TWI540128B - 醫藥組合物 - Google Patents
醫藥組合物 Download PDFInfo
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- TWI540128B TWI540128B TW102144088A TW102144088A TWI540128B TW I540128 B TWI540128 B TW I540128B TW 102144088 A TW102144088 A TW 102144088A TW 102144088 A TW102144088 A TW 102144088A TW I540128 B TWI540128 B TW I540128B
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- lower alkyl
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- pharmaceutical composition
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 25
- 239000000203 mixture Substances 0.000 claims description 37
- 239000008187 granular material Substances 0.000 claims description 26
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 19
- 239000000843 powder Substances 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 17
- 239000002245 particle Substances 0.000 claims description 14
- 239000004094 surface-active agent Substances 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- YCBPQSYLYYBPDW-UHFFFAOYSA-N 4-methyl-n-[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide;hydrate;hydrochloride Chemical compound O.Cl.C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 YCBPQSYLYYBPDW-UHFFFAOYSA-N 0.000 claims description 7
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 6
- 229960001021 lactose monohydrate Drugs 0.000 claims description 6
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical group C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 5
- 229920001983 poloxamer Polymers 0.000 claims description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 229960000502 poloxamer Drugs 0.000 claims description 4
- 229920001993 poloxamer 188 Polymers 0.000 claims description 4
- 229940044519 poloxamer 188 Drugs 0.000 claims description 4
- 238000012216 screening Methods 0.000 claims description 2
- 230000004580 weight loss Effects 0.000 claims description 2
- -1 pyrimidinylaminobenzamide compound Chemical class 0.000 description 66
- 150000001875 compounds Chemical class 0.000 description 50
- 125000000217 alkyl group Chemical group 0.000 description 49
- 230000001225 therapeutic effect Effects 0.000 description 35
- 239000002775 capsule Substances 0.000 description 31
- 150000003839 salts Chemical class 0.000 description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 15
- 125000003545 alkoxy group Chemical group 0.000 description 14
- 125000003282 alkyl amino group Chemical group 0.000 description 13
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 12
- 239000000314 lubricant Substances 0.000 description 12
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 11
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 10
- 238000005469 granulation Methods 0.000 description 10
- 230000003179 granulation Effects 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 229960001346 nilotinib Drugs 0.000 description 10
