JP6275645B2 - 4-Methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl ] Immediate release formulation of benzamide - Google Patents

Description

  The present invention relates to a pharmaceutical composition comprising a therapeutic nilotinib compound (formula I). In particular, the present invention is directed to a pharmaceutical composition comprising a nilotinib tablet core, and further comprising at least one polymer coating on the nilotinib core, wherein the rapidly disintegrating tablet has a lag time compared to an uncoated tablet formulation. provide.

  Nilotinib is 4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (tri Fluoromethyl) phenyl] benzamide. A particularly useful nilotinib salt is nilotinib hydrochloride monohydrate. These therapeutic compounds are useful as inhibitors of Bcr-Abl protein tyrosine kinase (TK) activity. Examples of conditions that can be treated with such therapeutic compounds include, but are not limited to, chronic myelogenous leukemia and gastrointestinal stromal tumors.

Nilotinib and other therapeutic compounds disclosed below need to be formulated into pharmaceutical compositions, particularly solid oral dosage forms, that can deliver the therapeutic effects of the compound to patients in need thereof. One problem for providing such a composition containing nilotinib is the physiochemical nature of nilotinib, which is a compound in which nilotinib and its salts are poorly water soluble and are formulated and delivered (ie, It is difficult to make it biologically available when taken orally. It is also difficult to achieve a corresponding pharmacokinetic profile using different dosage forms, i.e. tablets and capsules. Another problem is food effect because food increases the bioavailability of nilotinib. Compared to a fasted state, when a unit dose is administered shortly after food intake, systemic exposure to nilotinib is markedly increased, as reflected in AUC and _Cmax , resulting in potential adverse effects on the patient.

  The present invention relates to (i) 4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3. A solid formulation comprising a core comprising-(trifluoromethyl) phenyl] benzamide or a pharmaceutically acceptable salt thereof and an additive; and (ii) at least one polymer coating the core, the disintegration of the solid formulation Provides a solid formulation with a delay of 4-15 minutes.

  The present invention relates to (i) 4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3. A solid formulation comprising a core comprising-(trifluoromethyl) phenyl] benzamide or a pharmaceutically acceptable salt thereof and an additive; and (ii) at least one polymer coating the core, the disintegration of the solid formulation Is delayed for 4-15 minutes and the solid formulation is 4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazole-1- Also provided is a solid formulation with bioavailability in the fasted state equivalent to a hard gelatin capsule containing (yl) -3- (trifluoromethyl) phenyl] benzamide.

The present invention relates to (i) 4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3. A solid formulation comprising a core comprising-(trifluoromethyl) phenyl] benzamide or a pharmaceutically acceptable salt thereof and an additive; and (ii) at least one polymer coating the core, the disintegration of the solid formulation Is delayed for 4-15 minutes and the solid formulation is 4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazole-1- Also provided is a solid formulation having a reduced C _max compared to an uncoated solid formulation comprising yl) -3- (trifluoromethyl) phenyl] benzamide.

It is a figure which shows the outline | summary of the dissolution rate of a nilotinib tablet (wet granulation and roller compression) compared with a nilotinib capsule. It is a figure which shows the outline | summary of the dissolution rate in pH2.0 of a nilotinib film coating tablet (7-10% film coating). It is a figure which shows the outline | summary of the dissolution rate in pH2.0 of a nilotinib film coating tablet (10-13% film coating). FIG. 6 shows a summary of dissolution rate at pH 2.0 of nilotinib film-coated tablets (10% film coating) prepared by a roller compression method compared to uncoated nilotinib tablets prepared by a wet granulation method. . FIG. 6 shows a summary comparison of mean nilotinib concentration profiles over time for different nilotinib solid formulations.

  The present invention provides a crystalline pharmaceutical composition of nilotinib or a pharmaceutically acceptable salt thereof, formulated into a tablet form and having a bioequivalent pharmacokinetic profile to a commercially available nilotinib capsule form.

  As used herein, nilotinib is a compound of formula I:

4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) Means phenyl] benzamide.

