Nilotinib tablets and their manufacturing method

Abstract

To provide, with the object of preparing a pharmaceutical tablet with nilotinib hydrochloride as an active ingredient, a pharmaceutical tablet which further has a higher amount of nilotinib and which has a reduced size in view of the background of nilotinib hydrochloride which, despite tablets being an easier dosage form to swallow and being suitable for taking the drug, is currently provided as a capsule formulation, and thus tableting of nilotinib distributed as a capsule formulation is desired.SOLUTION: A pharmaceutical tablet contains nilotinib hydrochloride, sugar and / or sugar alcohol, crystalline cellulose, and a disintegrant. The tablet preferably contains granules containing nilotinib hydrochloride, sugar and / or sugar alcohol, crystalline cellulose, and a disintegrant.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical tablet containing nilotinib hydrochloride as an active ingredient, the tablet having a formulation for exhibiting appropriate dissolution, and a method for producing the same. [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 shown in general formula (1).

[0003] [ka]

[0004] Nilotinib is a tyrosine kinase inhibitor (TKI) with high selectivity and potent inhibitory activity against Bcr-Abl tyrosine kinase, and is thought to exhibit antitumor effects by competitively antagonizing ATP and inhibiting Bcr-Abl tyrosine kinase, thereby inducing apoptosis in Bcr-Abl-expressing cells. Nilotinib is formulated in the form of hydrochloride and is an antitumor agent used as a treatment for chronic or accelerated phase chronic myeloid leukemia, and is sold under the trade name Tasigna® Capsules (Non-Patent Document 1). Patent Document 1 discloses a capsule formulation of nilotinib hydrochloride, and describes a capsule in which the internal phase of granules containing the active ingredient 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. Capsule formulations are generally considered to be difficult to swallow. Therefore, the development of tablets with excellent swallowability is desirable for nilotinib. However, new tablet formulations are required to exhibit dissolution properties equivalent to those of existing nilotinib capsule formulations. Therefore, it is necessary to develop a formulation that exhibits a release behavior of the active ingredient similar to that of capsule formulations simply filled with granules, using tablets prepared by compression molding. In order to obtain nilotinib tablets with a dissolution profile equivalent to that of existing capsule formulations, it is necessary to delay disintegration, particularly in a pH 3.0 buffer solution, to suppress dissolution. In Patent Document 2, to prepare nilotinib tablets with a dissolution profile equivalent to that of capsule formulations, a film-coated tablet was prepared by coating a tablet core containing nilotinib hydrochloride, crystalline cellulose, hydroxypropyl cellulose, crospovidone, etc. with a coating material containing hydroxypropyl cellulose E50, thereby delaying disintegration by 4 to 15 minutes. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special Publication No. 2010-504942 [Patent Document 2] Special Publication No. 2014-533283 [Non-patent literature]

[0006] [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]

[0007] Generally, capsule formulations have the problem of being difficult to take due to the discomfort of sticking to the mouth and throat. Furthermore, the large diameter of the formulation makes it difficult to swallow. For this reason, tablets are considered to be a more suitable dosage form for administration because they are easier to swallow. Given this background, there is a demand for nilotinib, which is currently available as a capsule formulation, to be made into a tablet. Reducing the size of the formulation is particularly important for patients with poor swallowing ability, such as children and the elderly. The present invention aims to prepare a pharmaceutical tablet containing nilotinib hydrochloride as an active ingredient, and further aims to provide a pharmaceutical tablet having a high nilotinib content and a small size. [Means for solving the problem]

[0008] As a result of extensive research, the present inventors have found that the above problems can be solved by the following means. [1] A pharmaceutical tablet containing nilotinib hydrochloride, sugar and / or sugar alcohol, crystalline cellulose, and a disintegrant. [2] The pharmaceutical tablet according to [1], wherein the disintegrant is one or more selected from the group consisting of sodium carboxymethyl starch, crospovidone, and croscarmellose sodium, and the content of the disintegrant in the uncoated tablet mass of the pharmaceutical tablet is 5% by mass or more and 15% by mass or less. [3] The pharmaceutical tablet according to [1] or [2], wherein the content of crystalline cellulose in the uncoated tablet mass of the pharmaceutical tablet is 5% by mass or more and 20% by mass or less. [4] The pharmaceutical tablet according to any one of [1] to [3], wherein the sugar and / or sugar alcohol content in the uncoated tablet mass of the pharmaceutical tablet is 1% by mass or more and 20% by mass or less. [5] The pharmaceutical tablet according to any one of [1] to [4], wherein the content ratio of crystalline cellulose to disintegrant is [crystalline cellulose]:[disintegrant]=1:0.5 to 3.0. [6] The pharmaceutical tablet according to any one of [1] to [5], which contains carmellose sodium. [7] The pharmaceutical tablet according to any one of [1] to [6], which contains a granulation product comprising nilotinib hydrochloride, a sugar and / or a sugar alcohol, crystalline cellulose, and a disintegrant. [8] The pharmaceutical tablet according to any one of [1] to [7], which contains a wet granulation comprising nilotinib hydrochloride, a sugar and / or a sugar alcohol, crystalline cellulose, and a disintegrant. [9] The pharmaceutical tablet according to [7] or [8], wherein the content ratio of the crystalline cellulose to the disintegrant in the granules is [crystalline cellulose]:[disintegrant]=1:1.01 to 5.0.

