CN101516344A - 包含尼罗替尼或其盐的药物组合物 - Google Patents
包含尼罗替尼或其盐的药物组合物 Download PDFInfo
- Publication number
- CN101516344A CN101516344A CNA2007800353567A CN200780035356A CN101516344A CN 101516344 A CN101516344 A CN 101516344A CN A2007800353567 A CNA2007800353567 A CN A2007800353567A CN 200780035356 A CN200780035356 A CN 200780035356A CN 101516344 A CN101516344 A CN 101516344A
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- CN
- China
- Prior art keywords
- alkyl group
- low alkyl
- pharmaceutical composition
- group
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 40
- 150000003839 salts Chemical class 0.000 title claims abstract description 34
- 239000005536 L01XE08 - Nilotinib Substances 0.000 title claims abstract description 16
- 229960001346 nilotinib Drugs 0.000 title claims abstract description 16
- 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 title claims abstract description 16
- 239000002775 capsule Substances 0.000 claims abstract description 36
- 239000008187 granular material Substances 0.000 claims abstract description 26
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 26
- -1 heterocyclic radical Chemical class 0.000 claims description 79
- 125000000217 alkyl group Chemical group 0.000 claims description 63
- 150000001875 compounds Chemical class 0.000 claims description 57
- 239000000203 mixture Substances 0.000 claims description 48
- 230000001225 therapeutic effect Effects 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 35
- 238000005469 granulation Methods 0.000 claims description 22
- 230000003179 granulation Effects 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 239000000843 powder Substances 0.000 claims description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 239000000314 lubricant Substances 0.000 claims description 15
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 14
- 239000004094 surface-active agent Substances 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 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 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 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 8
- 229960001021 lactose monohydrate Drugs 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 125000001118 alkylidene group Chemical group 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 229920001983 poloxamer Polymers 0.000 claims description 7
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 7
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical group C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 229960000502 poloxamer Drugs 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 238000012216 screening Methods 0.000 claims description 6
- 239000005864 Sulphur Substances 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- 150000001204 N-oxides Chemical class 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 3
- 229940030721 nilotinib hydrochloride Drugs 0.000 claims 1
- 238000005550 wet granulation Methods 0.000 abstract description 10
- 239000002585 base Substances 0.000 description 22
- 125000001424 substituent group Chemical group 0.000 description 19
- 125000003282 alkyl amino group Chemical group 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 239000006186 oral dosage form Substances 0.000 description 9
- 150000001335 aliphatic alkanes Chemical class 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 238000011049 filling Methods 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000011230 binding agent Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 230000032050 esterification Effects 0.000 description 5
- 238000005886 esterification reaction Methods 0.000 description 5
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 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
- 238000002156 mixing Methods 0.000 description 4
- 229920001993 poloxamer 188 Polymers 0.000 description 4
- 229940044519 poloxamer 188 Drugs 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 125000005493 quinolyl group Chemical group 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 3
- 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
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- 238000010521 absorption reaction Methods 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 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
- 229910052799 carbon Inorganic materials 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
- 239000008119 colloidal silica Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000007922 dissolution test Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 125000005956 isoquinolyl group Chemical group 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 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
- 125000004173 1-benzimidazolyl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N1* 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[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
- 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
- 241000790917 Dioxys <bee> Species 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
- 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 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 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
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 125000004448 alkyl carbonyl 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
- 150000001412 amines Chemical class 0.000 description 2
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-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
- 230000037396 body weight Effects 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 230000008859 change Effects 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
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 238000004898 kneading Methods 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
- 239000001095 magnesium carbonate Substances 0.000 description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 125000002757 morpholinyl group Chemical group 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
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- KHUXNRRPPZOJPT-UHFFFAOYSA-N phenoxy radical Chemical compound O=C1C=C[CH]C=C1 KHUXNRRPPZOJPT-UHFFFAOYSA-N 0.000 description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
- 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
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GLGSZERYOLHNML-UHFFFAOYSA-N $l^{1}-oxidanyl(phenyl)methanone Chemical compound [O]C(=O)C1=CC=CC=C1 GLGSZERYOLHNML-UHFFFAOYSA-N 0.000 description 1
- SMDGVPQREIZILS-UHFFFAOYSA-N $l^{1}-oxidanylmethylbenzene Chemical compound [O]CC1=CC=CC=C1 SMDGVPQREIZILS-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- JZFSLMDLIPKTAO-UHFFFAOYSA-N 1,3-dihydroazepin-2-one Chemical compound O=C1CC=CC=CN1 JZFSLMDLIPKTAO-UHFFFAOYSA-N 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- VMFVHTNDRKKILX-UHFFFAOYSA-N 1-pyrrolidin-1-ylpyrrolidin-2-one Chemical compound O=C1CCCN1N1CCCC1 VMFVHTNDRKKILX-UHFFFAOYSA-N 0.000 description 1
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
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Abstract
本发明涉及药物组合物,特别是胶囊剂,该胶囊剂包含颗粒,所述的颗粒包含尼罗替尼或其盐以及至少一种可药用赋形剂。颗粒可以通过湿法制粒方法制备。
Description
发明领域
本发明涉及药物组合物,该药物组合物包含式I的治疗性化合物(参见下文)、例如尼罗替尼(nilotinib)。该药物组合物可以通过用于制备颗粒的湿法制粒方法制备,随后将颗粒填充至胶囊中。
发明背景
尼罗替尼是4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]-N-[5-(4-甲基-1H-咪唑-1-基)-3-(三氟甲基)苯基]苯甲酰胺。尼罗替尼的特别有用的盐是尼罗替尼盐酸盐一水合物。这些治疗性化合物具有Bcr-Abl的蛋白酪氨酸激酶(TK)活性抑制剂的作用。可以用该治疗性化合物治疗的病症的实例包括但不限于慢性粒细胞白血病和胃肠道基质肿瘤。
需要将尼罗替尼和下文公开的其它治疗性化合物配制为药物组合物,特别是固体口服剂型,以便可以将化合物的治疗性益处传递给需要的患者。本文提出了解决该需要的挑战是该治疗性化合物的物理化学性质。尼罗替尼及其盐是水溶性差的化合物并且很难配制和传递(即当口服摄入后使其生物可利用)。本发明的目的是提供通过制备患者可以摄入的固体口服剂型形式的药物组合物的示例性解决方法。
发明概述
本发明提供了新的药物组合物,该药物组合物包含式I的治疗性化合物、例如尼罗替尼或其盐。药物组合物是固体口服剂型、特别是胶囊剂形式。胶囊剂用与外相混合的治疗性化合物的颗粒填充,所述的外相包含至少一种可药用赋形剂。制备颗粒的特别有用的方法是湿法制粒方法。治疗性化合物和任何可药用赋形剂(例如表面活性剂)与纯化水(或有机溶剂)润湿成团,随后干燥以形成颗粒。特别有用的表面活性剂的实例是泊洛沙姆、例如泊洛沙姆188。已经发现表面活性剂的应用使其它赋形剂(例如润滑剂)的浓度降低。
在本发明另一个示例性实施方案中,制备颗粒的湿法制粒方法包括以下步骤:a)形成治疗性化合物(例如尼罗替尼或其盐)和至少一种可药用赋形剂的粉末混合物;b)在搅拌下将制粒液体加入至粉末混合物中以形成湿团块;c)将湿团块制粒以形成湿颗粒并且d)将湿颗粒干燥。
发明详述
本发明涉及包含治疗性化合物的药物组合物。该药物组合物可以通过将治疗性化合物与制粒液体进行湿法制粒以形成颗粒或颗粒混合物而制备。颗粒或颗粒混合可以随后包囊于硬明胶胶囊中、压制成片剂或填充至小药囊中以形成固体口服剂型。
本文所用的术语“治疗性化合物”指的是式I的嘧啶基氨基苯甲酰胺化合物以及该化合物的N-氧化物和可药用盐:
其中
R1代表氢、低级烷基、低级烷氧基-低级烷基、酰基氧基-低级烷基、羧基-低级烷基、低级烷氧基羰基-低级烷基或苯基-低级烷基;
R2代表氢、任选被一个或多个相同的或不同的基团R3取代的低级烷基、环烷基、苯并环烷基、杂环基、芳基或者包含0、1、2或3个环氮原子以及0或1个氧原子和0或1个硫原子的单-或二环杂芳基,在每种情况中该基团是未取代的或者是单-或多取代的;
并且R3代表羟基、低级烷氧基、酰基氧基、羧基、低级烷氧基羰基、氨基甲酰基、N-单-或N,N-二取代的氨基甲酰基、氨基、单-或二取代的氨基、环烷基、杂环基、芳基或者包含0、1、2或3个环氮原子以及0或1个氧原子和0或1个硫原子的单-或二环杂芳基,在每种情况中该基团是未取代的或者是单-或多取代的;
或者其中R1和R2一起代表具有4、5或6个碳原子的亚烷基,其任选被以下基团单-或二取代:低级烷基、环烷基、杂环基、苯基、羟基、低级烷氧基、氨基、单-或二取代的氨基、氧代、吡啶基、吡嗪基或嘧啶基;具有4或5个碳原子的苯亚烷基;具有一个氧原子和3或4个碳原子的氧杂亚烷基;或者具有一个氮原子和3或4个碳原子的氮杂亚烷基,其中氮原子是未取代的或者被以下基团取代:低级烷基、苯基-低级烷基、低级烷氧基羰基-低级烷基、羧基-低级烷基、氨基甲酰基-低级烷基、N-单-或N,N-二取代的氨基甲酰基-低级烷基、环烷基、低级烷氧基羰基、羧基、苯基、取代的苯基、吡啶基、嘧啶基或吡嗪基;
R4代表氢、低级烷基或卤素。
该治疗性化合物适于制备用于治疗激酶依赖性疾病、特别是Bcr-Abl和Tie-2激酶依赖性疾病、例如作为治疗一种或多种增殖性疾病的药物的药物组合物。
在“治疗性化合物”的定义中,前缀“低级”指的是具有至多并且包括最大值7、特别是至多并且包括最大值4个碳原子的基团,所述基团是直链的或者是具有一个或多个分支的支链的。
本文用于化合物、盐等的复数形式也指单数的化合物、盐等。
任何不对称碳原子可以以(R)-、(S)-或(R,S)-构型存在,例如以(R)-或(S)-构型存在。因此,化合物可以作为异构体的混合物或作为纯异构体存在,例如作为对映异构体-纯非对映异构体存在。本发明还涉及式I化合物的任何可能的互变异构体的用途。
低级烷基是例如具有从并且包括1至至多并且包括7个、例如从并且包括1至并且包括4个碳原子的烷基,并且其是直链的或支链的;例如低级烷基是丁基(例如正-丁基、仲-丁基、异丁基、叔-丁基)、丙基(例如正-丙基或异丙基)、乙基或甲基。例如低级烷基是甲基、丙基或叔-丁基。
低级酰基是例如甲酰基或低级烷基羰基,特别是乙酰基。
芳基是芳族基团,其通过位于基团的芳环碳原子上的键与分子键合。在一个示例性实施方案中,芳基是具有6至14个碳原子的芳族基团,特别是苯基、萘基、四氢萘基、芴基或菲基,并且其是未取代的或者被一个或多个、例如至多三个、特别是一个或两个取代基取代,所述的取代基特别选自氨基、单-或二取代的氨基、卤素、低级烷基、取代的低级烷基、低级链烯基、低级炔基、苯基、羟基、醚化的或酯化的羟基、硝基、氰基、羧基、酯化的羧基、烷酰基、苯甲酰基、氨基甲酰基、N-单-或N,N-二取代的氨基甲酰基、脒基、胍基、脲基、巯基、磺基、低级烷基硫代、苯基硫代、苯基-低级烷基硫代、低级烷基苯基硫代、低级烷基亚磺酰基、苯基亚磺酰基、苯基-低级烷基亚磺酰基、低级烷基苯基亚磺酰基、低级烷基磺酰基、苯基磺酰基、苯基-低级烷基磺酰基、低级烷基苯基磺酰基、卤素-低级烷基巯基、卤素-低级烷基磺酰基(例如特别是三氟甲磺酰基)、二羟基硼基(-B(OH)2)、杂环基、单-或二环杂芳基以及在环的相邻的C-原子上键合的低级亚烷基二氧基例如亚甲基二氧基。芳基是例如苯基、萘基或四氢萘基,其在每种情况中是未取代的或者独立地被一个或两个取代基取代,所述的取代基选自卤素,特别是氟、氯或溴;羟基;被低级烷基(例如甲基)、卤素-低级烷基(例如三氟甲基)或苯基醚化的羟基;与两个相邻的C-原子键合的低级亚烷基二氧基,例如亚甲基二氧基;低级烷基,例如甲基或丙基;卤素-低级烷基,例如三氟甲基;羟基-低级烷基,例如羟基甲基或2-羟基-2-丙基;低级烷氧基-低级烷基,例如甲氧基甲基或2-甲氧基乙基;低级烷氧基羰基-低级烷基,例如甲氧基-羰基甲基;低级炔基,例如1-丙炔基;酯化的羧基,特别是低级烷氧基羰基,例如甲氧基羰基、正-丙氧基羰基或异-丙氧基羰基;N-单-取代的氨基甲酰基,特别是被低级烷基(例如甲基、正-丙基或异-丙基)单取代的氨基甲酰基;氨基;低级烷基氨基,例如甲基氨基;二-低级烷基氨基,例如二甲基氨基或二乙基氨基;低级亚烷基-氨基,例如吡咯烷子基或哌啶子基;低级氧杂亚烷基-氨基,例如吗啉代;低级氮杂亚烷基-氨基,例如哌嗪子基;酰基氨基,例如乙酰基氨基或苯甲酰基氨基;低级烷基磺酰基,例如甲基磺酰基;氨磺酰基;或苯基磺酰基。
环烷基是例如环丙基、环戊基、环己基或环庚基,并且可以是未取代的或者被一个或多个、特别是一个或两个取代基取代,所述的取代基选自以上定义的芳基的取代基,例如低级烷基(例如甲基)、低级烷氧基(例如甲氧基或乙氧基)或羟基,并且进一步是氧代,或者与苯环稠合,例如苯并环戊基或苯并环己基。
取代的烷基是如以上定义的烷基,特别是低级烷基,例如甲基;其中可以存在一个或多个、特别是至多三个取代基,所述的取代基主要选自卤素(特别是氟)、氨基、N-低级烷基氨基、N,N-二-低级烷基氨基、N-低级烷酰基氨基、羟基、氰基、羧基、低级烷氧基羰基和苯基-低级烷氧基羰基。三氟甲基是特别有用的。
单-或二取代的氨基特别是被一个或两个基团取代的氨基,所述的基团彼此独立地选自低级烷基,例如甲基;羟基-低级烷基,例如2-羟基乙基;低级烷氧基低级烷基,例如甲氧基乙基;苯基-低级烷基,例如苄基或2-苯基乙基;低级烷酰基,例如乙酰基;苯甲酰基;取代的苯甲酰基,其中苯基特别是被一个或多个、例如一个或两个取代基取代,所述的取代基选自硝基、氨基、卤素、N-低级烷基氨基、N,N-二-低级烷基氨基、羟基、氰基、羧基、低级烷氧基羰基、低级烷酰基和氨基甲酰基;以及苯基-低级烷氧基羰基,其中苯基是未取代的或者特别是被一个或多个、例如一个或两个取代基取代,所述的取代基选自硝基、氨基、卤素、N-低级烷基氨基、N,N-二-低级烷基氨基、羟基、氰基、羧基、低级烷氧基羰基、低级烷酰基和氨基甲酰基;并且是例如N-低级烷基氨基(例如N-甲基氨基)、羟基-低级烷基氨基(例如2-羟基-乙基氨基或2-羟基丙基)、低级烷氧基低级烷基(例如甲氧基乙基)、苯基-低级烷基氨基(例如苄基氨基)、N,N-二-低级烷基氨基、N-苯基-低级烷基-N-低级烷基氨基、N,N-二-低级烷基苯基氨基、低级烷酰基氨基(例如乙酰基氨基),或者取代基选自苯甲酰基氨基和苯基-低级烷氧基羰基氨基,其中苯基在每种情况中是未取代的或者特别是被硝基或氨基或卤素、氨基、N-低级烷基氨基、N,N-二-低级烷基氨基、羟基、氰基、羧基、低级烷氧基羰基、低级烷酰基、氨基甲酰基或氨基羰基氨基取代。二取代的氨基也是低级亚烷基-氨基,例如吡咯烷子基、2-氧代吡咯烷子基或哌啶子基;低级氧杂亚烷基-氨基,例如吗啉代;或低级氮杂亚烷基-氨基,例如哌嗪子基或N-取代的哌嗪子基,例如N-甲基哌嗪子基或N-甲氧基羰基哌嗪子基。
卤素特别是氟、氯、溴或碘,特别是氟、氯或溴。
醚化的羟基特别是C8-C20烷氧基(例如正-癸氧基)、低级烷氧基(例如甲氧基、乙氧基、异丙氧基或叔-丁氧基)、苯基-低级烷氧基(例如苄基氧基、苯基氧基)、卤素-低级烷氧基(例如三氟甲氧基、2,2,2-三氟乙氧基或1,1,2,2-四氟乙氧基)或者被单-或二环杂芳基取代的低级烷氧基,所述的杂芳基包含一个或两个氮原子,例如被以下基团取代的低级烷氧基:咪唑基(例如1H-咪唑-1-基)、吡咯基、苯并咪唑基(例如1-苯并咪唑基)、吡啶基(特别是2-、3-或4-吡啶基)、嘧啶基(特别是2-嘧啶基)、吡嗪基、异喹啉基(特别是3-异喹啉基)、喹啉基、吲哚基或噻唑基。
酯化的羟基特别是低级烷酰基氧基、苯甲酰基氧基、低级烷氧基羰基氧基(例如叔-丁氧基羰基氧基)或苯基-低级烷氧基羰基氧基(例如苄基氧基羰基氧基)。
酯化的羧基特别是低级烷氧基羰基(例如叔-丁氧基羰基、异-丙氧基羰基、甲氧基羰基或乙氧基羰基)、苯基-低级烷氧基羰基或苯基氧基羰基。
烷酰基主要是烷基羰基,特别是低级烷酰基,例如乙酰基。
N-单-或N,N-二取代的氨基甲酰基特别被一个或两个取代基取代,所述的取代基独立地选自低级烷基、苯基-低级烷基和羟基-低级烷基或低级亚烷基、氧杂-低级亚烷基或任选在末端氮原子上被取代的氮杂-低级亚烷基。
包含0、1、2或3个环氮原子以及0或1个氧原子和0或1个硫原子的单-或二环杂芳基,该基团在每种情况中是未取代的或者是单-或多取代的,指的是将杂芳基与式I分子的其余部分连接的环是不饱和的杂环基并且例如是环,其中在连接的环中,但也任选在任何稠合的环中,至少一个碳原子被杂原子代替,所述的杂原子选自氮、氧和硫;其中连接的环例如具有5至12、例如5至6个环原子;并且其可以是未取代的或者被一个或多个、特别是一个或两个取代基取代,所述的取代基选自以上定义的芳基的取代基,最例如低级烷基(例如甲基)、低级烷氧基(例如甲氧基或乙氧基)或羟基。例如单-或二环杂芳基选自2H-吡咯基、吡咯基、咪唑基、苯并咪唑基、吡唑基、吲唑基、嘌呤基、吡啶基、吡嗪基、嘧啶基、哒嗪基、4H-喹嗪基、异喹啉基、喹啉基、2,3-二氮杂萘基、1,5-二氮杂萘基、喹喔啉基、喹唑啉基、喹啉基、蝶啶基、中氮茚基、3H-吲哚基、吲哚基、异吲哚基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、四唑基、呋咱基、苯并[d]吡唑基、噻吩基和呋喃基。例如单-或二环杂芳基选自吡咯基、咪唑基(例如1H-咪唑-1-基)、苯并咪唑基(例如1-苯并咪唑基)、吲唑基(特别是5-吲唑基)、吡啶基(特别是2-、3-或4-吡啶基)、嘧啶基(特别是2-嘧啶基)、吡嗪基、异喹啉基(特别是3-异喹啉基)、喹啉基(特别是4-或8-喹啉基)、吲哚基(特别是3-吲哚基)、噻唑基、苯并[d]吡唑基、噻吩基和呋喃基。在本发明的一个示例性实施方案中,吡啶基在氮原子的邻位被羟基取代并且因此至少部分以相应的互变异构体形式存在,其是吡啶-(1H)2-酮。在另一个示例性实施方案中,嘧啶基在2位和4位被羟基取代并且因此以多种互变异构体形式存在,例如作为嘧啶-(1H、3H)2,4-二酮。
杂环基特别是具有一个或两个选自氮、氧和硫的杂原子的5、6或7-元杂环系,其可以是不饱和的或者是全部或部分饱和的,并且是未取代的或者特别是被以下基团取代:低级烷基(例如甲基)、苯基-低级烷基(例如苄基)、氧代或杂芳基(例如2-哌嗪基);杂环基特别是2-或3-吡咯烷基、2-氧代-5-吡咯烷基、哌啶基、N-苄基-4-哌啶基、N-低级烷基-4-哌啶基、N-低级烷基-哌嗪基、吗啉基(例如2-或3-吗啉基)、2-氧代-1H-氮杂-3-基、2-四氢呋喃基或2-甲基-1,3-二氧戊环-2-基。
盐特别是式I化合物的可药用盐。
此类盐例如形成酸加成盐、例如与有机或无机酸形成酸加成盐,由式I化合物与碱性氮原子形成盐,特别是可药用盐。适合的无机酸包括但不限于氢卤酸(例如盐酸)、硫酸或磷酸。适合的有机酸是例如羧酸、膦酸、磺酸或氨基磺酸,例如乙酸、丙酸、辛酸、癸酸、十二烷酸、羟基乙酸、乳酸、富马酸、琥珀酸、己二酸、庚二酸、辛二酸、壬二酸、苹果酸、酒石酸、柠檬酸、氨基酸(例如谷氨酸或天冬氨酸)、马来酸、羟基马来酸、甲基马来酸、环己烷羧酸、金刚烷羧酸、苯甲酸、水杨酸、4-氨基水杨酸、邻苯二甲酸、苯基乙酸、扁桃酸、肉桂酸、甲-或乙磺酸、2-羟基乙磺酸、乙-1,2-二磺酸、苯磺酸、2-萘磺酸、1,5-萘-二磺酸、2-、3-或4-甲基苯磺酸、甲基硫酸、乙基硫酸、十二烷基硫酸、N-环己基氨基磺酸、N-甲基-、N-乙基-或N-丙基-氨基磺酸或其它有机质子酸,例如抗坏血酸。
在负电荷基团、例如羧基或磺基的存在下,盐也可以与碱形成,例如金属盐或铵盐,例如碱金属盐或碱土金属盐,例如钠盐、钾盐、镁盐或钙盐,或者与氨或适合的有机胺例如叔单胺,例如三乙胺或三(2-羟基乙基)胺,或者杂环碱,例如N-乙基-哌啶或N,N’-二甲基哌嗪形成的盐。
当碱性基团与酸性基团存在于同一分子中时,式I化合物也可以形成内盐。
对于分离或纯化目的,也可能应用不可药用盐,例如苦味酸盐或高氯酸盐。对于治疗应用,仅应用可药用盐或游离化合物(其中可以药物制剂的形式应用),并且因此,这些是特别有用的。
例如在新化合物的纯化或鉴别中,考虑到游离形式的新化合物与它们的盐(包括那些可以用作中间体的盐)形式之间的紧密关系,适当并且方便的话,上下文中任何涉及游离化合物的将被理解为也涉及相应的盐。
在式I范围内的化合物以及制备它们的方法在2004年1月15日公布的WO 04/005281中公开,将其全部内容并入本申请作为参考。本发明中特别有用的治疗性化合物是4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]-N-[5-(4-甲基-1H-咪唑-1-基)-3-(三氟甲基)苯基]苯甲酰胺(也称为尼罗替尼),其结构为:
尼罗替尼的特别有用的盐是尼罗替尼盐酸盐一水合物或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)氨基]苯甲酰胺盐酸盐水合物。尼罗替尼适合的盐及其多晶型物更通常在WO2007/015870和WO2007/015871中公开。
本文所用的术语“药物组合物”指的是例如包含在可药用载体中的特别量的治疗性化合物、例如治疗有效量的治疗性化合物、施用于哺乳动物、例如人类以治疗激酶依赖性疾病的混合物。
本文所用的术语“可药用的”指的是那些在正确的医学判断范围内,适合与哺乳动物(特别是人类)组织接触,没有过多的毒性、刺激、过敏反应和其它与适当的益处/风险比有关的问题并发症的化合物、物质、组合物和/或剂型。
治疗性化合物在药物组合物中的浓度以一定量存在,例如以治疗有效量存在,其取决于药物的吸收、失活和排泄速率以及其它本领域普通技术人员已知的因素。另外,需要指出的是剂量值也随着待缓和的病症的严重程度而不同。应当进一步理解的是,对于任何特别的受试者,应当根据个体需要和施用或管理药物组合物的施用的人员的个人判断随着时间调整特别的剂量方案。治疗性化合物可以施用一次或者可以分为多个较小的剂量在不同的时间间隔施用。因此,适合的量、例如适合的治疗有效量是本领域普通技术人员已知的。
例如,治疗性化合物的剂量范围将为每天约0.1至约100mg/kg受试者体重。可选择的是,可以给出较低剂量,例如剂量为每天0.5至100mg;0.5至50mg;或0.5至20mg/kg体重。可药用盐的有效剂量范围可以基于待传递的活性部分的重量计算。如果盐本身显示出活性,那么有效剂量可以如上计算,应用盐的重量或通过本领域技术人员已知的其它方法。
本文所用的术语“速释”指的是在相对短的时间内,例如在口服摄入后1小时、40分钟、30分钟或20分钟内快速释放大部分治疗性化合物,例如大于约50%、约55%、约60%、约65%、约70%、约75%、约80%或约90%。速释特别有用的条件是在口服摄入后30分钟内释放至少或等于约80%的治疗性化合物。对于特别的治疗性化合物,特别的速释条件将是本领域普通技术人员公认或已知的。
本文所用的术语“赋形剂”指的是通常用于制备颗粒和/或固体口服剂型制剂的制药技术的可药用成分。赋形剂种类的实例包括但不限于粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂。本领域普通技术人员可以就颗粒和/或固体口服剂型的特别的预期性质,通过常规试验并且无需任何负担选择一种或多种前述赋形剂。所用的每种赋形剂的量可以在本领域常规的范围内变化。以下并入本文作为参考的文献公开了用于配制口服剂型的技术和赋形剂。参见The Handbook of PharmaceuticalExcipients(药物赋形剂手册),第4版,Rowe等人编,AmericanPharmaceuticals Association(2003);和Remington:the Science andPractice of Pharmacy(雷明顿:药物科学与实践),第20版,Gennaro编,Lippincott Williams & Wilkins(2000)。
本文所用的术语“湿法制粒”指的是在制粒方法中应用制粒液体以随后形成颗粒的普通方法,如在Remington:The Science and Practice ofPharmacy(雷明顿:药物科学与实践),第20版(2000),第45章中公开的,将其并入本文作为参考。
在本发明的一个示例性实施方案中,湿法制粒包括以下步骤:混合;润湿和捏和,即润湿成团;制粒(即在高剪切混合的情况下捏和);干燥;和筛分。这些步骤在下文更详细地讨论。
湿法制粒方法从治疗性化合物与至少一种可药用赋形剂、特别是表面活性剂通过用例如药用制粒设备混合而形成粉末混合物开始,前述成分(即开始直接的接近)在适合的容器中,以形成混合物。药用制粒设备的实例包括但不限于剪切式制粒机(例如Hobart,Collette,Beken)与摇摆式制粒机组合;高速混合机/制粒机(例如Diosna,Fielder,Collette-Gral)和带有随后的筛分设备的流化床制粒机(例如Aeromatic,Glatt)。最初用于与治疗性化合物混合的赋形剂包括例如表面活性剂、粘合剂、填充剂、崩解剂、稀释剂和前述的任何组合。在粉末混合混合物中特别有用的是表面活性剂。
可药用表面活性剂的实例包括但不限于聚氧乙烯-聚氧丙烯嵌段共聚物(也称为泊洛沙姆)、烷基硫酸盐(例如十二烷基硫酸钠、十八烷基硫酸钠、油基硫酸钠和十六烷基硫酸钠)、烷基芳基磺酸盐(例如十二烷基苯磺酸钠和二烷基磺基丁二酸钠)、聚乙二醇和聚山梨酯。本文所用的术语“泊洛沙姆”指的是至少一种具有下式的聚合物:HO(C2H4)a(C3H6O)b(C2H4O)aH,其中“a”和“b”分别表示聚氧乙烯和聚氧丙烯单元的数目。特别有用的是泊洛沙姆188,其a和b值分别为75和30。表面活性剂可以以占组合物重量(例如占胶囊填充重量)的0至约1%的浓度存在。
可药用崩解剂的实例包括但不限于淀粉;粘土;纤维素;藻酸盐;胶;交联聚合物,例如交联聚乙烯吡咯烷酮或交联聚维酮,例如来自International Specialty Products(Wayne,NJ)的POLYPLASDONE XL;交联羧甲基纤维素钠,例如来自FMC的AC-DI-SOL;和交联羧甲基纤维素钙;大豆多糖;和瓜尔胶。崩解剂可以以占组合物重量(例如占胶囊填充重量)的约0至约50%的浓度存在。
可药用粘合剂的实例包括但不限于淀粉;纤维素及其衍生物,例如微晶纤维素,例如来自FMC(Philadelphia,PA)的AVICEL PH,羟丙基纤维素、羟乙基纤维素和羟丙基甲基纤维素,例如来自Dow Chemical Corp.(Midland,MI)的METHOCEL;蔗糖;右旋糖;玉米糖浆;多糖;聚维酮和明胶。粘合剂可以以占组合物重量(例如占胶囊填充重量)的约0至约50%的浓度存在。
可药用填充剂和可药用稀释剂的实例包括但不限于confectioner糖、可压糖、葡萄糖结合剂、糊精、右旋糖、乳糖、甘露醇、微晶纤维素、粉末纤维素、山梨醇和蔗糖。填充剂可以以占组合物重量(例如占胶囊填充重量)的约0至约80%的浓度存在。
在自动胶囊填充的过程中观察到本发明胶囊剂的粘结问题。令人惊奇的是,发现包含占组合物重量的低于约40%的量的乳糖一水合物的胶囊剂没有该粘结问题。因此,在一个实施方案中,本发明涉及本文描述的胶囊剂,该胶囊剂包含低于胶囊总重量的约40%w/w、更特别的是低于胶囊外相的约25%、更特别的是低于约20%w/w的量的乳糖一水合物。
下一个步骤是通过加入制粒液体将粉末混合物润湿成团,同时搅拌粉末混合物直至粉末混合物被制粒液体润湿以形成湿团块。例如,将10%至35%(w/w)制粒液体加入至粉末混合物中。可选择的是,可以将10%至15%(w/w)制粒液体加入至粉末混合物中。制粒液体,例如是可药用的并且是可挥发的。适合的制粒液体的实例包括但不限于水(例如纯化水)、有机溶剂(例如甲醇、乙醇、异丙醇、丙酮),它们单独或组合应用。组合的制粒液体的实例包括水、乙醇和异丙醇在一起。
可选择的是,湿法制粒方法可以从治疗性化合物本身作为粉末开始。
在润湿成团的过程中,引入至粉末中的制粒液体是包含或不包含一种或多种溶解的赋形剂、例如粘合剂和/或表面活性剂的溶剂。无论润湿成团如何进行,在润湿成团后,粉末混合物都要被制粒液体润湿。在一个示例性实施方案中,纯化水用作制粒液体。
随后,在用制粒液体处理后,湿团块可以任选进行筛分形成润湿的或潮湿的颗粒。湿团块例如可以通过5至至多10mm、例如6-或8-目的筛进行筛分。本领域普通技术人员可以选择适合大小的筛以形式最适合的粒径。
在可选择的实施方案中,可以应用粉碎机代替筛。粉碎机的实例包括但不限于Stokes振荡器、Colton旋转式制粒机、Fitzpatrick粉碎机、Stokes龙卷风式粉碎机。
在另一个可选择的实施方案中,安装有例如粉碎叶片的高速混合机可以用于代替筛或粉碎机。在这种情况中,制粒步骤称为捏和。例如允许润湿成团和制粒合并为一个步骤。
例如随后将湿颗粒干燥。例如,可以将湿颗粒收集在盘中并且转移至干燥箱中。可选择的是,可以将湿颗粒置于具有循环空气流和恒温热控制的干燥箱中。另外的选择是将湿颗粒在流化床干燥器中干燥。在该示例性实施方案中,将湿颗粒悬浮并且在温热的空气流中搅动以便湿颗粒保持在运动中。例如,空气温度可以是约室温至约90℃、例如70℃。将湿颗粒干燥至干燥失重(“LOD”)值小于或等于组合物重量的约5%、例如小于2%、例如0.5至2%。
另外的选择是单罐(single pot)方法,制粒和干燥在同一设备(例如具有用于干燥的双壁的高剪切混合机,如Zanchetta Roto P或TurbosphereMoritz)中进行。
干燥可以在药物制粒设备中进行或者不在药物制粒设备中进行。
干燥后,可以将颗粒进一步筛分,即干燥筛分,其单独或与至少一种赋形剂组合。其典型地产生更均匀的颗粒粒径,制备颗粒用于进一步处理为固体口服剂型。
可以将颗粒与另外的可药用赋形剂一起配制以形成直接的混合物,该混合物随后形成口服形式,例如固体口服剂型,例如片剂、丸剂、锭剂、胶囊形片剂、胶囊剂或小药囊。本文所用的术语“外相”指的是在形成最终的剂型前加入至颗粒中的另外的赋形剂。所用的任何另外的赋形剂可以如在前面提及的干燥筛分步骤中描述的与颗粒筛分分别进行或与颗粒的筛分一起进行。本领域普通技术人员将意识到每种组分需要的粒径,这是配制的特别的药物组合物所必须的。例如,适合的粒径包括那些小于等于1,000μm、750μm、500μm或250μm的粒径。颗粒与外相组装成直接的混合物可以应用任何常规的本领域普通技术人员已知的制药方法、例如混合、压制、共粉碎、压紧或共微粉化完成。
可以将混合的混合物例如随后压制成片剂(例如通过应用压片机)或填充至胶囊或小药囊中(例如通过应用包囊机)。本领域已知的任何胶囊可以用于将混合的混合物包囊。该胶囊的实例是硬明胶胶囊,例如Capsugel ofMorris Plains,New Jersey制备的CONI-SNAP。该胶囊适合的大小包括但不限于00号至5号。胶囊剂形式的药物组合物可以每粒胶囊包含例如5mg至500mg治疗性化合物;例如每粒胶囊包含25mg、50mg、100mg或200mg治疗性化合物。
通常应用的加入至外相的可药用赋形剂是助流剂。该赋形剂使混合的混合物在操作设备中易于流动。
可药用助流剂的实例包括但不限于胶态二氧化硅、三硅酸镁、淀粉、滑石粉、正磷酸钙、硬脂酸铝、碳酸镁、氧化镁和粉末纤维素。助流剂可以以占药物组合物总重量的约0至10%、例如0至10%、可选择的是约1%、例如1%重量的浓度存在。
另一种通常应用的加入至外相的可药用赋形剂是润滑剂。此类赋形剂帮助在操作设备中避免任何粘结。尽管润滑剂增强了可操作力,但是其可能影响治疗性化合物从剂型中的释放。通常,润滑剂是疏水的并且因此在速释剂型中延缓或减慢治疗性化合物的释放。令人惊奇的是,已经发现在湿法制粒方法中包含表面活性剂产生更可处理的颗粒并且使润滑剂减少。润滑剂浓度的降低比不应用表面活性剂产生具有更好溶出曲线的药物组合物。不联系任何特别的理论,润滑剂的应用可以防止水进入其它赋形剂,这是由于其疏水性,并且因此减慢溶出。例如,在本发明的示例性实施方案中,润滑剂的浓度占药物组合物重量的小于1%、例如0.5%。
润滑剂、例如可药用润滑剂的实例包括但不限于滑石粉、硬脂酸镁、硬脂酸铝、硬脂酸钙、碳酸镁、聚乙二醇、甘油二十二烷酸酯、硬脂酸、氢化蓖麻油、单硬脂酸甘油酯和硬脂酰醇富马酸钠。润滑剂可以以占药物组合物总重量的约0至10%、例如0至10%、可选择的是约2%、例如2%重量的浓度存在。
以下实施例说明本文描述的本发明,但不限制本文描述的本发明的范围。实施例仅意味着表明实践本发明的方法。
在每个实施例中应用的由占药物组合物重量的百分比表示的成分的定量在位于各自的描述之后的各自的表中列出。对于胶囊剂,当计算药物组合物的重量(即胶囊填充重量)时,将胶囊壳本身的重量从计算中排除。
实施例1
在该实施例中的治疗性化合物是尼罗替尼盐酸盐一水合物。该治疗性化合物在水性介质中具有低溶解度。另外,该治疗性化合物具有轻微的吸湿趋势。
表1显示实施例1的制剂
成分 | 每粒胶囊的量(mg) | 百分比(w%/w%) |
颗粒 | ||
尼罗替尼盐酸盐一水合物 | 220.60 | 55.2% |
泊洛沙姆188 | 3.18 | 0.8 |
乳糖一水合物 | 78.47 | 19.6% |
聚乙烯吡咯烷酮 | 15.91 | 4% |
外相 | ||
乳糖一水合物 | 77.64 | 19.4% |
胶态二氧化硅 | 2.10 | 0.5% |
硬脂酸镁 | 2.10 | 0.5% |
总计 | 400.0 |
将尼罗替尼盐酸盐一水合物、乳糖一水合物和聚乙烯吡咯烷酮应用高剪切混合机混合在一起以形成粉末混合物。将泊洛沙姆188用纯化水溶解,然后加入至粉末混合物中以润湿粉末混合物。然后,将混合物捏和并且在流化床干燥器中干燥以形成颗粒。应用具有0.8mm筛的摇摆式制粒机将乳糖一水合物和胶态二氧化硅(作为外相的一部分)与颗粒一起筛分。应用箱式混合机以提供另外的混合。分别将硬脂酸镁在1.9mm筛上筛分并且加入至混合物中,用于最终的混合。将混合物填充至胶囊中。
由于尼罗替尼盐酸盐一水合物的轻微的吸湿趋势,预期填充的硬明胶胶囊壳将随着时间而变形。令人惊奇的是,填充的硬明胶胶囊的物理稳定性在加速老化(即将胶囊进行更高温度和相对湿度条件(40℃/75%RH))的可视检查过程中基本没有变形。优选的是,为了获得该稳定性,胶囊的含水量应当很低以至于在80℃下将胶囊干燥10分钟,失重应当低于3.0%。
在自动胶囊填充的过程中观察到了本发明胶囊剂的粘结问题。令人惊奇的是,发现包含占胶囊剂总重量的低于约40%的量的乳糖一水合物的胶囊剂没有该粘结问题。
实施例2-溶出曲线
溶出试验应用转篮法根据Ph.Eur.2.9.3‘Dissolution test for soliddosage forms(固体剂型溶出试验)’和USP<711>‘Dissolution(溶出)’进行,100rpm,1000mL 0.1N HCl作为溶出介质。确定溶出的药物的量是用UV检测方法进行的。已经确认该方法的选择性、准确度、精密度和线性。
表2:实施例1的胶囊剂的溶出结果
时间点(分钟) | 溶出的尼罗替尼盐酸盐一水合物平均值,以%计 |
5 | 29.8 |
15 | 97.2 |
30 | 98.5 |
60 | 99.1 |
应当理解的是,本发明已经进行了详细描述,前面的描述旨在说明本发明并且不限制本发明的范围,本发明是由以下权利要求的范围定义的。其它方面、优点和修饰在权利要求的范围内。
Claims (21)
1.药物组合物,该药物组合物是胶囊剂形式,其包含:
在直接混合物中的包含治疗性化合物的颗粒以及至少一种可药用赋形剂,其中所述的治疗性化合物是式I的嘧啶基氨基苯甲酰胺化合物或所述的式I的嘧啶基氨基苯甲酰胺化合物的N-氧化物或可药用盐
其中
R1代表氢、低级烷基、低级烷氧基-低级烷基、酰基氧基-低级烷基、羧基-低级烷基、低级烷氧基羰基-低级烷基或苯基-低级烷基;
R2代表氢、任选被一个或多个相同的或不同的基团R3取代的低级烷基、环烷基、苯并环烷基、杂环基、芳基或者包含0、1、2或3个环氮原子以及0或1个氧原子和0或1个硫原子的单-或二环杂芳基,在每种情况中该基团是未取代的或者是单-或多取代的;
并且R3代表羟基、低级烷氧基、酰基氧基、羧基、低级烷氧基羰基、氨基甲酰基、N-单-或N,N-二取代的氨基甲酰基、氨基、单-或二取代的氨基、环烷基、杂环基、芳基或者包含0、1、2或3个环氮原子以及0或1个氧原子和0或1个硫原子的单-或二环杂芳基,在每种情况中该基团是未取代的或者是单-或多取代的;
或者其中R1和R2一起代表具有4、5或6个碳原子的亚烷基,其任选被以下基团单-或二取代:低级烷基、环烷基、杂环基、苯基、羟基、低级烷氧基、氨基、单-或二取代的氨基、氧代、吡啶基、吡嗪基或嘧啶基;具有4或5个碳原子的苯亚烷基;具有一个氧原子和3或4个碳原子的氧杂亚烷基;或者具有一个氮原子和3或4个碳原子的氮杂亚烷基,其中氮原子是未取代的或者被以下基团取代:低级烷基、苯基-低级烷基、低级烷氧基羰基-低级烷基、羧基-低级烷基、氨基甲酰基-低级烷基、N-单-或N,N-二取代的氨基甲酰基-低级烷基、环烷基、低级烷氧基羰基、羧基、苯基、取代的苯基、吡啶基、嘧啶基或吡嗪基;
R4代表氢、低级烷基或卤素;
其中前缀“低级”指的是具有至多并且包括最大值7个碳原子的基团,所述基团是直链的或者是具有一个和多个分支的支链的。
2.权利要求1的药物组合物,其中所述的治疗性化合物是尼罗替尼或其可药用盐。
3.权利要求2的药物组合物,其中所述的治疗性化合物是尼罗替尼盐酸盐一水合物。
4.权利要求1的药物组合物,其中所述的颗粒进一步包含表面活性剂。
5.权利要求4的药物组合物,其中所述的表面活性剂的浓度为占所述药物组合物重量的0至1%。
6.权利要求1的药物组合物,其中所述的药物组合物包含润滑剂,并且所述的润滑剂的浓度不超过药物组合物重量的1%。
7.权利要求6的药物组合物,其中所述的润滑剂是硬脂酸镁。
8.权利要求5的药物组合物,其中所述的表面活性剂是泊洛沙姆。
9.权利要求1至8中任意一项的药物组合物,其中乳糖一水合物的量小于组合物重量的约40%。
10.制备药物组合物的方法,该方法包括以下步骤:
形成权利要求1中描述的治疗性化合物或其可药用盐以及至少一种可药用赋形剂的粉末混合物;
将粉末混合物用制粒液体润湿成团并且捏和以形成湿颗粒;并且
将湿颗粒干燥以形成颗粒。
11.权利要求10的方法,其进一步包括将颗粒填入胶囊。
12.权利要求10的方法,其中所述的治疗性化合物是尼罗替尼或其可药用盐。
13.权利要求12的方法,其中所述的治疗性化合物是尼罗替尼盐酸盐一水合物。
14.权利要求10的方法,其中制粒液体包括水。
15.权利要求14的方法,其中制粒液体以占粉末混合物重量的约10%至约25%的浓度存在。
16.权利要求10的方法,其进一步包括筛分颗粒的步骤。
17.权利要求10的方法,其中将湿颗粒干燥至干燥失重值小于或等于干燥前湿颗粒重量的约2%。
18.权利要求10的方法,其中所述的粉末混合物包含表面活性剂。
19.权利要求18的方法,其中所述的表面活性剂是泊洛沙姆。
20.权利要求19的方法,其中所述的泊洛沙姆是泊洛沙姆188。
21.根据权利要求19的方法制备的药物组合物。
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CN107320460A (zh) * | 2017-08-04 | 2017-11-07 | 北京化工大学 | 一种尼罗替尼口服纳米制剂及其制备方法 |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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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 |
CN103930094A (zh) * | 2011-11-14 | 2014-07-16 | 诺华股份有限公司 | 即释4-甲基-3[[4-(3-吡啶基)-2-嘧啶基]氨基]-n-[5-(4-甲基-1h-咪唑-1-基)-3-(三氟甲基)苯基]苯甲酰胺剂型 |
CN114209702A (zh) * | 2016-03-17 | 2022-03-22 | 太阳制药工业公司 | 尼洛替尼的药物组合物 |
CN107320460A (zh) * | 2017-08-04 | 2017-11-07 | 北京化工大学 | 一种尼罗替尼口服纳米制剂及其制备方法 |
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 |
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