- 125000003277 amino group Chemical group 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 9
- 229910052736 halogen Inorganic materials 0.000 description 9
- 150000002367 halogens Chemical class 0.000 description 9
- 125000000623 heterocyclic group Chemical group 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 238000005550 wet granulation Methods 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 239000006186 oral dosage form Substances 0.000 description 7
- 125000004076 pyridyl group Chemical group 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000011230 binding agent Substances 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 description 6
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical group OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000002776 aggregation Effects 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 125000003373 pyrazinyl group Chemical group 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000000945 filler Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 125000004430 oxygen atom Chemical group O* 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 238000007873 sieving Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 3
- 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 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 230000037406 food intake Effects 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 3
- 238000004898 kneading Methods 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000010298 pulverizing process Methods 0.000 description 3
- 125000003226 pyrazolyl group Chemical group 0.000 description 3
- 125000002098 pyridazinyl group Chemical group 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- OQLZINXFSUDMHM-UHFFFAOYSA-N Acetamidine Chemical group CC(N)=N OQLZINXFSUDMHM-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
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- 230000009102 absorption Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 238000005054 agglomeration Methods 0.000 description 2
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 2
- 229940063655 aluminum stearate Drugs 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical group OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
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- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 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
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
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- 150000004676 glycans Chemical class 0.000 description 2
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- 125000005842 heteroatom Chemical group 0.000 description 2
- 239000008240 homogeneous mixture Substances 0.000 description 2
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 2
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- 229910000021 magnesium carbonate Inorganic materials 0.000 description 2
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- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
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- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- SFDJOSRHYKHMOK-UHFFFAOYSA-N nitramide Chemical group N[N+]([O-])=O SFDJOSRHYKHMOK-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 2
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- 150000007524 organic acids Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
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- 102000020233 phosphotransferase Human genes 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
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- 238000002360 preparation method Methods 0.000 description 2
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- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 2
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- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
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- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
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- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
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- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
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- 125000006413 ring segment Chemical group 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
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- GGHPAKFFUZUEKL-UHFFFAOYSA-M sodium;hexadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCOS([O-])(=O)=O GGHPAKFFUZUEKL-UHFFFAOYSA-M 0.000 description 1
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- 239000006188 syrup Substances 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
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- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- RSPCKAHMRANGJZ-UHFFFAOYSA-N thiohydroxylamine Chemical compound SN RSPCKAHMRANGJZ-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
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Description
本發明係關於一種包含式I之治療化合物(見下文)(例如尼羅替尼)之醫藥組合物。該醫藥組合物可藉由濕式造粒方法製備隨後填充至膠囊中之顆粒而製備。
尼羅替尼為4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]胺基]-N-[5-(4-甲基-1H-咪唑-1-基)-3-(三氟甲基)苯基]苯甲醯胺。特別有用之尼羅替尼之鹽為尼羅替尼鹽酸鹽單水合物。此等治療化合物具有作為Bcr-Abl蛋白質酪胺酸激酶(TK)活性抑制劑之效用。可藉由該等治療化合物治療之病症之實例包括(但不限於)慢性骨髓白血病及胃腸道基質腫瘤。
需要將尼羅替尼及下文揭示之其他治療化合物調配成醫藥組合物,尤其固體口服劑型,以便使化合物之治療益處可傳遞給有需要之患者。解決此需要所面臨之挑戰為該等治療化合物之生理化學性質。尼羅替尼及其鹽為不良水溶性化合物且其調配及傳遞(亦即,使其經口攝取時具生物可利用性)係困難的。本發明之一目標為藉由製備可為患者攝取之固體口服劑型形式之醫藥組合物提供一種示範性解決方法。
本發明提供一種包含式I之治療化合物(例如尼羅替尼)或其鹽之新穎醫藥組合物。該等醫藥組合物為固體口服劑型之形式,尤其為膠
囊之形式。膠囊填充有與包含至少一種醫藥學上可接受之賦形劑之外相摻合的治療化合物之顆粒。為製備該等顆粒,特別有用之方法為濕式造粒方法。用純水(或有機溶劑)使治療化合物及任何醫藥學上可接受之賦形劑(例如界面活性劑)濕潤聚集且隨後乾燥以形成顆粒。特別有用之界面活性劑之實例為泊洛沙姆(poloxamer),諸如泊洛沙姆188。已發現使用界面活性劑可允許其他賦形劑(諸如潤滑劑)濃度之降低。
在本發明之另一示範性實施例中,製備顆粒之濕式造粒方法包括以下步驟:a)形成治療化合物(例如尼羅替尼或其鹽)與至少一種醫藥學上可接受之賦形劑的粉末摻合物;b)在攪動下將造粒液體添加至該粉末摻合物中以形成濕潤塊;c)粒化該濕潤塊以形成潮濕顆粒;及d)使該等潮濕顆粒乾燥。
本發明係關於包含治療化合物之醫藥組合物。該等醫藥組合物可藉由使用造粒液體使該治療化合物經受濕式造粒以形成顆粒或粒狀混合物來製備。隨後可將該等顆粒或粒狀混合物封入硬明膠膠囊中,壓縮成錠劑或填充至藥囊中以形成固體口服劑型。
如本文所用之術語"治療化合物"係指式I之嘧啶基胺基苯甲醯胺化合物:
其中:R1表示氫、低碳烷基、低碳烷氧基-低碳烷基、醯氧基-低碳烷基、羧基-低碳烷基、低碳烷氧羰基-低碳烷基或苯基-低碳烷基;R2表示氫、視情況經一或多個相同或不同基團R3取代之低碳烷基、環烷基、苯幷環烷基、雜環基、芳基或包含0、1、2或3個環氮原子及0或1個氧原子及0或1個硫原子之單環或雙環雜芳基,該等基團在各狀況下未經取代或經單取代或多取代;且R3表示羥基、低碳烷氧基、醯氧基、羧基、低碳烷氧羰基、胺甲醯基、N-單取代或N,N-二取代胺甲醯基、胺基、單取代或二取代胺基、環烷基、雜環基、芳基或包含0、1、2或3個環氮原子及0或1個氧原子及0或1個硫原子之單環或雙環雜芳基,該等基團在各狀況下未經取代或經單取代或多取代;或其中R1及R2一起表示具有4、5或6個碳原子之伸烷基,其視情況經低碳烷基、環烷基、雜環基、苯基、羥基、低碳烷氧基、胺基、單取代或二取代胺基、側氧基、吡啶基、吡嗪基或嘧啶基單取代或二取代;具有4或5個碳原子之苯伸烷基;具有1個氧原子及3或4個碳原子之氧雜伸烷基;或具有1個氮原子及3或4個碳原子之氮雜伸烷基,其中氮未經取代或經低碳烷基、苯基-低碳烷基、低碳烷氧羰基-低碳烷基、羧基-低碳烷基、胺甲醯基-低碳烷基、N-單取代或N,N-二取代胺甲醯基-低碳烷基、環烷基、低碳烷氧羰基、羧基、苯基、經取代苯基、吡啶基、嘧啶基或吡嗪基取代;R4表示氫、低碳烷基或鹵素;以及該化合物之氮氧化物及醫藥學上可接受之鹽。該等治療化合物適於製備用於治療激酶依賴性疾病、尤其Bcr-Abl及Tie-2激酶依賴性疾病之醫藥組合物,例如作為用以治療一或多種增生性疾病之藥物。
在"治療化合物"之定義內,字首"低碳"表示具有至多七個且包括最大值七個、尤其至多四個且包括最大值四個之碳原子之基團,所討論之基團為直鏈或具有單個或多個分支之支鏈。
如本文所用,在針對化合物、鹽及其類似物使用複數形式之情況下,將此理解為亦意謂單一化合物、鹽或其類似物。
任何不對稱碳原子可存在於(R)-、(S)-或(R,S)-構型中,例如存在於(R)-或(S)-構型中。因此,化合物可以異構體混合物形式或以純異構體形式存在,例如以對映異構體-純非對映異構體形式存在。式I化合物之任何可能互變異構體之使用亦涵蓋於本發明內。
低碳烷基為(例如)具有自一個且包括一個直至七個且包括七個(例如自一個且包括一個至四個且包括四個)之碳原子之烷基,且為直鏈或支鏈;舉例而言,低碳烷基為丁基(諸如正丁基、第二丁基、異丁基、第三丁基)、丙基(諸如正丙基或異丙基)、乙基或甲基。低碳烷基例如為甲基、丙基或第三丁基。
低碳醯基例如為甲醯基或低碳烷基羰基,尤其乙醯基。
芳基為經由位於基團之芳環碳原子處之鍵與分子結合的芳族基。在一示範性實施例中,芳基為具有6至14個碳原子之芳族基,尤其苯基、萘基、四氫萘基、茀基或菲基,且其未經取代或經一或多個(例如達三個,尤其一或兩個)尤其選自以下各者之取代基取代:胺基、單取代或二取代胺基、鹵素、低碳烷基、經取代低碳烷基、低碳烯基、低碳炔基、苯基、羥基、醚化或酯化羥基、硝基、氰基、羧基、酯化羧基、烷醯基、苯甲醯基、胺甲醯基、N-單取代或N,N-二取代胺甲醯基、脒基、胍基、脲基、巰基、磺基、低碳烷硫基、苯硫基、苯基-低碳烷硫基、低碳烷基苯硫基、低碳烷基亞磺醯基、苯亞磺醯基、苯基-低碳烷基亞磺醯基、低碳烷基苯亞磺醯基、低碳烷基磺醯基、苯磺醯基、苯基-低碳烷基磺醯基、低碳烷基苯磺醯基、鹵
素-低碳烷基巰基、鹵素-低碳烷基磺醯基(諸如尤其三氟甲烷磺醯基)、二羥基硼雜(dihydroxybora)(-B(OH)2)、雜環基、單環或雙環雜芳基及結合於環之相鄰碳原子處之低碳伸烷二氧基(諸如亞甲二氧基)。芳基例如為苯基、萘基或四氫萘基,其在各狀況下未經取代或經一或兩個選自包含以下各者之群之取代基獨立地取代:鹵素,尤其氟、氯或溴;羥基;經低碳烷基(例如甲基)、鹵素-低碳烷基(例如三氟甲基)或苯基醚化之羥基;與兩個相鄰碳原子結合之低碳伸烷二氧基,例如亞甲二氧基;低碳烷基,例如甲基或丙基;鹵素-低碳烷基,例如三氟甲基;羥基-低碳烷基,例如羥甲基或2-羥基-2-丙基;低碳烷氧基-低碳烷基,例如甲氧基甲基或2-甲氧基乙基;低碳烷氧羰基-低碳烷基,例如甲氧羰基甲基;低碳炔基,諸如1-丙炔基;酯化羧基,尤其低碳烷氧羰基,例如甲氧羰基、正丙氧羰基或異丙氧基羰基;N-單取代胺甲醯基,尤其經低碳烷基(例如甲基、正丙基或異丙基)單取代之胺甲醯基;胺基;低碳烷基胺基,例如甲胺基;二低碳烷基胺基,例如二甲胺基或二乙胺基;低碳伸烷基-胺基,例如N-吡咯啶基或N-哌啶基;低碳氧雜伸烷基-胺基,例如N-嗎啉基;低碳氮雜伸烷基-胺基,例如N-哌嗪基;醯胺基,例如乙醯胺基或苄醯胺基;低碳烷基磺醯基,例如甲磺醯基;胺磺醯基;或苯磺醯基。
環烷基為例如環丙基、環戊基、環己基或環庚基,可未經取代或經一或多個(尤其一或兩個)選自以上定義之芳基之取代基之群的取代基取代,例如經低碳烷基(諸如甲基)、低碳烷氧基(諸如甲氧基或乙氧基)或羥基取代,及進一步經側氧基(oxo)取代或與苯幷環稠合,諸如苯幷環戊基或苯幷環己基。
經取代之烷基為如上定義之烷基,尤其低碳烷基,例如甲基;其中可存在一或多個(尤其達三個)主要選自以下之群之取代基:鹵素(尤其氟)、胺基、N-低碳烷基胺基、N,N-二低碳烷基胺基、N-低碳烷
醯基胺基、羥基、氰基、羧基、低碳烷氧羰基及苯基-低碳烷氧羰基。三氟甲基尤其有用。
單取代或二取代之胺基尤其為經一或兩個彼此獨立地選自以下之基團取代之胺基:低碳烷基,諸如甲基;羥基-低碳烷基,諸如2-羥乙基;低碳烷氧基低碳烷基,諸如甲氧基乙基;苯基-低碳烷基,諸如苯甲基或2-苯乙基;低碳烷醯基,諸如乙醯基;苯甲醯基;經取代之苯甲醯基,其中苯基尤其經一或多個(例如一或兩個)選自以下之取代基取代:硝基、胺基、鹵素、N-低碳烷基胺基、N,N-二-低碳烷基胺基、羥基、氰基、羧基、低碳烷氧羰基、低碳烷醯基及胺甲醯基;及苯基-低碳烷氧羰基,其中苯基未經取代或尤其經一或多個(例如一或兩個)選自以下之取代基取代:硝基、胺基、鹵素、N-低碳烷基胺基、N,N-二-低碳烷基胺基、羥基、氰基、羧基、低碳烷氧羰基、低碳烷醯基及胺甲醯基;例如為N-低碳烷基胺基(諸如N-甲胺基)、羥基-低碳烷基胺基(諸如2-羥基乙胺基或2-羥基丙胺基)、低碳烷氧基低碳烷基(諸如甲氧基乙基)、苯基-低碳烷基胺基(諸如苯甲胺基)、N,N-二-低碳烷基胺基、N-苯基-低碳烷基-N-低碳烷基胺基、N,N-二-低碳烷基苯胺基、低碳烷醯基胺基(諸如乙醯胺基),或選自包含苯甲醯胺基及苯基-低碳烷氧羰基胺基之群之取代基,其中在各狀況下苯基未經取代或尤其經硝基或胺基取代或亦經鹵素、胺基、N-低碳烷基胺基、N,N-二-低碳烷基胺基、羥基、氰基、羧基、低碳烷氧羰基、低碳烷醯基、胺甲醯基或胺基羰基胺基取代。二取代之胺基亦為低碳伸烷基-胺基,例如吡咯啶基、2-側氧基吡咯啶基或哌啶基;低碳氧雜伸烷基-胺基,例如嗎啉基;或低碳氮雜伸烷基-胺基,例如哌嗪基或N-經取代之哌嗪基,諸如N-甲基哌嗪基或N-甲氧羰基哌嗪基。
鹵素尤其為氟、氯、溴或碘,尤其氟、氯或溴。
醚化羥基尤其為C8-C20烷氧基(諸如正癸氧基)、低碳烷氧基(諸如甲氧基、乙氧基、異丙氧基或第三丁氧基)、苯基-低碳烷氧基(諸如苯甲氧基)、苯氧基、鹵素低碳烷氧基(諸如三氟甲氧基、2,2,2-三氟乙氧基或1,1,2,2-四氟乙氧基)或經包含一或兩個氮原子之單環或雙環雜芳基取代之低碳烷氧基,例如經咪唑基(諸如1H-咪唑-1-基)、吡咯基、苯幷咪唑基(諸如1-苯幷咪唑基)、吡啶基(尤其2-、3-或4-吡啶基)、嘧啶基(尤其2-嘧啶基)、吡嗪基、異喹啉基(尤其3-異喹啉基)、喹啉基、吲哚基或噻唑基取代之低碳烷氧基。
酯化羥基尤其為低碳烷醯氧基、苯甲醯氧基、低碳烷氧基羰氧基(諸如第三丁氧基羰氧基)或苯基-低碳烷氧基羰氧基(諸如苯甲氧基羰氧基)。
酯化羧基尤其為低碳烷氧羰基(諸如第三丁氧基羰基、異丙氧基羰基、甲氧羰基或乙氧羰基)、苯基-低碳烷氧羰基或苯氧基羰基。
烷醯基主要為烷基羰基,尤其低碳烷醯基,例如乙醯基。
N-單取代或N,N-二取代胺甲醯基尤其經一或兩個獨立地選自以下各者之取代基取代:低碳烷基、苯基-低碳烷基及羥基-低碳烷基或低碳伸烷基、氧雜低碳伸烷基或氮雜低碳伸烷基(視情況在末端氮原子處經取代)。
包含0、1、2或3個環氮原子及0或1個氧原子及0或1個硫原子且在各狀況下未經取代或經單取代或多取代之單環或雙環雜芳基係指一種雜環部分,其在雜芳基與式I中分子之其餘部分結合之環中為不飽和的且例如為如下之環,其中在結合環中但視情況亦在任何黏接環(annealed ring)中至少一個碳原子經選自由氮、氧及硫組成之群之雜原子置換;其中結合環(例如)具有5至12個(例如5或6個)環原子;且其可未經取代或經一或多個(尤其一或兩個)選自以上經定義為芳基之取代基之群的取代基取代,多數例如經低碳烷基(諸如甲基)、低碳烷氧
基(諸如甲氧基或乙氧基)或羥基取代。舉例而言,單環或雙環雜芳基係選自2H-吡咯基、吡咯基、咪唑基、苯幷咪唑基、吡唑基、吲唑基、嘌呤基、吡啶基、吡嗪基、嘧啶基、噠嗪基、4H-喹嗪基、異喹啉基、喹啉基、酞嗪基、啶基、喹喏啉基、喹唑啉基、喹啉基(quinnolinyl)、喋啶基、吲哚嗪基、3H-吲哚基、吲哚基、異吲哚基、噁唑基、異噁唑基、噻唑基、異噻唑基、三唑基、四唑基、呋吖基、苯幷[d]吡唑基、噻吩基及呋喃基。舉例而言,單環或雙環雜芳基係選自由以下各者組成之群:吡咯基、咪唑基(諸如1H-咪唑-1-基)、苯幷咪唑基(諸如1-苯幷咪唑基)、吲唑基(尤其5-吲唑基)、吡啶基(尤其2-、3-或4-吡啶基)、嘧啶基(尤其2-嘧啶基)、吡嗪基、異喹啉基(尤其3-異喹啉基)、喹啉基(尤其4-或8-喹啉基)、吲哚基(尤其3-吲哚基)、噻唑基、苯幷[d]吡唑基、噻吩基及呋喃基。在本發明之一示範性實施例中,吡啶基在氮原子之鄰位上經羥基取代,且因此至少部分地以相應互變異構體即吡啶-(1H)2-酮之形式存在。在另一示範性實施例中,嘧啶基在2位及4位上均經羥基取代且因此以若干互變異構形式存在,例如以嘧啶-(1H,3H)2,4-二酮形式存在。
雜環基尤其為具有一或兩個選自包含氮、氧及硫之群之雜原子的五、六或七員雜環系統,其可為不飽和或完全飽和或部分飽和,且未經取代或尤其經低碳烷基(諸如甲基)、苯基-低碳烷基(諸如苯甲基)、側氧基或雜芳基(諸如2-哌嗪基)取代;雜環基尤其為2-或3-吡咯啶基、2-側氧基-5-吡咯啶基、哌啶基、N-苯甲基-4-哌啶基、N-低碳烷基-4-哌啶基、N-低碳烷基-哌嗪基、嗎啉基(例如2-或3-嗎啉基)、2-側氧基-1H-氮雜卓-3-基、2-四氫呋喃基或2-甲基-1,3-二氧戊環-2-基。
鹽尤其為式I化合物之醫藥學上可接受之鹽。
該等鹽係例如由具有鹼性氮原子之式I化合物(例如)與有機酸或無機酸形成為酸加成鹽,尤其醫藥學上可接受之鹽。合適之無機酸包
括(但不限於)氫鹵酸(諸如氫氯酸)、硫酸或磷酸。合適之有機酸例如為羧酸、膦酸、磺酸或胺基磺酸,例如乙酸、丙酸、辛酸、癸酸、十二烷酸、乙醇酸、乳酸、反丁烯二酸、丁二酸、己二酸、庚二酸、辛二酸、壬二酸、蘋果酸、酒石酸、檸檬酸、胺基酸(諸如麩胺酸或天冬胺酸)、順丁烯二酸、羥基順丁烯二酸、甲基順丁烯二酸、環己烷甲酸、金剛烷甲酸、苯甲酸、水楊酸、4-胺基水楊酸、鄰苯二甲酸、苯乙酸、扁桃酸、肉桂酸、甲烷或乙烷磺酸、2-羥基乙烷磺酸、乙烷-1,2-二磺酸、苯磺酸、2-萘磺酸、1,5-萘-二磺酸、2-、3-或4-甲苯磺酸、甲基硫酸、乙基硫酸、十二烷基硫酸、N-環己基胺基磺酸、N-甲基-、N-乙基-或N-丙基-胺基磺酸或其他有機質子酸,諸如抗壞血酸。
在帶負電之基團(諸如羧基或磺基)存在下,鹽亦可與鹼形成,例如金屬鹽或銨鹽,諸如鹼金屬鹽或鹼土金屬鹽(例如鈉鹽、鉀鹽、鎂鹽或鈣鹽)或與氨或合適有機胺(諸如三級單胺,例如三乙胺或三(2-羥乙基)胺;或雜環鹼,例如N-乙基-哌啶或N,N'-二甲基哌嗪)形成之銨鹽。
當鹼基與酸基存在於同一分子中時,式I化合物亦可形成內鹽。
為達成分離或純化之目的,亦可能使用醫藥學上不可接受之鹽,例如苦味酸鹽或高氯酸鹽。為達成治療用途,僅使用醫藥學上可接受之鹽或游離化合物(在適用於醫藥製劑之形式時)且因此此等者特別有用。
合適及方便時,鑒於游離形式之新穎化合物與其鹽(包括例如在純化或鑑別新穎化合物時可用作中間物之彼等鹽)形式之彼等新穎化合物之間的緊密關係,上文及下文中對游離化合物之任何提及應理解為亦提及相應之鹽。
在式I之範疇內之化合物及其製造方法揭示於2004年1月15日公開
之WO 04/005281,該文獻據此以全部引用的方式併入本申請案中。本發明中特別有用之治療化合物為4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]胺基]-N-[5-(4-甲基-1H-咪唑-1-基)-3-(三氟甲基)苯基]苯甲醯胺(亦稱尼羅替尼),其具有以下結構:
特別有用之尼羅替尼之鹽為尼羅替尼鹽酸鹽單水合物或4-甲基-N-[3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯基]-3-[(4-吡啶-3-基嘧啶-2-基)胺基]苯甲醯胺鹽酸鹽水合物。更全面地,合適之尼羅替尼之鹽及其多晶型物揭示於WO2007/015870及WO2007/015871中。
如本文所用之術語"醫藥組合物"意謂(例如)待投與哺乳動物(例如人類)以治療激酶依賴性疾病的含有指定量之治療化合物(例如治療有效量之治療化合物)於醫藥學上可接受之載劑中之混合物。
如本文所用之術語"醫藥學上可接受"係指在合理醫學判斷之範疇內適於與哺乳動物(尤其人類)之組織接觸而無過度毒性、刺激、過敏反應及其他問題併發症且與合理利/弊比率相稱之彼等化合物、物質、組合物及/或劑型。
醫藥組合物中治療化合物之濃度係以一定量(例如治療有效量)存在,該量將視藥物之吸收率、失活率及排泄率以及一般技術者已知之其他因素而定。此外,應注意劑量值亦將隨待減輕之病症之嚴重程度而變化。應進一步瞭解對任何特定接受者而言,特定給藥方案應根據個體需要及投與或監督醫藥組合物投藥之人之專業判斷而隨時間調
整。治療化合物可一次投與或可分成多次較少劑量在不定時間間隔投與。因此,合適之量,例如合適之治療有效量為一般技術者所知。
舉例而言,治療化合物之劑量可在每天接受者每公斤體重約0.1至約100mg之範圍內。或者可給與較低劑量,例如每天每公斤體重0.5至100mg、0.5至50mg、或0.5至20mg之劑量。醫藥學上可接受之鹽之有效劑量範圍可基於欲傳遞之活性部分之重量計算。若鹽自身展現活性,則有效劑量可如上使用鹽之重量或藉由熟習此項技術者已知之其他方式來估計。
如本文所用之術語"即釋"係指經口攝取之後大部分治療化合物(例如大於約50%、約55%、約60%、約65%、約70%、約75%、約80%或約90%)在相當短時間內(例如在1小時、40分鐘、30分鐘或20分鐘內)快速釋放。特別有用之即釋情況為經口攝取之後至少或等於約80%之治療化合物在三十分鐘內釋放。特定治療化合物之特定即釋情況應為一般技術者所識或所知。
如本文所用之術語"賦形劑"係指醫藥技術中通用於製備顆粒及/或固體口服劑調配物的醫藥學上可接受之成份。賦形劑之種類之實例包括(但不限於)黏合劑、崩解劑、潤滑劑、助流劑、穩定劑、填充劑及稀釋劑。一般技術者可根據顆粒及/或固體口服劑型之特定所要性質藉由常規實驗且無需任何過度負擔來選擇一或多種上述賦形劑。所用各賦形劑之量可在此項技術中習知之範圍內變化。下列併入本文供參考之文獻揭示用於調配口服劑型之技術及賦形劑。參見The Handbook of Pharmaceutical Excipients,第4版,Rowe等人編,American Pharmaceuticals Association(2003);及Remington:the Science and Practice of Pharmacy,第20版,Gennaro編,Lippincott Williams & Wilkins(2000)。
如本文所用之術語"濕式造粒"係指在造粒過程中使用造粒液體以
隨後形成顆粒之通用方法,如Remington:The Science and Practice of Pharmacy,第20版(2000),第45章中討論,該文獻併入本文供參考。
在本發明之一示範性實施例中,濕式造粒包括混合、濕潤及捏製(亦即濕潤聚集)、粒化(亦即在高剪切混合物之狀況下捏製)、乾燥及篩分之步驟。此等步驟在下文更詳細論述。
濕式造粒方法始於治療化合物與至少一種醫藥學上可接受之賦形劑(尤其界面活性劑)之粉末摻合物的形成,該粉末摻合物藉由在一合適容器中用(例如)醫藥造粒設備混合上述成份(亦即,使上述成份密切接近)使得形成混合物來形成。醫藥造粒設備之實例包括(但不限於)與振盪造粒機組合之剪切造粒機(例如,Hobart、Collette、Beken)、高速混合器/造粒機(例如,Diosna、Fielder、Collette-Gral)及具有隨後篩分設備之流化床造粒機(例如,Aeromatic、Glatt)。適用於最初與治療化合物混合之賦形劑包括(例如)界面活性劑、黏合劑、填充劑、崩解劑、稀釋劑及上述賦形劑之任何組合。尤其適用於粉末摻合混合物的為界面活性劑。
醫藥學上可接受之界面活性劑之實例包括(但不限於)聚氧化乙烯-聚氧化丙烯嵌段共聚物(亦稱泊洛沙姆(poloxamer))、烷基硫酸鹽(例如,十二烷基硫酸鈉、十八烷基硫酸鈉、油烯基硫酸鈉及十六烷基硫酸鈉)、烷基芳基磺酸鹽(例如,十二烷基苯磺酸鈉及二烷基磺基丁二酸鈉)、聚乙二醇及聚山梨醇酯。如本文所用之術語"泊洛沙姆"係指至少一種具有下式之聚合物:HO(C2H4)a(C3H6O)b(C2H4O)aH,其中"a"及"b"分別表示聚氧化乙烯及聚氧化丙烯單元之數目。特別有用的為泊洛沙姆188,其具有分別為75及30之a及b值。界面活性劑可以組合物之0至約1wt%(例如,以膠囊填充重量計)之濃度存在。
醫藥學上可接受之崩解劑之實例包括(但不限於)澱粉;黏土;纖
維素;海藻酸鹽;樹膠;交聯聚合物,例如,交聯聚乙烯基吡咯啶酮或交聯聚乙烯吡咯酮,例如,來自International Specialty Products(Wayne,NJ)之POLYPLASDONE XL;交聯羧甲基纖維素鈉或交聯羧甲纖維素鈉,例如,來自FMC之AC-DI-SOL;及交聯羧甲基纖維素鈣;大豆多醣;及瓜爾膠。崩解劑可以組合物之約0至約50wt%(例如,以膠囊填充重量計)之濃度存在。
醫藥學上可接受之黏合劑之實例包括(但不限於)澱粉;纖維素及其衍生物,例如,微晶纖維素(例如,來自FMC(Philadelphia,PA)之AVICEL PH)、羥丙基纖維素羥乙基纖維素及羥丙基甲基纖維素(例如,來自Dow Chemical Corp.(Midland,Ml)之METHOCEL);蔗糖;右旋糖;玉米糖漿;多醣;聚乙烯吡咯酮及明膠。黏合劑可以組合物之約0至約50wt%(例如,以膠囊填充重量計)之濃度存在。
醫藥學上可接受之填充劑及醫藥學上可接受之稀釋劑之實例包括(但不限於)糖粉(confectioner's sugar)、可壓縮糖、葡萄糖結合劑、糊精、右旋糖、乳糖、甘露糖醇、微晶纖維素、粉末狀纖維素、山梨糖醇及蔗糖。填充劑可以組合物之約0至約80wt%(例如,以膠囊填充重量計)之濃度存在。
在自動膠囊填充期間觀測到本發明之膠囊之黏著問題。意外地發現含有少於組合物之約40wt%之量的乳糖單水合物之膠囊不會發生該等黏著問題。因此,在一實施例中,本發明係關於如本文所述之含有少於膠囊總重量之約40% w/w之量、更特定而言少於約25%之量、更佳少於膠囊外相之約20% w/w之量的乳糖單水合物之膠囊。