[0009]

[10] A method for producing a pharmaceutical tablet containing nilotinib hydrochloride, a sugar and / or a sugar alcohol, microcrystalline cellulose, and a disintegrant, comprising: (Step 1) preparing a granulation product containing nilotinib hydrochloride, a sugar and / or a sugar alcohol, microcrystalline cellulose, and a disintegrant; (Step 2) mixing the granules with any additives and molding the mixture; A method for producing a pharmaceutical tablet, comprising:

[11] The method for producing a pharmaceutical tablet according to

[10] , wherein (step 1) is a step of preparing a granulated product by adding an aqueous medium to a composition containing nilotinib hydrochloride, a sugar or sugar alcohol, crystalline cellulose, and a disintegrant, and granulating the mixture.

[12] The method for producing a pharmaceutical tablet according to

[10] or

[11] , wherein in (step 2), a disintegrant is mixed as an optional additive.

[13] The method for producing a pharmaceutical tablet according to any one of

[10] to

[12] , wherein carmellose sodium is contained in (Step 1) and / or (Step 2). [Effects of the Invention]

[0010] According to the present invention, it is possible to prepare pharmaceutical tablets containing nilotinib hydrochloride as an active ingredient, which have excellent compliance. DETAILED DESCRIPTION OF THE INVENTION

[0011] The pharmaceutical tablet of the present invention containing nilotinib hydrochloride as an active ingredient will be described below.

[0012] 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 It exists in various forms. Furthermore, Japanese Patent No. 5486012 discloses forms T1 to T19. In the present invention, any form of nilotinib hydrochloride can be used. 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.

[0013] The pharmaceutical tablet of the present invention preferably contains nilotinib (equivalent to the free base) at a content of 50% by mass or more in the uncoated tablet mass of the tablet. The uncoated tablet refers to the tablet base portion when tableted. In the case of tablets coated with a masking agent such as film-coated tablets or sugar-coated tablets, the uncoated tablet refers to the tablet base excluding the coating agent. Conventional nilotinib formulations have been capsule formulations that are difficult to swallow. However, by making them into tablets that are easy to take, and further increasing the active ingredient content and relatively reducing the tablet size, it is possible to further improve medication adherence. The content of nilotinib (equivalent to the free base) is preferably 50% by mass or more and 80% by mass or less. More preferably, it is more than 50% by mass and 70% by mass or less.

[0014] The pharmaceutical tablet of the present invention contains a sugar and / or sugar alcohol. The sugar and / or sugar alcohol is an additive used as a filler when preparing the pharmaceutical tablet. In the present invention, the sugar and / or sugar alcohol can be used without any particular limitation as long as it is an additive for pharmaceutical preparations. Examples include lactose, maltose, fructose, trehalose, sucrose, inositol, mannitol, xylitol, erythritol, sorbitol, etc. Preferably, the sugar and / or sugar alcohol is selected from the group consisting of lactose, maltose, trehalose, and mannitol. The amount of sugar and / or sugar alcohol applied is preferably 1% by mass or more and 20% by mass or less, more preferably 1% by mass or more and 12% by mass or less, in terms of the content in the uncoated pharmaceutical tablet.

[0015] The pharmaceutical tablet of the present invention contains a disintegrant. Examples of disintegrants include carboxymethyl starch sodium, crospovidone, carmellose calcium, croscarmellose sodium, partially pregelatinized starch, and low-substituted hydroxypropyl cellulose. It is preferable to use one or more disintegrants selected from the group consisting of carboxymethyl starch sodium, crospovidone, and croscarmellose sodium. These are also called super disintegrants and are more preferred disintegrants in the present invention. The content of the disintegrant in the pharmaceutical tablet is preferably 5% by mass or more and 20% by mass or less, more preferably 5% by mass or more and 15% by mass or less, based on the mass of the uncoated tablet.

