Nilotinib tablets

Abstract

To provide a pharmaceutical tablet having nilotinib hydrochloride as an active ingredient which is a tablet that can be easily ingested and has high content of nilotinib, preferably to provide a pharmaceutical tablet capable of controlling elution property in pH3.0 buffer solution.SOLUTION: A pharmaceutical tablet using nilotinib hydrochloride as an active ingredient which includes filler, disintegrator and binder inside the tablet. The pharmaceutical tablet has the content of nilotinib of 50 mass% or more. Further, optimizing the disintegrator, binder and filler makes it possible to control tablet collapsibility in pH3.0 buffer solution, and control elution property in a suppressed manner.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a pharmaceutical tablet containing nilotinib hydrochloride as an active ingredient, which is an easy-to-take tablet with an increased active ingredient content.

Background Art

[0002] Nilotinib is a compound having a structure represented by the general formula (1), with the chemical name 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide.

Chemical Formula

[0003] Nilotinib is a tyrosine kinase inhibitor (TKI) having a high selectivity and strong inhibitory activity against Bcr-Abl tyrosine kinase. It competitively antagonizes with ATP and inhibits Bcr-Abl tyrosine kinase, and is considered to exhibit an antitumor effect based on the induction of apoptosis of Bcr-Abl expressing cells. It is commercially available under the trademark Tasigna (registered trademark) capsules and is used as a therapeutic agent for chronic myeloid leukemia in the chronic or accelerated phase (Non-Patent Document 1). Patent Document 1 describes a pharmaceutical capsule preparation using granules containing nilotinib hydrochloride, and the inner phase of the granules contains a polyoxyethylene-polyoxypropylene block copolymer (the number of oxyethylene units and oxypropylene units is 150 and 30 respectively), lactose monohydrate, and polyvinylpyrrolidone, and the outer phase of the granules contains lactose monohydrate, colloidal silicon dioxide, and magnesium stearate. Generally, capsule formulations are said to be dosage forms that tend to be difficult to swallow. Therefore, it is desired to develop tablets of nilotinib with excellent swallowability. Furthermore, the tablets are required to exhibit elution properties equivalent to those of the existing capsule formulation of nilotinib. In order to obtain nilotinib tablets having an elution profile equivalent to that of the existing capsule formulation, it is necessary to delay the disintegration property and suppress the elution, particularly in a pH 3.0 buffer solution. In Patent Document 2, in preparing nilotinib tablets having an elution profile equivalent to that of a capsule formulation, film-coated tablets coated with a coating material containing hydroxypropyl cellulose E50 were prepared to delay the disintegration by 4 to 15 minutes.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0005]

Non-Patent Document 1

Disclosure of the Invention

Problems to be Solved by the Invention

[0006] An object of the present invention is to provide a pharmaceutical tablet containing nilotinib hydrochloride, an excipient, and a disintegrant, and having an increased nilotinib content. In particular, it is an object to provide a pharmaceutical tablet having a nilotinib content of 50% by mass or more in the mass of the core tablet of the pharmaceutical tablet.

Means for Solving the Problems

[0007] The invention of the present application has the following gist in [1] to [8]. [1] A pharmaceutical tablet containing nilotinib hydrochloride, an excipient, and a disintegrant, wherein the nilotinib content in the mass of the core tablet of the pharmaceutical tablet is 50% by mass or more. [2] The pharmaceutical tablet according to [1] above, wherein the content of the excipient is less than 35% by mass in the mass of the core tablet of the pharmaceutical tablet. [3] The pharmaceutical tablet according to [1] or [2] above, wherein the content of the disintegrant is 4% by mass or more and less than 10% by mass in the mass of the core tablet of the pharmaceutical tablet. [4] The pharmaceutical tablet according to any one of [1] to [3] above, wherein the excipient contains crystalline cellulose, and the content of crystalline cellulose is more than 10% by mass and less than 35% by mass in the mass of the core tablet of the pharmaceutical tablet. [5] The pharmaceutical tablet according to [4] above, wherein the content of the total mass of crystalline cellulose and the disintegrant is more than 15% by mass and less than 45% by mass in the mass of the core tablet of the pharmaceutical tablet. [6] The pharmaceutical tablet according to any one of [1] to [5] above, containing sodium carboxymethylcellulose. [7] The pharmaceutical tablet according to [6] above, wherein the content of the total mass of the disintegrant and sodium carboxymethylcellulose is more than 5% by mass and less than 12% by mass in the mass of the core tablet of the pharmaceutical tablet. [8] The pharmaceutical tablet according to [6] or [7] above, wherein the content ratio of the disintegrant to sodium carboxymethylcellulose is [disintegrant] / [sodium carboxymethylcellulose] = 1 to 5. [Advantages of the Invention]

[0008] According to the present invention, a pharmaceutical tablet containing 50% by mass or more of nilotinib can be prepared, whereby the tablet can be miniaturized, and a pharmaceutical tablet that is easy to take can be provided. [Embodiments for Carrying Out the Invention]

[0009] The pharmaceutical tablet containing nilotinib hydrochloride, an excipient, and a disintegrant of the present invention will be described below.

[0010] The present invention uses nilotinib hydrochloride as an active ingredient. Nilotinib is 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide, and its hydrochloride salt is used. It is preferable that nilotinib hydrochloride has a quality acceptable as a pharmaceutical product. Nilotinib hydrochloride is disclosed in Patent No. 5798101 in forms A (dihydrate), A' (monohydrate), A'' (anhydrate), B (monohydrate), B' (anhydrate), C (monohydrate), C' (anhydrate), S B , S B ', S C , D, S E are disclosed. Also, forms T1 to T19 are disclosed in Patent No. 5486012, and any of these forms can be used in the present invention. In the present invention, the nilotinib hydrochloride to be used is not particularly limited, but nilotinib hydrochloride dihydrate of form A or nilotinib hydrochloride monohydrate of form A', B or C is preferable.

[0011] The pharmaceutical tablets in the present invention contain 50% by mass or more of nilotinib (free base). Conventional nilotinib preparations were capsule preparations that were difficult to swallow. However, in addition to making tablets that are easy to take, by further increasing the active ingredient content and relatively reducing the size of the tablets, the compliance of taking medicine can be further improved. Nilotinib is preferably 50% by mass or more and 70% by mass or less. More preferably, it is 50% by mass or more and 60% by mass or less.

[0012] The pharmaceutical tablets of the present invention contain an excipient. Examples of the excipient include celluloses such as crystalline cellulose and powdered cellulose, starches such as corn starch, potato starch, rice starch, and wheat starch, and saccharides such as lactose, maltose, mannitol, erythritol, fructose, trehalose, sucrose, sucrose, sorbitol, xylitol, and inositol. It is preferable to use celluloses such as crystalline cellulose and powdered cellulose. The excipient preferably has a content in the tablet core mass of the pharmaceutical tablet according to the present invention of less than 35% by mass. The excipient preferably has a content of more than 15% by mass and less than 35% by mass, and more preferably a content of more than 20% by mass and less than 35% by mass. As the excipient, it is preferable to use celluloses such as crystalline cellulose and powdered cellulose, and it is more preferable to use crystalline cellulose. Crystalline cellulose is preferably used at a content of more than 10% by mass and less than 35% by mass in the tablet core mass of the pharmaceutical tablet, more preferably more than 15% by mass and less than 35% by mass, and particularly preferably a content of more than 20% by mass and less than 35% by mass. The excipient preferably does not contain the starches and the saccharides described above. More preferably, it is only the celluloses, and is an excipient composed of crystalline cellulose and / or powdered cellulose.

