Nilotinib tablet

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 has an increased content of the active ingredient and is easy to take. [Background technology]

[0002] Nilotinib is a compound 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 and has the structure represented by the general formula (1). [ka]

[0003] Nilotinib is a tyrosine kinase inhibitor (TKI) with high selectivity and potent inhibitory activity against Bcr-Abl tyrosine kinase. It is believed to exhibit antitumor effects by competitively antagonizing ATP and inhibiting Bcr-Abl tyrosine kinase, thereby inducing apoptosis in Bcr-Abl-expressing cells. It is commercially available under the trade name Tasigna® Capsules and is used as a treatment for chronic or accelerated phase chronic myeloid leukemia (Non-Patent Document 1). Patent Document 1 describes a pharmaceutical capsule formulation using granules containing nilotinib hydrochloride, in which the internal phase of the granules contains polyoxyethylene-polyoxypropylene block copolymer (the number of oxyethylene units and the number of oxypropylene units are 150 and 30, respectively), lactose monohydrate, and polyvinylpyrrolidone, and the external phase of the granules contains lactose monohydrate, colloidal silicon dioxide, and magnesium stearate. In general, capsule formulations are said to be dosage forms that tend to be difficult to swallow. Therefore, the development of nilotinib tablets with excellent swallowability is desired. Furthermore, the tablets are required to exhibit dissolution properties equivalent to those of existing nilotinib capsule formulations. To obtain nilotinib tablets with a dissolution profile equivalent to that of existing capsule formulations, it is necessary to retard disintegration, particularly in a pH 3.0 buffer solution, to inhibit dissolution. In Patent Document 2, in order to prepare nilotinib tablets with a dissolution profile equivalent to that of capsule formulations, film-coated tablets are prepared by coating with a coating material containing hydroxypropyl cellulose E50, thereby delaying disintegration by 4 to 15 minutes. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Special Publication No. 2010-504942 [Patent Document 2] Special Publication No. 2014-533283 [Non-patent literature]

[0005] [Non-Patent Document 1] Tasigna® Capsules 25 mg, 150 mg, and 200 mg Drug Interview Form (Revised December 2017 (18th Edition)) DISCLOSURE OF THE INVENTION [Problem 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, which has an increased nilotinib content, particularly a pharmaceutical tablet having a nilotinib content of 50% by mass or more of the uncoated tablet mass. [Means for solving the problem]

[0007] The present invention is summarized as follows [1] to [8]. [1] A pharmaceutical tablet containing nilotinib hydrochloride, an excipient, and a disintegrant, wherein the nilotinib content in the uncoated tablet of the pharmaceutical tablet is 50% by mass or more. [2] The pharmaceutical tablet according to [1], wherein the content of the excipient is less than 35% by mass of the uncoated tablet of the pharmaceutical tablet. [3] The pharmaceutical tablet according to [1] or [2], wherein the content of the disintegrant is 4% by mass or more and less than 10% by mass of the uncoated tablet of the pharmaceutical tablet. [4] The pharmaceutical tablet according to any one of [1] to [3], wherein the excipient comprises crystalline cellulose, and the content of crystalline cellulose is more than 10% by mass and less than 35% by mass of the uncoated tablet of the pharmaceutical tablet. [5] The pharmaceutical tablet according to [4], wherein the content of the total mass of the crystalline cellulose and the disintegrant is more than 15% by mass and less than 45% by mass of the uncoated tablet of the pharmaceutical tablet. [6] The pharmaceutical tablet according to any one of [1] to [5] above, which contains carmellose sodium. [7] The pharmaceutical tablet according to [6], wherein the content of the total mass of the disintegrant and carmellose sodium combined is more than 5% by mass and less than 12% by mass of the uncoated tablet of the pharmaceutical tablet. [8] The pharmaceutical tablet according to the above [6] or [7], wherein the content ratio of the disintegrant to carmellose sodium is [disintegrant] / [carmellose sodium]=1 to 5. [Effects of the Invention]

[0008] According to the present invention, it is possible to prepare a pharmaceutical tablet containing nilotinib at 50% by mass or more, thereby enabling the tablet to be made smaller and providing a pharmaceutical tablet that is easy to take. DETAILED DESCRIPTION OF THE INVENTION

[0009] The pharmaceutical tablet of the present invention containing nilotinib hydrochloride, excipients and a disintegrant is 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 is used. Nilotinib hydrochloride is preferably of pharmaceutically acceptable quality. Nilotinib hydrochloride is known in Patent No. 5798101 as Forms A (dihydrate), A' (monohydrate), A'' (anhydrous), B (monohydrate), B' (anhydrous), C (monohydrate), C' (anhydrous), S B , S B ', S C , D, S E In addition, Japanese Patent No. 5486012 discloses Forms T1 to T19, and any of these forms can be used in the present invention. In the present invention, the nilotinib hydrochloride used is not particularly limited, but Form A nilotinib hydrochloride dihydrate or Form A', B, or C nilotinib hydrochloride monohydrate is preferred.

[0011] The pharmaceutical tablet of the present invention contains nilotinib (free base) at 50% by mass or more. Conventional nilotinib formulations have been capsule formulations that are difficult to swallow. However, in addition to making the tablet easier to take, by further increasing the active ingredient content and relatively reducing the tablet size, it is possible to further improve medication compliance. Nilotinib is preferably contained at 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 tablet of the present invention contains 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 sugars such as lactose, maltose, mannitol, erythritol, fructose, trehalose, sucrose, sorbitol, xylitol, and inositol. Celluloses such as crystalline cellulose and powdered cellulose are preferably used. The content of the excipient in the pharmaceutical tablet of the present invention is preferably less than 35% by mass, more preferably more than 15% by mass but less than 35% by mass, and more preferably more than 20% by mass but less than 35% by mass, of the uncoated tablet. As the excipient, celluloses such as crystalline cellulose and powdered cellulose are preferably used, and crystalline cellulose is more preferably used. The crystalline cellulose is preferably used at a content of more than 10% by mass and less than 35% by mass, more preferably more than 15% by mass and less than 35% by mass, and particularly preferably more than 20% by mass and less than 35% by mass, based on the mass of the uncoated pharmaceutical tablet. The excipient is preferably one that does not contain the above-mentioned starches or sugars, and more preferably an excipient that contains only the above-mentioned celluloses, such as crystalline cellulose and / or powdered cellulose.

[0013] Examples of disintegrants used in the present invention include carboxymethyl starch sodium, crospovidone, carmellose calcium, croscarmellose sodium, partially pregelatinized starch, and low-substituted hydroxypropyl cellulose. Carboxymethyl starch sodium, crospovidone, and croscarmellose sodium are preferred. These are also known as super disintegrants, and because they function with small amounts, they can reduce the amount of additives used to produce compact tablets. The content of the disintegrant in the uncoated tablet of the pharmaceutical tablet of the present invention is preferably 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 preferred.

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

[0015] The pharmaceutical tablet of the present invention preferably uses carmellose sodium. In the present invention, carmellose sodium functions as a binder and can control the disintegration rate of the tablet. In preparing nilotinib tablets, it is preferable to suppress the dissolution of the tablet so that the dissolution is equivalent to that of existing nilotinib capsule formulations. When tableting, it is necessary to suppress the dissolution in, for example, a pH 3.0 buffer solution in order to achieve the same dissolution as the capsule formulation. By using carmellose sodium, the disintegration of the pharmaceutical tablet can be adjusted and the dissolution can be controlled. The content of carmellose sodium in the pharmaceutical tablet of the present invention is preferably more than 1% by mass and less than 10% by mass, more preferably more than 2% by mass and less than 8% by mass, and particularly preferably more than 2% by mass and less than 6% by mass, based on the weight of the uncoated tablet. It is preferable to use carmellose sodium whose viscosity when made into a 1% aqueous solution is greater than 10 mPa·s but less than 1000 mPa·s, and more preferably greater than 50 mPa·s but less than 500 mPa·s. The viscosity was measured by preparing a 1% aqueous solution, degassing it under reduced pressure, and using it as a sample solution. The sample solution was stirred uniformly until the liquid temperature reached 25°C, and then the value was measured at 60 rpm using a Brookfield viscometer.