[0016] The pharmaceutical tablet of the present invention contains crystalline cellulose. The content of crystalline cellulose in the pharmaceutical tablet is preferably 5% by mass or more and 20% by mass or less, more preferably 5% by mass or more and 15% by mass or less, based on the mass of the uncoated tablet.

[0017] In the present invention, crystalline cellulose is used in combination with a disintegrant. Microcrystalline cellulose is an additive that is usually used as an excipient, but it also has the function of assisting the disintegration of tablets. In order to control the appropriate dissolution of the active ingredient, it is preferable to control the combination ratio of crystalline cellulose and disintegrant. In the present invention, it is preferable to control the total mass content of crystalline cellulose and disintegrant, preferably more than 10% by mass and less than 30% by mass, more preferably more than 12% by mass and less than 25% by mass, of the uncoated tablet mass of the pharmaceutical tablet. The content ratio of crystalline cellulose to disintegrant is preferably [crystalline cellulose]:[disintegrant]=1:0.5 to 3.0, more preferably [crystalline cellulose]:[disintegrant]=1:0.7 to 3.0.

[0018] The pharmaceutical tablet of the present invention preferably uses carmellose sodium. In the present invention, carmellose sodium functions as a regulator of tablet swelling and disintegration properties, and can control the disintegration rate of the tablet. In preparing nilotinib tablets, it is desirable to control disintegration and dissolution properties to achieve dissolution properties equivalent to those of existing nilotinib capsule formulations. In order to obtain tablets with dissolution properties equivalent to those of capsule formulations, it is necessary to suppress dissolution in, for example, a pH 3.0 buffer solution. By using carmellose sodium, the disintegration property of the pharmaceutical tablet can be adjusted and dissolution property can be controlled. The amount of carmellose sodium applied is preferably more than 1% by mass and less than 12% by mass, more preferably more than 3% by mass and less than 10% by mass, of the uncoated pharmaceutical 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.

[0019] Since carmellose sodium is used to adjust the disintegration property of tablets, it is preferable to formulate the pharmaceutical tablet in consideration of the combination with the disintegrant, and it is preferable to design the pharmaceutical tablet formulation in consideration of the total mass of carmellose sodium and the disintegrant. The content of the total mass of carmellose sodium and the disintegrant is preferably more than 6% by mass and less than 30% by mass of the uncoated pharmaceutical tablet, and more preferably more than 10% by mass and less than 25% by mass. In addition, dissolution can be controlled appropriately by adjusting the content ratio of carmellose sodium to disintegrant to control disintegration. For example, increasing the content ratio of carmellose sodium can suppress the dissolution of nilotinib hydrochloride in a pH 3.0 buffer solution. On the other hand, increasing the content ratio of disintegrant can increase dissolution. The content ratio of carmellose sodium to disintegrant is preferably [carmellose sodium]:[disintegrant]=1:1.1-3.0, more preferably [carmellose sodium]:[disintegrant]=1:1.1-2.5. This allows the dissolution rate in 900 mL of test solution, pH 3.0 buffer solution, to be 45% or less at 30 minutes from the start of the test, 55% or less at 60 minutes, and 65% or less at 120 minutes, enabling the dissolution characteristics to be controlled to be similar to those of existing capsule formulations.

[0020] The pharmaceutical tablet of the present invention may contain other additives used in tablet preparation. Examples include excipients, binders, solubilizers, lubricants, flow agents, and colorants. These additives can be used without particular limitations as long as they are of a quality acceptable for pharmaceutical formulations. These additives may be used alone or in combination. These additives are optionally used when preparing the pharmaceutical tablet.

[0021] As the excipient, starches such as corn starch, potato starch, rice starch, wheat starch, etc. may be used in combination with the aforementioned sugars and / or sugar alcohols and crystalline cellulose. The content of the starches used as excipients in the weight of the uncoated pharmaceutical tablet is preferably less than 10% by mass, more preferably less than 8% by mass.

[0022] Examples of binders include water-soluble polymer components such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetate-polyvinyl pyrrolidone copolymer, and polyoxypropylene-polyoxyethylene copolymer. The content of the water-soluble polymer in the weight of the uncoated pharmaceutical tablet is preferably more than 1% by mass and less than 10% by mass.

