TWI738746B - 製備具有增強穩定性的依前列醇鈉的方法 - Google Patents
製備具有增強穩定性的依前列醇鈉的方法 Download PDFInfo
- Publication number
- TWI738746B TWI738746B TW106109275A TW106109275A TWI738746B TW I738746 B TWI738746 B TW I738746B TW 106109275 A TW106109275 A TW 106109275A TW 106109275 A TW106109275 A TW 106109275A TW I738746 B TWI738746 B TW I738746B
- Authority
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- Taiwan
- Prior art keywords
- sodium
- epoprostol
- salt
- sodium salt
- amount
- Prior art date
Links
- LMHIPJMTZHDKEW-XQYLJSSYSA-M Epoprostenol sodium Chemical compound [Na+].O1\C(=C/CCCC([O-])=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 LMHIPJMTZHDKEW-XQYLJSSYSA-M 0.000 title claims abstract description 31
- 238000000034 method Methods 0.000 title claims description 22
- 229960003013 epoprostenol sodium Drugs 0.000 title abstract description 3
- 238000002360 preparation method Methods 0.000 title description 7
- 230000008569 process Effects 0.000 title description 4
- 229940088679 drug related substance Drugs 0.000 claims abstract description 9
- 239000008186 active pharmaceutical agent Substances 0.000 claims abstract description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 111
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 239000011734 sodium Substances 0.000 claims description 26
- 229910052708 sodium Inorganic materials 0.000 claims description 25
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 23
- 159000000000 sodium salts Chemical class 0.000 claims description 21
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 18
- 229910052740 iodine Inorganic materials 0.000 claims description 18
- 239000011630 iodine Substances 0.000 claims description 18
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 17
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 230000008030 elimination Effects 0.000 claims description 13
- 238000003379 elimination reaction Methods 0.000 claims description 13
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 13
- 229910000043 hydrogen iodide Inorganic materials 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- 239000011541 reaction mixture Substances 0.000 claims description 11
- 238000007363 ring formation reaction Methods 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 9
- -1 sodium alkoxide salt Chemical class 0.000 claims description 6
- 235000009518 sodium iodide Nutrition 0.000 claims description 6
- 239000011697 sodium iodate Substances 0.000 claims description 5
- 229940032753 sodium iodate Drugs 0.000 claims description 5
- NALMPLUMOWIVJC-UHFFFAOYSA-N n,n,4-trimethylbenzeneamine oxide Chemical compound CC1=CC=C([N+](C)(C)[O-])C=C1 NALMPLUMOWIVJC-UHFFFAOYSA-N 0.000 claims description 4
- 235000015281 sodium iodate Nutrition 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 3
- IBXBZGSSVSLNAS-UHFFFAOYSA-L disodium diiodate Chemical compound I(=O)(=O)[O-].[Na+].I(=O)(=O)[O-].[Na+] IBXBZGSSVSLNAS-UHFFFAOYSA-L 0.000 claims 1
- 230000026045 iodination Effects 0.000 claims 1
- 238000006192 iodination reaction Methods 0.000 claims 1
- 150000007529 inorganic bases Chemical class 0.000 abstract description 7
- 229910017053 inorganic salt Inorganic materials 0.000 abstract description 7
- 239000000243 solution Substances 0.000 description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 229960001123 epoprostenol Drugs 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 229940001440 flolan Drugs 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- PJDMFGSFLLCCAO-NVRZHKMMSA-N PGF2alpha methyl ester Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(=O)OC PJDMFGSFLLCCAO-NVRZHKMMSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- KAQKFAOMNZTLHT-OZUDYXHBSA-N prostaglandin I2 Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-OZUDYXHBSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 150000004702 methyl esters Chemical class 0.000 description 5
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 230000003113 alkalizing effect Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 150000002084 enol ethers Chemical group 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 3
- 229930184489 Iodoether Natural products 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 229910000039 hydrogen halide Inorganic materials 0.000 description 3
- 239000012433 hydrogen halide Substances 0.000 description 3
- VSHDHKDWBUMJIJ-UHFFFAOYSA-N iodo hypoiodite Chemical compound IOI VSHDHKDWBUMJIJ-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- KWPQTFXULUUCGD-UHFFFAOYSA-N 3,4,5,7,8,9,10,10a-octahydropyrido[1,2-a][1,4]diazepine Chemical compound C1CCN=CC2CCCCN21 KWPQTFXULUUCGD-UHFFFAOYSA-N 0.000 description 2
- KFGOFTHODYBSGM-IJCBKZNRSA-N 6-Keto-prostaglandin F1a Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC(=O)CCCCC(O)=O KFGOFTHODYBSGM-IJCBKZNRSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 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 description 2
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- CWLQVJJNUZJEBW-UHFFFAOYSA-L disodium iodate iodide Chemical compound [Na+].I(=O)(=O)[O-].[I-].[Na+] CWLQVJJNUZJEBW-UHFFFAOYSA-L 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 2
- 229940001584 sodium metabisulfite Drugs 0.000 description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 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 description 1
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- IKEBGZWIHITZOJ-UHFFFAOYSA-N 3-bromo-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane-2,4-dione Chemical compound O=C1N(Br)C(=O)C2(C)CCC1C2(C)C IKEBGZWIHITZOJ-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
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- 229930188012 Bromoether Natural products 0.000 description 1
- OKRZHEVZYOJBJF-QMUYVUSTSA-N CCCCC[C@@H](/C=C/C(C(C1)[C@H](C2)O[C@@H]1C(CC)CCCC(O)=O)[C@@H]2O)O Chemical compound CCCCC[C@@H](/C=C/C(C(C1)[C@H](C2)O[C@@H]1C(CC)CCCC(O)=O)[C@@H]2O)O OKRZHEVZYOJBJF-QMUYVUSTSA-N 0.000 description 1
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- KFGOFTHODYBSGM-ZUNNJUQCSA-N CCCCC[C@@H](/C=C/[C@H]([C@@H](CC(CCCCC(O)=O)=O)[C@H](C1)O)[C@@H]1O)O Chemical compound CCCCC[C@@H](/C=C/[C@H]([C@@H](CC(CCCCC(O)=O)=O)[C@H](C1)O)[C@@H]1O)O KFGOFTHODYBSGM-ZUNNJUQCSA-N 0.000 description 1
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- 229920002307 Dextran Polymers 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
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- WJEIYVAPNMUNIU-UHFFFAOYSA-N [Na].OC(O)=O Chemical compound [Na].OC(O)=O WJEIYVAPNMUNIU-UHFFFAOYSA-N 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical class CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- HJCMMOODWZOXML-UHFFFAOYSA-N bromo hypobromite Chemical compound BrOBr HJCMMOODWZOXML-UHFFFAOYSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 239000008364 bulk solution Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- UKJFVOWPUXSBOM-UHFFFAOYSA-N hexane;oxolane Chemical compound C1CCOC1.CCCCCC UKJFVOWPUXSBOM-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229940050526 hydroxyethylstarch Drugs 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 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 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000012792 lyophilization process Methods 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- HWGNBUXHKFFFIH-UHFFFAOYSA-I pentasodium;[oxido(phosphonatooxy)phosphoryl] phosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O HWGNBUXHKFFFIH-UHFFFAOYSA-I 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- XXQBEVHPUKOQEO-UHFFFAOYSA-N potassium peroxide Inorganic materials [K+].[K+].[O-][O-] XXQBEVHPUKOQEO-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 235000019832 sodium triphosphate Nutrition 0.000 description 1
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 235000019801 trisodium phosphate Nutrition 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
- C07D307/937—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans with hydrocarbon or substituted hydrocarbon radicals directly attached in position 2, e.g. prostacyclins
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- C07—ORGANIC CHEMISTRY
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- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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Abstract
本發明提供一種穩定的依前列醇鈉藥物物質,其可在冷凍室(-20±5℃)儲存至少3年,其特徵在於,該經凍乾的藥物物質含有依前列醇鈉鹽,並且相對於依前列醇鈉鹽的量,其含有3-7.5質量%的無機鹼或鹼性水解無機鹽。
Description
本發明的主題為可在冷凍室(deep freezer)(-20±5℃)儲存至少3年的穩定依前列醇鈉(epoprostenol sodium)及其製備方法。
式I的依前列醇鈉為式IV的天然前列環素的合成生成的鈉鹽。前列環素鈉和依前列醇鈉是相同的。
依前列醇鈉的主要治療領域為肺動脈高壓(PAH)的治療(European Heart J.,2004,25,2243-2278)。
自從1976年(Nature,1976,263,663-665)分離以來,前列環素已知是花生四烯酸的代謝物,並且其具有強血管舒張和血小板聚集抑制作用。
還很快清楚的是,該分子是化學上高度不穩定的,在中性或酸性水溶液中,其轉化成生物非活性之式V的6-氧代-PGF1α(流程1)。
前列環素極快降解(其在生理pH值的水溶液中的半衰期為3-4分鐘)的原因是,除了烯醇-醚結構之外,鏈末端羧基還加速其質子化和離子化形式兩者的分解(J.C.S.Chem.Comm.,1979,129-130)。首次合成並且也是證明結構的合成由Corey及其團隊自THP2-PGF2α起始進行(J.A.Chem.Soc.,1977,99,2006-2008)。該操作如流程2所示。
在該過程中,式VI的THP2-PGF2α與N-溴代琥珀醯亞胺反應,獲得式VII和VIII的溴代醚非對映異構體。在除去THP基團(四氫吡喃基)後,藉由層析法分離式IX和X的非對映異構體。在空間位阻較小(外型(exo))位置上含有溴取代基的
式IX異構體,在第三丁醇中用第三丁醇鉀處理,在溴化氫消除下在1.5小時內轉化成式IV的烯醇-醚。藉由快速醚萃取將烯醇-醚從溫和酸性水溶液中分離,然後用重氮甲烷轉化成式XI的甲酯。
在空間位阻(內型(endo))位置含有溴取代基的式X異構體,在上述條件下反應的程度很小。
式XI的甲酯在酸性介質中被轉化成式XII的6-氧代-PGF1α甲酯,然而,這種轉化比前列環素的水解更慢(流程3)。
首次合成之後幾乎同時出現了多種其它製備方法。合成的關鍵步驟是PGF2α或其衍生物的鹵代環化,隨後在鹼的作用下消除鹵化氫。由於游離酸的化學不穩定性,產物總是以其鹽的形式分離和儲存。
Tömösközi及其同事首先證實(Tetrahedron Letters,1977,30,2627-2628):- 溴代-和碘代-環化反應也可自未經保護的PGF2α及其甲酯實現,- 兩種鹵代醚非對映異構體在鹼的作用下轉化成順式-乙烯基醚衍生物(前列環素),- 在碘代-衍生物的情況下,鹵化氫的消除較快速,甚至在碳酸鉀的作用下,碘化氫也自碘代-衍生物中消除。
在鹵代環化反應中- 使用KIO3+KI/乙酸-水混合物(作為溶劑)或I2/吡啶或ICl/乙腈作為碘源,
- 使用N-溴代琥珀醯亞胺/二氯甲烷或二溴二甲基乙內醯脲/二氯甲烷和乙腈或N-溴代樟腦醯亞胺/二氯甲烷中作為溴源。
用合適的醇中的乙醇鉀或第三丁醇鉀鹼進行鹵化氫消除。在碘代取代基的情況下,消除甚至在碳酸鉀的作用下進行。
Johnson及其同事(J.Am.Chem.Soc.,1977,99,4182-4184)首次製備了凍乾的前列環素鈉鹽:用於甲醇:水=1:1混合物中等量的氫氧化鈉水解式XI的甲酯,隨後凍乾所生成的含有依前列醇鈉鹽的反應混合物。凍乾物,即白色粉末,在-30℃保持穩定至少兩個月。
上述甲酯由PGF2α甲酯製備:在碳酸鈉存在下,使用在水中或在二氯甲烷溶劑中的KI-I2試劑作為碘源。
碘化氫消除的反應條件:- 在痕量的高氯酸存在下,用於四氫呋喃中的碳酸銀進行反應;- 在苯中用1,5-二氮雜雙環[4.3.0]壬-5-烯(DBN)鹼進行反應;- 在18-冠醚存在下用於二甲基甲醯胺中的過氧化鉀(KO2)進行反應。
Whittaker(Tetrahedron Letters,1977,32,2805-2808)自PGF2α甲酯製備了式XIV的碘代醚非對映異構體。將碘源(即KI-I2試劑水溶液)滴加至PGF2α甲酯的醚溶液中,該醚先前用碳酸氫鈉水溶液飽和。當碘溶於乙醚或二氯甲烷時達到更好的結果。
在甲醇中,將碘醚非對映異構體用10當量甲醇鈉處理。消除碘化氫後,用1N氫氧化鈉溶液水解酯基。依前列醇鈉鹽從濃縮的水性反應混合物中呈細針的形式結晶。
過濾出鹽,用1N氫氧化鈉洗滌並在空氣中乾燥,同時約3.5%的晶體表面被碳酸鈉覆蓋,其保護了烯醇-醚結構產物。將鈉鹽儲存在密封管中。
該操作示於流程4。
Nicolau及其同事(J.C.S.Chem.Comm.,1977,630-631)在碳酸鉀存在下使式XIII的PGF2α甲酯與碘在二氯甲烷中反應。在甲苯中,在110℃,用1,5-二氮雜雙環[5.4.0]十一碳-5-烯(DBU)鹼,或更較佳在甲醇中,在甲醇鈉存在下,自式XIV的非對映異構體中消除碘化氫。
如果式XIV的碘醚非對映異構體用甲醇鈉在含有5%水的甲醇中處理,除了碘化氫消除之外,也發生酯基的水解(流程5),並且所生成的依前列醇鈉鹽在溶液中保持穩定。前列環素鈉儲備液(stock solution)在進一步稀釋後用於生物學研究。
Johnson及其同事在1978年的著作(J.Am.Chem.Soc.,1978,100,7690-7705)
中描述前列環素鈉及其異構體雜質的製備。有關合成的最詳細說明係公開於1982年(Methods in Enzymology,1982,86,459-446),其涉及前列環素鈉的合成。
起始物質為式XIII的PGF2α甲酯,將其溶於二氯甲烷中,向溶液中添加飽和碳酸氫鈉溶液,並且在0℃在劇烈攪拌下向所生成的懸浮液中添加碘的二氯甲烷溶液。在反應結束時,分離各相,用二氯甲烷萃取水相,合併的有機相先用亞硫酸鈉溶液然後用飽和鹽溶液洗滌,然後以硫酸鈉乾燥,過濾並真空蒸發。產物為式XIV的碘-醚非對映體的10:1比例混合物。
將碘-醚非對映異構體溶於無水二乙醚中,並使用DBN或DBU鹼進行碘化氫消除。在反應結束時,真空蒸餾出醚,產物用乙醚:己烷:三乙胺=1:1:0.02混合物萃取,並藉由層析法純化。蒸發出的主餾分,即前列環素甲酯可直接進行下一步,或自乙醚:己烷:0.01%三乙胺溶劑混合物中結晶。產率:60%,mp:56-58℃。
將獲得的前列環素甲酯溶於不含二氧化碳的甲醇中,添加等莫耳量的1N氫氧化鈉溶液,使混合物在惰性氣氛中在40℃反應3小時。在水解結束時,添加甲醇並將反應混合物濃縮。將殘餘物溶於水並用乙腈結晶。將所生成的蓬鬆的前列環素鈉晶體保存在真空乾燥器中。
產率:82%。
根據專利說明書GB 1583961中描述的方法,將式XIII的PGF2α甲酯溶於乙醚,首先向該溶液中添加碳酸氫鈉水溶液,然後滴加碘化鉀-碘水溶液。將混合物在室溫攪拌過夜,然後添加乙醚,將混合物用硫代硫酸鈉水溶液洗滌,然後用水洗滌,乾燥並蒸發。將殘餘物(式XIV的碘-醚非對映異構體)與甲醇鈉在惰性氣氛中於甲醇中反應,然後真空除去甲醇。將殘餘物(式XI的前列環素甲酯,無定形固體物質)用苯洗滌並用1N氫氧化鈉處理,同時將其轉化為前列環素鈉的無色針狀物。
作者藉由省略碘-醚非對映異構體的蒸發而簡化了該方法,不同的是將1N氫氧化鈉水溶液添加至甲醇鈉的甲醇溶液中。在水解結束時,除去甲醇,並前列環素鈉自剩餘水溶液中以細針的形式結晶。
從所引用的文獻中可以看出,就化學反應而言,解決了自PGF2α起始製備依前列醇鈉(前列環素鈉)的問題。
然而,由於依前列醇的化學不穩定性,依然存在如何保存藥物物質和藥物產品的問題。
根據上述方法
- 將凍乾的鈉鹽在-30℃儲存兩個月,或- 藉由結晶分離,並且用碳酸鈉覆蓋和穩定晶體的表面,然後將其儲存在密封管中,避免空氣,或- 自鈉鹽製備儲備溶液,並將其以溶液形式儲存,或- 將結晶鹽儲存在真空乾燥器中。
一個重要目的是為了改善依前列醇鈉藥物物質和成品的穩定性,因為預期無菌醫藥組合物在室溫保持其藥物含量12小時,或者如果不能達到,則其必須在4℃穩定12小時。
含有依前列醇鈉藥物物質“配製用於靜脈內使用的注射用無菌鈉鹽”的藥物產品FLOLAN®(GlaxoSmithKline,1995)的穩定性藉由將其pH值設定為約10.5而確保。
FLOLAN®是一種白色或幾乎白色的粉末。每個安瓿含有相當於0.5mg或1.5mg依前列醇量的鈉鹽、3.76mg甘胺酸、2.93mg氯化鈉、50mg甘露醇,以及另外用於pH調節的氫氧化鈉。
對於靜脈內施用,必須將其溶於特定的溶解混合物(由94mg甘胺酸、73.3mg氯化鈉、適於注射製劑的水和氫氧化鈉組成的50ml無色緩衝溶液)。
FLOLAN®溶液的pH為10.2-10.8。如果不立即使用所製備的FLOLAN®溶液,則其在避光保存的情況下在2-8℃可儲存最多2天,並且可不再冷凍。
在較低的pH值下,FLOLAN®溶液的穩定性顯著降低。
專利申請案WO2007/092343中描述的方法的新穎性在於,在高pH值(即pH>11)下,在至少一種鹼化劑的存在下,依前列醇溶液的穩定性與FLOLAN®的穩定性相比顯著增加。
在本說明書中,描述了本體溶液的製備,其含有依前列醇或依前列醇鹽、一種鹼化劑和賦形劑,並且將溶液的pH設定為pH>11,較佳設定為12.5-13.5,較佳設定為13。然後將由此獲得的溶液凍乾,凍乾過程的參數也在說明書中給出。
在靜脈內施用之前,凍乾物溶解,所獲得的(稀釋的)溶液的pH也>11。
這種高pH的溶液可用於與FLOLAN®溶液相同的治療目的。由於其較高的pH,溶液在室溫保持其活性成分含量的90%達14-48小時。
由於這種增強的穩定性,不需要用於溶解的特定溶劑,可使用用於靜脈內施用的任何市售溶液。
該溶液對微生物更加耐受。
根據本專利說明書
- 依前列醇或依前列醇鹽和鹼化劑的量的比例可為1:25-1:200
鹼化劑確保介質鹼性但不含鹼性羥基,它可為精胺酸、賴胺酸、葡甲胺、N-甲基-葡糖胺、pKa>9.0胺基酸、三磷酸鈉、碳酸鈉、EDTA四鈉鹽。
- 賦形劑的量為1-10%
賦形劑可為羥乙基澱粉、山梨醇、乳糖、葡聚糖、麥芽糖、甘露糖、核糖、蔗糖、甘露糖、海藻糖、環糊精、甘胺酸和聚乙烯吡咯烷酮。
- 依前列醇鹽較佳為鈉鹽
- 用無機或有機鹼調節溶液的pH
無機鹼為氫氧化鈉、氫氧化鉀、氫氧化鎂或氫氧化銨。
有機鹼為芳族胺或芳族醇。
- 將該溶液在無菌小瓶中凍乾。
最有利的製劑的組合物含有0.5mg依前列醇(或等量的鹽)、50mg精胺酸和50mg甘露醇,然後將溶液的pH設定為13並凍乾。
將凍乾物溶於50ml溶劑,所獲得的溶液的pH>11(根據實施例:11.58-11.6)。
如此製備的依前列醇溶液在設定為相似的pH(pH=13)後比FLOLAN®溶液更穩定。
根據本發明,在自未經保護的PGF2α(式III)(流程6)起始的兩個反應步驟中以最短的方式製備依前列醇鈉。
與較早的方法相比,本方法的優點在於其不含鹵化的或其它對環境有害的溶劑。
兩個反應步驟在四氫呋喃中進行,因此,在第一步驟之後,足以濃縮反應混合物,可能危害式II的敏感碘代衍生物的長時間、耗時的完全蒸發是不必要的。
用於碘環化的碘源是在酸性介質中發生的碘化鈉-碘酸鈉的反應。
在反應期間,除了產物之外所形成的碘化鈉繼續與碘酸鈉反應,並且所生成的碘用於碘環化。
如果發明人選擇PGF2α:NaI:NaIO3=3:2:1比例的反應混合物,則碘的利用率接近100%,此表示本方法不會污染環境。
用甲醇鈉試劑進行碘化氫消除。在反應結束時,真空蒸出四氫呋喃,向殘餘物中添加氫氧化鈉溶液並使依前列醇Na鹽結晶。將沈澱的鈉鹽溶於水並凍乾。
發明人研究了用於形成鹽的氫氧化鈉量對酸敏感性依前列醇鈉的穩定性的影響。
為此目的,用強酸性陽離子交換樹脂DOWEX除去可能存在於依前列醇鈉鹽中的過量鹼,向不含過量鹼的鹽的水溶液中添加不同量的氫氧化鈉,將所獲得的溶液凍乾。
自1%凍乾物水溶液中,發明人測量pH並在室溫於封閉的玻璃容器中開始加速穩定性研究。
在0、24、48和144小時後,藉由HPLC跟蹤穩定性樣品的活性成分含量的變化。
自測得的活性成分含量計算依前列醇鈉的分解速率(表1)。
令人驚訝的是,發明人發現,在添加的氫氧化鈉過量的影響下,依前列醇鈉的穩定性顯著增加,直至約5.5質量%,則開始降低至較小的程度。
為了達到這種增強的穩定性,不需要存在胺基酸或其它緩衝效應賦形劑。
基於這些意想不到的實驗結果,發明人改進了其新技術,將漏斗濾濕的(funnel-wet)結晶性依前列醇鈉鹽溶於水中,向該水溶液中添加2M NaOH溶液,其量使得產物在凍乾後含有4質量%過量的氫氧化鈉。
藉由這種新方法製備的依前列醇鈉的穩定性極好,可在冷凍室(-20±5℃)中儲存至少3年。6-氧代-PGF1α雜質的量,即產物分解特徵,在儲存期間沒有顯示任何變化(表2)。
藉由新方法製備的依前列醇鈉可在冷藏室(5±3℃)中儲存至少6個月(表3)。
根據發明人的新方法,將PGF2α溶於四氫呋喃。用於碘環化的碘源為在酸性介質中進行的碘化鈉-碘酸鈉反應。在環化反應結束時,向反應混合物中添加飽和氯化鈉溶液並用四氫呋喃-己烷混合物萃取產物。用焦亞硫酸鈉溶液除去過量的碘。將產物溶液洗滌,乾燥,濃縮至確定重量,無需進一步純化即進行接下來的碘化氫消除步驟。
使用甲醇鈉鹼在四氫呋喃溶液中進行碘化氫消除。在反應結束時,向反應混合物中添加2M氫氧化鈉溶液,藉由蒸餾除去四氫呋喃,並使依前列醇鈉產物結晶。濾出晶體,洗滌,向產物中添加2M NaOH溶液,其量使得凍乾後的鈉鹽含有4質量%過量的氫氧化鈉。然後將溶液凍乾。
凍乾物為白色或幾乎白色的粉末,其可在冷凍室(-20±5℃)中儲存至少3年,在冷藏室(5±3℃)中儲存至少6個月。
與上述一致,本發明的主題為穩定的依前列醇鈉,其可在冷凍室(-20±5℃)中儲存至少3年,其特徵在於,依前列醇鈉和無機鹼或鹼性水解性無機鹽以相對於依前列醇鈉的3-7.5質量%量,以凍乾形式儲存。
本發明的另一個主題為穩定的依前列醇鈉的製備方法,其可在冷凍室(-
20±5℃)中儲存至少3年,其特徵在於,依前列醇鈉鹽的水溶液在確保介質pH>11的無機鹼或鹼性水解無機鹽存在下凍乾。
作為確保介質pH>11的無機鹼或鹼性水解無機鹽,使用含鈉陽離子的鹼或鹽。
該含有鈉陽離子的無機鹼可為氫氧化鈉或碳酸鈉,較佳氫氧化鈉,該鹼性水解無機鹽可為磷酸三鈉。
根據本發明,該依前列醇鈉凍乾物含有相對於鈉鹽為3-7.5質量%的無機鹼或鹼性水解無機鹽。
該過程包括在如下量的添加的氫氧化鈉溶液存在下將依前列醇鈉鹽的水溶液凍乾:凍乾物含有3-7.5質量%,較佳4-6質量%的過量的氫氧化鈉。發明人已經發現較佳的4-5-6% NaOH過量在儲存性能方面同樣良好。
本發明的另一個主題為藉由碘環化和碘化氫消除製備穩定的依前列醇鈉的方法,其中a.)使用未經保護的PGF2α作為起始物質,b.)使用碘化鈉-碘酸鈉(sodium iodate)混合物作為碘源,c.)在相同的溶劑中進行環化和碘化氫消除,d.)在確保介質pH>11的無機鹼或鹼性水解無機鹽存在下凍乾依前列醇鈉鹽的水溶液。
根據本發明的較佳實施方案,使用PGF2α:碘化鈉:碘酸鈉=3:2:1比率的反應混合物。
使用四氫呋喃作為溶劑。
本發明的進一步細節在實施例中說明,而非將本發明限制於實施例。
5ξ-碘-9-脫氧-6ξ,9α-環氧前列腺素F1α(5-I-PGI
1
)
1M硫酸氫鈉溶液自3升水、87.7毫升濃鹽酸、硫酸和247克硫酸鈉製備。向溶液中添加1.2升水,然後在攪拌下添加95.1克碘酸鈉在1.2升水中的溶液、473.4克前列腺素F2α在1.5升四氫呋喃中的溶液,最後添加148.1克碘化鈉在0.44升水中的溶液。在反應結束時,將飽和氯化鈉溶液和四氫呋喃:己烷=1:1混合物倒在反應混合物上。分離各相,水相用四氫呋喃:己烷=1:1混合物萃取。合併的有機相用5%焦亞硫酸鈉溶液洗滌,然後用飽和鹽溶液稀釋,以硫酸鈉乾燥並濃縮至大約1千克。
5-I-PGI1中間體無需進一步純化即可用於下一反應步驟。
(5Z,9α,11α,13E,15S)-6,9-環氧-11,15-二羥基前列腺素-5,13-二烯-1-酸鈉鹽(PGI
2
-Na)
向前一步驟中獲得的5-I-PGI 1 中間體(濃縮至約1千克)中添加12.4升無水四氫呋喃和721克甲醇鈉,並將混合物在室溫攪拌。在反應結束時,將2M氫氧化鈉溶液添加到反應混合物中,並真空蒸除四氫呋喃。將混合物在室溫攪拌直至大量的晶體沈澱,然後將其冷卻至0℃以完成晶體沈澱。濾出晶體,先後2M氫氧化鈉溶液和1M氫氧化鈉溶液洗滌。然後將晶體溶於這樣量的2M氫氧化鈉溶液中,使得產物含有4質量%過量的氫氧化鈉。將溶液凍乾。
產量:針對PGF2α計算為250克(50%),產物為白色粉末。
Claims (9)
- 一種凍乾形式之穩定的依前列醇鈉藥物物質,其可在冷凍室(-20±5℃)儲存至少3年,其特徵在於,其由依前列醇鈉鹽,以及相對於依前列醇鈉鹽的量為3-7.5質量%的氫氧化鈉所組成。
- 如請求項1的藥物物質,其特徵在於,其由依前列醇鈉鹽,以及相對於依前列醇鈉鹽的量為4質量%的氫氧化鈉所組成。
- 如請求項1的藥物物質,其特徵在於,其由依前列醇鈉鹽,以及相對於依前列醇鈉鹽的量為5質量%的氫氧化鈉所組成。
- 如請求項1的藥物物質,其特徵在於,其由依前列醇鈉鹽,以及相對於依前列醇鈉鹽的量為6質量%的氫氧化鈉所組成。
- 一種製備可在冷凍室(-20±5℃)儲存至少3年之穩定的依前列醇鈉的方法,該方法特徵在於,在確保介質pH>11之此量的氫氧化鈉存在下將依前列醇鈉鹽的水溶液凍乾,使得相對於依前列醇鈉鹽的量,凍乾物含有3-7.5質量%的過量氫氧化鈉。
- 如請求項5的方法,其特徵在於,在確保介質pH>11之此量的氫氧化鈉存在下將依前列醇鈉鹽的水溶液凍乾,使得相對於依前列醇鈉鹽的量,凍乾物含有4-6質量%的過量氫氧化鈉。
- 一種藉由用碘進行環化且藉由碘化氫消除來製備穩定的依前列醇鈉的方法,其特徵在於a.)使用未經保護的PGF2α作為起始物質,b.)使用碘化鈉-碘酸鈉混合物作為碘源,c.)在相同的溶劑中進行環化和碘化氫消除,d.)在確保介質pH>11之此量的氫氧化鈉存在下凍乾依前列醇鈉鹽的水溶液,使 得相對於依前列醇鈉鹽的量,凍乾物含有3-7.5質量%的過量氫氧化鈉。
- 如請求項7的方法,其特徵在於使用PGF2α:碘化鈉:碘酸鈉=3:2:1比率的反應混合物。
- 如請求項7的方法,其特徵在於使用四氫呋喃作為溶劑。
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US20040265238A1 (en) * | 2003-06-27 | 2004-12-30 | Imtiaz Chaudry | Inhalable formulations for treating pulmonary hypertension and methods of using same |
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CN103585119A (zh) * | 2013-11-13 | 2014-02-19 | 北京泰德制药股份有限公司 | 一种包含依前列醇及其药用盐的稳定化制剂及其制备方法 |
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2016
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2017
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- 2017-03-21 JP JP2018549828A patent/JP6871942B2/ja active Active
- 2017-03-21 CN CN201780031475.9A patent/CN109153660B/zh active Active
- 2017-03-21 DK DK17712755.2T patent/DK3433241T3/da active
- 2017-03-21 WO PCT/EP2017/056690 patent/WO2017162668A1/en active Application Filing
- 2017-03-21 TW TW106109275A patent/TWI738746B/zh active
- 2017-03-21 HU HUE17712755A patent/HUE053193T2/hu unknown
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- 2017-03-21 ES ES17712755T patent/ES2853699T3/es active Active
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CN101410119A (zh) * | 2006-02-03 | 2009-04-15 | 西多斯有限责任公司 | 新颖的依前列醇制剂及其制备方法 |
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WO2017162668A1 (en) | 2017-09-28 |
CN109153660A (zh) | 2019-01-04 |
HUE053193T2 (hu) | 2021-06-28 |
JP6871942B2 (ja) | 2021-05-19 |
TW201808303A (zh) | 2018-03-16 |
CY1123966T1 (el) | 2022-05-27 |
DK3433241T3 (da) | 2021-02-15 |
US10981884B2 (en) | 2021-04-20 |
KR20180127426A (ko) | 2018-11-28 |
HUP1600211A2 (en) | 2017-09-28 |
RU2018136065A3 (zh) | 2020-06-01 |
HU231031B1 (hu) | 2019-12-30 |
JP2019510765A (ja) | 2019-04-18 |
ES2853699T3 (es) | 2021-09-17 |
EP3433241A1 (en) | 2019-01-30 |
RU2018136065A (ru) | 2020-04-23 |
CN109153660B (zh) | 2022-10-11 |
EP3433241B1 (en) | 2020-11-25 |
RU2747646C2 (ru) | 2021-05-11 |
KR102376668B1 (ko) | 2022-03-21 |
US20200123124A1 (en) | 2020-04-23 |
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