  Nilotinib is a member of the compound of formula (II) and N-oxide and pharmaceutically acceptable salts of such compounds:

(Where
R ₁ represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;
R ₂ is hydrogen, lower alkyl, R ₃ optionally substituted with one or more identical or different groups, cycloalkyl, benzcycloalkyl, heterocyclyl, aryl groups, or 0, 1, 2 or 3 rings Represents a monocyclic or bicyclic heteroaryl group containing a nitrogen atom, 0 or 1 oxygen atom and 0 or 1 sulfur atom, where the group is in each case unsubstituted or mono- or polysubstituted Is;
And R ₃ is hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-monosubstituted or N, N-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, aryl group, or Represents a monocyclic or bicyclic heteroaryl group containing 0, 1, 2 or 3 ring nitrogen atoms, 0 or 1 oxygen atom and 0 or 1 sulfur atom, wherein the group Optionally unsubstituted or mono- or polysubstituted;
Or R ₁ and R _{2 taken} together are mono- or di-substituted with lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl. Optionally alkylene of 4, 5 or 6 carbon atoms; benzalkylene of 4 or 5 carbon atoms; 1 oxygen atom and oxaalkylene of 3 or 4 carbon atoms; or 1 nitrogen atom and Represents an azaalkylene of 3 or 4 carbon atoms, wherein the nitrogen is unsubstituted or lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, N-monosubstituted or N, N-disubstituted carba Yl - lower alkyl, cycloalkyl, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, which is substituted pyrimidinyl, or pyrazinyl;
R ₄ represents hydrogen, lower alkyl, or halogen.
Such therapeutic compounds are useful as pharmaceutical compositions for treating kinase-dependent diseases, in particular Bcr-Abl and Tie-2 kinase-dependent diseases, such as agents for treating one or more proliferative diseases. Suitable for the preparation of pharmaceutical compositions.

  In the definition of “therapeutic compound”, the prefix “lower” represents a group having up to 7 carbon atoms, in particular up to 4 carbon atoms, which group is straight-chain or branched with one or more branches. Is a chain.

  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 atom can be present in the (R), (S) or (R, S) configuration, such as the (R) or (S) configuration. Thus, the compounds may exist as a mixture of isomers or as pure diastereomers, for example as pure isomers, eg enantiomers. Furthermore, the use of any possible tautomers of the compounds of formula I is contemplated in the present invention.

  Lower alkyl is, for example, alkyl having 1 or more and 7 or less, such as 1 or more and 4 or less, and is linear or branched; for example, lower alkyl is n-butyl, sec-butyl, isobutyl, tert-butyl, etc. Propyl such as butyl, 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 group that is attached to a molecule through a bond located at the aromatic ring carbon atom of the group. In exemplary embodiments, aryl is an aromatic group having 6-14 carbon atoms, particularly phenyl, naphthyl, tetrahydronaphthyl, fluorenyl or phenanthrenyl, which is unsubstituted or has one or more, for example Up to 3, especially 1 or 2 substituents, especially 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-monosubstituted or N, N-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 alkyl mercapto, Halogen-lower alkylsulfonyl, especially trifluoromethanesulfonyl, etc., dihydroxybora (—B (OH) 2), heterocyclyl, monocyclic or bicyclic heteroaryl groups and lower alkylenedioxy bonded to adjacent carbon atoms of the ring ( Substituted with a substituent selected from, for example, methylenedioxy). Aryl is for example phenyl, naphthyl or tetrahydronaphthyl, which in each case is unsubstituted or independently halogen, in particular fluorine, chlorine or bromine; hydroxy; lower alkyl (eg methyl), halogen- Lower alkyl (eg trifluoromethyl) or hydroxy etherified with phenyl; lower alkylenedioxy (eg methylenedioxy, lower alkyl eg methyl or propyl) attached to two adjacent carbon atoms; halogen-lower Alkyl (eg trifluoromethyl); hydroxy-lower alkyl (eg hydroxymethyl or 2-hydroxy-2-propyl); lower alkoxy-lower alkyl (eg methoxymethyl or 2-methoxyethyl); lower alkoxy Rubonyl-lower alkyl (eg methoxycarbonylmethyl); lower alkynyl (eg 1-propynyl); esterified carboxy, especially lower alkoxycarbonyl (eg methoxycarbonyl, n-propoxycarbonyl or iso-propoxycarbonyl); N-1 Substituted carbamoyl, especially lower alkyl (eg, carbamoyl monosubstituted with methyl, n-propyl or iso-propyl); amino; lower alkylamino (eg, methylamino); di-lower alkylamino (eg, dimethylamino or diethylamino); Alkylene-amino (eg pyrrolidino or piperidino); lower oxaalkylene-amino (eg morpholino), lower azaalkylene-amino (eg piperazino), acylamino ( Example, if acetylamino or benzoylamino); have been substituted with or 1 or 2 substituents selected from the group comprising phenyl sulfonyl; lower alkylsulfonyl (e.g. methylsulfonyl); sulfamoyl.