[0016] Since carmellose sodium is used to adjust disintegration properties, it is preferable to design the formulation of the pharmaceutical tablet taking into consideration the total mass including the disintegrant. The content of the total mass including carmellose sodium and the disintegrant is preferably more than 5% by mass and less than 15% by mass, more preferably more than 5% by mass and less than 12% by mass, of the uncoated tablet mass of the pharmaceutical tablet. Furthermore, appropriate dissolution properties can be achieved by controlling the content ratio of carmellose sodium to disintegrant in order to control disintegration properties. That is, increasing the content ratio of carmellose sodium can suppress dissolution in a pH 3.0 buffer solution, while increasing the content ratio of disintegrant can enhance dissolution properties. In the present invention, the content ratio of disintegrant to carmellose sodium is preferably [disintegrant] / [carmellose sodium] = 0.5 to 5. By setting the content in this range, dissolution in a pH 3.0 buffer solution can be suppressed. More preferably, [disintegrant] / [carmellose sodium] = 1 to 5. This allows the dissolution rate in a 900 mL test solution of a pH 3.0 buffer solution to be 40% or less at 30 minutes, 50% or less at 60 minutes, and 60% or less at 120 minutes from the start of the test.

[0017] The pharmaceutical tablet of the present invention may use carmellose sodium alone as a binder, or may be used in combination with other binders such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone.

[0018] The pharmaceutical tablet of the present invention may contain other additives used in tablet preparation. Examples include solubilizers, dispersants, lubricants, fluidizing agents, masking agents, and colorants. These additives can be used without particular limitations as long as they have a purity acceptable for pharmaceutical formulations. These additives may be used alone or in combination. These additives are optionally used when preparing the pharmaceutical tablet.

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

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

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

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

[0023] Other additives such as disintegrants, binders, solubilizers, dispersants, lubricants, fluidizers, excipients, masking agents, and colorants may be used as granules prepared by premixing other additive compositions containing one or more of these additives. Premixing other additives to form a granule has the advantage of providing physical properties that make it easy to handle during tablet production operations.

[0024] The pharmaceutical tablet of the present invention may be film-coated. Examples of film-coating bases include hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, etc. As the film-coating base, an amino group-modified polymer additive may be included in the film-coated portion of the pharmaceutical tablet, as long as it does not interfere with the effects of the present invention. In addition to the coating base, the film-coated portion may contain any additives used in coating agents for pharmaceutical preparations, such as a masking agent, a coloring agent, a dispersing agent, etc. The masking agent, coloring agent, and dispersing agent used in the coating agent have the same meanings as those described above.

[0025] The pharmaceutical tablet of the present invention is preferably formulated to contain 53.5 to 80 parts by weight of nilotinib hydrochloride, 0.1 to 20 parts by weight of binder, 1 to 20 parts by weight of disintegrant, 0.1 to 7 parts by weight of lubricant, 0 to 5 parts by weight of glidant, and 10 to 35 parts by weight of excipient. The above-mentioned formulations are mixed and granulated to prepare granules, which are then compressed to prepare pharmaceutical tablets. These pharmaceutical tablets may then be film-coated. Preferably, the pharmaceutical tablet is formulated to contain 53.5 to 70 parts by weight of nilotinib hydrochloride, 1 to 10 parts by weight of binder, 1 to 10 parts by weight of disintegrant, 1 to 5 parts by weight of lubricant, 0 to 3 parts by weight of glidant, and 20 to 35 parts by weight of excipient. The shape of the pharmaceutical tablet of the present invention is not particularly limited as long as it has a normal shape and size suitable for oral administration.

[0026] The method for producing a pharmaceutical tablet in the present invention is a method for producing a pharmaceutical tablet, which includes the steps of mixing nilotinib hydrochloride with an excipient, a disintegrant, and other additives, and then compressing the mixture obtained in the above step to prepare a tablet.

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

[0028] In the method for producing pharmaceutical tablets of the present invention, it is preferable to carry out a granulation operation to prepare a granulated product before compressing the pharmaceutical tablets. The granulated product is a granular product having a certain particle size formed by the adhesion of a mixture containing an active ingredient and various additives, and is prepared to improve compression molding ability in a subsequent step. The granulation procedure for preparing the granules may be dry granulation or wet granulation. Dry granulation is a granulation method in which water is not added during granulation, while wet granulation is a procedure in which an appropriate amount of an aqueous medium, such as water, an organic solvent such as ethanol or methanol, or a mixture thereof, is added to the mixture, and mechanical pressure, such as a mixing operation, is applied to cause the mixture to adhere to each other, resulting in granulation into a granular product. Examples of granulation procedures include compression granulation, melt granulation, roller compactor method, tumbling granulation, fluidized bed granulation, stirring granulation, and extrusion granulation. The granulation procedure according to the present invention can be appropriately selected from these methods to prepare the granules.

[0029] The method for producing pharmaceutical tablets of the present invention includes a step of compressing the mixture obtained in the above step to form tablets. The composition contains the above-mentioned nilotinib hydrochloride as an active ingredient, an excipient, a disintegrant, and additives for preparing pharmaceutical tablets, and optionally a lubricant is added to the composition, which is then molded into a tablet form by tableting or the like to prepare the core tablet, which is the interior of the pharmaceutical tablet. The tablet hardness is preferably about 10 to 200 N, more preferably 50 to 150 N.

[0030] The method for producing pharmaceutical tablets of the present invention may further include a step of film-coating the uncoated tablets after compression molding. When film-coating is performed, the film-coated portion (exterior portion of the pharmaceutical tablet) can be film-coated by dissolving any additives used in the coating agent in a water-soluble solvent containing water or an organic solvent miscible with water in any ratio, pouring or spraying the solution into a coating pan containing the uncoated tablets (interior portion of the tablet), and then blowing hot air onto the tablet surface to remove the solvent from the tablet surface and dry it. The drying step is preferably performed at room temperature to about 80°C. Drying may also be performed under reduced pressure to volatilize the aqueous solvent.

[0031] The pharmaceutical tablet of the present invention is characterized by being a pharmaceutical tablet that exhibits delayed disintegration in a pH 3.0 buffer solution and can inhibit and control the dissolution of nilotinib. That is, it is a pharmaceutical tablet that exhibits a dissolution profile equivalent to that of known capsule formulations of nilotinib. In this specification, the dissolution test for evaluating dissolution is a dissolution test according to Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method).

[0032] By using a dissolution test method according to Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method), the active ingredient nilotinib hydrochloride is dissolved from the pharmaceutical tablet of the present invention into a test solution, and the dissolution rate of nilotinib into the test solution is evaluated using an ultraviolet-visible spectrophotometer or liquid chromatography, it can be confirmed that the pharmaceutical tablet of the present invention has a delayed disintegration in a pH 3.0 buffer solution, which is a characteristic of the pharmaceutical tablet of the present invention.