下一步為藉由添加造粒液體同時攪動粉末摻合物直至粉末摻合物為造粒液體所濕潤而使粉末摻合物濕潤聚集,從而形成濕潤塊。例如,將10%至35%(w/w)之造粒液體添加至粉末摻合物中。或者,可將10%至15%(w/w)之造粒液體添加至粉末摻合物中。造粒液體例如
為醫藥學上可接受及揮發性的。合適之造粒液體之實例包括(但不限於)單獨或組合之水(例如,純水)、有機溶劑(例如,甲醇、乙醇、異丙醇、丙酮)。組合造粒液體之實例包括水、乙醇及異丙醇一起。
或者,濕式造粒方法可始於粉末狀之治療化合物自身。
在濕潤聚集期間,引入粉末中之造粒液體為含有或不含有一或數種溶解賦形劑(例如黏合劑及/或界面活性劑)之溶劑。不管濕潤聚集怎樣發生,在濕潤聚集之後,粉末摻合物均為造粒液體所濕潤。在一示範性實施例中,純水用作造粒液體。
隨後在用造粒液體加工之後,濕潤塊視情況可經篩分,形成濕潤或潮濕顆粒。舉例而言,濕潤塊可經由諸如5至達10mm之篩網,例如6或8篩網篩分。一般技術者可選擇合適大小之篩以形成最合適之粒徑。
在另一實施例中,粉碎磨粉機可用於代替篩子或篩網。粉碎磨粉機之實例包括(但不限於)Stokes振盪器、Colton旋轉式造粒機、Fitzpatrick粉碎磨粉機、Stokes旋風磨粉機。
在又一實施例中,裝備有(例如)切碎機葉片之高速混合器可用以代替篩子或粉碎磨粉機。在此狀況下,造粒步驟稱為捏製。例如,此舉允許濕潤聚集及粒化組合為單一步驟。
例如隨後使潮濕顆粒乾燥。舉例而言,可將潮濕顆粒收集於托盤上且轉移至乾燥箱中。或者,可將潮濕顆粒置放於具有循環氣流及恆溫熱控制之乾燥箱中。而另一選擇為在流化床式乾燥機中將潮濕顆粒乾燥。在此示範性實施例中,將潮濕顆粒懸浮於熱氣流中且加以攪動使得潮濕顆粒保持運動狀態。舉例而言,空氣溫度可為約室溫至約90℃,例如70℃。將潮濕顆粒乾燥至乾燥失重("LOD")值小於或等於組合物之約5wt%,例如少於2wt%,例如0.5至2wt%。
另一選擇為造粒及乾燥在同一設備(例如,具有雙壁用於乾燥之
高剪切混合器,例如Zanchetta Roto P或Turbosphere Moritz)中之單罐式方法。
乾燥可發生在醫藥造粒設備內或離開醫藥造粒設備而發生。
繼乾燥之後,可將顆粒單獨地或與至少一種賦形劑相組合地作進一步篩分,亦即乾式篩分。此舉通常產生更均勻之顆粒粒徑,為顆粒進一步加工成固體口服劑型作準備。
可將顆粒與額外醫藥學上可接受之賦形劑一起調配以形成均勻混合物,隨後使該均勻混合物形成口服形式,例如固體口服劑型,諸如錠劑、丸劑、口含劑、囊片、膠囊或藥囊。如本文所用之術語"外相"係指在最終劑型形成之前添加至顆粒中之額外賦形劑。所用之任何額外賦形劑可與顆粒分開地進行篩分或如上述乾篩步驟中所述與顆粒篩分同時進行篩分。一般技術者應瞭解所調配之特定醫藥組合物所必需的各組份之必需粒徑。舉例而言,合適之粒徑包括小於等於1,000μm、750μm、500μm或250μm之粒徑。顆粒與外相組合成均勻混合物可使用一般技術者已知之任何習知製藥方法(例如,摻合、壓縮、共研磨、壓實或共微米尺寸化)來完成。
隨後可例如將經摻合之混合物壓縮為錠劑(例如,藉由使用製錠機)或填充至膠囊或藥囊中(例如,藉由使用封囊機)。如此項技術中已知之任何膠囊可用於囊封經摻合之混合物。該膠囊之一實例為硬明膠膠囊,例如由Capsugel of Morris Plains(New Jersey)製造之CONI-SNAP。該等膠囊之合適大小包括(但不限於)00至5號大小。膠囊形式之醫藥組合物可含有(例如)每一膠囊5mg至500mg之治療化合物;例如每一膠囊25mg、50mg、100mg或200mg之治療化合物。
添加於外相中之通用醫藥學上可接受之賦形劑為助流劑。該賦形劑有助於摻合混合物在加工設備中流動。
醫藥學上可接受之助流劑之實例包括(但不限於)膠狀二氧化矽、
三矽酸鎂、澱粉、滑石、磷酸三鈣、硬脂酸鋁、碳酸鎂、氧化鎂及粉末狀纖維素。助流劑可以醫藥組合物總重量之約0至10wt%(例如0至10wt%,或約1wt%,例如1wt%)的濃度存在。
另一添加於外相中之通用醫藥學上可接受之賦形劑為潤滑劑。該賦形劑有助於避免加工設備中任何黏著。雖然潤滑劑增強可加工性,但其可影響治療化合物自劑型之釋放。潤滑劑常為疏水性的且因此延遲或減慢即釋劑型之治療化合物的釋放。意外發現在濕式造粒方法期間包括界面活性劑產生可加工性較佳之顆粒且允許潤滑劑之減少。此潤滑劑濃度減少產生具有比不用界面活性劑時好之溶解概況的醫藥組合物。在不束縛於任何特定理論之情況下,歸因於疏水性,使用潤滑劑可預防水接觸其他賦形劑且因此減慢溶解。舉例而言,在本發明之示範性實施例中,潤滑劑濃度低於醫藥組合物之1wt%,例如0.5wt%。
潤滑劑(例如醫藥學上可接受之潤滑劑)之實例包括(但不限於)滑石、硬脂酸鎂、硬脂酸鋁、硬脂酸鈣、碳酸鎂、聚乙二醇、山萮酸甘油酯、硬脂酸、氫化蓖麻油、單硬脂酸甘油酯及硬脂醯反丁烯二酸鈉。潤滑劑可以醫藥組合物總重量之約0至10wt%(例如0至10wt%,或約2wt%,例如2wt%)的濃度存在。
以下實例為說明性的,而非用以限定本文所述之本發明之範疇。實例僅意謂提出實施本發明之方法。
用於各實例中由醫藥組合物之重量百分比表示之成份數量列於位於各自描述後之各自表中。對膠囊而言,當計算醫藥組合物之重量(亦即膠囊填充重量)時,膠囊殼自身重量排除在計算之外。
此實例中之治療化合物為尼羅替尼鹽酸鹽單水合物。此治療化合物在水性介質中具有低溶解度。此外,此治療化合物具有輕微吸濕
之傾向。
使用高剪切混合器將尼羅替尼鹽酸鹽單水合物、乳糖單水合物及聚乙烯吡咯啶酮混合在一起以形成粉末摻合物。將泊洛沙姆188用純水溶解且接著添加至粉末摻合物中以濕潤粉末摻合物。接著,將混合物捏製且在流化床乾燥器中乾燥以形成顆粒。使用具有0.8mm篩子之振動造粒機將乳糖單水合物及膠狀二氧化矽(作為外相之部分)與顆粒一起篩選。料箱摻合器用以提供額外摻合。將硬脂酸鎂以0.9mm篩子單獨篩分且添加至混合物中以最終摻合。將經摻合之混合物填充至膠囊中。
由於尼羅替尼鹽酸鹽單水合物之輕微吸濕傾向,所以可預期經填充之硬明膠膠囊殼將隨著老化而變形。驚人地,經填充之硬明膠膠囊之物理穩定性實質上在加速老化(亦即,使膠囊經受較高溫度及相對濕度之條件(40℃/75% RH))過程中在目測檢查期間並未變形。較佳地,為獲得此穩定性,膠囊之水含量應為低的,使得在80℃下將膠囊
乾燥10min之後重量損失應低於3.0%。
在自動膠囊填充期間觀測到本發明之膠囊之黏著問題。意外地發現含有少於膠囊總重量之約40% w/w之量的乳糖單水合物之膠囊不會發生該等黏著問題。
使用根據Ph.Eur.2.9.3 'Dissolution test for solid dosage forms'及USP<711>'Dissolution'之籃式方法以100rpm在1000ml作為溶解物質之0.1N HCl中進行溶解測試。對所溶解之藥物物質之量的測定係以UV偵測法來進行。驗證了該方法之選擇性、準確性、精確性及線性。
應瞭解雖然已對本發明結合其詳細說明進行了描述,但上文描述意欲說明而非限定本發明之範疇,本發明之範疇係由以下申請專利範圍之範疇界定。其他態樣、優點及修改屬於申請專利範圍之範疇內。
Claims (11)
- 一種製備醫藥組合物之方法,其包含以下步驟:(a)形成尼羅替尼(nilotinib)鹽酸鹽單水合物與至少一種醫藥學上可接受之賦形劑的粉末摻合物;(b)該粉末摻合物用造粒液體濕潤成團及捏製以形成潮濕顆粒;及(c)乾燥該等潮濕顆粒以形成顆粒;其中該粉末摻合物包含界面活性劑。
- 如請求項1之方法,其中該造粒液體包含水。
- 如請求項2之方法,其中該造粒液體係以該粉末摻合物之10wt%至25wt%之濃度存在。
- 如請求項1之方法,其進一步包含篩該等顆粒之步驟。
- 如請求項1之方法,其中將該等潮濕顆粒乾燥至乾燥失重值小於或等於乾燥前該等潮濕顆粒之2wt%。
- 如請求項1之方法,其中該界面活性劑為泊洛沙姆(poloxamer)。
- 如請求項6之方法,其中該泊洛沙姆為泊洛沙姆188。
- 如請求項1之方法,其中該粉末摻合物係由尼羅替尼鹽酸鹽單水合物、乳糖單水合物及聚乙烯吡咯啶酮所組成。
- 一種醫藥組合物,其藉由如請求項1之方法產生。
- 一種醫藥組合物,其藉由如請求項7之方法產生。
- 一種醫藥組合物,其藉由如請求項8之方法產生。
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TW102144088A TWI540128B (zh) | 2006-09-27 | 2007-09-26 | 醫藥組合物 |
TW103101056A TW201418245A (zh) | 2006-09-27 | 2007-09-26 | 醫藥組合物 |
TW096135768A TWI428333B (zh) | 2006-09-27 | 2007-09-26 | 醫藥組合物 |
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US (2) | US8293756B2 (zh) |
EP (4) | EP1923053A1 (zh) |
JP (2) | JP5567340B2 (zh) |
KR (2) | KR20090076931A (zh) |
CN (2) | CN101516344A (zh) |
AR (1) | AR062980A1 (zh) |
AU (1) | AU2007301977B2 (zh) |
BR (1) | BRPI0719438B1 (zh) |
CA (1) | CA2662571C (zh) |
CL (1) | CL2007002766A1 (zh) |
CO (1) | CO6160288A2 (zh) |
CY (2) | CY1117021T1 (zh) |
DK (2) | DK2068839T3 (zh) |
ES (3) | ES2951547T3 (zh) |
FI (2) | FI3984528T3 (zh) |
HK (1) | HK1133193A1 (zh) |
HR (2) | HRP20151383T4 (zh) |
HU (2) | HUE028204T2 (zh) |
IL (1) | IL197496A (zh) |
JO (1) | JO3757B1 (zh) |
LT (1) | LT3984528T (zh) |
MA (1) | MA30807B1 (zh) |
MX (1) | MX2009003184A (zh) |
MY (1) | MY148237A (zh) |
NO (2) | NO347404B1 (zh) |
NZ (1) | NZ575317A (zh) |
PE (2) | PE20081379A1 (zh) |
PL (2) | PL2068839T5 (zh) |
PT (2) | PT3984528T (zh) |
RU (1) | RU2469707C2 (zh) |
SI (2) | SI2068839T2 (zh) |
TN (1) | TN2009000093A1 (zh) |
TW (3) | TWI540128B (zh) |
WO (1) | WO2008037716A2 (zh) |
ZA (1) | ZA200901511B (zh) |
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CN102321073A (zh) * | 2011-08-12 | 2012-01-18 | 西安交通大学 | 一种尼罗替尼的制备方法 |
WO2013063000A1 (en) | 2011-10-28 | 2013-05-02 | Novartis Ag | Method of treating gastrointestinal stromal tumors |
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KR20140093230A (ko) * | 2011-11-14 | 2014-07-25 | 노파르티스 아게 | 즉시 방출 4-메틸-3-[[4-(3-피리디닐)-2-피리미디닐]아미노]-n-[5-(4-메틸-1h-이미다졸-1-일)-3-(트리플루오로메틸)페닐] 벤즈아미드 제제 |
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CN107582531B (zh) * | 2016-07-06 | 2020-12-29 | 四川科伦药物研究院有限公司 | 一种利伐沙班固体制剂及其制备方法 |
CN107320460B (zh) * | 2017-08-04 | 2020-11-03 | 北京化工大学 | 一种尼罗替尼口服纳米制剂及其制备方法 |
CN107441094B (zh) * | 2017-08-08 | 2020-05-22 | 南方医科大学 | 尼罗替尼作为治疗登革病毒感染的药物及其制药用途 |
CZ2017821A3 (cs) | 2017-12-20 | 2019-07-03 | Zentiva, K.S. | Léková forma obsahující krystalický nilotinib |
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