Method for suppressing fluctuation of disintegration time of apixaban-containing tablet caused by tableting pressure, apixaban-containing tablet, and method for producing the same

Abstract

To provide a method for suppressing fluctuation of a disintegration time of an apixaban-containing tablet caused by tableting pressure in producing an apixaban-containing tablet as a pharmaceutical effective component, a method for simply producing a tablet which contains apixaban as a pharmaceutical effective component and shows predetermined disintegration, and a tablet which contains apixaban as a pharmaceutical effective component, shows predetermined disintegration, and can be simply produced.SOLUTION: A method for suppressing fluctuation of a disintegration time of an apixaban-containing tablet caused by tableting pressure, is characterized by blending a first swellable disintegrator having the degree of swelling more than 100% and a second swellable disintegrator having a wetting time shorter than the first swellable disintegrator into tableting powder containing amorphous apixaban.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for suppressing variation in disintegration time of apixaban-containing tablets due to tableting pressure when producing tablets containing apixaban as a medicinal ingredient, a method for simply producing tablets containing apixaban as a medicinal ingredient and exhibiting predetermined disintegrability, and a tablet containing apixaban as a medicinal ingredient and exhibiting predetermined disintegrability that can be easily produced. [Background technology]

[0002] Apixaban (chemical name: 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide) inhibits factor Xa, which is the convergence point of the extrinsic and intrinsic blood coagulation pathways, thereby suppressing the downstream conversion of prothrombin to thrombin, thereby exhibiting direct anticoagulant and indirect antiplatelet effects (Non-Patent Document 1).

[0003] Because apixaban is practically insoluble in water (Non-Patent Document 1), various technologies have been developed to control the release of apixaban from formulations. For example, Patent Document 1 discloses a dosage form containing a solubility-improved form of apixaban for controlling the release of apixaban. Furthermore, Patent Document 2 discloses a composition containing amorphous apixaban that is efficient, more economical, less hazardous, and environmentally friendly. Patent Document 3 describes the relationship between the particle size of apixaban and the dissolution property of a formulation, and Patent Document 4 discloses a pharmaceutical composition with improved dissolution property by containing granules containing apixaban and hydroxyethyl cellulose.

[0004] The present inventors have found that the dissolution properties of apixaban, a medicinal ingredient, can be significantly improved by making the active ingredient apixaban amorphous using a specific crystallization inhibitor, and have filed a patent application for this finding (Patent Document 5). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special Publication No. 2012-530141 [Patent Document 2] International Publication No. 2013 / 164839 Brochure [Patent Document 3] International Publication No. 2017 / 182908 Brochure [Patent Document 4] International Publication No. 2020 / 127819 Brochure [Patent Document 5] Japanese Patent Application Publication No. 2023-8994 [Non-patent literature]

[0006] [Non-Patent Document 1] "Eliquis® Tablets 2.5 mg, Eliquis® Tablets 5 mg" package insert Summary of the Invention [Problem to be solved by the invention]

[0007] As mentioned above, various formulations containing apixaban as the active ingredient and having improved dissolution properties have been developed. However, in the case of tablets, if the disintegration property is within a predetermined range even when the tableting pressure is slightly changed, there is no need to strictly adjust the manufacturing conditions, and manufacturing can be simplified. Therefore, an object of the present invention is to provide a method for suppressing variation in disintegration time of apixaban-containing tablets due to tableting pressure when producing tablets containing apixaban as a medicinal ingredient, a method for simply producing tablets containing apixaban as a medicinal ingredient and exhibiting predetermined disintegrability, and a tablet which contains apixaban as a medicinal ingredient, exhibits predetermined disintegrability, and can be easily produced. [Means for solving the problem]

[0008] The present inventors have conducted extensive research to solve the above problems, and as a result, have found that by mixing amorphized apixaban with a specific disintegrant and compressing the mixture, it is possible to suppress fluctuations in disintegration time of apixaban-containing tablets due to tableting pressure, thereby completing the present invention. The present invention will now be described.

[0009] [1] A method for suppressing variation in disintegration time of an apixaban-containing tablet due to tableting pressure, comprising: A method for preparing tablets containing amorphous apixaban, comprising blending a first swellable disintegrant having a swelling degree of more than 100% and a second swellable disintegrant having a wetting time shorter than that of the first swellable disintegrant. [2] The method according to [1] above, wherein the first swelling disintegrant is at least one swelling disintegrant selected from croscarmellose sodium and sodium starch glycolate. [3] The method according to [1] or [2], wherein crospovidone is used as the second swelling disintegrant. [4] The method according to any one of [1] to [3] above, wherein the amorphous apixaban is contained in a solid dispersion, and the solid dispersion contains a sugar alcohol in addition to the amorphous apixaban. [5] The method according to [4] above, wherein the proportion of the sugar alcohol in the solid dispersion is 4% by mass or more and 10% by mass or less.

[0010] [6] A method for producing a tablet containing apixaban as an active ingredient, comprising: preparing a powder for tableting containing amorphous apixaban, a first swellable disintegrant having a swelling degree of more than 100%, and a second swellable disintegrant having a wetting time shorter than that of the first swellable disintegrant; The method comprises a step of compressing the tablet powder into tablets.

[0011] [7] A tablet comprising amorphous apixaban, a first swellable disintegrant having a swelling degree of more than 100%, and a second swellable disintegrant having a shorter wetting time than the first swellable disintegrant. [8] The tablet according to [7], wherein the amorphous apixaban is contained in a solid dispersion, and the solid dispersion contains a sugar alcohol in addition to the amorphous apixaban. [Effects of the Invention]

[0012] The apixaban-containing tablet according to the present invention has excellent disintegration properties, which result in excellent dissolution of the active ingredient apixaban, and the tableting pressure range over which the desired dissolution can be achieved is relatively wide, so that strict adjustment of the tableting pressure is not required and the tableting pressure can be easily adjusted, thereby enabling the tablet to be easily produced. Therefore, the apixaban-containing pharmaceutical composition according to the present invention is industrially very advantageous as one form of a formulation containing apixaban as the active ingredient. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 is a graph showing the relationship between tableting pressure and disintegration time for tablets of Examples according to the present invention and Comparative Examples. [Figure 2] FIG. 2 is a graph showing the relationship between the proportion of D-mannitol in a melt of apixaban alone or a mixture of apixaban and D-mannitol and the torque value required for extrusion. DETAILED DESCRIPTION OF THE INVENTION

[0014] The method of the present invention for suppressing variation in disintegration time of apixaban-containing tablets due to tableting pressure is characterized by blending a first swellable disintegrant having a swelling degree of more than 100% and a second swellable disintegrant having a shorter wetting time than the first swellable disintegrant with tableting powder containing amorphous apixaban. The present invention will be described below with reference to specific examples, but the present invention is not limited to these examples.

[0015] The apixaban-containing tablet according to the present invention contains apixaban as an active ingredient. The chemical name of apixaban is 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, and apixaban has the following chemical structure. Apixaban inhibits factor Xa, which is the convergence point of the extrinsic and intrinsic blood coagulation pathways, thereby suppressing the downstream conversion of prothrombin to thrombin, thereby exhibiting direct anticoagulant and indirect antiplatelet effects.

[0016] [ka]

[0017] Apixaban as a drug substance may be in the free form or a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts of apixaban include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, sulfamate, phosphate, and nitrate; and organic acid salts such as acetate, propionate, succinate, glycolate, stearate, lactate, malate, tartrate, citrate, ascorbate, pamoate, maleate, hydroxymaleate, phenylacetate, glutamate, benzoate, salicylate, sulfanilate, 2-acetoxybenzoate, fumarate, toluenesulfonate, methanesulfonate, ethanedisulfonate, oxalate, and isethionate.

[0018] Apixaban, the active pharmaceutical ingredient, is generally crystalline. However, in the present invention, it is made amorphous by melting. Therefore, the particle size is not particularly limited and may be adjusted appropriately. For example, the cumulative 50% particle diameter (D 50 The cumulative 90% particle diameter (D) on a volume basis can be 1 μm or more and 300 μm or less, and preferably 10 μm or more and 100 μm or less. 90) can be 50 μm or more and 500 μm or less, preferably 90 μm or more, more preferably 100 μm or more, and preferably 400 μm or less, more preferably 300 μm or less, and even more preferably 200 μm or less or 150 μm or less. In the present invention, a relatively large drug substance apixaban can be used, and therefore, tablet productivity is high. In the present disclosure, the volume-based cumulative 50% particle diameter (D 50 ) and cumulative 90% particle diameter (D 90 ) shall be measured on a volume basis using a laser diffraction particle size distribution analyzer.

[0019] The amount and proportion of apixaban in the tablet of the present invention may be appropriately adjusted within a range in which apixaban can exert its action and effect. For example, the amount of apixaban per tablet can be 1 mg or more and 100 mg or less, preferably 2 mg or more, more preferably 5 mg or more, and preferably 50 mg or less, more preferably 20 mg or less, and even more preferably 15 mg or less or 10 mg or less. Furthermore, the proportion of apixaban per tablet can be 0.5% by mass or more and 20% by mass or less, preferably 1% by mass or more, more preferably 2% by mass or more, and preferably 15% by mass or less, more preferably 10% by mass or less, and even more preferably 5% by mass or less. For example, the amount of apixaban per tablet can be 2.5±0.25 mg or 5±0.5 mg.

[0020] Hereinafter, each step of the method for producing an apixaban-containing tablet according to the present invention will be described. 1. Manufacturing process for tablet powder In this step, a powder for tableting is prepared containing amorphous apixaban, a first swellable disintegrant having a swelling degree of more than 100%, and a second swellable disintegrant having a wetting time shorter than that of the first swellable disintegrant.

[0021] As described above, apixaban drug substance is generally crystalline, and therefore, if necessary, it is made amorphous. The method for making it amorphous is not particularly limited, but for example, apixaban drug substance may be melted and then cooled.

[0022] The melting temperature may be adjusted as appropriate within the range in which the apixaban drug substance melts. For example, since the melting point of apixaban is 238 to 240°C, heating may be performed to a temperature equal to or higher than this melting point. Furthermore, it is preferable to prepare a solid dispersion in which apixaban is dispersed in a crystallization inhibitor that has a lower melting point than apixaban and inhibits the crystallization of apixaban. The crystallization inhibitor reduces the viscosity of the molten product, making it easier to extrude the molten product.

[0023] Examples of the crystallization inhibitor include one or more crystallization inhibitors selected from polyvinylpyrrolidone, hydroxypropyl cellulose, and sugar alcohols. For example, the active ingredient apixaban is generally crystalline, and after melting or dissolving it, it can be solidified in an amorphous state by the addition of a crystallization inhibitor.

[0024] The crystallization inhibitor has a relatively low melting point and inhibits the recrystallization of molten or dissolved apixaban. Specifically, it dissolves apixaban in the molten state and inhibits the crystallization of apixaban during the solidification process. The crystallization inhibitor may be used alone or in combination of two or more.

[0025] Among the crystallization inhibitors, polyvinylpyrrolidone is a water-soluble polymer compound formed by polymerization of N-vinyl-2-pyrrolidone. The molecular weight of the polyvinylpyrrolidone used as a crystallization inhibitor is not particularly limited, but for example, one with a weight average molecular weight of 5,000 or more and 3,000,000 or less can be used. The K value (viscosity characteristic value) of the polyvinylpyrrolidone is also not particularly limited, but for example, one with a K value of 10 or more and 120 or less can be used.

[0026] Hydroxypropyl cellulose is a cellulose derivative in which some or all of the hydroxyl groups of cellulose are substituted with 2-hydroxypropyl groups.

[0027] Sugar alcohols are a type of sugar produced by reducing the carbonyl group of aldoses or ketoses. Examples of sugar alcohols include glycerin, erythritol, and xylitol. and disaccharide alcohols such as 6-O-α-D-glucopyranosyl-D-sorbitol, 6-O-α-D-glucopyranosyl-D-mannitol, 4-O-α-D-glucopyranosyl-D-glucitol (maltitol), 6-O-α-D-glucopyranosyl-D-glucitol (isomaltitol), and 4-O-β-D-galactopyranosyl-D-glucitol (lactitol). Isomalt is a mixture of 6-O-α-D-glucopyranosyl-D-sorbitol and 6-O-α-D-glucopyranosyl-D-mannitol.

[0028] For example, the apixaban drug substance can be amorphized by mixing apixaban crystals (the drug substance) with a crystallization inhibitor, heating the mixture until at least the apixaban crystals melt, and then cooling until solidification occurs. Examples of methods for melting and dissolving the mixture of apixaban crystals and a crystallization inhibitor include a hot melt granulator and an extruder. The heating temperature can be adjusted appropriately within a range in which at least the apixaban crystals melt or dissolve, and can be, for example, 150°C or higher and 350°C or lower, with 300°C or lower being preferred. The cooling conditions can be adjusted appropriately within a range in which apixaban becomes amorphized, but because a crystallization inhibitor is used, the cooling rate does not necessarily need to be increased; the mixture can be allowed to cool to room temperature.

[0029] The amount of crystallization inhibitor used may be adjusted as needed to render apixaban amorphous. For example, when hydroxypropyl cellulose and a sugar alcohol are used in combination as crystallization inhibitors, it is preferable to mix hydroxypropyl cellulose in an amount between 2 and 50 times the mass of apixaban. The ratio is preferably 3 times or more, and 30 times or less, more preferably 20 times or less, and even more preferably 15 times or less. Furthermore, the ratio of sugar alcohol to the total mass of apixaban, hydroxypropyl cellulose, and sugar alcohol is preferably greater than 1% by mass and less than 20% by mass. Within this range, the viscosity of the melt containing apixaban, hydroxypropyl cellulose, and sugar alcohol is appropriate, enabling good melt extrusion. The ratio is preferably 2% by mass or more, even more preferably 4% by mass or more, and more preferably 15% by mass or less, even more preferably 10% by mass or less.

[0030] Since the solid dispersion obtained by cooling the molten mixture of apixaban and a crystallization inhibitor is usually a mass, it is preferable to crush it and then sieve it. For example, the cumulative 50% particle size (D) based on the volume of the sized powder of amorphous apixaban containing a crystallization inhibitor can be determined by the following method. 50 ) can be 30 μm or more and 1000 μm or less.

[0031] In this step, amorphous apixaban, a first swellable disintegrant with a swelling degree of more than 100%, and a second swellable disintegrant with a shorter wetting time than the first swellable disintegrant are mixed. In the present invention, by using a combination of disintegrants with different swelling properties, a sufficient swelling effect can be obtained and fluctuations in tablet disintegration time due to tableting pressure can be suppressed. Disintegrants are generally classified into swellable disintegrants and water-permeable disintegrants. Swellable disintegrants are disintegrants that absorb water and swell to disintegrate tablets. The wetting time and swelling degree of disintegrants are determined by reference to Li Chaojie and Sakamoto Mitsuo, Pharmaceutics, 67(2), 133-141 (2007).

[0032] Specifically, with the composition shown in Table 1, crystalline lactose (50 Mesh) as the core is placed in a stirring granulator, to which an ethanol solution of polyvinylpyrrolidone as a binder is added, followed by the sprinkling of lactose (200 Mesh) or ascorbic acid. After repeating this powder coating process, the powder-coated particles are dried at 40°C and then sieved to an 18-mesh size to produce coated particles. Granulated lactose, crystalline cellulose, powdered maltitol, and a disintegrant are added to the coated particles and mixed, after which a lubricant is added and mixed a second time, and flat tablets of 200 mg each and 8 mm in diameter are formed using a rotary tablet press. Crystalline lactose (50 Mesh) is mixed with ascorbic acid, granulated lactose, crystalline cellulose, powdered maltitol, and the disintegrant crospovidone in a stirring granulator. After mixing, an ethanol solution of polyvinylpyrrolidone as a binder is added and kneaded and granulated. The granules are dried at 40°C and then sieved to an 18-mesh screen. Magnesium stearate as a lubricant is added to this mixture, which is then mixed and pressed into flat tablets of 200 mg each and 8 mm in diameter in a tablet press.

[0033] [Table 1]

[0034] The wetting time is measured as follows: Place a piece of tissue paper folded in four in a petri dish, add water (6 mL) to it and wet it completely, place one tablet on top of it, and measure the time required for the entire surface of the tablet to become wet by visual inspection. Measurements are made three times and the average value is calculated.