[0013] In the present invention, examples of the disintegrant include sodium carboxymethyl starch, crospovidone, calcium carboxymethylcellulose, croscarmellose sodium, partially pregelatinized starch, low-substituted hydroxypropyl cellulose, and the like. As the disintegrant, it is preferable to use sodium carboxymethyl starch, crospovidone, and croscarmellose sodium. These are also referred to as super disintegrants and can function with a small amount of application, so that the amount of additives used can be reduced to achieve miniaturized tablets. The disintegrant preferably has a content in the tablet core mass of the pharmaceutical tablet according to the present invention of 4% by mass or more and less than 10% by mass. A content of 4% by mass or more and 8% by mass or less is more preferable.

[0014] Crystalline cellulose has a function of assisting the disintegration of tablets in the present invention. Therefore, it is preferable to use a combination of crystalline cellulose and a disintegrant because the amount of the disintegrant can be reduced. It is preferable to control the total mass of these combined. The content of the total mass of crystalline cellulose and the disintegrant is preferably more than 15% by mass and less than 45% by mass in the tablet core mass of the pharmaceutical tablet, and more preferably more than 25% by mass and less than 40% by mass.

[0015] For the pharmaceutical tablets of the present invention, it is preferable to apply sodium carboxymethyl cellulose. In the present invention, sodium carboxymethyl cellulose functions as a binder and can control the disintegration rate of the tablets. In the preparation of nilotinib tablets, in order to achieve the same dissolution property as the existing nilotinib capsule formulation, it is preferable that the dissolution property of the tablets is controllably suppressed. In order to achieve the same dissolution property as the capsule formulation when tableting, for example, it is required to suppress the dissolution property in a pH 3.0 buffer solution. By using sodium carboxymethyl cellulose, the disintegration property of the pharmaceutical tablets can be adjusted and the dissolution property can be controlled. It is preferable that the content of sodium carboxymethyl cellulose in the mass of the core tablets of the pharmaceutical tablets according to the present invention is more than 1% by mass and less than 10% by mass. A content rate of more than 2% by mass and less than 8% by mass is more preferable, and more preferably more than 2% by mass and less than 6% by mass. It is preferable to use sodium carboxymethyl cellulose having a viscosity of more than 10 mPa·s and less than 1000 mPa·s when made into a 1% aqueous solution, and more preferably having a viscosity of more than 50 mPa·s and less than 500 mPa·s. The viscosity is a value measured at 60 rpm with a B-type viscometer after preparing a 1% aqueous solution, degassing it under reduced pressure, using the sample solution obtained as the sample solution, uniformly stirring the sample solution, and confirming that the liquid temperature has reached 25°C.

[0016] Since sodium carboxymethyl cellulose is used to adjust the disintegration property, it is preferable to design the formulation of the pharmaceutical tablets in consideration of the total mass combined with the disintegrant. It is preferable that the content rate of the total mass of sodium carboxymethyl cellulose and the disintegrant is more than 5% by mass and less than 15% by mass in the mass of the core tablets of the pharmaceutical tablets, and more preferably more than 5% by mass and less than 12% by mass. In addition, in order to control the disintegration property, appropriate elution property can be imparted by considering the content ratio of sodium carboxymethyl cellulose and the disintegrant. That is, increasing the sodium carboxymethyl cellulose content ratio can suppress the elution property in a pH 3.0 buffer solution, and increasing the disintegrant content ratio can enhance the elution property. In the present invention, the content ratio of the disintegrant to sodium carboxymethyl cellulose is preferably [disintegrant] / [sodium carboxymethyl cellulose] = 0.5 to 5. By setting it within this range, the elution property in a pH 3.0 buffer solution can be suppressed. More preferably, [disintegrant] / [sodium carboxymethyl cellulose] = 1 to 5. Thereby, the dissolution rate of the test solution in 900 mL of a pH 3.0 buffer solution can be made 40% or less at 30 minutes from the start of the test, 50% or less at 60 minutes, and 60% or less at 120 minutes.

[0017] The pharmaceutical tablet of the present invention may use only sodium carboxymethyl cellulose as a binder, or may be used in combination with other binders. Examples of other binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, and the like.

[0018] The pharmaceutical tablet of the present invention may contain other additives used in tablet preparation. For example, solubilizers, dispersants, lubricants, fluidizing agents, masking agents, and coloring agents can be mentioned. These additives can be used without particular limitation as long as they have a purity acceptable for pharmaceutical formulation use. These additives may be used alone or as a mixture thereof. They are used arbitrarily when preparing the pharmaceutical tablet.

[0019] Examples of solubilizers and dispersants include sodium lauryl sulfate, polysorbate, glyceryl monostearate, polyoxyethylene hydrogenated castor oil, and the like.

[0020] Examples of the lubricant include stearic acid, magnesium stearate, zinc stearate, aluminum stearate, glycerin monostearate, sodium stearyl fumarate, calcium stearate, carnauba wax, etc.

[0021] Examples of the fluidizing agent include colloidal silicon dioxide, hydrous silicon dioxide, talc, etc.

[0022] Examples of the masking agent and the coloring agent include titanium oxide, yellow iron oxide, ferric sesquioxide, yellow ferric sesquioxide, black iron oxide, zinc oxide, brown iron oxide, talc, edible yellow pigments, edible blue pigments, edible red pigments, etc.

[0023] Other additives such as disintegrants, binders, solubilizers, dispersants, lubricants, fluidizing agents, excipients, masking agents and coloring agents may be used as other additive compositions containing one or more of these, and may be used as granules prepared by premixing these in advance. By making granules by premixing and integrating other additives, there is an advantage in that the physical properties are easy to handle in the tablet manufacturing operation.

[0024] The pharmaceutical tablets of the present invention may be film-coated. Examples of the film coating base include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, etc. As the film coating base, an amino group-modified polymer additive may be contained in the film coat portion that contacts the outside of the pharmaceutical tablet as long as the effects of the present invention are not impaired. In addition to the coating base, the film coat portion may contain any additives used in coating agents for pharmaceutical preparations such as masking agents, coloring agents, and dispersants. The masking agents, coloring agents, and dispersants used in the coating agent have the same meaning as described above.

[0025] The pharmaceutical tablets in the present invention preferably contain 53.5 to 80 parts by mass of nilotinib hydrochloride, 0.1 to 20 parts by mass of a binder, 1 to 20 parts by mass of a disintegrant, 0.1 to 7 parts by mass of a lubricant, 0 to 5 parts by mass of a fluidizing agent, and 10 to 35 parts by mass of an excipient. By mixing the above prescription composition, granulating to prepare granules, and compression molding this, pharmaceutical tablets can be prepared. Thereafter, this pharmaceutical tablet may be film-coated. Preferably, it is a pharmaceutical tablet according to a prescription containing 53.5 to 70 parts by mass of nilotinib hydrochloride, 1 to 10 parts by mass of a binder, 1 to 10 parts by mass of a disintegrant, 1 to 5 parts by mass of a lubricant, 0 to 3 parts by mass of a fluidizing agent, and 20 to 35 parts by mass of an excipient. The shape of the pharmaceutical tablets of the present invention is not particularly limited as long as it is a normal shape and size suitable for oral administration.

[0026] The manufacturing method of the pharmaceutical tablets in the present invention is a manufacturing method of pharmaceutical tablets including a step of mixing nilotinib hydrochloride, an excipient, a disintegrant, and other additives, and then a step of compression molding the mixture obtained in the above step to prepare tablets.

[0027] In the manufacturing method of the pharmaceutical tablets of the present invention, sodium carboxymethylcellulose may be mixed with nilotinib hydrochloride and other additives as a powder, or sodium carboxymethylcellulose may be dissolved in an aqueous medium such as water, an organic solvent such as ethanol or methanol, and a mixed solvent thereof, and then mixed with nilotinib hydrochloride and other additives. Also, after mixing nilotinib hydrochloride and other additives, sodium carboxymethylcellulose may be dissolved in the above aqueous medium and sprayed, etc. to form a mixture.

[0028] In the manufacturing method of the pharmaceutical tablets of the present invention, before compression molding the pharmaceutical tablets, it is preferable to perform a granulation operation to prepare granules. Granules are granular substances with a certain particle size formed by adhesion of mixtures containing an active ingredient and various additives, and are granular substances prepared to improve the compression molding ability in subsequent steps. The granulation operation for preparing the granulated product may be dry granulation or wet granulation. Dry granulation is a granulation method in which no water is added during granulation, and wet granulation is an operation in which an appropriate amount of an aqueous medium such as water, an organic solvent such as ethanol or methanol, and a mixed solvent thereof is added to the mixture, and mechanical pressure such as a mixing operation is applied to adhere the mixtures to each other and granulate them into granular substances. Examples of the granulation operation include a compression granulation method, a melt granulation method, a roller compactor method, a rolling granulation method, a fluidized bed granulation method, a stirring granulation method, an extrusion granulation method, and the like. As the granulation operation according to the present invention, the granulated product can be appropriately selected from these operation methods to prepare the granulated product.

[0029] The method for manufacturing a pharmaceutical tablet of the present invention includes a step of compression molding the mixture obtained in the above step into a tablet. Using the above-mentioned nilotinib hydrochloride as an active ingredient, an excipient, a disintegrant, and an additive for preparing a pharmaceutical tablet are optionally added to a composition containing them, and a lubricant is optionally added, and the composition is molded into a tablet shape by tableting or the like, whereby a core tablet inside the pharmaceutical tablet can be prepared. The hardness of the tablet is preferably about 10 to 200 N. More preferably, it is 50 to 150 N.

[0030] In the method for manufacturing a pharmaceutical tablet of the present invention, after compression molding, a step of film coating the core tablet may be added. When performing film coating, the film coat portion outside the pharmaceutical tablet dissolves any additive used for the coating agent in a water-soluble solvent containing water or an organic solvent that can be mixed with water in an arbitrary ratio, and is injected or sprayed into a coating pan containing the core tablet inside the tablet, and hot air is sent to the tablet surface to remove the solvent from the tablet surface and dry it, whereby film coating can be performed. The drying step is preferably performed at about room temperature to 80°C. It may be dried by volatilizing the aqueous solvent under reduced pressure.

[0031] The pharmaceutical tablets of the present invention are characterized in that the disintegration of the tablets is delayed in a pH 3.0 buffer solution, and the elution of nilotinib can be controllably suppressed. That is, it is a pharmaceutical tablet showing an elution profile equivalent to that of a known capsule formulation of nilotinib. In this specification, the dissolution test for evaluating the dissolution property is a dissolution test according to the second method (paddle method) of the Japanese Pharmacopoeia dissolution test.

[0032] By the dissolution test method according to the second method (paddle method) of the Japanese Pharmacopoeia dissolution test, eluting nilotinib hydrochloride, which is the active ingredient, from the pharmaceutical tablets of the present invention into the test solution, and evaluating the elution rate of nilotinib in the test solution using an ultraviolet-visible spectrophotometer or liquid chromatography, it can be confirmed that the pharmaceutical tablets of the present invention are those in which the disintegration is delayed in a pH 3.0 buffer solution.

[0033] The pharmaceutical tablets of the present invention are characterized in that the disintegration is delayed in a pH 3.0 buffer solution. More specifically, in the dissolution test according to the second method (paddle method) of the Japanese Pharmacopoeia dissolution test, when the test solution is 900 mL of a pH 3.0 buffer solution, the elution rate is 40% or less at 30 minutes from the start of the test, more preferably 40% or less at 30 minutes, 50% or less at 60 minutes, and 60% or less at 120 minutes.

[0034] The use of the pharmaceutical product using the pharmaceutical tablets of the present invention is not particularly limited as long as it is a disease having a therapeutic effect by nilotinib. For example, it can be applied to the treatment of malignant tumors. More specifically, non-small cell lung cancer, pancreatic cancer, glioma, colorectal cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, renal cancer, head and neck cancer, chronic myeloid leukemia, myelodysplastic syndrome, esophageal cancer can be mentioned. Although not limited to these diseases, they can be mentioned as preferred diseases to be applied.

[0035] The dosage of the pharmaceutical product using the pharmaceutical preparation of the present invention can naturally vary depending on the gender, age, physiological state, disease state, etc. of the patient. For example, for adults, a drug in the range of 10 mg to 1 g as nilotinib is administered per day. Although not limited to this dosage, it can be cited as a preferable dosage for application.

Examples

[0036] Hereinafter, the present invention will be further described with reference to examples. However, the present invention is not limited to these examples.

[0037] [Example 1] 1000.6 mg of nilotinib hydrochloride dihydrate (Form A), 550.4 mg of crystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation), 70.4 mg of sodium carboxymethylcellulose (manufactured by Gode Chemical Co., Ltd., viscosity of 1% aqueous solution: 390 mPa·s), 70.4 mg of crospovidone (manufactured by BASF), 17.6 mg of colloidal silicon dioxide (manufactured by Nippon Aerosil Co., Ltd.), and 15.4 mg of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) were mixed and then granulated by the compression granulation method. The granulated granules were sized using a sieve with an aperture of 0.5 mm, and 35.2 mg of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) was admixed to obtain tablet powder. Approximately 400 mg of this tablet powder was compression molded using a tableting machine to obtain the tablets of Example 1.

[0038] [Example 2] 1000.6 mg of nilotinib hydrochloride dihydrate (Form A), 532.8 mg of crystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation), 52.8 mg of sodium carboxymethylcellulose (manufactured by Gode Chemical Co., Ltd., viscosity of 1% aqueous solution: 390 mPa·s), 105.6 mg of crospovidone (manufactured by BASF), 17.6 mg of colloidal silicon dioxide (manufactured by Nippon Aerosil Co., Ltd.), and 15.4 mg of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) were mixed and then granulated by the compression granulation method. The granulated granules were sized using a sieve with an aperture of 0.5 mm, and 35.2 mg of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) was admixed to obtain tablet powder. Approximately 400 mg of this powder for tableting was compression molded using a tableting machine to obtain the tablets of Example 2.

[0039] [Example 3] 1023.3 mg of nilotinib hydrochloride dihydrate (Form A), 544.95 mg of crystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation), 54.0 mg of sodium carboxymethyl cellulose (manufactured by Daicel Finechem Ltd., viscosity of 1% aqueous solution: 734 mPa·s), 108.0 mg of crospovidone (manufactured by BASF), 18.0 mg of colloidal silicon dioxide (manufactured by Nippon Aerosil Co., Ltd.), and 15.75 mg of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) were mixed, and then granulation was carried out by the compression granulation method. The granulated particles were sized using a sieve with an aperture of 0.5 mm, and 36.0 mg of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) was admixed to obtain the powder for tableting. Approximately 400 mg of this powder for tableting was compression molded using a tableting machine to obtain the tablets of Example 3.

[0040] [Example 4] 1000.6 mg of nilotinib hydrochloride dihydrate (Form A), 437.1 mg of crystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation), 49.5 mg of sodium carboxymethyl cellulose (manufactured by Gode Chemical Co., Ltd., viscosity of 1% aqueous solution: 390 mPa·s), 99.0 mg of crospovidone (manufactured by BASF), 16.5 mg of colloidal silicon dioxide (manufactured by Nippon Aerosil Co., Ltd.), and 14.3 mg of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) were mixed, and then granulation was carried out by the compression granulation method. The granulated particles were sized using a sieve with an aperture of 0.5 mm, and 33.0 mg of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) was admixed to obtain the powder for tableting. Approximately 375 mg of this powder for tableting was compression molded using a tableting machine to obtain the tablets of Example 4.

[0041] [Example 5] 1455.4 mg of nilotinib hydrochloride dihydrate (Form A), 538.2 mg of crystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation), 67.2 mg of sodium carboxymethyl cellulose (manufactured by Gode Chemical Co., Ltd., viscosity of 1% aqueous solution: 390 mPa·s), and 134.4 mg of crospovidone (manufactured by BASF) were mixed, and then granulated by the compression granulation method. The granulated particles were sized using a sieve with an aperture of 0.5 mm, and 44.8 mg of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) was admixed to obtain powder for tableting. Approximately 350 mg of this powder for tableting was compression-molded using a tableting machine to obtain the tablets of Example 5.

[0042] [Example 6] 113.7 g of nilotinib hydrochloride dihydrate (Form A), 40.3 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation), 7.0 g of sodium carboxymethyl cellulose (manufactured by Daicel Finechem Ltd., viscosity of 1% aqueous solution: 168 mPa·s), 10.5 g of crospovidone (manufactured by BASF), and 1.75 g of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) were mixed, and then granulated by the compression granulation method. The granulated particles were sized using a sieve with an aperture of 0.5 mm, and 1.75 g of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) was admixed to obtain powder for tableting. Approximately 350 mg of this powder for tableting was compression-molded using a tableting machine to obtain the tablets of Example 6.

[0043] [Example 7] 113.7 g of nilotinib hydrochloride dihydrate (Form A), 43.8 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation), 7.0 g of sodium carboxymethyl cellulose (manufactured by Daicel Finechem Ltd., viscosity of 1% aqueous solution: 168 mPa·s), 7.0 g of crospovidone (manufactured by BASF), and 1.75 g of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) were mixed, and then granulated by the compression granulation method. The granulated particles were sized using a sieve with an aperture of 0.5 mm, and 1.75 g of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) was admixed to obtain powder for tableting. Approximately 350 mg of this powder for tableting was compression-molded using a tableting machine to obtain the tablets of Example 7.

[0044] [Comparative Example 1] 1023.3 mg of nilotinib hydrochloride dihydrate (Form A), 777.6 mg of crystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation), 63.0 mg of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.), 126.0 mg of crospovidone (manufactured by BASF), 20.7 mg of colloidal silicon dioxide (manufactured by Nippon Aerosil Co., Ltd.), and 18.0 mg of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) were mixed and then granulated by a compression granulation method. The granulated granules were sized using a sieve with an aperture of 0.5 mm, and 41.4 mg of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) was admixed to obtain powder for tableting. Approximately 460 mg of this powder for tableting was compression molded using a tableting machine to obtain the tablets of Comparative Example 1.

[0045] [Comparative Example 2] Based on Example 1 (200 mg tablet core) of the aforementioned Patent Document 2, the following tablets were prepared. 992.7 mg of nilotinib hydrochloride monohydrate (Form B), 808.2 mg of crystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation), 63.0 mg of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.), 126.0 mg of crospovidone (manufactured by BASF), 20.7 mg of colloidal silicon dioxide (manufactured by Nippon Aerosil Co., Ltd.), and 18.0 mg of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) were mixed and then granulated by a compression granulation method. The granulated granules were sized using a sieve with an aperture of 0.5 mm, and 41.4 mg of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) was admixed to obtain powder for tableting. Approximately 460 mg of this powder for tableting was compression molded using a tableting machine to obtain the tablets of Comparative Example 2.

[0046] [Comparative Example 3] A capsule formulation containing nilotinib hydrochloride monohydrate as an active ingredient (Tasigna (registered trademark) capsules 200 mg) was used.

[0047] The formulation prescriptions of the examples and comparative examples are summarized in Tables 1-1 and 1-2. [Table 1-1] TIFF0007704933000002.tif42124

[0048] [Table 1-2] TIFF0007704933000003.tif46124*1; Nilotinib hydrochloride monohydrate was used.

[0049] [Test Example 1] Dissolution Test The tablets obtained in Examples 1 to 7, Comparative Examples 1 to 5, and the capsule of Comparative Example 6 were evaluated for dissolution rate by the second method (paddle method) of the Japanese Pharmacopoeia dissolution test using diluted Mcllvaine buffer (pH 3.0). The detailed dissolution test conditions were set as follows. · Dissolution tester: NTR-6600A, manufactured by Toyama Sangyo Co., Ltd. · Volume of test solution: 900 mL · Temperature of test solution: 37 ± 0.5 °C · Paddle rotation speed: 50 rpm · Analytical instrument: Ultraviolet-visible spectrophotometer (UV-1900, manufactured by Shimadzu Corporation) · Measurement wavelength: 254 nm As a standard solution sample for quantitative analysis, a nilotinib hydrochloride solution was prepared at an arbitrary concentration using diluted Mcllvaine buffer (pH 3.0) as the test solution, and the absorbance at a wavelength of 254 nm was measured, which was used as the standard value in the test solution. In the dissolution test, the absorbance of the solution at each time point was measured to calculate the concentration of nilotinib hydrochloride in the solution at each time point and the dissolution rate was calculated. The results obtained are shown in Table 2.

[0050] [Table 2] TIFF0007704933000004.tif4980

[0051] From the results in Table 1, the tablets of Examples 1 to 7 according to the present invention are tablets with a nilotinib content of 50% by mass or more, and can surely elute the active ingredient. In particular, although the existing nilotinib preparation (Comparative Example 3; capsule preparation) has the characteristic that the initial dissolution is suppressed and dissolution is controlled, Examples 1 to 7 all have this characteristic. On the other hand, in Comparative Examples 1 and 2, the dissolution rates of nilotinib hydrochloride 30 minutes after the start of the dissolution test in a pH 3.0 buffer solution are significantly different. The tablets of Examples 1 to 7 can suppress the dissolution rate by delaying the disintegration in a pH 3.0 buffer solution. In contrast, the tablets of Comparative Examples 1 and 2 disintegrated rapidly immediately after the start of the dissolution test, so that the active ingredient eluted rapidly and a gentle rise of the dissolution curve could not be realized. In particular, Examples 2, 6 and 7 showed dissolution properties equivalent to those of Comparative Example 3 (capsule preparation), which is an existing preparation, and are pharmaceutical preparations equivalent to the existing capsule preparation. The nilotinib tablets according to the present invention are in a tablet form that is easier to swallow than the existing capsule preparation, and contain a higher content of nilotinib hydrochloride than the tablets shown in Patent Document 2 (Comparative Examples 1 and 2). Therefore, it is possible to provide a nilotinib preparation that is easier to swallow and has excellent pharmaceutical properties.

Claims

1. A pharmaceutical tablet containing nilotinib hydrochloride, an excipient, and a disintegrant, wherein in the mass of the core tablet of the pharmaceutical tablet, the nilotinib content is 50% by mass or more and 60% by mass or less, the excipient contains crystalline cellulose, and the content of crystalline cellulose is more than 15% by mass and less than 35% by mass, the content of the disintegrant is 4% by mass or more and less than 10% by mass, a pharmaceutical tablet in which the content of the total mass of crystalline cellulose and the disintegrant is more than 25% by mass and less than 40% by mass.

2. The pharmaceutical tablet according to Claim 1, containing sodium carboxymethyl cellulose.

3. The pharmaceutical tablet according to Claim 2, wherein the content of the total mass of the disintegrant and sodium carboxymethyl cellulose is more than 5% by mass and less than 12% by mass in the mass of the core tablet of the pharmaceutical tablet.

4. The pharmaceutical tablet according to Claim 2 or 3, wherein the content ratio of the disintegrant and sodium carboxymethyl cellulose is [disintegrant] / [sodium carboxymethyl cellulose] = 1 to 5.

Images