AU2012339829B8 - Immediate release 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-n-[5-(4-methyl- 1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide formulation - Google Patents
Immediate release 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-n-[5-(4-methyl- 1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide formulation Download PDFInfo
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- AU2012339829B8 AU2012339829B8 AU2012339829A AU2012339829A AU2012339829B8 AU 2012339829 B8 AU2012339829 B8 AU 2012339829B8 AU 2012339829 A AU2012339829 A AU 2012339829A AU 2012339829 A AU2012339829 A AU 2012339829A AU 2012339829 B8 AU2012339829 B8 AU 2012339829B8
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- Australia
- Prior art keywords
- weight
- methyl
- solid dosage
- dosage form
- nilotinib
- Prior art date
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- 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 description 100
- 239000000203 mixture Substances 0.000 title description 36
- 238000009472 formulation Methods 0.000 title description 13
- 229960001346 nilotinib Drugs 0.000 claims description 76
- 239000005536 L01XE08 - Nilotinib Substances 0.000 claims description 73
- 239000007909 solid dosage form Substances 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 28
- 239000011780 sodium chloride Substances 0.000 claims description 28
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 22
- 239000011248 coating agent Substances 0.000 claims description 18
- 238000000576 coating method Methods 0.000 claims description 18
- 229920000642 polymer Polymers 0.000 claims description 15
- 239000007888 film coating Substances 0.000 claims description 14
- 238000009501 film coating Methods 0.000 claims description 14
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 11
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 11
- 235000019359 magnesium stearate Nutrition 0.000 claims description 11
- 239000002775 capsule Substances 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 claims description 9
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 9
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 9
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 9
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 9
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 9
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 9
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- 239000008108 microcrystalline cellulose Substances 0.000 claims description 9
- 229920003084 Avicel® PH-102 Polymers 0.000 claims description 8
- 230000037242 Cmax Effects 0.000 claims description 8
- 229960000913 Crospovidone Drugs 0.000 claims description 8
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 8
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 7
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- 229910002016 Aerosil® 200 Inorganic materials 0.000 claims description 6
- 230000035533 AUC Effects 0.000 claims description 5
- 239000000945 filler Substances 0.000 claims description 5
- 239000011777 magnesium Substances 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 claims description 5
- 239000007884 disintegrant Substances 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 229910002012 Aerosil® Inorganic materials 0.000 claims description 3
- 239000003623 enhancer Substances 0.000 claims description 3
- 230000002708 enhancing Effects 0.000 claims description 3
- 239000007903 gelatin capsule Substances 0.000 claims description 3
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 claims description 2
- 150000003840 hydrochlorides Chemical class 0.000 claims 1
- -1 benzcycloalkyl Chemical group 0.000 description 62
- 239000003826 tablet Substances 0.000 description 52
- 125000000217 alkyl group Chemical group 0.000 description 43
- 150000001875 compounds Chemical class 0.000 description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 16
- 230000001225 therapeutic Effects 0.000 description 16
- 125000003282 alkyl amino group Chemical group 0.000 description 15
- 239000008194 pharmaceutical composition Substances 0.000 description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 14
- 238000004090 dissolution Methods 0.000 description 12
- 125000003545 alkoxy group Chemical group 0.000 description 11
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 11
- 125000004432 carbon atoms Chemical group C* 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 229910052736 halogen Inorganic materials 0.000 description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
- 239000007963 capsule composition Substances 0.000 description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 8
- 150000002367 halogens Chemical class 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 230000036912 Bioavailability Effects 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 230000035514 bioavailability Effects 0.000 description 7
- 125000001072 heteroaryl group Chemical group 0.000 description 7
- 125000002950 monocyclic group Chemical group 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 230000035832 Lag time Effects 0.000 description 6
- 230000035648 Lag-time Effects 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 125000001589 carboacyl group Chemical group 0.000 description 6
- 230000004584 weight gain Effects 0.000 description 6
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- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000007906 compression Methods 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 125000003373 pyrazinyl group Chemical class 0.000 description 5
- 125000000714 pyrimidinyl group Chemical class 0.000 description 5
- 150000003254 radicals Chemical class 0.000 description 5
- 238000009490 roller compaction Methods 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- 229960001375 Lactose Drugs 0.000 description 4
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
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- 201000010099 disease Diseases 0.000 description 4
- 229940079593 drugs Drugs 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 241000282412 Homo Species 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 125000005236 alkanoylamino group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 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 Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 230000037406 food intake Effects 0.000 description 3
- 229920001002 functional polymer Polymers 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 230000001965 increased Effects 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 150000002829 nitrogen Chemical group 0.000 description 3
- 239000006186 oral dosage form Substances 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 3
- 125000004430 oxygen atoms Chemical group O* 0.000 description 3
- 229920002689 polyvinyl acetate Polymers 0.000 description 3
- 239000011118 polyvinyl acetate Substances 0.000 description 3
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- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- 125000004434 sulfur atoms Chemical group 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
- 238000005550 wet granulation Methods 0.000 description 3
- PUSNGFYSTWMJSK-GSZQVNRLSA-N (2R,3R,4S,5R,6R)-2,3,4-trimethoxy-6-(methoxymethyl)-5-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxyoxane;1-[[(2R,3R,4S,5R,6S)-3,4,5-tris(2-hydroxypropoxy)-6-[(2R,3R,4S,5R,6R)-4,5,6-tris(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)oxan- Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](OC)O[C@@H]1COC.CC(O)CO[C@@H]1[C@@H](OCC(C)O)[C@H](OCC(C)O)[C@@H](COCC(O)C)O[C@H]1O[C@H]1[C@H](OCC(C)O)[C@@H](OCC(C)O)[C@H](OCC(C)O)O[C@@H]1COCC(C)O PUSNGFYSTWMJSK-GSZQVNRLSA-N 0.000 description 2
- WSVLPVUVIUVCRA-RJMJUYIDSA-N (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol;hydrate 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)OC(O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-RJMJUYIDSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
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- 125000004173 1-benzimidazolyl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N1* 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 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
- WNLRTRBMVRJNCN-UHFFFAOYSA-N Adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
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- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
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- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
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- 230000035489 relative bioavailability Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
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- JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid group Chemical class S(N)(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
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- 125000003831 tetrazolyl group Chemical group 0.000 description 1
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- 230000001988 toxicity Effects 0.000 description 1
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- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
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Description
IMMEDIATE RELEASE 4-Methyl-3-ff4-(3-pvridinvn-2-pyrinnidinvllanriinol-N-r5-(4-methvl-1 H-imidazol-1 -vl)-3-(trifluoromethvl)phenvll benzamide FORMULATION
Field of the Invention
The present invention relates to a pharmaceutical composition comprising a therapeutic compound of nilotinib (Formula I). In particular, the present invention is directed to a pharmaceutical composition that comprises a nilotinib tablet core and that further comprises at least one polymeric coating over the nilotinib core, providing a rapidly disintegrating tablet with a lag time, as compared to an uncoated tablet formulation.
Background of the Invention
Nilotinib is 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide. A particularly useful salt of nilotinib is nilotinib hydrochloride monohydrate. These therapeutic compounds have utility as inhibitors of the protein tyrosine kinase (TK) activity of Bcr-Abl. Examples of conditions that may be treated by such therapeutic compounds include, but are not limited to, chronic myeloid leukemia and gastrointestinal stromal tumors.
There is a need to formulate nilotinib and the other therapeutic compounds hereinafter disclosed into pharmaceutical compositions, especially solid oral dosage forms, such that the therapeutic benefits of the compounds may be delivered to a patient in need thereof. One problem to providing such compositions including nilotinib is the physiochemical properties of nilotinib, since nilotinib and its salts are poorly water soluble compounds and are difficult to formulate and deliver (i.e., made bioavailable when ingested orally). It is also difficult to achieve matching pharmacokinetic profiles with different dosage forms, i.e. tablets versus capsules. Another problem is a food effect, as food increases the bioavailability of nilotinib. Compared to a fasted state, nilotinib systemic exposure, as reflected by AUC and Cmax, increases markedly when the unit dosage is given shortly after food is ingested, leading to potential adverse effects in patients.
Summary of the Invention
The present invention provides a solid dosage form comprising: (i) a core comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1 -yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and excipients; and (ii) at least one polymer, said polymer coating said core, wherein disintegration of said solid dosage form is delayed by 4-15 minutes.
The present invention also provides a solid dosage form comprising: (i) a core comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1 -yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and excipients; and (ii) at least one polymer, said polymer coating said core, wherein disintegration of said solid dosage form is delayed by 4-15 minutes, said solid dosage form having a fasted state bioavailability equivalent to a hard-gelatin capsule comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide.
The present invention also provides a solid dosage form comprising: (i) a core comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1 -yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and excipients; and (ii) at least one polymer, said polymer coating said core, wherein disintegration of said solid dosage form is delayed by 4-15 minutes, said solid dosage form having a reduced Cmax as compared to an uncoated solid dosage form comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide.
The present invention also provides a solid dosage form in the form of a tablet comprising: (i) a core comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1 -yl)-3-(trifluoromethyl)phenyl] benzamide (nilotinib) ora pharmaceutically acceptable salt thereof and excipients; and (ii) at least one polymeric coating over the nilotinib core, wherein the polymeric coating comprises a polymer which is hydroxypropylmethyl cellulose, and wherein the film coating is 7-13 % of the solid dosage form.
The present invention also provides a film coated nilotinib tablet consisting of i) 43.60% AMN107 HCI; ii) 35.61 % Avicel PH102; iii) 2.73 % HPC EXF; iv) 5.45 % Crospovidone; v) 0.91% Aerosil 200; vi) 2.61 % Mg stearate; vii) 1.52 % hydroxy propyl methyl cellulose E50; viii) 7.32% Opadry White; ix) 0.24 % Opadry Yellow; x) 0.01% Opadry Red; wherein the % values refer to the % by weight of the excipients listed under i) to x).
The present invention also provides a film coated nilotinib tablet consisting of i) 43.57% AMN107 HCI; ii) 31.95% Avicel PH 102; iii) 2.73 % HPC EXF; iv) 9.08 % Crospovidone; v) 0.91% Aerosil 200; vi) 2.61 % Mg stearate; vii) 0.48% PEG 4000; viii) 3.23 % hydroxy propyl methyl cellulose E50; ix) 5.20 % Opadry White; x) 0.17 % Opadry Yellow; xi) 0.08 % Opadry Red. wherein the % values refer to the % by weight of the excipients listed under i) to xi).
The present invention also provides a method for preparing a solid dosage form comprising amorphous 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof comprising the steps of: (i) roller compacting a core comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]- N-[5-(4-methyl-1 H-imidazol-1 -yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and excipients; and (ii) coating said core with at least one polymer.
Brief Description of the Drawings
Figure 1 summarizes dissolution rates for nilotinib tablets (wet granulated and roller compacted) as compared to a nilotinib capsule.
Figure 2 summarizes dissolution rates for film coated nilotinib tablets (7-10 % film coating) at pH 2.0.
Figure 3 summarizes dissolution rates for film coated nilotinib tablets (10-13 % film coating) at pH 2.0.
Figure 4 summarizes dissolution rates for film coated nilotinib tablets prepared by roller compaction (10% film coating) as compared to uncoated nilotinib tablets prepared by wet granulation at pH 2.0.
Figure 5 summarizes a comparison of mean nilotinib concentration versus time profiles for different nilotinib solid dosage forms.
Detailed Description of the Invention
The present invention provides crystalline pharmaceutical compositions of nilotinib or a pharmaceutically acceptable salt thereof formulated in a tablet form to have bioequivalent pharmacokinetic profiles with that of commercially available nilotinib capsule forms
As used herein, nilotinib refers to 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide of formula I:
Nilotinib is a member of compounds of formula (II)
wherein R-t represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-Iower alkyl, lower a I koxy carbonyl-lower alkyl, or phenyl-lower alkyl; R2 represents hydrogen, lower alkyl, optionally substituted by one or more identical or different radicals R3, cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted; and R3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or Ν,Ν-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted; or wherein R-, and R2 together represent alkylene with four, five or six carbon atoms optionally mono- or disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms; oxaalkylene with one oxygen and three or four carbon atoms; or azaalkylene with one nitrogen and three or four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-Iower alkyl, carbamoyl-lower alkyl, N-mono- or Ν,Ν-disubstituted carbamoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl, or pyrazinyl; R4 represents hydrogen, lower alkyl, or halogen; and a N-oxide and to the pharmaceutically acceptable salts of such a compound. Such therapeutic compounds are suitable for the preparation of a pharmaceutical composition for the treatment of kinase dependent diseases, especially Bcr-Abl and Tie-2 kinase dependent diseases, for example, as drugs to treat one or more proliferative diseases.
Within the definition of “therapeutic compound,” the prefix "lower" denotes a radical having up to and including a maximum of seven, especially up to and including a maximum of four carbon atoms, the radicals in question being either linear or branched with single or multiple branching.
As used herein, where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.
Any asymmetric carbon atoms may be present in the (R)-, (S)- or (R.S)-configuration, for example in the (R)- or (S)-configuration. The compounds may thus be present as mixtures of isomers or as pure isomers, for example as enantiomer-pure diastereomers. Also contemplated within the present invention is the use of any possible tautomers of the compounds of formula I.
Lower alkyl is for example alkyl with from and including one up to and including seven, for example from and including one to and including four, and is linear or branched; for example, lower alkyl is butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or methyl. For example lower alkyl is methyl, propyl or tert-butyl.
Lower acyl is for example formyl or lower alkylcarbonyl, in particular acetyl.
An aryl group is an aromatic radical which is bound to the molecule via a bond located at an aromatic ring carbon atom of the radical. In an exemplary embodiment, aryl is an aromatic radical having six to fourteen carbon atoms, especially phenyl, naphthyl, tetrahydronaphthyl, fluorenyl or phenanthrenyl, and is unsubstituted or substituted by one or more, for example up to three, especially one or two substituents, especially selected from amino, mono- or disubstituted amino, halogen, lower alkyl, substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, benzoyl, carbamoyl, N-mono- or Ν,Ν-disubstituted carbamoyl, amidino, guanidino, ureido, mercapto, sulfo, lower alkylthio, phenylthio, phenyl-lower alkylthio, lower alkylphenylthio, lower alkylsulfinyl, phenylsulfinyl, phenyl-lower alkylsulfinyl, lower alkylphenylsulfinyl, lower alkylsulfonyl, phenylsulfonyl, phenyl-lower alkylsulfonyl, lower alkylphenylsulfonyl, halogen-lower alkylmercapto, halogen-lower alkylsulfonyl, such as especially trifluoromethanesulfonyl, dihydroxybora (-B(OH)2), heterocyclyl, a mono- or bicyclic heteroaryl group and lower alkylene dioxy bound at adjacent C-atoms of the ring, such as methylene dioxy. Aryl is for example phenyl, naphthyl or tetrahydronaphthyl, which in each case is either unsubstituted or independently substituted by one or two substituents selected from the group comprising halogen, especially fluorine, chlorine, or bromine; hydroxy; hydroxy etherified by lower alkyl, e.g. by methyl, by halogen-lower alkyl, e.g. trifluoromethyl, or by phenyl; lower alkylene dioxy bound to two adjacent C-atoms, e.g. methylenedioxy, lower alkyl, e.g. methyl or propyl; halogen-lower alkyl, e.g. trifluoromethyl; hydroxy-lower alkyl, e.g. hydroxymethyl or 2-hydroxy-2-propyl; lower alkoxy-lower alkyl; e.g. methoxymethyl or 2-methoxyethyl; lower alkoxycarbonyl-lower alkyl, e.g. methoxycarbonylmethyl; lower alkynyl, such as 1-propynyl; esterified carboxy, especially lower alkoxycarbonyl, e.g. methoxycarbonyl, n-propoxy carbonyl or iso-propoxy carbonyl; N-mono-substituted carbamoyl, in particular carbamoyl monosubstituted by lower alkyl, e.g. methyl, n-propyl or iso-propyl; amino; lower alkylamino, e.g. methylamino; di-lower alkylamino, e.g. dimethylamino or diethylamino; lower alkylene-amino, e.g. pyrrolidino or piperidino; lower oxaalkylene-amino, e.g. morpholino, lower azaalkylene-amino, e.g. piperazino, acylamino, e.g. acetylamino or benzoylamino; lower alkylsulfonyl, e.g. methylsulfonyl; sulfamoyl; or phenylsulfonyl. A cycloalkyl group is for example cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, and may be unsubstituted or substituted by one or more, especially one or two, substitutents selected from the group defined above as substituents for aryl, e.g., by lower alkyl, such as methyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy, and further by oxo or fused to a benzo ring, such as in benzcyclopentyl or benzcyclohexyl.
Substituted alkyl is alkyl as last defined, especially lower alkyl, for example methyl; where one or more, especially up to three, substituents may be present, primarily from the group selected from halogen, especially fluorine, amino, N-lower alkylamino, N,N-di-lower alkylamino, N-lower alkanoylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, and phenyl-lower alkoxycarbonyl. Trifluoromethyl is especially useful.
Mono- or disubstituted amino is especially amino substituted by one or two radicals selected independently of one another from lower alkyl, such as methyl; hydroxy-lower alkyl, such as 2-hydroxyethyl; lower alkoxy lower alkyl, such as methoxy ethyl; phenyl-lower alkyl, such as benzyl or 2-phenylethyl; lower alkanoyl, such as acetyl; benzoyl; substituted benzoyl, wherein the phenyl radical is especially substituted by one or more, for example one or two, substituents selected from nitro, amino, halogen, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; and phenyl-lower alkoxycarbonyl, wherein the phenyl radical is unsubstituted or especially substituted by one or more, for example one or two, substituents selected from nitro, amino, halogen, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; and is for example N-lower alkylamino, such as N-methylamino, hydroxy-lower alkylamino, such as 2-hydroxyethylamino or 2-hydroxypropyl, lower alkoxy lower alkyl, such as methoxy ethyl, phenyl-lower alkylamino, such as benzylamino, N,N-di-lower alkylamino, N-phenyl-lower alkyl-N-lower alkylamino, N,N-di-lower alkylphenylamino, lower alkanoylamino, such as acetylamino, or a substituent selected from the group comprising benzoylamino and phenyl-lower alkoxycarbonylamino, wherein the phenyl radical in each case is unsubstituted or especially substituted by nitro or amino, or also by halogen, amino, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, carbamoyl or aminocarbonylamino. Disubstituted amino is also lower alkylene-amino, e.g. pyrrolidino, 2-oxopyrrolidino or piperidino; lower oxaalkylene-amino, e.g. morpholino, or lower azaalkylene-amino, e.g. piperazino or N-substituted piperazino, such as N-methylpiperazino or N-methoxycarbonylpiperazino.
Halogen is especially fluorine, chlorine, bromine, or iodine, especially fluorine, chlorine, or bromine.
Etherified hydroxy is especially C8-C20alkyloxy, such as n-decyloxy, lower alkoxy, such as methoxy, ethoxy, isopropyloxy, or tert-butyloxy, phenyl-lower alkoxy, such as benzyloxy, phenyloxy, halogen-lower alkoxy, such as trifluoromethoxy, 2,2,2-trifIuoroethoxy or 1,1,2,2-tetrafluoroethoxy, or lower alkoxy which is substituted by mono- or bicyclic heteroaryl comprising one or two nitrogen atoms, for example lower alkoxy which is substituted by imidazolyl, such as 1H-imidazol-1-yl, pyrrolyl, benzimidazolyl, such as 1-benzimidazolyl, pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, isoquinolinyl, especially 3-isoquinolinyl, quinolinyl, indolyl or thiazolyl.
Esterified hydroxy is especially lower alkanoyloxy, benzoyloxy, lower alkoxycarbonyloxy, such as tert-butoxycarbonyloxy, or phenyl-lower alkoxycarbonyloxy, such as benzyloxycarbonyloxy.
Esterified carboxy is especially lower alkoxycarbonyl, such as tert-butoxycarbonyl, iso-propoxycarbonyl, methoxycarbonyl or ethoxycarbonyl, phenyl-lower alkoxycarbonyl, or phenyloxycarbonyl.
Alkanoyl is primarily alkylcarbonyl, especially lower alkanoyl, e.g. acetyl. N-Mono- or Ν,Ν-disubstituted carbamoyl is especially substituted by one or two substituents independently selected from lower alkyl, phenyl-lower alkyl and hydroxy-lower alkyl, or lower alkylene, oxa-lower alkylene or aza-lower alkylene optionally substituted at the terminal nitrogen atom. A mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted, refers to a heterocyclic moiety that is unsaturated in the ring binding the heteroaryl radical to the rest of the molecule in formula I and is for example a ring, where in the binding ring, but optionally also in any annealed ring, at least one carbon atom is replaced by a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; where the binding ring for example has five to twelve, e.g., five or six ring atoms; and which may be unsubstituted or substituted by one or more, especially one or two, substitutents selected from the group defined above as substitutents for aryl, most for example by lower alkyl, such as methyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy. For example the mono-or bicyclic heteroaryl group is selected from 2H-pyrrolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, purinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinnolinyl, pteridinyl, indolizinyl, 3H-indolyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, furazanyl, benzo[d]pyrazolyl, thienyl and furanyl. For example the mono- or bicyclic heteroaryl group is selected from the group consisting of pyrrolyl, imidazolyl, such as 1H-imidazol-1-yl, benzimidazolyl, such as 1-benzimidazolyl, indazolyl, especially 5-indazolyl, pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, isoquinolinyl, especially 3-isoquinolinyl, quinolinyl, especially 4- or 8-quinolinyl, indolyl, especially 3-indolyl, thiazolyl, benzo[d]pyrazolyl, thienyl, and furanyl. In one exemplary embodiment of the invention the pyridyl radical is substituted by hydroxy in ortho position to the nitrogen atom and hence exists at least partially in the form of the corresponding tautomer which is pyridin-(1H)2-one. In another exemplary embodiment, the pyrimidinyl radical is substituted by hydroxy both in position 2 and 4 and hence exists in several tautomeric forms, e.g. as pyrimidine-(1H, 3H)2,4-dione.
Heterocyclyl is especially a five, six or seven-membered heterocyclic system with one or two heteroatoms selected from the group comprising nitrogen, oxygen, and sulfur, which may be unsaturated or wholly or partly saturated, and is unsubstituted or substituted especially by lower alkyl, such as methyl, phenyl-lower alkyl, such as benzyl, oxo, or heteroaryl, such as 2-piperazinyl; heterocyclyl is especially 2- or 3-pyrrolidinyl, 2-oxo-5-pyrrolidinyl, piperidinyl, N-benzyl-4-piperidinyl, N-lower alkyl-4-piperidinyl, N-lower alkyl-piperazinyl, morpholinyl, e.g. 2- or 3-morpholinyl, 2-oxo-1H-azepin-3-yl, 2-tetrahydrofuranyl, or 2-methyl-1,3-dioxolan-2-yl.
Salts are especially the pharmaceutically acceptable salts of compounds of formula I. Such salts are formed, for example, as acid addition salts, for example with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom, especially the pharmaceutically acceptable salts. Suitable inorganic acids include, but are not limited to, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthaIene-disulfonic acid, 2-, 3- or 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.
One useful salt of nilotinib is nilotinib hydrochloride monohydrate, or 4-Methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluromethyl)phenyl]-3-[(4-pyridine-3-ylpyrimidin-2-yl)amino]benzamide hydrochloride hydrate. Suitable salts of nilotinib and polymorphs thereof are disclosed in more general in W02007/015870 and W02007/015871.
As used herein the term "pharmaceutical composition" means, for example, a mixture containing a specified amount of a therapeutic compound, e.g. a therapeutically effective amount, of a therapeutic compound in a pharmaceutically acceptable carrier to be administered to a mammal, e.g., a human in order to treat kinase dependent diseases.
As used herein the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.
The concentration of therapeutic compound in the pharmaceutical composition is present in an amount, e.g. in a therapeutically effective amount, which will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to one of ordinary skill in the art. Furthermore, it is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular recipient, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions. The therapeutic compound may be administered once, or may be divided into a number of smaller doses to be administered at varying intervals of time. Thus, an appropriate amount, e.g. an appropriate therapeutically effective amount, is known to one of ordinary skill in the art.
For example, the dose of the therapeutic compound will be in the range from about 0.1 to about 100 mg per kilogram body weight of the recipient per day. Alternatively lower doses may be given, for example doses of 0.5 to 100 mg; 0.5 to 50 mg; or 0.5 to 20 mg per kilogram body weight per day. The effective dosage range of the pharmaceutically acceptable salts may be calculated based on the weight of the active moiety to be delivered. If the salt exhibits activity itself, the effective dosage may be estimated as above using the weight of the salt, or by other means known to those skilled in the art.
As used herein the term "immediate-release" refers to the rapid release of the majority of the therapeutic compound, e.g., greater than about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, or about 90% within a relatively short time, e.g., within 1 hour, 40 minutes, 30 minutes or 20 minutes after oral ingestion. Particularly useful conditions for immediate-release are release of at least or equal to about 80% of the therapeutic compound within thirty minutes after oral ingestion. The particular immediate-release conditions for a specific therapeutic compound will be recognized or known by one of ordinary skill in the art.
As used herein the term "lag time" refers to period of time the majority of the therapeutic compound is delayed from being released after oral ingestion.
As used herein the term “excipient” refers to a pharmaceutically acceptable ingredient that is commonly used in the pharmaceutical technology for preparing granule and/or solid oral dosage formulations. Examples of categories of excipients include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers and diluents. One of ordinary skill in the art may select one or more of the aforementioned excipients with respect to the particular desired properties of the granule and/or solid oral dosage form by routine experimentation and without any undue burden. The amount of each excipient used may vary within ranges conventional in the art. The following references which are all hereby incorporated by reference disclose techniques and excipients used to formulate oral dosage forms. See The Handbook of Pharmaceutical Excipients, 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2000).
In an exemplary embodiment of the present invention, the invented solid dosage forms of nilotinib are prepared by roller compacting nilotinib tablet cores and film-coating the nilotinib tablet cores with a functional polymer, wherein disintegration of said solid dosage form is delayed by 4-15 minutes.
The present invention also provides a method of increasing bioavailability by administering the composition or the pharmaceutical composition of the invention, respectively, to an animal or to a patient, wherein the increased bioavailability is determined by comparing the Cmax value or the AUC value of the composition or the pharmaceutical composition of the invention with the composition disclosed in the present invention. Preferably the method increases bioavailability of a drug in administered animal or patient by least 1.3 fold, preferably at least two fold, even more preferably by at least three fold.
In one preferred embodiment of the method, the composition or the pharmaceutical composition of the invention, respectively, comprises 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-A/-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide and has comparable bioavailability when compared with 4-methyl-3-[[4-(3-pyridinyI)-2-pyrimidinyl]amino]-/\/-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide in the marketed, commercially available Tasigna ™ hard-gelatin capsule manufactured by Novartis. Comparable is defined as 90% Cl of Cmax and AUC within the range of 0.8 and 1.25 when expressed as ratio between the tested (invention formulation) and reference (Tasigna ™ capsule formulation) for Cmax and AUC.
Bioavailability can be measured by skilled artisan by conventional methods. For example, tablets, capsules, liquids, powders, etc., are given orally to humans or animals and blood levels are measured.
The composition or the pharmaceutical composition according to the invention may also comprise one or more binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, effervescent agents and other excipients. Such excipients are known in the art. Examples of filling agents are lactose monohydrate, lactose anhydrous, microcrystalline cellulose, such as Avicel® PH101 and Avicel® PH102, microcrystalline cellulose and silicified microcrystalline cellulose (ProSolv SMCC®), and various starches; examples of binding agents are various celluloses and cross-linked polyvinylpyrrolidone. Suitable lubricants, including agents that act on the flowability of the powder to be compressed, are colloidal silicon dioxide, such as Aerosil® 200, talc, stearic acid, magnesium stearate, calcium stearate and silica gel. Examples of sweeteners are any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, sucralose, maltitol and acsulfame. Examples of flavoring agents are Magnasweet® (trademark of MAFCO), bubble gum flavor, and fruit flavors, and the like. Suitable diluents include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides and/or mixtures of any of the foregoing. Examples of diluents include microcrystalline cellulose, such as Avicel® PH101 and Avicel® PH1 02; lactose, such as lactose monohydrate, lactose anhydrous, and Pharmatose® DCL21; dibasic calcium phosphate, such as Emcompress®; mannitol; starch; sorbitol; sucrose; and glucose. Examples of effervescent agents are effervescent couples, such as an organic acid and a carbonate or bicarbonate.
Niliotinib exhibits compressibility problem, coupled with high drug loading > 45%, the formulation is also prone to sticking and picking on punches thus requiring high Mg stearate level. The formulation also has friability issues if a suitable binder is not present. To overcome all these challenges, the formulation needs the selected excipients in their optimized amounts.
In one embodiment, the invented core tablets comprise nilotinib in amounts from 30-70 % by weight based on the weight of the tablet, Avicel® PH102 (microcrystalline cellulose) as a filler in the range 20-60 % by weight, HPC EXF as a binder in the range of 2- 6 % by weight, crospovidone as a super disintegrant in the range of 2-14 % by weight, Aerosil as a glidant or flow enhancer with the range of 0.25 to 4 % by weight, Magnesium stearate as an intra-granular(l) component in the range of 0.25-2 % by weight and Magnesium stearate as an extragranular (II) componernt in the range of 0.7-3.5 % by weight based on the weight of the tablet.
In one embodiment, the composition is in an oral solid dosage form. The oral solid dosage form includes tablets, pills, capsules, powders. The oral liquid dosage form includes solutions and suspensions. In one embodiment, the solid dosage form is a polymeric film coated tablet.
Different classes of polymers that may be used to delay the initial release from the tablet are selected from: hydroxypropyl cellulose, hydroxy propyl methyl cellulose, hydroxy propyl ethyl cellulose, ethyl cellulose, shellac, polyvinyl pyrrolidone (e.g K30, K90), polyvinyl acetate,Kollidon VA 64 {Copovidone or (Polyvinyl acetate 40% and polyvinyl pyrrolidone 60%), Kollidon SR (Polyvinyl acetate 80% and polyvinyl pyrrolidone20%), methacrylic acid (polymers and graft co polymers), carbomer polymers (e.g Carbopol 971P NF, Carbopol 974P NF), veegum, glyceryl behenate / di behenate (Compritol®, hydroxy propyl methyl cellulose acetate succinate (HPMC AS) and hydroxy propyl methyl cellulose phthallate (HPMC-P).
In one aspect, the present invention provides a process of making the composition comprising the steps of blending nilotinib and excipients and roller compacting them to form granules. The granules are compressed into tablets or pills. The nilotinib tablet cores are then film coated to various thicknesses with a polymer coating, providing a lag time before disintegration.
The following examples are given to illustrate the present invention. It should be understood, however, that the invention is not to be limited to the specific conditions or details described in the examples below. The following examples are illustrative, but do not serve to limit the scope of the invention described herein. The examples are meant only to suggest a method of practicing the present invention.
Quantities of ingredients, represented by percentage by weight of the pharmaceutical composition, used in each example are set forth in the respective tables located after the respective descriptions. For a capsule, when calculating the weight of the pharmaceutical composition (i.e. the capsule fill weight), the weight of the capsule shell itself is excluded from the calculation.
Example 1 Nilotinib Tablet Core
One example of a nilotinib tablet core (Formulation A) is summarized in Table 1. The nilotinib tablet cores were prepared by roller compaction. Compared to a commercially available nilotinib capsule formulation developed using a wet granulation technique, the invented nilotinib tablet cores prepared by roller compaction consistently provides nilotinib tablet cores exhibiting excellent compression characteristics, including but not limited to a 6-10 kp compression window, tablet cores having low friability, fast disintegration times (1-2 minutes) and tablet cores that can be compressed at a high speeds.
Table 1. Nilotinib Tablet Core (Formu ation A)
Unit dosages of 50mg and 100mg were also manufactured from nilotinib tablet core formulation A. The unit dosages were prepared in proportion to the 200mg, 300mg and 400mg unit doses.
Example 2 Nilotinib Tablet Core
Another example of a nilotinib tablet core (Formulation B) is summarized in Table 2. The nilotinib tablet cores were prepared by roller compaction. Compared to a commercially available nilotinib capsule formulation developed using a wet granulation technique, the invented nilotinib tablet cores prepared by roller compaction consistently provides nilotinib tablet cores exhibiting excellent compression characteristics, including but not limited to a 6-10 kp compression window, tablet cores having low friability, fast disintegration times (1-2 minutes) and tablet cores that can be compressed at a high speeds.
Table 2. Nilotinib Tablet Core (Formulation B)
Unit dosages of 50mg and 100mg were also manufactured from nilotinib tablet core formulation A. The unit dosages were prepared in proportion to the 200mg, 300mg and 400mg unit doses.
Manufacturing process
Nilotinib was mixed with Aerosil 200 PH, HPC EXF, and Crospovidone. Microcrystalline cellulose was added and the mixture was blended. The blended mixture was then sieved through a #16 to #35 screen. Magnesium stearate (I) was added to the sieved mixture and was again blended to distribute Magnesium stearate. This mixture was roller compacted using a compaction force of 15-40 kN on a 50mm roller compactor. The ribbons were then milled through a sieve (range 10-18 US mesh size). Milled granules were blended with magnesium stearate (II) to distribute magnesium stearate.
Dissolution
Two step dissolution conditions were used for the following nilotinib table cores (formulation A and B), wet granulated nilotinib formulation capsule, and nilotinib capsule formulation: 37°C; Step 1, 0-60 minutes 500ml pH 2 buffer, Step 2, > 60 minutes 1000ml pH 6.8 buffer; Paddle at 75rpm.
The invented nilotinib tablet cores prepared from roller compacted nilotinib formulations A and B exhibit fast disintegration times (< 2min), irrespective of the compression force and hardness of the tablet, as compared to the commercially available nilotinib capsule formulation (Figure 1). For the invented nilotinib tablet cores to be bio-equivalent with the commercial nilotinib capsule formulation, a dissolution lag time was required to delay the disintegration time of the nilotinib tablet cores. This lag time (4-12 minutes) is achieved using a functional polymer based coating over core tablets, preventing the tablets from disintegrating before the lag time.
Film Coated Nilotinib Tablet Cores
The composition of film coated nilotinib tablets is summarized in Table 3. Film coated nilotinib tablet cores were prepared from nilotinib formulations A and B.
Table 3. Composition of film coated nilotinib tablets (Formulations A and B)
Film coating thickness can be varied based upon weight gain of nilotinib tablet cores. An increased disintegration time is observed with corresponding increase in the weight gain of film coating.
The opadry white, yellow and red impart a pale yellow color to the tablets and are only present for aesthetic value, whereas HPMC E50 is the functional polymer that delays the disintegration time.
The functional coating provides a unique dissolution profile with the following characterstics: 1) For 7% functional coating weight gain the following dissolution profile in 900ml pH 2.0 is observed » 0 - 8% dissolved at 5 minutes • 20-30% dissolved at 10 minutes • 35 - 45% dissolved at 15 minutes • 45 - 60% dissolved in 30 minutes 2) For 10% functional coating weight gain the following dissolution profile in 900ml pH 2.0 is observed • 0 - 5% dissolved at 5 minutes • 10 - 25% dissolved at 10 minutes • 25 - 45% dissolved at 15 minutes • 45 - 55% dissolved in 30 minutes 3) For 13% functional coating weight gain the following dissolution profile in 900ml pH 2.0 is observed • 0 % dissolved at 5 minutes • 2 - 10% dissolved at 10 minutes • 20 - 35% dissolved at 15 minutes • 45 - 55% dissolved in 30 minutes
Table 4: Dissolution profiles of different weight % functional coating weight gain at pH 2.0
Human PK results
In the first study the tablet formulation without any functional coating were tested in humans. The results are as given below
It can be seen above that none of the formulations was bioequivalent to the reference marketed capsule formulation, whereas the all dosage forms exhibited a higher Cmax as compared with the reference marketed capsule formulation, whereas the ratio of Cmax is disproportionally higher than the ratio of AUC.
In another study, 300mg RC variants with 10% film coating were tested for BE and the results are as shown below . PK results of the variants BB ( RC1 with 10% film coating) and Variant CC ( RC2 with 10% film coating).
Bioequivalence was demonstrated for RC1 and RC2 variants with functional film coating for 300mg strength.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.
Claims (17)
- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:1. A solid dosage form in the form of a tablet comprising: (i) a core comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H- imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide (nilotinib) or a pharmaceutically acceptable salt thereof and excipients; and (ii) at least one polymeric coating over the nilotinib core, wherein the polymeric coating comprises a polymer which is hydroxypropylmethyl cellulose, and wherein the film coating is 7-13 % of the solid dosage form.
- 2. The solid dosage form according to claim 1, wherein the film coating is 7-10 % of the solid dosage core.
- 3. The solid dosage form according to claim 1, wherein the film coating is 10-13 % of the solid dosage core.
- 4. The solid dosage form according to any one of claims 1-3, wherein disintegration of said solid dosage form is delayed by 4-15 minutes.
- 5. The solid dosage form of any one of claims 1 -4, wherein 0-8 % of the solid dosage form is dissolved after 5 minutes at pH 2.0.
- 6. The solid dosage form of any one of claims 1 -5, wherein 45-60 % of the solid dosage form is dissolved after 30 minutes at pH 2.0.
- 7. The solid dosage form of any one of the preceding claims, having a fasted state bioavailabilty equivalent to a hard gelatin capsule, wherein its Cmax and AUC are in the bioequivalent range when compared with capsules comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof.
- 8. The solid dosage form of any one of the preceding claims wherein the pharmaceutically acceptable salt of nilotinib is nilotinib hydrochloride monohydrate.
- 9. The solid dosage form of any one of the preceding claims wherein the nilotinib core comprises nilotinib in amounts from 30-70 % by weight, based on the weight of the tablet Avicel® PH102 (microcrystalline cellulose) as a filler in the range 20-60 % by weight, HPC EXF as a binder in the range of 2- 6 % by weight, crospovidone as a super disintegrant in the range of 2-14 % by weight, aerosil as a glidant or flow enhancer with the range of 0.25 to 4 % by weight, magnesium stearate as an intra-granular(l) component in the range of 0.25-2 % by weight and magnesium stearate as an extragranular (II) component in the range of 0.7-3.5 % by weight based on the weight of the tablet.
- 10. A film coated nilotinib tablet consisting of i) 43.60 %AMN107 HCI; ii) 35.61 % Avicel PH102; iii) 2.73 % HPC EXF; iv) 5.45 % Crospovidone; v) 0.91% Aerosil 200; vi) 2.61 % Mg stearate; vii) 1.52 % hydroxy propyl methyl cellulose E50; viii) 7.32% Opadry White; ix) 0.24 % Opadry Yellow; x) 0.01% Opadry Red; wherein the % values refer to the % by weight of the excipients listed under i) to x).
- 11. A film coated nilotinib tablet consisting of i) 43.57% AMN107 HCI; ii) 31.95% Avicel PH102; iii) 2.73 % HPC EXF; iv) 9.08 % Crospovidone; v) 0.91% Aerosil 200; vi) 2.61 % Mg stearate; vii) 0.48 % PEG 4000; viii) 3.23 % hydroxy propyl methyl cellulose E50; ix) 5.20 % Opadry White; x) 0.17 % Opadry Yellow; xi) 0.08 % Opadry Red. wherein the % values refer to the % by weight of the excipients listed under i) to xi).
- 12. A method for preparing a solid dosage form comprising amorphous 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof comprising the steps of: (i) roller compacting a core comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]- N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and excipients; and (ii) coating said core with at least one polymer.
- 13. The method of claim 12 wherein the solid dosage form is a tablet.
- 14. The method of claim 13 wherein the polymer is hydroxypropylmethyl cellulose.
- 15. The method of claim 14 wherein disintegration of said solid dosage form is delayed by 4-15 minutes.
- 16. The method of any one of claims 12-15, wherein the core comprises nilotinib in amounts from 30-70 % by weight based on the weight of the tablet, Avicel® PH102 (microcrystalline cellulose) as a filler in the range 20-60 % by weight, HPC EXF as a binder in the range of 2- 6 % by weight, crospovidone as a super disintegrant in the range of 2-14 % by weight, Aerosil as a glidant or flow enhancer with the range of 0.25 to 4 % by weight, Magnesium stearate as an intra- granular(l) component in the range of 0.25-2 % by weight and Magnesium stearate as an extra-granular (II) component in the range of 0.7-3.5 % by weight based on the weight of the tablet.
- 17. The method of any one of claims 12-16, wherein the pharmaceutically acceptable salt of 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1 -yl)-3-(trifluoromethyl)phenyl] benzamide is the hydrochloride salt.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US201161559281P | 2011-11-14 | 2011-11-14 | |
US61/559,281 | 2011-11-14 | ||
PCT/US2012/064610 WO2013074432A1 (en) | 2011-11-14 | 2012-11-12 | Immediate release 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-n-[5-(4-methyl- 1h-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide formulation |
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Publication Number | Publication Date |
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AU2012339829A1 AU2012339829A1 (en) | 2014-05-29 |
AU2012339829B2 AU2012339829B2 (en) | 2016-05-12 |
AU2012339829B8 true AU2012339829B8 (en) | 2016-06-09 |
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