  Cycloalkyl groups are, for example, cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, which are unsubstituted or selected from the group defined above as one or more, especially 1 or 2, aryl substituents Substituents such as lower alkyl (eg methyl), lower alkoxy (eg methoxy or ethoxy), or hydroxy, may be further substituted with oxo or fused to a benzo ring For example, it may be benzcyclopentyl or benzcyclohexyl.

  Substituted alkyl is alkyl as defined above, in particular lower alkyl, such as methyl; here one or more, in particular up to 3, substituents may be present, mainly halogen, in particular fluorine, amino, N A lower alkylamino, N, N-di-lower alkylamino, N-lower alkanoylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, and phenyl-lower alkoxycarbonyl. Trifluoromethyl is particularly useful.

  Mono- or disubstituted amino is in particular independently of one another lower alkyl, such as methyl; hydroxy-lower alkyl (eg 2-hydroxyethyl); lower alkoxy lower alkyl (eg methoxyethyl); phenyl-lower alkyl (eg benzyl Or 2-phenylethyl); lower alkanoyl (eg acetyl); benzoyl; substituted benzoyl (where the phenyl group is in particular one or more, eg 1 or 2, nitro, amino, halogen, N-lower alkylamino , N, N-di-lower alkylamino, substituted with a substituent selected from hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl); and phenyl-lower alkoxycarbonyl (wherein the phenyl group) Is unsubstituted Or in particular one or more, for example 1 or 2, nitro, amino, halogen, N-lower alkylamino, N, N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, Amino substituted with one or two groups selected from lower alkanoyl, and substituted with a substituent selected from carbamoyl; and, for example, N-lower alkylamino (eg, N-methylamino) ) Hydroxy-lower alkylamino (eg 2-hydroxyethylamino or 2-hydroxypropyl), lower alkoxy lower alkyl (eg methoxyethyl), phenyl-lower alkylamino (eg benzylamino), N, N-di-lower alkylamino N-phenyl-lower alkyl-N-lower Alkylamino, N, N-di-lower alkylphenylamino, lower alkanoylamino (eg acetylamino) or a substituent selected from the group comprising benzoylamino and phenyl-lower alkoxycarbonylamino (wherein The phenyl group is in each case unsubstituted or in particular nitro or amino, or likewise halogen, amino, N-lower alkylamino, N, N-di-lower alkylamino, hydroxy, cyano, carboxy, Substituted with lower alkoxycarbonyl, lower alkanoyl, carbamoyl or aminocarbonylamino). Also, the disubstituted amino may be a lower alkylene-amino (eg pyrrolidino, 2-oxopyrrolidino or piperidino); a lower oxaalkylene-amino (eg morpholino), or a lower azaalkylene-amino (eg piperazino or N-substituted piperazino, eg N- Methylpiperazino or N-methoxycarbonylpiperazino).

  Halogen is in particular fluorine, chlorine, bromine or iodine, in particular fluorine, chlorine or bromine.

Etherified hydroxy is in particular C ₈ -C ₂₀ alkyloxy, such as n-decyloxy, lower alkoxy (eg methoxy, ethoxy, isopropyloxy or tert-butyloxy), phenyl-lower alkoxy (eg benzyloxy, phenyloxy) , Halogen-lower alkoxy (eg trifluoromethoxy, 2,2,2-trifluoroethoxy or 1,1,2,2-tetrafluoroethoxy), or mono- or bicyclic heteros containing 1 or 2 nitrogen atoms Lower alkoxy substituted with aryl (eg lower alkoxy substituted with imidazolyl, eg 1H-imidazol-1-yl, pyrrolyl, benzimidazolyl, eg 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 (eg tert-butoxycarbonyloxy) or phenyl-lower alkoxycarbonyloxy (eg benzyloxycarbonyloxy).