[0023] Examples of the solubilizer include sodium lauryl sulfate, polysorbate, glycerin monostearate, polyoxyethylene hydrogenated castor oil, polyoxypropylene-polyoxyethylene copolymer, and the like. The solubilizer is preferably used in an amount of 0.1% by mass or more and 5.0% by mass or less based on the mass of the uncoated pharmaceutical tablet. Examples of lubricants include stearic acid, magnesium stearate, zinc stearate, aluminum stearate, glycerin monostearate, sodium stearyl fumarate, calcium stearate, carnauba wax, and the like. The lubricant is preferably used in an amount of 0.1% by mass or more and 5.0% by mass or less based on the mass of the uncoated pharmaceutical tablet. Examples of the fluidizing agent include colloidal silicon dioxide, hydrous silicon dioxide, and talc. Examples of coloring agents 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. Other additives such as excipients, binders, solubilizers, lubricants, flow agents, and colorants may be used as granules prepared by mixing a part or all of an additive composition containing one or more of these. Premixing other additives to form a granule has the advantage of making it easier to handle during tablet production operations.

[0024] The pharmaceutical tablet of the present invention may be film-coated. Examples of film-coating bases include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, etc. In addition to the coating base, the film-coated portion may contain any additives used in coating agents for pharmaceutical preparations, such as colorants and plasticizers.

[0025] The pharmaceutical tablet of the present invention preferably contains 53.5 to 80 parts by weight of nilotinib hydrochloride, 1 to 20 parts by weight of sugar and / or sugar alcohol, 5 to 20 parts by weight of microcrystalline cellulose, 5 to 20 parts by weight of disintegrant, 0 to 10 parts by weight of optional excipient, 1 to 10 parts by weight of binder, 0.1 to 5 parts by weight of solubilizer, and 0.1 to 5 parts by weight of lubricant. More preferably, the pharmaceutical tablet of the present invention further contains 1 to 12 parts by weight of carmellose sodium. The pharmaceutical tablet of the present invention can be prepared by mixing the above-mentioned components, optionally granulating them to prepare granules, and compressing them. The pharmaceutical tablet may then be film-coated. 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 pharmaceutical tablet of the present invention can be produced by mixing nilotinib hydrochloride with a sugar and / or sugar alcohol and a disintegrant, followed by compression molding. Preferably, the pharmaceutical tablet is produced by compressing a mixture further containing carmellose sodium. In another embodiment, the pharmaceutical tablet is produced by compressing a mixture containing a water-soluble polymer component as a binder. Furthermore, the pharmaceutical tablet is produced by compressing a mixture containing carmellose sodium and a water-soluble polymer component. Carmellose sodium may be mixed with nilotinib hydrochloride and other additives as a powder, or 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 sprayed to form a mixture. Preferably, the powder is used as is for the mixture. The water-soluble polymer component may be mixed with nilotinib hydrochloride and other additives as a powder, or 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, the water-soluble polymer component may be dissolved in the aqueous medium and sprayed to form a mixture. Preferably, the water-soluble polymer component is mixed as a powder. The pharmaceutical tablet of the present invention includes a step of compressing a mixture of the granules and optional additives to form a tablet.

[0027] Pharmaceutical tablets can be prepared by optionally adding a lubricant to the composition for preparing pharmaceutical tablets containing nilotinib hydrochloride described above and molding the mixture into tablets by tableting or the like. The tablet hardness is preferably about 10 to 250 N, more preferably 50 to 200 N.

[0028] The pharmaceutical tablet of the present invention may be prepared by adding a step of film-coating or mask-coating the uncoated tablets after compression molding. Film-coated tablets are preferred. When coating, the film-coated portion, which is the exterior 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 at any ratio, pouring or spraying the solution into a coating pan containing the uncoated tablets, which are the interior 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 carried out at room temperature to about 80°C. Drying may also be carried out under reduced pressure to volatilize the aqueous solvent.

[0029] The pharmaceutical tablet of the present invention preferably contains a granulated composition containing nilotinib hydrochloride, a sugar and / or sugar alcohol, crystalline cellulose, and a disintegrant. The granulated composition 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 process. A pharmaceutical tablet is preferably prepared by previously mixing and granulating nilotinib hydrochloride, a sugar and / or sugar alcohol, crystalline cellulose, and a disintegrant to form a granular compact, which is then mixed with any additives and compressed to form a pharmaceutical tablet. The granules may contain, in addition to nilotinib hydrochloride, sugar and / or sugar alcohol, microcrystalline cellulose, and disintegrant, a water-soluble polymer component serving as a binder. They may also contain carmellose sodium. They may also contain a solubilizer. The sugar and / or sugar alcohol, disintegrant, binder, and solubilizer are as defined above. The granules preferably have a composition of 60 to 80 parts by mass of nilotinib hydrochloride, 1 to 20 parts by mass of sugar and / or sugar alcohol, 3 to 20 parts by mass of crystalline cellulose, 5 to 20 parts by mass of disintegrant, 0 to 10 parts by mass of optional binder, 0 to 5 parts by mass of solubilizer, and 0 to 10 parts by mass of carmellose sodium.

[0030] The granules may be dry granules or wet granules prepared by adding an aqueous medium such as water. Because the manufacturing process and control of the granules are easy, wet granules prepared by a wet method are preferred. When the granules are wet granules, they are prepared by mixing nilotinib hydrochloride, sugar and / or sugar alcohol, crystalline cellulose, a disintegrant, and an optional water-soluble polymer component as a binder, carmellose sodium, adding an optional aqueous medium containing a solubilizer to prepare a wet mixture, applying mechanical pressure such as a mixing operation to cause the mixture to adhere to each other, and granulating the mixture into granules. When the granules are dry granules, they are prepared by physically adhering the mixture to each other by a compression operation or the like to granulate the mixture. Examples of the granulation procedure include compression granulation, melt granulation, roller compactor method, tumbling granulation, fluidized bed granulation, stirring granulation, extrusion granulation, etc. The granulation procedure according to the present invention can be appropriately selected from these procedures to prepare the granules.

[0031] The pharmaceutical tablet of the present invention is preferably a pharmaceutical tablet obtained by preparing a granule containing the above-mentioned nilotinib hydrochloride, sugar and / or sugar alcohol, crystalline cellulose, and a disintegrant in advance, adding and mixing any additives to the granule, and compressing the mixture. Optional additives that can be mixed with the granules include carmellose sodium, other excipients, lubricants, glidants, colorants, etc. Sugars and / or sugar alcohols, crystalline cellulose, and disintegrants may be contained in both the components contained within the granules and the components added later outside the granules. When sugars and / or sugar alcohols are contained outside the granules, the content is preferably 1% by mass or more and 15% by mass or less, more preferably 1% by mass or more and 10% by mass or less, relative to the weight of the uncoated tablet. When crystalline cellulose is contained outside the granules, the content is preferably 1% by mass or more and 15% by mass or less, more preferably 1% by mass or more and 10% by mass or less, relative to the weight of the uncoated tablet. When a disintegrant is contained outside the granules, the content is preferably 1% by mass or more and 15% by mass or less, more preferably 1% by mass or more and 10% by mass or less, relative to the weight of the uncoated tablet.

[0032] The pharmaceutical tablet of the present invention is prepared by compressing a mixture of the granules and any additives into tablets. Pharmaceutical tablets can be prepared by adding a lubricant to a composition containing optional excipients, disintegrants, and other additives to the granules containing nilotinib hydrochloride described above, and molding the mixture into tablets by tableting or the like. The tablet hardness is preferably about 10 to 250 N, more preferably 50 to 200 N. In the present invention, when a pharmaceutical tablet contains granules prepared by wet granulation, the pharmaceutical tablet may contain water. If the pharmaceutical tablet contains water, the pharmaceutical tablet has a moisture content of 0.1% by mass or more and 5% by mass or less. More specifically, the moisture content is 0.5% by mass or more and 3% by mass or less. The moisture content in the present invention is a value measured by the loss on drying method, in which the pharmaceutical tablet is precisely weighed, spread on a baking sheet, and dried at atmospheric pressure at 80°C for 15 minutes or more, and the weight loss is calculated as the moisture content when the tablet reaches a constant weight.

[0033] The pharmaceutical tablet of the present invention may be prepared by adding a step of film-coating or mask-coating the tablet after compression molding. Film-coated tablets are preferred. When coating, the film-coated portion, which is the exterior 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 at any ratio, pouring or spraying the solution into a coating pan containing the uncoated tablet, which is the interior 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 carried out at room temperature to about 80°C. Drying may also be carried out under reduced pressure to volatilize the aqueous solvent.

[0034] The pharmaceutical tablet of the present invention exhibits delayed disintegration in a pH 3.0 buffer solution, allowing for appropriate control of the dissolution of nilotinib. That is, the pharmaceutical tablet allows for control of dissolution in a manner similar to that of existing capsule formulations of nilotinib. In this specification, the dissolution test for evaluating dissolution is a dissolution test according to Method 2 (paddle method) of the Japanese Pharmacopoeia. By dissolving the active ingredient nilotinib hydrochloride from the pharmaceutical tablet of the present invention into a test solution using a dissolution test method according to Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method), and evaluating the dissolution rate of nilotinib in the test solution using an ultraviolet-visible spectrophotometer or liquid chromatography, it is possible to confirm that the pharmaceutical tablet of the present invention is a pharmaceutical tablet that exhibits delayed disintegration in a pH 3.0 buffer solution, which is a characteristic of the pharmaceutical tablet of the present invention. More specifically, in a dissolution test according to Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method), the average dissolution rate of 6 tablets in a 900 mL pH 3.0 buffer solution from the start of the test is 60% or less at 30 minutes, more preferably 45% or less at 30 minutes, 55% or less at 60 minutes, and 65% or less at 120 minutes.

[0035] 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:

[0036] 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 800 mg of nilotinib per day. This dosage is not limited to, but can be cited as a preferred dosage. [Example]

[0037] The present invention will be further described below with reference to examples, although the present invention is not limited to these examples.

[0038] Example 1 Nilotinib hydrochloride dihydrate (11.37 g), lactose hydrate (1.05 g), microcrystalline cellulose (1.265 g), crospovidone (1.75 g), and polyvinylpyrrolidone (0.70 g) were mixed and mixed for 2 minutes using a high-speed mixer. An aqueous solution containing 0.14 g of Poloxamer 188 (BASF) was added to the mixture to achieve a solid-liquid ratio of 30%, and the mixture was wet-granulated for 6 minutes (agitator rotation speed: 400 rpm, chopper rotation speed: 3000 rpm). The resulting granulated powder was then dried in a ventilated tray dryer to reduce the moisture content to 3% or less. The granules were crushed and sized in a speed mill, and then 0.875 g of carmellose sodium, 0.175 g of crospovidone, and 0.175 g of magnesium stearate were added and mixed to form a powder for tableting. The powder was compressed into tablets using a tablet press and punches and dies with a diameter of 8.5 mm to obtain tablets weighing 350 mg, having a tablet height of 4.80 mm and a hardness of 55 N.

[0039] Example 2 Nilotinib hydrochloride dihydrate (11.37 g), lactose hydrate (1.05 g), microcrystalline cellulose (1.265 g), crospovidone (1.75 g), and polyvinylpyrrolidone (0.70 g) were mixed and mixed for 2 minutes using a high-speed mixer. An aqueous solution containing 0.14 g of Poloxamer 188 (BASF) was added to the mixture to achieve a solid-liquid ratio of 30%, and the mixture was wet-granulated for 6 minutes (agitator rotation speed: 400 rpm, chopper rotation speed: 3000 rpm). The resulting granulated powder was then dried in a ventilated tray dryer to reduce the moisture content to 3% or less. The granules were crushed and sized in a speed mill, and then mixed with 1.05 g of carmellose sodium, 1.0 g of crystalline cellulose, and 0.175 g of magnesium stearate to form a powder for tableting. The powder was compressed into tablets using a tablet press and punches and dies with a diameter of 8.5 mm to obtain tablets weighing 373.1 mg, having a tablet height of 5.03 mm and a hardness of 97 N.

[0040] Example 3 Nilotinib hydrochloride dihydrate (11.37 g), lactose hydrate (0.525 g), microcrystalline cellulose (0.915 g), crospovidone (1.05 g), polyvinylpyrrolidone (0.70 g), and carmellose sodium (0.70 g) were mixed and mixed for 2 minutes using a high-speed mixer. An aqueous solution containing 0.14 g of poloxamer 188 (BASF) was added to the mixture to a solid-liquid ratio of 30%, and the mixture was wet-granulated for 6 minutes (agitator rotation speed: 400 rpm, chopper rotation speed: 3000 rpm). The resulting granulated powder was then dried in a ventilated tray dryer to a moisture content of 3% or less. The granules were crushed and sized in a speed mill, and then mixed with 0.35 g of crospovidone, 0.70 g of carmellose sodium, 0.875 g of crystalline cellulose, and 0.175 g of magnesium stearate to form a powder for tableting. The powder was compressed into tablets using a tablet press and punches and dies with a diameter of 8.5 mm to obtain tablets weighing 350 mg, having a tablet height of 4.80 mm and a hardness of 77 N.

[0041] Example 4 Nilotinib hydrochloride dihydrate (11.37 g), lactose hydrate (0.525 g), microcrystalline cellulose (0.915 g), crospovidone (1.05 g), polyvinylpyrrolidone (0.70 g), and carmellose sodium (0.70 g) were mixed and mixed for 2 minutes using a high-speed mixer. An aqueous solution containing 0.14 g of poloxamer 188 (BASF) was added to the mixture to a solid-liquid ratio of 35%, and the mixture was wet-granulated for 6 minutes (agitator rotation speed: 400 rpm, chopper rotation speed: 3000 rpm). The resulting granulated powder was then dried in a ventilated tray dryer to a moisture content of 3% or less. The granules were crushed and sized in a speed mill, and then mixed with 1.05 g of crospovidone, 0.70 g of carmellose sodium, 0.175 g of colloidal silicon dioxide, and 0.175 g of magnesium stearate to form a powder for tableting. The powder was compressed into tablets using a tablet press and punches and dies with a diameter of 8.5 mm to obtain tablets weighing 350 mg, having a tablet height of 4.87 mm and a hardness of 59 N.

[0042] Example 5 Nilotinib hydrochloride dihydrate (11.37 g), lactose hydrate (0.525 g), microcrystalline cellulose (0.915 g), crospovidone (1.05 g), polyvinylpyrrolidone (0.70 g), and carmellose sodium (0.70 g) were mixed and mixed for 2 minutes using a high-speed mixer. An aqueous solution containing 0.14 g of poloxamer 188 (BASF) was added to the mixture to a solid-liquid ratio of 35%, and the mixture was wet-granulated for 6 minutes (agitator rotation speed: 400 rpm, chopper rotation speed: 3000 rpm). The resulting granulated powder was then dried in a ventilated tray dryer to a moisture content of 3% or less. The granules were crushed and sized in a speed mill, and then mixed with 0.525 g of crospovidone, 0.525 g of carmellose sodium, 0.70 g of microcrystalline cellulose, 0.175 g of colloidal silicon dioxide, and 0.175 g of magnesium stearate to form a powder for tableting. The powder was compressed into tablets using a tablet press and punches and dies with a diameter of 8.5 mm to obtain tablets weighing 350 mg, having a tablet height of 4.85 mm and a hardness of 82 N.

[0043] Example 6 Nilotinib hydrochloride dihydrate (11.37 g), lactose hydrate (0.525 g), microcrystalline cellulose (0.565 g), crospovidone (1.05 g), polyvinylpyrrolidone (0.70 g), carmellose sodium (0.70 g), and croscarmellose sodium (0.70 g) were mixed and mixed for 2 minutes using a high-speed mixer. An aqueous solution containing 0.14 g of Poloxamer 188 (BASF) was added to the mixture to a solid-liquid ratio of 35%, and the mixture was wet-granulated for 6 minutes (agitator rotation speed: 400 rpm, chopper rotation speed: 3000 rpm). The resulting granulated powder was then dried in a ventilated tray dryer to a moisture content of 3% or less. The granules were crushed and sized in a speed mill, and then mixed with 0.525 g of crospovidone, 1.05 g of carmellose sodium, 0.525 g of microcrystalline cellulose, 0.175 g of colloidal silicon dioxide, and 0.175 g of magnesium stearate to form a powder for tableting. The powder was compressed into tablets using a tablet press and punches and dies with a diameter of 8.5 mm to obtain tablets weighing 350 mg, having a tablet height of 4.85 mm and a hardness of 82 N.

[0044] (Comparative Example 1) Nilotinib hydrochloride dihydrate (11.37 g), lactose hydrate (2.67 g), crospovidone (1.40 g), and polyvinylpyrrolidone (0.70 g) were mixed for 2 minutes using a high-speed mixer (Earth Technica). An aqueous solution containing 0.14 g of Poloxamer 188 (BASF) was added to the mixture to achieve a solid-liquid ratio of 40%, and the mixture was wet-granulated for 6 minutes (agitator rotation speed: 400 rpm, chopper rotation speed: 3000 rpm). The resulting granulated powder was then dried in a ventilated tray dryer to a moisture content of 3% or less. The granules were crushed and sized in a speed mill, and then mixed with 0.525 g of crospovidone, 0.525 g of carmellose sodium, and 0.175 g of magnesium stearate to prepare a powder for tableting. The powder for tableting was compressed into tablets using a tablet press and 8.5 mm diameter punches and dies to obtain tablets weighing 350 mg, with a tablet height of 4.82 mm and a hardness of 147 N.

[0045] (Comparative Example 2) 113.7 g of nilotinib hydrochloride dihydrate, 30.15 g of microcrystalline cellulose, 10.5 g of crospovidone, and 7.0 g of polyvinylpyrrolidone were mixed and mixed for 2 minutes using a high-speed mixer. 1.4 g of an aqueous solution of Poloxamer 188 (BASF) was added to the mixture to a solid-liquid ratio of 40%, and the mixture was wet-granulated for 6 minutes (agitator rotation speed: 400 rpm, chopper rotation speed: 3000 rpm). The resulting granulated powder was then dried in a ventilated tray dryer to reduce the moisture content to 3% or less. The granules were crushed and sized in a speed mill, and then mixed with 5.25 g of carmellose sodium, 5.25 g of crospovidone, and 1.75 g of magnesium stearate to form a powder for tableting. The powder was compressed into tablets using a tablet press and punches and dies with a diameter of 8.5 mm to obtain tablets weighing 350 mg, having a tablet height of 4.85 mm and a hardness of 144 N.

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

[0047] Tables 1-1 and 1-2 summarize the formulations of the examples and comparative examples. [Table 1-1] TIFF0007776275000002.tif82146[Table 1-2] TIFF0007776275000003.tif62100

[0048] [Test Example 1] Dissolution test The dissolution rates of the tablets of Examples 1 to 6 and Comparative Examples 1 and 2, as well as the existing capsule of Comparative Example 3 (Tasigna (registered trademark) capsule) 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 solution (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 obtained are shown in Table 2.

[0049] [Table 2] TIFF0007776275000004.tif5779

[0050] The results of Test Example 1 indicate that the pharmaceutical tablet according to the present application contains 50% or more by mass of nilotinib and ensures the active ingredient is released. The existing nilotinib formulation (Comparative Example 3; capsule formulation) is characterized by its dissolution in a pH 3.0 test solution, with the dissolution rate at 120 minutes being suppressed to 50% or less, and all of Examples 1 to 5 share this characteristic. It can be seen that the selection of excipients plays a major role in this release control characteristic. These results suggest that the present invention can provide a pharmaceutical in a new dosage form that can replace existing capsule formulations of nilotinib hydrochloride. The nilotinib tablet according to the present invention is a tablet that is easier to swallow than existing capsule formulations, and is a miniaturized tablet containing a high content of nilotinib hydrochloride, making it possible to provide a nilotinib formulation that is easier to swallow and has excellent compliance.

Claims

1. A pharmaceutical tablet containing nilotinib hydrochloride, a sugar and / or a sugar alcohol, crystalline cellulose, and a disintegrant, wherein the disintegrant is one or more selected from the group consisting of sodium carboxymethyl starch, crospovidone, and croscarmellose sodium.

2. A pharmaceutical tablet as described in claim 1, wherein the content of disintegrant in the uncoated tablet mass of the pharmaceutical tablet is 5% by mass or more and 15% by mass or less.

3. The pharmaceutical tablet according to claim 1 or 2, wherein the content of crystalline cellulose in the uncoated tablet mass of the pharmaceutical tablet is 5% by mass or more and 20% by mass or less.

4. The pharmaceutical tablet according to any one of claims 1 to 3, wherein the content of sugar and / or sugar alcohol in the uncoated tablet mass of the pharmaceutical tablet is 1% by mass or more and 20% by mass or less.

5. The pharmaceutical tablet according to any one of claims 1 to 4, wherein the content ratio of crystalline cellulose to disintegrant is [crystalline cellulose]:[disintegrant]=1:0.5 to 3.

0.

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

7. The pharmaceutical tablet according to any one of claims 1 to 6, comprising a granulation product comprising nilotinib hydrochloride, a sugar and / or a sugar alcohol, crystalline cellulose, and a disintegrant.

8. The pharmaceutical tablet according to any one of claims 1 to 7, comprising a wet granulation product comprising nilotinib hydrochloride, a sugar and / or a sugar alcohol, microcrystalline cellulose, and a disintegrant.

9. The pharmaceutical tablet according to claim 7 or 8, wherein the content ratio of the crystalline cellulose to the disintegrant in the granules is [crystalline cellulose]:[disintegrant]=1:1.01 to 5.

0.

10. A method for producing a pharmaceutical tablet containing nilotinib hydrochloride, a sugar and / or a sugar alcohol, microcrystalline cellulose, and a disintegrant, wherein the disintegrant is at least one selected from the group consisting of sodium carboxymethyl starch, crospovidone, and croscarmellose sodium; (Step 1) preparing a granulation product containing nilotinib hydrochloride, a sugar and / or a sugar alcohol, microcrystalline cellulose, and a disintegrant; (Step 2) mixing the granules with any additives and molding the mixture; A method for producing a pharmaceutical tablet, comprising:

11. The method for producing a pharmaceutical tablet according to claim 10, wherein in (Step 1), an aqueous medium is added to a composition containing nilotinib hydrochloride, a sugar and / or a sugar alcohol, crystalline cellulose, and a disintegrant, followed by granulation to prepare a granulated product.

12. The method for producing a pharmaceutical tablet according to claim 10 or 11, wherein a disintegrant is mixed as an optional additive in (Step 2).

13. In (Step 1) and / or (Step 2), carmellose sodium is contained. A method for producing the pharmaceutical tablet according to any one of claims 10 to 12.

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