CN116583269A - 药物组合物 - Google Patents
药物组合物 Download PDFInfo
- Publication number
- CN116583269A CN116583269A CN202180085110.0A CN202180085110A CN116583269A CN 116583269 A CN116583269 A CN 116583269A CN 202180085110 A CN202180085110 A CN 202180085110A CN 116583269 A CN116583269 A CN 116583269A
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- China
- Prior art keywords
- amine
- hydroxy
- pharmaceutical composition
- compound
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 26
- 150000001412 amines Chemical class 0.000 claims abstract description 49
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- ZCGNOVWYSGBHAU-UHFFFAOYSA-N favipiravir Chemical compound NC(=O)C1=NC(F)=CNC1=O ZCGNOVWYSGBHAU-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000007864 aqueous solution Substances 0.000 claims description 17
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 12
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 10
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims description 10
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 10
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 10
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 10
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 10
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 10
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 10
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 10
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims description 9
- 229960004194 lidocaine Drugs 0.000 claims description 9
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 claims description 7
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- AKNUHUCEWALCOI-UHFFFAOYSA-N N-ethyldiethanolamine Chemical compound OCCN(CC)CCO AKNUHUCEWALCOI-UHFFFAOYSA-N 0.000 claims description 6
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 claims description 6
- 229940043276 diisopropanolamine Drugs 0.000 claims description 6
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 5
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 claims description 5
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 claims description 5
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 5
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 5
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 5
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 5
- SLINHMUFWFWBMU-UHFFFAOYSA-N Triisopropanolamine Chemical compound CC(O)CN(CC(C)O)CC(C)O SLINHMUFWFWBMU-UHFFFAOYSA-N 0.000 claims description 5
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 5
- 239000012964 benzotriazole Substances 0.000 claims description 5
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 claims description 5
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 claims description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 5
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 claims description 5
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 5
- 150000003536 tetrazoles Chemical class 0.000 claims description 5
- 150000003852 triazoles Chemical class 0.000 claims description 5
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 239000012973 diazabicyclooctane Substances 0.000 claims 2
- 229940126062 Compound A Drugs 0.000 description 17
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 17
- -1 optical Chemical class 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 14
- 239000000725 suspension Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 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 8
- 239000012669 liquid formulation Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 159000000000 sodium salts Chemical class 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 description 3
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 208000001528 Coronaviridae Infections Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229960003194 meglumine Drugs 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 2
- 229960004919 procaine Drugs 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- HOMROMWVNDUGRI-RVZXSAGBSA-N (2s)-2-aminopentanedioic acid;(2s)-2,6-diaminohexanoic acid Chemical compound NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CCC(O)=O HOMROMWVNDUGRI-RVZXSAGBSA-N 0.000 description 1
- AEQDJSLRWYMAQI-UHFFFAOYSA-N 2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 description 1
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 1
- IIFFFBSAXDNJHX-UHFFFAOYSA-N 2-methyl-n,n-bis(2-methylpropyl)propan-1-amine Chemical compound CC(C)CN(CC(C)C)CC(C)C IIFFFBSAXDNJHX-UHFFFAOYSA-N 0.000 description 1
- NJBCRXCAPCODGX-UHFFFAOYSA-N 2-methyl-n-(2-methylpropyl)propan-1-amine Chemical compound CC(C)CNCC(C)C NJBCRXCAPCODGX-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
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- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
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- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000004376 Sucralose Substances 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
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- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- GZCGUPFRVQAUEE-SLPGGIOYSA-N aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-SLPGGIOYSA-N 0.000 description 1
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- 230000000840 anti-viral effect Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
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- 229940043279 diisopropylamine Drugs 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
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- 235000012907 honey Nutrition 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
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- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
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- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
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- 229950008882 polysorbate Drugs 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 description 1
- 229940043349 potassium metabisulfite Drugs 0.000 description 1
- 235000010263 potassium metabisulphite Nutrition 0.000 description 1
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- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[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 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- VYGBQXDNOUHIBZ-UHFFFAOYSA-L sodium formaldehyde sulphoxylate Chemical compound [Na+].[Na+].O=C.[O-]S[O-] VYGBQXDNOUHIBZ-UHFFFAOYSA-L 0.000 description 1
- 239000000176 sodium gluconate Substances 0.000 description 1
- 235000012207 sodium gluconate Nutrition 0.000 description 1
- 229940005574 sodium gluconate Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229940048086 sodium pyrophosphate Drugs 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
- 229940001474 sodium thiosulfate Drugs 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 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
- 230000009385 viral infection Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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Classifications
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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Abstract
一种药物组合物，其含有成分(1)及(2)：(1)6‑氟‑3‑羟基‑2‑吡嗪羧酰胺或其盐、(2)指定的胺。
Description
本发明涉及包含6-氟-3-羟基-2-吡嗪羧酰胺(以下，也有时称为“化合物A”)及胺的药物组合物。
背景技术
化合物A或其盐具有优异的抗病毒活性，且作为病毒感染症的治疗剂有用(专利文献1)。已知化合物A对水的溶解度低，但化合物A的钠盐(专利文献2)及葡甲胺(meglumine)盐(专利文献3)溶解度比较高，作为注射用制剂有用。
此外，近年已清楚知悉化合物A对于新型冠状病毒感染症也有效。如依据非专利文献1，化合物A对新型冠状病毒感染症的给药量被设定合计18000mg(3600mg(1800mg BID)(第1天)+1600mg(800mg BID)(第2～10天)、10天间)。这成为对流行性感冒的给药量的合计8000mg(3200mg(1600mg BID)(第1天)+1200mg(600mg BID)(第2～5天))的2倍以上。
现有技术文献
专利文献
专利文献1：国际公开WO00/10569号小册
专利文献2：国际公开WO2012/043700号小册
专利文献3：国际公开WO2012/043696号小册
非专利文献
非专利文献1对COVID-19的药物治疗的看法，第6版，日本感染症学会，第5、6页
发明内容
发明要解决的课题
将化合物A用于新型冠状病毒感染症的治疗时，预期化合物A的给药量会增加。将化合物A作为注射用制剂或糖浆剂等的液剂而使用的情形，若可将化合物A的溶解度提高至化合物A的钠盐或葡甲胺盐以上(＝获得化合物A的高浓度水溶液)，则于制剂的保管空间及对患者的给药的观点上更为便利。本发明的课题可提供进一步提升化合物A的溶解度的药物组合物。
用于解决课题的手段
本发明人等为了解决上述课题而专心检讨的结果，发现通过组合化合物A与指定的胺，可提供解决上述课题的药物组合物，进而完成本发明。
以下表示本发明的一个方面。
＜1＞一种药物组合物，其为含有成分(1)及(2)的药物组合物：
(1)6-氟-3-羟基-2-吡嗪羧酰胺或其盐，
(2)胺，
其中胺选自通式[1]所表示的胺、通式[2]所表示的胺、通式[3]所表示的胺、DABCO、利多卡因(lidocaine)、吡咯、吡啶、咪唑、吡唑、噁唑、噻唑、咪唑啉、噻嗪、三唑、四唑、哒嗪、嘧啶、吡嗪、吲哚、异吲哚、苯并咪唑、嘌呤、苯并三唑、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉、喋啶、蒽、及咔唑：
【化1】
(式中，R1表示可被羟基或硫醇基取代的C3～6烷基)，
【化2】
(式中，R2及R3相同或不同，表示可被羟基或硫醇基取代的C1～5烷基，R4表示氢原子、或可被羟基或硫醇基取代的C1～5烷基)、
【化3】
(式中，R5表示氢原子、或可被羟基或硫醇基取代的C1～5烷基，R6及R7相同或不同，表示可被羟基或硫醇基取代的C1～5亚烷基，Y表示键结键、氧原子、硫原子、或NH)。
＜2＞如＜1＞记载的药物组合物，其中胺选自下述的化合物群组：由异丙基胺、丙醇胺、二乙醇胺、二异丙醇胺、三异丙醇胺、三乙醇胺、乙基二乙醇胺、三乙基胺、Bis-Tris、DABCO、利多卡因、吡咯、吡啶、咪唑、吡唑、噁唑、噻唑、咪唑啉、噻嗪、三唑、四唑、哒嗪、嘧啶、吡嗪、吲哚、异吲哚、苯并咪唑、嘌呤、苯并三唑、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉、喋啶、蒽、及咔唑组成的化合物群组。
＜3＞如＜1＞或＜2＞记载的药物组合物，其中相对于6-氟-3-羟基-2-吡嗪羧酰胺或其盐，含有胺0.2当量以上。
＜4＞如＜1＞～＜3＞中任一项记载的药物组合物，其进一步含有成分(3)，且为水溶液：
(3)水。
＜5＞如＜4＞记载的药物组合物，其中6-氟-3-羟基-2-吡嗪羧酰胺或其盐的浓度为100mg/mL以上。
＜6＞如＜1＞～＜3＞中任一项记载的药物组合物，其为冷冻干燥制剂。
发明的效果
如依据本发明，则可提供能够在水中以高浓度含有化合物A的药物组合物。
具体实施方式
在本说明书中使用“～”所表示的数值范围意指将“～”的前后所记载的数值分别作为最小值及最大值所包含的范围。在一个方面中，在最小值及最大值的任一者或两者中，也可排除该值本身(即，“x以上”可替换成“超过x”，及“x以下”可替换成“小于x”)。
在本说明书中，组合物中的各成分的量，在符合各成分的物质在组合物中存在多种的情形时，若未特别指明，则意指存在于组合物中的多种物质的合计量。
在本说明书中，若未特别指明，则各用语具有下列意义。
C3～6烷基意指例如，丙基、异丙基、丁基、仲丁基、异丁基、叔丁基、戊基、异戊基、己基等的直链状或分枝链状的碳原子数3～6的烷基。
C1～5烷基意指例如，甲基、乙基、丙基、异丙基、丁基、仲丁基、异丁基、叔丁基、戊基、异戊基等的直链状或分枝链状的碳原子数1～5的烷基。
＜化合物A＞
在本发明中，使用化合物A(6-氟-3-羟基-2-吡嗪羧酰胺)或其盐作为有效成分。盐若为药学上可容许的盐即可，优选为钠盐或葡甲胺盐。
在化合物A中存在异构物(例如，光学异构物、几何异构物及互变异构物等)的情形，本发明包含那些全部的异构物，又包含水合物、溶剂合物及全部的结晶形。
＜胺＞
本发明中所使用的胺，若为可通过与化合物A组合而使化合物A对水的溶解度提升(＝有作为增溶剂的功能)的胺即可。溶解度的提升程度并未特别限定，但优选为与化合物A的钠盐及葡甲胺盐比较而使化合物A对水的溶解度提升1.4倍以上的胺，更优选为使提升2倍以上的胺，进一步优选为使提升2.5倍以上的胺。胺可混合一种或二种以上使用。胺也可与氢氧化钠等的无机碱、葡甲胺等的胺基糖组合而使用。
胺的结构虽未特别限定，但优选为通式[1]所示的胺。在通式[1]所示的胺中，R1优选为丙基、异丙基、2-羟基丙基、3-羟基丙基、仲丁基、异丁基、或叔丁基，更优选为2-羟基丙基或异丙基。R1在被羟基或硫醇基取代的情形时，取代基优选为一个。
作为其它方面，胺优选为通式[2]所示的胺。
对于通式[2]所示的胺，
R2及R3相同或相异，优选为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、1-羟基乙基、2-羟基乙基、1-羟基丙基、2-羟基丙基、3-羟基丙基、或三(羟基甲基)甲基，更优选为乙基、2-羟基乙基、2-羟基丙基、或三(羟基甲基)甲基；
R4优选为氢原子、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、1-羟基乙基、2-羟基乙基、1-羟基丙基、2-羟基丙基、3-羟基丙基、或三(羟基甲基)甲基，更优选为氢原子、乙基、2-羟基乙基、或三(羟基甲基)甲基。
R2、R3、或R4在被羟基或硫醇基取代的情形时，取代基优选为对各烷基有一个。
作为通式[2]所示的胺，优选为二乙基胺、二丙基胺、二异丙基胺、二丁基胺、二异丁基胺、二(叔丁基)胺、三甲基胺、三乙基胺、三丙基胺、三异丙基胺、三丁基胺、三异丁基胺、三(叔丁基)胺、二乙醇胺、二异丙醇胺、三异丙醇胺、三乙醇胺、甲基二乙醇胺、乙基二乙醇胺、或双(2-羟基乙基)亚胺基三(羟基甲基)甲烷(Bis-Tris)，更优选为三乙基胺、二乙醇胺、二异丙醇胺、三乙醇胺、乙基二乙醇胺、或Bis-Tris。
作为其它方面，胺优选为通式[3]所示的胺。在通式[3]所示的胺中，R5优选为氢原子、甲基、乙基、或羟基甲基，更优选为氢原子；
R6及R7相同或相异，优选为亚甲基、亚乙基、或亚丙基，更优选为亚乙基；
Y优选为键结键、氧原子、或NH。
作为通式[3]所示的胺，优选为吡咯啶、哌啶、哌嗪或吗啉。
作为其它方面，胺优选为异丙基胺、丙醇胺、二乙醇胺、二异丙醇胺、三异丙醇胺、三乙醇胺、乙基二乙醇胺、三乙基胺、Bis-Tris、1,4-二氮杂双环[2.2.2]辛烷(DABCO)、利多卡因、吡咯、吡啶、咪唑、吡唑、噁唑、噻唑、咪唑啉、噻嗪、三唑、四唑、哒嗪、嘧啶、吡嗪、吲哚、异吲哚、苯并咪唑、嘌呤、苯并三唑、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉、喋啶、蒽、及咔唑。
胺的使用量若为使化合物A对水的溶解度提升的量则未特别限定，但相对于化合物A，优选为0.2当量以上，更优选为0.2～10当量，进一步优选为0.3～5当量，更进一步优选为0.4～2当量，特别优选为0.5～1当量。
胺通过本身公知的方法或适当组合那些方法而制造，或使用市售者即可。
＜水＞
本发明中所使用的水若为适合药物组合物的制造则未特别限定，但优选为纯水、与纯水同等以上等级的水、或注射用水。
＜药物组合物＞
本发明的药物组合物，除了将化合物A或其盐与胺一起溶解于水而成的组合物(＝液剂)以外，也包含将该液剂冷冻干燥而成的组合物(＝冷冻干燥制剂)。液剂、冷冻干燥制剂任一者都可作为注射用制剂、糖浆剂等使用。液剂的情形，化合物A的浓度优选为100mg/mL以上，更优选为200mg/mL以上。
[液剂的制造方法]
步骤(1)：
将化合物A或其盐与胺一起溶解于水，调制化合物A的水溶液。“与胺一起”是指可将化合物A与胺同时地加到水中，也可先将任一成分加到水中后再添加剩余的成分。
步骤(2)：
将步骤(1)所获得的水溶液填充至制剂容器(例如，小瓶)后，进行封栓，获得液剂。步骤(1)与步骤(2)也可同时地进行。即，也可于制剂容器内直接调制化合物A的水溶液而获得液剂。
[冷冻干燥制剂的制造方法]
步骤(1)：
将化合物A或其盐与胺一起溶解于水中，调制化合物A的水溶液。“与胺一起”是指可将化合物A与胺同时地添加至水中，也可先将任一成分添加至水中后再添加剩余的成分。
步骤(2)：
将步骤(1)所获得的水溶液填充至制剂容器(例如，小瓶)。步骤(1)与步骤(2)也可同时地进行。即，可于制剂容器内直接调制化合物A的水溶液。
步骤(3)：
按照通常实施的冷冻干燥的方法，使步骤(1)所获得的水溶液冷冻干燥。步骤(2)与步骤(3)的顺序未限定。即，如以下：
在步骤(2)之后步骤(3)：
将步骤(2)中填充于制剂容器的水溶液，以步骤(3)冷冻干燥。
在步骤(3)之后步骤(2)：
将步骤(1)所获得的水溶液以步骤(3)冷冻干燥后，将冷冻干燥体以步骤(2)填充于制剂容器。
步骤(4)：
将步骤(2)及(3)所获得的填充于制剂容器的冷冻干燥体进行封栓，获得冷冻干燥制剂。
药物组合物的给药
本发明的药物组合物的给药方法、给药量及给药次数可根据患者的年龄、体重及症状而适当选择，但通常，可将能发挥药效的量，1日1次至分成数次注射到肌肉内或静脉内，也也可以经口给药。
＜其它添加物＞
本发明的药物组合物也可根据需要添加通常使用的渗透压调节剂、pH调节剂、缓冲剂、稳定化剂、表面活性剂、镇痛剂、甜味料及/或防腐剂等。
就渗透压调节剂而言，可列举氯化钠、甘油及丙二醇等。
就pH调节剂及/或缓冲剂而言，可列举盐酸、磷酸、硫酸、甲烷磺酸、乙酸、乳酸、马来酸、柠檬酸、酒石酸、抗坏血酸及苯甲酸等的酸；碳酸氢钠、碳酸钠、磷酸二氢钠、磷酸二氢钾、磷酸氢二钠、磷酸氢二钾、磷酸三钠、柠檬酸二钠、脱氧胆酸钠及亚硫酸钠等的盐；氢氧化钠、三羟甲基氨基甲烷、一乙醇胺、二乙醇胺、三乙醇胺、L-精氨酸及L-赖氨酸等的碱。
就稳定化剂而言，可列举亚硫酸氢钠、焦亚硫酸钠、焦亚硫酸钾、焦磷酸钠、硫代硫酸钠、间磺基苯甲酸钠、甲醛次硫酸氢钠(formaldehyde sulfoxylate sodium)、乙二胺、乙二胺四乙酸钠、巯基乙酸、葡萄糖酸钠、L-谷氨酸钾、L-赖氨酸-L-谷氨酸盐、硫酸软骨素钠盐、白蛋白、L-天冬氨酸、L-半胱氨酸及二丁基羟基甲苯等。
就表面活性剂而言，可列举山梨糖醇酐脂肪酸酯、聚氧乙烯硬化蓖麻油、聚氧乙烯山梨糖醇酐单月桂酸酯、聚氧乙烯聚氧丙烯二醇及聚山梨酯等。
就镇痛剂而言，可列举利多卡因、普鲁卡因(procaine)、美普卡因(meprylcaine)及苯甲醇等。
就防腐剂而言，可列举甲酚、酚、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、氯苯扎氯铵及苄索氯铵等。
就甜味料而言，可列举果糖、葡萄糖、液体糖、蜂蜜、赤藻糖醇、木糖醇、糖精、蔗糖素、阿斯巴甜及安塞蜜钾等。
实施例
通过以下的试验例及实施例进一步详细说明本发明，但本发明并不被限制于此等。
试验例1溶解度
为了考察胺的增溶效果，而使化合物A悬浮于水，添加相对于化合物为1当量的胺或其水溶液，在室温搅拌2小时以上。接着，以孔径0.45μm的过滤器过滤，测定滤液的药物浓度。将结果示于表1。此外，在实施例1、3、4、5、7、10、11中，化合物A完全溶解。
[表1]
实施例1
向1500mg化合物A的水2.49mL悬浮液中，添加二乙醇胺的40％(w/w)水溶液2.51g，以试验例1所示的方法测定溶解度。
实施例2
向500mg化合物A的水0.29mL悬浮液中，添加三乙醇胺的40％(w/w)水溶液1.21g，以试验例1所示的方法测定溶解度。
实施例3
向1500mg化合物A的水1.82mL悬浮液中，添加二异丙醇胺的40％(w/w)水溶液3.18g，以试验例1所示的方法测定溶解度。
实施例4
向1500mg化合物A的水1.82mL悬浮液中，添加N-乙基二乙醇胺的40％(w/w)水溶液3.18g，以试验例1所示的方法测定溶解度。
实施例5
向1500mg化合物A的水4.03mL悬浮液中，添加0.97g的三乙基胺，以试验例1所示的方法测定溶解度。
实施例6
向500mg化合物A的水1.5mL悬浮液中，添加0.62g的三异丙醇胺，以试验例1所示的方法测定溶解度。
实施例7
向500mg化合物A的水1.5mL悬浮液中，添加0.36g的DABCO，以试验例1所示的方法测定溶解度。
实施例8
向500mg化合物A的水1.5mL悬浮液中，添加0.76g的利多卡因，以试验例1所示的方法测定溶解度。
实施例9
向500mg化合物A的水1.5mL悬浮液中，添加0.68g的Bis-Tris，以试验例1所示的方法测定溶解度。
实施例10
向500mg化合物A的水1.5mL悬浮液中，添加0.24g的丙醇胺，以试验例1所示的方法测定溶解度。
实施例11
向500mg化合物A的水1.5mL悬浮液中，添加0.28mL的异丙基胺，以试验例1所示的方法测定溶解度。
比较例1
向500mg化合物A的水4mL悬浮液中，添加0.13g的氢氧化钠，以试验例1所示的方法测定溶解度。
比较例2
向500mg化合物A的水4mL悬浮液中，添加0.64g的葡甲胺，以试验例1所示的方法测定溶解度。
显示与钠盐(比较例1)或葡甲胺盐(比较例2)比较，任一实施例都进一步提高化合物A对水的溶解度。特别是实施例2的三乙醇胺，即使为0.5当量也显示与比较例同等以上的优异溶解度。
Claims (6)
1.一种药物组合物，含有成分(1)及(2)的药物组合物：
(1)6-氟-3-羟基-2-吡嗪羧酰胺或其盐、
(2)胺，
其中，胺选自通式[1]所表示的胺、通式[2]所表示的胺、通式[3]所表示的胺、DABCO、利多卡因(lidocaine)、吡咯、吡啶、咪唑、吡唑、噁唑、噻唑、咪唑啉、噻嗪、三唑、四唑、哒嗪、嘧啶、吡嗪、吲哚、异吲哚、苯并咪唑、嘌呤、苯并三唑、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉、喋啶、蒽、及咔唑，
【化1】
式中，R1表示可被羟基或硫醇基取代的C3～6烷基，
【化2】
式中，R2及R3相同或不同，表示可被羟基或硫醇基取代的C1～5烷基，R4表示氢原子、或可被羟基或硫醇基取代的C1～5烷基，
【化3】
式中，R5表示氢原子、或可被羟基或硫醇基取代的C1～5烷基，R6及R7相同或不同，表示可被羟基或硫醇基取代的C1～5亚烷基，Y表示键结键、氧原子、硫原子、或NH。
2.如权利要求1的药物组合物，其中胺选自下述的化合物群组：
由异丙基胺、丙醇胺、二乙醇胺、二异丙醇胺、三异丙醇胺、三乙醇胺、乙基二乙醇胺、三乙基胺、Bis-Tris、DABCO、利多卡因、吡咯、吡啶、咪唑、吡唑、噁唑、噻唑、咪唑啉、噻嗪、三唑、四唑、哒嗪、嘧啶、吡嗪、吲哚、异吲哚、苯并咪唑、嘌呤、苯并三唑、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉、喋啶、蒽、及咔唑组成的化合物群组。
3.如权利要求1或2的药物组合物，其中相对于6-氟-3-羟基-2-吡嗪羧酰胺或其盐，含有胺0.2当量以上。
4.如权利要求1至3中任一项的药物组合物，其进一步含有成分(3)，且为水溶液，
(3)水。
5.如权利要求4的药物组合物，其中6-氟-3-羟基-2-吡嗪羧酰胺或其盐的浓度为100mg/mL以上。
6.如权利要求1至3中任一项的药物组合物，其为冷冻干燥制剂。
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| JP3659801B2 (ja) * | 1998-04-21 | 2005-06-15 | キッセイ薬品工業株式会社 | トラニラスト水溶液製剤 |
| KR100585240B1 (ko) | 1998-08-20 | 2006-06-01 | 토야마 케미칼 컴퍼니 리미티드 | 질소함유 복소환 카르복사미드 유도체 또는 그 염 및 이를함유하는 항바이러스제 |
| JP2007119422A (ja) * | 2005-10-31 | 2007-05-17 | Santen Pharmaceut Co Ltd | 合成樹脂成形物に吸着しやすい薬物の吸着抑制方法 |
| JP2009143922A (ja) * | 2007-11-22 | 2009-07-02 | Fujiyakuhin Co Ltd | 注射剤 |
| CN103209966B (zh) | 2010-09-30 | 2015-06-10 | 富山化学工业株式会社 | 6-氟-3-羟基-2-吡嗪甲酰胺的钠盐 |
| SI2623497T1 (sl) | 2010-09-30 | 2016-04-29 | Toyama Chemical Co., Ltd. | Megluminska sol 6-fluoro-3-hidroksi-2-pirazinkarboksamida |
| WO2018003946A1 (ja) * | 2016-06-30 | 2018-01-04 | 富山化学工業株式会社 | 凍結乾燥製剤の製造方法 |
| BR112020009101A2 (pt) * | 2017-12-28 | 2020-10-20 | Fujifilm Toyama Chemical Co., Ltd. | método para produção de formulação congelada |
-
2021
- 2021-12-09 CN CN202180085110.0A patent/CN116583269A/zh active Pending
- 2021-12-09 WO PCT/JP2021/045265 patent/WO2022131112A1/ja active Application Filing
- 2021-12-09 US US18/256,603 patent/US20240041867A1/en active Pending
- 2021-12-09 JP JP2022569919A patent/JPWO2022131112A1/ja active Pending
- 2021-12-09 EP EP21906475.5A patent/EP4265252A1/en active Pending
- 2021-12-17 TW TW110147371A patent/TW202241432A/zh unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP4265252A1 (en) | 2023-10-25 |
| TW202241432A (zh) | 2022-11-01 |
| US20240041867A1 (en) | 2024-02-08 |
| JPWO2022131112A1 (zh) | 2022-06-23 |
| WO2022131112A1 (ja) | 2022-06-23 |
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