JP4834553B2 - 医薬組成物 - Google Patents
医薬組成物 Download PDFInfo
- Publication number
- JP4834553B2 JP4834553B2 JP2006535174A JP2006535174A JP4834553B2 JP 4834553 B2 JP4834553 B2 JP 4834553B2 JP 2006535174 A JP2006535174 A JP 2006535174A JP 2006535174 A JP2006535174 A JP 2006535174A JP 4834553 B2 JP4834553 B2 JP 4834553B2
- Authority
- JP
- Japan
- Prior art keywords
- chloro
- methoxy
- cyclopropylaminocarbonyl
- aminophenoxy
- quinolinecarboxamide
- 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.)
- Active
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 67
- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 claims abstract description 59
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 43
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims abstract description 40
- 239000012453 solvate Substances 0.000 claims abstract description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 239000007864 aqueous solution Substances 0.000 claims abstract description 15
- 238000001879 gelation Methods 0.000 claims abstract description 14
- 239000007900 aqueous suspension Substances 0.000 claims abstract description 9
- 239000013078 crystal Substances 0.000 claims description 173
- 239000002904 solvent Substances 0.000 claims description 105
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 87
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 80
- 238000004519 manufacturing process Methods 0.000 claims description 46
- -1 cyclopropylaminocarbonyl Chemical group 0.000 claims description 41
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 24
- 239000000395 magnesium oxide Substances 0.000 claims description 20
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 20
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical group [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 claims description 9
- 239000000378 calcium silicate Substances 0.000 claims description 8
- 229910052918 calcium silicate Inorganic materials 0.000 claims description 8
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 8
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 8
- HWLFIUUAYLEFCT-UHFFFAOYSA-N lenvatinib mesylate Chemical compound CS(O)(=O)=O.C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 HWLFIUUAYLEFCT-UHFFFAOYSA-N 0.000 claims description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- NGHMEZWZOZEZOH-UHFFFAOYSA-N silicic acid;hydrate Chemical compound O.O[Si](O)(O)O NGHMEZWZOZEZOH-UHFFFAOYSA-N 0.000 claims description 6
- 239000001509 sodium citrate Substances 0.000 claims description 6
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- PGXWDLGWMQIXDT-UHFFFAOYSA-N methylsulfinylmethane;hydrate Chemical compound O.CS(C)=O PGXWDLGWMQIXDT-UHFFFAOYSA-N 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 claims description 4
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 4
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000292 calcium oxide Substances 0.000 claims description 4
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims description 3
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 claims description 3
- PGZIKUPSQINGKT-UHFFFAOYSA-N dialuminum;dioxido(oxo)silane Chemical compound [Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O PGZIKUPSQINGKT-UHFFFAOYSA-N 0.000 claims description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000391 magnesium silicate Substances 0.000 claims description 3
- 229910052919 magnesium silicate Inorganic materials 0.000 claims description 3
- 235000019792 magnesium silicate Nutrition 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- QRQWKDUXMMGRMK-UHFFFAOYSA-N 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide;hydrochloride Chemical group Cl.C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 QRQWKDUXMMGRMK-UHFFFAOYSA-N 0.000 claims description 2
- ZOSJSDBLOUPRDS-UHFFFAOYSA-N acetic acid 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonic acid Chemical compound C(C)(=O)O.CS(=O)(=O)O.ClC=1C=C(OC2=CC=NC3=CC(=C(C=C23)C(=O)N)OC)C=CC1NC(=O)NC1CC1 ZOSJSDBLOUPRDS-UHFFFAOYSA-N 0.000 claims description 2
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 claims description 2
- 238000003860 storage Methods 0.000 abstract description 18
- 238000000354 decomposition reaction Methods 0.000 abstract description 13
- 230000002829 reductive effect Effects 0.000 abstract description 4
- 239000004480 active ingredient Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 80
- 239000003814 drug Substances 0.000 description 55
- 229940079593 drug Drugs 0.000 description 50
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 45
- 238000010438 heat treatment Methods 0.000 description 42
- 239000000047 product Substances 0.000 description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
- 239000008187 granular material Substances 0.000 description 37
- 239000000758 substrate Substances 0.000 description 36
- 238000002156 mixing Methods 0.000 description 33
- 239000000546 pharmaceutical excipient Substances 0.000 description 32
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 29
- 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 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 27
- 239000011230 binding agent Substances 0.000 description 27
- 150000003857 carboxamides Chemical class 0.000 description 27
- 229920002785 Croscarmellose sodium Polymers 0.000 description 26
- 229960001681 croscarmellose sodium Drugs 0.000 description 26
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 26
- 239000000203 mixture Substances 0.000 description 26
- 229910002012 Aerosil® Inorganic materials 0.000 description 22
- 239000007884 disintegrant Substances 0.000 description 22
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 22
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 22
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 239000000314 lubricant Substances 0.000 description 19
- 239000003381 stabilizer Substances 0.000 description 19
- 229920003114 HPC-L Polymers 0.000 description 18
- 239000003795 chemical substances by application Substances 0.000 description 18
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 18
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 18
- 229920002678 cellulose Polymers 0.000 description 16
- 239000001913 cellulose Substances 0.000 description 16
- 235000010980 cellulose Nutrition 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 235000010355 mannitol Nutrition 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 13
- 239000004615 ingredient Substances 0.000 description 13
- QVPZNUIZEVRITP-UHFFFAOYSA-N 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea Chemical compound ClC1=CC(O)=CC=C1NC(=O)NC1CC1 QVPZNUIZEVRITP-UHFFFAOYSA-N 0.000 description 12
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 12
- 229940011051 isopropyl acetate Drugs 0.000 description 12
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000010521 absorption reaction Methods 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 11
- 238000001816 cooling Methods 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 235000019700 dicalcium phosphate Nutrition 0.000 description 9
- 238000010828 elution Methods 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 238000010583 slow cooling Methods 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 8
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 8
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 229920000881 Modified starch Polymers 0.000 description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- ZBTVNIDMGKZSGC-UHFFFAOYSA-N 4-chloro-7-methoxyquinoline-6-carboxamide Chemical compound C1=CC(Cl)=C2C=C(C(N)=O)C(OC)=CC2=N1 ZBTVNIDMGKZSGC-UHFFFAOYSA-N 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 238000007922 dissolution test Methods 0.000 description 6
- 239000003349 gelling agent Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 6
- 230000001629 suppression Effects 0.000 description 6
- 239000000654 additive Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- BROQXILFDWZSAC-UHFFFAOYSA-N 1,2-dimethylimidazolidine Chemical compound CC1NCCN1C BROQXILFDWZSAC-UHFFFAOYSA-N 0.000 description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 239000012296 anti-solvent Substances 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- RJCOXHKWGVCJNS-UHFFFAOYSA-N 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide;ethanesulfonic acid Chemical compound CCS(O)(=O)=O.C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 RJCOXHKWGVCJNS-UHFFFAOYSA-N 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 3
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 3
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 3
- 239000002870 angiogenesis inducing agent Substances 0.000 description 3
- 239000004037 angiogenesis inhibitor Substances 0.000 description 3
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 229950008138 carmellose Drugs 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 229960000913 crospovidone Drugs 0.000 description 3
- 239000007857 degradation product Substances 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- JEIPFZHSYJVQDO-UHFFFAOYSA-N ferric oxide Chemical compound O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000007951 isotonicity adjuster Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000004570 mortar (masonry) Substances 0.000 description 3
- 229940068196 placebo Drugs 0.000 description 3
- 239000000902 placebo Substances 0.000 description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 229940033134 talc Drugs 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- DZDLGOCEYWMNEI-UHFFFAOYSA-N CS(=O)C.C(C)S(=O)(=O)O Chemical compound CS(=O)C.C(C)S(=O)(=O)O DZDLGOCEYWMNEI-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 235000006679 Mentha X verticillata Nutrition 0.000 description 2
- 235000002899 Mentha suaveolens Nutrition 0.000 description 2
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 229940014259 gelatin Drugs 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229960003511 macrogol Drugs 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 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
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- LBDLNHLYEKFAHH-UHFFFAOYSA-N phenyl n-(2-chloro-4-hydroxyphenyl)carbamate Chemical compound ClC1=CC(O)=CC=C1NC(=O)OC1=CC=CC=C1 LBDLNHLYEKFAHH-UHFFFAOYSA-N 0.000 description 2
- 229960005235 piperonyl butoxide Drugs 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000009492 tablet coating Methods 0.000 description 2
- 239000002700 tablet coating Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 2
- 210000003556 vascular endothelial cell Anatomy 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- YGZFYDFBHIDIBH-UHFFFAOYSA-N 2-[bis(2-hydroxyethyl)amino]icosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCC(CO)N(CCO)CCO YGZFYDFBHIDIBH-UHFFFAOYSA-N 0.000 description 1
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 1
- AEDQNOLIADXSBB-UHFFFAOYSA-N 3-(dodecylazaniumyl)propanoate Chemical compound CCCCCCCCCCCCNCCC(O)=O AEDQNOLIADXSBB-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- PNLPXABQLXSICH-UHFFFAOYSA-N 4-amino-3-chlorophenol Chemical compound NC1=CC=C(O)C=C1Cl PNLPXABQLXSICH-UHFFFAOYSA-N 0.000 description 1
- RTQLMSZMCBAZIX-UHFFFAOYSA-N 4-methylbenzenesulfonic acid;sulfuric acid Chemical compound OS(O)(=O)=O.CC1=CC=C(S(O)(=O)=O)C=C1 RTQLMSZMCBAZIX-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 229920001817 Agar Polymers 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
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 1
- WCFDYIBIWZOOIH-UHFFFAOYSA-N COc(cc(c1c2)N=CCC1O)c2C(N)=O Chemical compound COc(cc(c1c2)N=CCC1O)c2C(N)=O WCFDYIBIWZOOIH-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 244000223760 Cinnamomum zeylanicum Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 description 1
- 239000004287 Dehydroacetic acid Substances 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- ZPJXNCMFTWDDEL-UHFFFAOYSA-N O.CS(=O)(=O)O.ClC=1C=C(OC2=CC=NC3=CC(=C(C=C23)C(=O)N)OC)C=CC1NC(=O)NC1CC1 Chemical compound O.CS(=O)(=O)O.ClC=1C=C(OC2=CC=NC3=CC(=C(C=C23)C(=O)N)OC)C=CC1NC(=O)NC1CC1 ZPJXNCMFTWDDEL-UHFFFAOYSA-N 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 108091005682 Receptor kinases Proteins 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- ZXPJBQLFCRVBDR-UHFFFAOYSA-N acetic acid;methanesulfonic acid Chemical compound CC(O)=O.CS(O)(=O)=O ZXPJBQLFCRVBDR-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000002257 antimetastatic agent Substances 0.000 description 1
- 230000003078 antioxidant 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
- 208000006673 asthma Diseases 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 235000013734 beta-carotene Nutrition 0.000 description 1
- 239000011648 beta-carotene Substances 0.000 description 1
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 description 1
- 229960002747 betacarotene Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
- 239000001354 calcium citrate Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000013736 caramel Nutrition 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 235000012730 carminic acid Nutrition 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 235000017803 cinnamon Nutrition 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 235000019258 dehydroacetic acid Nutrition 0.000 description 1
- 229940061632 dehydroacetic acid Drugs 0.000 description 1
- JEQRBTDTEKWZBW-UHFFFAOYSA-N dehydroacetic acid Chemical compound CC(=O)C1=C(O)OC(C)=CC1=O JEQRBTDTEKWZBW-UHFFFAOYSA-N 0.000 description 1
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- FVTCRASFADXXNN-SCRDCRAPSA-N flavin mononucleotide Chemical compound OP(=O)(O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O FVTCRASFADXXNN-SCRDCRAPSA-N 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 229960003681 gluconolactone Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229940031705 hydroxypropyl methylcellulose 2910 Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 208000000516 mast-cell leukemia Diseases 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229960000292 pectin Drugs 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- BNMGPDZKAHVEQH-UHFFFAOYSA-N phenyl n-[4-(6-carbamoyl-7-methoxyquinolin-4-yl)oxy-2-chlorophenyl]carbamate Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)OC1=CC=CC=C1 BNMGPDZKAHVEQH-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004263 retinal angiogenesis Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229950001574 riboflavin phosphate Drugs 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 239000002893 slag Substances 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 229960005196 titanium dioxide Drugs 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 208000027930 type IV hypersensitivity disease Diseases 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Description
(i)5%(W/W)水溶液または懸濁液のpHが8以上となる化合物、および/または
(ii)ケイ酸もしくはその塩またはそれらの溶媒和物
とを含有する医薬組成物。
本発明の医薬組成物は、式(1)で表される化合物もしくはその塩またはそれらの溶媒和物を薬効成分として含む。式(1)で表される薬効成分は、以下に述べる多形結晶(A’)または多形結晶(B’)であってもよい。
式(1)で表される化合物の製造方法は、国際公開 WO 02/32872号 パンフレットの記載を参照できる。多形結晶(A’)および多形結晶(B’)については以下のとおりである。
本発明の医薬組成物は、上述した式(1)で表される化合物もしくはその塩またはそれらの溶媒和物からなる薬効成分の他に、
(i)5%(W/W)水溶液または懸濁液のpHが8以上となる化合物、および/または
(ii)ケイ酸もしくはその塩またはそれらの溶媒和物
を含有するものである。
(製造例1) 4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドの製造(1)
国際公開第02/32872号パンフレットに記載の、フェニル N−(4−(6−カルバモイル−7−メトキシ−4−キノリル)オキシ−2−クロロフェニル)カルバメート(17.5g、37.7mmol)をN,N−ジメチルホルムアミド(350mL)に溶解し、窒素雰囲気下にて反応液にシクロプロピルアミン(6.53mL、94.25mmol)を加え、室温で一晩攪拌した。反応液を水(1.75L)に加え、攪拌した。析出した粗結晶を濾取して、水洗後、70℃で50分間乾燥した。得られた粗結晶にエタノール(300mL)を加え、約30分間加熱還流して溶解させ、その後、攪拌下にて一晩かけて室温まで徐冷した。析出した結晶を濾取した後、吸引乾燥し、さらに70℃で8時間乾燥して、標記結晶(12.91g、80.2%)を得た。
(1)フェニル N−(2−クロロ−4−ヒドロキシフェニル)カーバメートの製造
1H-NMR Spectrum (CDCl3)δ(ppm): 5.12 (1h, br s), 6.75 (1H, dd, J=9.2, 2.8 Hz), 6.92 (1H, d, J=2.8 Hz), 7.18-7.28 (4H, m), 7.37-7.43 (2H, m), 7.94 (1H, br s)
1H-NMR Spectrum (CDCl3)δ(ppm): 0.72-0.77 (2H, m), 0.87-0.95 (2H, m), 2.60-2.65 (1H, m), 4.89 (1H, br s), 5.60 (1H, br s), 6.71 (1H, dd, J=8.8, 2.8 Hz), 6.88 (1H, d, J=2.8 Hz), 7.24-7.30 (1H, br s), 7.90 (1H, d, J=8.8 H)
ジメチルスルホキシド(20mL)に、7−メトキシ−4−クロロキノリン−6−カルボキサミド(0.983g)、1−(2−クロロ−4−ヒドロキシフェニル)−3−シクロプロピルウレア(1.13g)および炭酸セシウム(2.71g)を加え、70℃にて23時間加熱攪拌した。反応液を室温に戻した後、水(50mL)を加え、生じた結晶を濾取することで標記化合物1.56gを得た。(収率88%)
窒素雰囲気下、反応容器に7−メトキシ−4−クロロキノリン−6−カルボキサミド(5.00kg、21.13mol)、ジメチルスルホキシド(55.05kg)、1−(2−クロロ−4−ヒドロキシフェニル)−3−シクロプロピルウレア(5.75kg、25.35mol)およびカリウムt−ブトキシド(2.85kg、25.35mol)を順次投入した。その後、20℃で30分攪拌し、その後、2.5時間かけて温度を65℃まで上昇させた。同温度で19時間攪拌した後、33%(v/v)アセトン水(5.0L)および水(10.0L)を3.5時間かけて滴下した。滴下終了後、60℃で2時間攪拌し、33%(v/v)アセトン水(20.0L)および水(40.0L)を55℃以上で1時間かけて滴下した。40℃で16時間攪拌した後、析出した結晶を窒素圧式ろ過器を用いてろ取し、33%(v/v)アセトン水(33.3L)、水(66.7L)およびアセトン(50.0L)で順次結晶を洗浄した。得られた結晶をコニカル式減圧乾燥機を用いて、60℃で22時間乾燥し、標記化合物7.78kgを得た。(収率96.3%)
上記「薬物(薬効成分)の製造」で合成した4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミド(薬物X)のメタンスルホン酸塩の結晶(C)(以下「薬物Y」という。)を、以下の表1に示す10種の化合物(5%(W/W)水溶液または懸濁液を作製したときのpHが異なる。各pHを表中に示す。)と共存させ、薬物Yの安定性を評価した。
(実施例1) 10mg錠:酸化マグネシウム配合
薬物Y2.5g、酸化マグネシウム(安定化剤、富田製薬株式会社)10g、D−マンニトール(賦形剤、東和化成工業株式会社)48.5g、部分アルファー化でんぷん(崩壊剤、商品名PCS(薬添規)、旭化成工業株式会社)10g、結晶セルロース(賦形剤、商品名アビセルPH101、旭化成工業株式会社)22.5g、ヒドロキシプロピルセルロース(結合剤、商品名HPC−L、日本曹達株式会社)3gを1L−スーパーミキサーで混合した。その後、精製水適量を添加し、造粒、乾燥後、整粒し、顆粒を得た。この顆粒に、クロスカルメロースナトリウム(崩壊剤、商品名Ac−Di−Sol、FMCInternational Inc.)3g、ステアリン酸マグネシウム(滑沢剤)0.5gを混合後、打錠機で打錠し、1錠あたり薬物Yを10mg含む錠剤(1錠あたりの総質量400mg)を得た。
薬物Y2.5g、リン酸水素カルシウム(賦形剤)10g、D−マンニトール(賦形剤、東和化成工業株式会社)48.5g、部分アルファー化でんぷん(崩壊剤、商品名PCS(薬添規)、旭化成工業株式会社、)10g、結晶セルロース(賦形剤、商品名アビセルPH101、旭化成工業株式会社)22.5g、ヒドロキシプロピルセルロース(結合剤、商品名HPC−L、日本曹達株式会社)3gを1L−スーパーミキサーで混合した。その後、精製水適量を添加し、造粒、乾燥後、整粒し、顆粒を得た。この顆粒に、クロスカルメロースナトリウム(崩壊剤、商品名Ac−Di−Sol、FMCInternational Inc.)3g、ステアリン酸マグネシウム(滑沢剤)0.5gを混合後、打錠機で打錠し、1錠あたり薬物Yを10mg含む錠剤(1錠あたりの総質量400mg)を得た。
(実施例2) 1mg錠
薬物Y24gと軽質無水ケイ酸(ゲル化防止剤、商品名AEROSIL(登録商標)200、日本アエロジル株式会社)192gを20Lスーパーミキサーで混合後、さらにD−マンニトール(賦形剤、東和化成工業株式会社)1236g、結晶セルロース(賦形剤、商品名アビセルPH101、旭化成工業株式会社)720g、ヒドロキシプロピルセルロース(結合剤、商品名HPC−L、日本曹達株式会社)72gを加えて混合した。その後、無水エタノールを適量添加し薬物Yを含有する造粒物を得た。この造粒物を棚式乾燥機(60℃)で乾燥後、パワーミルを用いて整粒し、顆粒を得た。この顆粒とともに、クロスカルメロースナトリウム(崩壊剤、商品名Ac−Di−Sol、FMCInternational Inc.)120g、フマル酸ステアリルナトリウム(滑沢剤、JRS Pharma LP)36gを20Lタンブラーミキサーに入れて混合後、打錠機で製錠し、1錠あたり総質量100mgの錠剤を得た。さらに錠剤コーティング機で、コーティング液として10%オパドライイエロー(OPADRY03F42069 YELLOW、日本カラコン株式会社)水溶液を用いて、錠剤にコーティングし、1錠あたり総質量105mgのコーティング錠を得た。
薬物Y60gと軽質無水ケイ酸(ゲル化防止剤、商品名AEROSIL(登録商標)200、日本アエロジル株式会社)192gを20Lスーパーミキサーで混合後、さらにD−マンニトール(賦形剤、東和化成工業株式会社)1200g、結晶セルロース(賦形剤、商品名アビセルPH101、旭化成工業株式会社)720g、ヒドロキシプロピルセルロース(結合剤、商品名HPC−L、日本曹達株式会社)72gを加えて混合した。その後、無水エタノールを適量添加し薬物Yを含有する造粒物を得た。この造粒物を棚式乾燥機(60℃)で乾燥後、パワーミルを用いて整粒し、顆粒を得た。この顆粒とともに、クロスカルメロースナトリウム(崩壊剤、商品名Ac−Di−Sol、FMCInternational Inc.)120g、フマル酸ステアリルナトリウム(滑沢剤、JRS Pharma LP)36gを20Lタンブラーミキサーに入れて混合後、打錠機で製錠し、1錠あたり総質量400mgの錠剤を得た。さらに錠剤コーティング機で、コーティング液として10%オパドライイエロー(OPADRY03F42069 YELLOW、日本カラコン株式会社)水溶液を用いて、錠剤にコーティングし、1錠あたり総質量411mgのコーティング錠を得た。
薬物Y31.4gと軽質無水ケイ酸(ゲル化防止剤、商品名AEROSIL(登録商標)200、日本アエロジル株式会社)4gを1Lスーパーミキサーで混合後、さらに、無水リン酸水素カルシウム(賦形剤、協和化学工業株式会社)40.1g、低置換度ヒドロキシプロピルセルロース(結合剤、商品名L-HPC(LH−21)、信越化学工業株式会社)10g、ヒドロキシプロピルセルロース(結合剤、商品名HPC−L、日本曹達株式会社)3gを加えて混合した。その後、無水エタノールを適量添加し薬物Yを含有する造粒物を得た。この造粒物を棚式乾燥機(60℃)で乾燥後、パワーミルを用いて整粒し、顆粒を得た。この顆粒とともに、クロスカルメロースナトリウム(崩壊剤、商品名Ac−Di−Sol、FMCInternational Inc.)10g、フマル酸ステアリルナトリウム(滑沢剤、JRS Pharma LP)1.5gを混合後、打錠機で製錠し、1錠あたり総質量400mgの錠剤を得た。
薬物Y31.4g、無水リン酸水素カルシウム(賦形剤、協和化学工業株式会社)44.1g、低置換度ヒドロキシプロピルセルロース(結合剤、商品名L-HPC(LH−21)、信越化学工業株式会社)10g、ヒドロキシプロピルセルロース(結合剤、商品名HPC−L、日本曹達株式会社)3gを1Lスーパーミキサーで混合した。その後、無水エタノールを適量添加し薬物Yを含有する造粒物を得た。この造粒物を棚式乾燥機(60℃)で乾燥後、パワーミルを用いて整粒し、顆粒を得た。この顆粒とともに、クロスカルメロースナトリウム(崩壊剤、商品名Ac−Di−Sol、FMCInternational Inc.)10g、フマル酸ステアリルナトリウム(滑沢剤、JRS Pharma LP)1.5gを混合後、打錠機で製錠し、1錠あたり総質量400mgの錠剤を得た。
薬物Y31.4gと軽質無水ケイ酸(ゲル化防止剤、商品名AEROSIL(登録商標)200、日本アエロジル株式会社)8gを1Lスーパーミキサーで混合後、さらに、無水リン酸水素カルシウム(賦形剤、協和化学工業株式会社)42.1g、低置換度ヒドロキシプロピルセルロース(結合剤、商品名L-HPC(LH−21)、信越化学工業株式会社)10gを加え混合し、さらにヒドロキシプロピルセルロース(結合剤、商品名HPC−L、日本曹達株式会社)2gを分散させた無水エタノールを適量添加し本発明の薬物を含有する造粒物を得た。この造粒物を棚式乾燥機(60℃)で乾燥後、パワーミルを用いて整粒し、顆粒を得た。この顆粒とともに、クロスカルメロースナトリウム(崩壊剤、商品名Ac−Di−Sol、FMCInternational Inc.)5g、フマル酸ステアリルナトリウム(滑沢剤、JRS Pharma LP)1.5gを混合後、打錠機で製錠し1錠あたり総質量400mgの錠剤を得た。
薬物Y31.4gと軽質無水ケイ酸(ゲル化防止剤、商品名AEROSIL(登録商標)200、日本アエロジル株式会社)6gを1Lスーパーミキサーで混合後、さらに、無水リン酸水素カルシウム(賦形剤、協和化学工業株式会社)44.1g、低置換度ヒドロキシプロピルセルロース(結合剤、商品名L-HPC(LH−21)、信越化学工業株式会社)10gを加え混合し、さらにヒドロキシプロピルセルロース(結合剤、商品名HPC−L、日本曹達株式会社)2gを分散させた無水エタノールを適量添加し本発明の薬物を含有する造粒物を得た。この造粒物を棚式乾燥機(60℃)で乾燥後、パワーミルを用いて整粒し、顆粒を得た。この顆粒とともに、クロスカルメロースナトリウム(崩壊剤、商品名Ac−Di−Sol、FMCInternational Inc.)5g、フマル酸ステアリルナトリウム(滑沢剤、JRS Pharma LP)1.5gを混合後、打錠機で製錠し1錠あたり総質量400mgの錠剤を得た。
薬物Y31.4gと軽質無水ケイ酸(ゲル化防止剤、商品名AEROSIL(登録商標)200、日本アエロジル株式会社)4gを1Lスーパーミキサーで混合後、さらに、無水リン酸水素カルシウム(賦形剤、協和化学工業株式会社)46.1g、低置換度ヒドロキシプロピルセルロース(結合剤、商品名L-HPC(LH−21)、信越化学工業株式会社)10gを加え混合し、さらにヒドロキシプロピルセルロース(結合剤、商品名HPC−L、日本曹達株式会社)2gを分散させた無水エタノールを適量添加し本発明の薬物を含有する造粒物を得た。この造粒物を棚式乾燥機(60℃)で乾燥後、パワーミルを用いて整粒し、顆粒を得た。この顆粒とともに、クロスカルメロースナトリウム(崩壊剤、商品名Ac−Di−Sol、FMCInternational Inc.)5g、フマル酸ステアリルナトリウム(滑沢剤、JRS Pharma LP)1.5gを混合後、打錠機で製錠し1錠あたり総質量400mgの錠剤を得た。
(保存試験)
錠剤をガラスビンに入れ、蓋は開放したまま、5℃、60℃75%RH、40℃75%(RH)、または30℃65%(RH)で保存した。
(溶出試験)
溶出試験は日本薬局方第十四局に従い、パドル法を用いて、以下の条件で行った。試験液:0.1mol/L塩酸溶液900mL。回転数:50rpm。試験液温度37℃
実施例2および実施例3の錠剤を用いて保存試験(保存期間3ヶ月)を実施した。すべての実施例について、5℃、30℃65%(RH)、40℃75%(RH)いずれの保存条件でも溶出遅延は認められなかった。結果をそれぞれ、図2および図3に示す。
実施例4および比較例2で得られた錠剤を60℃75%(RH)で7日間保存し、その後、溶出試験を行った。その結果を図4に示す。比較例2は、初期品でも錠剤表面にゲル層を生じていることが確認された。さらに保存試験後、著しい溶出遅延を生じることが確認された。一方、実施例4は、保存前後、いずれの錠剤でも、錠剤表面にゲル層は認められなかった。また、保存後の溶出遅延も抑制することが確認された。
実施例5〜実施例7で得られた錠剤を60℃75%(RH)で7日間保存し、その後、溶出試験を行った。軽質無水ケイ酸の配合量の影響を確認するため、30分後の溶出率で比較した。その結果を図5に示す。薬物Y100mgに対し、軽質無水ケイ酸の配合が、16mg〜32mgでは、比較例2のような溶質遅延は生じないことが確認された。特に、軽質無水ケイ酸32mg配合した実施例5は、保存後もほとんど遅延しなかった。
薬物Y7.85gにD−マンニトール(賦形剤、東和化成工業株式会社)22.4g、結晶セルロース(賦形剤、商品名アビセルPH101、旭化成工業株式会社)15.0g、ヒドロキシプロピルセルロース(結合剤、商品名HPC−L、日本曹達株式会社)1.5gを加えて混合した。その後、無水エタノールを適量添加し薬物Yを含有する造粒物を得た。この造粒物を棚式乾燥機(60℃)で乾燥後、小型スピードミルを用いて整粒し、顆粒を得た。この顆粒とともに、クロスカルメロースナトリウム(崩壊剤、商品名Ac−Di−Sol、FMCInternational Inc.)2.5g、フマル酸ステアリルナトリウム(滑沢剤、JRS Pharma LP)0.8gを混合後、打錠機で製錠し1錠あたり総質量200mgの錠剤を得た。
薬物Y7.85gと軽質無水ケイ酸(ゲル化防止剤、商品名AEROSIL(登録商標)200、日本アエロジル株式会社)6gを1Lスーパーミキサーで混合後、さらにD−マンニトール(賦形剤、東和化成工業株式会社)16.4g、結晶セルロース(賦形剤、商品名アビセルPH101、旭化成工業株式会社)15.0g、ヒドロキシプロピルセルロース(結合剤、商品名HPC−L、日本曹達株式会社)1.5gを加えて混合した。その後、無水エタノールを適量添加し薬物Yを含有する造粒物を得た。この造粒物を棚式乾燥機(60℃)で乾燥後、小型スピードミルを用いて整粒し、顆粒を得た。この顆粒とともに、クロスカルメロースナトリウム(崩壊剤、商品名Ac−Di−Sol、FMCInternational Inc.)2.5g、フマル酸ステアリルナトリウム(滑沢剤、JRS Pharma LP)0.8gを混合後、打錠機で製錠し1錠あたり総質量200mgの錠剤を得た。
薬物Y7.85gと軽質無水ケイ酸(ゲル化防止剤、商品名AEROSIL(登録商標)200、日本アエロジル株式会社)10gを1Lスーパーミキサーで混合後、さらにD−マンニトール(賦形剤、東和化成工業株式会社)12.4g、結晶セルロース(賦形剤、商品名アビセルPH101、旭化成工業株式会社)15.0g、ヒドロキシプロピルセルロース(結合剤、商品名HPC−L、日本曹達株式会社)1.5gを加えて混合した。その後、無水エタノールを適量添加し薬物Yを含有する造粒物を得た。この造粒物を棚式乾燥機(60℃)で乾燥後、小型スピードミルを用いて整粒し、顆粒を得た。この顆粒とともに、クロスカルメロースナトリウム(崩壊剤、商品名Ac−Di−Sol、FMCInternational Inc.)2.5g、フマル酸ステアリルナトリウム(滑沢剤、JRS Pharma LP)0.8gを混合後、打錠機で製錠し1錠あたり総質量200mgの錠剤を得た。
薬物Y15.7gと軽質無水ケイ酸(ゲル化防止剤、商品名AEROSIL(登録商標)200、日本アエロジル株式会社)8gを1Lスーパーミキサーで混合後、さらに、酸化マグネシウム(安定化剤、富田製薬株式会社)3g、D−マンニトール(賦形剤、東和化成工業株式会社)33.8g、結晶セルロース(賦形剤、商品名アビセルPH101、旭化成工業株式会社)30g、ヒドロキシプロピルセルロース(結合剤、商品名HPC−L、日本曹達株式会社)3gを加えて混合した。その後、無水エタノールを適量添加し薬物Yを含有する造粒物を得た。この造粒物を棚式乾燥機(60℃)で乾燥後、小型スピードミルを用いて整粒し、顆粒を得た。この顆粒とともに、クロスカルメロースナトリウム(崩壊剤、商品名Ac−Di−Sol、FMCInternational Inc.)5g、フマル酸ステアリルナトリウム(滑沢剤、JRS Pharma LP)1.5gを混合後、打錠機で製錠し1錠あたり総質量200mgの錠剤を得た。
薬物Y7.85gと軽質無水ケイ酸(ゲル化防止剤、商品名AEROSIL(登録商標)200、日本アエロジル株式会社)4gを1Lスーパーミキサーで混合後、さらに、リン酸水素二ナトリウム(安定化剤、関東化学株式会社)2.5g、D−マンニトール(賦形剤、東和化成工業株式会社)15.9g、結晶セルロース(賦形剤、商品名アビセルPH101、旭化成工業株式会社)15g、ヒドロキシプロピルセルロース(結合剤、商品名HPC−L、日本曹達株式会社)1.5gを加えて混合した。その後、無水エタノールを適量添加し薬物Yを含有する造粒物を得た。この造粒物を棚式乾燥機(60℃)で乾燥後、小型スピードミルを用いて整粒し、顆粒を得た。この顆粒とともに、クロスカルメロースナトリウム(崩壊剤、商品名Ac−Di−Sol、FMCInternational Inc.)2.5g、フマル酸ステアリルナトリウム(滑沢剤、JRS Pharma LP)0.8gを混合後、打錠機で製錠し1錠あたり総質量200mgの錠剤を得た。
薬物Y7.85gと無水ケイ酸水加物(ゲル化防止剤、商品名サイリシア、富士シリシア化学株式会社)4gを1Lスーパーミキサーで混合後、さらにD−マンニトール(賦形剤、東和化成工業株式会社)18.4g、結晶セルロース(賦形剤、商品名アビセルPH101、旭化成工業株式会社)15.0g、ヒドロキシプロピルセルロース(結合剤、商品名HPC−L、日本曹達株式会社)1.5gを加えて混合した。その後、無水エタノールを適量添加し薬物Yを含有する造粒物を得た。この造粒物を棚式乾燥機(60℃)で乾燥後、小型スピードミルを用いて整粒し、顆粒を得た。この顆粒とともに、クロスカルメロースナトリウム(崩壊剤、商品名Ac−Di−Sol、FMCInternational Inc.)2.5g、フマル酸ステアリルナトリウム(滑沢剤、JRS Pharma LP)0.8gを混合後、打錠機で製錠し1錠あたり総質量200mgの錠剤を得た。
薬物Y7.85gとケイ酸カルシウム(ゲル化防止剤、商品名フローライト(登録商標)、株式会社トクヤマ)4gを1Lスーパーミキサーで混合後、さらにD−マンニトール(賦形剤、東和化成工業株式会社)18.4g、結晶セルロース(賦形剤、商品名アビセルPH101、旭化成工業株式会社)15.0g、ヒドロキシプロピルセルロース(結合剤、商品名HPC−L、日本曹達株式会社)1.5gを加えて混合した。その後、無水エタノールを適量添加し薬物Yを含有する造粒物を得た。この造粒物を棚式乾燥機(60℃)で乾燥後、小型スピードミルを用いて整粒し、顆粒を得た。この顆粒とともに、クロスカルメロースナトリウム(崩壊剤、商品名Ac−Di−Sol、FMCInternational Inc.)2.5g、フマル酸ステアリルナトリウム(滑沢剤、JRS Pharma LP)0.8gを混合後、打錠機で製錠し1錠あたり総質量200mgの錠剤を得た。
上記「薬物(薬効成分)の製造」で合成した4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミド(薬物X)のメタンスルホン酸塩の結晶(C)を含有する、製剤処方例を示す。表5は10mg錠(コーティング錠)の処方を示し、表6は100mg錠(コーティング錠)の処方を示す。
Claims (25)
- (i)5%(W/W)水溶液または懸濁液のpHが8以上となる化合物は、酸化マグネシウム、酸化カルシウム、炭酸ナトリウム、リン酸水素二ナトリウム、クエン酸ナトリウム、リン酸水素二カリウム、酢酸ナトリウム、炭酸水素ナトリウムおよび水酸化ナトリウムからなる群より選ばれる少なくとも1つである、請求項1記載の医薬組成物。
- (ii)ケイ酸もしくはその塩またはそれらの溶媒和物は、軽質無水ケイ酸、無水ケイ酸水加物、ケイ酸カルシウム、ケイ酸マグネシウム、ケイ酸アルミン酸マグネシウム、メタケイ酸アルミン酸マグネシウム、ケイ酸マグネシウムアルミニウム、合成ケイ酸アルミニウムおよび含水二酸化ケイ素からなる群より選ばれる少なくとも1つである請求項1または2記載の医薬組成物。
- 薬効成分が、4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドの塩酸塩、臭化水素酸塩、p−トルエンスルホン酸塩、硫酸塩、メタンスルホン酸塩もしくはエタンスルホン酸塩またはそれらの溶媒和物の結晶である請求項1〜3のいずれか一項に記載の医薬組成物。
- 薬効成分が、4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドのメタンスルホン酸塩またはその溶媒和物の結晶である請求項1〜3のいずれか一項に記載の医薬組成物。
- 薬効成分が、4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドのメタンスルホン酸塩の結晶である請求項1〜3のいずれか一項に記載の医薬組成物。
- 薬効成分が、4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドのメタンスルホン酸塩の水和物の結晶である請求項1〜3のいずれか一項に記載の医薬組成物。
- 薬効成分が、4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドのメタンスルホン酸塩のジメチルスルホキシド和物の結晶である請求項1〜3のいずれか一項に記載の医薬組成物。
- 薬効成分が、4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドのメタンスルホン酸塩の酢酸和物の結晶である請求項1〜3のいずれか一項に記載の医薬組成物。
- 4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドのメタンスルホン酸塩の結晶が、粉末X線回折において、回折角度(2θ±0.2°)9.65°および18.37°に回折ピークを有する結晶(A)である請求項6記載の医薬組成物。
- 4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドのメタンスルホン酸塩の結晶が、粉末X線回折において、回折角度(2θ±0.2°)5.72°および13.84°に回折ピークを有する結晶(B)である請求項6記載の医薬組成物。
- 4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドのメタンスルホン酸塩の結晶が、粉末X線回折において、回折角度(2θ±0.2°)14.20°および17.59°に回折ピークを有する結晶(C)である請求項6記載の医薬組成物。
- 4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドのメタンスルホン酸塩の水和物の結晶が、粉末X線回折において、回折角度(2θ±0.2°)8.02°および18.14°に回折ピークを有する結晶(F)である請求項7記載の医薬組成物。
- 4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドのメタンスルホン酸塩の酢酸和物の結晶は、粉末X線回折において、回折角度(2θ±0.2°)9.36°および12.40°に回折ピークを有する結晶(I)である請求項9記載の医薬組成物。
- 粉末X線回折において、回折角度(2θ±0.2°)9.65°および18.37°に回折ピークを有する結晶(A)が、4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミド、溶媒およびメタンスルホン酸を混合し、溶解させる製造方法により得られたものである、請求項10記載の医薬組成物。
- 粉末X線回折において、回折角度(2θ±0.2°)9.65°および18.37°に回折ピークを有する結晶(A)が、4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミド、酢酸およびメタンスルホン酸を混合し、溶解させる製造方法により得られたものである、請求項10記載の医薬組成物。
- 粉末X線回折において、回折角度(2θ±0.2°)5.72°および13.84°に回折ピークを有する結晶(B)が、4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドのメタンスルホン酸塩の酢酸和物の結晶(I)を乾燥させて、酢酸を除去する製造方法により得られたものである、請求項11記載の医薬組成物。
- 粉末X線回折において、回折角度(2θ±0.2°)14.20°および17.59°に回折ピークを有する結晶(C)が、4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドのメタンスルホン酸塩のジメチルスルホキシド和物の結晶を加熱する製造方法により得られたものである、請求項12記載の医薬組成物。
- 粉末X線回折において、回折角度(2θ±0.2°)14.20°および17.59°に回折ピークを有する結晶(C)が、4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドのメタンスルホン酸塩の酢酸和物の結晶(I)および溶媒を混合する製造方法により得られたものである、請求項12記載の医薬組成物。
- 粉末X線回折において、回折角度(2θ±0.2°)14.20°および17.59°に回折ピークを有する結晶(C)が、4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミド、酢酸およびメタンスルホン酸を混合し、溶解させる製造方法により得られたものである、請求項12記載の医薬組成物。
- 粉末X線回折において、回折角度(2θ±0.2°)14.20°および17.59°に回折ピークを有する結晶(C)が、4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドのメタンスルホン酸塩の結晶(B)を加湿する製造方法により得られたものである、請求項12記載の医薬組成物。
- 粉末X線回折において、回折角度(2θ±0.2°)8.02°および18.14°に回折ピークを有する結晶(F)が、4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミド、酢酸およびメタンスルホン酸を混合し、溶解させる製造方法により得られたものである、請求項13記載の医薬組成物。
- 粉末X線回折において、回折角度(2θ±0.2°)9.36°および12.40°に回折ピークを有する結晶(I)が、4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミド、酢酸およびメタンスルホン酸を混合し、溶解させる製造方法により得られたものである、請求項14記載の医薬組成物。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006535174A JP4834553B2 (ja) | 2004-09-17 | 2005-09-14 | 医薬組成物 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2004272625 | 2004-09-17 | ||
JP2004272625 | 2004-09-17 | ||
JP2006535174A JP4834553B2 (ja) | 2004-09-17 | 2005-09-14 | 医薬組成物 |
PCT/JP2005/016941 WO2006030826A1 (ja) | 2004-09-17 | 2005-09-14 | 医薬組成物 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPWO2006030826A1 JPWO2006030826A1 (ja) | 2008-05-15 |
JP4834553B2 true JP4834553B2 (ja) | 2011-12-14 |
Family
ID=36060077
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2006535174A Active JP4834553B2 (ja) | 2004-09-17 | 2005-09-14 | 医薬組成物 |
Country Status (12)
Country | Link |
---|---|
US (2) | US8969379B2 (ja) |
EP (1) | EP1797881B1 (ja) |
JP (1) | JP4834553B2 (ja) |
KR (1) | KR20070053205A (ja) |
CN (1) | CN101001629B (ja) |
AT (1) | ATE428421T1 (ja) |
AU (1) | AU2005283422C1 (ja) |
CA (1) | CA2579810C (ja) |
DE (1) | DE602005013990D1 (ja) |
ES (1) | ES2322175T3 (ja) |
IL (1) | IL181697A (ja) |
WO (1) | WO2006030826A1 (ja) |
Families Citing this family (60)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE60126997T2 (de) * | 2000-10-20 | 2007-10-25 | Eisai R&D Management Co., Ltd. | Stickstoff-enthaltende aromatische ringverbindungen zur behandlung von tumorerkrankungen |
JPWO2004080462A1 (ja) | 2003-03-10 | 2006-06-08 | エーザイ株式会社 | c−Kitキナーゼ阻害剤 |
WO2005044788A1 (ja) | 2003-11-11 | 2005-05-19 | Eisai Co., Ltd. | ウレア誘導体およびその製造方法 |
RS54033B1 (en) * | 2003-12-25 | 2015-10-30 | Eisai R&D Management Co. Ltd. | CRYSTAL FORM OF THE SALTS 4- (3-CHLORO-4- (CYCLOPROPYLAMINOCARBONYL) AMINO-PHENOXY) -7-METHOXY-6-HINOLINKARBOXAMIDE OR ITS SOLVATES AND THE PROCESS FOR THEIR PRODUCTION |
KR20070053205A (ko) | 2004-09-17 | 2007-05-23 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 의약 조성물 |
US7550483B2 (en) | 2005-06-23 | 2009-06-23 | Eisai R&D Management Co., Ltd. | Amorphous salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and process for preparing the same |
US20100105031A1 (en) * | 2005-08-01 | 2010-04-29 | Esai R & D Management Co., Ltd. | Method for prediction of the efficacy of vascularization inhibitor |
WO2007015578A1 (ja) | 2005-08-02 | 2007-02-08 | Eisai R & D Management Co., Ltd. | 血管新生阻害物質の効果を検定する方法 |
US20090053236A1 (en) * | 2005-11-07 | 2009-02-26 | Eisai R & D Management Co., Ltd. | USE OF COMBINATION OF ANTI-ANGIOGENIC SUBSTANCE AND c-kit KINASE INHIBITOR |
US20090247576A1 (en) * | 2005-11-22 | 2009-10-01 | Eisai R & D Management Co., Ltd. | Anti-tumor agent for multiple myeloma |
RU2448708C3 (ru) * | 2006-05-18 | 2017-09-28 | Эйсай Ар Энд Ди Менеджмент Ко., Лтд. | Противоопухолевое средство против рака щитовидной железы |
WO2008026748A1 (fr) | 2006-08-28 | 2008-03-06 | Eisai R & D Management Co., Ltd. | Agent antitumoral pour cancer gastrique non différencié |
CN101600694A (zh) * | 2007-01-29 | 2009-12-09 | 卫材R&D管理有限公司 | 未分化型胃癌治疗用组合物 |
JP2008208277A (ja) * | 2007-02-27 | 2008-09-11 | Fujifilm Corp | 有機化合物結晶の製造方法 |
JP5638244B2 (ja) | 2007-11-09 | 2014-12-10 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 血管新生阻害物質と抗腫瘍性白金錯体との併用 |
JP5399926B2 (ja) * | 2008-01-29 | 2014-01-29 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 血管阻害物質とタキサンとの併用 |
CA2766067A1 (en) * | 2009-07-02 | 2011-01-06 | Wyeth Llc | 3-cyanoquinoline tablet formulations and uses thereof |
AU2010285740C1 (en) * | 2009-08-19 | 2016-03-17 | Eisai R&D Management Co., Ltd. | Quinoline derivative-containing pharmaceutical composition |
CA2802644C (en) * | 2010-06-25 | 2017-02-21 | Eisai R & D Management Co., Ltd. | Antitumor agent using compounds having kinase inhibitory effect in combination |
US20130142849A1 (en) * | 2010-08-17 | 2013-06-06 | Lupin Limited | Controlled release formulations of dronedarone |
TWI501950B (zh) * | 2011-02-09 | 2015-10-01 | Eisai R&D Man Co Ltd | 含喹啉衍生物的藥學組成物 |
CA2828946C (en) | 2011-04-18 | 2016-06-21 | Eisai R&D Management Co., Ltd. | Therapeutic agent for tumor |
WO2012166899A2 (en) | 2011-06-03 | 2012-12-06 | Eisai R&D Management Co., Ltd. | Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds |
JP6062422B2 (ja) * | 2012-03-29 | 2017-01-18 | 杏林製薬株式会社 | カプセル製剤 |
JP6050322B2 (ja) * | 2012-03-29 | 2016-12-21 | 杏林製薬株式会社 | カプセル製剤 |
BR112015009004A8 (pt) | 2012-12-21 | 2021-07-20 | Eisai R&D Man Co Ltd | forma amorfa de derivado de quinolina e método de produção da mesma |
EP2952196A4 (en) * | 2013-01-31 | 2016-08-03 | Sawai Seiyaku Kk | MULTILAYER TABLET CONTAINING TELMISARTAN AND HYDROCHLOROTHIAZIDE |
CA2910121A1 (en) | 2013-04-25 | 2014-10-30 | Kyorin Pharmaceutical Co., Ltd. | A pharmaceutical composition comprising a 1,4-dihydroquinoline carboxylic acid a cellulosic excipient and a salting-out agent |
ES2768651T3 (es) | 2013-04-25 | 2020-06-23 | Kyorin Seiyaku Kk | Composición farmacéutica sólida |
CA2912219C (en) | 2013-05-14 | 2021-11-16 | Eisai R&D Management Co., Ltd. | Biomarkers for predicting and assessing responsiveness of endometrial cancer subjects to lenvatinib compounds |
CA2946538A1 (en) | 2014-04-04 | 2015-10-08 | Del Mar Pharmaceuticals | Use of dianhydrogalactitol and analogs or derivatives thereof to treat non-small-cell carcinoma of the lung and ovarian cancer |
KR20230043234A (ko) * | 2014-08-28 | 2023-03-30 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 고순도의 퀴놀린 유도체 및 이를 제조하는 방법 |
CA2965473A1 (en) | 2014-10-23 | 2016-04-28 | Kyorin-Pharmaceutical Co., Ltd. | Solid pharmaceutical composition |
CN106139156B (zh) * | 2014-11-14 | 2019-01-29 | 江苏恒瑞医药股份有限公司 | 一种含有喹啉衍生物或其盐的药物组合物 |
AU2016224583B2 (en) * | 2015-02-25 | 2021-06-03 | Eisai R&D Management Co., Ltd. | Method for suppressing bitterness of quinoline derivative |
KR20170122809A (ko) | 2015-03-04 | 2017-11-06 | 머크 샤프 앤드 돔 코포레이션 | 암을 치료하기 위한 pd-1 길항제 및 vegfr/fgfr/ret 티로신 키나제 억제제의 조합 |
CN106660965A (zh) * | 2015-03-27 | 2017-05-10 | 江苏恒瑞医药股份有限公司 | 乐伐替尼的对甲苯磺酸盐、其结晶形式及制备方法 |
CN106075456A (zh) * | 2015-04-27 | 2016-11-09 | 南京圣和药业股份有限公司 | 一种含乐伐替尼的药物组合物及其应用 |
US10246418B2 (en) | 2015-05-21 | 2019-04-02 | Crystal Pharmatech Co., Ltd. | Crystal form of lenvatinib methanesulfonate salt and preparation method thereof |
CN104876864B (zh) * | 2015-06-05 | 2017-03-08 | 北京康立生医药技术开发有限公司 | 一种乐伐替尼的制备方法 |
CA2988707C (en) | 2015-06-16 | 2023-10-10 | Eisai R&D Management Co., Ltd. | Combination of cbp/catenin inhibitor and immune checkpoint inhibitor for treating cancer |
CN106999483B (zh) * | 2015-08-17 | 2019-05-03 | 江苏恒瑞医药股份有限公司 | 一种含有喹啉衍生物或其盐的药物组合物 |
CN106551935B (zh) * | 2015-09-24 | 2020-04-14 | 江苏奥赛康药业有限公司 | 含有乐伐替尼的药物组合物及其制备方法 |
CZ2016240A3 (cs) | 2016-04-27 | 2017-11-08 | Zentiva, K.S. | Soli lenvatinibu |
CN105801481A (zh) * | 2016-05-20 | 2016-07-27 | 湖南欧亚生物有限公司 | 一种乐伐替尼的合成方法 |
EP3299360A1 (en) | 2016-09-21 | 2018-03-28 | INDENA S.p.A. | Crystal forms of lenvatinib |
EP3384901A1 (en) | 2017-04-04 | 2018-10-10 | Synthon B.V. | Pharmaceutical composition comprising lenvatinib mesylate |
CA3073229A1 (en) * | 2017-08-18 | 2019-02-21 | Abbvie Inc. | Pharmaceutical formulations for treating endometriosis, uterine fibroids, polycystic ovary syndrome or adenomyosis |
CN107739335A (zh) * | 2017-12-01 | 2018-02-27 | 南京奇可药业有限公司 | 一种乐伐替尼的合成方法 |
CN109988112A (zh) * | 2017-12-29 | 2019-07-09 | 四川科伦药物研究院有限公司 | 仑伐替尼甲磺酸盐的晶型及其制备方法 |
US10583133B2 (en) | 2018-03-12 | 2020-03-10 | Shilpa Medicare Limited | Pharmaceutical compositions of lenvatinib |
PT3632436T (pt) | 2018-10-04 | 2022-07-22 | Synthon Bv | Composição farmacêutica compreendendo sais de lenvatinib |
AU2019352722A1 (en) | 2018-10-04 | 2021-04-01 | Synthon B.V. | Crystalline forms and processes of lenvatinib besylate |
CN111053772A (zh) * | 2018-10-16 | 2020-04-24 | 四川科伦药物研究院有限公司 | 一种乐伐替尼的药物组合物及其用途 |
CN111689897B (zh) * | 2019-03-13 | 2024-02-06 | 齐鲁制药有限公司 | 一种高纯度甲磺酸乐伐替尼晶型c的制备方法 |
CN112190583B (zh) * | 2019-07-08 | 2021-10-29 | 成都苑东生物制药股份有限公司 | 一种乐伐替尼药物组合物及其制备方法 |
WO2021185006A1 (zh) * | 2020-03-18 | 2021-09-23 | 上海博志研新药物技术有限公司 | 一种仑伐替尼药物组合物、其制备方法及应用 |
JP7466642B2 (ja) * | 2020-04-24 | 2024-04-12 | 成都苑東生物制薬股▲フン▼有限公司 | レンバチニブメシル酸塩結晶形xi及びその調製方法 |
WO2021226738A1 (zh) * | 2020-05-09 | 2021-11-18 | 北京睿创康泰医药研究院有限公司 | 包含仑伐替尼的分子水平的药物组合物及其制备方法和应用 |
EP4147689A1 (en) | 2021-09-13 | 2023-03-15 | Lotus Pharmaceutical Co., Ltd. | Lenvatinib formulation |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6328427A (ja) * | 1986-07-22 | 1988-02-06 | Eisai Co Ltd | 調湿剤 |
WO2000071097A1 (fr) * | 1999-05-20 | 2000-11-30 | Takeda Chemical Industries, Ltd. | Composition contenant du sel d'acide ascorbique |
WO2002032872A1 (en) * | 2000-10-20 | 2002-04-25 | Eisai Co., Ltd. | Nitrogenous aromatic ring compounds |
JP2003026576A (ja) * | 2001-05-09 | 2003-01-29 | Eisai Co Ltd | 味覚改善製剤 |
JP2004155773A (ja) * | 2002-10-16 | 2004-06-03 | Takeda Chem Ind Ltd | 安定な固形製剤 |
WO2004080462A1 (ja) * | 2003-03-10 | 2004-09-23 | Eisai Co., Ltd. | c-Kitキナーゼ阻害剤 |
WO2005063713A1 (ja) * | 2003-12-25 | 2005-07-14 | Eisai Co., Ltd. | 4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドの塩またはその溶媒和物の結晶およびそれらの製造方法 |
Family Cites Families (245)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CU22545A1 (es) | 1994-11-18 | 1999-03-31 | Centro Inmunologia Molecular | Obtención de un anticuerpo quimérico y humanizado contra el receptor del factor de crecimiento epidérmico para uso diagnóstico y terapéutico |
JPS6328427Y2 (ja) | 1979-06-28 | 1988-08-01 | ||
JPS5944869U (ja) | 1982-09-17 | 1984-03-24 | 近畿アルミニユ−ム工業株式会社 | プレートの間隔修正工具を備えた蝶番 |
US4526988A (en) * | 1983-03-10 | 1985-07-02 | Eli Lilly And Company | Difluoro antivirals and intermediate therefor |
EP0154434B1 (en) * | 1984-02-17 | 1993-01-27 | Genentech, Inc. | Human transforming growth factor and precursor or fragment thereof, cells, dna, vectors and methods for their production, compositions and products containing them, and related antibodies and diagnostic methods |
US4582789A (en) * | 1984-03-21 | 1986-04-15 | Cetus Corporation | Process for labeling nucleic acids using psoralen derivatives |
US4563417A (en) * | 1984-08-31 | 1986-01-07 | Miles Laboratories, Inc. | Nucleic acid hybridization assay employing antibodies to intercalation complexes |
ATE92499T1 (de) * | 1984-12-04 | 1993-08-15 | Lilly Co Eli | Tumorbehandlung bei saeugetieren. |
JPS62168137A (ja) * | 1985-12-20 | 1987-07-24 | Fuji Photo Film Co Ltd | ハロゲン化銀カラ−写真感光材料およびその処理方法 |
CA1339136C (en) | 1987-07-01 | 1997-07-29 | Sailesh Amilal Varia | Amorphous form of aztreonam |
AU4128089A (en) * | 1988-09-15 | 1990-03-22 | Rorer International (Overseas) Inc. | Monoclonal antibodies specific to human epidermal growth factor receptor and therapeutic methods employing same |
US5143854A (en) * | 1989-06-07 | 1992-09-01 | Affymax Technologies N.V. | Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof |
US4983615A (en) | 1989-06-28 | 1991-01-08 | Hoechst-Roussel Pharmaceuticals Inc. | Heteroarylamino- and heteroaryloxypyridinamine compounds which are useful in treating skin disorders |
US5180818A (en) * | 1990-03-21 | 1993-01-19 | The University Of Colorado Foundation, Inc. | Site specific cleavage of single-stranded dna |
US5210015A (en) | 1990-08-06 | 1993-05-11 | Hoffman-La Roche Inc. | Homogeneous assay system using the nuclease activity of a nucleic acid polymerase |
EP0562047A4 (en) * | 1990-12-06 | 1995-11-02 | Affymax Tech Nv | Sequencing by hybridization of a target nucleic acid to a matrix of defined oligonucleotides |
GB9105677D0 (en) | 1991-03-19 | 1991-05-01 | Ici Plc | Heterocyclic compounds |
US5367057A (en) * | 1991-04-02 | 1994-11-22 | The Trustees Of Princeton University | Tyrosine kinase receptor flk-2 and fragments thereof |
US5721237A (en) | 1991-05-10 | 1998-02-24 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylation properties |
US5710158A (en) | 1991-05-10 | 1998-01-20 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
ATE159009T1 (de) | 1991-05-10 | 1997-10-15 | Rhone Poulenc Rorer Int | Bis mono- und bicyclische aryl- und heteroarylderivate mit inhibierender wirkung auf die egf und/oder pdgf-rezeptor tyrosinkinase |
JPH04341454A (ja) | 1991-05-16 | 1992-11-27 | Canon Inc | シート収納装置 |
US5750376A (en) * | 1991-07-08 | 1998-05-12 | Neurospheres Holdings Ltd. | In vitro growth and proliferation of genetically modified multipotent neural stem cells and their progeny |
US5211951A (en) * | 1991-07-24 | 1993-05-18 | Merck & Co., Inc. | Process for the manufacture of bioerodible poly (orthoester)s and polyacetals |
AU678764B2 (en) * | 1992-06-03 | 1997-06-12 | Case Western Reserve University | Bandage for continuous application of biologicals |
GB9221220D0 (en) | 1992-10-09 | 1992-11-25 | Sandoz Ag | Organic componds |
JPH06153952A (ja) | 1992-11-26 | 1994-06-03 | Nobuaki Tamamaki | 微量未知二重鎖dna分子の増幅、標識を行うための前処理方法 |
GB9323290D0 (en) | 1992-12-10 | 1994-01-05 | Zeneca Ltd | Quinazoline derivatives |
JP2637899B2 (ja) * | 1993-05-19 | 1997-08-06 | 鹿島建設株式会社 | プレストレストコンクリートの製造方法およびプレストレストコンクリート |
US6027880A (en) * | 1995-08-02 | 2000-02-22 | Affymetrix, Inc. | Arrays of nucleic acid probes and methods of using the same for detecting cystic fibrosis |
DE69323192T2 (de) | 1993-08-02 | 1999-06-17 | Cooper Automotive Prod Inc | Zündkerzenelektroden |
US6156501A (en) | 1993-10-26 | 2000-12-05 | Affymetrix, Inc. | Arrays of modified nucleic acid probes and methods of use |
DK0732936T3 (da) | 1993-12-09 | 2000-09-04 | Heinrich Exner | Adjuvans til antigener, fremgangsmåde til fremstilling og anvendelse |
JPH07176103A (ja) | 1993-12-20 | 1995-07-14 | Canon Inc | 光磁気記録再生システムならびにこれに用いる磁気ヘッド及び光磁気記録媒体 |
GB9326136D0 (en) | 1993-12-22 | 1994-02-23 | Erba Carlo Spa | Biologically active 3-substituted oxindole derivatives useful as anti-angiogenic agents |
IL112249A (en) | 1994-01-25 | 2001-11-25 | Warner Lambert Co | Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds |
US6811779B2 (en) * | 1994-02-10 | 2004-11-02 | Imclone Systems Incorporated | Methods for reducing tumor growth with VEGF receptor antibody combined with radiation and chemotherapy |
US5607939A (en) | 1994-04-28 | 1997-03-04 | Takeda Chemical Industries, Ltd. | Condensed heterocyclic compounds, their production and use |
JP3660391B2 (ja) | 1994-05-27 | 2005-06-15 | 株式会社東芝 | 半導体装置の製造方法 |
JPH0848078A (ja) | 1994-08-05 | 1996-02-20 | Nippon Paper Ind Co Ltd | 感熱記録体 |
GB9510757D0 (en) | 1994-09-19 | 1995-07-19 | Wellcome Found | Therapeuticaly active compounds |
US5656454A (en) * | 1994-10-04 | 1997-08-12 | President And Fellows Of Harvard College | Endothelial cell-specific enhancer |
IL115256A0 (en) * | 1994-11-14 | 1995-12-31 | Warner Lambert Co | 6-Aryl pyrido (2,3-d) pyrimidines and naphthyridines and their use |
JP3081477B2 (ja) | 1994-11-28 | 2000-08-28 | 三洋電機株式会社 | プリント基板の絶縁方法 |
JPH08176138A (ja) | 1994-12-19 | 1996-07-09 | Mercian Corp | イソクマリン誘導体 |
US5948438A (en) * | 1995-01-09 | 1999-09-07 | Edward Mendell Co., Inc. | Pharmaceutical formulations having improved disintegration and/or absorptivity |
US5556496A (en) | 1995-01-10 | 1996-09-17 | Sumerak; Joseph E. | Pultrusion method for making variable cross-section thermoset articles |
US5658374A (en) | 1995-02-28 | 1997-08-19 | Buckman Laboratories International, Inc. | Aqueous lecithin-based release aids and methods of using the same |
US5624937A (en) * | 1995-03-02 | 1997-04-29 | Eli Lilly And Company | Chemical compounds as inhibitors of amyloid beta protein production |
DE69536015D1 (de) | 1995-03-30 | 2009-12-10 | Pfizer Prod Inc | Chinazolinone Derivate |
GB9508538D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
DK0831829T3 (da) | 1995-06-07 | 2003-12-15 | Pfizer | Heterocykliske, ringkondenserede pyrimidinderivater |
US5880141A (en) * | 1995-06-07 | 1999-03-09 | Sugen, Inc. | Benzylidene-Z-indoline compounds for the treatment of disease |
JPH0923885A (ja) | 1995-07-12 | 1997-01-28 | Dai Ichi Seiyaku Co Ltd | 遺伝子発現ライブラリー及びその製造法 |
GB9514265D0 (en) | 1995-07-13 | 1995-09-13 | Wellcome Found | Hetrocyclic compounds |
GB9520822D0 (en) | 1995-10-11 | 1995-12-13 | Wellcome Found | Therapeutically active compounds |
AR004010A1 (es) | 1995-10-11 | 1998-09-30 | Glaxo Group Ltd | Compuestos heterociclicos |
US6346398B1 (en) | 1995-10-26 | 2002-02-12 | Ribozyme Pharmaceuticals, Inc. | Method and reagent for the treatment of diseases or conditions related to levels of vascular endothelial growth factor receptor |
US6143764A (en) * | 1995-11-07 | 2000-11-07 | Kirin Beer Kabushiki Kaisha | Quinoline and quinazoline derivatives inhibiting platelet-derived growth factor receptor autophosphorylation and pharmaceutical compositions containing the same |
US5849759A (en) | 1995-12-08 | 1998-12-15 | Berlex Laboratories, Inc. | Naphthyl-substituted benzimidazole derivatives as anti-coagulants |
GB9604361D0 (en) | 1996-02-29 | 1996-05-01 | Pharmacia Spa | 4-Substituted pyrrolopyrimidine compounds as tyrosine kinase inhibitors |
JPH09234074A (ja) | 1996-03-04 | 1997-09-09 | Sumitomo Electric Ind Ltd | アダプター二本鎖dna及びそれを用いたdna増幅方法 |
AU2733997A (en) | 1996-04-17 | 1997-11-07 | Du Pont Pharmaceuticals Company | N-(amidinophenyl)-n'-(subst.)-3h-2,4-benzodiazepin-3-one derivatives as factor xa inhibitors |
WO1997046313A1 (en) * | 1996-06-07 | 1997-12-11 | Eos Biotechnology, Inc. | Immobilised linear oligonucleotide arrays |
AU721130B2 (en) | 1996-06-28 | 2000-06-22 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
ATE227283T1 (de) | 1996-07-13 | 2002-11-15 | Glaxo Group Ltd | Kondensierte heterozyklische verbindungen als protein kinase inhibitoren |
AU3693697A (en) | 1996-07-13 | 1998-02-09 | Glaxo Group Limited | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
HRP970371A2 (en) | 1996-07-13 | 1998-08-31 | Kathryn Jane Smith | Heterocyclic compounds |
CA2263479A1 (en) | 1996-09-25 | 1998-04-02 | Zeneca Limited | Quinoline derivatives inhibiting the effect of growth factors such as vegf |
EP0930305B1 (en) | 1996-09-30 | 2003-05-14 | Nihon Nohyaku Co., Ltd. | 1,2,3-thiadiazole derivatives and salts thereof, disease controlling agents for agricultural and horticultural use, and method for the use thereof |
EP0837063A1 (en) | 1996-10-17 | 1998-04-22 | Pfizer Inc. | 4-Aminoquinazoline derivatives |
WO1998023613A1 (en) | 1996-11-27 | 1998-06-04 | Pfizer Inc. | Fused bicyclic pyrimidine derivatives |
CA2275777A1 (en) | 1997-01-29 | 1998-07-30 | Louise Richman Levine | Treatment for premenstrual dysphoric disorder |
CO4950519A1 (es) | 1997-02-13 | 2000-09-01 | Novartis Ag | Ftalazinas, preparaciones farmaceuticas que las comprenden y proceso para su preparacion |
JP3040486U (ja) | 1997-02-13 | 1997-08-19 | 有限会社ザップ | フィッシングジャケット |
DK0968206T3 (da) | 1997-02-19 | 2007-03-26 | Berlex Inc | N-heterocykliske derivater som NOS-inhibitorer |
US6090556A (en) | 1997-04-07 | 2000-07-18 | Japan Science & Technology Corporation | Method for quantitatively determining the expression of a gene |
WO1998050346A2 (en) | 1997-04-18 | 1998-11-12 | Smithkline Beecham Plc | Acetamide and urea derivatives, process for their preparation and their use in the treatment of cns disorders |
DE1019040T1 (de) | 1997-05-23 | 2001-02-08 | Bayer Ag | Hemmung von p38 kinase aktivität durch arylharnstoff |
US6093742A (en) | 1997-06-27 | 2000-07-25 | Vertex Pharmaceuticals, Inc. | Inhibitors of p38 |
WO1999001738A2 (en) | 1997-06-30 | 1999-01-14 | University Of Maryland, Baltimore | Heparin binding-epidermal growth factor in the diagnosis of interstitial cystitis |
JP3765918B2 (ja) * | 1997-11-10 | 2006-04-12 | パイオニア株式会社 | 発光ディスプレイ及びその駆動方法 |
JP4194678B2 (ja) | 1997-11-28 | 2008-12-10 | キリンファーマ株式会社 | キノリン誘導体およびそれを含む医薬組成物 |
KR100253378B1 (ko) * | 1997-12-15 | 2000-04-15 | 김영환 | 주문형반도체의외부표시장치 |
ATE529109T1 (de) | 1997-12-22 | 2011-11-15 | Bayer Healthcare Llc | Hemmung der p38 kinase aktivität durch substituierte heterocyclische harnstoffe |
HU227711B1 (en) | 1997-12-22 | 2011-12-28 | Bayer Healthcare Llc | Inhibition of raf kinase using symmetrical and unsymmetrical substituted diphenyl ureas and pharmaceutical compositions containing them |
NZ505844A (en) | 1997-12-22 | 2003-10-31 | Bayer Ag | Inhibition of raf kinase using substituted heterocyclic ureas |
DE69836563T2 (de) | 1997-12-22 | 2007-05-16 | Bayer Pharmaceuticals Corp., West Haven | INHIBIERUNG DER p38 KINASE-AKTIVITÄT DURCH DIE VERWENDUNG VON ARYL- UND HETEROARYL-SUBSTITUIERTEN HARNSTOFFEN |
GB9800575D0 (en) | 1998-01-12 | 1998-03-11 | Glaxo Group Ltd | Heterocyclic compounds |
GB9800569D0 (en) | 1998-01-12 | 1998-03-11 | Glaxo Group Ltd | Heterocyclic compounds |
CN1310706A (zh) | 1998-02-25 | 2001-08-29 | 遗传研究所有限公司 | 磷脂酶抑制剂 |
JPH11322596A (ja) | 1998-05-12 | 1999-11-24 | Shionogi & Co Ltd | 白金錯体および環状リン酸エステルアミドを含有する抗癌剤 |
UA60365C2 (uk) | 1998-06-04 | 2003-10-15 | Пфайзер Продактс Інк. | Похідні ізотіазолу, спосіб їх одержання, фармацевтична композиція та спосіб лікування гіперпроліферативного захворювання у ссавця |
WO2000031048A1 (en) | 1998-11-19 | 2000-06-02 | Warner-Lambert Company | N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, an irreversible inhibitor of tyrosine kinases |
WO2000042012A1 (en) | 1999-01-13 | 2000-07-20 | Bayer Corporation | φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS |
UA73492C2 (en) | 1999-01-19 | 2005-08-15 | Aromatic heterocyclic compounds as antiinflammatory agents | |
DE60033857T2 (de) | 1999-01-22 | 2007-10-25 | Kirin Beer K.K. | Derivate des N-((Chinolinyl)oxy)-phenyl)-Harnstoffs und des N-((Chinazolinyl)oxy)-phenyl)-Harnstoffs mit Antitumor Aktivität |
JP3270834B2 (ja) | 1999-01-27 | 2002-04-02 | ファイザー・プロダクツ・インク | 抗がん剤として有用なヘテロ芳香族二環式誘導体 |
UA71945C2 (en) | 1999-01-27 | 2005-01-17 | Pfizer Prod Inc | Substituted bicyclic derivatives being used as anticancer agents |
PL205557B1 (pl) * | 1999-02-10 | 2010-05-31 | Astrazeneca Ab | Pochodne indolu |
GB9904103D0 (en) | 1999-02-24 | 1999-04-14 | Zeneca Ltd | Quinoline derivatives |
JP2000328080A (ja) | 1999-03-12 | 2000-11-28 | Shin Etsu Chem Co Ltd | シートベルト用低摩擦化処理剤 |
YU13200A (sh) * | 1999-03-31 | 2002-10-18 | Pfizer Products Inc. | Postupci i intermedijeri za dobijanje anti-kancernih jedinjenja |
CN101073668A (zh) * | 1999-04-28 | 2007-11-21 | 德克萨斯大学董事会 | 用于通过选择性抑制vegf来治疗癌症的组合物和方法 |
JP4304357B2 (ja) | 1999-05-24 | 2009-07-29 | 独立行政法人理化学研究所 | 完全長cDNAライブラリーの作成法 |
PE20010306A1 (es) | 1999-07-02 | 2001-03-29 | Agouron Pharma | Compuestos de indazol y composiciones farmaceuticas que los contienen utiles para la inhibicion de proteina kinasa |
WO2001012600A1 (en) * | 1999-08-12 | 2001-02-22 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
AR025752A1 (es) | 1999-09-28 | 2002-12-11 | Bayer Corp | Piridinas y piridacinas sustituidas con actividad de inhibicion de angiogenesis |
UA75054C2 (uk) | 1999-10-13 | 2006-03-15 | Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг | Заміщені в положенні 6 індолінони, їх одержання та їх застосування як лікарського засобу |
JP2001131071A (ja) | 1999-10-29 | 2001-05-15 | Meiji Seika Kaisha Ltd | 非晶質および非晶質を含有する医薬組成物 |
AU784338B2 (en) | 1999-11-01 | 2006-03-16 | Curagen Corporation | Differentially expressed genes involved in angiogenesis, the polypeptides encoded thereby, and methods of using the same |
US20080241835A1 (en) * | 1999-11-01 | 2008-10-02 | Genentech, Inc. | Differentially expressed genes involved in angiogenesis, the polypeptides encoded thereby, and methods of using the same |
MXPA02004879A (es) | 1999-11-16 | 2002-08-30 | Boehringer Ingelheim Pharma | Derivados de urea como agentes antiinflamatorios. |
US6274638B1 (en) | 1999-11-19 | 2001-08-14 | Nippon Shokubai Co., Ltd. | Method for production of porous cross-linked polymer material |
UA75055C2 (uk) | 1999-11-30 | 2006-03-15 | Пфайзер Продактс Інк. | Похідні бензоімідазолу, що використовуються як антипроліферативний засіб, фармацевтична композиція на їх основі |
JP4348506B2 (ja) | 1999-12-20 | 2009-10-21 | 三菱電機株式会社 | 放電加工方法及び装置 |
MXPA02006263A (es) | 1999-12-22 | 2004-02-26 | Sugen Inc | Metodos de modulacion de la funcion de la cinasa de tirosina c-kit de la proteina con compuestos de indolinona. |
DE60018216T2 (de) * | 1999-12-24 | 2006-02-16 | Kyowa Hakko Kogyo Co., Ltd. | Kondensierte purinderivate |
WO2001047890A1 (fr) | 1999-12-24 | 2001-07-05 | Kirin Beer Kabushiki Kaisha | Quinoline, derives de la quinazoline et medicaments contenant ces substances |
ME00415B (me) | 2000-02-15 | 2011-10-10 | Pharmacia & Upjohn Co Llc | Pirol supstituisani 2-indol protein kinazni inhibitori |
JP3657203B2 (ja) | 2000-04-21 | 2005-06-08 | エーザイ株式会社 | 銅クロロフィリン塩含有液剤組成物 |
JP2004512023A (ja) * | 2000-06-09 | 2004-04-22 | コリクサ コーポレイション | 結腸癌の治療および診断のための組成物および方法 |
JP4033605B2 (ja) * | 2000-06-19 | 2008-01-16 | ライオン株式会社 | エアゾール型制汗剤組成物 |
AU2001277621A1 (en) | 2000-08-09 | 2002-03-04 | Astrazeneca Ab | Antiangiogenic bicyclic derivatives |
AU2001253557A1 (en) | 2000-08-24 | 2002-03-04 | Union Carbide Chemicals And Plastics Technology Corporation | Processes for the manufacture of lactones |
TWI283575B (en) | 2000-10-31 | 2007-07-11 | Eisai Co Ltd | Medicinal compositions for concomitant use as anticancer agent |
WO2002041882A2 (en) | 2000-11-22 | 2002-05-30 | Novartis Ag | Combination comprising an agent decreasing vegf activity and an agent decreasing egf activity |
JP2004517080A (ja) | 2000-11-29 | 2004-06-10 | グラクソ グループ リミテッド | Tie−2および/またはvegfr−2の阻害剤として有用なベンゾイミダゾール誘導体 |
CN100523216C (zh) * | 2001-03-02 | 2009-08-05 | 匹兹堡大学 | Pcr方法 |
AU2002254152A1 (en) | 2001-03-08 | 2002-09-24 | Millennium Pharmaceuticals | (homo) piperazine substituted quinolines for inhibiting the phosphorylation of kinases |
JP2004525950A (ja) | 2001-04-06 | 2004-08-26 | ワイス | ラパマイシンとゲムシタビンまたはフルオロウラシルなどの、抗腫瘍剤の組み合わせ |
US20040171068A1 (en) * | 2001-04-19 | 2004-09-02 | Juergen Wehland | Method for producing stable, regeneratable antibody arrays |
TWI324154B (ja) * | 2001-04-27 | 2010-05-01 | Kyowa Hakko Kirin Co Ltd | |
JP3602513B2 (ja) | 2001-04-27 | 2004-12-15 | 麒麟麦酒株式会社 | アゾリル基を有するキノリン誘導体およびキナゾリン誘導体 |
US6812341B1 (en) | 2001-05-11 | 2004-11-02 | Ambion, Inc. | High efficiency mRNA isolation methods and compositions |
AU2002342335B2 (en) | 2001-05-16 | 2006-02-02 | Novartis Ag | Combination comprising N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2pyrimidine-amine and a chemotherapeutic agent |
EP2258366B1 (en) | 2001-06-22 | 2013-04-03 | Kirin Pharma Kabushiki Kaisha | Quinoline derivatives capable of inhibiting autophosphorylation of hepatocyte growth factor receptors, and pharmaceutical composition comprising the same |
GB0117144D0 (en) | 2001-07-13 | 2001-09-05 | Glaxo Group Ltd | Process |
US20030013208A1 (en) * | 2001-07-13 | 2003-01-16 | Milagen, Inc. | Information enhanced antibody arrays |
JP4827154B2 (ja) | 2001-07-25 | 2011-11-30 | 株式会社オーイズミ | 遊技装置 |
GB0119467D0 (en) | 2001-08-09 | 2001-10-03 | Smithkline Beecham Plc | Novel compound |
WO2003023360A2 (en) * | 2001-09-10 | 2003-03-20 | Meso Scale Technologies, Llc | Methods and apparatus for conducting multiple measurements on a sample |
WO2003028711A2 (en) | 2001-09-27 | 2003-04-10 | Novartis Ag | Use of c-kit inhibitors for the treatment of myeloma |
AU2002341881B2 (en) | 2001-09-27 | 2008-05-08 | Allergan, Inc. | 3-(arylamino)methylene-1, 3-dihydro-2h-indol-2-ones as kinase inhibitors |
EP1435959A2 (en) * | 2001-10-09 | 2004-07-14 | University of Cincinnati | Inhibitors of the egf receptor for the treatment of thyroid cancer |
EP1447405A4 (en) | 2001-10-17 | 2005-01-12 | Kirin Brewery | QUINOLINE OR QUINAZOLINE DERIVATIVES INHIBITING THE AUTOPHOSPHORYLATION OF FIBROBLAST GROWTH FACTOR RECEPTORS |
ATE370123T1 (de) | 2001-11-27 | 2007-09-15 | Wyeth Corp | 3-cyanochinoline als inhibitoren von egf-r- und her2-kinasen |
GB0201508D0 (en) * | 2002-01-23 | 2002-03-13 | Novartis Ag | Organic compounds |
EP1481678A4 (en) * | 2002-03-05 | 2009-12-30 | Eisai R&D Man Co Ltd | ANTITUMORAL AGENT CONTAINING A SULFONAMIDE-CONTAINING HETEROCYCLIC COMPOUND AND AN ANGIOGENESIS INHIBITOR |
JP2005520834A (ja) | 2002-03-20 | 2005-07-14 | ダナ−ファーバー キャンサー インスティテュート,インコーポレイテッド | 小細胞肺癌の同定、診断、および治療のための方法および組成物 |
AU2003235838A1 (en) | 2002-05-01 | 2003-11-17 | Kirin Beer Kabushiki Kaisha | Quinoline derivatives and quinazoline derivatives inhibiting autophosphorylation of macrophage colony stimulating factor receptor |
UA77303C2 (en) * | 2002-06-14 | 2006-11-15 | Pfizer | Derivatives of thienopyridines substituted by benzocondensed heteroarylamide useful as therapeutic agents, pharmaceutical compositions and methods for their use |
AU2003251968A1 (en) | 2002-07-16 | 2004-02-02 | Children's Medical Center Corporation | A method for the modulation of angiogenesis |
US7169936B2 (en) * | 2002-07-23 | 2007-01-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Indolinone derivatives substituted in the 6-position, their preparation and their use as medicaments |
US7252976B2 (en) * | 2002-08-28 | 2007-08-07 | Board Of Regents The University Of Texas System | Quantitative RT-PCR to AC133 to diagnose cancer and monitor angiogenic activity in a cell sample |
MXPA05001536A (es) | 2002-08-30 | 2005-04-19 | Eisai Co Ltd | Derivados aromaticos que contienen nitrogeno. |
BR0315169A (pt) | 2002-10-09 | 2005-08-23 | Kosan Biosciences Inc | Referência cruzada a pedidos de patente relacionados |
GB0223380D0 (en) | 2002-10-09 | 2002-11-13 | Astrazeneca Ab | Combination therapy |
US8697094B2 (en) | 2002-10-16 | 2014-04-15 | Takeda Pharmaceutical Company Limited | Stable solid preparations |
DE60305724T2 (de) | 2002-10-21 | 2006-11-09 | Warner-Lambert Co. Llc | Tetrahydrochinolin-derivate als crth2 antagonisten |
WO2004039782A1 (ja) | 2002-10-29 | 2004-05-13 | Kirin Beer Kabushiki Kaisha | Flt3自己リン酸化を阻害するキノリン誘導体およびキナゾリン誘導体並びにそれらを含有する医薬組成物 |
DE10250711A1 (de) * | 2002-10-31 | 2004-05-19 | Degussa Ag | Pharmazeutische und kosmetische Zubereitungen |
GB0225535D0 (en) | 2002-11-01 | 2002-12-11 | Glaxo Group Ltd | Medicinal compounds |
CA2502979A1 (en) | 2002-11-06 | 2004-05-21 | Cyclacel Limited | Pharmaceutical composition comprising a cdk inhibitor and gemcitabine |
GB0226434D0 (en) | 2002-11-13 | 2002-12-18 | Astrazeneca Ab | Combination product |
AR042042A1 (es) | 2002-11-15 | 2005-06-08 | Sugen Inc | Administracion combinada de una indolinona con un agente quimioterapeutico para trastornos de proliferacion celular |
ES2387909T3 (es) | 2003-01-14 | 2012-10-03 | Cytokinetics, Inc. | Compuestos, composiciones y procedimientos de tratamiento de la insuficiencia cardiaca |
US6944063B2 (en) | 2003-01-28 | 2005-09-13 | Sandisk Corporation | Non-volatile semiconductor memory with large erase blocks storing cycle counts |
JP3581361B1 (ja) | 2003-02-17 | 2004-10-27 | 株式会社脳機能研究所 | 脳活動測定装置 |
WO2004078144A2 (en) | 2003-03-05 | 2004-09-16 | Celgene Corporation | Diphenylethylene compounds and uses thereof |
ITMI20030479A1 (it) | 2003-03-13 | 2004-09-14 | Adorkem Technology S P A | Procedimento per la preparazione di un ciano-isobenzofurano. |
JPWO2004081047A1 (ja) * | 2003-03-14 | 2006-06-29 | 大正製薬株式会社 | モノクローナル抗体及びこれを産生するハイブリドーマ |
TW201018661A (en) * | 2003-03-14 | 2010-05-16 | Ono Pharmaceutical Co | Heterocyclic rinf having nitrogen atom derivatives and medicament containing the derivatives as active ingredient |
US20070117842A1 (en) * | 2003-04-22 | 2007-05-24 | Itaru Arimoto | Polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide and a process for the preparation of the same |
JP2005008534A (ja) | 2003-06-17 | 2005-01-13 | Soc De Conseils De Recherches & D'applications Scientifiques (Scras) | 抗癌剤及び癌の治療方法 |
WO2005004870A1 (en) | 2003-07-10 | 2005-01-20 | Astrazeneca Ab | Use of the quinazoline derivative zd6474 combined with platinum compounds and optionally ionising radiation in the treatment of diseases associated with angiogenesis and/or increased vascular permeability |
ATE395052T1 (de) * | 2003-08-15 | 2008-05-15 | Ab Science | Verwendung von c-kit-inhibitoren für die behandlung von typ-2-diabetes |
US7485658B2 (en) * | 2003-08-21 | 2009-02-03 | Osi Pharmaceuticals, Inc. | N-substituted pyrazolyl-amidyl-benzimidazolyl c-Kit inhibitors |
DE602004017623D1 (de) | 2003-08-21 | 2008-12-18 | Osi Pharm Inc | N-substituierte pyrazolyl-amidyl-benzimidazolyl-c-kit-inhibitoren |
CA2535896A1 (en) * | 2003-08-21 | 2005-03-10 | Osi Pharmaceuticals, Inc. | N-substituted benzimidazolyl c-kit inhibitors |
JP2007505938A (ja) | 2003-09-23 | 2007-03-15 | ノバルティス アクチエンゲゼルシャフト | Vegf受容体阻害剤と化学療法剤の組み合わせ |
EP2392564B1 (en) | 2003-09-26 | 2013-10-23 | Exelixis, Inc. | c-Met modulators and methods of use |
WO2005044788A1 (ja) | 2003-11-11 | 2005-05-19 | Eisai Co., Ltd. | ウレア誘導体およびその製造方法 |
CA2546673A1 (en) | 2003-11-28 | 2005-06-09 | Novartis Ag | Diaryl urea derivatives in the treatment of protein kinase dependent diseases |
AU2004296376B2 (en) | 2003-12-05 | 2010-03-04 | Bristol-Myers Squibb Company | Inhibitors of type 2 vascular endothelial growth factor receptors |
CA2543859A1 (en) | 2004-02-27 | 2005-09-09 | Eisai Co., Ltd. | Novel pyridine derivative and pyrimidine derivative (1) |
KR20050091462A (ko) | 2004-03-12 | 2005-09-15 | 한국과학기술연구원 | 푸로피리미딘 화합물 및 이를 포함하는 ddr2 티로신키나아제 활성 저해제 |
KR100986945B1 (ko) | 2004-06-03 | 2010-10-12 | 에프. 호프만-라 로슈 아게 | 젬시타빈 및 egfr-억제제로의 치료 |
US20050288521A1 (en) | 2004-06-29 | 2005-12-29 | Phytogen Life Sciences Inc. | Semi-synthetic conversion of paclitaxel to docetaxel |
WO2006029193A2 (en) * | 2004-09-08 | 2006-03-16 | Pacific Scientific Energetic Materials Company | Process for preparing substituted tetrazoles from aminotetrazole |
WO2006030947A1 (ja) | 2004-09-13 | 2006-03-23 | Eisai R & D Management Co., Ltd. | スルホンアミド含有化合物の血管新生阻害物質との併用 |
US8772269B2 (en) * | 2004-09-13 | 2014-07-08 | Eisai R&D Management Co., Ltd. | Use of sulfonamide-including compounds in combination with angiogenesis inhibitors |
KR20070053205A (ko) | 2004-09-17 | 2007-05-23 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 의약 조성물 |
US20060079494A1 (en) * | 2004-09-27 | 2006-04-13 | Santi Daniel V | Specific kinase inhibitors |
EP1827445A2 (en) | 2004-11-22 | 2007-09-05 | King Pharmaceuticals Research and Development Inc. | Enhancing treatment of cancer and hif-1 mediated disoders with adenosine a3 receptor antagonists |
EP1824843A2 (en) | 2004-12-07 | 2007-08-29 | Locus Pharmaceuticals, Inc. | Inhibitors of protein kinases |
AU2006217692A1 (en) | 2005-02-28 | 2006-08-31 | Eisai R & D Management Co., Ltd. | Novel combinational use of sulfonamide compound |
JP5106098B2 (ja) | 2005-02-28 | 2012-12-26 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | スルホンアミド化合物の抗癌剤との新規併用 |
US7846941B2 (en) | 2005-05-17 | 2010-12-07 | Plexxikon, Inc. | Compounds modulating c-kit and c-fms activity and uses therefor |
US7369245B2 (en) | 2005-05-27 | 2008-05-06 | Honeywell International, Inc. | Sensing coil assembly and method for attaching a sensing coil in a fiber optic gyroscope |
PE20070100A1 (es) | 2005-06-22 | 2007-03-10 | Plexxikon Inc | DERIVADOS DE PIRROLO[2,3-b]PIRIDINA COMO MODULADORES DE QUINASAS |
US7550483B2 (en) * | 2005-06-23 | 2009-06-23 | Eisai R&D Management Co., Ltd. | Amorphous salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and process for preparing the same |
CA2606719C (en) | 2005-06-23 | 2010-08-10 | Eisai R & D Management Co., Ltd. | Amorphous salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and process for producing the same |
WO2007000347A2 (en) | 2005-06-29 | 2007-01-04 | Roselli, Patrizia | Agonistic and antagonistic peptide mimetics of the vegf alpha-helix binding region for use in therapy |
US8101799B2 (en) | 2005-07-21 | 2012-01-24 | Ardea Biosciences | Derivatives of N-(arylamino) sulfonamides as inhibitors of MEK |
US7820664B2 (en) | 2007-01-19 | 2010-10-26 | Bayer Schering Pharma Ag | Inhibitors of MEK |
JP2009502960A (ja) | 2005-07-27 | 2009-01-29 | ザ・ボード・オブ・リージェンツ・オブ・ザ・ユニバーシティ・オブ・テキサス・システム | 膵臓癌の処置のためのゲムシタビンおよびチロシンキナーゼ阻害剤を含む組み合わせ |
US20100105031A1 (en) * | 2005-08-01 | 2010-04-29 | Esai R & D Management Co., Ltd. | Method for prediction of the efficacy of vascularization inhibitor |
WO2007015578A1 (ja) | 2005-08-02 | 2007-02-08 | Eisai R & D Management Co., Ltd. | 血管新生阻害物質の効果を検定する方法 |
WO2007023768A1 (ja) | 2005-08-24 | 2007-03-01 | Eisai R & D Management Co., Ltd. | 新規ピリジン誘導体およびピリミジン誘導体(3) |
US20090053236A1 (en) * | 2005-11-07 | 2009-02-26 | Eisai R & D Management Co., Ltd. | USE OF COMBINATION OF ANTI-ANGIOGENIC SUBSTANCE AND c-kit KINASE INHIBITOR |
US20090247576A1 (en) * | 2005-11-22 | 2009-10-01 | Eisai R & D Management Co., Ltd. | Anti-tumor agent for multiple myeloma |
AR059066A1 (es) | 2006-01-27 | 2008-03-12 | Amgen Inc | Combinaciones del inhibidor de la angiopoyetina -2 (ang2) y el inhibidor del factor de crecimiento endotelial vascular (vegf) |
KR100728926B1 (ko) | 2006-03-20 | 2007-06-15 | 삼성전자주식회사 | 3축 힌지 구조를 갖는 휴대용 전자기기 |
RU2448708C3 (ru) * | 2006-05-18 | 2017-09-28 | Эйсай Ар Энд Ди Менеджмент Ко., Лтд. | Противоопухолевое средство против рака щитовидной железы |
EP2062886B1 (en) * | 2006-08-23 | 2011-11-30 | Eisai R&D Management Co., Ltd. | Salt of phenoxypyridine derivative or crystal thereof and process for producing the same |
WO2008026748A1 (fr) | 2006-08-28 | 2008-03-06 | Eisai R & D Management Co., Ltd. | Agent antitumoral pour cancer gastrique non différencié |
EP2061331A4 (en) | 2006-09-05 | 2010-02-24 | Mcneil Nutritionals Llc | LACTASE-EATABLE EDIBLE PRODUCTS AND APPROPRIATE PROCEDURES |
KR20080022761A (ko) | 2006-09-07 | 2008-03-12 | 삼성전자주식회사 | 화상형성장치의 화소간 정렬 오류 검출 장치 및 방법 |
CN101616671A (zh) | 2007-01-19 | 2009-12-30 | 卫材R&D管理有限公司 | 胰腺癌治疗用组合物 |
CN101600694A (zh) | 2007-01-29 | 2009-12-09 | 卫材R&D管理有限公司 | 未分化型胃癌治疗用组合物 |
JPWO2008111441A1 (ja) | 2007-03-05 | 2010-06-24 | 協和発酵キリン株式会社 | 医薬組成物 |
KR20090116794A (ko) | 2007-03-05 | 2009-11-11 | 교와 핫꼬 기린 가부시키가이샤 | 의약 조성물 |
PE20090368A1 (es) | 2007-06-19 | 2009-04-28 | Boehringer Ingelheim Int | Anticuerpos anti-igf |
CA2694646C (en) | 2007-07-30 | 2017-09-05 | Ardea Biosciences, Inc. | Combinations of mek inhibitors and raf kinase inhibitors and uses thereof |
JP5638244B2 (ja) | 2007-11-09 | 2014-12-10 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 血管新生阻害物質と抗腫瘍性白金錯体との併用 |
JP2009132660A (ja) | 2007-11-30 | 2009-06-18 | Eisai R & D Management Co Ltd | 食道癌治療用組成物 |
JP5399926B2 (ja) | 2008-01-29 | 2014-01-29 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 血管阻害物質とタキサンとの併用 |
GB2456907A (en) | 2008-01-30 | 2009-08-05 | Astrazeneca Ab | Method for determining subsequent VEGFR2 inhibitor therapy comprising measuring baseline VEGF level. |
CA2753844A1 (en) * | 2008-03-05 | 2009-09-11 | Vicus Therapeutics, Llc | Compositions and methods for mucositis and oncology therapies |
US8044240B2 (en) | 2008-03-06 | 2011-10-25 | Ardea Biosciences Inc. | Polymorphic form of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide and uses thereof |
KR20110014149A (ko) | 2008-04-14 | 2011-02-10 | 아디아 바이오사이언스즈 인크. | 조성물 및 이것의 제조 및 사용 방법 |
WO2009140549A1 (en) | 2008-05-14 | 2009-11-19 | Amgen Inc. | Combinations vegf(r) inhibitors and hepatocyte growth factor (c-met) inhibitors for the treatment of cancer |
WO2009150255A2 (en) | 2008-06-13 | 2009-12-17 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Markers for predicting response and survival in anti-egfr treated patients |
CA2729914A1 (en) | 2008-07-11 | 2010-01-14 | Novartis Ag | Combination of (a) a phosphoinositide 3-kinase inhibitor and (b) a modulator of ras/raf/mek pathway |
EP2350663A2 (en) | 2008-10-21 | 2011-08-03 | Bayer HealthCare LLC | Identification of signature genes associated with hepatocellular carcinoma |
AU2010279359A1 (en) | 2009-08-07 | 2012-02-16 | The Wistar Institute | Compositions containing JARID1B inhibitors and methods for treating cancer |
AU2010285740C1 (en) * | 2009-08-19 | 2016-03-17 | Eisai R&D Management Co., Ltd. | Quinoline derivative-containing pharmaceutical composition |
CA2771606A1 (en) * | 2009-08-21 | 2011-02-24 | Mount Sinai School Of Medicine Of New York University | Methods of using cd44 fusion proteins to treat cancer |
EP2293071A1 (en) | 2009-09-07 | 2011-03-09 | Universität Zu Köln | Biomarker for colorectal cancer |
CA2802644C (en) | 2010-06-25 | 2017-02-21 | Eisai R & D Management Co., Ltd. | Antitumor agent using compounds having kinase inhibitory effect in combination |
SG190735A1 (en) * | 2011-02-28 | 2013-07-31 | Calitor Sciences Llc | Substituted quinoline compounds and methods of use |
CA2864394C (en) * | 2011-03-02 | 2021-10-19 | Jack Roth | A method of predicting a response to a tusc2 therapy |
WO2012122444A1 (en) * | 2011-03-10 | 2012-09-13 | Provectus Pharmaceuticals, Inc. | Combination of local and systemic immunomodulative therapies for enhanced treatment of cancer |
WO2012166899A2 (en) | 2011-06-03 | 2012-12-06 | Eisai R&D Management Co., Ltd. | Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds |
-
2005
- 2005-09-14 KR KR1020077001347A patent/KR20070053205A/ko not_active Application Discontinuation
- 2005-09-14 AU AU2005283422A patent/AU2005283422C1/en active Active
- 2005-09-14 US US11/662,425 patent/US8969379B2/en active Active
- 2005-09-14 WO PCT/JP2005/016941 patent/WO2006030826A1/ja active Application Filing
- 2005-09-14 JP JP2006535174A patent/JP4834553B2/ja active Active
- 2005-09-14 CA CA2579810A patent/CA2579810C/en active Active
- 2005-09-14 EP EP05783232A patent/EP1797881B1/en active Active
- 2005-09-14 ES ES05783232T patent/ES2322175T3/es active Active
- 2005-09-14 AT AT05783232T patent/ATE428421T1/de not_active IP Right Cessation
- 2005-09-14 CN CN2005800264687A patent/CN101001629B/zh active Active
- 2005-09-14 DE DE602005013990T patent/DE602005013990D1/de active Active
-
2007
- 2007-03-04 IL IL181697A patent/IL181697A/en active IP Right Grant
-
2013
- 2013-04-25 US US13/870,507 patent/US9504746B2/en active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6328427A (ja) * | 1986-07-22 | 1988-02-06 | Eisai Co Ltd | 調湿剤 |
WO2000071097A1 (fr) * | 1999-05-20 | 2000-11-30 | Takeda Chemical Industries, Ltd. | Composition contenant du sel d'acide ascorbique |
WO2002032872A1 (en) * | 2000-10-20 | 2002-04-25 | Eisai Co., Ltd. | Nitrogenous aromatic ring compounds |
JP2003026576A (ja) * | 2001-05-09 | 2003-01-29 | Eisai Co Ltd | 味覚改善製剤 |
JP2004155773A (ja) * | 2002-10-16 | 2004-06-03 | Takeda Chem Ind Ltd | 安定な固形製剤 |
WO2004080462A1 (ja) * | 2003-03-10 | 2004-09-23 | Eisai Co., Ltd. | c-Kitキナーゼ阻害剤 |
WO2005063713A1 (ja) * | 2003-12-25 | 2005-07-14 | Eisai Co., Ltd. | 4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドの塩またはその溶媒和物の結晶およびそれらの製造方法 |
Also Published As
Publication number | Publication date |
---|---|
US9504746B2 (en) | 2016-11-29 |
ATE428421T1 (de) | 2009-05-15 |
KR20070053205A (ko) | 2007-05-23 |
DE602005013990D1 (de) | 2009-05-28 |
EP1797881B1 (en) | 2009-04-15 |
CN101001629B (zh) | 2010-05-05 |
EP1797881A1 (en) | 2007-06-20 |
CN101001629A (zh) | 2007-07-18 |
US20130237565A1 (en) | 2013-09-12 |
ES2322175T3 (es) | 2009-06-17 |
US20080214604A1 (en) | 2008-09-04 |
AU2005283422C1 (en) | 2017-02-02 |
JPWO2006030826A1 (ja) | 2008-05-15 |
AU2005283422B2 (en) | 2010-05-13 |
WO2006030826A1 (ja) | 2006-03-23 |
CA2579810C (en) | 2012-01-24 |
CA2579810A1 (en) | 2006-03-23 |
EP1797881A4 (en) | 2007-10-10 |
AU2005283422A1 (en) | 2006-03-23 |
US8969379B2 (en) | 2015-03-03 |
IL181697A (en) | 2012-01-31 |
IL181697A0 (en) | 2007-07-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4834553B2 (ja) | 医薬組成物 | |
JP4648835B2 (ja) | 4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドの塩またはその溶媒和物の結晶およびそれらの製造方法 | |
AU2010285740B2 (en) | Quinoline derivative-containing pharmaceutical composition | |
US11524939B2 (en) | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid | |
US20080241077A1 (en) | Benzoylguanidine salt and hydrates thereof | |
WO2015130110A1 (ko) | 무정형 솔리페나신 또는 그의 염을 포함하는 안정성이 증가된 고체분산체 조성물 및 그 제조방법 | |
US20070135446A1 (en) | Benzoylguanidlne salt and hydrates thereof | |
AU2018325267B2 (en) | Crystalline forms of compounds for preventing or treating sensory hair cell death | |
JP2004525969A (ja) | 抗不整脈化合物としての3,7−ジアザビシクロ[3.3.1]製剤 | |
JP4608087B2 (ja) | 固形製剤の製造法 | |
US11795180B2 (en) | Formulation of a pan-JAK inhibitor | |
CN103664880A (zh) | 一种新型抗凝血药物及其制备方法与应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20080801 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20110920 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20110926 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 4834553 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140930 Year of fee payment: 3 |
|
R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |
|
R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |
|
R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |