JP2016535791A - Cftr媒介性疾患の処置のための医薬組成物を調製する方法 - Google Patents
Cftr媒介性疾患の処置のための医薬組成物を調製する方法 Download PDFInfo
- Publication number
- JP2016535791A JP2016535791A JP2016553220A JP2016553220A JP2016535791A JP 2016535791 A JP2016535791 A JP 2016535791A JP 2016553220 A JP2016553220 A JP 2016553220A JP 2016553220 A JP2016553220 A JP 2016553220A JP 2016535791 A JP2016535791 A JP 2016535791A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- weight
- pharmaceutical composition
- cftr
- tablet
- 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
- 238000000034 method Methods 0.000 title claims abstract description 214
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 220
- 108010079245 Cystic Fibrosis Transmembrane Conductance Regulator Proteins 0.000 title abstract description 66
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title abstract description 46
- 201000010099 disease Diseases 0.000 title abstract description 39
- 230000001404 mediated effect Effects 0.000 title abstract description 13
- 102000008371 intracellularly ATP-gated chloride channel activity proteins Human genes 0.000 title abstract 2
- 238000011282 treatment Methods 0.000 title description 28
- 229940125782 compound 2 Drugs 0.000 claims abstract description 218
- 229940125904 compound 1 Drugs 0.000 claims abstract description 190
- 239000007962 solid dispersion Substances 0.000 claims abstract description 59
- 239000000203 mixture Substances 0.000 claims description 284
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 74
- 239000007787 solid Substances 0.000 claims description 60
- 239000004094 surface-active agent Substances 0.000 claims description 48
- 239000008187 granular material Substances 0.000 claims description 47
- 239000002245 particle Substances 0.000 claims description 38
- 239000011230 binding agent Substances 0.000 claims description 33
- 239000000945 filler Substances 0.000 claims description 33
- 239000007884 disintegrant Substances 0.000 claims description 32
- 238000002360 preparation method Methods 0.000 claims description 30
- 239000000314 lubricant Substances 0.000 claims description 27
- 238000001035 drying Methods 0.000 claims description 25
- 230000008569 process Effects 0.000 claims description 19
- 238000002156 mixing Methods 0.000 claims description 14
- 239000011248 coating agent Substances 0.000 claims description 9
- 238000004458 analytical method Methods 0.000 claims description 8
- 238000000576 coating method Methods 0.000 claims description 7
- 238000001069 Raman spectroscopy Methods 0.000 claims description 5
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 5
- 238000009826 distribution Methods 0.000 claims description 4
- 238000003801 milling Methods 0.000 claims description 3
- 238000012544 monitoring process Methods 0.000 claims description 2
- 238000004497 NIR spectroscopy Methods 0.000 claims 1
- 201000003883 Cystic fibrosis Diseases 0.000 abstract description 69
- PURKAOJPTOLRMP-UHFFFAOYSA-N ivacaftor Chemical compound C1=C(O)C(C(C)(C)C)=CC(C(C)(C)C)=C1NC(=O)C1=CNC2=CC=CC=C2C1=O PURKAOJPTOLRMP-UHFFFAOYSA-N 0.000 abstract description 7
- UFSKUSARDNFIRC-UHFFFAOYSA-N lumacaftor Chemical compound N1=C(C=2C=C(C=CC=2)C(O)=O)C(C)=CC=C1NC(=O)C1(C=2C=C3OC(F)(F)OC3=CC=2)CC1 UFSKUSARDNFIRC-UHFFFAOYSA-N 0.000 abstract description 7
- 239000003826 tablet Substances 0.000 description 228
- 150000001875 compounds Chemical class 0.000 description 109
- 239000000243 solution Substances 0.000 description 82
- 229920000642 polymer Polymers 0.000 description 68
- 210000004027 cell Anatomy 0.000 description 67
- 102000012605 Cystic Fibrosis Transmembrane Conductance Regulator Human genes 0.000 description 64
- 230000000694 effects Effects 0.000 description 52
- 239000002904 solvent Substances 0.000 description 51
- 108020001823 ΔF508-CFTR Proteins 0.000 description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 230000035772 mutation Effects 0.000 description 47
- 239000000654 additive Substances 0.000 description 46
- 238000006243 chemical reaction Methods 0.000 description 41
- 238000009472 formulation Methods 0.000 description 40
- -1 Compound 2 Chemical class 0.000 description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 241000124008 Mammalia Species 0.000 description 37
- 101150029409 CFTR gene Proteins 0.000 description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- 206010064571 Gene mutation Diseases 0.000 description 34
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 33
- 239000003814 drug Substances 0.000 description 33
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 33
- 239000003795 chemical substances by application Substances 0.000 description 32
- 239000003086 colorant Substances 0.000 description 32
- 239000000306 component Substances 0.000 description 32
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 32
- 108091006146 Channels Proteins 0.000 description 30
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 27
- 210000004379 membrane Anatomy 0.000 description 27
- 239000012528 membrane Substances 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 238000007792 addition Methods 0.000 description 26
- 238000003556 assay Methods 0.000 description 26
- 229910052799 carbon Inorganic materials 0.000 description 26
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 26
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 26
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 26
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 238000010922 spray-dried dispersion Methods 0.000 description 24
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- 102200128219 rs75527207 Human genes 0.000 description 22
- 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 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 230000015572 biosynthetic process Effects 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 229920002785 Croscarmellose sodium Polymers 0.000 description 18
- 101000907783 Homo sapiens Cystic fibrosis transmembrane conductance regulator Proteins 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 229960001681 croscarmellose sodium Drugs 0.000 description 18
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 18
- 239000012530 fluid Substances 0.000 description 18
- 102000056427 human CFTR Human genes 0.000 description 18
- 230000037427 ion transport Effects 0.000 description 18
- 239000007995 HEPES buffer Substances 0.000 description 17
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 17
- 239000001913 cellulose Substances 0.000 description 17
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 17
- 238000001694 spray drying Methods 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 16
- 235000010980 cellulose Nutrition 0.000 description 16
- 229920002678 cellulose Polymers 0.000 description 16
- 229940079593 drug Drugs 0.000 description 16
- 235000019359 magnesium stearate Nutrition 0.000 description 16
- 239000000463 material Substances 0.000 description 16
- 229940016286 microcrystalline cellulose Drugs 0.000 description 16
- 239000008108 microcrystalline cellulose Substances 0.000 description 16
- 239000000843 powder Substances 0.000 description 16
- 239000002002 slurry Substances 0.000 description 16
- 238000007906 compression Methods 0.000 description 15
- 230000006835 compression Effects 0.000 description 15
- 239000010410 layer Substances 0.000 description 15
- 102200092601 rs34536353 Human genes 0.000 description 15
- 150000003839 salts Chemical group 0.000 description 15
- 229940124597 therapeutic agent Drugs 0.000 description 15
- 230000000996 additive effect Effects 0.000 description 14
- 239000006185 dispersion Substances 0.000 description 14
- 230000003287 optical effect Effects 0.000 description 14
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 14
- 238000005550 wet granulation Methods 0.000 description 14
- 230000006872 improvement Effects 0.000 description 13
- 239000004615 ingredient Substances 0.000 description 13
- 239000002609 medium Substances 0.000 description 13
- 239000000523 sample Substances 0.000 description 13
- 239000011734 sodium Substances 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 12
- 238000004113 cell culture Methods 0.000 description 12
- 239000000546 pharmaceutical excipient Substances 0.000 description 12
- 102200128203 rs121908755 Human genes 0.000 description 12
- 102200128204 rs121909005 Human genes 0.000 description 12
- 102200128220 rs121909013 Human genes 0.000 description 12
- 102200132013 rs121909041 Human genes 0.000 description 12
- 102200132025 rs150212784 Human genes 0.000 description 12
- 102200132105 rs193922525 Human genes 0.000 description 12
- 102200132035 rs200321110 Human genes 0.000 description 12
- 102200132017 rs267606723 Human genes 0.000 description 12
- 102220020559 rs397508453 Human genes 0.000 description 12
- 102200132015 rs74503330 Human genes 0.000 description 12
- 102200084783 rs749452002 Human genes 0.000 description 12
- 102200030785 rs749758687 Human genes 0.000 description 12
- 239000011780 sodium chloride Substances 0.000 description 12
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 11
- 238000009501 film coating Methods 0.000 description 11
- 239000007888 film coating Substances 0.000 description 11
- 238000005469 granulation Methods 0.000 description 11
- 230000003179 granulation Effects 0.000 description 11
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 11
- 239000000976 ink Substances 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 230000032258 transport Effects 0.000 description 11
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- 230000009477 glass transition Effects 0.000 description 10
- 238000005259 measurement Methods 0.000 description 10
- 239000007921 spray Substances 0.000 description 10
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical group CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 9
- 230000004071 biological effect Effects 0.000 description 9
- 229940045109 genistein Drugs 0.000 description 9
- 235000006539 genistein Nutrition 0.000 description 9
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 description 9
- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 description 9
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 9
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 9
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 9
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- ILNJBIQQAIIMEY-UHFFFAOYSA-N 4-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CN=C21 ILNJBIQQAIIMEY-UHFFFAOYSA-N 0.000 description 8
- 229920002261 Corn starch Polymers 0.000 description 8
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 230000008901 benefit Effects 0.000 description 8
- 239000001506 calcium phosphate Substances 0.000 description 8
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 8
- 238000012937 correction Methods 0.000 description 8
- 239000000975 dye Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000009478 high shear granulation Methods 0.000 description 8
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 8
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- 239000000411 inducer Substances 0.000 description 8
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 8
- 229940011051 isopropyl acetate Drugs 0.000 description 8
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 102200128582 rs113993958 Human genes 0.000 description 8
- 102200132106 rs11971167 Human genes 0.000 description 8
- 102200128167 rs121908753 Human genes 0.000 description 8
- 102220020608 rs186045772 Human genes 0.000 description 8
- 102200132034 rs202179988 Human genes 0.000 description 8
- 102200092599 rs33971270 Human genes 0.000 description 8
- 102200132016 rs34911792 Human genes 0.000 description 8
- 102220020411 rs397508256 Human genes 0.000 description 8
- 102220020548 rs397508442 Human genes 0.000 description 8
- 102220020628 rs397508537 Human genes 0.000 description 8
- 102200086162 rs61754278 Human genes 0.000 description 8
- 102200132008 rs75541969 Human genes 0.000 description 8
- NEMQZDZEKFZZJT-UHFFFAOYSA-N (5-amino-2,4-ditert-butylphenyl) methyl carbonate Chemical compound COC(=O)OC1=CC(N)=C(C(C)(C)C)C=C1C(C)(C)C NEMQZDZEKFZZJT-UHFFFAOYSA-N 0.000 description 7
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 7
- 229930182555 Penicillin Natural products 0.000 description 7
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 7
- 150000001450 anions Chemical class 0.000 description 7
- 229910002091 carbon monoxide Inorganic materials 0.000 description 7
- 210000000170 cell membrane Anatomy 0.000 description 7
- 239000008120 corn starch Substances 0.000 description 7
- 238000000113 differential scanning calorimetry Methods 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 210000000981 epithelium Anatomy 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 208000015700 familial long QT syndrome Diseases 0.000 description 7
- 239000012894 fetal calf serum Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 229940049954 penicillin Drugs 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 238000005070 sampling Methods 0.000 description 7
- 229960005322 streptomycin Drugs 0.000 description 7
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 6
- OGDSGFSPCQGELG-UHFFFAOYSA-N 2-(2,2-difluoro-1,3-benzodioxol-5-yl)acetonitrile Chemical compound C1=C(CC#N)C=C2OC(F)(F)OC2=C1 OGDSGFSPCQGELG-UHFFFAOYSA-N 0.000 description 6
- 239000005711 Benzoic acid Substances 0.000 description 6
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 6
- 206010010356 Congenital anomaly Diseases 0.000 description 6
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 229930006000 Sucrose Natural products 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000002441 X-ray diffraction Methods 0.000 description 6
- 210000003050 axon Anatomy 0.000 description 6
- 235000010233 benzoic acid Nutrition 0.000 description 6
- 239000001768 carboxy methyl cellulose Substances 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 6
- 230000008878 coupling Effects 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 230000007547 defect Effects 0.000 description 6
- 230000007812 deficiency Effects 0.000 description 6
- 230000001419 dependent effect Effects 0.000 description 6
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 6
- 229940038472 dicalcium phosphate Drugs 0.000 description 6
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 238000011067 equilibration Methods 0.000 description 6
- 210000002950 fibroblast Anatomy 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 235000019634 flavors Nutrition 0.000 description 6
- 239000011521 glass Substances 0.000 description 6
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 6
- 150000003840 hydrochlorides Chemical class 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 238000007639 printing Methods 0.000 description 6
- 102200128182 rs74551128 Human genes 0.000 description 6
- 102200128591 rs78655421 Human genes 0.000 description 6
- 239000005720 sucrose Substances 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- VCNWUOJJDJYPBK-UHFFFAOYSA-N 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane-1-carboxamide Chemical compound C=1C=C2OC(F)(F)OC2=CC=1C1(C(=O)N)CC1 VCNWUOJJDJYPBK-UHFFFAOYSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 5
- 208000019693 Lung disease Diseases 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 108010067035 Pancrelipase Proteins 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 150000001412 amines Chemical group 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 239000003623 enhancer Substances 0.000 description 5
- 230000001939 inductive effect Effects 0.000 description 5
- 238000007726 management method Methods 0.000 description 5
- 229960001855 mannitol Drugs 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 229920001592 potato starch Polymers 0.000 description 5
- 238000000634 powder X-ray diffraction Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 230000028327 secretion Effects 0.000 description 5
- 238000007873 sieving Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 239000007916 tablet composition Substances 0.000 description 5
- RZGNTHQZYZRDDB-UHFFFAOYSA-N tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate Chemical compound CC1=CC=C(N)N=C1C1=CC=CC(C(=O)OC(C)(C)C)=C1 RZGNTHQZYZRDDB-UHFFFAOYSA-N 0.000 description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 5
- 210000001215 vagina Anatomy 0.000 description 5
- 239000001993 wax Substances 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- RGKFSYDEMAFDQP-UHFFFAOYSA-N 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane-1-carbonitrile Chemical compound C1=C2OC(F)(F)OC2=CC=C1C1(C#N)CC1 RGKFSYDEMAFDQP-UHFFFAOYSA-N 0.000 description 4
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 4
- VJLDRFCNFNQTTH-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carboxylic acid Chemical compound OC(=O)C1=CC=C2OC(F)(F)OC2=C1 VJLDRFCNFNQTTH-UHFFFAOYSA-N 0.000 description 4
- TWIROCHBZRSMEC-UHFFFAOYSA-N 5-(chloromethyl)-2,2-difluoro-1,3-benzodioxole Chemical compound C1=C(CCl)C=C2OC(F)(F)OC2=C1 TWIROCHBZRSMEC-UHFFFAOYSA-N 0.000 description 4
- 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 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 4
- 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 4
- 239000001856 Ethyl cellulose Substances 0.000 description 4
- 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 4
- 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 4
- 102220471624 Interleukin-10 receptor subunit alpha_P67A_mutation Human genes 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- ABEOIACPXJLEFO-UHFFFAOYSA-N N1=C(C=2C(=C(C(O)=O)C=CC=2)C(C)(C)C)C(C)=CC=C1NC(=O)C1(C=2C=C3OC(F)(F)OC3=CC=2)CC1 Chemical compound N1=C(C=2C(=C(C(O)=O)C=CC=2)C(C)(C)C)C(C)=CC=C1NC(=O)C1(C=2C=C3OC(F)(F)OC3=CC=2)CC1 ABEOIACPXJLEFO-UHFFFAOYSA-N 0.000 description 4
- 206010033645 Pancreatitis Diseases 0.000 description 4
- 208000021386 Sjogren Syndrome Diseases 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 102100026383 Vasopressin-neurophysin 2-copeptin Human genes 0.000 description 4
- 229940081735 acetylcellulose Drugs 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 239000012736 aqueous medium Substances 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 239000004203 carnauba wax Substances 0.000 description 4
- 235000013869 carnauba wax Nutrition 0.000 description 4
- 229920002301 cellulose acetate Polymers 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 230000000875 corresponding effect Effects 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 201000010064 diabetes insipidus Diseases 0.000 description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 4
- 230000002708 enhancing effect Effects 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 235000019325 ethyl cellulose Nutrition 0.000 description 4
- 229920001249 ethyl cellulose Polymers 0.000 description 4
- 210000001508 eye Anatomy 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 229940050410 gluconate Drugs 0.000 description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 4
- 238000000227 grinding Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 4
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 4
- 235000015097 nutrients Nutrition 0.000 description 4
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 4
- 201000009266 primary ciliary dyskinesia Diseases 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 4
- 238000012023 real time release testing Methods 0.000 description 4
- 102200128186 rs121908752 Human genes 0.000 description 4
- 102200128612 rs368505753 Human genes 0.000 description 4
- 102200128244 rs397508288 Human genes 0.000 description 4
- 102220057650 rs730881913 Human genes 0.000 description 4
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 4
- 230000006641 stabilisation Effects 0.000 description 4
- 238000011105 stabilization Methods 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 238000002636 symptomatic treatment Methods 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- PJPDSEYHEHGLOH-UHFFFAOYSA-N (2,2-difluoro-1,3-benzodioxol-5-yl)methanol Chemical compound OCC1=CC=C2OC(F)(F)OC2=C1 PJPDSEYHEHGLOH-UHFFFAOYSA-N 0.000 description 3
- QBDLLAFFRJOLHZ-UHFFFAOYSA-N (2,4-ditert-butyl-5-nitrophenyl) methyl carbonate Chemical compound COC(=O)OC1=CC([N+]([O-])=O)=C(C(C)(C)C)C=C1C(C)(C)C QBDLLAFFRJOLHZ-UHFFFAOYSA-N 0.000 description 3
- FVNYSBKXILOVTD-UHFFFAOYSA-N 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl chloride Chemical compound C1=C2OC(F)(F)OC2=CC=C1C1(C(Cl)=O)CC1 FVNYSBKXILOVTD-UHFFFAOYSA-N 0.000 description 3
- IELWGOUPQRHXLS-UHFFFAOYSA-N 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane-1-carboxylic acid Chemical compound C=1C=C2OC(F)(F)OC2=CC=1C1(C(=O)O)CC1 IELWGOUPQRHXLS-UHFFFAOYSA-N 0.000 description 3
- AEQDJSLRWYMAQI-UHFFFAOYSA-N 2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 description 3
- ICKWICRCANNIBI-UHFFFAOYSA-N 2,4-di-tert-butylphenol Chemical compound CC(C)(C)C1=CC=C(O)C(C(C)(C)C)=C1 ICKWICRCANNIBI-UHFFFAOYSA-N 0.000 description 3
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 3
- 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 3
- VYOPZMJTHXGKID-UHFFFAOYSA-N 4-oxo-2,3-dihydro-1h-quinoline-2-carboxylic acid Chemical group C1=CC=C2NC(C(=O)O)CC(=O)C2=C1 VYOPZMJTHXGKID-UHFFFAOYSA-N 0.000 description 3
- 108700028369 Alleles Proteins 0.000 description 3
- 108091006515 Anion channels Proteins 0.000 description 3
- 102000037829 Anion channels Human genes 0.000 description 3
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 3
- 102000011045 Chloride Channels Human genes 0.000 description 3
- 108010062745 Chloride Channels Proteins 0.000 description 3
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- 229920001328 Polyvinylidene chloride Polymers 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 238000002820 assay format Methods 0.000 description 3
- 238000000889 atomisation Methods 0.000 description 3
- 230000002146 bilateral effect Effects 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 229940124630 bronchodilator Drugs 0.000 description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 3
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 229940125846 compound 25 Drugs 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 108010040974 cystic fibrosis transmembrane conductance regulator delta F508 Proteins 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 3
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 3
- 239000003172 expectorant agent Substances 0.000 description 3
- 239000007941 film coated tablet Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000006194 liquid suspension Substances 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 229940066491 mucolytics Drugs 0.000 description 3
- 210000003097 mucus Anatomy 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 230000002572 peristaltic effect Effects 0.000 description 3
- 229920000573 polyethylene Polymers 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920000915 polyvinyl chloride Polymers 0.000 description 3
- 239000004800 polyvinyl chloride Substances 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 210000001533 respiratory mucosa Anatomy 0.000 description 3
- 102200132108 rs80034486 Human genes 0.000 description 3
- 102200128229 rs80055610 Human genes 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 239000000176 sodium gluconate Substances 0.000 description 3
- 235000012207 sodium gluconate Nutrition 0.000 description 3
- 229940005574 sodium gluconate Drugs 0.000 description 3
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 3
- 239000008109 sodium starch glycolate Substances 0.000 description 3
- 229940079832 sodium starch glycolate Drugs 0.000 description 3
- 229920003109 sodium starch glycolate Polymers 0.000 description 3
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 229910001220 stainless steel Inorganic materials 0.000 description 3
- 239000010935 stainless steel Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- GABVOLXSMGHLPI-UHFFFAOYSA-N tert-butyl 3-(3-methyl-1-oxidopyridin-1-ium-2-yl)benzoate Chemical compound CC1=CC=C[N+]([O-])=C1C1=CC=CC(C(=O)OC(C)(C)C)=C1 GABVOLXSMGHLPI-UHFFFAOYSA-N 0.000 description 3
- VNFCTMXMAKNWDJ-UHFFFAOYSA-N tert-butyl 3-(3-methylpyridin-2-yl)benzoate Chemical compound CC1=CC=CN=C1C1=CC=CC(C(=O)OC(C)(C)C)=C1 VNFCTMXMAKNWDJ-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 229960000707 tobramycin Drugs 0.000 description 3
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 229920003169 water-soluble polymer Polymers 0.000 description 3
- MRZZXDUZVJNFQL-UHFFFAOYSA-N (2,4-ditert-butylphenyl) methyl carbonate Chemical compound COC(=O)OC1=CC=C(C(C)(C)C)C=C1C(C)(C)C MRZZXDUZVJNFQL-UHFFFAOYSA-N 0.000 description 2
- 0 *=C(C1=CNc2ccccc2C1=O)O Chemical compound *=C(C1=CNc2ccccc2C1=O)O 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- PZSISEFPCYMBDL-UHFFFAOYSA-N 2-bromo-3-methylpyridine Chemical compound CC1=CC=CN=C1Br PZSISEFPCYMBDL-UHFFFAOYSA-N 0.000 description 2
- OOUGLTULBSNHNF-UHFFFAOYSA-N 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(C=2N=C(ON=2)C=2C(=CC=CC=2)F)=C1 OOUGLTULBSNHNF-UHFFFAOYSA-N 0.000 description 2
- TZBFDPNSDFVMAL-UHFFFAOYSA-N 3-amino-6-(4-fluorophenyl)-n-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)pyridine-2-carboxamide Chemical group C1=C(N)C(C(=O)NCC(O)(C)C(F)(F)F)=NC(C=2C=CC(F)=CC=2)=C1C(F)(F)F TZBFDPNSDFVMAL-UHFFFAOYSA-N 0.000 description 2
- USHQRIKZLHNPQR-SNVBAGLBSA-N 3-amino-6-methoxy-n-[(2r)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5-(trifluoromethyl)pyridine-2-carboxamide Chemical compound COC1=NC(C(=O)NC[C@@](C)(O)C(F)(F)F)=C(N)C=C1C(F)(F)F USHQRIKZLHNPQR-SNVBAGLBSA-N 0.000 description 2
- DOVVSHMLCFFGGB-SECBINFHSA-N 3-amino-n-[(2r)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5,6-bis(trifluoromethyl)pyridine-2-carboxamide Chemical compound FC(F)(F)[C@@](O)(C)CNC(=O)C1=NC(C(F)(F)F)=C(C(F)(F)F)C=C1N DOVVSHMLCFFGGB-SECBINFHSA-N 0.000 description 2
- IZENJCCFGYRCGJ-UHFFFAOYSA-N 4-[3-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]isoquinolin-1-yl]benzoic acid Chemical group C1=CC(C(=O)O)=CC=C1C1=NC(NC(=O)C2(CC2)C=2C=C3OC(F)(F)OC3=CC=2)=CC2=CC=CC=C12 IZENJCCFGYRCGJ-UHFFFAOYSA-N 0.000 description 2
- SZRHWHHXVXSGMT-UHFFFAOYSA-N 5-bromo-2,2-difluoro-1,3-benzodioxole Chemical compound C1=C(Br)C=C2OC(F)(F)OC2=C1 SZRHWHHXVXSGMT-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical class CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 2
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 description 2
- 206010006474 Bronchopulmonary aspergillosis allergic Diseases 0.000 description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- 206010011732 Cyst Diseases 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 208000024940 Dent disease Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 206010014561 Emphysema Diseases 0.000 description 2
- XRHVZWWRFMCBAZ-UHFFFAOYSA-L Endothal-disodium Chemical compound [Na+].[Na+].C1CC2C(C([O-])=O)C(C(=O)[O-])C1O2 XRHVZWWRFMCBAZ-UHFFFAOYSA-L 0.000 description 2
- 208000002091 Febrile Seizures Diseases 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 108010024636 Glutathione Proteins 0.000 description 2
- 238000012369 In process control Methods 0.000 description 2
- 102000004310 Ion Channels Human genes 0.000 description 2
- 108090000862 Ion Channels Proteins 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 240000003183 Manihot esculenta Species 0.000 description 2
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010061533 Myotonia Diseases 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- HVJDVHCPCSZDSR-UHFFFAOYSA-N [3-[(2-methylpropan-2-yl)oxycarbonyl]phenyl]boronic acid Chemical compound CC(C)(C)OC(=O)C1=CC=CC(B(O)O)=C1 HVJDVHCPCSZDSR-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 description 2
- YWJVTJTVZCWOEL-UHFFFAOYSA-N acetonitrile 2-(2,2-difluoro-1,3-benzodioxol-5-yl)ethyl acetate Chemical compound C(C)#N.C(C)(=O)OCCC1=CC2=C(OC(O2)(F)F)C=C1 YWJVTJTVZCWOEL-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 description 2
- 208000006778 allergic bronchopulmonary aspergillosis Diseases 0.000 description 2
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 2
- 229940009868 aluminum magnesium silicate Drugs 0.000 description 2
- 229940063655 aluminum stearate Drugs 0.000 description 2
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 2
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 2
- 229960003942 amphotericin b Drugs 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 238000000149 argon plasma sintering Methods 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 2
- 229960003644 aztreonam Drugs 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 239000000168 bronchodilator agent Substances 0.000 description 2
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 2
- XSIFPSYPOVKYCO-UHFFFAOYSA-N butyl benzoate Chemical compound CCCCOC(=O)C1=CC=CC=C1 XSIFPSYPOVKYCO-UHFFFAOYSA-N 0.000 description 2
- 102000043927 cAMP-dependent protein kinase catalytic subunit Human genes 0.000 description 2
- 108700038308 cAMP-dependent protein kinase catalytic subunit Proteins 0.000 description 2
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- 238000011088 calibration curve Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000001886 ciliary effect Effects 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 239000004927 clay Substances 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000010924 continuous production Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 229960000913 crospovidone Drugs 0.000 description 2
- 238000002447 crystallographic data Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 2
- 208000031513 cyst Diseases 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 2
- GVGUFUZHNYFZLC-UHFFFAOYSA-N dodecyl benzenesulfonate;sodium Chemical compound [Na].CCCCCCCCCCCCOS(=O)(=O)C1=CC=CC=C1 GVGUFUZHNYFZLC-UHFFFAOYSA-N 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000011143 downstream manufacturing Methods 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 230000001037 epileptic effect Effects 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 2
- YBEOYBKKSWUSBR-UHFFFAOYSA-N ethyl 4-oxo-1h-quinoline-3-carboxylate Chemical compound C1=CC=C2C(=O)C(C(=O)OCC)=CNC2=C1 YBEOYBKKSWUSBR-UHFFFAOYSA-N 0.000 description 2
- 230000004204 exocrine pancreatic function Effects 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 206010016284 febrile convulsion Diseases 0.000 description 2
- 230000035558 fertility Effects 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229960003180 glutathione Drugs 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 229940049654 glyceryl behenate Drugs 0.000 description 2
- 230000005484 gravity Effects 0.000 description 2
- 229920000591 gum Polymers 0.000 description 2
- 229920001903 high density polyethylene Polymers 0.000 description 2
- 239000004700 high-density polyethylene Substances 0.000 description 2
- 230000001744 histochemical effect Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000010965 in-process control Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 229920001684 low density polyethylene Polymers 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- 239000004702 low-density polyethylene Substances 0.000 description 2
- 108010082117 matrigel Proteins 0.000 description 2
- 230000028161 membrane depolarization Effects 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 230000000420 mucociliary effect Effects 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229960000988 nystatin Drugs 0.000 description 2
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000008203 oral pharmaceutical composition Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000005022 packaging material Substances 0.000 description 2
- 229940045258 pancrelipase Drugs 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 229960005455 polacrilin Drugs 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 229920000193 polymethacrylate Polymers 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 2
- 229940116317 potato starch Drugs 0.000 description 2
- 238000011533 pre-incubation Methods 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 238000004886 process control Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 102200093459 rs397517963 Human genes 0.000 description 2
- 102200128617 rs75961395 Human genes 0.000 description 2
- 102200128169 rs77932196 Human genes 0.000 description 2
- 229960002052 salbutamol Drugs 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 229960003310 sildenafil Drugs 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 229940080264 sodium dodecylbenzenesulfonate Drugs 0.000 description 2
- 239000012064 sodium phosphate buffer Substances 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 235000011078 sorbitan tristearate Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical class [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 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 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 238000010200 validation analysis Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- QSIRXSYRKZHJHX-TWXHAJHVSA-N (2s)-6-amino-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-6-amino-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-6-amino-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-6-amino-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2,6-diaminohexanoyl]amino]-4-methylpen Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O QSIRXSYRKZHJHX-TWXHAJHVSA-N 0.000 description 1
- YZBBUYKPTHDZHF-KNVGNIICSA-N (3R)-7,2'-dihydroxy-4'-methoxyisoflavanol Chemical compound OC1=CC(OC)=CC=C1[C@H]1C(O)C2=CC=C(O)C=C2OC1 YZBBUYKPTHDZHF-KNVGNIICSA-N 0.000 description 1
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 1
- MJUVRTYWUMPBTR-MRXNPFEDSA-N 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-n-[1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide Chemical group FC=1C=C2N(C[C@@H](O)CO)C(C(C)(CO)C)=CC2=CC=1NC(=O)C1(C=2C=C3OC(F)(F)OC3=CC=2)CC1 MJUVRTYWUMPBTR-MRXNPFEDSA-N 0.000 description 1
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-Hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 description 1
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 1
- GHHURQMJLARIDK-UHFFFAOYSA-N 2-hydroxypropyl octanoate Chemical compound CCCCCCCC(=O)OCC(C)O GHHURQMJLARIDK-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 1
- YNVODGKBKZCGGN-UHFFFAOYSA-N 3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic acid;hydrochloride Chemical compound Cl.N1=C(C=2C=C(C=CC=2)C(O)=O)C(C)=CC=C1NC(=O)C1(C=2C=C3OC(F)(F)OC3=CC=2)CC1 YNVODGKBKZCGGN-UHFFFAOYSA-N 0.000 description 1
- UWWNIBQLEBYWJZ-UHFFFAOYSA-N 3-amino-5,6-bis(trifluoromethyl)pyridine-2-carboxylic acid Chemical compound NC1=CC(C(F)(F)F)=C(C(F)(F)F)N=C1C(O)=O UWWNIBQLEBYWJZ-UHFFFAOYSA-N 0.000 description 1
- KGUOYCPINMKTEY-HNNXBMFYSA-N 3-amino-6-(2,4-dichlorophenyl)-N-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5-(trifluoromethyl)pyridine-2-carboxamide Chemical compound C1=C(N)C(C(=O)NC[C@@](O)(C)C(F)(F)F)=NC(C=2C(=CC(Cl)=CC=2)Cl)=C1C(F)(F)F KGUOYCPINMKTEY-HNNXBMFYSA-N 0.000 description 1
- GJQPKGWZJDQMIQ-UHFFFAOYSA-N 3-amino-6-(4-fluorophenyl)-n-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)pyridine-2-carboxamide Chemical compound C1=C(N)C(C(=O)NCC(C)(O)C)=NC(C=2C=CC(F)=CC=2)=C1C(F)(F)F GJQPKGWZJDQMIQ-UHFFFAOYSA-N 0.000 description 1
- USHQRIKZLHNPQR-JTQLQIEISA-N 3-amino-6-methoxy-n-[(2s)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5-(trifluoromethyl)pyridine-2-carboxamide Chemical compound COC1=NC(C(=O)NC[C@](C)(O)C(F)(F)F)=C(N)C=C1C(F)(F)F USHQRIKZLHNPQR-JTQLQIEISA-N 0.000 description 1
- CDOUZKKFHVEKRI-UHFFFAOYSA-N 3-bromo-n-[(prop-2-enoylamino)methyl]propanamide Chemical compound BrCCC(=O)NCNC(=O)C=C CDOUZKKFHVEKRI-UHFFFAOYSA-N 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-M 4-phenylbutyrate Chemical compound [O-]C(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-M 0.000 description 1
- AJSFRSHQRVBBKB-UHFFFAOYSA-N 5-(bromomethyl)-2,2-difluoro-1,3-benzodioxole Chemical compound C1=C(CBr)C=C2OC(F)(F)OC2=C1 AJSFRSHQRVBBKB-UHFFFAOYSA-N 0.000 description 1
- MULRCSHSGFGADL-UHFFFAOYSA-N 5-cyclopropyl-2,2-difluoro-1,3-benzodioxole Chemical compound C1=C2OC(F)(F)OC2=CC=C1C1CC1 MULRCSHSGFGADL-UHFFFAOYSA-N 0.000 description 1
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 description 1
- SDDSJMXGJNWMJY-BRHAQHMBSA-N 7-[(2r,4ar,5r,7ar)-2-[(3s)-1,1-difluoro-3-methylpentyl]-2-hydroxy-6-oxo-3,4,4a,5,7,7a-hexahydrocyclopenta[b]pyran-5-yl]heptanoic acid Chemical compound O1[C@](C(F)(F)C[C@@H](C)CC)(O)CC[C@@H]2[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]21 SDDSJMXGJNWMJY-BRHAQHMBSA-N 0.000 description 1
- 102100034452 Alternative prion protein Human genes 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000009575 Angelman syndrome Diseases 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 229920003084 Avicel® PH-102 Polymers 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 206010006448 Bronchiolitis Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 206010059027 Brugada syndrome Diseases 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- KJSSIXIXEIMNCU-UHFFFAOYSA-N CC1=CC=CN=C1C1=CC=CC(C(O)=O)=C1C(C)(C)C Chemical compound CC1=CC=CN=C1C1=CC=CC(C(O)=O)=C1C(C)(C)C KJSSIXIXEIMNCU-UHFFFAOYSA-N 0.000 description 1
- QQXDYWHKPKEBJU-UHFFFAOYSA-N CCCCCCCCCCCCCCCCCC[Na] Chemical compound CCCCCCCCCCCCCCCCCC[Na] QQXDYWHKPKEBJU-UHFFFAOYSA-N 0.000 description 1
- 101100518972 Caenorhabditis elegans pat-6 gene Proteins 0.000 description 1
- 101100283604 Caenorhabditis elegans pigk-1 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000015374 Central core disease Diseases 0.000 description 1
- 101710163595 Chaperone protein DnaK Proteins 0.000 description 1
- 208000010693 Charcot-Marie-Tooth Disease Diseases 0.000 description 1
- 206010008631 Cholera Diseases 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 206010062264 Congenital hyperthyroidism Diseases 0.000 description 1
- 206010056370 Congestive cardiomyopathy Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 1
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 1
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 101000785279 Dictyostelium discoideum Calcium-transporting ATPase PAT1 Proteins 0.000 description 1
- 101001129314 Dictyostelium discoideum Probable plasma membrane ATPase Proteins 0.000 description 1
- 201000010046 Dilated cardiomyopathy Diseases 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 206010013883 Dwarfism Diseases 0.000 description 1
- 208000017701 Endocrine disease Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000003837 Epithelial Sodium Channels Human genes 0.000 description 1
- 108090000140 Epithelial Sodium Channels Proteins 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 229920003137 Eudragit® S polymer Polymers 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 208000024720 Fabry Disease Diseases 0.000 description 1
- 201000011240 Frontotemporal dementia Diseases 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 208000019683 Gorham-Stout disease Diseases 0.000 description 1
- 101710178376 Heat shock 70 kDa protein Proteins 0.000 description 1
- 101710152018 Heat shock cognate 70 kDa protein Proteins 0.000 description 1
- 206010019860 Hereditary angioedema Diseases 0.000 description 1
- 208000028782 Hereditary disease Diseases 0.000 description 1
- 208000033981 Hereditary haemochromatosis Diseases 0.000 description 1
- 206010067265 Heterotaxia Diseases 0.000 description 1
- 101000779309 Homo sapiens Amyloid protein-binding protein 2 Proteins 0.000 description 1
- 101000736368 Homo sapiens PH and SEC7 domain-containing protein 4 Proteins 0.000 description 1
- 101000713296 Homo sapiens Proton-coupled amino acid transporter 1 Proteins 0.000 description 1
- 101000713293 Homo sapiens Proton-coupled amino acid transporter 2 Proteins 0.000 description 1
- 101000713298 Homo sapiens Proton-coupled amino acid transporter 4 Proteins 0.000 description 1
- 101000999322 Homo sapiens Putative insulin-like growth factor 2 antisense gene protein Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- SHBUUTHKGIVMJT-UHFFFAOYSA-N Hydroxystearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OO SHBUUTHKGIVMJT-UHFFFAOYSA-N 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 208000000563 Hyperlipoproteinemia Type II Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020844 Hyperthermia malignant Diseases 0.000 description 1
- 206010051125 Hypofibrinogenaemia Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 208000000038 Hypoparathyroidism Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 208000003892 Kartagener syndrome Diseases 0.000 description 1
- 241001175904 Labeo bata Species 0.000 description 1
- 206010023642 Lacrimation decreased Diseases 0.000 description 1
- DAQAKHDKYAWHCG-UHFFFAOYSA-N Lactacystin Natural products CC(=O)NC(C(O)=O)CSC(=O)C1(C(O)C(C)C)NC(=O)C(C)C1O DAQAKHDKYAWHCG-UHFFFAOYSA-N 0.000 description 1
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 description 1
- 208000015439 Lysosomal storage disease Diseases 0.000 description 1
- 208000007466 Male Infertility Diseases 0.000 description 1
- 208000018717 Malignant hyperthermia of anesthesia Diseases 0.000 description 1
- 208000024556 Mendelian disease Diseases 0.000 description 1
- 208000029725 Metabolic bone disease Diseases 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 208000008955 Mucolipidoses Diseases 0.000 description 1
- 206010072928 Mucolipidosis type II Diseases 0.000 description 1
- 208000002678 Mucopolysaccharidoses Diseases 0.000 description 1
- 206010028289 Muscle atrophy Diseases 0.000 description 1
- 108010021466 Mutant Proteins Proteins 0.000 description 1
- 102000008300 Mutant Proteins Human genes 0.000 description 1
- 102100026784 Myelin proteolipid protein Human genes 0.000 description 1
- 206010068871 Myotonic dystrophy Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- HSVIINWFPKEOEQ-NSHDSACASA-N Ofloxacin methyl ester Chemical compound C([C@H](C)N1C=C(C(C(=C11)C=C2F)=O)C(=O)OC)OC1=C2N1CCN(C)CC1 HSVIINWFPKEOEQ-NSHDSACASA-N 0.000 description 1
- 206010031243 Osteogenesis imperfecta Diseases 0.000 description 1
- 206010049088 Osteopenia Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 102100036232 PH and SEC7 domain-containing protein 4 Human genes 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 208000017493 Pelizaeus-Merzbacher disease Diseases 0.000 description 1
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 1
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 1
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 1
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 108091000054 Prion Proteins 0.000 description 1
- 208000024777 Prion disease Diseases 0.000 description 1
- 201000005660 Protein C Deficiency Diseases 0.000 description 1
- 102100036920 Proton-coupled amino acid transporter 1 Human genes 0.000 description 1
- 102100036919 Proton-coupled amino acid transporter 2 Human genes 0.000 description 1
- 102100036914 Proton-coupled amino acid transporter 4 Human genes 0.000 description 1
- 102100036485 Putative insulin-like growth factor 2 antisense gene protein Human genes 0.000 description 1
- 238000001237 Raman spectrum Methods 0.000 description 1
- 108010000303 Secretory Proteinase Inhibitory Proteins Proteins 0.000 description 1
- 102000002255 Secretory Proteinase Inhibitory Proteins Human genes 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 208000031733 Situs inversus totalis Diseases 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 229920001304 Solutol HS 15 Polymers 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- WBWWGRHZICKQGZ-UHFFFAOYSA-N Taurocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)C(O)C2 WBWWGRHZICKQGZ-UHFFFAOYSA-N 0.000 description 1
- 201000008188 Timothy syndrome Diseases 0.000 description 1
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 1
- 206010045261 Type IIa hyperlipidaemia Diseases 0.000 description 1
- PGAVKCOVUIYSFO-XVFCMESISA-N UTP Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 PGAVKCOVUIYSFO-XVFCMESISA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- IJCWFDPJFXGQBN-RYNSOKOISA-N [(2R)-2-[(2R,3R,4S)-4-hydroxy-3-octadecanoyloxyoxolan-2-yl]-2-octadecanoyloxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCCCCCCCCCCCC IJCWFDPJFXGQBN-RYNSOKOISA-N 0.000 description 1
- PXQMFCILDOBUGK-UUWRZZSWSA-N [(2R)-2-[12-(2-diazo-3,3,3-trifluoropropanoyl)oxydodecanoyloxy]-3-hexadecanoyloxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCOC(=O)C(=[N+]=[N-])C(F)(F)F PXQMFCILDOBUGK-UUWRZZSWSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 210000001552 airway epithelial cell Anatomy 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 229960002105 amrinone Drugs 0.000 description 1
- RNLQIBCLLYYYFJ-UHFFFAOYSA-N amrinone Chemical compound N1C(=O)C(N)=CC(C=2C=CN=CC=2)=C1 RNLQIBCLLYYYFJ-UHFFFAOYSA-N 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- KZNIFHPLKGYRTM-UHFFFAOYSA-N apigenin Chemical compound C1=CC(O)=CC=C1C1=CC(=O)C2=C(O)C=C(O)C=C2O1 KZNIFHPLKGYRTM-UHFFFAOYSA-N 0.000 description 1
- 229940117893 apigenin Drugs 0.000 description 1
- XADJWCRESPGUTB-UHFFFAOYSA-N apigenin Natural products C1=CC(O)=CC=C1C1=CC(=O)C2=CC(O)=C(O)C=C2O1 XADJWCRESPGUTB-UHFFFAOYSA-N 0.000 description 1
- 235000008714 apigenin Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 229960003995 ataluren Drugs 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WNRBERXEBGAUGT-UHFFFAOYSA-N benzo[c]quinolizin-11-ium Chemical group C1=CC=[N+]2C3=CC=CC=C3C=CC2=C1 WNRBERXEBGAUGT-UHFFFAOYSA-N 0.000 description 1
- 150000001562 benzopyrans Chemical class 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- QLFNUXTWJGXNLH-UHFFFAOYSA-N bis(2-methoxyethoxy)alumane Chemical compound COCCO[AlH]OCCOC QLFNUXTWJGXNLH-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000010256 bone deposition Effects 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 230000010478 bone regeneration Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 229960001714 calcium phosphate Drugs 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- WZNRVWBKYDHTKI-UHFFFAOYSA-N cellulose, acetate 1,2,4-benzenetricarboxylate Chemical compound OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O.OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O.CC(=O)OCC1OC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(COC(C)=O)O1.CC(=O)OCC1OC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(COC(C)=O)O1.OC(=O)C1=CC(C(=O)O)=CC=C1C(=O)OCC1C(OC2C(C(OC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)C(OC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)C(COC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)O2)OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)O1 WZNRVWBKYDHTKI-UHFFFAOYSA-N 0.000 description 1
- 201000007303 central core myopathy Diseases 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 210000000254 ciliated cell Anatomy 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 229950005980 cobiprostone Drugs 0.000 description 1
- 238000001246 colloidal dispersion Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 210000002777 columnar cell Anatomy 0.000 description 1
- 238000012777 commercial manufacturing Methods 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000011437 continuous method Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 210000000399 corneal endothelial cell Anatomy 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 229940092125 creon Drugs 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 229940109262 curcumin Drugs 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 235000012754 curcumin Nutrition 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 1
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 description 1
- AUQDITHEDVOTCU-UHFFFAOYSA-N cyclopropyl cyanide Chemical compound N#CC1CC1 AUQDITHEDVOTCU-UHFFFAOYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 description 1
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940018602 docusate Drugs 0.000 description 1
- 108010067396 dornase alfa Proteins 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 238000002036 drum drying Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 208000030172 endocrine system disease Diseases 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 1
- FYUWIEKAVLOHSE-UHFFFAOYSA-N ethenyl acetate;1-ethenylpyrrolidin-2-one Chemical compound CC(=O)OC=C.C=CN1CCCC1=O FYUWIEKAVLOHSE-UHFFFAOYSA-N 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 201000001386 familial hypercholesterolemia Diseases 0.000 description 1
- 229940083280 fd&c blue #1 aluminum lake Drugs 0.000 description 1
- 229960003580 felodipine Drugs 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical class CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 239000013022 formulation composition Substances 0.000 description 1
- 229960000308 fosfomycin Drugs 0.000 description 1
- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N gamma-phenylbutyric acid Natural products OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011086 glassine Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 229960002706 gusperimus Drugs 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 238000013038 hand mixing Methods 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000010370 hearing loss Effects 0.000 description 1
- 231100000888 hearing loss Toxicity 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 239000003481 heat shock protein 90 inhibitor Substances 0.000 description 1
- 208000013746 hereditary thrombophilia due to congenital protein C deficiency Diseases 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N hexane carboxylic acid Natural products CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- 229940072106 hydroxystearate Drugs 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- 229940039009 isoproterenol Drugs 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 238000010902 jet-milling Methods 0.000 description 1
- DAQAKHDKYAWHCG-RWTHQLGUSA-N lactacystin Chemical compound CC(=O)N[C@H](C(O)=O)CSC(=O)[C@]1([C@@H](O)C(C)C)NC(=O)[C@H](C)[C@@H]1O DAQAKHDKYAWHCG-RWTHQLGUSA-N 0.000 description 1
- 238000002356 laser light scattering Methods 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000003591 leukocyte elastase inhibitor Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 201000007004 malignant hyperthermia Diseases 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002779 membrane potential assay Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- UQRORFVVSGFNRO-UTINFBMNSA-N miglustat Chemical compound CCCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO UQRORFVVSGFNRO-UTINFBMNSA-N 0.000 description 1
- 229960001512 miglustat Drugs 0.000 description 1
- PZRHRDRVRGEVNW-UHFFFAOYSA-N milrinone Chemical compound N1C(=O)C(C#N)=CC(C=2C=CN=CC=2)=C1C PZRHRDRVRGEVNW-UHFFFAOYSA-N 0.000 description 1
- 229960003574 milrinone Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000008722 morphological abnormality Effects 0.000 description 1
- 208000020460 mucolipidosis II alpha/beta Diseases 0.000 description 1
- 206010028093 mucopolysaccharidosis Diseases 0.000 description 1
- 230000020763 muscle atrophy Effects 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 208000000638 myeloperoxidase deficiency Diseases 0.000 description 1
- IDINUJSAMVOPCM-INIZCTEOSA-N n-[(1s)-2-[4-(3-aminopropylamino)butylamino]-1-hydroxy-2-oxoethyl]-7-(diaminomethylideneamino)heptanamide Chemical compound NCCCNCCCCNC(=O)[C@H](O)NC(=O)CCCCCCN=C(N)N IDINUJSAMVOPCM-INIZCTEOSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- 150000002825 nitriles Chemical group 0.000 description 1
- 230000008518 non respiratory effect Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- GLZWNFNQMJAZGY-UHFFFAOYSA-N octaethylene glycol Chemical compound OCCOCCOCCOCCOCCOCCOCCOCCO GLZWNFNQMJAZGY-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 208000002865 osteopetrosis Diseases 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000008823 permeabilization Effects 0.000 description 1
- 235000020030 perry Nutrition 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000005426 pharmaceutical component Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 108010023917 phylloxin Proteins 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 1
- 108010040003 polyglutamine Proteins 0.000 description 1
- 229920000155 polyglutamine Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 238000011057 process analytical technology Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 1
- KIDBBTHHMJOMAU-UHFFFAOYSA-N propan-1-ol;hydrate Chemical compound O.CCCO KIDBBTHHMJOMAU-UHFFFAOYSA-N 0.000 description 1
- 230000012846 protein folding Effects 0.000 description 1
- 229940107568 pulmozyme Drugs 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000010925 quality by design Methods 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000002165 resonance energy transfer Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229950005741 rolipram Drugs 0.000 description 1
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
- 229960004017 salmeterol Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229910052594 sapphire Inorganic materials 0.000 description 1
- 239000010980 sapphire Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 238000005029 sieve analysis Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229960000802 sinapultide Drugs 0.000 description 1
- 108010081062 sinapultide Proteins 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 208000008797 situs inversus Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 229940045845 sodium myristate Drugs 0.000 description 1
- 229940045870 sodium palmitate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940080350 sodium stearate Drugs 0.000 description 1
- GGXKEBACDBNFAF-UHFFFAOYSA-M sodium;hexadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCC([O-])=O GGXKEBACDBNFAF-UHFFFAOYSA-M 0.000 description 1
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 description 1
- JUQGWKYSEXPRGL-UHFFFAOYSA-M sodium;tetradecanoate Chemical compound [Na+].CCCCCCCCCCCCCC([O-])=O JUQGWKYSEXPRGL-UHFFFAOYSA-M 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 239000001589 sorbitan tristearate Substances 0.000 description 1
- IJCWFDPJFXGQBN-BIFNRIDTSA-N sorbitan tristearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)[C@H]1OC[C@@H](O)[C@@H]1OC(=O)CCCCCCCCCCCCCCCCC IJCWFDPJFXGQBN-BIFNRIDTSA-N 0.000 description 1
- 229960004129 sorbitan tristearate Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 229960000835 tadalafil Drugs 0.000 description 1
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 description 1
- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 description 1
- LYDRKKWPKKEMNZ-UHFFFAOYSA-N tert-butyl benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=CC=C1 LYDRKKWPKKEMNZ-UHFFFAOYSA-N 0.000 description 1
- ZVSYJXPDCPCFET-UHFFFAOYSA-N tert-butylphosphane hexane Chemical compound C(C)(C)(C)P.CCCCCC ZVSYJXPDCPCFET-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- 229940054369 ultrase Drugs 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 208000013464 vaginal disease Diseases 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 229940053446 vitamin E d-alpha Drugs 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
Images
Classifications
-
- 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—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
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- 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
-
- 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
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 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
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
- G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
- G01J3/28—Investigating the spectrum
- G01J3/44—Raman spectrometry; Scattering spectrometry ; Fluorescence spectrometry
- G01J3/4406—Fluorescence spectrometry
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (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)
- Physics & Mathematics (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Pulmonology (AREA)
- General Physics & Mathematics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
本発明は、3−(6−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)シクロプロパンカルボキサミド)−3−メチルピリジン−2−イル)安息香酸(化合物1)の形態I、および実質的にアモルファスなN−(5−ヒドロキシ−2,4−ジtert−ブチル−フェニル)−4−オキソ−1H−キノリン−3−カルボキサミド(化合物2)を含む固体分散体を含む医薬組成物を調製する方法、処置方法、投与方法、ならびにそのキットに関する。
嚢胞性線維症(CF)は、米国では、およそ30,000人の児童および成人、ならびに欧州ではおよそ30,000人の児童および成人が罹患している、劣性遺伝性疾患である。CFの処置は進歩しているにもかかわらず、治癒しない。
CF患者では、呼吸器上皮において内因的に発現されるCFTRの変異により、イオンおよび流体輸送における不均衡を引き起こす低下した頂端陰イオン分泌がもたらされる。その結果として生じる陰イオン輸送の低下は、肺における粘液蓄積の増強、およびCF患者において最終的に死を引き起こす付随する微生物感染に寄与する。呼吸器疾患に加えて、CF患者は、通常、胃腸の問題および処置されないまま放置されると死に至る膵臓の機能不全を受ける。さらに、嚢胞性線維症の男性の大部分は、生殖能力がなく、嚢胞性線維症の女性の間では、生殖能力が低下する。2つのコピーのCF関連遺伝子の深刻な影響とは対照的に、1つのコピーのCF関連遺伝子を有する個体は、コレラ、および下痢に起因する脱水に対して増大した耐性を示し、おそらく、集団内のCF遺伝子が比較的高い頻度で存在していることが説明される。
化合物2などのCFTRポテンシエーターである化合物、および化合物1などのCFTRコレクターである化合物は、独立して、嚢胞性線維症などのCFTR関連疾患の処置に有用であることが示されている。
本発明は、以下の構造を有する、3−(6−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)シクロプロパンカルボキサミド)−3−メチルピリジン−2−イル)安息香酸である、化合物1の形態I
以下の構造を有する、実質的にアモルファスなN−(5−ヒドロキシ−2,4−ジtert−ブチル−フェニル)−4−オキソ−1H−キノリン−3−カルボキサミドである化合物2の固体分散体
a. 化合物1の形態I、
b. 実質的にアモルファスな化合物2を含む固体分散体、
c. 充填剤、
d. 崩壊剤、
e. 界面活性剤、および
f. 結合剤
を含む、医薬組成物を調製する方法を特徴とする。
a. 化合物1の形態I、
b. 実質的にアモルファスな化合物2を含む固体分散体、
c. 充填剤、
d. 崩壊剤、
e. 界面活性剤、
f. 結合剤、および
g. 滑沢剤
を含む、医薬組成物を調製する方法を特徴とする。
a. 化合物1の形態I、
b. 実質的にアモルファスな化合物2を含む固体分散体、
c. 充填剤、
d. 崩壊剤、
e. 界面活性剤、および
f. 結合剤
を湿式造粒するステップを含む、粒状医薬組成物を調製する方法を特徴とする。
i) 以下の構成成分:
a. 化合物1の形態I、
b. 実質的にアモルファスな化合物2を含む固体分散体、
c. 充填剤、
d. 崩壊剤、
e. 界面活性剤、および
f. 結合剤
を含む、複数の粒状医薬組成物、
ii) 崩壊剤、
iii) 充填剤、および
iv) 滑沢剤
を圧縮するステップを含む、錠剤を調製する方法を特徴とする。
定義
本明細書で使用する場合、「CFTR」は、嚢胞性線維症膜貫通コンダクタンス制御因子を表す。
医薬組成物
a. 化合物1の形態I、
b. 実質的にアモルファスな化合物2の固体分散体、
c. 充填剤、
d. 崩壊剤、
e. 界面活性剤、および
f. 結合剤
を含む、医薬組成物を提供する。
a. 組成物の重量基準で、約43重量%の化合物1の形態I、
b. 組成物の重量基準で、実質的にアモルファスな化合物2を含む約34重量%の固体分散体、
c. 組成物の重量基準で、約17重量%の微結晶性セルロース、
d. 組成物の重量基準で、約2重量%のクロスカルメロースナトリウム、
e. 組成物の重量基準で、約1重量%のラウリル硫酸ナトリウム、および
f. 組成物の重量基準で、約3重量%のポリビニルピロリドン
を含む、粒状医薬組成物である。
a. 組成物の重量基準で、約35重量%の化合物1の形態I、
b. 組成物の重量基準で、実質的にアモルファスな化合物2を含む約28重量%の固体分散体、
c. 組成物の重量基準で、約26重量%の微結晶性セルロース、
d. 組成物の重量基準で、約6重量%のクロスカルメロースナトリウム、
e. 組成物の重量基準で、約3重量%のポリビニルピロリドン、
f. 組成物の重量基準で、約1重量%のラウリル硫酸ナトリウム、および
g. 組成物の重量基準で、約1重量%のステアリン酸マグネシウム
を含む、錠剤である。
a. 組成物の重量基準で、約34重量%の化合物1の形態I、
b. 組成物の重量基準で、実質的にアモルファスな化合物2を含む約27重量%の固体分散体、
c. 組成物の重量基準で、約26重量%の微結晶性セルロース、
d. 組成物の重量基準で、約6重量%のクロスカルメロースナトリウム、
e. 組成物の重量基準で、約2重量%のポリビニルピロリドン、
f. 組成物の重量基準で、約1重量%のラウリル硫酸ナトリウム、
g. 組成物の重量基準で、約1重量%のステアリン酸マグネシウム、
h. 組成物の重量基準で、約3重量%の着色剤、および
i. 組成物の重量基準で、約0.010重量%のワックス
を含む、錠剤である。
a. 約150〜250mgの化合物1の形態I、
b. 約100〜150mgの実質的にアモルファスな化合物2、
c. 約125〜175mgの微結晶性セルロース、
d. 約20〜40mgのクロスカルメロースナトリウム、
e. 約10〜20mgのポリビニルピロリドン、
f. 約2〜6mgのラウリル硫酸ナトリウム、および
g. 約3〜7mgのステアリン酸マグネシウム
を含む。
a. 約200mgの化合物1の形態I、
b. 約125mgの実質的にアモルファスな化合物2、
c. 約150mgの微結晶性セルロース、
d. 約34mgのクロスカルメロースナトリウム、
e. 約15mgのポリビニルピロリドン、
f. 約4mgのラウリル硫酸ナトリウム、および
g. 約6mgのステアリン酸マグネシウム
を含む。
a. 約200mgの化合物1の形態I、
b. 約125mgの実質的にアモルファスな化合物2、
c. 約150mgの微結晶性セルロース、
d. 約34mgのクロスカルメロースナトリウム、
e. 約15mgのポリビニルピロリドン、
f. 約4mgのラウリル硫酸ナトリウム、
g. 約6mgのステアリン酸マグネシウム、
h. 約17mgの着色剤、および
i. 約0.06mgのワックス
を含む。
a. 組成物の重量基準で、約38重量%の化合物1の形態I、
b. 組成物の重量基準で、実質的にアモルファスな化合物2を含む約40重量%の固体分散体、
c. 組成物の重量基準で、約16重量%の微結晶性セルロース、
d. 組成物の重量基準で、約2重量%のクロスカルメロースナトリウム、
e. 組成物の重量基準で、約1重量%のラウリル硫酸ナトリウム、および
f. 組成物の重量基準で、約3重量%のポリビニルピロリドン
を含む、粒状医薬組成物である。
a. 組成物の重量基準で、約31重量%の化合物1の形態I、
b. 組成物の重量基準で、実質的にアモルファスな化合物2を含む約32重量%の固体分散体、
c. 組成物の重量基準で、約26重量%の微結晶性セルロース、
d. 組成物の重量基準で、約6重量%のクロスカルメロースナトリウム、
e. 組成物の重量基準で、約3重量%のポリビニルピロリドン、
f. 組成物の重量基準で、約1重量%のラウリル硫酸ナトリウム、
g. 組成物の重量基準で、約1重量%のステアリン酸マグネシウム、および
h. 組成物の重量基準で、約3重量%の着色剤
を含む、錠剤である。
a. 約100〜200mgの化合物1の形態I、
b. 約100〜150mgの実質的にアモルファスな化合物2、
c. 約100〜150mgの微結晶性セルロース、
d. 約20〜40mgのクロスカルメロースナトリウム、
e. 約10〜20mgのポリビニルピロリドン、
f. 約2〜6mgのラウリル硫酸ナトリウム、および
g. 約3〜7mgのステアリン酸マグネシウム
を含む。
a. 約150mgの化合物1の形態I、
b. 約125mgの実質的にアモルファスな化合物2、
c. 約129mgの微結晶性セルロース、
d. 約29mgのクロスカルメロースナトリウム、
e. 約13mgのポリビニルピロリドン、
f. 約4mgのラウリル硫酸ナトリウム、
g. 約5mgのステアリン酸マグネシウム、および
h. 約15mgの着色剤
を含む。
化合物1の形態Iおよび実質的にアモルファスな化合物2を含む固体分散体を作製する方法
化合物1
スキーム2.酸塩化物部分の代替合成。
スキーム3.アミン部分の合成。
スキーム4.3−(6−(1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)シクロプロパンカルボキサミド)−3−メチルピリジン−2−イル)安息香酸の酸塩の形成。
化合物1の形態I
化合物2
スキーム5:4−オキソ−ジヒドロキノリンカルボン酸部分の合成。
化合物2から始めて、化合物2のアモルファス形態は、スプレー乾燥法により調製することができる。スプレー乾燥は、液体フィードを乾燥粒子形態に変換する方法である。任意選択で、流動床乾燥または真空乾燥などの第2の乾燥方法を使用して、残留溶媒を薬学的に許容されるレベルまで低下させてもよい。通常、スプレー乾燥には、高度に分散された液状懸濁液または溶液と十分な量の熱風とを接触させて、蒸発および液滴の乾燥を生じさせることが含まれる。スプレー乾燥される調製物は、選択されるスプレー乾燥装置を使用して噴霧化することができる、任意の溶液、粗懸濁液、スラリー、コロイド状分散液、またはペーストであり得る。標準的手順では、調製物は、溶媒を蒸発させて乾燥済み生成物を収集機(例えば、サイクロン)に運ぶ、温かい濾過空気流にスプレーされる。次に、消費された空気を溶媒と一緒に排気するか、または代替として消費された空気をコンデンサーに送り、溶媒を捕捉および可能性として再利用する。市販タイプの装置を使用して、スプレー乾燥を行うことができる。例えば、市販のスプレー乾燥器は、Buchi Ltd.およびNiro(例えば、Niroにより製造されているスプレー乾燥器のPSDライン)(US2004/0105820;US2003/0144257を参照されたい)により製造されている。
医薬組成物を作製する方法
造粒および圧縮
医薬組成物を投与する方法
組成物の治療的使用
方法2
方法2
方法2
造粒器:ConsiGmaまたはLeistritzまたはThermo Fisher2軸造粒器。
造粒用液−SLSおよび結合剤を精製水に加え、溶解するまで混合する。好適な比は、水中で、2.5%w/wSLSと10.0%w/w PVP K30である。
造粒−化合物1および添加剤を含有するブレンドは、10kg/時の速度のロスインウェイトフィーダーを使用して、2軸造粒器に投入することができる。造粒用液は、3.5kg/時の速度の蠕動ポンプを使用して加えることができる。造粒器は、400RPMの速度で操作することができる。本2軸湿式造粒法の注目に値する利点は、湿潤性の向上により、より優れた造粒のための界面活性剤および結合剤の両方を含む造粒用液を使用する点である。一実施形態では、界面活性剤は、SLSである。別の注目に値する利点は、本方法が連続的であり、かつ時間内のいつでも、限られた量の材料だけが加工されるので、本方法が良好に制御され、生成物が高品質になることである。
アッセイ
化合物のΔF508−CFTRモジュレーション特性をアッセイするための膜電位光学法
ポテンシエーター化合物の同定
溶液
細胞培養物
ウッシングチャンバーアッセイ
ポテンシエーター化合物の同定
パッチクランプ記録
ポテンシエーター化合物の同定
細胞培養物
単一チャネル記録
細胞培養物
補正化合物の同定
ポテンシエーター化合物の同定
溶液
細胞培養物
ウッシングチャンバーアッセイ
補正化合物の同定
ポテンシエーター化合物の同定
溶液
細胞培養物
ホールセル記録
補正化合物の同定
ポテンシエーター化合物の同定
溶液
細胞培養物
単一チャネル記録
溶液
細胞培養物
Claims (3)
- 化合物1の形態I、および実質的にアモルファスな化合物2を含む固体分散体を含む錠剤の連続調製方法であって、
a) ブレンダー中で、化合物1の形態I、実質的にアモルファスな化合物2を含む固体分散体、充填剤および崩壊剤を混合して、ブレンドを形成するステップ、
b) 水、結合剤および界面活性剤を含む造粒用溶液を調製するステップ、
c) ステップa)から得られた前記ブレンドを、ステップb)から得られた前記造粒用溶液を添加しながら連続2軸造粒器にフィードして、顆粒を製造するステップ、
d) ステップc)から得られた前記顆粒を乾燥して、前記顆粒をミル粉砕するステップ、
e) ステップd)から得られた前記ミル粉砕顆粒を充填剤、崩壊剤および滑沢剤とブレンドしてブレンドを形成するステップ、ならびに
f) ステップe)から得られた前記ブレンドを圧縮して錠剤にするステップ
を含み、
上記ステップの少なくとも1つが、プロセス分析技法を含む、
方法。 - 前記プロセス分析技法が、規定基準をモニタリングするためのNIRまたはラマン分光技法を含む、請求項1に記載の方法。
- 前記規定基準が、ブレンド均質性、顆粒均質性、水分、粒子サイズ分布、活性医薬品成分の固体形態の同一性、重量、厚さ、硬度またはコーティング厚さから選択される、請求項2に記載の方法。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2021112157A JP2021165300A (ja) | 2013-11-12 | 2021-07-06 | Cftr媒介性疾患の処置のための医薬組成物を調製する方法 |
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361903010P | 2013-11-12 | 2013-11-12 | |
US61/903,010 | 2013-11-12 | ||
US201461929604P | 2014-01-21 | 2014-01-21 | |
US61/929,604 | 2014-01-21 | ||
US201462000659P | 2014-05-20 | 2014-05-20 | |
US62/000,659 | 2014-05-20 | ||
PCT/US2014/063506 WO2015073231A1 (en) | 2013-11-12 | 2014-10-31 | Process of preparing pharmaceutical compositions for the treatment of cftr mediated diseases |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021112157A Division JP2021165300A (ja) | 2013-11-12 | 2021-07-06 | Cftr媒介性疾患の処置のための医薬組成物を調製する方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2016535791A true JP2016535791A (ja) | 2016-11-17 |
JP6963896B2 JP6963896B2 (ja) | 2021-11-10 |
Family
ID=53057872
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016553220A Active JP6963896B2 (ja) | 2013-11-12 | 2014-10-31 | Cftr媒介性疾患の処置のための医薬組成物を調製する方法 |
JP2021112157A Withdrawn JP2021165300A (ja) | 2013-11-12 | 2021-07-06 | Cftr媒介性疾患の処置のための医薬組成物を調製する方法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021112157A Withdrawn JP2021165300A (ja) | 2013-11-12 | 2021-07-06 | Cftr媒介性疾患の処置のための医薬組成物を調製する方法 |
Country Status (23)
Country | Link |
---|---|
US (1) | US10231932B2 (ja) |
EP (1) | EP3068392B9 (ja) |
JP (2) | JP6963896B2 (ja) |
KR (1) | KR102280372B1 (ja) |
CN (1) | CN105848657B (ja) |
AU (1) | AU2014349010C1 (ja) |
BR (1) | BR112016010403A2 (ja) |
CA (1) | CA2930199C (ja) |
DK (1) | DK3068392T5 (ja) |
ES (1) | ES2865600T3 (ja) |
HR (1) | HRP20210516T2 (ja) |
HU (1) | HUE054389T2 (ja) |
IL (2) | IL245584A0 (ja) |
MX (1) | MX2016006118A (ja) |
NZ (1) | NZ720958A (ja) |
PL (1) | PL3068392T3 (ja) |
PT (1) | PT3068392T (ja) |
RS (1) | RS61790B1 (ja) |
RU (2) | RU2718044C2 (ja) |
SG (1) | SG10201803930QA (ja) |
SI (1) | SI3068392T1 (ja) |
WO (1) | WO2015073231A1 (ja) |
ZA (1) | ZA201603973B (ja) |
Families Citing this family (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100074949A1 (en) | 2008-08-13 | 2010-03-25 | William Rowe | Pharmaceutical composition and administration thereof |
WO2006002421A2 (en) | 2004-06-24 | 2006-01-05 | Vertex Pharmaceuticals Incorporated | Modulators of atp-binding cassette transporters |
KR101331768B1 (ko) | 2005-11-08 | 2013-11-22 | 버텍스 파마슈티칼스 인코포레이티드 | Atp 결합 카세트 수송체의 헤테로사이클릭 조정제 |
ES2624554T3 (es) | 2005-12-28 | 2017-07-14 | Vertex Pharmaceuticals Incorporated | Formas sólidas de n- [2,4 - bis (1,1 - dimetiletil) - 5 - hidroxifenil] - 1,4 - dihidro - 4 - oxoquinolina - 3 - carboxamida |
US7645789B2 (en) | 2006-04-07 | 2010-01-12 | Vertex Pharmaceuticals Incorporated | Indole derivatives as CFTR modulators |
NZ571803A (en) | 2006-04-07 | 2011-12-22 | Vertex Pharma | Amide indole derivatives as modulators of ATP-binding cassette transporters |
US10022352B2 (en) | 2006-04-07 | 2018-07-17 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
US8802868B2 (en) | 2010-03-25 | 2014-08-12 | Vertex Pharmaceuticals Incorporated | Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide |
CN102917692A (zh) | 2010-04-07 | 2013-02-06 | 弗特克斯药品有限公司 | 3-(6-(1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)环丙甲酰胺基)-3-甲基吡啶-2-基)苯甲酸的药物组合物和其给药方法 |
CA2797118C (en) | 2010-04-22 | 2021-03-30 | Vertex Pharmaceuticals Incorporated | Process of producing cycloalkylcarboxamido-indole compounds |
US20130186801A1 (en) * | 2012-01-25 | 2013-07-25 | Vertex Pharmaceuticals Incorporated | Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid |
BR112014021090B1 (pt) | 2012-02-27 | 2023-01-24 | Vertex Pharmaceuticals Incorporated | Composição farmacêutica e uso de n-[2,4-bis(1,1-dimetiletil)-5-hidróxifenil]-1,4-di-hidro-4-oxoquinolina3-carboxamida na preparação da mesma |
WO2014014841A1 (en) | 2012-07-16 | 2014-01-23 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions of (r)-1-(2,2-diflurorbenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl) cyclopropanecarboxamide and administration thereof |
EP3131582B1 (en) | 2014-04-15 | 2018-05-23 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases |
CN107690281B (zh) | 2014-10-06 | 2020-11-17 | 弗特克斯药品有限公司 | 囊性纤维化跨膜转导调节因子调节剂 |
US10653622B1 (en) * | 2015-04-13 | 2020-05-19 | Pharmacoustics Technologies LLC | Individualized solid dosage products and a system and method for the globally integrated pharmaceutical manufacturing and its monitoring thereof |
US20180250232A1 (en) * | 2015-09-03 | 2018-09-06 | Merck Sharp & Dohme Corp. | Process for preparing spray dried solid dispersions of (s)-n-(3-(6-isopropoxypyridin-3-yl)-1h-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2h)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide for pharmaceutical preparations |
WO2017170858A1 (ja) | 2016-03-31 | 2017-10-05 | 大日本住友製薬株式会社 | 溶出性に優れた経口製剤 |
US10383865B2 (en) | 2016-04-25 | 2019-08-20 | Druggability Technologies Ip Holdco Limited | Pharmaceutical combination composition comprising complex formulations of Ivacaftor and Lumacaftor and their salts and derivatives, process for their preparation thereof and pharmaceutical compositions containing them |
HUP1600271A2 (hu) | 2016-04-25 | 2017-10-30 | Druggability Tech Ip Holdco Ltd | Ivacaftor és Lumacaftor sóinak és származékainak komplexei, eljárás azok elõállítására és azok gyógyszerészetileg elfogadható készítményei |
US10206915B2 (en) | 2016-04-25 | 2019-02-19 | Druggability Technologies Ip Holdco Limited | Complexes of Ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
HUP1600269A2 (hu) | 2016-04-25 | 2017-10-30 | Druggability Tech Ip Holdco Ltd | Lumacaftornak, sóinak és származékainak komplexei, eljárás azok elõállítására és azok gyógyászati készítményei |
HUP1600270A2 (hu) | 2016-04-25 | 2017-10-30 | Druggability Tech Ip Holdco Ltd | Ivacaftornak, sóinak és származékainak komplexei, eljárás azok elõállítására és azok gyógyszerészetileg elfogadott készítményei |
US10376501B2 (en) | 2016-04-25 | 2019-08-13 | Druggability Technologies Ip Holdco Limited | Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
WO2018037350A1 (en) * | 2016-08-23 | 2018-03-01 | Laurus Labs Limited | Solid forms of lumacaftor, process for its preparation and pharmaceutical compositions thereof |
DK3519401T3 (da) | 2016-09-30 | 2021-11-22 | Vertex Pharma | Modulator af cystisk fibrosetransmembrankonduktansregulator, farmaceutiske sammensætninger, fremgangsmåder til behandling og fremgangsmåde til fremstilling af modulatoren |
IL294237A (en) | 2016-12-09 | 2022-08-01 | Vertex Pharma | Modulatory modulation of transmembrane conductance in cystic fibrosis, pharmaceutical preparations, treatment methods, and a process for creating the modulator |
AU2018279646B2 (en) | 2017-06-08 | 2023-04-06 | Vertex Pharmaceuticals Incorporated | Methods of treatment for cystic fibrosis |
CA3069226A1 (en) | 2017-07-17 | 2019-01-24 | Vertex Pharmaceuticals Incorporated | Methods of treatment for cystic fibrosis |
AR112467A1 (es) | 2017-08-02 | 2019-10-30 | Vertex Pharma | Procesos para preparar compuestos |
JP7175966B2 (ja) * | 2017-08-31 | 2022-11-21 | ノバルティス アーゲー | 顆粒剤を調製する方法 |
IL273831B1 (en) | 2017-10-19 | 2024-06-01 | Vertex Pharma | Crystal forms and preparations of CFTR modulators |
JP7245834B2 (ja) | 2017-12-08 | 2023-03-24 | バーテックス ファーマシューティカルズ インコーポレイテッド | 嚢胞性線維症膜コンダクタンス制御因子のモジュレーターを作成するためのプロセス |
EP3746078A4 (en) * | 2018-02-02 | 2021-11-17 | Eustralis Pharmaceuticals Limited (Trading as Pressura Neuro) | ORAL FORMULATIONS AND USES THEREOF |
TWI810243B (zh) | 2018-02-05 | 2023-08-01 | 美商維泰克斯製藥公司 | 用於治療囊腫纖化症之醫藥組合物 |
MD3752510T2 (ro) | 2018-02-15 | 2023-06-30 | Vertex Pharma | Macrociclii ca modulatori ai regulatorului conductanței transmembranare în fibroza chistică, compoziții farmaceutice ale acestora, utilizarea lor în tratamentul fibrozei chistice, și procedeu pentru fabricarea acestora |
WO2019200246A1 (en) | 2018-04-13 | 2019-10-17 | Alexander Russell Abela | Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator |
TW202115092A (zh) | 2019-08-14 | 2021-04-16 | 美商維泰克斯製藥公司 | 囊腫纖維化跨膜傳導調節蛋白之調節劑 |
CN114599657A (zh) | 2019-08-14 | 2022-06-07 | 弗特克斯药品有限公司 | Cftr调节剂的结晶形式 |
TW202120517A (zh) | 2019-08-14 | 2021-06-01 | 美商維泰克斯製藥公司 | 製備cftr調節劑之方法 |
EP3818975A1 (en) * | 2019-11-08 | 2021-05-12 | Roquette Freres | Use of sodium octenyl-succinate starches as a binder in continuous wet granulation |
US20230372247A1 (en) * | 2022-05-17 | 2023-11-23 | Sigachi Industries Limited | Self-disintegrating excipient composition for solid oral dosage forms |
Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2000258345A (ja) * | 1999-03-09 | 2000-09-22 | Pfizer Inc | 粉末の分析方法 |
JP2004175779A (ja) * | 2002-10-02 | 2004-06-24 | Meiji Seika Kaisha Ltd | 経口吸収性が改善された抗菌性医薬組成物 |
JP2008516639A (ja) * | 2004-06-09 | 2008-05-22 | スミスクライン・ビーチャム・コーポレイション | 薬剤を製造するための装置及び方法 |
JP2008183168A (ja) * | 2007-01-30 | 2008-08-14 | Ebara Corp | 錠剤製造システム |
JP2009536317A (ja) * | 2006-04-05 | 2009-10-08 | ザ サイエンス アンド テクノロジー ファシリティーズ カウンシル | ラマン分析 |
JP2009537478A (ja) * | 2006-05-13 | 2009-10-29 | ノヴォ ノルディスク アクティーゼルスカブ | レパグリニドとメトホルミンを含む錠剤配合物 |
JP2011022014A (ja) * | 2009-07-16 | 2011-02-03 | Dainippon Sumitomo Pharma Co Ltd | 顕微ラマン分光法による固体材料中の分散粒子の粒径の測定法 |
JP2011511011A (ja) * | 2008-02-05 | 2011-04-07 | ハーバー バイオサイエンシーズ,インコーポレイテッド | 医薬的固体状態形態 |
JP2012522059A (ja) * | 2009-03-30 | 2012-09-20 | イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー | 口腔ケアシステムのためのペプチド組成物 |
JP2013029323A (ja) * | 2011-07-26 | 2013-02-07 | Fuji Electric Co Ltd | 医薬品製造制御装置、医薬品製造制御方法、医薬品製造制御プログラム、医薬品製造システム |
JP2013040193A (ja) * | 2004-03-25 | 2013-02-28 | Astellas Pharma Inc | ソリフェナシンまたはその塩の固形製剤用組成物 |
US20130131107A1 (en) * | 2010-04-22 | 2013-05-23 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions and administrations thereof |
WO2013112804A1 (en) * | 2012-01-25 | 2013-08-01 | Vertex Pharmaceuticals Incorporated | Formulations of 3-(6-(1-(2.2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid |
Family Cites Families (224)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3758475A (en) | 1971-07-20 | 1973-09-11 | Sandoz Ag | Pyrido(2,3-d)pyrimidin 2 ones |
DE3263567D1 (en) | 1981-12-14 | 1985-06-20 | Medea Res Srl | New compounds with antiinflammatory and antitussive activity, process for their preparation and relative pharmaceutical compositions |
IT1226048B (it) | 1981-12-14 | 1990-12-10 | Medea Res Srl | Composti ad attivita'antiinfiammatoria, processo per la loro preparazione e composizioni farmaceutiche relative |
US4501729A (en) | 1982-12-13 | 1985-02-26 | Research Corporation | Aerosolized amiloride treatment of retained pulmonary secretions |
US5981714A (en) | 1990-03-05 | 1999-11-09 | Genzyme Corporation | Antibodies specific for cystic fibrosis transmembrane conductance regulator and uses therefor |
JP3167762B2 (ja) | 1990-11-27 | 2001-05-21 | 武田薬品工業株式会社 | ピリドピリダジン誘導体およびその用途 |
US5612360A (en) | 1992-06-03 | 1997-03-18 | Eli Lilly And Company | Angiotensin II antagonists |
CA2107196A1 (en) | 1992-09-29 | 1994-03-30 | Mitsubishi Chemical Corporation | Carboxamide derivatives |
GB9317764D0 (en) | 1993-08-26 | 1993-10-13 | Pfizer Ltd | Therapeutic compound |
WO1995011231A1 (en) | 1993-10-21 | 1995-04-27 | G. D. Searle & Co. | Amidino derivatives useful as nitric oxide synthase inhibitors |
DE4405712A1 (de) | 1994-02-23 | 1995-08-24 | Basf Ag | Substituierte Naphthyridine und deren Verwendung |
IL113313A (en) | 1994-04-11 | 1999-09-22 | Sankyo Co | Heterocyclic compounds and pharmaceutical compositions containing the same |
CN1068880C (zh) | 1994-09-27 | 2001-07-25 | 詹森药业有限公司 | N-取代的哌啶基双环苯甲酸酯衍生物 |
US5656256A (en) | 1994-12-14 | 1997-08-12 | The University Of North Carolina At Chapel Hill | Methods of treating lung disease by an aerosol containing benzamil or phenamil |
US5510379A (en) | 1994-12-19 | 1996-04-23 | Warner-Lambert Company | Sulfonate ACAT inhibitors |
US5585115A (en) | 1995-01-09 | 1996-12-17 | Edward H. Mendell Co., Inc. | Pharmaceutical excipient having improved compressability |
CA2249615A1 (en) | 1996-04-03 | 1997-10-09 | Robert Gomez | Inhibitors of farnesyl-protein transferase |
DK0984778T3 (da) | 1996-08-23 | 2002-09-16 | Agouron Pharma | Neuropeptid-Y-ligander |
CA2276081A1 (en) | 1996-12-30 | 1998-07-09 | Lekhanh O. Tran | Inhibitors of farnesyl-protein transferase |
CO4920215A1 (es) | 1997-02-14 | 2000-05-29 | Novartis Ag | Tabletas de oxacarbazepina recubiertas de una pelicula y metodo para la produccion de estas formulaciones |
US5948814A (en) | 1997-02-20 | 1999-09-07 | The Curators Of The University Of Missouri | Genistein for the treatment of cystic fibrosis |
WO1998047868A1 (en) | 1997-04-18 | 1998-10-29 | Smithkline Beecham Plc | Heterocycle-containing urea derivatives as 5ht1a, 5ht1b and 5ht1d receptor antagonists |
IL135177A0 (en) | 1997-10-02 | 2001-05-20 | Sankyo Co | Amidocarboxylic acid derivatives and pharmaceutical compositions containing the same |
US6277626B1 (en) | 1998-02-17 | 2001-08-21 | G.D. Searle & Co. | Process for the enzymatic resolution of lactams |
AR019626A1 (es) | 1998-06-08 | 2002-02-27 | Schering Corp | Antagonistas receptores y5 de neuropeptidos. |
US6426331B1 (en) | 1998-07-08 | 2002-07-30 | Tularik Inc. | Inhibitors of STAT function |
AUPP609198A0 (en) | 1998-09-22 | 1998-10-15 | Curtin University Of Technology | Use of non-peptidyl compounds for the treatment of insulin related ailments |
US6444686B1 (en) | 1998-12-18 | 2002-09-03 | Brsitol-Myers Squibb Pharma Company | N-ureidoalkyl-piperidines as modulators of chemokine receptor activity |
RU2236402C2 (ru) | 1999-02-24 | 2004-09-20 | Ф.Хоффманн-Ля Рош Аг | Производные 3-фенилпиридина и фармацевтическая композиция на их основе |
ES2226622T3 (es) | 1999-02-24 | 2005-04-01 | F. Hoffmann-La Roche Ag | Derivados de 4-fenil piridina y su empleo como antagonistas del receptor nk-1. |
CA2364665C (en) | 1999-02-24 | 2009-09-15 | F. Hoffmann-La Roche Ag | Phenyl- and pyridinyl derivatives |
UA71971C2 (en) | 1999-06-04 | 2005-01-17 | Agoron Pharmaceuticals Inc | Diaminothiazoles, composition based thereon, a method for modulation of protein kinases activity, a method for the treatment of diseases mediated by protein kinases |
BR0012291A (pt) | 1999-06-18 | 2002-03-26 | Bayer Ag | Fenoxifluorpirimidinas |
UA74539C2 (en) | 1999-12-08 | 2006-01-16 | Pharmacia Corp | Crystalline polymorphous forms of celecoxib (variants), a method for the preparation thereof (variants), a pharmaceutical composition (variants) |
WO2001046165A2 (en) | 1999-12-16 | 2001-06-28 | Novartis Ag | N-heteroaryl-amides and their use as parasiticides |
WO2001051919A2 (en) | 2000-01-07 | 2001-07-19 | Transform Pharmaceuticals, Inc. | High-throughput formation, identification, and analysis of diverse solid-forms |
AU2001233069A1 (en) | 2000-01-28 | 2001-08-07 | Biogen, Inc. | Pharmaceutical compositions containing anti-beta 1 integrin compounds and uses |
US20020065303A1 (en) | 2000-02-01 | 2002-05-30 | Bing-Yan Zhu | Bivalent phenylene inhibitors of factor Xa |
US20010047100A1 (en) | 2000-04-26 | 2001-11-29 | Kjaersgaard Hans Joergen | Chiral imidazoyl intermediates for the synthesis of 2-(4-imidazoyl)-cyclopropyl derivatives |
WO2001083517A1 (en) | 2000-05-03 | 2001-11-08 | Tularik Inc. | Stat4 and stat6 binding dipeptide derivatives |
US6499984B1 (en) | 2000-05-22 | 2002-12-31 | Warner-Lambert Company | Continuous production of pharmaceutical granulation |
EP1268450A1 (en) | 2000-06-01 | 2003-01-02 | Bristol-Myers Squibb Pharma Company | Lactams substituted by cyclic succinates as inhibitors of a-beta protein production |
TWI259180B (en) | 2000-08-08 | 2006-08-01 | Hoffmann La Roche | 4-Phenyl-pyridine derivatives |
PE20020451A1 (es) | 2000-09-15 | 2002-06-06 | Vertex Pharma | Compuestos de pirazol utiles como inhibidores de cinasa proteina |
JP4272338B2 (ja) | 2000-09-22 | 2009-06-03 | バイエル アクチェンゲゼルシャフト | ピリジン誘導体 |
AU2002211379A1 (en) | 2000-10-04 | 2002-04-15 | The Children's Hospital Of Philadelphia | Compositions and methods for treatment of cystic fibrosis |
GB2367816A (en) | 2000-10-09 | 2002-04-17 | Bayer Ag | Urea- and thiourea-containing derivatives of beta-amino acids |
DE60104014T2 (de) | 2000-10-20 | 2005-08-11 | Merck Patent Gmbh | Chirale binaphtol-verbindungen |
US6884782B2 (en) | 2000-11-08 | 2005-04-26 | Amgen Inc. | STAT modulators |
CA2430363C (en) | 2000-12-01 | 2010-04-13 | Guilford Pharmaceuticals Inc. | Compounds and their uses |
GB0102687D0 (en) | 2001-02-02 | 2001-03-21 | Pharmacia & Upjohn Spa | Oxazolyl-pyrazole derivatives active as kinase inhibitors,process for their preparation and pharmaceutical compositions comprising them |
US20100074949A1 (en) | 2008-08-13 | 2010-03-25 | William Rowe | Pharmaceutical composition and administration thereof |
US6531597B2 (en) | 2001-02-13 | 2003-03-11 | Hoffmann-La Roche Inc. | Process for preparation of 2-phenyl acetic acid derivatives |
JP2005520171A (ja) | 2001-04-10 | 2005-07-07 | トランス テック ファーマ,インコーポレイテッド | ドラッグディスカバリーに関する、プローブ、システム、および方法 |
PT1385577E (pt) | 2001-04-23 | 2006-08-31 | Hoffmann La Roche | Utilizacao de antagonistas do receptor nk-1 contra a hiperplasia prostatica benigna |
SK15432003A3 (sk) | 2001-05-22 | 2004-05-04 | Neurogen Corporation | 5-Substituované 2-arylpyridíny |
US20030083345A1 (en) | 2001-07-10 | 2003-05-01 | Torsten Hoffmann | Method of treatment and/or prevention of brain, spinal or nerve injury |
US6627646B2 (en) | 2001-07-17 | 2003-09-30 | Sepracor Inc. | Norastemizole polymorphs |
WO2003007945A1 (en) | 2001-07-20 | 2003-01-30 | Boehringer Ingelheim (Canada) Ltd. | Viral polymerase inhibitors |
US20030144350A1 (en) | 2001-07-20 | 2003-07-31 | Adipogenix, Inc. | Fat accumulation-modulation compounds |
JP2005508904A (ja) | 2001-09-11 | 2005-04-07 | スミスクライン ビーチャム コーポレーション | 血管新生阻害剤としてのフロ−及びチエノピリミジン誘導体 |
PA8557501A1 (es) | 2001-11-12 | 2003-06-30 | Pfizer Prod Inc | Benzamida, heteroarilamida y amidas inversas |
JP2003155285A (ja) | 2001-11-19 | 2003-05-27 | Toray Ind Inc | 環状含窒素誘導体 |
JP2003221386A (ja) | 2001-11-26 | 2003-08-05 | Takeda Chem Ind Ltd | 二環性誘導体、その製造法およびその用途 |
PL370989A1 (en) | 2001-12-21 | 2005-06-13 | Novo Nordisk A/S | Amide derivatives as gk activators |
TW200307539A (en) | 2002-02-01 | 2003-12-16 | Bristol Myers Squibb Co | Cycloalkyl inhibitors of potassium channel function |
TW200304820A (en) | 2002-03-25 | 2003-10-16 | Avanir Pharmaceuticals | Use of benzimidazole analogs in the treatment of cell proliferation |
TW200403058A (en) | 2002-04-19 | 2004-03-01 | Bristol Myers Squibb Co | Heterocyclo inhibitors of potassium channel function |
FR2840807B1 (fr) | 2002-06-12 | 2005-03-11 | Composition cosmetique de soin et/ou de maquillage, structuree par des polymeres silicones et des organogelateurs, sous forme rigide | |
JP2005535710A (ja) | 2002-08-09 | 2005-11-24 | トランス テック ファーマ,インコーポレイテッド | アリールおよびヘテロアリール化合物ならびに凝固を調節する方法 |
GB0221443D0 (en) | 2002-09-16 | 2002-10-23 | Glaxo Group Ltd | Pyridine derivates |
AU2003287160A1 (en) | 2002-10-15 | 2004-05-04 | Rigel Pharmaceuticals, Inc. | Substituted indoles and their use as hcv inhibitors |
US7514431B2 (en) | 2002-10-30 | 2009-04-07 | Merck & Co., Inc. | Piperidinyl cyclopentyl aryl benzylamide modulators of chemokine receptor activity |
US7910030B2 (en) | 2002-11-26 | 2011-03-22 | Universiteit Gent | Process and apparatus for continuous wet granulation of powder material |
EP1569645A2 (en) | 2002-12-12 | 2005-09-07 | Pharmacia Corporation | Method of using aminocyanopyridine compounds as mitogen activated protein kinase-activated protein kinase-2 inhibitors |
SI1585739T1 (sl) | 2003-01-06 | 2011-07-29 | Lilly Co Eli | Substituirani arilciklopropilacetamidi kot aktivatorji glukokinaze |
NZ542153A (en) | 2003-02-10 | 2009-01-31 | Vertex Pharma | Processes for the preparation of N-heteroaryl-N-aryl-amines by reacting an N-aryl carbamic acid ester with a halo-heteroaryl and analogous processes |
US7223788B2 (en) | 2003-02-14 | 2007-05-29 | Sanofi-Aventis Deutschland Gmbh | Substituted N-aryl heterocycles, process for their preparation and their use as medicaments |
WO2004080972A1 (en) | 2003-03-12 | 2004-09-23 | Vertex Pharmaceuticals Incorporated | Pirazole modulators of atp-binding cassette transporters |
US7358364B2 (en) | 2003-04-30 | 2008-04-15 | The Institute For Pharmaceutical Discovery Llc | Substituted carboxylic acids |
ATE440825T1 (de) | 2003-06-06 | 2009-09-15 | Vertex Pharma | Pyrimidin-derivate zur verwendung als modulatoren von atp-bindende kassette transportern |
ATE554766T1 (de) | 2003-06-27 | 2012-05-15 | Jackson H M Found Military Med | Amphiphile pyridinium-verbindungen, herstellungsverfahren und ihre verwendung |
GB0315111D0 (en) | 2003-06-27 | 2003-07-30 | Cancer Rec Tech Ltd | Substituted 5-membered ring compounds and their use |
JP2005053902A (ja) | 2003-07-18 | 2005-03-03 | Nippon Nohyaku Co Ltd | フェニルピリジン類、その中間体及びこれを有効成分とする除草剤 |
EA200600372A1 (ru) | 2003-09-05 | 2006-08-25 | Ньюроджин Корпорейшн | Конденсированные с гетероарилом пиридины, пиразины и пиримидины в качестве лигандов рецептора кортикотропин-рилизинг-фактора (crf 1) |
US7973169B2 (en) | 2003-09-06 | 2011-07-05 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-Binding Cassette transporters |
US7534894B2 (en) | 2003-09-25 | 2009-05-19 | Wyeth | Biphenyloxy-acids |
US20050070718A1 (en) | 2003-09-30 | 2005-03-31 | Abbott Gmbh & Co. Kg | Heteroaryl-substituted 1,3-dihydroindol-2-one derivatives and medicaments containing them |
MXPA06004005A (es) | 2003-10-08 | 2006-06-28 | Vertex Pharma | Moduladores de transportadores con casete de union con atp. |
US20070078120A1 (en) | 2003-10-21 | 2007-04-05 | Hitoshi Ban | Novel piperidine derivative |
FR2861304B1 (fr) | 2003-10-23 | 2008-07-18 | Univ Grenoble 1 | Modulateurs des canaux cftr |
GB0325956D0 (en) | 2003-11-06 | 2003-12-10 | Addex Pharmaceuticals Sa | Novel compounds |
ATE437640T1 (de) | 2003-11-14 | 2009-08-15 | Vertex Pharma | Thiazole udn oxazole als modulatoren von atp- bindungs-kassetten-transportern |
EP1687001A2 (en) | 2003-11-19 | 2006-08-09 | Glaxo Group Limited | Use of cyclooxygenase-2 selective inhibitors for the treatment of schizophrenic disorders |
ES2238001B1 (es) | 2004-01-21 | 2006-11-01 | Vita Cientifica, S.L. | Nuevas formas polimorficas de ondansetron, procedimientos para su preparacion, composiciones farmaceuticas que los contienen y su uso como aantiemeticos. |
US7977322B2 (en) | 2004-08-20 | 2011-07-12 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
WO2005075435A1 (en) | 2004-01-30 | 2005-08-18 | Vertex Pharmaceuticals Incorporated | Modulators of atp-binding cassette transporters |
EP1719765A4 (en) | 2004-02-19 | 2009-01-07 | Banyu Pharma Co Ltd | NEW SULFONAMIDE DERIVATIVE |
ES2241496B1 (es) | 2004-04-15 | 2006-12-01 | Almirall Prodesfarma, S.A. | Nuevos derivados de piridina. |
US20080015196A1 (en) | 2004-04-16 | 2008-01-17 | Neurogen Corporation | Imidazopyrazines, Imidazopyridines, and Imidazopyrimidines as Crf1 Receptor Ligands |
EP1740575A2 (en) | 2004-04-22 | 2007-01-10 | Eli Lilly And Company | Pyrrolidine derivatives useful as bace inhibitors |
US7585885B2 (en) | 2004-04-22 | 2009-09-08 | Eli Lilly And Company | Pyrrolidine derivatives useful as BACE inhibitors |
AU2005249154B2 (en) | 2004-06-01 | 2011-02-10 | Luminex Molecular Diagnostics, Inc. | Method of detecting cystic fibrosis associated mutations |
US20140343098A1 (en) | 2004-06-24 | 2014-11-20 | Vertex Pharmaceuticals Incorporated | Modulators of atp-binding cassette transporters |
US8354427B2 (en) | 2004-06-24 | 2013-01-15 | Vertex Pharmaceutical Incorporated | Modulators of ATP-binding cassette transporters |
WO2006002421A2 (en) | 2004-06-24 | 2006-01-05 | Vertex Pharmaceuticals Incorporated | Modulators of atp-binding cassette transporters |
WO2006003504A1 (en) | 2004-07-01 | 2006-01-12 | Warner-Lambert Company Llc | Preparation of pharmaceutical compositions containing nanoparticles |
CA2572292A1 (en) | 2004-07-02 | 2006-02-09 | Advancis Pharmaceutical Corporation | Tablet for pulsed delivery |
WO2006014012A2 (en) | 2004-08-06 | 2006-02-09 | Otsuka Pharmaceutical Co., Ltd. | Aromatic compounds |
US20060069110A1 (en) | 2004-09-27 | 2006-03-30 | Andersen Denise L | Substituted heterocyclic compounds and methods of use |
ES2378772T3 (es) | 2004-10-12 | 2012-04-17 | Astrazeneca Ab | Derivados de quinazolina |
JP2008519818A (ja) | 2004-11-15 | 2008-06-12 | ファイザー・プロダクツ・インク | Cns障害の治療のためのアザベンゾオキサゾール |
SI1856031T1 (sl) | 2004-12-15 | 2009-08-31 | Dompe Pha R Ma Spa Res & Mfg | Derivati 2-arilpropionske kisline in farmacevtski sestavki, ki jih vsebujejo |
JP4790260B2 (ja) | 2004-12-22 | 2011-10-12 | 出光興産株式会社 | アントラセン誘導体を用いた有機エレクトロルミネッセンス素子 |
US20080146612A1 (en) | 2005-01-27 | 2008-06-19 | Astrazeneca Ab | Novel Biaromatic Compounds, Inhibitors of the P2X7-Receptor |
US7888374B2 (en) | 2005-01-28 | 2011-02-15 | Abbott Laboratories | Inhibitors of c-jun N-terminal kinases |
EP1845081A4 (en) | 2005-02-01 | 2009-03-25 | Takeda Pharmaceutical | amide |
JP5385605B2 (ja) | 2005-03-11 | 2014-01-08 | バーテックス ファーマシューティカルズ インコーポレイテッド | Atp結合カセットトランスポーターのモジュレーター |
US7402596B2 (en) | 2005-03-24 | 2008-07-22 | Renovis, Inc. | Bicycloheteroaryl compounds as P2X7 modulators and uses thereof |
TWI377206B (en) | 2005-04-06 | 2012-11-21 | Theravance Inc | Crystalline form of a quinolinone-carboxamide compound |
EP1710246A1 (en) | 2005-04-08 | 2006-10-11 | Schering Aktiengesellschaft | Sulfoximine-pyrimidine Macrocycles and the salts thereof, a process for making them, and their pharmaceutical use against cancer |
TW200716594A (en) | 2005-04-18 | 2007-05-01 | Neurogen Corp | Substituted heteroaryl CB1 antagonists |
US20090215780A1 (en) | 2005-04-19 | 2009-08-27 | Bayer Pharmaceuticals Corporation | Preparation and Use of Aryl Alkyl Acid Derivatives for the Treatment of Obesity |
JP2008538561A (ja) | 2005-04-20 | 2008-10-30 | メルク エンド カムパニー インコーポレーテッド | アンジオテンシンii受容体アンタゴニスト |
MX2007013179A (es) | 2005-04-22 | 2008-01-16 | Wyeth Corp | Formas cristalinas de clorhidrato de {[(2r)-7-(diclorofenil)-5- fluoro-2,3-dihidro-1-benzofurano-2-il]metil}amina. |
GB0510139D0 (en) | 2005-05-18 | 2005-06-22 | Addex Pharmaceuticals Sa | Novel compounds B1 |
US8822451B2 (en) | 2005-05-24 | 2014-09-02 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
JP2008545744A (ja) | 2005-06-02 | 2008-12-18 | バイエル・クロツプサイエンス・アクチエンゲゼルシヤフト | フェニルアルキル置換ヘテロアリール誘導体 |
EP1919875A2 (en) | 2005-06-21 | 2008-05-14 | Astex Therapeutics Limited | Pyrazole derivatives and their use as pka and pkb modulators |
CA2618057A1 (en) | 2005-08-11 | 2007-02-22 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
ZA200802172B (en) | 2005-08-11 | 2009-06-24 | Vertex Pharma | Modulators of cystic fibrosis transmembrane conductance regulator |
EP2336136A1 (en) | 2005-09-09 | 2011-06-22 | GlaxoSmithKline LLC | Pyridine derivatives and their use in the treatment of psychotic disorders |
ES2335922T3 (es) | 2005-09-23 | 2010-04-06 | F.Hoffmann-La Roche Ag | Nueva formulacion de dosificacion. |
CA2624683A1 (en) | 2005-10-06 | 2007-04-19 | Vertex Pharmaceuticals Incorporated | Modulators of atp-binding cassette transporters |
CA2625189A1 (en) | 2005-10-19 | 2007-04-26 | Gruenenthal Gmbh | Novel vanilloid receptor ligands and their use for producing medicaments |
US20120232059A1 (en) | 2005-11-08 | 2012-09-13 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-Binding Cassette Transporters |
KR101331768B1 (ko) | 2005-11-08 | 2013-11-22 | 버텍스 파마슈티칼스 인코포레이티드 | Atp 결합 카세트 수송체의 헤테로사이클릭 조정제 |
WO2007054480A1 (en) | 2005-11-08 | 2007-05-18 | N.V. Organon | 2-(benzimidazol-1-yl)-acetamide biaryl derivatives and their use as inhibitors of the trpv1 receptor |
EP1971606B1 (en) | 2005-12-05 | 2013-04-24 | GlaxoSmithKline LLC | 2-pyrimidinyl pyrazolopyridine erbb kinase inhibitors |
CA2634113A1 (en) | 2005-12-24 | 2007-07-05 | Vertex Pharmaceuticals Incorporated | Quinolin- 4 - one derivatives as modulators of abc transporters |
AU2006331565A1 (en) | 2005-12-27 | 2007-07-05 | Vertex Pharmaceuticals Incorporated | Compounds useful in CFTR assays and methods therewith |
ES2624554T3 (es) | 2005-12-28 | 2017-07-14 | Vertex Pharmaceuticals Incorporated | Formas sólidas de n- [2,4 - bis (1,1 - dimetiletil) - 5 - hidroxifenil] - 1,4 - dihidro - 4 - oxoquinolina - 3 - carboxamida |
US7671221B2 (en) | 2005-12-28 | 2010-03-02 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-Binding Cassette transporters |
ES2398319T3 (es) | 2005-12-28 | 2013-03-15 | Vertex Pharmaceuticals Incorporated | Derivados de 1-(benzo[D][1,3]dioxol-5-il)-N-(fenil)ciclopropano-carboxamida y compuestos relacionados como moduladores de transportadores de casetes de unión a ATP para el tratamiento de la fibrosis quística |
WO2007079257A2 (en) | 2005-12-30 | 2007-07-12 | Caliper Life Sciences, Inc. | Integrated dissolution processing and sample transfer system |
NZ571803A (en) | 2006-04-07 | 2011-12-22 | Vertex Pharma | Amide indole derivatives as modulators of ATP-binding cassette transporters |
US7645789B2 (en) | 2006-04-07 | 2010-01-12 | Vertex Pharmaceuticals Incorporated | Indole derivatives as CFTR modulators |
US10022352B2 (en) | 2006-04-07 | 2018-07-17 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
AU2007249269A1 (en) | 2006-05-12 | 2007-11-22 | Vertex Pharmaceuticals Incorporated | Compositions of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide |
AU2007351454B2 (en) | 2006-11-03 | 2013-07-18 | Vertex Pharmaceuticals Incorporated | Azaindole derivatives as CFTR modulators |
US8563573B2 (en) | 2007-11-02 | 2013-10-22 | Vertex Pharmaceuticals Incorporated | Azaindole derivatives as CFTR modulators |
US7754739B2 (en) | 2007-05-09 | 2010-07-13 | Vertex Pharmaceuticals Incorporated | Modulators of CFTR |
MX2009005622A (es) | 2006-11-27 | 2009-06-12 | Novartis Ag | Dihidro-imidazoles sustituidos y su uso en el tratamiento de tumores. |
US20080260820A1 (en) | 2007-04-19 | 2008-10-23 | Gilles Borrelly | Oral dosage formulations of protease-resistant polypeptides |
AU2008247435A1 (en) | 2007-05-02 | 2008-11-13 | Portola Pharmaceuticals, Inc. | Combination therapy with a compound acting as a platelet ADP receptor inhibitor |
WO2008141119A2 (en) | 2007-05-09 | 2008-11-20 | Vertex Pharmaceuticals Incorporated | Modulators of cftr |
ES2548292T3 (es) | 2007-05-25 | 2015-10-15 | Vertex Pharmaceuticals Incorporated | Moduladores del regulador de la conductancia transmembrana de la fibrosis quística |
WO2009023509A2 (en) | 2007-08-09 | 2009-02-19 | Vertex Pharmaceuticals Incorporated | Therapeutic combinations useful in treating cftr related diseases |
JP5389030B2 (ja) | 2007-08-24 | 2014-01-15 | バーテックス ファーマシューティカルズ インコーポレイテッド | (特に)嚢胞性線維症の処置に有用なイソチアゾロピリジノン |
DE102007042754A1 (de) | 2007-09-07 | 2009-03-12 | Bayer Healthcare Ag | Substituierte 6-Phenylnikotinsäuren und ihre Verwendung |
CN101821266B (zh) | 2007-09-14 | 2014-03-12 | 沃泰克斯药物股份有限公司 | 囊性纤维化跨膜通道调节因子的调节剂 |
BRPI0816345A2 (pt) | 2007-09-14 | 2015-02-24 | Vertex Pharma | Formas sólidas de n-[2,4-bis-(1,1-dimetiletil)-5-hidroxifenil]-1,4-diidro-4-o xoquinolin-3-carboxamida |
FR2921657A1 (fr) | 2007-09-28 | 2009-04-03 | Sanofi Aventis Sa | Derives de nicotinamide, leur preparation et leur application en therapeutique |
JP5646338B2 (ja) | 2007-11-16 | 2014-12-24 | バーテックス ファーマシューティカルズ インコーポレイテッドVertex Pharmaceuticals Incorporated | Atp結合カセットトランスポーターのイソキノリン調節因子 |
US20100036130A1 (en) | 2007-12-07 | 2010-02-11 | Vertex Pharmaceuticals Incorporated | Processes for producing cycloalkylcarboxamido-pyridine benzoic acids |
UA102534C2 (en) | 2007-12-07 | 2013-07-25 | Вертекс Фармасьютикалз Инкорпорейтед | Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]-dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid |
SI2639224T1 (sl) | 2007-12-07 | 2016-12-30 | Vertex Pharmaceuticals Incorporated | Postopek za pripravo cikloalkilkarboksiamido-piridinskih benzojskih kislin |
WO2009076141A2 (en) | 2007-12-07 | 2009-06-18 | Vertex Pharmaceuticals Incorporated | Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cycklopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid |
AU2008335031B2 (en) | 2007-12-13 | 2013-11-28 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
EP2271622B1 (en) | 2008-02-28 | 2017-10-04 | Vertex Pharmaceuticals Incorporated | Heteroaryl derivatives as CFTR Modulators |
ES2442945T3 (es) | 2008-03-31 | 2014-02-14 | Vertex Pharmaceuticals Inc. | Derivados de piridilo como moduladores del CFTR |
GB0813709D0 (en) | 2008-07-26 | 2008-09-03 | Univ Dundee | Method and product |
KR20240066199A (ko) | 2008-08-13 | 2024-05-14 | 버텍스 파마슈티칼스 인코포레이티드 | 제약 조성물 및 그의 투여 |
US20100256184A1 (en) | 2008-08-13 | 2010-10-07 | Vertex Pharmaceuticals Incorporated | Pharmaceutical composition and administrations thereof |
RU2011117177A (ru) | 2008-09-29 | 2012-11-10 | Вертекс Фармасьютикалз Инкорпорейтед (Us) | ДОЗИРОВАННЫЕ ЛЕКАРСТВЕННЫЕ ФОРМЫ 3-(6-(1-(2,2-ДИФТОРБЕНЗО[d][1,3]ДИОКСОЛ-5-ИЛ)ЦИКЛОПРОПАНКАРБОКСАМИДО)-3-МЕТИЛПИРИДИН-2-ИЛ)БЕНЗОЙНОЙ КИСЛОТЫ |
US20110257223A1 (en) | 2008-10-23 | 2011-10-20 | Vertex Pharmaceuticals Incorporated | Modulators of Cystic Fibrosis Transmembrane Conductance Regulator |
US8314239B2 (en) | 2008-10-23 | 2012-11-20 | Vertex Pharmaceutical Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
DK2358680T3 (da) | 2008-10-23 | 2013-06-24 | Vertex Pharma | Faste former af n-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluormethyl)phenyl)-3-oxo-5-(trifluormethyl)-1,4-dihydroquinolin-3-carboxamid |
NZ592685A (en) | 2008-10-23 | 2013-04-26 | Vertex Pharma | Modulators of cystic fibrosis transmembrane conductance regulator |
UA104876C2 (uk) | 2008-11-06 | 2014-03-25 | Вертекс Фармасьютікалз Інкорпорейтед | Модулятори atф-зв'язувальних касетних транспортерів |
KR20160013251A (ko) | 2008-11-06 | 2016-02-03 | 버텍스 파마슈티칼스 인코포레이티드 | Atp-결합 카세트 수송자의 조절자 |
EP2382197B1 (en) | 2008-12-30 | 2016-10-05 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
DK2408749T3 (en) | 2009-03-20 | 2018-08-13 | Vertex Pharma | CYSTIC FIBROSE TRANSMEMBRAN CONDUCTOR CONTROLLER MODULATORS |
CA2756031C (en) | 2009-03-20 | 2018-01-02 | Vertex Pharmaceuticals Incorporated | Process for making modulators of cystic fibrosis transmembrane conductance regulator |
CN102438578A (zh) * | 2009-05-07 | 2012-05-02 | 基伊埃制药系统有限公司 | 药片生产模块和用于连续生产药片的方法 |
MX2012003343A (es) | 2009-09-17 | 2012-08-17 | Vertex Pharma | Proceso para preparar compuestos azabiciclicos. |
CA2777245A1 (en) | 2009-10-22 | 2011-04-28 | Vertex Pharmaceuticals Incorporated | Compositions for treatment of cystic fibrosis and other chronic diseases |
BR112012009583A2 (pt) | 2009-10-23 | 2015-09-29 | Vertex Pharma | processo para preparação de moduladores de regulador de condutância de transmembrana de fibrose cística |
NZ599703A (en) | 2009-10-23 | 2014-06-27 | Vertex Pharma | Solid forms of n-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide |
US8471029B2 (en) | 2010-03-19 | 2013-06-25 | Vertex Pharmaceutical Incorporated | Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
US8802868B2 (en) | 2010-03-25 | 2014-08-12 | Vertex Pharmaceuticals Incorporated | Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide |
NZ700556A (en) | 2010-03-25 | 2016-04-29 | Vertex Pharma | Solid forms of (r)-1(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl) cyclopropanecarboxamide |
EP2555754B1 (en) | 2010-04-07 | 2016-04-06 | Vertex Pharmaceuticals Incorporated | Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid |
CN102917692A (zh) | 2010-04-07 | 2013-02-06 | 弗特克斯药品有限公司 | 3-(6-(1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)环丙甲酰胺基)-3-甲基吡啶-2-基)苯甲酸的药物组合物和其给药方法 |
CA2797118C (en) | 2010-04-22 | 2021-03-30 | Vertex Pharmaceuticals Incorporated | Process of producing cycloalkylcarboxamido-indole compounds |
EP3138563A1 (en) | 2010-04-22 | 2017-03-08 | Vertex Pharmaceuticals Inc. | Pharmaceutical compositions and administrations thereof |
AU2011242457A1 (en) | 2010-04-22 | 2012-11-08 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions and administrations thereof |
TW201202250A (en) | 2010-05-20 | 2012-01-16 | Vertex Pharma | Processes for producing modulators of cystic fibrosis transmembrane conductance regulator |
CA2798412A1 (en) | 2010-05-20 | 2011-11-24 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions and administrations thereof |
US8563593B2 (en) | 2010-06-08 | 2013-10-22 | Vertex Pharmaceuticals Incorporated | Formulations of (R)-1-(2,2-difluorobenzo[D] [1,3] dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide |
JP2013536231A (ja) | 2010-08-23 | 2013-09-19 | バーテックス ファーマシューティカルズ インコーポレイテッド | (r)−1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)−n−(1−(2,3−ジヒドロキシプロピル)−6−フルオロ−2−(1−ヒドロキシ−2−メチルプロパン−2−イル)−1h−インドール−5−イル)シクロプロパンカルボキサミドを含む医薬組成物およびその投与 |
WO2012027731A2 (en) | 2010-08-27 | 2012-03-01 | Vertex Pharmaceuticals Incorporated | Pharmaceutical composition and administrations thereof |
CN102058889A (zh) | 2010-11-05 | 2011-05-18 | 王定豪 | 包含抗凝血类药物的分散片及其应用 |
US8802700B2 (en) | 2010-12-10 | 2014-08-12 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-Binding Cassette transporters |
WO2012148953A1 (en) * | 2011-04-25 | 2012-11-01 | Stc.Unm | Solid compositions for pharmaceutical use |
EP2773349A1 (en) | 2011-11-02 | 2014-09-10 | Vertex Pharmaceuticals Incorporated | Use of (n- [2, 4 -bis (1, 1 -dimethylethyl) - 5 - hydroxyphenyl]- 1, 4 - dihydro - 4 - oxoquinoline - 3 - carboxamide) for treating cftr mediated diseases |
US20140127901A1 (en) | 2012-11-08 | 2014-05-08 | Taiwan Semiconductor Manufacturing Company, Ltd. | Low-k damage free integration scheme for copper interconnects |
US9254291B2 (en) | 2011-11-08 | 2016-02-09 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
BR112014021090B1 (pt) | 2012-02-27 | 2023-01-24 | Vertex Pharmaceuticals Incorporated | Composição farmacêutica e uso de n-[2,4-bis(1,1-dimetiletil)-5-hidróxifenil]-1,4-di-hidro-4-oxoquinolina3-carboxamida na preparação da mesma |
US8674108B2 (en) | 2012-04-20 | 2014-03-18 | Vertex Pharmaceuticals Incorporated | Solid forms of N-[2,4-bis(1,1-dimethylethy)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
EP2659890A1 (en) * | 2012-04-30 | 2013-11-06 | Orphan Synergy Europe - Pharma | Methods and compositions for the treatment of fibrosis |
WO2013185112A1 (en) | 2012-06-08 | 2013-12-12 | Vertex Pharmaceuticals Incorporated | Pharmaceuticl compositions for the treatment of cftr -mediated disorders |
WO2014014841A1 (en) | 2012-07-16 | 2014-01-23 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions of (r)-1-(2,2-diflurorbenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl) cyclopropanecarboxamide and administration thereof |
US20140092376A1 (en) | 2012-10-01 | 2014-04-03 | Momentive Performance Materials, Inc. | Container and method for in-line analysis of protein compositions |
FI2914248T4 (fi) | 2012-11-02 | 2023-12-19 | Vertex Pharma | Farmaseuttisia koostumuksia cftr-välitteisten tautien hoitamiseksi |
US20140221424A1 (en) | 2013-01-30 | 2014-08-07 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions for use in the treatment of cystic fibrosis |
EP3131582B1 (en) | 2014-04-15 | 2018-05-23 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases |
CN107690281B (zh) | 2014-10-06 | 2020-11-17 | 弗特克斯药品有限公司 | 囊性纤维化跨膜转导调节因子调节剂 |
WO2016057730A1 (en) | 2014-10-07 | 2016-04-14 | Strohmeier Mark | Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator |
WO2016086136A1 (en) | 2014-11-26 | 2016-06-02 | Catabasis Pharmaceuticals, Inc. | Fatty acid cysteamine conjugates of cftr modulators and their use in treating medical disorders |
MA41031A (fr) | 2014-11-26 | 2017-10-03 | Catabasis Pharmaceuticals Inc | Conjugués cystéamine-acide gras et leur utilisation comme activateurs de l'autophagie |
CA2969587A1 (en) | 2014-12-05 | 2016-06-09 | Centre National De La Recherche Scientifique (Cnrs) | Compounds for treating cystic fibrosis |
WO2016123028A1 (en) | 2015-01-26 | 2016-08-04 | Rigel Pharmaceuticals, Inc. | Tetrazolones as carboxylic acid bioisosteres |
UY36680A (es) | 2015-05-19 | 2016-12-30 | Glaxosmithkline Ip Dev Ltd | Amidas heterocíclicas como inhibidores de quinasa |
-
2014
- 2014-10-31 PT PT148625049T patent/PT3068392T/pt unknown
- 2014-10-31 BR BR112016010403A patent/BR112016010403A2/pt not_active Application Discontinuation
- 2014-10-31 CA CA2930199A patent/CA2930199C/en active Active
- 2014-10-31 SG SG10201803930QA patent/SG10201803930QA/en unknown
- 2014-10-31 EP EP14862504.9A patent/EP3068392B9/en active Active
- 2014-10-31 CN CN201480071195.7A patent/CN105848657B/zh active Active
- 2014-10-31 SI SI201431804T patent/SI3068392T1/sl unknown
- 2014-10-31 DK DK14862504.9T patent/DK3068392T5/da active
- 2014-10-31 PL PL14862504T patent/PL3068392T3/pl unknown
- 2014-10-31 KR KR1020167015564A patent/KR102280372B1/ko active IP Right Grant
- 2014-10-31 NZ NZ720958A patent/NZ720958A/en unknown
- 2014-10-31 RU RU2019107168A patent/RU2718044C2/ru active
- 2014-10-31 US US15/035,969 patent/US10231932B2/en active Active
- 2014-10-31 ES ES14862504T patent/ES2865600T3/es active Active
- 2014-10-31 JP JP2016553220A patent/JP6963896B2/ja active Active
- 2014-10-31 MX MX2016006118A patent/MX2016006118A/es unknown
- 2014-10-31 RU RU2016122882A patent/RU2016122882A/ru not_active Application Discontinuation
- 2014-10-31 AU AU2014349010A patent/AU2014349010C1/en active Active
- 2014-10-31 HU HUE14862504A patent/HUE054389T2/hu unknown
- 2014-10-31 WO PCT/US2014/063506 patent/WO2015073231A1/en active Application Filing
- 2014-10-31 RS RS20210500A patent/RS61790B1/sr unknown
-
2016
- 2016-05-10 IL IL245584A patent/IL245584A0/en unknown
- 2016-06-10 ZA ZA2016/03973A patent/ZA201603973B/en unknown
-
2020
- 2020-09-21 IL IL277470A patent/IL277470A/en unknown
-
2021
- 2021-03-30 HR HRP20210516TT patent/HRP20210516T2/hr unknown
- 2021-07-06 JP JP2021112157A patent/JP2021165300A/ja not_active Withdrawn
Patent Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2000258345A (ja) * | 1999-03-09 | 2000-09-22 | Pfizer Inc | 粉末の分析方法 |
JP2004175779A (ja) * | 2002-10-02 | 2004-06-24 | Meiji Seika Kaisha Ltd | 経口吸収性が改善された抗菌性医薬組成物 |
JP2013040193A (ja) * | 2004-03-25 | 2013-02-28 | Astellas Pharma Inc | ソリフェナシンまたはその塩の固形製剤用組成物 |
JP2008516639A (ja) * | 2004-06-09 | 2008-05-22 | スミスクライン・ビーチャム・コーポレイション | 薬剤を製造するための装置及び方法 |
JP2009536317A (ja) * | 2006-04-05 | 2009-10-08 | ザ サイエンス アンド テクノロジー ファシリティーズ カウンシル | ラマン分析 |
JP2009537478A (ja) * | 2006-05-13 | 2009-10-29 | ノヴォ ノルディスク アクティーゼルスカブ | レパグリニドとメトホルミンを含む錠剤配合物 |
JP2008183168A (ja) * | 2007-01-30 | 2008-08-14 | Ebara Corp | 錠剤製造システム |
JP2011511011A (ja) * | 2008-02-05 | 2011-04-07 | ハーバー バイオサイエンシーズ,インコーポレイテッド | 医薬的固体状態形態 |
JP2012522059A (ja) * | 2009-03-30 | 2012-09-20 | イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー | 口腔ケアシステムのためのペプチド組成物 |
JP2011022014A (ja) * | 2009-07-16 | 2011-02-03 | Dainippon Sumitomo Pharma Co Ltd | 顕微ラマン分光法による固体材料中の分散粒子の粒径の測定法 |
US20130131107A1 (en) * | 2010-04-22 | 2013-05-23 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions and administrations thereof |
JP2013029323A (ja) * | 2011-07-26 | 2013-02-07 | Fuji Electric Co Ltd | 医薬品製造制御装置、医薬品製造制御方法、医薬品製造制御プログラム、医薬品製造システム |
WO2013112804A1 (en) * | 2012-01-25 | 2013-08-01 | Vertex Pharmaceuticals Incorporated | Formulations of 3-(6-(1-(2.2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid |
Non-Patent Citations (1)
Title |
---|
平山令明編, 有機化合物結晶作製ハンドブック −原理とノウハウ−, JPN6011053065, 25 July 2008 (2008-07-25), pages 57 - 84, ISSN: 0004012477 * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20230364073A1 (en) | Pharmaceutical compositions for the treatment of cftr mediated diseases | |
JP6963896B2 (ja) | Cftr媒介性疾患の処置のための医薬組成物を調製する方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20171013 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20180620 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20180919 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20181219 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20190408 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190806 |
|
C60 | Trial request (containing other claim documents, opposition documents) |
Free format text: JAPANESE INTERMEDIATE CODE: C60 Effective date: 20190806 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20190815 |
|
C21 | Notice of transfer of a case for reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C21 Effective date: 20190816 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20190927 |
|
C211 | Notice of termination of reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C211 Effective date: 20191001 |
|
C22 | Notice of designation (change) of administrative judge |
Free format text: JAPANESE INTERMEDIATE CODE: C22 Effective date: 20200603 |
|
C22 | Notice of designation (change) of administrative judge |
Free format text: JAPANESE INTERMEDIATE CODE: C22 Effective date: 20201002 |
|
C13 | Notice of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: C13 Effective date: 20210106 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20210405 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20210430 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20210604 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210706 |
|
C54 | Written response to inquiry |
Free format text: JAPANESE INTERMEDIATE CODE: C54 Effective date: 20210706 |
|
C23 | Notice of termination of proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C23 Effective date: 20210825 |
|
C03 | Trial/appeal decision taken |
Free format text: JAPANESE INTERMEDIATE CODE: C03 Effective date: 20210930 |
|
C30A | Notification sent |
Free format text: JAPANESE INTERMEDIATE CODE: C3012 Effective date: 20210930 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20211018 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6963896 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |