CN1053569C - 可注射溶液的制备方法 - Google Patents
可注射溶液的制备方法 Download PDFInfo
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- CN1053569C CN1053569C CN90109756A CN90109756A CN1053569C CN 1053569 C CN1053569 C CN 1053569C CN 90109756 A CN90109756 A CN 90109756A CN 90109756 A CN90109756 A CN 90109756A CN 1053569 C CN1053569 C CN 1053569C
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- Prior art keywords
- zinc
- gluconate
- alcohol
- solution
- alkaloid
- Prior art date
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- Expired - Fee Related
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- 229940102223 injectable solution Drugs 0.000 title description 5
- 238000004519 manufacturing process Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000011701 zinc Substances 0.000 claims abstract description 17
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 16
- TYGUTURXHKSOBP-UHFFFAOYSA-N 10-bromo-5,12-dihydroindolo[2,3-g]carbazole-2,3-diol Chemical compound C1=C(Br)C=C2NC3=C(C4=C(C=C(C(=C4)O)O)N4)C4=CC=C3C2=C1 TYGUTURXHKSOBP-UHFFFAOYSA-N 0.000 claims abstract description 12
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 claims abstract description 11
- 229940050410 gluconate Drugs 0.000 claims abstract description 11
- 229910052751 metal Inorganic materials 0.000 claims abstract description 10
- 239000002184 metal Substances 0.000 claims abstract description 10
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 150000005846 sugar alcohols Polymers 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 15
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 230000002421 anti-septic effect Effects 0.000 claims description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 8
- 229910052791 calcium Inorganic materials 0.000 claims description 8
- 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 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
- 229910052749 magnesium Inorganic materials 0.000 claims description 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- 229960003415 propylparaben Drugs 0.000 claims description 5
- 239000007853 buffer solution Substances 0.000 claims description 4
- 239000004227 calcium gluconate Substances 0.000 claims description 4
- 235000013927 calcium gluconate Nutrition 0.000 claims description 4
- 229960004494 calcium gluconate Drugs 0.000 claims description 4
- 210000000936 intestine Anatomy 0.000 claims description 4
- 210000002784 stomach Anatomy 0.000 claims description 4
- 229960002110 vincristine sulfate Drugs 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims description 3
- 229960001763 zinc sulfate Drugs 0.000 claims description 3
- 229910000368 zinc sulfate Inorganic materials 0.000 claims description 3
- WHMDKBIGKVEYHS-IYEMJOQQSA-L Zinc gluconate Chemical compound [Zn+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O WHMDKBIGKVEYHS-IYEMJOQQSA-L 0.000 claims description 2
- 239000001755 magnesium gluconate Substances 0.000 claims description 2
- 235000015778 magnesium gluconate Nutrition 0.000 claims description 2
- 229960003035 magnesium gluconate Drugs 0.000 claims description 2
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 claims description 2
- 229960004982 vinblastine sulfate Drugs 0.000 claims description 2
- 235000011478 zinc gluconate Nutrition 0.000 claims description 2
- 239000011670 zinc gluconate Substances 0.000 claims description 2
- 229960000306 zinc gluconate Drugs 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 14
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 abstract description 13
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 abstract description 11
- 229960003048 vinblastine Drugs 0.000 abstract description 6
- 229960004528 vincristine Drugs 0.000 abstract description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 abstract description 3
- 206010028980 Neoplasm Diseases 0.000 abstract 1
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- 238000002512 chemotherapy Methods 0.000 abstract 1
- 238000007911 parenteral administration Methods 0.000 abstract 1
- 239000003755 preservative agent Substances 0.000 abstract 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 19
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 8
- 239000011575 calcium Substances 0.000 description 8
- 229960005069 calcium Drugs 0.000 description 7
- 239000000470 constituent Substances 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- LPGWZGMPDKDHEP-HLTPFJCJSA-N Leurosine Chemical compound C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC LPGWZGMPDKDHEP-HLTPFJCJSA-N 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 239000003708 ampul Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 4
- 229940091250 magnesium supplement Drugs 0.000 description 4
- 239000001117 sulphuric acid Substances 0.000 description 4
- 235000011149 sulphuric acid Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- RZLVQBNCHSJZPX-UHFFFAOYSA-L zinc sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Zn+2].[O-]S([O-])(=O)=O RZLVQBNCHSJZPX-UHFFFAOYSA-L 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- ZKHFSIMBFARVHY-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;hydrochloride Chemical compound Cl.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O ZKHFSIMBFARVHY-BTVCFUMJSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- HIMNALZNLAOESZ-YHPRVSEPSA-L disodium;5-[[4-anilino-6-(2-hydroxyethylamino)-1,3,5-triazin-2-yl]amino]-2-[(e)-2-[4-[[4-anilino-6-(2-hydroxyethylamino)-1,3,5-triazin-2-yl]amino]-2-sulfonatophenyl]ethenyl]benzenesulfonate Chemical compound [Na+].[Na+].N=1C(NC=2C=C(C(\C=C\C=3C(=CC(NC=4N=C(NC=5C=CC=CC=5)N=C(NCCO)N=4)=CC=3)S([O-])(=O)=O)=CC=2)S([O-])(=O)=O)=NC(NCCO)=NC=1NC1=CC=CC=C1 HIMNALZNLAOESZ-YHPRVSEPSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940124508 injectable medicine Drugs 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- IAKLPCRFBAZVRW-XRDLMGPZSA-L magnesium;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanoate;hydrate Chemical compound O.[Mg+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O IAKLPCRFBAZVRW-XRDLMGPZSA-L 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 230000000771 oncological effect Effects 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical group 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- KDQAABAKXDWYSZ-JKDPCDLQSA-N vincaleukoblastine sulfate Chemical compound OS(O)(=O)=O.C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 KDQAABAKXDWYSZ-JKDPCDLQSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
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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
- A61K9/08—Solutions
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- 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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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本发明是有关新的不经肠胃道使用的稳定的含水药物组合物，主要含有双吲哚生物碱的可注射溶液。该组合物含有双吲哚生物碱的锌络合物、最好是长春新碱，长春花碱或5-去甲脱水长春碱以及二价金属葡萄糖酸盐和溶解在单元醇或多元醇中的防腐剂。
此外，本发明还有关制备上述组合物的一种方法。
本发明的组合物可用于癌的化学疗法双吲生物碱的不经肠胃道给药。
Description
本发明涉及新的不经肠胃道使用的稳定的含水药物组合物，特别是含有双吲哚生物碱，最好是长春新碱(下文中以VCR表示)，长春花碱(下文中以VBL表示)和5-去甲脱水长春花碱(下文中以5′-去甲VBL表示)的锌络合物的可注射的溶液。另外，本发明还涉及通过使用防腐剂制备这些组合物的一种方法。
已知双吲哚化合物、生物碱，无论是出自于天然来源的VCR和VBL还是近来人工合成的5′-去甲VBL，在抗肿瘤治疗中起着突出的作用。这些化合物以盐形式的各种药品(主要是硫酸盐或富马酸氢盐)分别被商售或描述。
还已知上述活性剂的注射剂在抗癌治疗中具有决定性作用。因此在八十年代对于各种可注射的药物形成的研究和开发占据了主导地位。在该领域中应该强调在美国专利说明书4,619,935中描述的注射剂，发明人摆脱了早期使用的冷冻干燥技术和配制的待吸入注射器中的组合物以水溶液形式装在一个安瓿中。
上述说明书中描述的溶液的组成部份包括把VCR或以后公开的(参阅例如匈牙利专利说明书191,538)VBL或长春碱酰胺，在有乙酸盐缓冲体存在的情况下以它们的硫酸盐形式溶解于水中，然后为得到稳定的肿瘤学组合物(stable oncological compo-Sition)需要将一种微生物学的稳定剂加入到该溶液中。早已众所周知的4-羟基苯甲酸甲酯或丙酯被用作为这样的稳定剂。存在于上述溶液中的一个重要成份是其水溶液中含有较高浓度(100mg/ml)的甘露醇。
然而，在那些有关识别不容置疑的先进特性的数据中只找到了少数几个表示真正稳定的数据。在上述的匈牙利专利说明书中，仅仅公布了在5℃贮藏了九个月之后只保留该VCR硫酸盐注射溶液94-99％的原始浓度。而对于VBl，发明人公布在12个月之后的稳定性为98.7-100％。
在九个月之后94％的稳定度不能认为是足够的，由于该可注射溶液含有较多数目的组分，因而上述溶液还存在其他缺点。众所周知，除了活性组份之外，总是希望把最必须的添加物，并以尽可能低的量加入到可注射的组合物中。
由于上述缺点的存在，所以在寻找另外的更理想的溶液。例如，在匈牙利专利说明书195,531中报道了这样一种溶液，该发明人通过稳定性数据的充份支持发现，该水溶液中可以通过双吲哚与某些二价金属，主要是锌(Zn2+)、钙(Ca2+)或镁(Mg2+)分别形成络合物，使双吲哚化合物的水溶液得到很好的稳定。络合物的存在通过极谱检验得到证实。由这种确实有说服力的工作所得到的产品被证明是足够稳定的，但是显示出它含有组分数量多的缺点，例如实例1的产品除了活性组份之外还含有8种组份。也就是说，一个由乙酸和乙酸钠组成的缓冲体系以及与早期溶液相类似，除了防腐剂之外还需要较高浓度的甘露醇。
在欧洲专利说明书0,243,278中公布的产品以同样的观点考虑也证明其具有缺点。按照这后一篇专利说明书，使用了以质量计0.1-2.2％的甘氨酸，含磷酸根离子的缓冲体系和各种防腐剂(在一些情况中甚至有6种组份)来制备稳定的双吲哚注射液。除了使用许多添加剂外，产品的稳定性能还是不够的。按照这篇专利说明书，在PH值为4.15时，该溶液即使经过2年仍然保持稳定。但是根据我们自己的重复测定，该产品在贮藏六个月之后含有未分解的活性组份的量仅为93-93.5％。
因此，本发明的目的是研制一种药物组合物及其制备方法，该组合物比至今已知的组合物更稳定。同时根据当今的要求含有辅助剂的数量最少浓度最小。
本发明是基于以下的认识：即在双吲哚的金属络合物中，锌的络合物显示最佳的稳定性能，因此我们的研制工作就是基于这一事实。
出乎意料地发现，在先前的溶液中在所有情况下均以高含量(约100mg/ml)存在的甘露醇不仅可以减少而且可以完全省去。也就是说，出乎意料地，可以通过将某些二价金属的葡萄糖盐酸分批地添加到上述生物碱-锌的络合物水溶液中来制备一种非常稳定的不需要特定的缓冲体系或甘露醇的含水注射液。
因此，本发明是关于一种用于不经肠胃道的含有双吲哚生物碱的药物组合物，其中包括有双吲哚生物碱盐的锌络合物，二价金属葡萄糖酸盐和溶解在一元醇或多元醇水溶液中的防腐剂。
