WO2017187338A1 - Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them - Google Patents
Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them Download PDFInfo
- Publication number
- WO2017187338A1 WO2017187338A1 PCT/IB2017/052372 IB2017052372W WO2017187338A1 WO 2017187338 A1 WO2017187338 A1 WO 2017187338A1 IB 2017052372 W IB2017052372 W IB 2017052372W WO 2017187338 A1 WO2017187338 A1 WO 2017187338A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- complex
- lumacaftor
- recited
- pharmaceutically acceptable
- disease
- Prior art date
Links
- 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 title claims abstract description 168
- 229960000998 lumacaftor Drugs 0.000 title claims abstract description 168
- 238000000034 method Methods 0.000 title claims abstract description 46
- 230000008569 process Effects 0.000 title claims abstract description 39
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 28
- 150000003839 salts Chemical class 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 123
- 238000009472 formulation Methods 0.000 claims abstract description 97
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 47
- 230000035699 permeability Effects 0.000 claims abstract description 42
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 27
- 238000010668 complexation reaction Methods 0.000 claims abstract description 22
- 230000009246 food effect Effects 0.000 claims abstract description 16
- 235000021471 food effect Nutrition 0.000 claims abstract description 16
- 238000004090 dissolution Methods 0.000 claims abstract description 11
- 238000010521 absorption reaction Methods 0.000 claims abstract description 10
- 238000004088 simulation Methods 0.000 claims abstract description 10
- 239000000243 solution Substances 0.000 claims description 55
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 35
- 229920001577 copolymer Polymers 0.000 claims description 35
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 35
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 32
- 229940117958 vinyl acetate Drugs 0.000 claims description 31
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 30
- 238000013149 parallel artificial membrane permeability assay Methods 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- 239000008187 granular material Substances 0.000 claims description 25
- 239000002245 particle Substances 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 24
- 229910001868 water Inorganic materials 0.000 claims description 22
- 239000007864 aqueous solution Substances 0.000 claims description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
- -1 poly(2-ethyl-2- oxazoline) Polymers 0.000 claims description 21
- 239000007787 solid Substances 0.000 claims description 20
- 229910016860 FaSSIF Inorganic materials 0.000 claims description 19
- 201000010099 disease Diseases 0.000 claims description 18
- 229920001223 polyethylene glycol Polymers 0.000 claims description 18
- 108010079245 Cystic Fibrosis Transmembrane Conductance Regulator Proteins 0.000 claims description 17
- 229910005429 FeSSIF Inorganic materials 0.000 claims description 16
- 239000002202 Polyethylene glycol Substances 0.000 claims description 16
- 230000001404 mediated effect Effects 0.000 claims description 15
- 201000009266 primary ciliary dyskinesia Diseases 0.000 claims description 15
- 239000006185 dispersion Substances 0.000 claims description 14
- 208000025678 Ciliary Motility disease Diseases 0.000 claims description 12
- 102100026383 Vasopressin-neurophysin 2-copeptin Human genes 0.000 claims description 12
- 239000008139 complexing agent Substances 0.000 claims description 12
- 230000007812 deficiency Effects 0.000 claims description 12
- 201000010064 diabetes insipidus Diseases 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 11
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 10
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims description 10
- 239000013543 active substance Substances 0.000 claims description 10
- 239000000084 colloidal system Substances 0.000 claims description 10
- 239000002552 dosage form Substances 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 229960004508 ivacaftor Drugs 0.000 claims description 9
- 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 claims description 9
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 8
- 229960004106 citric acid Drugs 0.000 claims description 8
- 229920002554 vinyl polymer Polymers 0.000 claims description 8
- CDOUZKKFHVEKRI-UHFFFAOYSA-N 3-bromo-n-[(prop-2-enoylamino)methyl]propanamide Chemical compound BrCCC(=O)NCNC(=O)C=C CDOUZKKFHVEKRI-UHFFFAOYSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- 229960001927 cetylpyridinium chloride Drugs 0.000 claims description 7
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 claims description 7
- 229960003964 deoxycholic acid Drugs 0.000 claims description 7
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 claims description 7
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 7
- 206010006474 Bronchopulmonary aspergillosis allergic Diseases 0.000 claims description 6
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 206010067265 Heterotaxia Diseases 0.000 claims description 6
- 208000015439 Lysosomal storage disease Diseases 0.000 claims 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 claims description 6
- 206010033645 Pancreatitis Diseases 0.000 claims description 6
- 238000001069 Raman spectroscopy Methods 0.000 claims description 6
- 208000031733 Situs inversus totalis Diseases 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 208000006778 allergic bronchopulmonary aspergillosis Diseases 0.000 claims description 6
- 210000000988 bone and bone Anatomy 0.000 claims description 6
- 229960003194 meglumine Drugs 0.000 claims description 6
- 238000003801 milling Methods 0.000 claims description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 208000008797 situs inversus Diseases 0.000 claims description 6
- 239000001632 sodium acetate Substances 0.000 claims description 6
- 235000017281 sodium acetate Nutrition 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- SHBUUTHKGIVMJT-UHFFFAOYSA-N Hydroxystearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OO SHBUUTHKGIVMJT-UHFFFAOYSA-N 0.000 claims description 5
- 229920002675 Polyoxyl Polymers 0.000 claims description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 5
- ZAKOWWREFLAJOT-ADUHFSDSSA-N [2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-yl] acetate Chemical group CC(=O)OC1=C(C)C(C)=C2OC(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-ADUHFSDSSA-N 0.000 claims description 5
- 239000012861 aquazol Substances 0.000 claims description 5
- 229920006187 aquazol Polymers 0.000 claims description 5
- 229920001400 block copolymer Polymers 0.000 claims description 5
- 150000005690 diesters Chemical class 0.000 claims description 5
- 125000005456 glyceride group Chemical group 0.000 claims description 5
- 229920000578 graft copolymer Polymers 0.000 claims description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- 229940072106 hydroxystearate Drugs 0.000 claims description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 5
- 239000011976 maleic acid Substances 0.000 claims description 5
- XJRBAMWJDBPFIM-UHFFFAOYSA-N methyl vinyl ether Chemical compound COC=C XJRBAMWJDBPFIM-UHFFFAOYSA-N 0.000 claims description 5
- 229920001983 poloxamer Polymers 0.000 claims description 5
- 229940113116 polyethylene glycol 1000 Drugs 0.000 claims description 5
- 229960004249 sodium acetate Drugs 0.000 claims description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 5
- 238000011200 topical administration Methods 0.000 claims description 5
- 150000003626 triacylglycerols Chemical class 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- 230000000112 colonic effect Effects 0.000 claims description 4
- 238000007912 intraperitoneal administration Methods 0.000 claims description 4
- 238000012545 processing Methods 0.000 claims description 4
- 230000002685 pulmonary effect Effects 0.000 claims description 4
- 230000001603 reducing effect Effects 0.000 claims description 4
- 239000007962 solid dispersion Substances 0.000 claims description 4
- 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 compound 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 claims description 3
- 102100034452 Alternative prion protein Human genes 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 102100032187 Androgen receptor Human genes 0.000 claims description 3
- 208000009575 Angelman syndrome Diseases 0.000 claims description 3
- 206010002961 Aplasia Diseases 0.000 claims description 3
- 206010003591 Ataxia Diseases 0.000 claims description 3
- 208000012904 Bartter disease Diseases 0.000 claims description 3
- 208000010062 Bartter syndrome Diseases 0.000 claims description 3
- 208000006386 Bone Resorption Diseases 0.000 claims description 3
- 206010006458 Bronchitis chronic Diseases 0.000 claims description 3
- 208000031976 Channelopathies Diseases 0.000 claims description 3
- 208000010693 Charcot-Marie-Tooth Disease Diseases 0.000 claims description 3
- 206010010356 Congenital anomaly Diseases 0.000 claims description 3
- 206010062264 Congenital hyperthyroidism Diseases 0.000 claims description 3
- 206010010774 Constipation Diseases 0.000 claims description 3
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 claims description 3
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 claims description 3
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 claims description 3
- 208000024940 Dent disease Diseases 0.000 claims description 3
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 3
- 206010013883 Dwarfism Diseases 0.000 claims description 3
- 206010014561 Emphysema Diseases 0.000 claims description 3
- 208000024720 Fabry Disease Diseases 0.000 claims description 3
- 201000011240 Frontotemporal dementia Diseases 0.000 claims description 3
- 208000019683 Gorham-Stout disease Diseases 0.000 claims description 3
- 206010019860 Hereditary angioedema Diseases 0.000 claims description 3
- 208000033981 Hereditary haemochromatosis Diseases 0.000 claims description 3
- 101000775732 Homo sapiens Androgen receptor Proteins 0.000 claims description 3
- 201000000101 Hyperekplexia Diseases 0.000 claims description 3
- 206010058271 Hyperexplexia Diseases 0.000 claims description 3
- 208000000563 Hyperlipoproteinemia Type II Diseases 0.000 claims description 3
- 206010051125 Hypofibrinogenaemia Diseases 0.000 claims description 3
- 208000000038 Hypoparathyroidism Diseases 0.000 claims description 3
- 208000003892 Kartagener syndrome Diseases 0.000 claims description 3
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 claims description 3
- 208000019693 Lung disease Diseases 0.000 claims description 3
- 208000007466 Male Infertility Diseases 0.000 claims description 3
- 208000029725 Metabolic bone disease Diseases 0.000 claims description 3
- 208000008955 Mucolipidoses Diseases 0.000 claims description 3
- 206010072928 Mucolipidosis type II Diseases 0.000 claims description 3
- 208000002678 Mucopolysaccharidoses Diseases 0.000 claims description 3
- 208000010316 Myotonia congenita Diseases 0.000 claims description 3
- 206010068871 Myotonic dystrophy Diseases 0.000 claims description 3
- 208000012902 Nervous system disease Diseases 0.000 claims description 3
- 208000025966 Neurological disease Diseases 0.000 claims description 3
- 206010031243 Osteogenesis imperfecta Diseases 0.000 claims description 3
- 206010049088 Osteopenia Diseases 0.000 claims description 3
- 208000001132 Osteoporosis Diseases 0.000 claims description 3
- 208000035467 Pancreatic insufficiency Diseases 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 208000000609 Pick Disease of the Brain Diseases 0.000 claims description 3
- 208000025237 Polyendocrinopathy Diseases 0.000 claims description 3
- 108091000054 Prion Proteins 0.000 claims description 3
- 208000024777 Prion disease Diseases 0.000 claims description 3
- 201000005660 Protein C Deficiency Diseases 0.000 claims description 3
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 3
- 208000035954 Thomsen and Becker disease Diseases 0.000 claims description 3
- 206010045261 Type IIa hyperlipidaemia Diseases 0.000 claims description 3
- 208000006269 X-Linked Bulbo-Spinal Atrophy Diseases 0.000 claims description 3
- 208000004622 abetalipoproteinemia Diseases 0.000 claims description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 230000002146 bilateral effect Effects 0.000 claims description 3
- 230000010256 bone deposition Effects 0.000 claims description 3
- 230000008468 bone growth Effects 0.000 claims description 3
- 230000010478 bone regeneration Effects 0.000 claims description 3
- 230000024279 bone resorption Effects 0.000 claims description 3
- 206010006451 bronchitis Diseases 0.000 claims description 3
- 208000007451 chronic bronchitis Diseases 0.000 claims description 3
- 210000004081 cilia Anatomy 0.000 claims description 3
- 230000001886 ciliary effect Effects 0.000 claims description 3
- 230000007547 defect Effects 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000005538 encapsulation Methods 0.000 claims description 3
- 206010015037 epilepsy Diseases 0.000 claims description 3
- 201000001386 familial hypercholesterolemia Diseases 0.000 claims description 3
- 230000035876 healing Effects 0.000 claims description 3
- 208000013746 hereditary thrombophilia due to congenital protein C deficiency Diseases 0.000 claims description 3
- 238000000265 homogenisation Methods 0.000 claims description 3
- 150000002632 lipids Chemical class 0.000 claims description 3
- 208000019423 liver disease Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 208000020460 mucolipidosis II alpha/beta Diseases 0.000 claims description 3
- 206010028093 mucopolysaccharidosis Diseases 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 108010040003 polyglutamine Proteins 0.000 claims description 3
- 229920000155 polyglutamine Polymers 0.000 claims description 3
- 230000000750 progressive effect Effects 0.000 claims description 3
- 230000020978 protein processing Effects 0.000 claims description 3
- 230000008439 repair process Effects 0.000 claims description 3
- 201000009890 sinusitis Diseases 0.000 claims description 3
- 239000000779 smoke Substances 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 229950005823 tezacaftor Drugs 0.000 claims description 3
- 210000001177 vas deferen Anatomy 0.000 claims description 3
- 102000008371 intracellularly ATP-gated chloride channel activity proteins Human genes 0.000 claims 4
- 230000008030 elimination Effects 0.000 abstract description 7
- 238000003379 elimination reaction Methods 0.000 abstract description 7
- 239000007788 liquid Substances 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
- 102000012605 Cystic Fibrosis Transmembrane Conductance Regulator Human genes 0.000 description 13
- 239000003826 tablet Substances 0.000 description 11
- 230000003993 interaction Effects 0.000 description 7
- 239000008186 active pharmaceutical agent Substances 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 235000015165 citric acid Nutrition 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- YQCGOSZYHRVOFW-UHFFFAOYSA-N n-(2,4-ditert-butyl-5-hydroxyphenyl)-4-oxo-1h-quinoline-3-carboxamide;3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic acid Chemical compound C1=C(O)C(C(C)(C)C)=CC(C(C)(C)C)=C1NC(=O)C1=CNC2=CC=CC=C2C1=O.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 YQCGOSZYHRVOFW-UHFFFAOYSA-N 0.000 description 6
- 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 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 229940080152 orkambi Drugs 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 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 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 229920003083 Kollidon® VA64 Polymers 0.000 description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 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
- 210000004027 cell Anatomy 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 239000002304 perfume Substances 0.000 description 4
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 239000004375 Dextrin Substances 0.000 description 3
- 229920001353 Dextrin Polymers 0.000 description 3
- 239000004606 Fillers/Extenders Substances 0.000 description 3
- 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 3
- 239000005913 Maltodextrin Substances 0.000 description 3
- 229920002774 Maltodextrin Polymers 0.000 description 3
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229940096516 dextrates Drugs 0.000 description 3
- 235000019425 dextrin Nutrition 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940088679 drug related substance Drugs 0.000 description 3
- 238000007908 dry granulation Methods 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 229940035034 maltodextrin Drugs 0.000 description 3
- 229960002160 maltose Drugs 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 2
- NUFKRGBSZPCGQB-FLBSXDLDSA-N (3s)-3-amino-4-oxo-4-[[(2r)-1-oxo-1-[(2,2,4,4-tetramethylthietan-3-yl)amino]propan-2-yl]amino]butanoic acid;pentahydrate Chemical compound O.O.O.O.O.OC(=O)C[C@H](N)C(=O)N[C@H](C)C(=O)NC1C(C)(C)SC1(C)C.OC(=O)C[C@H](N)C(=O)N[C@H](C)C(=O)NC1C(C)(C)SC1(C)C NUFKRGBSZPCGQB-FLBSXDLDSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- SERLAGPUMNYUCK-DCUALPFSSA-N 1-O-alpha-D-glucopyranosyl-D-mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-DCUALPFSSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 2
- 239000004377 Alitame Substances 0.000 description 2
- 108010011485 Aspartame Proteins 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 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
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 2
- 239000001329 FEMA 3811 Substances 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 229920001202 Inulin Polymers 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
- 229930195725 Mannitol Natural products 0.000 description 2
- 239000012901 Milli-Q water Substances 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- 239000004384 Neotame Substances 0.000 description 2
- 238000001237 Raman spectrum Methods 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000004376 Sucralose Substances 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- 235000010358 acesulfame potassium Nutrition 0.000 description 2
- 229960004998 acesulfame potassium Drugs 0.000 description 2
- 239000000619 acesulfame-K Substances 0.000 description 2
- 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 2
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 2
- 239000001361 adipic acid Substances 0.000 description 2
- 235000011037 adipic acid Nutrition 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 235000019409 alitame Nutrition 0.000 description 2
- 108010009985 alitame Proteins 0.000 description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000000605 aspartame Substances 0.000 description 2
- 235000010357 aspartame Nutrition 0.000 description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 2
- 229960003438 aspartame Drugs 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 229960003563 calcium carbonate Drugs 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 229960004424 carbon dioxide Drugs 0.000 description 2
- 229940000425 combination drug Drugs 0.000 description 2
- 238000005056 compaction Methods 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 2
- 229940038472 dicalcium phosphate Drugs 0.000 description 2
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229960002449 glycine Drugs 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 description 2
- 229940029339 inulin Drugs 0.000 description 2
- 239000000905 isomalt Substances 0.000 description 2
- 235000010439 isomalt Nutrition 0.000 description 2
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 description 2
- BJHIKXHVCXFQLS-PQLUHFTBSA-N keto-D-tagatose Chemical compound OC[C@@H](O)[C@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-PQLUHFTBSA-N 0.000 description 2
- 239000000832 lactitol Substances 0.000 description 2
- 235000010448 lactitol Nutrition 0.000 description 2
- 229960003451 lactitol Drugs 0.000 description 2
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 2
- 235000005772 leucine Nutrition 0.000 description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 2
- 239000001095 magnesium carbonate Substances 0.000 description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 2
- 229960001708 magnesium carbonate Drugs 0.000 description 2
- 235000014380 magnesium carbonate Nutrition 0.000 description 2
- 239000000395 magnesium oxide Substances 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- 229960000869 magnesium oxide Drugs 0.000 description 2
- 235000012245 magnesium oxide Nutrition 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 235000010449 maltitol Nutrition 0.000 description 2
- 239000000845 maltitol Substances 0.000 description 2
- 229940035436 maltitol Drugs 0.000 description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 229940041616 menthol Drugs 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 235000019426 modified starch Nutrition 0.000 description 2
- 230000003020 moisturizing effect Effects 0.000 description 2
- ITVGXXMINPYUHD-CUVHLRMHSA-N neohesperidin dihydrochalcone Chemical compound C1=C(O)C(OC)=CC=C1CCC(=O)C(C(=C1)O)=C(O)C=C1O[C@H]1[C@H](O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 ITVGXXMINPYUHD-CUVHLRMHSA-N 0.000 description 2
- 229940089953 neohesperidin dihydrochalcone Drugs 0.000 description 2
- 235000010434 neohesperidine DC Nutrition 0.000 description 2
- 235000019412 neotame Nutrition 0.000 description 2
- HLIAVLHNDJUHFG-HOTGVXAUSA-N neotame Chemical compound CC(C)(C)CCN[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 HLIAVLHNDJUHFG-HOTGVXAUSA-N 0.000 description 2
- 108010070257 neotame Proteins 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068917 polyethylene glycols Drugs 0.000 description 2
- 229920002689 polyvinyl acetate Polymers 0.000 description 2
- 239000011118 polyvinyl acetate Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 235000019204 saccharin Nutrition 0.000 description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 2
- 229940081974 saccharin Drugs 0.000 description 2
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 2
- 229940085605 saccharin sodium Drugs 0.000 description 2
- 238000009491 slugging Methods 0.000 description 2
- 229960001462 sodium cyclamate Drugs 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000012916 structural analysis Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000019408 sucralose Nutrition 0.000 description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000000892 thaumatin Substances 0.000 description 2
- 235000010436 thaumatin Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229940074410 trehalose Drugs 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- SGHZXLIDFTYFHQ-UHFFFAOYSA-L Brilliant Blue Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 SGHZXLIDFTYFHQ-UHFFFAOYSA-L 0.000 description 1
- 206010052360 Colorectal adenocarcinoma Diseases 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 108010010803 Gelatin Proteins 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
- 239000002033 PVDF binder Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229910007261 Si2N3 Inorganic materials 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 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 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 229940027983 antiseptic and disinfectant quaternary ammonium compound Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000000823 artificial membrane Substances 0.000 description 1
- 238000000498 ball milling Methods 0.000 description 1
- 231100001125 band 2 compound Toxicity 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 235000012730 carminic acid Nutrition 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 239000011258 core-shell material Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- SZVJSHCCFOBDDC-UHFFFAOYSA-N ferrosoferric oxide Chemical compound O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000013561 fixed dose combination tablet Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000023611 glucuronidation Effects 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000037427 ion transport Effects 0.000 description 1
- 229940052950 ivacaftor and lumacaftor Drugs 0.000 description 1
- 238000010902 jet-milling Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229940057917 medium chain triglycerides Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940032007 methylethyl ketone Drugs 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000000541 pulsatile effect Effects 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 239000012905 visible particle Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
-
- 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
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
-
- 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
- A61K9/145—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 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
- A61K9/141—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
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/10—Laxatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- 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
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the invention is directed to a stable complexes with controlled particle size, increased apparent solubility and increased dissolution rate comprising as active compound Lumacaftor, or its salts, or derivatives thereof, which is useful in the treatment of cystic fibrosis transmembrane conductance regulator (CFTR) mediated disease. More specifically, the complexes of the present invention possess instantaneous redispersibility, increased apparent solubility and permeability in fasted and fed state simulation that is expected to deliver full absorption and eliminate the food effect.
- the invention also relates to methods of formulating and manufacturing complexes according to the invention, pharmaceutical compositions containing it, its uses and methods of treatment using the complex and its compositions.
- Lumacaftor is one of the active ingredients in ORKAMBI® tablets, which has the following chemical name: 3-[6-( ⁇ [l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl ⁇ amino)-3-methylpyridin-2-yl]benzoic acid.
- the molecular formula for lumacaftor is C 24 H 18 F 2 N 2 0 5 .
- the molecular weight for Lumacaftor is 452.41.
- the structural formula is:
- Lumacaftor is a white to off-white powder that is practically insoluble in water mg/mL).
- ORKAMBI® is available as a pink, oval-shaped, film-coated tablet for oral administration containing 200 mg of Lumacaftor and 125 mg of Ivacaftor.
- Each ORKAMBI® tablet contains 200 mg of Lumacaftor and 125 mg of Ivacaftor, and the following inactive ingredients: microcrystalline cellulose; croscarmellose sodium; hypromellose acetate succinate; magnesium stearate; povidone; and sodium lauryl sulfate.
- the tablet film coat contains carmine, FD&C Blue #1, FD&C Blue #2, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
- the printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac.
- Lumacaftor improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. ln-vitro studies have demonstrated that Lumacaftor acts directly on the CFTR protein in primary human bronchial epithelial cultures and other cell lines harboring the F508del-CFTR mutation to increase the quantity, stability, and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport.
- Lumacaftor Following multiple oral dose administrations of Lumacaftor, the exposure of Lumacaftor increased roughly proportionally with dose from 50 to 1000 mg qd. In subjects with cystic fibrosis (CF), the Lumacaftor C max and AUC also increases approximately proportional with the dose over the Lumacaftor 25 mg qd to 400 mg ql2h dose range. The exposure of Lumacaftor increased approximately 1.6-to 2.0-fold when given with fat containing food. The median (range) time of the maximum concentration (t ⁇ ) is approximately 4.0 (2.0, 9.0) hours in the fed state.
- CF cystic fibrosis
- Lumacaftor exposure was approximately 2 times higher and Ivacaftor exposure was approximately 3 times higher than when taken in a fasting state.
- Lumacaftor Following multiple oral dose administration of Lumacaftor in combination with Ivacaftor, the exposure of Lumacaftor generally increased proportional to dose over the range of 200 mg every 24 hours to 400 mg every 12 hours.
- the median (range) of Lumacaftor is approximately 4.0 hours (2.0; 9.0) in the fed state.
- Lumacaftor is approximately 99% bound to plasma proteins, primarily to albumin. After oral administration of 200 mg every 24 hours for 28 days to patients with CF in a fed state, the mean (+SD) for apparent volumes of distribution was 86.0 (69.8) L. [0010] The half-life of Lumacaftor is approximately 26 hours in patients with CF. The typical apparent clearance, CL/F (CV), of Lumacaftor was estimated to be 2 38 L/hr (29.4%) for patients with CF.
- Lumacaftor is not extensively metabolized in humans with the majority (51%) of Lumacaftor excreted unchanged in the feces. There was minimal elimination of Lumacaftor and its metabolites in urine (only 8.6% of total radioactivity was recovered in the urine with 0.18% as unchanged parent). ln-vitro and in vivo data indicate that Lumacaftor is mainly metabolized via oxidation and glucuronidation.
- Lumacaftor has low aqueous solubility and high permeability assessed via the colorectal adenocarcinoma (Caco-2) cell system. Although pH-dependent solubility was observed, the Lumacaftor drug substance is practically insoluble in water and buffer solutions of pH 1.0 to pH 8.0. Therefore, Lumacaftor is suggested to be a BCS Class 2 (low solubility/high permeability) compound.
- Lumacaftor is considered a BCS class II
- the drug substance was jet-milled early in development to reduce the particle size and potentially improve bioavailability. Based on these studies a control on Lumacaftor particle size in the drug substance specification was established.
- Lumacaftor alone and in combination which includes suspension, capsules and tablets. Comparative exposure of the different formulations of Lumacaftor was seen in single dose studies in healthy volunteers. Exposure of the suspension is lower than that seen for capsules and tablets. Early clinical studies were conducted with the co-administration of both Ivacaftor and Lumacaftor. A cross-over study (007) was conducted to evaluate the relative bioavailability of the fixed dose combination tablet as compared to the separate tablets.
- the tablet and FDC appear to be bioequivalent, and the only parameter that did not meet standard bioequivalence criteria is the C max of Ivacaftor (GLSMR [90% CI] - 1.20 [1.09, 1.33]). However, for practical purposes, this is acceptable and the PK results from tablet formulation can be considered applicable to the FDC as well.
- novel complex formulations of Lumacaftor or its salts or its derivatives thereof and complexation agents and pharmaceutically acceptable excipients were prepared. Novel complex formulations of the present invention are characterized by instantaneous redispersibility, increased apparent solubility, instantaneous dissolution, increased apparent permeability in fasted and fed state simulation that is expected to deliver full absorption and the elimination of the food effect.
- a stable complex with improved physicochemical characteristics and enhanced biological performance comprising i. Lumacaftor, or a salt or derivative thereof; ii. at least one complexation agent chosen from polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol, hydroxypropylcellulose, poloxamers (copolymers of ethylene oxide and propylene oxide blocks), copolymer of vinylpyrrolidone and vinyl acetate, poly(2-ethyl-2- oxazoline), polyvinylpyrrolidone, , poly(maleic acid/methyl vinyl ether), (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyoxyl 15 hydroxystearate, ethylene oxide/ propylene oxide tetra functional block copolymer, and d-alpha tocopheryl polyethylene glycol 1000 succinate; and iii.
- said complex has a particle size is between 10 nm and 500 nm, and possesses one or more among the following features: a) is instantaneously redispersable in physiological relevant media; b) is stable in solid form and in colloid solution and/ or dispersion; c) has an apparent solubility in water of at least 1 mg/mL; d) has a PAMPA permeability of at least 2xlCT 6 cm/s when dispersed in FaSSIF or FeSSIF biorelevant media, which does not decrease in time at least for 12 month.
- the complex according to Point 6 wherein said complex possesses instantaneous redispersibility, has an apparent solubility in water of at least 1 mg/mL, and has a PAMPA permeability of at least 2x10 "6 cm/ s in FaSSIF and FeSSIF biorelevant media.
- said complexing agent is a copolymer of vinylpyrrolidone and vinylacetate.
- the complex according to Point 1 comprising a) Lumacaftor; b) as complexation agent a copolymer of vinylpyrrolidone and vinylacetate; c) as an excipient sodium lauryl sulfate; wherein said complex is characterized by infrared (ATR) peaks at 635 cm 4 , 703 cm 4 , 747 cm 4 , 837 cm 4 , 1021 cm 4 , 1165 cm 4 , 1231 cm , 1288 cm , 1369 cm , 1423 cm 4 , 1462 cm 4 , 1494 cm 4 , 1667 cm 4 and 1731 cm 4 ; and is characterized by Raman shifts at 553 cm 4 , 602 cm 4 , 635 cm 4 , 654 cm , 747 cm 4 , 841 cm 4 , 899 cm 4 , 934 cm 1 , 1002 cm 4 , 1021 cm 4 , 1117 cm , 1205 cm 4 , 1232 cm 4 , 1310 cm , 1352 cm
- a complex according to either of Point 1 or Point 13 comprising a complexation agent which is a copolymer of vinylpyrrolidone and vinylacetate and pharmaceutically acceptable excipient which is sodium lauryl sulfate, in a total amount ranging from about 1.0 weight % to about 95.0 weight % based on the total weight of the complex.
- a complex according to either of Point 1 or Point 15 comprising a complexing agent which is a copolymer of vinylpyrrolidone and vinylacetate and pharmaceutically acceptable excipient which is sodium lauryl sulfate, in a total amount ranging from about 50 weight % to about 95.0 weight % based on the total weight of the complex.
- a process for the preparation of a stable complex according to Point 1 comprising the step of mixing a pharmaceutically acceptable solution containing Lumacaftor, and at least one complexing agent which is a copolymer of vinylpyrrolidone and vinylacetate with an aqueous solution containing at least one pharmaceutically accepted excipient selected from the group of sodium deoxycholate, dioctyl sodium sulfosuccinate, sodium acetate, cetylpyridinium chloride, citric acid, meglumine and sodium lautyl sulfate.
- a pharmaceutical composition comprising the stable complex according to Point 1 together with a pharmaceutically acceptable carrier.
- composition according to Point 24, wherein said composition is suitable for oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, otic, local, buccal, nasal, or topical administration.
- composition comprising the complex according to Point 26, wherein said composition comprises fast dissolving granules of the complex formulation according to Point 1.
- composition comprising the complex according to Point 27, wherein said granules are suitable for the preparation of sachet dosage form.
- CFTR mediated diseases are selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseud
- a method of treatment of CFTR mediated diseases comprising administration of a therapeutically effective amount of the complex according to Point 1 or the pharmaceutical composition according to Point 24.
- 32. A stable complex comprising a) 5— 40% by weight of Lumacaftor, or its salt; b) 50— 90% by weight of a copolymer of vinylpyrrolidone and vinylacetate; and c) 0.01— 50 % by weight of sodium lauryl sulfate wherein said complex has a controlled particle size in the range between 10 nm and 500 nm; and wherein said complex is not obtained via a milling process, high pressure homogenization process, encapsulation process or solid dispersion processes.
- 33. The complex according to Point 1, wherein said complex further comprises one or more additional active agents.
- stable complexes comprising as active compound Lumacaftor, or salts or derivatives thereof; and at least one complexation agent.
- said complex further comprises at least one pharmaceutically acceptable excipient.
- complexing agents themselves or together with the pharmaceutically acceptable excipients have the function to form a complex structure with an active pharmaceutical ingredient through non-covalent secondary interactions.
- the secondary interactions can form through electrostatic interactions such as ionic interactions, H-bonding, dipole-dipole interactions, dipole-induced dipole interactions, London dispersion forces, ⁇ - ⁇ interactions, and hydrophobic interactions.
- said complex has improved physicochemical characteristics and enhanced biological performance and comprises
- Lumacaftor or a salt thereof; ii. at least one complexation agent chosen from polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol, hydroxypropylcellulose, poloxamers (copolymers of ethylene oxide and propylene oxide blocks), copolymer of vinylpyrrolidone and vinyl acetate, poly(2- ethyl-2-oxazoline), polyvinylpyrrolidone, , poly(maleic acid/methyl vinyl ether),
- complexation agent chosen from polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol, hydroxypropylcellulose, poloxamers (copolymers of ethylene oxide and propylene oxide blocks), copolymer of vinylpyrrolidone and vinyl acetate, poly(2- ethyl-2-oxazoline), polyvinylpyrrolidone,
- said complex has a particle size is between 10 nm and 500 nm, and possesses one or more among the following features: a) is instantaneously redispersable in physiological relevant media; b) is stable in solid form and in colloid solution and/ or dispersion; c) has an apparent solubility in water of at least 1 mg/ mL; and d) has a PAMPA permeability of at least 2x10 "6 cm/s when dispersed in FaSSIF or FeSSIF biorelevant media, which does not decrease in time at least for 12 month.
- said complexation agent is chosen from polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol, hydroxypropylcellulose, poloxamers (copolymers of ethylene oxide and propylene oxide blocks), copolymer of vinylpyrrolidone and vinyl acetate, poly(2-ethyl-2-oxazoline), polyvinylpyrrolidone, poly(maleic acid/methyl vinyl ether), (polyvinyl caprolactam-polyvinyl acetate -polyethylene glycol graft copolymer, polyoxyl 15 hydroxystearate, ethylene oxide/propylene oxide tetra functional block copolymer, and d-alpha tocopheryl polyethylene glycol 1000 succinate, polyethylene- glycols.
- said complexation agent is copolymer of vinylpyrrolidone and vinyl acetate.
- said copolymer of vinylpyrrolidone and vinyl acetate has a 60:40 weight ratio of vinylpyrrolidone:vinyl acetate monomers.
- said pharmaceutically acceptable excipient is chosen from sodium lauryl sulfate (SDS), dioctyl sodium sulfosuccinate (DSS), cetylpyridinium chloride (CPC), sodium acetate (NaOAC), sodium deoxycholate (SDC), meglumine, D-mannitol, Kollicoat-IR, citric acid and lactose.
- said pharmaceutically acceptable excipient is chosen from sodium deoxycholate, dioctyl sodium sulfosuccinate, sodium acetate, cetylpyridinium chloride, citric acid, meglumine and sodium lauryl sulfate.
- said pharmaceutically acceptable excipient is sodium lauryl sulfate.
- compositions may additionally include one or more pharmaceutically acceptable excipients, auxiliary materials, carriers, active agents or combinations thereof.
- said complexes have particle size between 10 nm and 500 nm. [0031] In an embodiment, said particle size is between 10 nm and 250 nm.
- said complex has increased dissolution rate compared to crystalline Lumacaftor.
- said complex is stable in solid form and in colloid solution and/or dispersion.
- said complex has apparent solubility in water is at least 1 mg/ mL.
- said complex exhibits X-ray amorphous character in the solid form.
- said complex has a PAMPA permeability of at least 2x10 "6 cm/ s when dispersed in FaSSIF media, which does not decrease in time at least for 12 months.
- the variability of exposure of the complex is significantly reduced compared to the commercially available form (ORKAMBI®).
- said complex has no observable food effect in-vitro, which allows the opportunity of precise dosing and ease of administration of the reconstituted complex in solution form.
- said complex or its pharmaceutical composition according to the invention characterized by Raman spectrum shown in Figure 7 and ATR spectrum shown in Figure 8.
- said complex is characterized by Raman shifts at 553 cm 4 , 602 cm 4 , 635 cm , 654 cm 4 , 747 cm 1 , 841 cm , 899 cm 4 , 934 cm 4 , 1002 cm 4 , 1021 cm , 1117 cm , 1205 cm 4 , 1232 cm 4 , 1310 cm 4 , 1352 cm , 1372 cm 4 , 1428 cm 4 , 1444 cm , 1497 cm 4 , 1592 cm 4 , 1609 cm , 1677 cm 4 and 1737 cm 4 .
- said complex is characterized by infrared (ATR) peaks at 635 cm 4 , 703 cm 4 , 747 cm 4 , 837 cm , 1021 cm 4 , 1165 cm , 1231 cm , 1288 cm , 1369 cm 1 , 1423 cm 1 , 1462 cm 1 , 1494 cm 1 , 1667 cm 1 and 1731 cm .
- ATR infrared
- said complex comprises a) Lumacaftor; or a combination of active compounds including Lumacaftor; b) a complexing agent which is a copolymer of vinylpyrrolidone and vinyl acetate; and c) sodium lauryl sulfate as an excipient.
- said complex comprises complexation agent which is a copolymer of vinylpyrrolidone and vinylacetate and a pharmaceutically acceptable excipient which is sodium lauryl sulfate, in a total amount ranging from about 1.0 weight % to about 95.0 weight % based on the total weight of the complex.
- said complex comprises complexation agent which is copolymer of vinylpyrrolidone and vinylacetate and pharmaceutically acceptable excipient which is sodium lauryl sulfate comprise 50 weight % to about 95 weight % of the total weight of the complex.
- a stable complex comprising i. 5— 40% by weight of Lumacaftor, its salt, or derivatives thereof; ii. 50— 90% by weight of copolymer of vinylpyrrolidone and vinylacetate; iii. 0.01 - 30 % by weight of sodium lauryl sulfate.
- a process for the preparation of a stable complex of Lumacaftor comprising the step of mixing a pharmaceutically acceptable solution containing the active agent and at least one complexing agent and optionally one or more pharmaceutically acceptable excipient with an aqueous solution containing optionally least one pharmaceutically acceptable excipient.
- said complex is obtained via a mixing process.
- said complex is obtained via a continuous flow mixing process.
- said process is performed in a continuous flow instrument.
- said continuous flow instrument is a microfluidic flow instrument.
- said complex is not obtained via a milling process, high pressure homogenization process, encapsulation process and solid dispersion processes.
- the pharmaceutically acceptable solvent of said pharmaceutically acceptable solution is chosen from methanol, ethanol, 1-propanol, 2-propanol, acetone, acetonitrile, dimethyl-sulfoxide, tetrahydrofuran, methyl-ethyl ketone or combinations thereof.
- said pharmaceutically acceptable solvent is methanol.
- said pharmaceutically acceptable solution and said aqueous solution are miscible with each other.
- said aqueous solution comprises 0.1 to 99.9% weight of the final solution.
- said aqueous solution comprises 50 to 90% weight of the final solution.
- said aqueous solution comprises 50 to 80% weight of the final solution.
- said aqueous solution comprises 50 to 70% weight of the final solution.
- said aqueous solution comprises 50 to 60% weight of the final solution. [0060] In an embodiment, said aqueous solution comprises 45 to 55% weight of the final solution.
- said aqueous solution comprises 50 % weight of the final solution.
- said aqueous solution comprises 35 to 45 % weight of the final solution.
- said aqueous solution comprises 25 to 35 % weight of the final solution.
- said aqueous solution comprises 15 to 25 % weight of the final solution.
- said aqueous solution comprises 5 to 15 % weight of the final solution.
- a pharmaceutical composition comprising the complex together with pharmaceutically acceptable carriers.
- said pharmaceutical composition is suitable for oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, otic, local, buccal, nasal, or topical administration.
- said pharmaceutical compositions are suitable for oral administration.
- said pharmaceutical composition comprises fast dissolving granules.
- said granules are suitable for the preparation of sachet dosage form.
- said complexes are for use in the manufacture of a medicament for the treatment of CFTR mediated diseases.
- said complexes are used for the treatment of CFTR mediated diseases.
- CFTR mediated disease is selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs,
- a method of treatment of CFTR mediated diseases comprises administration of a therapeutically effective amount of complexes or pharmaceutical compositions as described herein.
- a method for reducing the therapeutically effective dosage of Lumacaftor compared to commercially available ORKAMBI® comprises oral administration of a pharmaceutical composition as described herein.
- said complexes further comprise one or more additional active agents.
- said additional active agent is Ivacaftor, Tezacaftor or chosen from agents used for the treatment of CFTR mediated diseases.
- said complex comprises Lumacaftor; or a combination of active compounds including Lumacaftor; a complexing agent which is copolymers of vinylpyrrolidone and vinyl acetate and sodium lauryl sulfate as an excipient; said complexes characterized in that they possess at least one of the following properties: a) is instantaneously redispersible in physiological relevant media; b) is stable in solid form and in colloid solution and/ or dispersion; c) has apparent solubility in water of at least 1 mg/ mL; and d) has a PAMPA permeability of at least 2xl0 ⁇ 6 cm/s when dispersed in FaSSIF or FeSSIF biorelevant media, which does not decrease in time at least for 12 month.
- said complex possesses at least two of the properties described in a)- d).
- said complex possesses at least three of the properties described in a)- d).
- novel complexes of the present invention possess instantaneous redispersibility, increased apparent solubility and permeability in fasted and fed state simulation that is expected to deliver full absorption and eliminate the food effect which deliver the opportunity of precise dosing and ease of administration of the reconstituted complex in solution form.
- Lumacaftor is generally used for Lumacaftor, or its salts or its derivatives.
- said complexation agent is chosen from polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol, hydroxypropylcellulose, poloxamers (copolymers of ethylene oxide and propylene oxide blocks), copolymer of vinylpyrrolidone and vinyl acetate, poly(2-ethyl-2-oxazoline), polyvinylpyrrolidone, poly(maleic acid/methyl vinyl ether), (polyvinyl caprolactam-polyvinyl acetate -polyethylene glycol graft copolymer, polyoxyl 15 hydroxystearate, ethylene oxide/propylene oxide tetra functional block copolymer, and d-alpha tocopheryl polyethylene glycol 1000 succinate.
- polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol, hydroxypropylcellulose, poloxamers (cop
- said complexation agent is a copolymer of vinylpyrrolidone and vinyl acetate and said pharmaceutically acceptable excipient is sodium lauryl sulfate
- a) is characterized by Raman shifts at 553 cm 4 , 602 cm 4 , 635 cm 4 , 654 cm 4 , 747 cm 4 , 841 cm 4 , 899 cm , 934 cm 4 , 1002 cm , 1021 cm 4 , 1117 cm , 1205 cm , 1232 cm , 1310 cm , 1352 cm 4 , 1372 cm , 1428 cm , 1444 cm 4 , 1497 cm , 1592 cm 4 , 1609 cm 4 , 1677 cm 1 and 1737 cm 4 ; and b) is characterized by infrared (ATR) peaks at 635 cm 4 , 703 cm 4 , 747 cm 4 , 837 cm 4 , 1021 cm 4 , 1165 cm 4 , 1231 cm 4 , 1288 cm
- ATR infrare
- compositions may additionally include one or more pharmaceutically acceptable excipients, auxiliary materials, carriers, active agents or combinations thereof.
- active agents may include agents useful for the treatment of CFTR mediated diseases.
- Another aspect of the invention is the complex formulations of the Lumacaftor with complexation agents and pharmaceutically acceptable excipients in which the complexation agents and pharmaceutically acceptable excipients preferably are associated or interacted with the Lumacaftor, such as the results of a mixing process or a continuous flow mixing process.
- the structure of the complex Lumacaftor formulation is different from the core-shell type milled particle, precipitated encapsulated particles, micelles and solid dispersions.
- the pharmaceutical composition of the invention can be formulated: (a) for administration selected from the group consisting of oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, otic, local, buccal, nasal, and topical administration; (b) into a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, lyophilized formulations, tablets, capsules; (c) into a dosage form selected from the group consisting of controlled release formulations, fast melt formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; or (d) any combination of (a), (b), and (c).
- compositions can be formulated by adding different types of pharmaceutically acceptable excipients for oral administration in solid, liquid, local (powders, ointments or drops), or topical administration, and the like.
- the dosage form of the invention is a solid dosage form, although any pharmaceutically acceptable dosage form can be utilized.
- Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders (sachet), and granules.
- the complex formulation of Lumacaftor is admixed with at least one of the following: one or more inert excipients (or carriers): (a) fillers or extenders, such as, lactose, sucrose, glucose, mannitol, sorbitol, dextrose, dextrates, dextrin, etythritol, fructose, isomalt, lactitol, maltitol, maltose, maltodextrin, trehalose, xylitol, starches, microcrystalline cellulose, dicalcium phosphate, calcium carbonate, magnesium carbonate, magnesium oxide; (b) sweetening, flavoring, aromatizing and perfuming agents such as saccharin, saccharin sodium, acesulfame potassium, alitame, aspartame, glycine, inulin, neohesperidin dihydrochalcone, neotam
- the dosage form of the invention is a liquid dispersible granules in a sachet form.
- said liquid dispersible granules comprise the complex formulation of Lumacaftor of the present invention together with pharmaceutically acceptable excipients selected from the group of fillers or extenders, such as, lactose, sucrose, glucose, mannitol, sorbitol, dextrose, dextrates, dextrin, erythritol, fructose, isomalt, lactitol, maltitol, maltose, maltodextrin, trehalose, xylitol, starches, microcrystalline cellulose, dicalcium phosphate, calcium carbonate, magnesium carbonate, magnesium oxide.
- pharmaceutically acceptable excipients selected from the group of fillers or extenders, such as, lactose, sucrose, glucose, mannitol, sorbitol, dextrose, dextrates, dextrin, erythritol, fructose, isomalt, lactitol, maltitol
- said liquid dispersible granules comprise the complex formulation of Lumacaftor of the present invention together with pharmaceutically acceptable excipients selected from the group of sweetening, flavoring, aromatizing and perfuming agents such as saccharin, saccharin sodium, acesulfame potassium, alitame, aspartame, glycine, inulin, neohesperidin dihydrochalcone, neotame, sodium cyclamate, sucralose, tagatose, thaumatin, citric acid, adipic acid, fumaric acid, leucine, malic acid, menthol, propionic acid, tartaric acid.
- pharmaceutically acceptable excipients selected from the group of sweetening, flavoring, aromatizing and perfuming agents such as saccharin, saccharin sodium, acesulfame potassium, alitame, aspartame, glycine, inulin, neohesperidin di
- liquid dispersible granules comprising a) 25—95 % stable complex formulation of Lumacaftor of the present invention
- said dispersion time is between 0.1 min and 10 min.
- said dispersion time is between 0.1 min and 5 min.
- said dispersion time is between 0.1 min and 3 min.
- said dispersion time is between 0.1 min and 1 min.
- Hausner-ratio of the said liquid dispersible granules of complex Lumacaftor formulations is less than 1.25, more preferably 1.00-1.18
- Hausner-ratio of the said liquid dispersible granules of complex Lumacaftor formulations is between 1.00 and 1.18.
- the particle size (D(90)) of said solid aggregates of complex Lumacaftor formulations is less than 2000 micrometers.
- 60-99 % of the said solid aggregates of complex Lumacaftor formulations are in the size range of 160-1200 micrometers
- said liquid is water, saliva, other physiologically or biologically acceptable fluid.
- the dosage form is chosen from a tablet and a capsule.
- Advantages of the complex Lumacaftor formulation of the invention include, but are not limited to (1) physical and chemical stability, (2) instantaneous redispersibility, (3) stability in colloid solution or dispersion in the therapeutic time window, (4) increased apparent solubility and permeability compared to the conventional Lumacaftor formulation in fasted and fed state simulation that is expected to deliver full absorption and the elimination of the food effect, (5) good processability.
- said complex possesses instantaneous redispersibility, has an apparent solubility in water of at least 1 mg/ mL, improved permeability in fasted and fed state simulation, exhibits no observable food effect which deliver full absorption and the opportunity of precise dosing and ease of administration of the reconstituted complex Lumacaftor in solution form.
- said complex possesses instantaneous redispersibility, has a
- the complex Lumacaftor formulation of the present invention has increased apparent solubility and permeability.
- the apparent solubility and permeability of the complex Lumacaftor formulation is at least 1 mg/mL and 2xl0 ⁇ 6 cm/s in FaSSIF and FeSSIF biorelevant media, respectively.
- said complex possesses instantaneous redispersibility, has an apparent solubility in water of at least 1 mg/ mL, and has a PAMPA permeability of at least 2x10 "6 cm/ s in FaSSIF and FeSSIF biorelevant media.
- the complex Lumacaftor formulations of the present invention have an enhanced pharmacokinetic performance with improved solubility and permeability in fasted and fed state simulation that is expected to deliver full absorption and the elimination of the food effect.
- Figure 1 shows redispersibility of complex Lumacaftor compositions in ultrapurified water.
- Figure 2 shows redispersibility and PAMPA permeability of complex Lumacaftor compositions in purified water.
- Figure 3 shows PAMPA permeability of complex Lumacaftor formulations containing vinylpyrrolidone and vinylacetate copolymer and sodium lauryl sulfate in different ratios.
- Figure 4. shows optimization of production parameters.
- Figure 5 shows Lumacaftor dissolution from crystalline Lumacaftor and complex Lumacaftor formulation.
- Figure 6 shows PAMPA permeabilities of Lumacaftor formulations measured at different time points.
- Figure 7. shows SEM photo of complex Lumacaftor formulation.
- Figure 8 shows Raman spectra of crystalline Lumacaftor (A), amorphous Lumacaftor (B), complex Lumacaftor formulation (C), placebo (D), Kollidon VA64 (E), SDS (F).
- Figure 9 shows ATR spectra of crystalline Lumacaftor (A), amorphous Lumacaftor (B), complex Lumacaftor formulation (C), placebo (D), Kollidon VA64 (E), SDS (F).
- Figure 10 shows XRD diffractograms of crystalline Lumacaftor and complex Lumacaftor formulation.
- Figurell. shows apparent solubility of Lumacaftor formulations.
- Figurel2. shows PAMPA permeability of Lumacaftor formulations.
- the receiver compartment was phosphate buffered saline (pH 7.0) supplemented with 1 % sodium dodecyl sulfate.
- the assay was performed at room temperature; incubation time was 4 hours in ultrapurified water, FaSSIF and FeSSIF, respectively.
- the concentration in the receiver compartment was determined by UV-VIS spectrophotometry (VWR UV-3100PC Scanning Spectrophotometer).
- Copolymer of vinylpyrrolidone and vinylacetate was selected as complexing agents and sodium lauryl sulfate was selected as pharmaceutically acceptable excipient in order to prepare complex Lumacaftor formulations having improved material characteristics.
- the ratio of the selected complexation agent and pharmaceutically acceptable excipient was optimized. Solid complexes of Lumacaftor were prepared by using different ratios of complexation agent and pharmaceutically acceptable excipient. PAMPA permeability measurements were used to select the best performing complex formulation ( Figure 3) . The optimal ratio of the copolymer of vinylpyrrolidone and vinylacetate : sodium lauryl sulfate: Lumacaftor (API) was found to be 9:1.2:2. Production of complex Lumacaftor formulations [00119] A solution mixture of Lumacaftor complex formulation was prepared by continuous flow mixing approach.
- Solution 1 20 mL Solution 1 was prepared by dissolving 40 mg Lumacaftor and 180 mg copolymer of vinylpyrrolidone and vinylacetate in 20 mL methanol.
- the prepared Solution 1 was mixed with Solution 2 containing 24 mg sodium lauryl sulfate in 80 mL water at 1:4 volume ratio in order to produce complex Lumacaftor formulation with different flow rates.
- the solution mixture of the complex Lumacaftor formulation was produced at atmospheric pressure and ambient temperature. The appearance and the particle size of the produced colloid solution were monitored. Based on the physical appearance and particle size of the produced complex Lumacaftor formulation in colloid solution, the best composition was selected for further experiments (Figure 4).
- the produced solution mixture was frozen on dry-ice and then it was lyophilized using a freeze drier equipped with -110°C ice condenser, with a vacuum pump. Spray-drying was also applicable to produce solid powder from the solution mixture of complex Lumacaftor formulation.
- a colloid solution of complex Lumacaftor formulation of the present invention was prepared by mixing process.
- Solution 1 containing 200 mg Ivacaftor and 900 mg copolymer of vinylpyrrolidone and vinylacetate in 20 mL methanol was mixed with aqueous Solution 2 containing 120 mg sodium lauryl sulfate in 80 mL ultrapurified water at 1:4 volume ratio in order to produce complex Lumacaftor formulation.
- the produced solution mixture was frozen on dry-ice and then it was lyophilized using a freeze drier equipped with -110°C ice condenser, with a vacuum pump.
- Spray-drying was also applicable to produce solid powder from the solution mixture of complex
- Liquid dispersible granules comprising the complex Lumacaftor formulations of the present invention can be obtained by wet or dry granulation processes.
- [00122]Dry granulation process includes, but not limited to the slugging or roll compaction of the powder formulation of complex Lumacaftor into compacts and breaking of the compacts into granules with appropriate mesh size.
- the obtained granules can be mixed with pharmaceutically acceptable excipients.
- Powder blend consists of the powder formulation of complex Lumacaftor and pharmaceutically acceptable excipients and prepared by mixing of powders. Slugging or roll compaction are used to manufacture compacts from the powder blend. Then the compacts are broken into granules with appropriate mesh size.
- Wet granulation process covers the moisturizing of the powder formulations of complex Lumacaftor (direct granulation) or moisturizing the pharmaceutically acceptable excipients with aqueous solution of pharmaceutically acceptable binders and mixing it with the powder formulations of complex Lumacaftor (indirect granulation).
- the particle size of the granules can be controlled by physical impact before and after the drying step.
- Liquid dispersible granules of complex Lumacaftor formulation of the present invention were prepared by compacting appropriate amount of complex Lumacaftor powder blend using 0.5 ton load.
- the powder blend comprised of the solid formulation of the complex of Lumacaftor and pharmaceutically acceptable excipients selected from the group of sweetening, flavoring, aromatizing and perfuming agents.
- the height of the compact was found to be optimal between 0.8-1.0 mm.
- the compacts were broken up by physical impact to form granulates.
- the particle size of the granules was controlled by sieving with appropriate mesh size to achieve 160- 800 micrometers particle size.
- the Hausner-ratio of the granule was between 1.00 and 1.18 and the Carr's index was ⁇ 15.
- the apparent solubility of complex Lumacaftor formulation of the present invention was measured by UV-VIS spectroscopy at room temperature.
- the solid complex Lumacaftor formulations were dispersed in ultrapurified in 1, 10 and 20 mg/mL Lumacaftor equivalent concentration range.
- the resulting solutions were filtered by 100 nm disposable syringe filter.
- the Lumacaftor content in the filtrate was measured by UV-Vis spectrophotometry and the apparent solubility was calculated.
- the filtrate may contain Lumacaftor complex particles which could not be filtrated out using 100 nm pore size filter.
- the apparent solubility of complex Lumacaftor formulation of the present invention was 0.950, 9.839 and 14.913 mg/mL, when 1, 10 and 20 mg/mL Lumacaftor equivalent formulations were dispersed in ultrapurified water, respectively.
- the apparent solubility of unformulated crystalline Lumacaftor was found to be 0.032 mg/mL.
- Solubility of complex Lumacaftor formula was 1 mg/mL. Comparative dissolution tests
- PAMPA permeabilities of amorphous Lumacaftor, crystalline Lumacaftor and complex Lumacaftor formulation were measured and compared in simulated fasted state.
- PAMPA permeability of amorphous Lumacaftor, crystalline Lumacaftor and complex Lumacaftor formulation was 1.1798xl0 ⁇ 6 cm/s, 0.53053xl0 ⁇ 6 cm/s and 3.9615x10 6 cm/ s, respectively.
- PAMPA permeabilities of the solid complex Lumacaftor formulations were used to monitor the physical stability of the formulations. PAMPA permeability was measured in FaSSIF biorelevant media and after storage at different conditions. 1 month storage at RT or 40 °C 75% relative humidity showed no significant decrease in the measured PAMPA permeability ( Figure 6).
- Complex Lumacaftor formulation of the present invention comprises spherical particles in the size range of less than 100 nm ( Figure 7).
- Complex Lumacaftor formulation or its pharmaceutical composition is characterized by characteristic Raman shifts at 553 cm 4 , 654 cm 4 , 747 cm 4 , 841 cm 4 , 899 cm 4 , 1117 cm , 1205 cm , 1310 cm 4 , 1372 cm , 1428 cm 4 , 1677 cm 1 and 1737 cm .
- Complex Lumacaftor formulation or its pharmaceutical composition is characterized by characteristic infrared (ATR) peaks at 635 cm 4 , 703 cm 4 , 747 cm 4 , 837 cm 4 , 1021 cm 4 , 1165 cm , 1231 cm 4 , 1288 cm , 1369 cm 4 , 1423 cm , 1462 cm , 1494 cm 4 , 1667 cm 1 and 1731 cm 4 shown in Figure 9.
- ATR characteristic infrared
- Crystalline Lumacaftor was ball milled in the absence of complexation agent (Kollidon VA64) and pharmaceutically acceptable excipient (SDS) and in the presence of them. Ball milling parameters were the following:
- the vessel was washed out with 5 mL Milli-Q water.
- the product was frozen on salted ice and then it was lyophilized using a freeze drier equipped with -110°C ice condenser, with a vacuum pump.
- the material and in-vitro properties of the resulted formulations were compared to the complex Lumacaftor formulation of the present invention.
- PAMPA permeability of the formulations was measured in FaSSIF biorelevant media and compared.
- PAMPA permeability of the complex Lumacaftor formulation was 4.651x10 6 cm/s, while it was 0.288xl0 ⁇ 6 cm/s for the ball milled crystalline Lumacaftor ( Figure 12).
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2018555731A JP2019514897A (en) | 2016-04-25 | 2017-04-25 | Complexes of lumacafitol and its salts and derivatives, processes for their preparation and pharmaceutical compositions containing them |
EP17731268.3A EP3448385A1 (en) | 2016-04-25 | 2017-04-25 | Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
CA3021941A CA3021941A1 (en) | 2016-04-25 | 2017-04-25 | Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
CN201780039665.5A CN109475547A (en) | 2016-04-25 | 2017-04-25 | The compound of Lu Makatuo and its salt and derivative, preparation method and the pharmaceutical composition containing them |
AU2017256182A AU2017256182A1 (en) | 2016-04-25 | 2017-04-25 | Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
IL262490A IL262490A (en) | 2016-04-25 | 2018-10-21 | Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU1600269A HUP1600269A2 (en) | 2016-04-25 | 2016-04-25 | Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
HUP1600269 | 2016-04-25 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2017187338A1 true WO2017187338A1 (en) | 2017-11-02 |
WO2017187338A4 WO2017187338A4 (en) | 2017-12-28 |
Family
ID=89992147
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2017/052372 WO2017187338A1 (en) | 2016-04-25 | 2017-04-25 | Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP3448385A1 (en) |
JP (1) | JP2019514897A (en) |
CN (1) | CN109475547A (en) |
AU (1) | AU2017256182A1 (en) |
CA (1) | CA3021941A1 (en) |
HU (1) | HUP1600269A2 (en) |
IL (1) | IL262490A (en) |
WO (1) | WO2017187338A1 (en) |
Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7495103B2 (en) | 2004-06-24 | 2009-02-24 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
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 |
WO2011127290A2 (en) | 2010-04-07 | 2011-10-13 | 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 |
WO2011127241A2 (en) | 2010-04-07 | 2011-10-13 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyriodin-2-yl)benzoic acid and administration 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 |
US8507534B2 (en) | 2007-12-07 | 2013-08-13 | 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 |
US8716338B2 (en) | 2008-09-29 | 2014-05-06 | Vertex Pharmaceuticals Incorporated | Dosage units of 3-(6-(1-(2,2-difluorobenzo[D] [1,3] dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid |
US20140163068A1 (en) | 2012-11-02 | 2014-06-12 | Vertex Pharmaceuticals Incorporated | Pharmaceutical Compositions for the Treatment of CFTR Mediated Diseases |
US8993600B2 (en) | 2005-11-08 | 2015-03-31 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
US20150132388A1 (en) * | 2013-11-12 | 2015-05-14 | Druggability Technologies Holdings Limited | Complexes of fulvestrant and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
WO2015071837A1 (en) * | 2013-11-12 | 2015-05-21 | Druggability Technologies Holdings Limited | Complexes of cyclosporine a and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
WO2015071841A1 (en) * | 2013-11-12 | 2015-05-21 | Druggability Technologies Holdings Limited | Complexes of dabigatran and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
WO2015073231A1 (en) | 2013-11-12 | 2015-05-21 | Vertex Pharmaceuticals Incorporated | Process of preparing pharmaceutical compositions for the treatment of cftr mediated diseases |
WO2015121836A1 (en) * | 2014-02-14 | 2015-08-20 | Druggability Technologies Ip Holdco Limited | Complexes of sirolimus and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
WO2015175773A1 (en) | 2014-05-15 | 2015-11-19 | Celgene Corporation | Use of pde4 inhibitors and combinations thereof for the treatment of cystic fibrosis |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013130669A1 (en) * | 2012-02-27 | 2013-09-06 | Vertex Pharmaceuticals Incorporated | Pharmaceutical composition and administration thereof |
-
2016
- 2016-04-25 HU HU1600269A patent/HUP1600269A2/en unknown
-
2017
- 2017-04-25 CA CA3021941A patent/CA3021941A1/en not_active Abandoned
- 2017-04-25 WO PCT/IB2017/052372 patent/WO2017187338A1/en active Application Filing
- 2017-04-25 JP JP2018555731A patent/JP2019514897A/en not_active Withdrawn
- 2017-04-25 CN CN201780039665.5A patent/CN109475547A/en active Pending
- 2017-04-25 AU AU2017256182A patent/AU2017256182A1/en not_active Abandoned
- 2017-04-25 EP EP17731268.3A patent/EP3448385A1/en not_active Withdrawn
-
2018
- 2018-10-21 IL IL262490A patent/IL262490A/en unknown
Patent Citations (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7495103B2 (en) | 2004-06-24 | 2009-02-24 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
US8993600B2 (en) | 2005-11-08 | 2015-03-31 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
US8846718B2 (en) | 2007-12-07 | 2014-09-30 | Vertex Pharmaceuticals Incorporated | Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxo1-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid |
US8507534B2 (en) | 2007-12-07 | 2013-08-13 | 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 |
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 |
US8653103B2 (en) | 2007-12-07 | 2014-02-18 | 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 |
US8716338B2 (en) | 2008-09-29 | 2014-05-06 | Vertex Pharmaceuticals Incorporated | Dosage units of 3-(6-(1-(2,2-difluorobenzo[D] [1,3] dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid |
US20160039800A1 (en) | 2008-09-29 | 2016-02-11 | Vertex Pharmaceuticals Incorporated | Dosage units of 3-(6-(1-(2,2-difluorobenzo[d] [1,3] dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid |
US20130296379A1 (en) | 2010-04-07 | 2013-11-07 | 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 |
WO2011127241A2 (en) | 2010-04-07 | 2011-10-13 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyriodin-2-yl)benzoic acid and administration thereof |
WO2011127290A2 (en) | 2010-04-07 | 2011-10-13 | 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 |
US20140221430A1 (en) | 2010-04-07 | 2014-08-07 | 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 |
US20150140094A1 (en) | 2010-04-07 | 2015-05-21 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid and administration thereof |
US20130085158A1 (en) | 2010-04-07 | 2013-04-04 | 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 |
US20150196539A1 (en) | 2010-04-07 | 2015-07-16 | Vertex Phamraceuticals Incorporated | Solid Forms of 3-(6-(1-(2,2-Difluorobenzo[D][1,3]Dioxol-5-yl)Cyclopropanecarboxamido)-3-Methylpyridin-2-yl)Benzoic Acid |
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 |
US20140163068A1 (en) | 2012-11-02 | 2014-06-12 | Vertex Pharmaceuticals Incorporated | Pharmaceutical Compositions for the Treatment of CFTR Mediated Diseases |
WO2015071841A1 (en) * | 2013-11-12 | 2015-05-21 | Druggability Technologies Holdings Limited | Complexes of dabigatran and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
WO2015073231A1 (en) | 2013-11-12 | 2015-05-21 | Vertex Pharmaceuticals Incorporated | Process of preparing pharmaceutical compositions for the treatment of cftr mediated diseases |
WO2015071837A1 (en) * | 2013-11-12 | 2015-05-21 | Druggability Technologies Holdings Limited | Complexes of cyclosporine a and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
US20150132388A1 (en) * | 2013-11-12 | 2015-05-14 | Druggability Technologies Holdings Limited | Complexes of fulvestrant and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
WO2015121836A1 (en) * | 2014-02-14 | 2015-08-20 | Druggability Technologies Ip Holdco Limited | Complexes of sirolimus and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
WO2015175773A1 (en) | 2014-05-15 | 2015-11-19 | Celgene Corporation | Use of pde4 inhibitors and combinations thereof for the treatment of cystic fibrosis |
Non-Patent Citations (4)
Title |
---|
CURTIS J ROSEBRAUGH: "HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ORKAMBI safely and effectively. See full prescribing information for ORKAMBI", 1 July 2015 (2015-07-01), XP055400867, Retrieved from the Internet <URL:https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206038Orig1s000lbl.pdf> [retrieved on 20170824] * |
M. KANSI ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 41, 1998, pages 1007 |
RASK MALTE BILLE ET AL: "Influence of PVP/VA copolymer composition on drug-polymer solubility", EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 85, 28 January 2016 (2016-01-28), pages 10 - 17, XP029449537, ISSN: 0928-0987, DOI: 10.1016/J.EJPS.2016.01.026 * |
S. BENDELS ET AL., PHARMACEUTICAL RESEARCH, vol. 23, 2006, pages 2525 |
Also Published As
Publication number | Publication date |
---|---|
EP3448385A1 (en) | 2019-03-06 |
IL262490A (en) | 2018-12-31 |
HUP1600269A2 (en) | 2017-10-30 |
AU2017256182A1 (en) | 2018-12-13 |
WO2017187338A4 (en) | 2017-12-28 |
CA3021941A1 (en) | 2017-11-02 |
CN109475547A (en) | 2019-03-15 |
JP2019514897A (en) | 2019-06-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10675277B2 (en) | Complexes of ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them | |
ES2857152T3 (en) | Pharmaceutical composition and administrations thereof | |
US20200022969A1 (en) | 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 | |
US20210228489A1 (en) | Compositions for treating cystic fibrosis | |
US20150010628A1 (en) | Pharmaceutical composition and administrations thereof | |
KR101953270B1 (en) | Amorphous letermovir and solid pharmaceutical formulations thereof for oral administration | |
US10688110B2 (en) | Complexes of Celecoxib and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them | |
US20150132388A1 (en) | Complexes of fulvestrant and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them | |
US20190388408A1 (en) | Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them | |
EP3448384A1 (en) | 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 | |
EP3548029A1 (en) | Pharmaceutical formulation containing tadalafil | |
WO2017187338A1 (en) | Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them | |
WO2017187336A1 (en) | Complexes of ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them | |
KR101956586B1 (en) | Pharmaceutical composition and preparation method thereof | |
WO2015199115A1 (en) | Pharmaceutical composition for oral administration | |
CN106913542B (en) | Prasugrel tablet and preparation method thereof | |
JP2004307377A (en) | Itraconazole composition having improved absorbability and used for oral administration |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
ENP | Entry into the national phase |
Ref document number: 3021941 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2018555731 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2017731268 Country of ref document: EP |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 17731268 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2017731268 Country of ref document: EP Effective date: 20181126 |
|
ENP | Entry into the national phase |
Ref document number: 2017256182 Country of ref document: AU Date of ref document: 20170425 Kind code of ref document: A |