JP2018515587A - 医薬組成物およびその使用 - Google Patents
医薬組成物およびその使用 Download PDFInfo
- Publication number
- JP2018515587A JP2018515587A JP2017561336A JP2017561336A JP2018515587A JP 2018515587 A JP2018515587 A JP 2018515587A JP 2017561336 A JP2017561336 A JP 2017561336A JP 2017561336 A JP2017561336 A JP 2017561336A JP 2018515587 A JP2018515587 A JP 2018515587A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- micronized
- pharmaceutical composition
- capsule
- value
- 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.)
- Granted
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 88
- 229940126062 Compound A Drugs 0.000 claims abstract description 178
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 178
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 78
- 150000003839 salts Chemical class 0.000 claims description 49
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 40
- 235000019359 magnesium stearate Nutrition 0.000 claims description 39
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 37
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 37
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 37
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 37
- -1 2- (dimethylamino) ethyl Chemical group 0.000 claims description 28
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 27
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 27
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 24
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 23
- 229930195725 Mannitol Natural products 0.000 claims description 23
- 229920002472 Starch Polymers 0.000 claims description 23
- 239000000594 mannitol Substances 0.000 claims description 23
- 235000010355 mannitol Nutrition 0.000 claims description 23
- 239000008107 starch Substances 0.000 claims description 23
- 235000019698 starch Nutrition 0.000 claims description 23
- 239000003085 diluting agent Substances 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 230000005764 inhibitory process Effects 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 15
- 229940023144 sodium glycolate Drugs 0.000 claims description 15
- JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 claims description 15
- 239000000377 silicon dioxide Substances 0.000 claims description 12
- 235000012239 silicon dioxide Nutrition 0.000 claims description 12
- 239000007884 disintegrant Substances 0.000 claims description 11
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 10
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 claims description 7
- 239000004375 Dextrin Substances 0.000 claims description 7
- 229920001353 Dextrin Polymers 0.000 claims description 7
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 claims description 7
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 claims description 7
- 235000019425 dextrin Nutrition 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 6
- 239000008101 lactose Substances 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 6
- 239000000600 sorbitol Substances 0.000 claims description 6
- 235000010356 sorbitol Nutrition 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000009826 distribution Methods 0.000 claims description 2
- BHNHHSOHWZKFOX-UHFFFAOYSA-N 2-methyl-1H-indole Chemical compound C1=CC=C2NC(C)=CC2=C1 BHNHHSOHWZKFOX-UHFFFAOYSA-N 0.000 claims 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 4
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims 4
- 239000002775 capsule Substances 0.000 description 115
- 150000001875 compounds Chemical class 0.000 description 72
- 239000000203 mixture Substances 0.000 description 54
- 201000011519 neuroendocrine tumor Diseases 0.000 description 48
- 239000003826 tablet Substances 0.000 description 34
- 206010028980 Neoplasm Diseases 0.000 description 30
- 208000016065 neuroendocrine neoplasm Diseases 0.000 description 25
- 239000008186 active pharmaceutical agent Substances 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 22
- 239000008187 granular material Substances 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 229940032147 starch Drugs 0.000 description 21
- 239000004615 ingredient Substances 0.000 description 19
- 206010052399 Neuroendocrine tumour Diseases 0.000 description 18
- 241000282472 Canis lupus familiaris Species 0.000 description 17
- 239000011230 binding agent Substances 0.000 description 17
- 230000001186 cumulative effect Effects 0.000 description 16
- 239000008109 sodium starch glycolate Substances 0.000 description 14
- 229920003109 sodium starch glycolate Polymers 0.000 description 14
- 229940079832 sodium starch glycolate Drugs 0.000 description 14
- 239000000843 powder Substances 0.000 description 13
- 239000000523 sample Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 11
- 201000011510 cancer Diseases 0.000 description 9
- 230000033115 angiogenesis Effects 0.000 description 8
- 208000021010 pancreatic neuroendocrine tumor Diseases 0.000 description 8
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 238000005550 wet granulation Methods 0.000 description 8
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000002246 antineoplastic agent Substances 0.000 description 7
- 229940126864 fibroblast growth factor Drugs 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 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 6
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 238000011088 calibration curve Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 238000003260 vortexing Methods 0.000 description 6
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 229920003081 Povidone K 30 Polymers 0.000 description 5
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 210000004204 blood vessel Anatomy 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 239000007963 capsule composition Substances 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 5
- 238000006731 degradation reaction Methods 0.000 description 5
- 229960001375 lactose Drugs 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229960001855 mannitol Drugs 0.000 description 5
- TTZSNFLLYPYKIL-UHFFFAOYSA-N n-[2-(dimethylamino)ethyl]-1-[3-[[4-[(2-methyl-1h-indol-5-yl)oxy]pyrimidin-2-yl]amino]phenyl]methanesulfonamide Chemical compound CN(C)CCNS(=O)(=O)CC1=CC=CC(NC=2N=C(OC=3C=C4C=C(C)NC4=CC=3)C=CN=2)=C1 TTZSNFLLYPYKIL-UHFFFAOYSA-N 0.000 description 5
- 201000002120 neuroendocrine carcinoma Diseases 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 238000013112 stability test Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 108091008794 FGF receptors Proteins 0.000 description 4
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 4
- 239000012980 RPMI-1640 medium Substances 0.000 description 4
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 4
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 4
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 4
- 238000010609 cell counting kit-8 assay Methods 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 201000007028 gastrointestinal neuroendocrine tumor Diseases 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 229960003893 phenacetin Drugs 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000003908 quality control method Methods 0.000 description 4
- 230000010076 replication Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 244000215068 Acacia senegal Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 229920000084 Gum arabic Polymers 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 206010047700 Vomiting Diseases 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 239000000205 acacia gum Substances 0.000 description 3
- 206010064930 age-related macular degeneration Diseases 0.000 description 3
- 239000012496 blank sample Substances 0.000 description 3
- 230000032823 cell division Effects 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 208000002780 macular degeneration Diseases 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 230000006920 protein precipitation Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 230000008673 vomiting Effects 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 102000010792 Chromogranin A Human genes 0.000 description 2
- 108010038447 Chromogranin A Proteins 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 206010052360 Colorectal adenocarcinoma Diseases 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 239000012625 DNA intercalator Substances 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 208000033383 Neuroendocrine tumor of pancreas Diseases 0.000 description 2
- 206010067517 Pancreatic neuroendocrine tumour Diseases 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 229940034982 antineoplastic agent Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229940044683 chemotherapy drug Drugs 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000000132 electrospray ionisation Methods 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 238000002552 multiple reaction monitoring Methods 0.000 description 2
- 230000000955 neuroendocrine Effects 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000007493 shaping process Methods 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012439 solid excipient Substances 0.000 description 2
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 2
- 229940075620 somatostatin analogue Drugs 0.000 description 2
- 238000000527 sonication Methods 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000000528 statistical test Methods 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- PUDHBTGHUJUUFI-SCTWWAJVSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-p Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 PUDHBTGHUJUUFI-SCTWWAJVSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- IVHKZCSZELZKSJ-UHFFFAOYSA-N 2-hydroxyethyl sulfonate Chemical compound OCCOS(=O)=O IVHKZCSZELZKSJ-UHFFFAOYSA-N 0.000 description 1
- SJZRECIVHVDYJC-UHFFFAOYSA-M 4-hydroxybutyrate Chemical compound OCCCC([O-])=O SJZRECIVHVDYJC-UHFFFAOYSA-M 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 102100038238 Aromatic-L-amino-acid decarboxylase Human genes 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 108010072135 Cell Adhesion Molecule-1 Proteins 0.000 description 1
- 102100024649 Cell adhesion molecule 1 Human genes 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 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
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 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 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 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
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000003971 Fibroblast Growth Factor 1 Human genes 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- 102100035308 Fibroblast growth factor 17 Human genes 0.000 description 1
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 1
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 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 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 208000011092 Hand injury Diseases 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 101000878124 Homo sapiens Fibroblast growth factor 17 Proteins 0.000 description 1
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 102000001284 I-kappa-B kinase Human genes 0.000 description 1
- 108060006678 I-kappa-B kinase Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102000015731 Peptide Hormones Human genes 0.000 description 1
- 108010038988 Peptide Hormones Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000037323 Rare tumor Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 102000004874 Synaptophysin Human genes 0.000 description 1
- 108090001076 Synaptophysin Proteins 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 108010035075 Tyrosine decarboxylase Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 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 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 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 1
- 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 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 229920006318 anionic polymer Polymers 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- JPNZKPRONVOMLL-UHFFFAOYSA-N azane;octadecanoic acid Chemical class [NH4+].CCCCCCCCCCCCCCCCCC([O-])=O JPNZKPRONVOMLL-UHFFFAOYSA-N 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 210000004534 cecum Anatomy 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000008199 coating composition Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000011254 conventional chemotherapy Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000003890 endocrine cell Anatomy 0.000 description 1
- 201000011523 endocrine gland cancer Diseases 0.000 description 1
- 230000004528 endothelial cell apoptotic process Effects 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000007773 growth pattern Effects 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- DOUHZFSGSXMPIE-UHFFFAOYSA-N hydroxidooxidosulfur(.) Chemical compound [O]SO DOUHZFSGSXMPIE-UHFFFAOYSA-N 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229960000829 kaolin Drugs 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 108010021336 lanreotide Proteins 0.000 description 1
- 229960002437 lanreotide Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 1
- 208000004995 necrotizing enterocolitis Diseases 0.000 description 1
- 230000017128 negative regulation of NF-kappaB transcription factor activity Effects 0.000 description 1
- 210000005170 neoplastic cell Anatomy 0.000 description 1
- 210000004412 neuroendocrine cell Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 210000000277 pancreatic duct Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 238000007415 particle size distribution analysis Methods 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 238000010827 pathological analysis Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- 239000000813 peptide hormone Substances 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
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000013062 quality control Sample Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 231100000161 signs of toxicity Toxicity 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 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 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229960000575 trastuzumab 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
- 230000005751 tumor progression Effects 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
-
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
少なくとも1種類の薬学上許容可能な賦形剤と、
化合物Aおよびその薬学上許容可能な塩から選択される少なくとも1種類の有効成分と
を含んでなる有効な量の医薬組成物を投与することを含んでなる方法も開示される。いくつかの実施態様では、少なくとも1種類の有効成分は化合物Aである。いくつかの実施態様では、化合物AはI型である。いくつかの実施態様では、化合物Aは実質的に純粋なI型である。いくつかの実施態様では、化合物AはII型である。いくつかの実施態様では、化合物Aは実質的に純粋なII型である。いくつかの実施態様では、化合物A、I型、実質的に純粋なI型、II型、または実質的に純粋なII型は、20.0μm以下、例えば、1.0〜20.0μmの範囲、または2.0〜12.0μmの範囲のD90値で微粉化されている。いくつかの実施態様では、D90値は、1.0から2.0μmまで、2.0より大きく3.0μmまで、3.0より大きく4.0μmまで、4.0より大きく6.0μmまで、6.0より大きく8.0μmまで、8.0より大きく10.0μmまで、または10.0より大きく12.0μmまでの範囲である。いくつかの実施態様では、D90値は、2.0から5.0μmまでの範囲であり、例えば、D90値は、3.0、3.5、または4.0μmである。いくつかの実施態様では、D90値は、9.0から12.0μmまでの範囲であり、例えば、D90値は、9.5または10.0μmである。好ましい実施態様では、D90値は、11.0μm以下であるか、または10.0μm以下である。より好ましい実施態様では、D90値は6.0μm以下である。特定の実施態様では、D90値は4.0μm以下である。
微粉化された化合物Aおよび/または
微粉化された、化合物Aの少なくとも1種類の薬学上許容可能な塩と
少なくとも1種類の薬学上許容可能な賦形剤と
を含んでなる第1の医薬組成物も開示される。
微粉化された化合物Aと、
少なくとも1種類の薬学上許容可能な賦形剤と
を含んでなる第2の医薬組成物も開示される。
化合物A、その薬学上許容可能な塩、および化合物AのI型、実質的に純粋なI型、II型または実質的に純粋なII型から選択される少なくとも1種類の有効医薬成分を少なくとも1種類の薬学上許容可能な賦形剤と混合すること(ここで、化合物A、その薬学上許容可能な塩、および化合物AのI型、実質的に純粋なI型、II型または実質的に純粋なII型は、20μm以下のPSD D90で微粉化されている)、
得られた混合物を乾燥ブレンド、湿式造粒、またはローラー圧縮すること、および
乾燥ブレンド、湿式造粒、もしくはローラー圧縮混合物をカプセルに充填すること、または乾燥ブレンド、湿式造粒、もしくはローラー圧縮混合物を錠剤化すること
を含んでなる。
特に断りのない限り、D90値は、粒子屈折率1.59、吸収指数0.01、および撹拌速度2500rpmを備え、超音波を用いないMalvern 3000およびHYDRO MVまたは同等機を用いたレーザー粒径分布分析法によって取得した。湿式測定のためのサンプル調製は、およそ30mgのサンプルを20mlのガラス瓶に入れること;湿潤サンプルに20滴の0.25%トリトンX−100(w/v)−水を加えた後に10mlの精製水を加えること、2分間音波処理を施すことを含んだ。サンプルは2分以内に分析した。
A.50mgカプセル剤、200mgカプセル剤
200mgカプセル処方物(200mgカプセル剤No.1)(成分は表1に示される通り)を、500グラムの微粉化化合物A(PSD、D90=9.6μm)、277.5グラムのマンニトール、150グラムの微晶質セルロース、50グラムのグリコール酸ナトリウムデンプン、12.5グラムのポリビニルピロリドン(PVP)K30、および10グラムのステアリン酸マグネシウムから調製した。微粉化化合物A(500g、D90=9.6μm)、マンニトール(277.5g)、微晶質セルロース(150g)、およびグリコール酸ナトリウムデンプン(50g)を一緒に混合した。PVP−K30(12.5g)の5%(W/V)水溶液を調製し、結合剤として加えて湿式造粒法により顆粒を作製した。ステアリン酸マグネシウム(10g)を加え、3分間ブレンドした。200mgの化合物Aを含有する最終ブレンドをサイズ#0の各カプセルに充填し、化合物A200mgカプセル製品(200mgカプセル剤No.1)を調製した。この200mgカプセル剤からの化合物Aの累積放出は30分で86.7%であった。安定性試験は、このカプセル剤サンプルが25℃/60%RHで12か月間および40℃/75%RHで6か月間安定であり、含量アッセイに変化は無く、分解も検出されなかったことを示した。安定性試験は継続中である。
300mg錠剤処方物(成分は表3に示される通り)を、4200グラムの微粉化化合物A(PSD、D90=4.8μm)、3360グラムのマンニトール、1512グラムの微晶質セルロース、504グラムのグリコール酸ナトリウムデンプン、403.2グラムのポビドン(PVP)K30、および100.8グラムのステアリン酸マグネシウムから調製した。微粉化化合物A、マンニトール、微晶質セルロースおよびグリコール酸ナトリウムデンプンを一緒に混合した。PVP−K30の12%(W/V)水溶液を調製し、結合剤として加えて湿式造粒法により顆粒を調製した。湿潤顆粒を乾燥させた後、その乾燥顆粒にステアリン酸マグネシウムを加え、その後、3分間ブレンドした。最終ブレンドを300mg錠剤は184kg、250mg錠剤は164kg、200mg錠剤は116kgの圧縮力で圧縮して、300mgの化合物A/錠を含有する長楕円錠とした。錠剤をオパドライ(登録商標)IIの噴霧によりフィルムコーティングした。この300mg錠剤からの化合物Aの累積放出は30分で90.3%であった。
A.50mgカプセル剤
微粉化化合物AのI型(150g、D90=10.0μm)および微晶質セルロース(238.05g)を篩い、均質に混合した。次に、ステアリン酸マグネシウム(1.95g)を加え、ブレンドした。50mgの化合物Aを含有する最終ブレンドをサイズ#3の各カプセルに充填し、表4に示される成分を含む50mg化合物Aカプセル製品(50mgカプセル剤No.5)を調製した。この50mgカプセル剤からの化合物Aの累積放出は30分で96.5%であった。
微粉化化合物AのI型(200g、D90=10.0μm)、微晶質セルロース(178g)、グリコール酸ナトリウムデンプン(9g)、および二酸化ケイ素(9g)を篩い、均質に混合した。次に、ステアリン酸マグネシウム(4g)を加え、3分間ブレンドした。200mgの化合物Aを含有する最終ブレンドをサイズ#0の各カプセルに充填することにより、200mgの微粉化化合物Aカプセル剤(200mgカプセル剤No.2)を得た。この200mgカプセル剤からの化合物Aの累積放出は30分で75.1%であった。安定性試験は、このカプセル剤サンプルが25℃/60%RHで12か月間および40℃/75%RHで6か月間安定であり、含量アッセイに変化は無く、分解も検出されなかったことを示した。
微粉化化合物AのI型(27.8g、D90=3.3μm)および微晶質セルロース(205.1g)を篩い、均質に混合した。次に、ステアリン酸マグネシウム(0.67g)を加え、5分間ブレンドした。25mgの化合物Aを含有する最終ブレンドをサイズ#1の各カプセルに充填し、25mg化合物Aカプセル製品を調製した。25mgカプセル剤からの化合物Aの累積放出は30分で100%であった。
ヒト結腸直腸腺癌細胞株NCI−H716は、ドーパデカルボキシラーゼ活性および細胞質に富む核顆粒などの内分泌細胞の特徴を有することが報告されている。この細胞株の神経内分泌特性を確認するために、ヌードマウスにおいてNCI−H716の皮下腫瘍を確立し、皮下異種移植モデルからの腫瘍組織においてヘマトキシリンおよびエオジン(HE)染色および免疫組織化学(IHC)染色を用いた病理診断を行った。NCI−H716細胞は形態学的に分散成長パターンを示した。新生細胞は均一であり、顕著な核小体を伴うことの多い大きな核を持っていた。IHC染色は、腫瘍組織がCgA(クロモグラニンA)、Syn(シナプトフィジン)およびCD56(神経系細胞接着分子1)であったことを示し、これは神経内分泌腫瘍診断の重要な標準であった。Ki−67指数は80%前後であった。形態学的および免疫組織化学的所見に基づき、NCI−H716異種移植片は神経内分泌癌と見なすことができた。
ヒト腫瘍細胞株:NCI−H716細胞株をATCC(CCL−251(商標))から購入し、5%CO2インキュベーター内で37℃にて10%ウシ胎仔血清(FBS)を加えたRPMI1640培地(Rosewell Park Memorial Institute 1640)中でインキュベートした。
TGI=[1−(Vt−V0)薬物処理/(Vt−V0)ビヒクル]×100%
IRTW(%)=[(TWビヒクル−TW処置)/TWビヒクル]×100%
図1が示すように、化合物Aは、NCI−H716モデルにおいて用量依存的抗腫瘍効果を示した。試験の終了時に、H716腫瘍成長は、化合物A20、40および80mg/kg bidにおいてそれぞれ57.1%、73.9%および80.0%で表された。また、化合物Aは、中用量および高用量で60%を超える腫瘍重量の低下を示した。化合物A処置群をビヒクル処置群と比べた場合に統計的に有意な差が見られた(表7)。化合物A処置マウスに毒性の臨床徴候は見られなかった。
細胞株
NCI−H716:ATCC(American Type Culture Collection)から購入したヒト盲腸結腸直腸腺癌細胞株
培養培地:10%FBSを含有するRPMI 1640
化合物:化合物A(ロット#100223、化合物純度96.7%)は、Hutchison Medipharma Limitedで合成された;
CCK−8キット(Cell Counting Kit−8):銘柄:Dojindo、カタログ番号CK04−01;
マイクロプレートリーダー:モデル:Labsystems Multiskan K3、銘柄:Thermo。
NCI−H716細胞を、10%FBSを含有するRPMI−1640培地で希釈した。90μLの希釈細胞を96ウェルプレートの各ウェルに、各ウェルが1×104細胞を含むように加えた。次に、これらの細胞を37℃、5%CO2で一晩インキュベートした。
10μLのCCK−8溶液を細胞に加え、37℃、5%CO2でさらに1時間インキュベートした。各ウェルの光学密度をLabsystems Multiskan K3により450nmおよび630nmのそれぞれで測定した。
[OD細胞]450−630:化合物処理無しの細胞を含むウェルの光学密度;
[ODバックグラウンド]450−630:培養培地のみを含むウェルの光学密度。
このイヌでのPK試験は、クロスオーバー試験計画の2期間と1週間の休薬期間を含んだ。12個体のビーグル犬を、各群雄3個体と雌3個体の2群に分けた。用量は30mg/kg、イヌ1個体につき1カプセルとした。期間1では、群1にカプセル剤A(微粉化化合物A処方物、実施例1で調製した50mgカプセル剤No.8)を投与し、群2にはカプセル剤B(非微粉化化合物A処方物)を投与した。カプセル剤Bは、上記50mgカプセル剤No.8に関して記載した方法で調製した。各カプセル剤Aおよびカプセル剤Bは50mgの化合物Aを含有した。カプセル剤Aとカプセル剤Bの違いは、カプセル剤Aの化合物Aは微粉化されたD90=8.1μmの化合物AのI型であり、一方、カプセル剤Bの化合物Aは、D90=39.2μmの非微粉化化合物AのI型であるということである。化合物Aの累積放出は30分で、50mgカプセル剤No.8からは98.1%、カプセル剤Bからは75.1%であった。
Symmetry C18カラム(2.1×50mm、3.5μm)をサンプル分析に使用した。多重反応モニタリング(MRM)およびエレクトロスプレーイオン化法(ESI)による陽性モードを適用し、化合物Aの対応する検出イオン(Q1/Q3)は481.2/329.3であった。PKパラメーターは、Kineticaソフトウエアのノンコンパートメント分析を用いて計算した。2種類のカプセル剤の生体内利用率等価性を、信頼区間法による血漿中の化合物Aの暴露に関する、およびフリードマン順位和検定による血漿中の化合物AのTmaxに関する統計検定によって評価した。
化合物A粉末(23.68mg)を秤量し、942μLのDMSOに溶かした。粉末が完全に溶けるまでボルテックスおよび超音波処理を行った。化合物A一次保存溶液は25mg/mLで得られた。化合物A保存溶液(40μL)を960μLアセトニトリルに添加した。ボルテックス後、化合物A二次保存溶液が1.0mg/mLで得られた。
較正標準(C)または品質管理(QC)検量線用溶液(10μL)をナイーブのイヌの血漿190μLに添加した。1分間のボルテックスの後、添加を行った血漿(50μL)をブランク1.5mL管に移した。500ng/mLフェナセチン(内部標準、IS)を含有する150μLのアセトニトリルをタンパク質沈降のために加えた。この管を2分間ボルテックスにかけた後、14000rpmにて4℃で10分間遠心分離した。上清(150μL)を1.5mLブランク管に移し、次いで、150μLの脱イオン水を加えた。1分間のボルテックスの後、最終溶液の1アリコート(10μL)を分析に使用した。
動物試験から得た血漿サンプル(各50μL)を1.5mLブランク管に移し、タンパク質沈降のために500ng/mLフェナセチンを含有する150μLのアセトニトリルを加えた。2分間のボルテックスの後、混合物を遠心分離した(14000rpm、4℃、10分間)。上清(150μL)を1.5mLブランク管に移し、次いで、150μLの脱イオン水を加えた。1分間のボルテックスの後、最終溶液の1アリコート(10μL)を分析のためにLC−MS/MSシステムに注入した。
化合物AおよびISのピーク面積をソフトウエアAnalyst 1.4.1により積分した。標準サンプルから、化合物AとISのピーク面積比を化合物Aの理論濃度に対してプロットすることによって標準曲線を得た。化合物Aの回帰曲線は加重係数1/x2で線形であった。較正標準における化合物Aの理論濃度はそれぞれ2.50、5.0、10、20、50、200、500および1000ng/mLであった。イヌ血漿サンプル中の化合物Aの濃度を、標準曲線を用いて決定した。薬物動態パラメーターは、Thermo Kinetica(登録商標)ソフトウエア(バージョン4.4.1、Thermo Electron Corporation)を用い、血漿濃度−時間データに基づいて計算した。ノンコンパートメント分析を行った。2種類のカプセル剤の生体内利用率等価性を、信頼区間法によるイヌ血漿中の化合物Aの暴露に関する、およびフリードマン順位和検定によるイヌ血漿中の化合物AのTmaxに関する統計検定によって評価した。
各イヌにおける化合物AのPKプロフィールを図2〜図5に示す。時点に対してプロットした化合物Aの平均血漿濃度を図6に示す。
Claims (12)
- 微粉化された化合物A、および/または
微粉化された、化合物Aの少なくとも1種類の薬学上許容可能な塩と、
少なくとも1種類の薬学上許容可能な賦形剤と
を含んでなる医薬組成物であって、
前記微粉化された化合物Aおよび/または微粉化された、化合物Aの少なくとも1種類の薬学上許容可能な塩が、20μm以下の粒径分布(PSD)D90値を有し、
化合物Aが、式:
- 少なくとも1種類の薬学上許容可能な賦形剤と20μm以下のD90値を有する微粉化された化合物Aとを含んでなる医薬組成物であって、
化合物Aが、式:
- 前記微粉化された化合物Aが、微粉化されたI型N−(2−(ジメチルアミノ)エチル)−1−(3−((4−((2−メチル−1H−インドール−5−イル)オキシ)ピリミジン−2−イル)アミノ)フェニル)メタンスルホンアミドである、請求項1または2に記載の医薬組成物。
- 前記微粉化された化合物Aが、微粉化された実質的に純粋なI型N−(2−(ジメチルアミノ)エチル)−1−(3−((4−((2−メチル−1H−インドール−5−イル)オキシ)ピリミジン−2−イル)アミノ)フェニル)メタンスルホンアミドである、請求項1または2に記載の医薬組成物。
- 前記微粉化された化合物Aが、微粉化されたII型N−(2−(ジメチルアミノ)エチル)−1−(3−((4−((2−メチル−1H−インドール−5−イル)オキシ)ピリミジン−2−イル)アミノ)フェニル)メタンスルホンアミドである、請求項1または2に記載の医薬組成物。
- 前記微粉化された化合物Aが、微粉化された実質的に純粋なII型N−(2−(ジメチルアミノ)エチル)−1−(3−((4−((2−メチル−1H−インドール−5−イル)オキシ)ピリミジン−2−イル)アミノ)フェニル)メタンスルホンアミドである、請求項1または2に記載の医薬組成物。
- 前記D90値が11.0μm以下である、請求項1〜6のいずれか一項に記載の医薬組成物。
- 前記D90値が4.0μm以下である、請求項1〜6のいずれか一項に記載の医薬組成物。
- 前記少なくとも1種類の薬学上許容可能な賦形剤が、希釈剤(例えば、マンニトール、微晶質セルロース、デンプン、ラクトース、デキストリン、ソルビトール)、崩壊剤(例えば、グリコール酸ナトリウムデンプン)、造粒結合剤(例えば、ポリビニルピロリドン)、および流動促進剤(例えば、二酸化ケイ素およびステアリン酸マグネシウム)から選択される、請求項1〜8のいずれか一項に記載の医薬組成物。
- FGFR1阻害に応答する少なくとも1つの疾患および/またはKDR阻害に応答する少なくとも1つの疾患に対する処置の必要が認識されている被験体を処置する方法であって、それを必要とする前記被験体に有効な量の請求項1〜9のいずれか一項に記載の医薬組成物を投与することを含んでなる、方法。
- FGFR1阻害に応答する少なくとも1つの疾患および/またはKDR阻害に応答する少なくとも1つの疾患の処置のための、請求項1〜9のいずれか一項に記載の医薬組成物。
- FGFR1阻害に応答する少なくとも1つの疾患および/またはKDR阻害に応答する少なくとも1つの疾患の処置のための薬剤の製造における、請求項1〜9のいずれか一項に記載の医薬組成物の使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2015/079650 WO2016187767A1 (en) | 2015-05-25 | 2015-05-25 | Pharmaceutical compositions and use thereof |
CNPCT/CN2015/079650 | 2015-05-25 | ||
PCT/CN2016/083098 WO2016188399A1 (en) | 2015-05-25 | 2016-05-24 | Pharmaceutical compositions and use thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2018515587A true JP2018515587A (ja) | 2018-06-14 |
JP6878309B2 JP6878309B2 (ja) | 2021-05-26 |
Family
ID=57392304
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017561336A Active JP6878309B2 (ja) | 2015-05-25 | 2016-05-24 | 医薬組成物およびその使用 |
Country Status (26)
Country | Link |
---|---|
US (1) | US20180153890A1 (ja) |
EP (1) | EP3302483B1 (ja) |
JP (1) | JP6878309B2 (ja) |
KR (1) | KR102573278B1 (ja) |
CN (1) | CN107613984B (ja) |
AU (1) | AU2016269304B2 (ja) |
BR (1) | BR112017024126B8 (ja) |
CA (1) | CA2985379C (ja) |
CY (1) | CY1123408T1 (ja) |
DK (1) | DK3302483T3 (ja) |
ES (1) | ES2796575T3 (ja) |
HK (1) | HK1245113A1 (ja) |
HR (1) | HRP20200935T1 (ja) |
HU (1) | HUE050697T2 (ja) |
LT (1) | LT3302483T (ja) |
MX (1) | MX2017014880A (ja) |
MY (1) | MY188169A (ja) |
PH (1) | PH12017502148A1 (ja) |
PL (1) | PL3302483T3 (ja) |
PT (1) | PT3302483T (ja) |
RS (1) | RS60355B1 (ja) |
RU (1) | RU2712187C2 (ja) |
SG (1) | SG10202106375UA (ja) |
SI (1) | SI3302483T1 (ja) |
TW (1) | TWI714588B (ja) |
WO (2) | WO2016187767A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP7486482B2 (ja) | 2018-11-15 | 2024-05-17 | ハチメド リミテッド | フルキンチニブの医薬製剤及びその使用 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3541808A4 (en) * | 2016-11-18 | 2020-07-22 | Hutchison Medipharma Limited | SOLID TUMOR TREATMENT PROCESS |
US20220073642A1 (en) * | 2020-09-07 | 2022-03-10 | Hutchison Medipharma Limited | Methods of using surufatinib in treating advanced pancreatic and extra-pancreatic neuroendocrine tumors |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013511475A (ja) * | 2009-11-23 | 2013-04-04 | ハッチソン メディファーマ リミテッド | 化合物、その一定の新形態、その医薬組成物ならびに製剤化および使用の方法 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6506783B1 (en) * | 1997-05-16 | 2003-01-14 | The Procter & Gamble Company | Cancer treatments and pharmaceutical compositions therefor |
GB9914258D0 (en) * | 1999-06-18 | 1999-08-18 | Celltech Therapeutics Ltd | Chemical compounds |
CA2479665C (en) * | 2002-03-20 | 2011-08-30 | Elan Pharma International Ltd. | Nanoparticulate compositions of angiogenesis inhibitors |
CA2559408C (en) * | 2004-03-15 | 2014-05-13 | Ptc Therapeutics, Inc. | Carboline derivatives useful in the inhibition of angiogenesis |
US8119655B2 (en) * | 2005-10-07 | 2012-02-21 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
JO2860B1 (en) * | 2009-05-07 | 2015-03-15 | ايلي ليلي اند كومباني | Phenylendazolyl compounds |
CN102775385A (zh) * | 2011-05-10 | 2012-11-14 | 湖南有色凯铂生物药业有限公司 | N-取代苯基-n’-取代杂环脲类化合物及其作为抗癌药物的应用 |
-
2015
- 2015-05-25 WO PCT/CN2015/079650 patent/WO2016187767A1/en active Application Filing
-
2016
- 2016-05-24 KR KR1020177035672A patent/KR102573278B1/ko active IP Right Grant
- 2016-05-24 SI SI201630796T patent/SI3302483T1/sl unknown
- 2016-05-24 DK DK16799287.4T patent/DK3302483T3/da active
- 2016-05-24 BR BR112017024126A patent/BR112017024126B8/pt active IP Right Grant
- 2016-05-24 RS RS20200625A patent/RS60355B1/sr unknown
- 2016-05-24 CA CA2985379A patent/CA2985379C/en active Active
- 2016-05-24 AU AU2016269304A patent/AU2016269304B2/en active Active
- 2016-05-24 SG SG10202106375UA patent/SG10202106375UA/en unknown
- 2016-05-24 WO PCT/CN2016/083098 patent/WO2016188399A1/en active Application Filing
- 2016-05-24 ES ES16799287T patent/ES2796575T3/es active Active
- 2016-05-24 HU HUE16799287A patent/HUE050697T2/hu unknown
- 2016-05-24 EP EP16799287.4A patent/EP3302483B1/en active Active
- 2016-05-24 US US15/576,404 patent/US20180153890A1/en not_active Abandoned
- 2016-05-24 CN CN201680026140.3A patent/CN107613984B/zh active Active
- 2016-05-24 PL PL16799287T patent/PL3302483T3/pl unknown
- 2016-05-24 RU RU2017139880A patent/RU2712187C2/ru active
- 2016-05-24 JP JP2017561336A patent/JP6878309B2/ja active Active
- 2016-05-24 LT LTEP16799287.4T patent/LT3302483T/lt unknown
- 2016-05-24 MY MYPI2017704513A patent/MY188169A/en unknown
- 2016-05-24 PT PT167992874T patent/PT3302483T/pt unknown
- 2016-05-24 MX MX2017014880A patent/MX2017014880A/es unknown
- 2016-05-25 TW TW105116234A patent/TWI714588B/zh active
-
2017
- 2017-11-24 PH PH12017502148A patent/PH12017502148A1/en unknown
-
2018
- 2018-04-09 HK HK18104617.5A patent/HK1245113A1/zh unknown
-
2020
- 2020-06-10 HR HRP20200935TT patent/HRP20200935T1/hr unknown
- 2020-06-11 CY CY20201100535T patent/CY1123408T1/el unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013511475A (ja) * | 2009-11-23 | 2013-04-04 | ハッチソン メディファーマ リミテッド | 化合物、その一定の新形態、その医薬組成物ならびに製剤化および使用の方法 |
Non-Patent Citations (1)
Title |
---|
原島秀吉 編集, 新薬剤学(改訂第3版), vol. pp.363-364, JPN6020003304, 15 December 2011 (2011-12-15), ISSN: 0004388178 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP7486482B2 (ja) | 2018-11-15 | 2024-05-17 | ハチメド リミテッド | フルキンチニブの医薬製剤及びその使用 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR101943230B1 (ko) | 항암제로서 라파마이신 및 알부민을 포함하는 나노입자 | |
CN112165958A (zh) | 调制激酶的化合物的制剂 | |
US10561618B2 (en) | Orally available pharmaceutical formulation suitable for improved management of movement disorders | |
CN110191876A (zh) | 用于施用依氟鸟氨酸的制剂 | |
JP2013538200A (ja) | 癌治療用の新規併用療法 | |
RU2769251C2 (ru) | Комбинированная терапия для лечения гепатоцеллюлярной карциномы | |
JP6878309B2 (ja) | 医薬組成物およびその使用 | |
CN110636862A (zh) | 用于治疗乳腺癌的组合疗法 | |
KR20210005714A (ko) | 비스플루오로알킬-1,4-벤조디아제피논 화합물을 포함하는 조합 조성물 및 이의 사용 방법 | |
WO2021154976A1 (en) | Methods of treating brain cancer with panobinostat | |
KR102486126B1 (ko) | 알펠리십을 포함하는 제약 조성물 | |
NZ737544B2 (en) | Micronized compound a, compositions and use thereof | |
KR20200121302A (ko) | 간세포성 암종의 치료를 위한 조합 요법 | |
ES2870718T3 (es) | Formulación de liberación mantenida de la colchicina y métodos para establecer los mismos |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190327 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20200122 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200131 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20200430 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200630 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20201117 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210212 |
|
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: 20210330 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210428 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6878309 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |