NZ623844B2 - 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

Abstract

Provided is a solid dosage form in the form of a film coated tablet that comprises: (i) a core comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-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 core, wherein the polymeric coating comprises hydroxypropylmethyl cellulose, and the coating is 7-13% of the dosage form. Also provided is a method for preparing a solid dosage form comprising amorphous 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino-N-[5-(4-methyl-1H-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-1H-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. and (ii) at least one polymeric coating over the core, wherein the polymeric coating comprises hydroxypropylmethyl cellulose, and the coating is 7-13% of the dosage form. Also provided is a method for preparing a solid dosage form comprising amorphous 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino-N-[5-(4-methyl-1H-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-1H-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.

Description

W0 2013/074432 PCT/U52012/064610 IMMEDIATE RELEASE 4-Meth I 1H-imidazolyl2(trifluoromethyliphenyl] benzamide FORMULATION Field of the invention The present invention relates to a pharmaceutical composition sing a therapeutic compound of niiotinib (Formula l). in particular, the present invention is ed to a pharmaceutical composition that comprises a nilotinibtablet core and that r comprises at least one polymeric g over the nilotinib core, providing a rapidly disintegrating tablet with a lag time, as compared to an ed tablet formulation.

Background of the invention Niiotinib is 4~Methyl[[4—(3-pyndinyl)—2—pyrimidinyl]amino]-N-[5-(4-methyl—1H~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 (l'K) activity of Bcr—Abl. Examples of conditions that may be treated by such therapeutic compounds include, but are not limited to, chronic myeloid leukemia gastrointestinal stromal tumors.

There is a need to ate n'ilotinib and the other therapeutic compounds hereinafter disclosed into pharmaceutical itions, especially solid oral dosage forms, such that the therapeutic benefits of the nds may be delivered to a patient in need thereof. One problem to providing Such compositions including nilotinib is the chemical properties of nilotinib, since nilotinib and its salts are poorly water soluble compounds and are lt 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 bioavailabiiity of nilotinib.

Compared to a fasted state, nilotinib ic exposure, as reflected by AUC and CW, ses markedly when the unit dosage is given shortly after food is ingested, leading to potential adverse effects in patients.

Summary of the Invention In one aspect, there is ed a solid dosage form in the form of a film coated tablet comprising: (i) a core comprising 4-MethyI[[4~(3-pyridinyl)—2-pyrimidinyl]amino]-N-[5-(4—methyI-1 H- imidazolyl)-3—(trifluoromethyl)phenyl] benzamide (nilotinib) or a pharmaceuticaliy acceptable salt f and ents; and (ii) at least one poiymeric coating over the nilotinib core, wherein the polymeric coating comprises a r which is hydroxypropylmethyi cellulose, and wherein the film coating is 7- 13 % of the solid dosage form.

In a further aspect, there is provided a film coated niiotinib tablet consisting of i) 43.60 % nilotinib hydrochloride; ii) 35.61 % microcrystalline cellulose (Avicel PH102); iii) 2.73 % ypropyl cellulose (HPC EXF); iv) 5.45 % crospovidone; v) 0.91% colloidal silicon dioxide (Aerosil 200); vi) 2.61 % Mg stearate; vii) 1.52 % hydroxy propyl methyl celiuiose E50; viii) 7.32% white colorant; ix) 0.24 % yeIlow nt; x) 0.01% red colorant; wherein the % values refer to the % by weight of the excipients listed under i) to x).

In a further aspect, there is provided a film coated nilotinib tablet consisting of i) 43.57 % Nilotinib Hydrochioride; ii) 31.95 % microcrystalline cellulose (Avicel® PH102); iii) 2.73 % hydroxypropyicellulose (HPC EXF); iv) 9.08 % crospovidone; [followed by page 2a] v) 0.91% colloidal silicon dioxide (Aerosil 200); vi) 2.61 % Mg te; vii) 0.48 % PEG 4000; viii) 3.23 % hydroxy propyl methyl cellulose E50; ix) 5.20 % white colorant; x) 0.17 % yellow colorant; xi) 0.08 % red colorant. wherein the % values refer to the % by weight of the excipients listed under i) to xi).

In a further aspect, there is ed a method for preparing a solid dosage form comprising amorphous 4—Methyi[i4—(3-pyridinyl)—2-pyrimidinyl]amino]-N-[5-(4-methyI-1H- imidazol-1~yl)—3~(trifluoromethyl)phenyi] ide or a pharmaceutically acceptable salt thereof comprising the steps of: (i) roller compacting a core comprising 4-Methyi-3—[[4-(3-pyridinyl)pyrimidinyl]aminc}- N-[5-(4-methyl-1H-imidazolyl)—3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and excipients; and (ii) coating said core with at least one polymer.

The present ion provides a solid dosage form comprising: (i) a core comprising 4— Methyl-3—[[4-(3-pyridinyl)pyrimidinyl]amino]—N-[5—(4—methyl—1 H-imidazol—1 - (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 s.

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—methyI—1H-imidazol-t-yl) (trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and excipients; and (ii) at least one r, said polymer coating said core, wherein disintegration of said soiid dosage form is delayed by 4-15 minutes, said solid dosage form having a fasted state [followed by page 2b] bioavailability equivalent to a hard-gelatin capsule comprising 4-Methyl[[4-(3- pyridinyl)pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol—1-yl)-3—(trifluoromethyl)phenyl] benzamide.

The present invention also provides a solid dosage form comprising: (i) a core comprising 4wMethyl—3-[[4-(3—pyridinyl)—2~pyrimidinyl]amino]—N-[5-(4-methyl-1H-imidazol—i-yl) (trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and excipients; and (ii) at least one polymer, said polymer coating said core, n 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[[4-(3—pyridinyl) pyrimidinyl]amino]—N-[5-(4-methyl—i H-imidazol-i —yl)(trifluoromethyl)phenyl] benzamide.

Brief Description of the Drawings Figure 1 summarizes dissolution rates for nilotinib s (wet granulated and roller compacted) as compared to a nib capsule.

Figure 2 summarizes dissolution rates for film coated nilotinib tablets (7-10 % film g) at pH 2.0.

Figure 3 summarizes dissolution rates for film coated nib tablets (10-13 % film coating) at pH 2.0. followed b a e 3 W0 2013/074432 PCT/USZOIZ/064610 Figure 4 summarizes dissolution rates for film coated nilotinib tablets prepared by roller compaction (10% film coating) as ed to uncoated nilotinib tablets prepared by wet granulation at pH 2.0.

Figure 5 summarizes a comparison of mean nilotinib concentration versus time es for different nilotinib solid dosage forms.

Detailed Description of the invention The present invention provides crystalline pharmaceutical compositions of nib or a pharmaceutically acceptable salt f 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-1H-imidazolyl)(trifl‘uoromethyl)phenyl] benzamide of formula l: nib is a member of compounds of formula (ll) PCT/U32012/064610 \ NAM-i / R4 N rm (I!) wherein R1 represents en, lower alkyl, lower alkoxy-lower alkyi, y—lower alkyl, carboxy-Iower aikyl, lower alkoxycarbonyl—lower alkyi, or phenyl—lower alkyl; R2 represents hydrogen, lower alkyl, optionally substituted by one or more identical or different radicals R3, ikyl, benzcycloaikyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group sing 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 N,N—disubstituted carbamoyl, amino, mono- or disubstituted amino, cycioalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryi 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 poiysubstituted; or wherein R1 and R2 together represent aikyiene with tour, five or six carbon atoms optionally mono— or disubstituted by lower aikyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower aikoxy, amino, mono— or disubstituted amino, oxo, pyridyi, pyrazinyl or pyrimidinyi; benzaikylene with four or five carbon atoms; oxaaikylene with one oxygen and three or four carbon atoms; or azaalkylene with one en and three or four carbon atoms wherein nitrogen is unsubstituted or Substituted by lower alkyi, phenyI-lower alkyi, lower alkoxycarbonyl—lower alkyl, carboxy—lower alkyl, carbamoyl—lower alkyl, - or N,N-disubstituted carbamoyi—lower aikyl, cycioalkyl, lower alkoxycarbonyl, y, phenyl, substituted phenyl, pyridinyl, pyrimidinyt, or nyl; R4 represents hydrogen, lower alkyi, or halogen; PCT/U52012/064610 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 le 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 e in the (R)- or (S)-configuration. The compounds may thus be present as mixtures of isomers or as pure s, for example as enantiomer—pure diastereomers. Also contemplated within the present invention is the use of any possible tautomers of the compounds of formula l.

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 ed; for example, lower alkyl is butyl, such as n—butyl, tyl, isobutyl, tart—butyl, propyl, such as n—propyi or isopropyl, ethyl or methyl. For e lower alkyl is methyl, propyl or tart—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, ally phenyl, naphthyl, ydronaphthyl, tluorenyl or phenanthrenyl, and is unsubstituted or substituted by one or more, for example up to three, ally one or two substituents, especially selected from amino, mono- or tituted 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 N,N—disubstituted carbamoyl, o, guanidino, ureido, to, sulfo, lower alkylthio, phenylthio, —lower alkylthio, lower alkylphenylthio, lower alkylsulfinyl, sulfinyl, phenyl—lower alkylsulfinyl, lower alkylphenylsultinyi, lower W0 2013/074432 PCT/U52012/064610 alkylsulfonyl, phenylsulfonyi, phenyl-lower alkylsulfonyl, lower alkylphenylsulfonyl, halogen- lower alkylmercapto, n-lower alkylsulfonyl, such as especially romethanesulfonyl, dihydroxybora (—B(OH)2), heterocyclyl, a mono- or bicyclic heteroaryl group and lower alkyiene dioxy bound at adjacent C-atoms of the ring, such as methylene dioxy. Aryl is for example phenyi, naphthyl or tetrahydronaphthyl, which in each case is either tituted 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. trifiuoromethyl, 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. ymethyl or 2-hydroxy-2—propyl; lower alkoxy~lower alkyl; e.g. methoxymethyl or 2—methoxyethyl; lower alkoxycarbonyl-lower alkyl, e.g. methoxycarbonyimethyl; lower alkynyl, such as 1—propynyl; esterified carboxy, especially lower alkoxycarbonyl, e.g. methoxycarbonyl, n—propoxy carbonyl or iso—propoxy carbonyl; N—mono— substituted carbamoy|,_ in particular carbamoyl monosubstituted by lower alkyl, e.g. methyl, n— propyl or iso-propyl; amino; lower mino, e.g. methylamino; di—lower mino, e.g. dimethylamino or diethylamino; lower alkylene-amino, e.g. pyrrolidino or dino; lower oxaalkylene-amino, e.g. morpholino, lower azaalkyiene-amino, e.g. piperazino, acylamino, e.g. acetylamino or benzoylamino; lower alkylsulfonyl, e.g. methylsulfonyl; sulfamoyl; or phenylsulfonyl.

A cycloalkyl group is for example ropyl, 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 tuents for aryl, e.g., by lower alkyl, such as methyl, lower alkoxy, such as methoxy or , or hydroxy, and further by 0x0 or fused to a benzo ring, such as in benzcyclopentyl or benzcyclohexyl.

Substituted alkyl is alkyl as last defined, especially lower alkyl, for example ; 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 ally amino substituted by one or two radicals selected independently of one another from lower alkyl, such as methyl; hydroxy-lower alkyl, PCT/U52012/064610 such as roxyethyl; lower alkoxy lower alkyl, such as methoxy ethyl; phenyl-lower alkyl, such as benzyl or 2-phenylethyl; lower alkanoyl, such as ; 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, —lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; and is for example N—lower alkylamino, such as N—m'ethylamino, 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, yl—Iower 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, r 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. pyrroliclino, 2-oxopyrrolidino or 'piperidino; lower oxaalkylene-amino, e.g. morpholino, or lower ylene-amino, eg. piperazinc or N~substituted piperazino, such as N- methylpiperazino or N-methoxycarbonylpiperazino.

Halogen is ally fluorine, chlorine, e, or iodine, especially fluorine, chlorine, or bromine.

Etherified hydroxy is especially CB—Czoalkyloxy, such as n—decyloxy, lower alkoxy, such as y, ethoxy, isopropyloxy, or utyloxy, phenyl~lower alkoxy, such as benzyloxy, phenyloxy, n-lower alkoxy, such as trifluoromethoxy, 2,2,2-tritiuoroethoxy or 1,1 2,2- tetrafluoroethoxy, or lower alkoxy which is substituted by mono- or bicyclic heteroaryl comprising one or two en 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, inyl, indolyl or thiazolylt PCT/U$2012/064610 fied hydroxy is especially lower alkanoyloxy, benzoyloxy, lower alkoxycarbonyloxy, such as tert—butoxycarbonyloxy, or phenyl-Iower alkoxycarbonyloxy, such as benzyloxycarbonyioxy.

Esterified carboxy is especially lower alkoxycarbonyl, such as tert—butoxycarbonyl, iso- propoxycarbonyl, methoxycarbonyl or ethoxycarbonyl, phenyl—lower alkoxycarbonyl, or oxycarbonyl.

Aikanoyl is primarily alkylcarbonyl, especially lower alkanoyl, e.g. acetyl.

N—Mono— or substituted oyl 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 aryl 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 l and is for example a ring, where in the g ring, but optionally also in any annealed ring, at least one carbon atom is replaced by a heteroatom selected from the group consisting otnitrogen, 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 e 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, benzimidazolyi, lyl, indazolyl, purinyl, pyridyl, pyrazinyl, pyrimidinyl, zinyl, 4H—quinolizinyl, isoquinolyl, yl, phthalazinyl, yridinyl, quinoxalyl, quinazolinyl, quinnolinyl, pteridinyl, zinyl, olyi, indolyl, isoindolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, furazanyl, benzoldjlpyrazolyl, thienyl and furanyl. For example the mono- or bicyclic heteroaryl group is selected from the group consisting of pyrrolyl, imidazolyt, such as 1H— imidazolyi, benzimidazolyi, such as 1-benzimidazolyl, indazolyl, especially 5-indazolyl, pyridyl, especialiy 2-, 3— or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, isoquinoiinyl, especially 3-isoquinolinyl, quinolinyl, especially 4- or 8-quinolinyl, indoiyl, ally lyl, thiazolyl, benzoldlpyrazolyl, thienyl, and furanyl. in one exemplary _ 3 _ PCT/US2012/O64610 embodiment of the invention the pyridyl radical is substituted by hydroXy in ortho position to the en atom and hence exists at least partially in the form of the corresponding er which is pyridin—(1l-l)2-one. in another exemplary embodiment, the dinyl 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.

Heterocyciyl is especially a five, six or seven-membered heterocyclic system with one or two heteroatoms selected from the group comprising en, oxygen, and sulfur, which may be unsaturated or wholly or partly saturated, and is unsubstituted or tuted especially by lower alkyl, such as methyl, phenyl—lower alkyl, such as benzyl, oxo, or heteroaryl, such as 2- piperaz-inyl; heterocyclyl is especially 2- or 3—pyrrolidinyl, 5-pyrrolidinyl, piperidinyl, N- benzyl—4—piperidinyl, N—lower alkyl~4—piperidinyl, N—Iower alkyl—piperazinyl, morpholinyl, e.g. 2— or 3—morpholinyl, 2-oxo—1H-azepin—3—yl, 2~tetrahydroturanyl, or 2—methyl~1,3—dioxolan—2—yl.

Salts are especially the pharmaceutically able salts of compounds of formula l.

Such salts are formed, for example, as acid addition salts, for e with organic or inorganic acids, from compounds of formula l 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 ic acids, for example acetic acid, propionic acid, octanoic acid, ic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, maiic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, maleic 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, benzenesultonic acid, 2- naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2-, 3- or 4-methylbenzenesuifonic acid, sulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexyisulfamic acid, N- -, N-ethyl- or N-propyI-suifamic acid, or other organic protonic acids, such as ascorbic acid.

One useful salt of nilotinib is nilotinib hloride monohydrate, or 4Methyl-N-[3—(4- methyl-1 H-imidazol—1~yl)-5~(trifluromethyl)phenyl}-3—[(4-pyridine—3—ylpyrimidin—2- - 9 _ W0 2013/074432 PCT/U82012/064610 yl)aminoibenzamide hydrochloride hydrate. Suitable salts of nilotinib and polymorphs thereof are disclosed in more general in WOZOO7/015870 and I01587t.

As used herein the term "pharmaceutical composition" means, for example, a mixture containing a specified amount of a therapeutic compound, eg a therapeutically effective amount, of a therapeutic compound in a ceutically acceptable carrier to be administered to a mammal, e.g., a human in order to treat kinase ent 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 s 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, eg. 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 ion 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 stration 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 als 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 am body weight of the ent per day. Alternatively lower doses may be given, for e 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 ated 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.

WO 74432 PCT/U52012/064610 As used herein the term "immediate-reiease" refers to the rapid release of the majority of the therapeutic nd, 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 orai ingestion. ularly useful conditions for immediate-release are release of at least or equal to about 80% of the therapeutic compound within thirty s after oral ingestion. The particular immediate—releasa 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 able ingredient that is commonly used in the pharmaceutical technology for preparing granule and/or solid oral dosage formulations. es of categories of excipients include, but are not d to, binders, disintegrants, lubricants, glidants, izers, fillers and ts. 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 e 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, 4‘" edition, Rowe et al., Eds, American Pharmaceuticals Association (2003); and Remington: the Science and Practice ofPharmacy, 20th edition, Gennaro, Ed., Lippincott ms & VWlkins (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 tabiet 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 ion, respectively, to an animal or to a patient, n the increased bioavailability is determined by comparing the Cmax value the AUC value of the composition or the ceutical composition of the invention with the composition disclosed in the present invention. Preferably the method increases bioavailability W0 2013/074432 PCT/U52012/064610 of a drug in administered animal or t 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 ceutical composition of the invention, respectively, comprises yl[l4—(3~pyridinyl)—2— dinyl]amino]~N—[_5-(4—methyl—1 H—imidazol—1~yl)-3—(trifiuoromethyl)phenyl] benzamide and has able bioavailability when compared with 4—methyl—3«{[4-(3-pyridinyl)~2- pyrimidinyllaminol—N—[5—(4—methyl-1H—imidazol-t-yl)—3—(trifluoromethyl)phenyl] benzamide in the ed, commercially available Tasigna TM 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 sed as ratio between the tested (invention formulation) and reference (Tasigna TM capsule formulation) for Cmax and AUC.

Bioavailability can be measured by skilled artisan by conventional s. 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 , lubricating , suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, effervescent agents and other excipients. Such ents 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 fied 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 dal 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 ng agents are Magnasweet® (trademark of O), 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® PHl 02; lactose, such lactose monohydrate, e anhydrous, and Pharmatose® DCL2’l; dibasic calcium phosphate, PCT/USZOIZ/064610 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 m, coupled with high drug loading > 45%, the formulation is also prone to sticking and picking on s thus requiring high Mg stearate level. The formulation also has friability issues if a suitable binder is not present. To overcome all these nges, the formulation needs the selected excipients in their optimized amounts. in one embodiment, the invented core tablets comprise nib in amounts from 30~70 % by weight based on the weight ofthe tablet, Avicel® PH102 (mlcrocrystalline 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 glldant 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 025-2 % by weight and Magnesium te as an extra- granular (ll) 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 ons and suspensions- in one embodiment, the solid dosage form is a polymeric film coated tablet.

Different classes of rs that may be used to delay the initial release from the tablet selected from: yprcpyl cellulose, hydroxy propyl methyi cellulose, hydroxy propyi ethyl ose, ethyl cellulose, shellac, polyvinyl pyrrolldone (eg K30, K90), polyvinyl acetate,Kollidon VA 64 {Copovidone or (Polyvinyi acetate 40% and polyvinyl pyrrolidone 60%}, Kollidon SR (Polyvinyl acetate 80% and polyvinyi pyrroiidone20%) , methacrylic acid (polymers and graft co polymers), carbomer rs (eg Carbopol 971 P NF, ol 974P NF), veegum, yl behenate I di behenate (Compritol®, hydroxy propyl methyl cellulose acetate succinate (HPMC AS) and hydroxy propyl methyi cellulose phthallate (HPMC—P). in one aspect, the present invention provides a s of making the composition comprising the steps of blending niiotinib and excipients and rolier compacting them to form granules. The PCT/U52012/064610 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 ing examples are given to illustrate the present invention. it should be understood, r, 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 method of practicing the present invention. ties of ingredients, represented by percentage by weight of the pharmaceutical ition, used in each example are set forth in the tive tables located after the respective descriptions. For a capsule, when calculating the weight of the pharmaceuticai composition (i.e. the capsule fill weight), the weight of the capsule shell itseif is excluded from the ation Example 1 Nilotinib Tablet Core One exampie of a nilotinib tabiet core (Formulation A) is summarized in Table 1. The nilotinib tablet cores were prepared by roller compaction. ed to a commercially available nilotinib capsule formulation developed using a wet granulation technique, the invented nilotinib tablet cores prepared by rolier compaction consistently provides nilotinib tabiet 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.

PCT/U52012/064610 Table 1. Nilotinib Tablet Core Formulation A Component % 200 mg 300mg AMN107 (Nilotinib Hydrochloride) 220.6 330.9 441.2 47 96 Microcrystalline cellulose 359.2 39.04 Hydroxypropylcellulose (HPC EXF) 28.0 3 04 Crospovidone 28.0 42.0 56.0 6.09 Aerosil 200 PH 4.6 6.9 9.2 1.00 Magnesium stearate (l) 4.0 6.0 0.87 Magnesium stearate (ii) 9.2 13.8 18.4 2.00 Core tablet weight . 460.0 690.0 920.0 100.00 Unit dosages of 50mg and 100mg were also manufactured from nilotinib tablet core ation A. The unit dosages were prepared in proportion to the 200mg, 300mg and 400mg unit doses.

Examgle 2 Nilotinib Tablet Core Another example of a nilotinib tablet core lation 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 tently es nilotinib tablet cores exhibiting excellent compression characteristics, including but not limited to a 6-10 kp compression , tablet cores having low inability, fast egration times (1—2 minutes) and tablet cores that can be compressed at a high speeds.

Table 2. Nilotinib Tablet Core (Formulation B) _ 15 - PCT/U52012/064610 Component % 300mg AMN107 (Nilotinib Hydrochloride) 220.6 330.9 441.2 47 96 Microcrystalline cellulose 161 6 242 4 323.2 13 H droY XYProDYlcellulose Crospovidone 1 0.00 l 200 PH 4.6 Magnesium stearate (I) 4.0 6.0 0.87 ium stearate (ll) 9.2 13.8 18.4 2.00 ‘ Core tablet weight 460.0 690.0 920.0 100.00 Unit s of 50mg and 100mg were also manufactured from nilotinib tablet core formulation A. The unit dosages were ed 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 (l) was added to the sieved mixture and was again blended to bute 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 (ll) to distribute magnesium stearate.

Dissolution —16- PCT/U52012/064610 Two step dissolution conditions were used for the following nilotinib table cores (formulation A and B), wet granulated nilotinib formulation capsule, and nilotin'ib capsule ation: 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 nib tablet cores ed 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 capsuie formulation, a dissolution lag time was required to delay the egration 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 nib TabletCores The composition of film coated nilotinib tablets is summarized in Table 3. Film coated nilotinib tablet cores were prepared from nib formulations A and B.

PCT/U52012/064610 Table 3. Composition of film coated nilotinib tablets Formulations A and B) RC Formulation A RC Formulation B Composition % ' m 9: AMN107 H01 4357 330.90 Avicel PH1 02 31.95 242.70 HPC EXF 2.73 20.70 vidone 9.08 69.00 l 200 0.91 6.90 Mg stearate 2.61 19.80 PEG 4000 0.48 3.68 HPMC E50 3.23 24.50 Opaolry White 5.20 39.46 Opadry Yellow 0.17 1.31 O ad Red 0.08 0.60 100.00 759.00 100.00 759.55 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. -18— W0 2013/074432 PCT/U82012/064610 The onal coating provides a unique dissoiution profile with the following characterstics: 1) For 7% functional coating weight gain the following dissolution profile in 900ml pH 2.0 is observed a 0 —- 8% dissolved at 5 minutes a ‘20 —— 30% dissolved at 10 minutes o 35 —- 45% dissolved at 15 minutes 9 45 — 60% ved in 30 minutes 2) For 10% functional coating weight gain the following dissolution profile in 900ml pH 2.0 is observed e 0 — 5% dissolved at 5 minutes s 10 — 25% dissolved at 10 minutes 9 25 — 45% ved at 15 minutes a 45 — 55% dissolved in 30 minutes 3) For 13% functional coating weight gain the ing dissolution profile in 900ml pH 2.0 is observed a 0 % dissolved at 5 minutes e 2 — 10% dissolved at 10 minutes a 20 — 35% dissoived at 15 minutes 0 45 — 55% dissolved in 30 minutes PCT/U52012/064610 Table 4: Dissolution arofiles of different wei-ht % functional coatino wei-ht . ain at H 2.0 Averae % released at time min PEQQE Tran—27040841005 Rm IIIZIHIEII: TRD084__13% RC1 TRD—27o4~os210% RC2 21 36 45 56 7-0 AEU82010-0116 10% n=12 R01 21 32 41 51 61 67 —0’117 10% n=12 RC2 20 35 45 55 64 7O III-III Tan—2704-042 7% RC2 III-II Human PK results in the first study the tablet formulation without any functional coating were tested in humans. The results are as given below PCT/U82012/064610 210i Pilot PK Data Summary Var B = RC-1 Var c = Rc-Z It can be seen above that none of the formulations was bioequivalent to the reference marketed capsule ation, whereas the all dosage forms ted 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 ( R02 with 10% film coating) .

PCT/U52012/064610 Results ofAMN107CZ'104: y of PK parameters — geometric mean ratio for all formulations within BE range 5%) Parameter (N = 18) Cw 449.27 479.97 453.18 478.66 (ng/mL) (29.8) (25.4) (33.6) (37.4) 10948.35 10193.73 10026.16 9898.25 (32.2) (27.2) (33.5) (37.3) 12151.57 10632.62 11303.04 10784.07 (38.6) (29.1) (36.8) (42.7) 4.00(2.05, 4.00(2.00, 4009.00, 4.00(2.DO; t.” (h) .00) . 10.02) 10.00) 10.00) A: FMI capsule; [3: WG ltablet; Q: RC-1 tablet; Q: RC—2 tablet Bioequivalence was demonstrated for RC1 and RC2 ts with functional film coating for 300mg strength.

Claims (18)

What is Claimed:

1. A solid dosage form in the form of a film coated tablet comprising: (i) a core comprising 4-Methyl[[4-(3—pyridinyl)-2—pyrimidinyl]amino]-N-[5—(4—methyI—1 H- imidazolyl)—3-(trif|uoromethyl)phenyl] benzamide (nilotinib) or a pharmaceutically acceptable salt thereof and ents; and (ii) at least one polymeric coating over the nilotinib core, n the polymeric coating comprises a polymer which is hydroxypropylmethyl cellulose, and wherein the film coating is 7-13 % of the solid dosage form.

2. A solid dosage form of claim 1, wherein the film coating is 7-10 %.

3. A solid dosage form of claim 1, wherein the film coating is 10—13 %.

4. A solid dosage form of claim 1, 2 or 3, wherein disintegration of said solid dosage form is delayed by 4-15 minutes.

5. The solid dosage form of claim 1, 2 or 3, wherein 0-8 % of the solid dosage form is dissolved after 5 minutes at pH 2.0.

6. The solid dosage form of claim 1, 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 n capsule, wherein its Cmax and AUC are in the bioequivalent range when compared with capsules comprising 4-Methyl[[4-(3-pyridinyI) dinyliamino]-N-[5-(4—methyl—1H-imidazolyl)(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 drate.

9. The solid dosage form of any one of the preceding claims wherein the nib core comprises nilotinib in amounts from 30-70 % by weight, based on the weight of the tablet microcrystalline cellulose (Avicel® PH102) as a filler in the range 20—60 % by weight, hydroxypropylcellulose (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, colloidal silicon dioxide (Aerosil) as a glidant or flow enhancer with the range of 0.25 to 4 % by weight, magnesium te as an intra- ar (l) component in the range of 0.25-2 % by weight and magnesium stearate as an extragranular (ll) 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 l) 43.60 % nilotinib hydrochloride; ii) 35.61 % microcrystalline cellulose (Avicel PH102); iii) 2.73 % hydroxypropyl cellulose (HPC EXF); iv) 5.45 % vidone; v) 0.91% colloidal silicon dioxide (Aerosil 200); ' vi) 2.61 % Mg stearate; vii) 1.52 % hydroxy propyl methyl cellulose E50; viii) 7.32% white colorant; ix) 0.24 % yellow colorant; x) 0.01% red colorant; wherein the % values refer to the % by weight of the excipients listed under i) to x).

11. A film coated nilotinib tablet ting of i) 43.57 % nilotinib hydrochloride; ii) 31.95 % microcrystalline cellulose (Avicel® PH102); iii) 2.73 % hydroxypropylcellulose (HPC EXF); iv) 9.08 °/o crospovidone; v) 0.91% colloidal silicon dioxide (Aerosil 200); vi) 261 % Mg stearate; vii) 0.48 % PEG 4000; viii) 3.23 % hydroxy propyl methyl cellulose E50; ix) 5.20 °/o white colorant; x) 0.17 % yellow nt; xi) 0.08 % red colorant. 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 sing amorphous 4-Methyl—3-[[4-(3~ pyridinyi)—2-pyrimidiny|]amino]-N-[5-(4-methyl-1H-imidazol—1—yl)-3—(trifluor0methyl)phenyl] benzamide or a pharmaceuticaily acceptable salt thereof comprising the steps of: (i) roller compacting a core comprising yl-3—[[4—(3-pyridinyl)pyrimidinyl]amino]-N-[5~(4- methyl-1H-imidazol-1~yl)(trifluoromethyl)phenyl] benzamide or a pharmaceuticaily 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, microcrystalline cellulose (Avice|® PH102) as a filler in the range 20-60 % by weight, hydroxypropyl cellulose (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, colloidal silicon dioxide il) as a glidant or flow enhancer with the range of 0.25 to 4 % by weight, ium stearate as an intra- granular(i) component in the range of 0.25-2 % by weight and magnesium stearate as an granular (ll) component in the range of 5 % by weight based on the weight of the .

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—methyI—1 H-imidazolyl)—3- (trifluoromethyl)phenyl] benzamide is the hydrochloride salt.

18. The solid dosage form of any one of claims 1 to 11, substantially as herein described with reference to any one of the Examples and/or