JP2019510827A5 - - Google Patents
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- JP2019510827A5 JP2019510827A5 JP2019502548A JP2019502548A JP2019510827A5 JP 2019510827 A5 JP2019510827 A5 JP 2019510827A5 JP 2019502548 A JP2019502548 A JP 2019502548A JP 2019502548 A JP2019502548 A JP 2019502548A JP 2019510827 A5 JP2019510827 A5 JP 2019510827A5
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- cancer
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- 239000012669 liquid formulation Substances 0.000 claims description 79
- 150000001875 compounds Chemical class 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 23
- 235000003599 food sweetener Nutrition 0.000 claims description 21
- 239000003765 sweetening agent Substances 0.000 claims description 21
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- 238000009472 formulation Methods 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- 208000011654 childhood malignant neoplasm Diseases 0.000 claims description 16
- 239000000796 flavoring agent Substances 0.000 claims description 16
- 201000011510 cancer Diseases 0.000 claims description 15
- 208000029824 high grade glioma Diseases 0.000 claims description 13
- 201000011614 malignant glioma Diseases 0.000 claims description 13
- 229960000999 sodium citrate dihydrate Drugs 0.000 claims description 13
- 108090000623 proteins and genes Proteins 0.000 claims description 12
- 206010065859 Congenital fibrosarcoma Diseases 0.000 claims description 11
- 229920000858 Cyclodextrin Polymers 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 235000013355 food flavoring agent Nutrition 0.000 claims description 11
- 235000019596 Masking bitterness Nutrition 0.000 claims description 10
- 206010039491 Sarcoma Diseases 0.000 claims description 10
- 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 9
- 206010010356 Congenital anomaly Diseases 0.000 claims description 8
- 201000008808 Fibrosarcoma Diseases 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 7
- 230000014509 gene expression Effects 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 230000035772 mutation Effects 0.000 claims description 7
- 208000032612 Glial tumor Diseases 0.000 claims description 5
- 206010018338 Glioma Diseases 0.000 claims description 5
- 241000232901 Nephroma Species 0.000 claims description 5
- 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 claims description 5
- 229930006000 Sucrose Natural products 0.000 claims description 5
- 230000008482 dysregulation Effects 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 235000019634 flavors Nutrition 0.000 claims description 5
- 108020001507 fusion proteins Proteins 0.000 claims description 5
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- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 4
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 4
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 claims description 4
- 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 claims description 4
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 4
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 4
- 208000021712 Soft tissue sarcoma Diseases 0.000 claims description 4
- 201000000270 spindle cell sarcoma Diseases 0.000 claims description 4
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 4
- 101150111783 NTRK1 gene Proteins 0.000 claims description 3
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- 101150056950 Ntrk2 gene Proteins 0.000 claims description 3
- 239000004376 Sucralose Substances 0.000 claims description 3
- 235000011187 glycerol Nutrition 0.000 claims description 3
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 3
- 235000019408 sucralose Nutrition 0.000 claims description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 3
- 206010000830 Acute leukaemia Diseases 0.000 claims description 2
- 206010003571 Astrocytoma Diseases 0.000 claims description 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 208000006050 Hemangiopericytoma Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 208000009277 Neuroectodermal Tumors Diseases 0.000 claims description 2
- 206010033701 Papillary thyroid cancer Diseases 0.000 claims description 2
- 206010072450 Spitzoid melanoma Diseases 0.000 claims description 2
- 208000026563 adrenal gland neuroblastoma Diseases 0.000 claims description 2
- 201000010420 adrenal neuroblastoma Diseases 0.000 claims description 2
- 210000000133 brain stem Anatomy 0.000 claims description 2
- 230000001413 cellular effect Effects 0.000 claims description 2
- 201000007455 central nervous system cancer Diseases 0.000 claims description 2
- 208000025997 central nervous system neoplasm Diseases 0.000 claims description 2
- 201000006392 childhood kidney cancer Diseases 0.000 claims description 2
- 208000013549 childhood kidney neoplasm Diseases 0.000 claims description 2
- 230000007773 growth pattern Effects 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 208000029340 primitive neuroectodermal tumor Diseases 0.000 claims description 2
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 claims description 2
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims 6
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims 4
- 125000003275 alpha amino acid group Chemical group 0.000 claims 3
- 239000001509 sodium citrate Substances 0.000 claims 3
- 238000006467 substitution reaction Methods 0.000 claims 3
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 claims 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 claims 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 claims 2
- 239000002253 acid Substances 0.000 claims 2
- 229960004106 citric acid Drugs 0.000 claims 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims 2
- 229960002216 methylparaben Drugs 0.000 claims 2
- 239000004302 potassium sorbate Substances 0.000 claims 2
- 235000010241 potassium sorbate Nutrition 0.000 claims 2
- 229940069338 potassium sorbate Drugs 0.000 claims 2
- 239000000600 sorbitol Substances 0.000 claims 2
- 210000001685 thyroid gland Anatomy 0.000 claims 2
- 208000034951 Genetic Translocation Diseases 0.000 claims 1
- 102100035108 High affinity nerve growth factor receptor Human genes 0.000 claims 1
- 101000596894 Homo sapiens High affinity nerve growth factor receptor Proteins 0.000 claims 1
- 206010038389 Renal cancer Diseases 0.000 claims 1
- 208000006265 Renal cell carcinoma Diseases 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 1
- 235000021028 berry Nutrition 0.000 claims 1
- 210000003716 mesoderm Anatomy 0.000 claims 1
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- 201000010174 renal carcinoma Diseases 0.000 claims 1
- 102200027165 rs201383094 Human genes 0.000 claims 1
- 102200049395 rs2070863 Human genes 0.000 claims 1
- WZWGGYFEOBVNLA-UHFFFAOYSA-N sodium;dihydrate Chemical compound O.O.[Na] WZWGGYFEOBVNLA-UHFFFAOYSA-N 0.000 claims 1
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 claims 1
- 239000006068 taste-masking agent Substances 0.000 claims 1
- 238000000034 method Methods 0.000 description 100
- 239000002904 solvent Substances 0.000 description 14
- DOMVYDBGOVLUEL-UHFFFAOYSA-N 2-hydroxypyrrolidine-1-carboxamide Chemical compound NC(=O)N1CCCC1O DOMVYDBGOVLUEL-UHFFFAOYSA-N 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 4
- 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 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 4
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- 239000001116 FEMA 4028 Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960004853 betadex Drugs 0.000 description 3
- PVNSIYAUPJNAMQ-UHFFFAOYSA-K trisodium 2-hydroxypropane-1,2,3-tricarboxylate heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PVNSIYAUPJNAMQ-UHFFFAOYSA-K 0.000 description 3
- TUMCWFMHZOUPDA-UHFFFAOYSA-N 2-ethylsulfanyl-1,3-benzothiazol-6-amine Chemical compound C1=C(N)C=C2SC(SCC)=NC2=C1 TUMCWFMHZOUPDA-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
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 206010061309 Neoplasm progression Diseases 0.000 description 2
- SOQQBSNVBABHLO-UHFFFAOYSA-K O.O.O.O.O.O.C(CC(O)(C(=O)[O-])CC(=O)[O-])(=O)[O-].[K+].[K+].[K+] Chemical compound O.O.O.O.O.O.C(CC(O)(C(=O)[O-])CC(=O)[O-])(=O)[O-].[K+].[K+].[K+] SOQQBSNVBABHLO-UHFFFAOYSA-K 0.000 description 2
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 2
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- UCCRMEIIRRVQNN-UHFFFAOYSA-H tricalcium 2-hydroxypropane-1,2,3-tricarboxylate hexahydrate Chemical compound O.O.O.O.O.O.C(CC(O)(C(=O)[O-])CC(=O)[O-])(=O)[O-].[Ca+2].C(CC(O)(C(=O)[O-])CC(=O)[O-])(=O)[O-].[Ca+2].[Ca+2] UCCRMEIIRRVQNN-UHFFFAOYSA-H 0.000 description 2
- OHGJCWABWSRBNC-UHFFFAOYSA-H tricalcium;2-hydroxypropane-1,2,3-tricarboxylate;hydrate Chemical compound O.[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 OHGJCWABWSRBNC-UHFFFAOYSA-H 0.000 description 2
- HFNBEHZHDROQEC-UHFFFAOYSA-H tricalcium;2-hydroxypropane-1,2,3-tricarboxylate;trihydrate Chemical compound O.O.O.[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 HFNBEHZHDROQEC-UHFFFAOYSA-H 0.000 description 2
- MCWYAHIQJSBPDX-UHFFFAOYSA-K tripotassium 2-hydroxypropane-1,2,3-tricarboxylate trihydrate Chemical compound O.O.O.[K+].[K+].[K+].OC(CC([O-])=O)(CC([O-])=O)C([O-])=O MCWYAHIQJSBPDX-UHFFFAOYSA-K 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- OBKARMSLSGWHQK-UHFFFAOYSA-K tripotassium;2-hydroxypropane-1,2,3-tricarboxylate;dihydrate Chemical compound O.O.[K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O OBKARMSLSGWHQK-UHFFFAOYSA-K 0.000 description 2
- PKIDNTKRVKSLDB-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;hydrate Chemical compound O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PKIDNTKRVKSLDB-UHFFFAOYSA-K 0.000 description 2
- DVBIMNUZCMCPRL-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O DVBIMNUZCMCPRL-UHFFFAOYSA-K 0.000 description 2
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