4 carbon atoms, preferably 3%-10% (w/v) monohydric alcohol containing 1-4 carbon atoms; more preferably 3%-8% (w/v) monohydric alcohol containing 1-4 carbon atoms; more preferably 3%-6% (w/v) monohydric alcohol containing 1-4 carbon atoms or 4%-8% (w/v) monohydric alcohol containing 1-4 carbon atoms.
In some embodiments of the invention, the reconstituted solvent composition comprises an appropriate amount of pH regulator, and the pH of the reconstituted solvent composition is 9-12, preferably pH 10-12, and further preferably pH 11-12.
In some embodiments of the invention, in the reconstituted solvent composition, when the pH regulator is carbonate, its mass-volume percentage is 0.10-0.15% (w/v) , preferably 0.12 % (w/v) .
In some embodiments of the invention, the reconstituted solvent composition comprises the following components by mass volume percentage (w/v) : 10%-15%polyethylene glycol, 3%- 10%Surfactant, 2%-8%monohydric alcohol containing 1-4 carbon atoms, pH regulator, water, the pH of the reconstituted solvent is 10-12.
In some embodiments of the invention, the reconstituted solvent composition comprises the following components by mass volume percentage (w/v) : 11%-13%polyethylene glycol, 4%-8%surfactant, 3%-6%monohydric alcohol containing 1-4 carbon atoms, pH regulator, water, the pH of the reconstituted solvent composition is 11-12,
In some embodiments of the invention, the reconstituted solvent composition comprises the following components by mass volume percentage (w/v) : 11%-13%polyethylene glycol, 4%-8%surfactant, 4%-8%monohydric alcohol containing 1-4 carbon atoms, pH regulator, water, and the pH of the reconstituted solvent composition is 9-10.
In some embodiments of the invention, when the pH regulator in the reconstituted solvent composition is carbonate, the concentration is 10-13 mmol/L, preferably 11-13 mmol/L.
In some embodiments of the invention, when the pH regulator in the reconstituted solvent composition is bicarbonate, the concentration is 60-70 mmol/L, preferably 65-70 mmol/L.
In some embodiments of the invention, the reconstituted solvent composition is composed of the following components by mass-volume percentage (w/v) : 11%polyethylene glycol 400, 8%Solutol HS-15, 6%absolute ethanol, 0.12%sodium carbonate, and the rest is water for injection.
In some embodiments of the invention, when reconstituted, the mass-volume ratio of the compound 1 and the reconstituted solvent composition may be ≤20 mg/mL; for example, 18 mg/mL, 16 mg/mL, 10 mg/mL, 8mg/mL, 6mg/mL.
In some embodiments of the invention, wherein the reconstituted solvent composition is prepared by a preparation method including the following steps:
Weigh the components of the reconstituted solvent composition as described in any one of the above embodiments,
Mix the polyethylene glycol, surfactant, monohydric alcohol containing 1-4 carbon atoms, and part of water, add the pH regulator, dissolve, and finally add the remaining water to make the volume constant, mix uniformly to obtain the reconstituted solvent composition.
In some embodiments of the invention, wherein the freeze-dried formulation is prepared by a preparation method including the following steps:
Weigh each component according to the raw material components of the freeze-dried formulation as described in any of the above embodiments,
(1) Mix the co-solvent with the compound 1 and the freeze-dried skeleton material to obtain a mixed solution 1,
(2) Mix the mixed solution 1 with water and an appropriate amount of pH regulator, and filter to obtain solution 2,
(3) Fill and freeze-dry to obtain the freeze-dried formulation.
The present invention provides a reconstituted solvent composition for reconstitute freeze-dried formulation. The reconstituted solvent composition may be the reconstituted solvent composition described in any of the above-mentioned formulation combinations.
The present invention provides a freeze-dried formulation of Compound 1, which may be the freeze-dried formulation described in any of the above-mentioned formulation combinations. The present invention also provides a medicine kit, which comprises: a medicinal container containing a freeze-dried formulation, and another medicinal container containing a reconstituted solvent composition, The definition of the freeze-dried formulation and the reconstituted solvent composition is as described in any of the formulation combinations described above.
The medicinal container in the present invention can be an amber or colorless glass medicine bottle with an elastic stopper and a crimped aluminum lid, or any amber or colorless container suitable for immediate use systems. The medical container in the present invention includes, but is not limited to, an ampoule or a vial, preferably a vial.
As used herein, "Q.S. " and "a.q. " mean "appropriate amount" .
On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred embodiments of the present invention.
The reagents and raw materials used in the present invention are all commercially available.
The positive and progressive effect of the present invention is that: the formulation combination of the present invention comprising the reconstituted solvent composition and the freeze-dried formulation which can be configured on-site to obtain a clinical formulation containing compound 1 or its pharmaceutically acceptable salt when apply. The reconstitution prescription finally screened by the present invention can meet the requirements of reconstitution time, osmotic pressure, reconstitution pH, clarity and the like.
Description of the drawings
Figure 1 shows the clarity of the diluted solution (3.2mg/ml) in Example 4 at 2-8℃ for 0 hours and 26 hours; at 0 hours, the left vial contained the dilute solution of freeze-dried powder , and the right vial contained 1#turbidity standard solution; at 26 hours, the left vial contained the liquid sample of the diluted solution of freeze-dried powder, the right vial contained the 1#turbidity standard solution.
Embodiment
The present invention will be further explained by way of examples below, but the present invention is not limited to the scope of the described examples. In the following examples, the experimental methods without specific conditions are selected according to conventional methods and conditions, or according to the product specification.
Example 1 Preparation of freeze-dried powder of the present invention
1. The prescription composition of the freeze-dried solution (g/vial)
1-1. Compound 1 0.1 g, α, α-trehalose 1.6 g, tert-butanol 9.15 g, water for injection 9.15 g, 10N NaOH/5N HCl appropriate amount.
1-2. Compound 1 0.16g, α, α-trehalose 2.6 g, tert-butanol 14.6 g, water for injection 14.6 g, 10N NaOH/5N HCl appropriate amount.
1-3. Compound 1 0.1g, sucrose 2.0g, ethanol 10g, water for injection 10g, 10N NaOH/5N HCl appropriate amount.
1-4. Compound 1 0.1 g, mannitol 1.5 g, tert-butanol 12.0 g, water for injection 12.0 g, 10N NaOH/5N HCl appropriate amount.
1-5. Compound 1 0.1 g, dextran 0.8 g, tert-butanol 7.0 g, water for injection 7.0 g, 10N NaOH/5N HCl appropriate amount.
1-6. Compound 1 0.1 g, glucose 1.3 g, tert-butanol 7.0 g, water for injection 7.0 g, 10N NaOH/5N HCl appropriate amount.
2. Take Example 1-1 as an example for preparation:
1.1 Weigh the compound 1 and trehalose of the prescription amount into a suitable container, label it as container #1,
1.2 Weigh the tert-butanol of the prescription amount and place it into the container #1 in step 1.1, and stir at 40℃ until it becomes a uniform dispersion,
1.3 Weigh the water for injection of prescription amount and an appropriate amount of pH regulator, and slowly add them to the container #1 in step 1.2, and stir while adding, until the solution becomes clear,
1.4 Pass through a suitable filter membrane and transfer some quantity of the above after-filtered solution into a suitable vial (theoretical filling mass is 20g, filling accuracy ±3%) , after filling, half open the stopper, then load into the freeze dryer; and initiate the lyophilization cycle.
The freeze-dried powder in Example 1-2 to Example 1-6, were prepared according to the method referring to Example 1-1.
Example 2 Development of reconstituted solvent
The pH of injection should equal to or similar to that of human blood. The general requirement for the pH of injection ranges from 4 to 9; therefore, the pH value of reconstituted solution is required less than 9, the osmotic pressure should be within 280-320 mOsm/kg, and also the injection should comply with the requirements for clarity of China Pharmacopoeia (taking 1#turbidity standard solution as a control solution) .
Firstly, the effect of different types of co-solvents and surfactants on the solubility of compound 1 was investigated. Experimental method: The solubility was determined by using equilibrium solubility method which was equilibrated for 24 hours at 25℃. The results are summarized as follows in table 1:
Table 1 The solubility of compound 1 in different solvents
It can be seen from the data that the water solubility of compound 1 is extremely low, the solubility in most solvents is not good. But it has the largest solubility in solvent PEG. PEG in the formulation can dissolve the compound 1 well, but its dosage directly affects the osmotic pressure.
Therefore, it’s a great technical challenge to develop a reconstituted solvent that can reconstitute the freeze-dried formulation of compound 1 as to meet the requirements of injection for clinical administration (pH, osmotic pressure, clarity) .
The freeze-dried powders used in the following development tests are all the freeze-dried powders prepared in Example 1-1 (0.1g compound 1 per vial) , and the volume of reconstituted solvent is 10ml. The general operation for reconstitution is as follows: add 10ml of solvent to the freeze-dried product vial, observe the phenomenon and check the pH value. If it is clear, dilution will be conducted, the pH and osmotic pressure should be tested, and the experimental phenomena and results should be recorded.
Example 2-1
In view of the insoluble problem of compound 1, the inventor also tried other methods to solve the problem, which mainly focused on cyclodextrin inclusion complex, complexation of meglumine, and almighty solvent of DMA, etc. :
Table 2
The appearance of all the reconstituted solutions were all clear, but the pH were all over the limit, and after adjusting the pH＜9.0, the reconstituted solutions returbid.
Example 2-2
Table 3-1 The prescription of reconstituted solvent are as follows:
Table 3-2
Although the system of PEG400, surfactant ELP, and absolute ethanol can redissolve the freeze-dried powder, but the pH and osmotic pressure after reconstitution were all over the limit and cannot meet the injection requirements.
Example 2-3 Screening of the amount of ethanol
Table 4-1
Table 4-2
By comparison, increasing the amount of PEG400 or ethanol can reduce the reconstitution time, but the pH after reconstitution exceeds the limit.
Example 2-4 Screening of Surfactant and Buffer Solution
Table 5-1
Table 5-2
By adjusting the alkali to sodium bicarbonate aqueous solution (75 mmol/L) and the surfactant to Tween 80 or HS-15, the pH and clarity can meet the requirements of injection solution, but the osmotic pressure cannot meet the requirements of injection solution. Therefore, consider reducing the amount of PEG400 and surfactants and increasing the amount of ethanol.
Table 5-3
Table 5-4
If the amount of HS15 is only 4.4%w/v, the sample cannot be completely reconstituted and clarified. In the 4.4%w/v HS15 system, it is difficult to meet the requirements of injection solution.
Embodiment 2-5
In order to ensure that the product is feasible, we have increased the amount of HS15, ensuring not to exceed the daily maximum dosage of the marketed product, so that the concentration of HS15 in the reconstituted solvent can reach 8%w/v. The experimental prescription design and results are shown below.
Table 6-1
Table 6-2 Reconstituted Solution
It can be seen that the 2-5-4 and 2-5-5 groups can meet the injection requirements in terms of clarity, pH after reconstitution, and osmotic pressure after dilution.
Example 3
Based on the above test,
① The main component compound 1 has the highest solubility in PEG400. The concentration range of 13% (w/v) to 30% (w/v) of PEG 400 combining with other components can make the solution clarified after reconstitution, but PEG400 contributes more to the osmotic pressure of the diluted solution which need to be combined with other components for screening. In order to obtain a good prescription ratio, 3 concentrations of 11% (w/v) , 13% (w/v) , 15% (w/v) are selected in this experiment
② Increasing the amount of ethanol can shorten the reconstitution time of the lyophilized product, and has less effect on the osmotic pressure and pH value.
③ Surfactant can be choosed from the solubilizing surfactant known in the art. HS-15 as a surfactant can reduce the amount of PEG400 and alkali in the reconstituted solvent. 3 concentrations of 4% (w/v) , 6% (w/v) , and 8% (w/v) were selected for screening, The optional surfactants are Tween 80 and Solutol HS15; Solutol HS15 was used in this prescription screening.
④ Using sodium carbonate to replace sodium bicarbonate can reduce the amount of alkali.
According to the pre-experimental results, the 4 components in the reconstituted solvent are screened based on multi-factor experiments. The prescription and experimental results that meet the requirements of the injection are as follows
Table 7-1
*: Water for injection is used as the diluent, the concentration of diluted solution is 3.2mg/ml.
It can be seen that under the above conditions, it can meet the standard requirements of clarity, pH, and osmotic pressure after reconstitution
Table 7-2 The prefered prescription 3-5
| Raw material | mg/ml | w/v % |
| PEG400 | 110 | 11 |
| HS-15 | 80 | 8 |
| Absolute Ethanol | 60 | 6 |
| Sodium carbonate | 1.2 | 0.12 |
| water for injection | add to 1ml | the rest |
Preparation process: Weigh the excipients according to the above prescription, add the prescription amount of PEG400, HS-15, absolute ethanol, add 30% (w/v) water for injection, mix well, add the prescription amount of sodium carbonate, stir to dissolve. Finally, add water for injection to make the volume constant, stir and mix well, and filter to obtain it.
Example 4
Stability test:
Weigh the materials according to the above optimal prescription 3-5, take PEG400, HS-15 and absolute ethanol into a 100mL volumetric flask, add a small amount of water to dissolve, add the prescription amount of sodium carbonate, continue to add water to dissolve and dilute to scale, take 0.22μm Hydrophilic PTFE membrane to filtrate,
The preparation process of 3.2mg/ml diluted solution:
Step 1: Take 2 parts of 10mL reconstitution solvent respectively, then add 10ml reconstitution solvent to 1 vial of of freeze-dried powder prepared in Example 1-1 at room temperature, repeat the above operation, manually mix, record the reconstitution time of each vial, observe the appearance of the reconstituted solution of each vial and compare against with 1#turbidity standard solution, the results are shown in Figure 1.
Step 2: Precisely pipette 18ml of the reconstituted solution, then dilute to 50ml with water for injection. Then take out 10ml of the diluted solution separately for non-HPLC testing; the remaining volume is used for HPLC testing.
Stability study conditions: Hold for 8 hours at 2-8℃ and protected from light.
Measurement indicators: appearance, pH value, assay, related substances and osmotic pressure (only for 0h sample)
Study time point: 2-8℃, sampling and testing at 0h, 2h, 4h, 6h, and 8h respectively.
Table 8: The stability study results of diluted solution (3.2mg/ml)
It can be seen that the diluted solution can remain stable within 8 hours at 2-8℃. The stable time of the prepared injection solution is much longer than the administration time (including the time-consuming factors such as preparation time and injection administration time) , therefore safe administration can be achieved clinically.
Claims (10)
- A formulation combination, which comprises: a freeze-dried formulation and a reconstituted solvent composition,wherein, the freeze-dried formulation is obtained by lyophilizing a lyophilized solution comprising the following raw material components: compound 1 or its pharmaceutically acceptable salt, freeze-dried skeleton material, co-solvent, water, and optionally pH regulator, the structure of compound 1 is as follows:
the reconstituted solvent composition comprises the following components by mass volume percentage (w/v) : 10%-15%polyethylene glycol, 3%-10%surfactant, 2%-20%monohydric alcohol containing 1-4 carbon atoms, pH regulator, water, and the pH of the reconstituted solvent is 9-12. - The formulation combination of claim 1, wherein:in the raw material components of the freeze-dried formulation, the freeze-dried skeleton material is one or more of glucose, sucrose, xylitol, sorbitol, mannitol, dextran, polyethylene glycol, lactose, raffinose, arginine, glycine, histidine and trehalose,and/or, in the raw material components of the freeze-dried formulation, the co-solvent is monohydric alcohol containing 1 to 4 carbon atoms,and/or, in the raw material components of the freeze-dried formulation, the water is deionized water, purified water, and water for injection,and/or, in the raw material components of the freeze-dried formulation, the pH regulator is selected from the group consisting of hydroxide, phosphate, dihydrogen phosphate, citrate, tartrate, arginine acid, carbonate, bicarbonate, acetate, meglumine, borate, Tris and HCl,and/or, in the raw material components of the freeze-dried formulation, based on 1 mass part of compound 1, the mass parts of the freeze-dried skeleton material is 4-20,and/or, in the raw material components of the freeze-dried formulation, based on 1 mass part of compound 1, the mass parts of the co-solvent is 60-120,and/or, in the raw material components of the freeze-dried formulation, based on 1 mass part of compound 1, the mass parts of the water is 60-120,and/or, the freeze-dried formulation is obtained by lyophilizing a lyophilized solution containing the following mass parts of raw material components: 1 part of compound 1, 4-20 parts of freeze-dried skeleton material, 60-120 parts of co-solvent, and 60-120 parts of water, optionally may also contain an appropriate amount of pH regulator,and/or, in the reconstituted solvent composition, the polyethylene glycol is selected from polyethylene glycol PEG200-PEG1000,and/or, in the reconstituted solvent composition, the surfactant is selected from the group of nonionic surfactants consisting of copolymer of hydroxystearic acid and polyvinyl alcohol and its analogs, polymer of hydroxyl-stearic acid and α-hydrogen-Ω-hydroxy poly (oxy-1, 2-ethane dimethyl) and its analogues, polyethylene glycol-15 hydroxystearate and its analogues, bile acid, sodium cholate, Tween, Span, poloxamer and castor oil polyoxyester,and/or, in the reconstituted solvent composition, the monohydric alcohol containing 1-4 carbon atoms is one or more of methanol, ethanol, propanol and tert-butanol,and/or, in the reconstituted solvent composition, the pH regulator is selected from the group consisting of hydroxide, phosphate, dihydrogen phosphate, citrate, carbonate, and bicarbonate.and acetate,and/or, in the reconstituted solvent composition, the water is deionized water, purified water, or water for injection,and/or, in the reconstituted solvent composition, the mass-volume percentage of the polyethylene glycol is 11%-13%,and/or, in the reconstituted solvent composition, the mass volume percentage of the surfactant is 4%-8%,and/or, in the reconstituted solvent composition, the mass volume percentage of the monohydric alcohol containing 1-4 carbon atoms is 3%-10%,and/or, the pH of the reconstituted solvent composition is 10-12,and/or, the reconstituted solvent composition comprises the following components by mass volume percentage: 10%-15%polyethylene glycol, 3%-10%surfactant, 2%-8%monohydric alcohol containing 1-4 carbon atoms, pH regulator, water, and the pH of the reconstituted solvent is 10-12.
- The formulation combination of claim 2, wherein:in the raw material components of the freeze-dried formulation, the freeze-dried skeleton material is trehalose,and/or, in the raw material components of the freeze-dried formulation, the co-solvent is one or more of methanol, ethanol, propanol and tert-butanol,and/or, in the raw material components of the freeze-dried formulation, the water is water for injection,and/or, in the raw material components of the freeze-dried formulation, the pH regulator is selected from the group consisting of sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, sodium citrate, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, sodium acetate and HCl,and/or, in the raw material components of the freeze-dried formulation, based on 1 part of compound 1, the mass parts of the freeze-dried skeleton material are 10-20 parts,and/or, in the raw material components of the freeze-dried formulation, based on 1 part of compound 1, the mass parts of the co-solvent are 80-100 parts,and/or, in the raw material components of the freeze-dried formulation, based on 1 part of compound 1, the mass parts of the water are 80-100 parts,and/or, the freeze-dried formulation is obtained by lyophilizing a lyophilized solution containing the following raw material components by mass parts: 1 part of compound 1, 10-20 parts of freeze-dried skeleton material, 80-100 parts of co-solvent, and 80-100 parts of water, optionally containing an appropriate amount of pH regulator,and/or, in the reconstitution solvent composition, the polyethylene glycol is one or more of polyethylene glycol PEG200, PEG300, PEG400 and PEG600,and/or, in the reconstituted solvent composition, when the surfactant is a copolymer of hydroxystearic acid and polyvinyl alcohol and its analogues, the copolymer of hydroxystearic acid and polyvinyl alcohol and its analogues is the copolymer of 12-hydroxystearic acid-polyvinyl alcohol and its analogues,and/or, in the reconstituted solvent composition, when the surfactant is a polymer of hydroxy-stearic acid and α-hydrogen-Ω-hydroxy poly (oxy-1, 2-ethanedimethyl) and its analogs, the polymer of hydroxy-stearic acid and α-hydrogen-Ω-hydroxy poly (oxy-1, 2-ethane dimethyl) and its analogs is the polymer of 12-hydroxy-stearic acid and α-hydrogen-Ω-hydroxy poly (oxy-1,2-ethane dimethyl) and its analogues,and/or, in the reconstituted solvent composition, when the surfactant is polyethylene glycol-15 hydroxystearate and its analogs, the polyethylene glycol-15 hydroxystearate and its analogs is polyethylene glycol-15 hydroxystearateand its analogs,
and/or, in the reconstituted solvent composition, when the surfactant is Tween, the Tween is one or more of Tween 20, Tween 60 and Tween 80,and/or, in the reconstituted solvent composition, when the surfactant is Span, the Span is one or more of Span 20, Span 60, and Span 65,and/or, in the reconstituted solvent composition, when the surfactant is castor oil polyoxyl ester, the castor oil polyoxyl ester is castor oil polyoxyl ester (35) ,and/or, in the reconstituted solvent composition, the monohydric alcohol containing 1-4 carbon atoms is ethanol and/or propanol,and/or, in the reconstituted solvent composition, the pH regulator is selected from the group consisting of sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, sodium citrate, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate and sodium acetate,and/or, in the reconstituted solvent composition, the water is water for injection,and/or, in the reconstituted solvent composition, the mass volume percentage of the monohydric alcohol containing 1-4 carbon atoms is 3%-8%,and/or, the pH of the reconstituted solvent composition is 11-12,and/or, in the reconstituted solvent composition, when the pH regulator is carbonate, its mass volume percentage is 0.10-0.15%. - The formulation combination of claim 3, wherein:in the raw material components of the freeze-dried formulation, the freeze-dried skeleton material is α, α-trehalose,and/or, in the raw material components of the freeze-dried formulation, the co-solvent is tert-butanol,and/or, in the raw material components of the freeze-dried formulation, the pH regulator is NaOH and/or HCl,and/or, in the raw material components of the freeze-dried formulation, based on 1 part of compound 1, the mass parts of the freeze-dried skeleton material is16 parts,and/or, in the raw material components of the freeze-dried formulation, based on 1 part of compound 1, the mass parts of the co-solvent is 90-92 parts,and/or, in the raw material components of the freeze-dried formulation, based on 1 part of compound 1, the mass parts of the water is 90-92 parts,and/or, the raw material components of the freeze-dried formulation comprise the following components by mass part: 1 part of compound 1, 16 parts of freeze-dried skeleton material, 90-92 parts of co-solvent, 90-92 parts of water, optionally contains an appropriate amount of pH regulator,and/or, in the reconstituted solvent composition, the polyethylene glycol is PEG400,and/or, in the reconstituted solvent composition, the surfactant isHS-15,
and/or, in the reconstituted solvent composition, the pH regulator is sodium carbonate and/or sodium bicarbonate,and/or, in the reconstituted solvent composition, the mass volume percentage of the monohydric alcohol containing 1-4 carbon atoms is 3%-6%,and/or, the reconstituted solvent composition comprises the following components by mass volume percentage: 11%-13%polyethylene glycol, 4%-8%surfactant, 3%-6%monohydric alcohol containing 1-4 carbon atoms, pH regulator, water, the pH of the reconstituted solvent composition is 11-12,and/or, the reconstituted solvent composition comprising the following components by mass volume percentage: 11%-13%polyethylene glycol, 4%-8%surfactant, 4%-8%monohydric alcohol containing 1-4 carbon atoms, pH regulator, water, and the pH of the reconstituted solvent composition is 9-10. - The formulation combination of claim 4, wherein:in the raw material components of the freeze-dried formulation, the pH regulator is 10N NaOH and/or 5N HCl,and/or, in the raw material components of the freeze-dried formulation, based on 1 part of compound 1, the mass parts of the co-solvent are 91.5 parts,and/or, in the raw material components of the freeze-dried formulation, based on 1 part of compound 1, the mass parts of the water are 91.5 parts,and/or, the freeze-dried formulation is obtained by lyophilizing a lyophilized solution containing the following raw material components by mass parts: 1 part of compound 1, 16 parts of α, α-trehalose, 91.5 parts of tert-butanol, 91.5 parts of water, appropriate amount of pH regulator,and/or, the reconstituted solvent composition is consisting of the following components by mass volume percentage: 11%polyethylene glycol 400, 8%Solutol HS-15, 6%absolute ethanol, 0.12%sodium carbonate, the rest is water for injection.