[0033] The pharmaceutical tablet of the present invention is characterized by being a pharmaceutical tablet whose disintegration is delayed in a pH 3.0 buffer solution. More specifically, in a dissolution test according to Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method), when the test solution is 900 mL of a pH 3.0 buffer solution, the dissolution rate is 40% or less 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 using the pharmaceutical tablet of the present invention is not particularly limited as long as it is a disease for which nilotinib has a therapeutic effect. 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, and esophageal cancer can be mentioned. Although not limited to these diseases, preferred examples of the applicable diseases include:

[0035] The dosage of the pharmaceutical preparation of the present invention may vary depending on the patient's gender, age, physiological condition, pathological condition, etc., but for example, an adult is administered 10 mg to 1 g of nilotinib per day. This dosage is not limited to this amount, but can be cited as a preferred dosage. [Example]

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

[0037] [Example 1] Nilotinib hydrochloride dihydrate (Form A) 1000.6 mg, microcrystalline cellulose (Asahi Kasei Chemicals Corporation) 550.4 mg, carmellose sodium (Gotoku Pharmaceutical Co., Ltd., viscosity of 1% aqueous solution 390 mPa·s) 70.4 mg, crospovidone (BASF) 70.4 mg, colloidal silicon dioxide (Nippon Aerosil Co., Ltd.) 17.6 mg, and magnesium stearate (Japanese Pharmacopoeia Magnesium Stearate) 15.4 mg were mixed and granulated by compression granulation. The granulated granules were sieved using a 0.5 mm mesh sieve and mixed with 35.2 mg of magnesium stearate (Japanese Pharmacopoeia Magnesium Stearate) to obtain a powder for tableting. Approximately 400 mg of this powder for tableting was compressed in a tableting machine to form tablets of Example 1.

[0038] [Example 2] Nilotinib hydrochloride dihydrate (Form A) 1000.6 mg, microcrystalline cellulose (Asahi Kasei Chemicals Corporation) 532.8 mg, carmellose sodium (Gotoku Pharmaceutical Co., Ltd., viscosity of 1% aqueous solution 390 mPa·s) 52.8 mg, crospovidone (BASF) 105.6 mg, colloidal silicon dioxide (Nippon Aerosil Co., Ltd.) 17.6 mg, and magnesium stearate (Japanese Pharmacopoeia Magnesium Stearate) 15.4 mg were mixed and granulated by compression granulation. The granulated granules were sieved using a 0.5 mm mesh sieve and mixed with 35.2 mg of magnesium stearate (Japanese Pharmacopoeia Magnesium Stearate) to obtain a powder for tableting. Approximately 400 mg of this powder for tableting was compressed in a tableting machine to form tablets of Example 2.

[0039] [Example 3] Nilotinib hydrochloride dihydrate (Form A) 1023.3 mg, microcrystalline cellulose (Asahi Kasei Chemicals Corporation) 544.95 mg, carmellose sodium (Daicel FineChem, 1% aqueous solution viscosity 734 mPa·s) 54.0 mg, crospovidone (BASF) 108.0 mg, colloidal silicon dioxide (Nippon Aerosil Co., Ltd.) 18.0 mg, and magnesium stearate (Japanese Pharmacopoeia Magnesium Stearate) 15.75 mg were mixed and granulated by compression granulation. The granulated granules were sieved using a 0.5 mm mesh sieve and mixed with 36.0 mg of magnesium stearate (Japanese Pharmacopoeia Magnesium Stearate) to obtain a powder for tableting. Approximately 400 mg of this powder for tableting was compressed in a tableting machine to form tablets of Example 3.

[0040] [Example 4] Nilotinib hydrochloride dihydrate (Form A) 1000.6 mg, microcrystalline cellulose (Asahi Kasei Chemicals Corporation) 437.1 mg, carmellose sodium (Gotoku Pharmaceutical Co., Ltd., viscosity of 1% aqueous solution 390 mPa·s) 49.5 mg, crospovidone (BASF) 99.0 mg, colloidal silicon dioxide (Nippon Aerosil Co., Ltd.) 16.5 mg, and magnesium stearate (Japanese Pharmacopoeia Magnesium Stearate) 14.3 mg were mixed and granulated by compression granulation. The granulated granules were sieved using a 0.5 mm mesh sieve and mixed with 33.0 mg of magnesium stearate (Japanese Pharmacopoeia Magnesium Stearate) to obtain a powder for tableting. Approximately 375 mg of this powder for tableting was compressed in a tableting machine to form tablets of Example 4.