本发明的组合物含有：
作为双吲哚生物碱的长春新碱、长春花碱或5′-去甲脱水长春花碱；
作为二价金属葡萄糖酸盐的钙、锌或镁的葡萄糖酸盐；
作为防腐剂的4-羟基苯甲酸甲酯和/或丙酯，以及
作为一元醇或多元醇的乙醇、正丙醇、异丙醇或乙二醇。
本发明的另一方面提供了一种制备含双吲哚生物碱的药物组合物的方法，该方法包括在水中溶解双吲哚生物碱盐，将它与硫酸锌水溶液混合，然后用二价金属葡萄糖酸盐的水溶液处理如此得到的生物碱-锌络合物并通过添加溶解在一元醇或多元醇中的防腐剂于所得到的水溶液中。
在本发明的方法中：
硫酸长春新碱，硫酸长春碱或5′去甲脱水长春碱作为双吲哚生物碱盐使用。
钙或镁或锌的葡萄糖酸盐作为二价金属葡萄糖酸盐使用；
乙醇、正丙醇、异丙醇或乙二醇作为一元醇或多元醇使用，以及
4-羟基苯甲酸甲酯和/或4-羟基苯甲酸丙酯作为防腐剂使用。
按本发明方法的优选实施方案，含VCR-锌络合物的水溶液是如下制备的：先制备一种含硫酸锌络液的浓度为1.0-1.5mg/ml的VCR硫酸盐溶液，然后加入二价金属葡萄糖酸盐，最好是锌、镁或钙的葡萄糖酸盐至上述溶液中，使其浓度达到1.5-2mg/ml。
按照本发明方法，含VBL锌或5′-去甲VBL-锌络合物的稳定水溶液可用上述方法同样制备。
本发明方法的最重要优点是利用简单的工艺过程在有少量添加剂存在的情况下，适于制备一种用于不经肠胃道的含双吲哚活性组份并具有至少24个月稳定期限的组合物。
稳定性数据的测定是用下文所述方法进行的：
按实施例制备的含双吲哚活性组份的注射液的稳定性是用高压液相色谱(HPLC)方法(参阅：pharmacopoea of the USA第XXI版，第1118页)核实的。 HPLC方法也用于长春花碱盐溶液的情况(参阅PHarmacopoea of the USA第XXI版、付刊、3，第2453页)。
对于VCR的HPLC法是如下进行的：用Nucleosil5μC8装柱(250×4.6mm)，流速为2.0ml/min，波长为297nm。洗提是用甲醇、水和二乙胺的混合物(PH7.5)进行的，保持时间约为7.0分。
对照外部标准测定活性组份的含量，即用具有与该注射液中硫酸长春新碱浓度相同而且其中的硫酸长春新碱来源相同的纯水溶液来测定该溶液。
用下述非限制性的实施例对本发明进行详细的说明。
实施例1
组 份 克硫酸VCR 0.10004-羟基苯甲酸甲酯 0.13004-羟基苯甲酸丙酯 0.0200硫酸锌七水化合物(ZnSO4·7H2O) 0.0375葡萄糖酸钙—水化物 0.1900乙醇(96％) 5.0000加入注射用水 直至 100ml然后在无菌条件下过滤至无菌，并分装到100个灭菌的安瓿中。
该组合物按下述步骤制备：
将上述量的硫酸VCR溶解在40ml水中并将溶解在5ml水中的硫酸锌加入。由此得到的锌络合物与溶解在30ml水中的葡萄糖酸钙混合，并将分别配制的4-羟基苯甲酸酯的乙醇溶液加入到上述溶液中，将得到的溶液用注射用蒸馏水添加到100ml，并在无菌条件下分装到安瓿中。
实施例2
组 份 克硫酸VBL 0.10004-羟基苯甲酸甲酯 0.13004-羟基苯甲酸丙酯 0.0200硫酸锌七水合物 0.0375葡萄糖酸钙—水合物 0.1900乙醇(96％) 5.0000加入注射用水 直至100ml
然后在无菌条件下过滤至无菌，并分装到容积为5ml的20个灭菌安瓿中。
按实施例1描述的步骤制备可注射溶液。实施例3
组 份 克5′-去甲-VBL酒石酸氢盐 0.50004-羟基苯甲酸甲酯 0.13004-羟基苯甲酸丙酯 0.0200硫酸锌七水合物 0.0400葡萄糖酸钙—水合物 0.2000乙 醇 5.000注射用蒸馏水加至 100ml按实施例1所述的方法制备该注射液。
实施例4
除了用0.1500克葡萄糖酸镁代替0.1900克葡萄糖酸钙之外，均与实施例1相同。
实施例5
除了用0.2500克葡萄糖酸锌代替0.1900克葡萄糖酸钙以外，均与实施例1相同。
实施例6
除了将得到的100ml灭菌溶液分装到容积为2ml的50个安瓿中以使每安瓿含VCR活性组份为2mg/2ml不同于实施例1外，其它均与实施例1相同。
实施例7
除了用硫酸VBL代替硫酸VCR和用异丙醇代替乙醇之外，均与实施例1相同。
实施例8
除了用乙二醇代替异丙醇之外，与实施例7相同。
实施例1所述组合物的稳定性试验贮藏的方式 活性组分含量(按起 杂质和时间 始浓度的百分数计) 合计 N-Deformyl-VCR 其他0 100,00 1,48 0,33 ＜2制冷器 97,80 2,82 1,29 ＜26个月制冷器 97,20 2,60 1,51 ＜29个月制冷器 96,80 3,12 1,81 ＜212个月室温3个月 93,16 5,43 3,04 ＜2(避光)室温3个月 89,40 6,85 3,17 ＞2(漫射光)3个月40℃ 80,90 12,40 7,12 ＞22个月50℃ 53,40 27,4 15,6 ＞2
实施例2所述组合物的稳定性试验贮藏的方式 活性组分含量(按起 杂 质和时间 始浓度的百分数计) 总 计0 100,00 1,27制冷器6个月 100,80 1,25制冷器9个月 98,5 1,22制冷器12个月 97,3 1,50制冷器24个月 97,1 1,62室温3个月 98,8 1,82室温6个月 95,8 2,36室温12个月 95,5 2,48室温3个月(漫射光) 99,0 2,053个月40℃ 92,7 5,123个月50℃ 69,7 15,60
Claims (3)
1.制备含有双吲哚生物碱的用于不经肠胃道的药物组合物的方法，其包括将双吲哚生物碱盐溶解在水中，用硫酸锌的水溶液与其混合，然后用二价金属葡萄糖酸盐的水溶液处理所得到的生物碱-锌络合物并在所得到的水溶液中加入溶解于单元醇或多元醇中的防腐剂，其中不需要特定的缓冲体系或甘露醇。
2.如权利要求1所述的方法，包括利用硫酸长春新碱或硫酸长春花碱作为双吲哚生物碱盐。
3.如权利要求1所述的方法，包括利用钙、镁或锌的葡萄糖酸盐作为二价金属的葡萄糖酸盐，利用乙醇、正丙醇、异丙醇或乙二醇作为单元醇或多元醇，利用4-羟基苯甲酸甲酯和/或4-羟基苯甲酸丙酯作为防腐剂。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4684638A (en) * | 1984-10-16 | 1987-08-04 | Richter Gedeon Vegyeszeti Gyar Rt. | Metal complexes of bis-indole compounds and aqueous pharmaceutical compositions containing them |
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