- The formulation combination according to any one of claims 1-5, wherein:the reconstituted solvent composition is prepared by a preparation method comprising the following steps:weigh the components of the reconstituted solvent composition according to any one of claims 1-5,mix the polyethylene glycol, surfactant, monohydric alcohol containing 1-4 carbon atoms, and part of water, add the pH regulator, dissolve, and finally add the remaining water to make the volume constant, mix uniformly to obtain the reconstituted solvent composition,and/or, wherein the freeze-dried formulation is prepared by a preparation method comprising the following steps:weigh each component according to the raw material components of the freeze-dried formulation according to any one of claims 1 to 5,(1) mix the co-solvent with the compound 1 and the freeze-dried skeleton material to obtain a mixed solution 1,(2) mix the mixed solution 1 with water and an appropriate amount of pH regulator, filter to obtain solution 2,(3) fill and freeze-dry to obtain the freeze-dried formulation.
- A preparation method of a formulation combination, characterized in that the conditions and operations of the preparation method of the reconstituted solvent composition are the same as those described in claim 6; the conditions and operations of the preparation method of the freeze-dried formulation are the same as described in claim 6.
- A reconstituted solvent composition for freeze-dried formulation, characterized in that, the reconstituted solvent composition is as described in the formulation combination of any one of claims 1-6.
- A medicine kit, characterized in that it comprises: a medicinal container containing a freeze-dried formulation, and another medicinal container containing a reconstituted solvent composition, the definition of the freeze-dried formulation and the reconstitution solvent composition is as described in any one of claims 1-6.
- The kit according to claim 9, wherein the medicinal container is an amber or colorless glass medicine bottle with an elastic stopper and a crimped aluminum lid or any amber or colorless container suitable for immediate use system, and/or, the medical container is an ampoule or a vial.
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2021/133660 WO2022111647A1 (en) | 2020-11-27 | 2021-11-26 | Formulation combination containing freeze-dried formulation and reconstituted solvent, preparation method and application thereof |
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| Country | Link |
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| WO (1) | WO2022111647A1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070116729A1 (en) * | 2005-11-18 | 2007-05-24 | Palepu Nageswara R | Lyophilization process and products obtained thereby |
| CN105246882A (en) * | 2013-01-16 | 2016-01-13 | 密执安大学评议会 | BCL-2/Bcl-xL inhibitors and therapeutic methods using the same |
| CN108042498A (en) * | 2017-12-26 | 2018-05-18 | 西安医学院 | A kind of ABT-199 nano-emulsions dispersant and preparation method thereof |
| WO2020135647A1 (en) * | 2018-12-28 | 2020-07-02 | Ascentage Pharma (Suzhou) Co., Ltd. | Pharmaceutical composition and preparation method thereof |
| CN111410666A (en) * | 2019-01-04 | 2020-07-14 | 苏州亚盛药业有限公司 | Process for preparing sulfonamide compound |
-
2021
- 2021-11-26 WO PCT/CN2021/133660 patent/WO2022111647A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070116729A1 (en) * | 2005-11-18 | 2007-05-24 | Palepu Nageswara R | Lyophilization process and products obtained thereby |
| CN105246882A (en) * | 2013-01-16 | 2016-01-13 | 密执安大学评议会 | BCL-2/Bcl-xL inhibitors and therapeutic methods using the same |
| CN108042498A (en) * | 2017-12-26 | 2018-05-18 | 西安医学院 | A kind of ABT-199 nano-emulsions dispersant and preparation method thereof |
| WO2020135647A1 (en) * | 2018-12-28 | 2020-07-02 | Ascentage Pharma (Suzhou) Co., Ltd. | Pharmaceutical composition and preparation method thereof |
| CN111410666A (en) * | 2019-01-04 | 2020-07-14 | 苏州亚盛药业有限公司 | Process for preparing sulfonamide compound |
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