[0041] [Example 5] Nilotinib hydrochloride dihydrate (Form A) 1455.4 mg, crystalline cellulose (Asahi Kasei Chemicals Corporation) 538.2 mg, carmellose sodium (Gotoku Pharmaceutical Co., Ltd., viscosity of 1% aqueous solution 390 mPa·s) 67.2 mg, and crospovidone (BASF) 134.4.0 mg were mixed and then granulated by compression granulation. The granulated granules were sieved using a 0.5 mm mesh sieve and mixed with 44.8 mg of magnesium stearate (Japanese Pharmacopoeia Magnesium Stearate) to obtain a powder for tableting. Approximately 350 mg of this powder for tableting was compressed in a tableting machine to form tablets of Example 5.

[0042] [Example 6] Nilotinib hydrochloride dihydrate (Form A) (113.7 g), microcrystalline cellulose (Asahi Kasei Chemicals Corporation) (40.3 g), carmellose sodium (Daicel FineChem, 1% aqueous solution viscosity 168 mPa·s) (7.0 g), crospovidone (BASF) (10.5 g), and magnesium stearate (Japanese Pharmacopoeia, Magnesium Stearate) (1.75 g) were mixed and granulated by compression granulation. The granulated granules were sieved using a 0.5 mm mesh sieve and mixed with 1.75 g of magnesium stearate (Japanese Pharmacopoeia, Magnesium Stearate) to obtain a powder for tableting. Approximately 350 mg of this powder for tableting was compressed in a tableting machine to form tablets of Example 6.

[0043] [Example 7] Nilotinib hydrochloride dihydrate (Form A) (113.7 g), microcrystalline cellulose (Asahi Kasei Chemicals Corporation) (43.8 g), carmellose sodium (Daicel FineChem, 1% aqueous solution viscosity 168 mPa·s) (7.0 g), crospovidone (BASF) (7.0 g), and magnesium stearate (Japanese Pharmacopoeia, Magnesium Stearate) (1.75 g) were mixed and granulated by compression granulation. The granulated granules were sieved using a 0.5 mm mesh sieve and mixed with 1.75 g of magnesium stearate (Japanese Pharmacopoeia, Magnesium Stearate) to obtain a powder for tableting. Approximately 350 mg of this powder for tableting was compressed in a tableting machine to form tablets of Example 7.

[0044] [Comparative Example 1] Nilotinib hydrochloride dihydrate (Form A) 1023.3 mg, crystalline cellulose (Asahi Kasei Chemicals Corporation) 777.6 mg, hydroxypropyl cellulose (Nippon Soda Co., Ltd.) 63.0 mg, crospovidone (BASF) 126.0 mg, colloidal silicon dioxide (Nippon Aerosil Co., Ltd.) 20.7 mg, and magnesium stearate (Japanese Pharmacopoeia Magnesium Stearate) 18.0 mg were mixed and then granulated by compression granulation. The granulated granules were sieved using a 0.5 mm mesh sieve and mixed with 41.4 mg of magnesium stearate (Japanese Pharmacopoeia Magnesium Stearate) to obtain a powder for tableting. Approximately 460 mg of this powder for tableting was compressed in a tableting machine to form 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. Nilotinib hydrochloride monohydrate (form B) 992.7 mg, crystalline cellulose (Asahi Kasei Chemicals Corporation) 808.2 mg, hydroxypropyl cellulose (Nippon Soda Co., Ltd.) 63.0 mg, crospovidone (BASF) 126.0 mg, colloidal silicon dioxide (Nippon Aerosil Co., Ltd.) 20.7 mg, and magnesium stearate (Japanese Pharmacopoeia Magnesium Stearate) 18.0 mg were mixed and then granulated by compression granulation. The granulated granules were sieved using a 0.5 mm mesh sieve and mixed with 41.4 mg of magnesium stearate (Japanese Pharmacopoeia Magnesium Stearate) to obtain a powder for tableting. Approximately 460 mg of this powder for tableting was compressed in a tableting machine to form tablets of Comparative Example 2.

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

[0047] Tables 1-1 and 1-2 summarize the formulations of the examples and comparative examples. [Table 1-1] TIFF2025123520000002.tif42124

[0048] [Table 1-2] TIFF2025123520000003.tif46124*1;Nilotinib hydrochloride monohydrate was used.

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

[0050] [Table 2] TIFF2025123520000004.tif4980

[0051] From the results in Table 1, the tablets of Examples 1 to 7 according to the present invention have a nilotinib content of 50% by mass or more and can reliably release the active ingredient. In particular, the existing nilotinib formulation (Comparative Example 3; capsule formulation) is characterized by suppressed dissolution control in the initial stage of dissolution, and all of Examples 1 to 7 share this characteristic. Meanwhile, Comparative Examples 1 and 2 show significant differences in the dissolution rate of nilotinib hydrochloride 30 minutes after the start of the dissolution test in a pH 3.0 buffer solution. The tablets of Examples 1 to 7 can suppress the dissolution rate by delaying disintegration in a pH 3.0 buffer solution. In contrast, the tablets of Comparative Examples 1 and 2 rapidly disintegrated immediately after the start of the dissolution test, resulting in rapid dissolution of the active ingredient and failing to achieve a gradual rise in the dissolution curve. In particular, Examples 2, 6, and 7 exhibited dissolution properties comparable to those of the existing formulation, Comparative Example 3 (capsule formulation), and are pharmaceutical formulations equivalent to the existing capsule formulation. The nilotinib tablet of the present invention is in a tablet form that is easier to swallow than existing capsule formulations, and contains a higher amount of nilotinib hydrochloride than the tablets shown in Patent Document 2 (Comparative Examples 1 and 2). Therefore, it is possible to provide a nilotinib formulation that is easier to swallow and has excellent compliance.

Claims

1. A pharmaceutical tablet comprising nilotinib hydrochloride, an excipient, and a disintegrant, wherein the nilotinib content in the uncoated tablet mass of the pharmaceutical tablet is 50% by mass or more.

2. 2. The pharmaceutical tablet according to claim 1, wherein the content of excipients is less than 35% by weight of the uncoated tablet of the pharmaceutical tablet.

3. 3. The pharmaceutical tablet according to claim 1, wherein the content of the disintegrant is 4% by mass or more and less than 10% by mass of the uncoated tablet of the pharmaceutical tablet.

4. The pharmaceutical tablet according to any one of claims 1 to 3, wherein the excipient comprises crystalline cellulose, and the content of crystalline cellulose is more than 10% by mass and less than 35% by mass of the uncoated tablet of the pharmaceutical tablet.

5. The pharmaceutical tablet according to claim 4, wherein the content of the total mass of the crystalline cellulose and the disintegrant is more than 15% by mass and less than 45% by mass of the uncoated tablet of the pharmaceutical tablet.

6. The pharmaceutical tablet according to any one of claims 1 to 5, comprising carmellose sodium.

7. 7. The pharmaceutical tablet according to claim 6, wherein the content of the total mass of the disintegrant and carmellose sodium is more than 5% by mass and less than 12% by mass of the uncoated tablet of the pharmaceutical tablet.

8. 8. The pharmaceutical tablet according to claim 6, wherein the content ratio of the disintegrant to the carmellose sodium is [disintegrant] / [carmellose sodium]=1 to 5.

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