  Esterified carboxy is especially lower alkoxycarbonyl (eg tert-butoxycarbonyl, iso-propoxycarbonyl, methoxycarbonyl or ethoxycarbonyl), phenyl-lower alkoxycarbonyl, or phenyloxycarbonyl.

  Alkanoyl is primarily alkylcarbonyl, especially lower alkanoyl, such as acetyl.

  N-monosubstituted or N, N-disubstituted carbamoyl is especially lower alkyl, phenyl-lower alkyl and hydroxy-lower alkyl, or lower alkylene, oxa-lower alkylene or an aza optionally substituted at the terminal nitrogen atom Substituted with 1 or 2 substituents independently selected from lower alkylene.

  Monocyclic or bicyclic heteroaryl groups containing 0, 1, 2 or 3 ring nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 sulfur atom are in each case unsubstituted Or a monocyclic or polysubstituted heterocyclic moiety that is unsaturated in the ring that attaches the heteroaryl group to the rest of the molecule in Formula I, such as in the linking ring, but also optionally In an annealed ring, a ring in which at least one carbon atom is replaced with a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and the number of linking rings is, for example, 5-12, such as 5 or 6 Said monocyclic or bicyclic heteroaryl group may be unsubstituted or in groups defined above as aryl substituents, especially examples For example, it may be substituted with one or more, in particular 1 or 2, substituents selected from lower alkyl (eg methyl), lower alkoxy (methoxy or ethoxy) or hydroxy. For example, a monocyclic or bicyclic heteroaryl group is 2H-pyrrolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, purinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4H-quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthylidinyl, quinoxalyl , Quinazolinyl, quinolinyl, pteridinyl, indolizinyl, 3H-indolyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, furazanyl, benzo [d] pyrazolyl, thienyl and furanyl. For example, monocyclic or bicyclic heteroaryl groups include pyrrolyl, imidazolyl (eg, 1H-imidazol-1-yl), benzimidazolyl (1-benzoimidazolyl), 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 group is substituted with hydroxy in the ortho position relative to the nitrogen atom, and is therefore at least partially corresponding to the corresponding tautomer, ie pyridine- (1H) 2- Present in on form. In another exemplary embodiment, the pyrimidinyl group is substituted with hydroxy at both the 2 and 4 positions, and thus some tautomerism such as pyrimidine- (1H, 3H) 2,4-dione. Exists in type.

  Heterocyclyl is a 5, 6 or 7 membered heterocyclic system containing 1 or 2 heteroatoms, particularly selected from the group comprising nitrogen, oxygen, and sulfur, which may be unsaturated or fully or partially saturated. Substituted or in particular substituted by lower alkyl (eg methyl), phenyl-lower alkyl (eg benzyl), oxo, or heteroaryl (eg 2-piperazinyl), heterocyclyl being especially 2- or 3-pyrrolidinyl 2-oxo-5-pyrrolidinyl, piperidinyl, N-benzyl-4-piperidinyl, N-lower alkyl-4-piperidinyl, N-lower alkyl-piperazinyl, morpholinyl, such as 2- or 3-morpholinyl, 2-oxo-1H -Azepine-3-yl, 2-tetrahydrofuranyl, or 2- Chill-1,3-dioxolan-2-yl.

  A salt is in particular a pharmaceutically acceptable salt of a compound of formula I. Such salts are formed, for example, from compounds of the formula I having a basic nitrogen atom, for example as acid addition salts with organic or inorganic acids, in particular as pharmaceutically acceptable salts. Suitable inorganic acids include, but are not limited to, halogen acids (eg hydrochloric acid), sulfuric acid, or phosphoric acid.

  Suitable organic acids are, for example, carboxylic acids, phosphonic acids, sulfonic acids or sulfamic acids such as 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-amino Salicylic 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-Naphthalene- Sulfonic 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 others Organic protic acids such as ascorbic acid.

  One useful nilotinib salt is nilotinib hydrochloride monohydrate, or 4-methyl-N- [3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl]- 3-[(4-Pyridin-3-ylpyrimidin-2-yl) amino] benzamide hydrochloride hydrate. Suitable salts of nilotinib and their polymorphs are more generally disclosed in WO2007 / 015870 and WO2007 / 015877.

  As used herein, the term “pharmaceutical composition” includes a specific amount, eg, a therapeutically effective amount, of a therapeutic compound, eg, in a pharmaceutically acceptable carrier, to treat a kinase-dependent disorder. Means a mixture administered to a mammal, eg, a human.

  As used herein, the term “pharmaceutically acceptable” includes, within reasonable medical judgment, excessive toxicity, inflammation, allergic reaction to a reasonable benefit / risk ratio balance. And compounds, materials, compositions and / or dosage forms suitable for contact with mammalian, particularly human tissue, without causing other problematic complications.

  The concentration of the therapeutic compound in the pharmaceutical composition is present in an amount, eg, a therapeutically effective amount, which will depend on the rate of absorption, inactivation and excretion of the pharmaceutical agent and other factors known to those skilled in the art. Furthermore, it should be noted that the dose value will also vary depending on the severity of the condition to be alleviated. Furthermore, for any particular subject, the individual dosing regimen should be adjusted over time according to the individual needs and the professional judgment of the pharmaceutical composition administrator or the administrator of the pharmaceutical composition administration Should be understood. The therapeutic compound may be administered at once, or may be administered at various time intervals divided into several smaller doses. Thus, an appropriate amount, eg, an appropriate therapeutically effective amount, is known to those skilled in the art.

  For example, the dose of the therapeutic compound will range from about 0.1 to about 100 mg / body weight (kg) / day of the subject. Alternatively, it may be administered at lower doses, for example 0.5-100 mg, 0.5-50 mg, or 0.5-20 mg / kg body weight / day. The effective dose range of a pharmaceutically acceptable salt can be calculated based on the weight of the active moiety to be delivered. If the salt itself is active, the effective dose can be estimated as described above using the weight of the salt or by other methods known to those skilled in the art.

  As used herein, the term “immediate release” means that the majority of therapeutic compounds are, for example, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%. %, Or more than about 90%, refers to a rapid release in a relatively short time, such as within 1 hour, 40 minutes, 30 minutes, or 20 minutes after oral administration. A particularly useful condition for immediate release is that at least about 80% or more of the therapeutic compound is released within 30 minutes of oral administration. Specific immediate release conditions for specific therapeutic compounds will be recognized or known by those skilled in the art.

  As used herein, the term “lag time” refers to the period during which the release of most of the therapeutic compound is delayed after ingestion.

  As used herein, the term “additive” refers to a pharmaceutically acceptable ingredient commonly used in pharmaceutical technology to prepare granule and / or solid oral dosage formulations. Examples of additive types include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers and diluents. One of ordinary skill in the art can select one or more of the above-described additives by routine experimentation without undue burden regarding the particular desired properties of the granule and / or solid oral dosage form. The amount of each additive used can vary within the general range in the art. The following references disclose techniques and additives used to formulate oral dosage forms, all of which are incorporated herein by reference. 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) See

  In an exemplary embodiment of the invention, an invented nilotinib solid formulation is prepared by roller compressing a nilotinib tablet core and film coating the nilotinib tablet core with a functional polymer, wherein the disintegration of the solid formulation is between 4 and Delay 15 minutes.

  The present invention also provides a method for increasing bioavailability by administering a composition or pharmaceutical composition of the present invention to an animal or patient, respectively, the increased bioavailability of the present invention The Cmax value or AUC value of the composition or pharmaceutical composition is determined by comparison with the composition disclosed in the present invention. Preferably, the method increases the bioavailability of the drug in the administered animal or patient by at least 1.3 times, preferably at least 2 times, more preferably at least 3 times.

In one preferred embodiment of the method, the composition or pharmaceutical composition of the invention is 4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- 4- (Methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl] benzamide in a commercially available Tasigna ™ hard gelatin capsule manufactured by Novartis Methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl] benzamide Have comparable bioavailability when compared to. And _comparable, when expressed as a ratio between _{C max} and AUC for the test product (Formulation of invention) and the reference product (Tasigna (TM) capsule _{formulation), C max} and AUC of 90% CI is 0.8 Defined as being in the range of 1.25.

  Bioavailability can be measured by those skilled in the art by common methods. For example, tablets, capsules, liquids, powders, etc. are given orally to humans or animals, and the blood concentration is measured.

  The composition or pharmaceutical composition according to the present invention comprises one or more binders, fillers, lubricants, suspending agents, sweeteners, flavoring agents, preservatives, buffering agents, wetting agents, foaming agents and other Additives can also be included. Such additives are known in the art. Examples of bulking agents are lactose monohydrate, lactose anhydride, microcrystalline cellulose (eg Avicel® PH101 and Avicel® PH102), microcrystalline cellulose and silicified microcrystalline cellulose (ProSolv SMCC® )), As well as various starches, examples of binders are various celluloses and crosslinked polyvinylpyrrolidone. Suitable lubricants include agents that affect the fluidity of the powder to be compressed and are colloidal silicon dioxide (eg 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 acesulfame. Examples of flavoring agents are Magnasweet (R) (trademark of MAFCO), bubble gum flavor, fruit flavor, and the like. Suitable diluents include pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, calcium hydrogen phosphate, sugars and / or mixtures of any of the foregoing. . Examples of diluents include microcrystalline cellulose (eg, Avicel® PH101 and Avicel® PH102); lactose (eg, lactose monohydrate, lactose anhydride, and Pharmatose® DCL21). ); Calcium hydrogen phosphate (eg Emcompress®); mannitol; starch; sorbitol; sucrose; Examples of foaming agents are foamable pairs, such as organic acids and carbonates or bicarbonates.

  Nilotinib exhibits compressibility problems associated with high drug loading of over 45% and also requires high magnesium stearate because the formulation also has a tendency to stick and pick on the wrinkles. The formulation also has friability problems in the absence of a suitable binder. To overcome all these challenges, the formulation requires an optimized amount of selected additives.

  In one embodiment, the invented core tablet comprises nilotinib in an amount of 30-70% by weight relative to the weight of the tablet, Avicel® in the range of 20-60% by weight as filler relative to the weight of the tablet. ) PH102 (microcrystalline cellulose), HPC EXF in the range of 2-6% by weight as binder, crospovidone in the range of 2-14% by weight as superdisintegrant, glidant or flow enhancer (flow) enhancer) in the range of 0.25 to 4% by weight Aerosil, the internal granular component (I) in the range of 0.25 to 2% by weight magnesium stearate and the external granular component (II) 0.7 to 3.5 Contains magnesium stearate in the range of weight percent.

  In one embodiment, the composition is a solid oral dosage form. Examples of solid oral dosage forms include tablets, pills, capsules, and powders. Liquid oral dosage forms include solutions and suspensions. In one embodiment, the solid formulation is a polymer film coated tablet.

  Different classes of polymers that can be used to delay initial release from tablets include hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, ethylcellulose, shellac, polyvinylpyrrolidone (eg, K30, K90), polyvinyl acetate, Kollidon VA 64 {Copvidone Or (polyvinyl acetate 40% and polyvinyl pyrrolidone 60%)}, Kollidon SR (polyvinyl acetate 80% and polyvinyl pyrrolidone 20%) methacrylic acid (polymers and graft copolymers), carbomer polymers (eg, Carbopol 971P NF, Carbopol 974P NF), Veegum, glyceryl behenate / Divehe Over preparative (Compritol (R), is selected from hydroxypropyl methylcellulose acetate succinate (HPMC AS) and hydroxypropylmethylcellulose phthalate (HPMC-P).

  In one aspect, the present invention provides a method for producing a composition comprising blending nilotinib and an additive and roller compacting them to form granules. The granules are compressed into tablets or pills. The nilotinib tablet core is then film coated to various thicknesses using a polymer coating, resulting in a lag time before disintegration.

  The following examples are provided to illustrate the present invention. However, it should be understood that the invention is not limited to the specific conditions or details described in the following examples. The following examples are illustrative and do not limit the scope of the invention described herein. This example is only intended to suggest a method of practicing the invention.

  The amounts of the ingredients are expressed as weight percent with respect to the pharmaceutical composition, and the amounts used in each example are listed in the respective tables after each description. For capsules, when calculating the weight of the pharmaceutical composition (ie, capsule fill), the weight of the capsule shell itself is excluded from the calculation.

Example 1 Nilotinib Tablet Core An example (formulation A) of nilotinib tablet core is summarized in Table 1. Nilotinib tablet cores were prepared by the roller compression method. Invented nilotinib tablet cores prepared by roller compression method compared to commercial nilotinib capsule formulations developed using wet granulation technology, realized nilotinib tablet cores consistently showing excellent compression properties , 6-10 kp compression window, tablet cores with low friability, fast disintegration time (1-2 minutes) and tablet cores that can be compressed at high speeds, but are not limited thereto.

50 mg and 100 mg unit dosage forms were also produced from Nilotinib Tablet Core Formula A. Unit dosage forms were prepared for unit doses in amounts of 200 mg, 300 mg and 400 mg.

Example 2 Nilotinib Tablet Core Another example of a nilotinib tablet core (Formulation B) is summarized in Table 2. Nilotinib tablet cores were prepared by the roller compression method. Invented nilotinib tablet cores prepared by roller compression method compared to commercial nilotinib capsule formulations developed using wet granulation technology, realized nilotinib tablet cores consistently showing excellent compression properties , 6-10 kp compression window, tablet cores with low friability, fast disintegration time (1-2 minutes) and tablet cores that can be compressed at high speeds, but are not limited thereto.

50 mg and 100 mg unit dosage forms were also produced from Nilotinib Tablet Core Formula A. Unit dosage forms were prepared for unit doses in amounts of 200 mg, 300 mg and 400 mg.

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 mesh to 35 mesh screen. Magnesium stearate (I) was added to the sieved mixture and mixed again to disperse the magnesium stearate. This mixture was roller-compressed with a 50 mm roller compressor using a compression force of 15-40 kN. The ribbon was then crushed through a sieve (range 10-18 US mesh size). The ground granule was mixed with magnesium stearate (II) to disperse the magnesium stearate.

Dissolution Two-step dissolution conditions were used for the following nilotinib tablet cores (formulations A and B), wet granulated nilotinib formulation capsules, and nilotinib capsule formulations: 37 ° C; steps 1, 0-60 minutes 500 ml, pH 2 buffer, step 2,> 60 min, 1000 ml, pH 6.8 buffer; paddle 75 rpm.

  Invented nilotinib tablet cores prepared from roller-compressed nilotinib formulations A and B showed a fast disintegration rate (<2 minutes) independent of tablet compression force and hardness compared to commercial nilotinib capsule formulations (FIG. 1). In order for the invented nilotinib tablet core to be bioequivalent to a commercially available nilotinib capsule formulation, a disintegration lag time was required to delay the disintegration time of the nilotinib tablet core. This lag time (4-12 minutes) was achieved using a functional polymer-based coating on the core tablet to prevent the tablet from collapsing before the lag time.

Film Coated Nilotinib Tablet Core 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.

The film coating thickness can be varied based on the weight increase of the nilotinib tablet core. An increase in disintegration time was observed corresponding to an increase in weight increase of the film coating.

  While Opadry White, Yellow and Red color the tablets pale yellow and exist only for aesthetic value, HPMC E50 is a functional polymer that delays disintegration time.

The functional coating provides a unique dissolution profile with the following characteristics:
1) The following dissolution profiles are observed at pH 2.0, 900 ml for a 7% functional coating weight increase: 0-8% dissolution in 5 minutes, 20-30% dissolution in 10 minutes, 35 in 15 minutes -45% dissolution -45-60% dissolution in 30 minutes 2) Regarding the weight increase of 10% functional coating, the following dissolution profile is observed at 900 ml pH 2.0 -0-5% dissolution in 5 minutes- 10-25% dissolution in 10 minutes, 25-45% dissolution in 15 minutes, 45-55% dissolution in 30 minutes 3) With respect to 13% functional coating weight increase, the following dissolution profile at 900 ml pH 2.0 Observed-0% dissolution in 5 minutes-2-10% dissolution in 10 minutes-20-35% dissolution in 15 minutes-45-55% dissolution in 30 minutes

Human PK Results In the first study, tablet formulations without any functional coating were tested in humans. The results are as follows.

As noted above, none of the formulations are bioequivalent to the reference capsule formulation on the market and all dosage forms show higher C _max compared to the reference capsule formulation on the market. However, the _Cmax ratio was disproportionately higher than the AUC ratio.

  In another study, a 10% film coated 300 mg RC variant was tested for BE and the results are as follows:

  PK results for modified BB (10% film coated RC1) and modified CC (10% film coated RC2).

Bioequivalence was demonstrated for the RC1 and RC2 variants with a functional film coating concentration of 300 mg.
The invention described in the scope of the original claims of the present application will be added below.
[1]
(I) 4-Methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoro (Ii) a solid formulation comprising a core comprising methyl) phenyl] benzamide or a pharmaceutically acceptable salt thereof and an additive; and (ii) at least one polymer coating the core, wherein the disintegration of the solid formulation is 4 Solid formulation delayed ~ 15 minutes.
[2]
The solid preparation according to [1], wherein the polymer is hydroxypropylmethylcellulose.
[3]
The solid preparation according to [2], wherein 7 to 13% of the solid preparation is a polymer that coats the core.
[4]
The solid preparation according to [1], wherein 0 to 8% of the solid preparation dissolves after 5 minutes at pH 2.0.
[5]
The solid preparation according to [1], wherein 45 to 60% of the solid preparation dissolves after 30 minutes at pH 2.0.
[6]
(I) 4-Methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoro A solid formulation comprising a core comprising (methyl) phenyl] benzamide or a pharmaceutically acceptable salt thereof and an additive; and (ii) at least one polymer coating said core,
Has bioavailability in the fasted state equivalent to hard gelatin capsules,
Its C _max and AUC are 4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3 Compared to capsules containing-(trifluoromethyl) phenyl] benzamide or a pharmaceutically acceptable salt thereof, in a biologically equivalent range
Solid formulation.
[7]
The solid preparation according to [6], wherein the polymer is hydroxypropylmethylcellulose.
[8]
The solid preparation according to [6], wherein 7 to 13% by weight of the solid preparation is a polymer that coats the core.
[9]
The solid preparation according to [6], wherein 0 to 8% by weight of the solid preparation dissolves after 5 minutes at pH 2.0.
[10]
The solid preparation according to [6], wherein 45 to 60% by weight of the solid preparation dissolves after 30 minutes at pH 2.0.
[11]
(I) 4-Methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoro Methyl) phenyl] benzamide or a pharmaceutically acceptable salt and core containing the additive and roller compacting; and (ii) coating the core with at least one polymer. -Methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl] A method for preparing a solid preparation comprising benzamide or a pharmaceutically acceptable salt thereof.
[12]
The method according to [11], wherein the solid preparation is a tablet.
[13]
The method according to [12], wherein the polymer is hydroxypropylmethylcellulose.

Claims (9)

(I) 4-Methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoro Methyl) phenyl] benzamide or a core comprising pharmaceutically acceptable salts and additives thereof;
(Ii) a solid formulation comprising at least one polymer, wherein the polymer is hydroxypropylmethylcellulose E50 , and the polymer coats the core, wherein the coating is 7-13 of the solid formulation The solid preparation in which disintegration of the solid preparation is delayed by 4 to 15 minutes.   The solid preparation according to claim 1, wherein the polymer coating is 7 to 10% by weight of the solid preparation.   The solid preparation according to claim 1, wherein the polymer coating is 10 to 13% by weight of the solid preparation.   The solid preparation according to claim 1, wherein 0-8% of the solid preparation dissolves after 5 minutes at pH 2.0.   The solid preparation according to claim 1, wherein 45 to 60% of the solid preparation dissolves after 30 minutes at pH 2.0. Has bioavailability in the fasted state equivalent to hard gelatin capsules,
Its C _max and AUC are 4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3 The solid preparation according to claim 1, which is in a biologically equivalent range as compared to a capsule containing-(trifluoromethyl) phenyl] benzamide or a pharmaceutically acceptable salt thereof. (I) 4-Methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoro Methyl) phenyl] benzamide or a core comprising a pharmaceutically acceptable salt thereof and additives and roller compacting; (ii) coating the core with at least one polymer , wherein the polymer is hydroxypropyl and a step is methylcellulose E50, amorphous 4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino]-N-[5-(4-methyl -1H- imidazole - A method for preparing a solid preparation comprising 1-yl) -3- (trifluoromethyl) phenyl] benzamide or a pharmaceutically acceptable salt thereof.   The method according to claim 7, wherein the solid preparation is a tablet. 9. The method of claim 8 , wherein disintegration of the solid formulation is delayed for 4-15 minutes.