[0035] The degree of swelling is measured as follows. The diameter and thickness of a tablet whose entire surface has been wetted by measuring the wetting time and an unwetted tablet are measured with a vernier caliper, and the volume is calculated. The difference between the two volumes is the swollen volume, and the difference (%) between the volume of the two and that of the unwetted tablet is the swelling degree. The wetting time is measured as follows. Measurements are carried out three times, and the average value is calculated.

[0036] The first swelling disintegrant may be, for example, at least one selected from croscarmellose sodium and sodium starch glycolate.

[0037] In the present invention, amorphous apixaban and a first swellable disintegrant are further mixed with a second swellable disintegrant, which has a shorter wetting time than the first swellable disintegrant.

[0038] The second disintegrant is not particularly limited as long as it has a shorter wetting time than the first disintegrant, and examples thereof include polyvinylpyrrolidone disintegrants such as crospovidone. The swelling degree and wetting time of major disintegrants are shown below.

[0039] [Table 2]

[0040] The amount of each swellable disintegrant used may be adjusted appropriately. For example, the ratio of the first swellable disintegrant and the second swellable disintegrant to apixaban may be 0.5 times or more by mass and 2.5 times or less by mass, respectively. The ratio of the first swellable disintegrant is preferably 0.8 times or more by mass or 1 time or more by mass, more preferably 1.2 times or more by mass or 1.5 times or more by mass, and preferably 2 times or less by mass, more preferably 1.8 times or less by mass. The ratio of the second swellable disintegrant is preferably 0.8 times or more by mass, and 2 times or less by mass or 1.8 times or less by mass. The ratio of the first swellable disintegrant to the second swellable disintegrant is preferably 0.5 to 2.5 times by mass, more preferably 1.5 to 1.2 times by mass, and more preferably 1.5 to 1.2 times by mass. The ratio of the first swellable disintegrant to the second swellable disintegrant can be 0.5 to 2.5 times by mass. The ratio is preferably 0.8 to 1 time by mass, and more preferably 2 to 1.8 times by mass.

[0041] In the present invention, the tableting powder containing at least amorphous apixaban or a solid dispersion containing amorphous apixaban, a first swellable disintegrant, and a second swellable disintegrant may further contain additives commonly used in pharmaceutical preparations. Examples of additives include excipients, binders, lubricants, glidants, surfactants, sweeteners, and flavors. In addition to the first swellable disintegrant and the second swellable disintegrant, the tableting powder may also contain a disintegrant other than the first swellable disintegrant and the second swellable disintegrant, such as a water-permeable disintegrant, but it is not necessary to use disintegrants other than the first swellable disintegrant and the second swellable disintegrant.

[0042] An excipient is an additive that is blended to dilute a medicinal ingredient or increase the amount of a formulation to improve the formability and ease of administration of the formulation. Examples of excipients include lactose, crystalline cellulose, ethyl cellulose, hydroxypropyl cellulose, mannitol, dextrin, and sucrose. The amount of excipient can be adjusted appropriately, and can be, for example, 20% by mass or more and 80% by mass or less of the total formulation, preferably 30% by mass or more, more preferably 40% by mass or more, and preferably 70% by mass or less, and more preferably 60% by mass or less.

[0043] Binders are added to bind the various components together and increase the strength of granules or tablets. Binders are not particularly limited, and examples include hypromellose (hydroxypropyl methylcellulose), hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and ethyl cellulose. The amount and proportion of binder in a formulation may be adjusted appropriately depending on the desired formulation strength and granule strength. For example, the binder content may be 0.1% by mass or more and 10% by mass or less relative to the total formulation. The proportion is preferably 0.5% by mass or more, more preferably 1% by mass or more, even more preferably 2% by mass or more, and preferably 5% by mass or less.

[0044] Lubricants are added to adhere to the surfaces of each component to increase its fluidity or to prevent the components from adhering to the equipment. The lubricant is not particularly limited, but examples of lubricants that can be used include magnesium stearate, talc, hydrogenated vegetable oil, polyglycerol fatty acid ester, sucrose fatty acid ester, and sodium stearyl fumarate, with magnesium stearate being preferred. The amount and proportion of the lubricant may be adjusted appropriately within a range that allows for smooth mixing of the components and tableting. For example, the lubricant content can be set to 0.05% by mass or more and 5% by mass or less of the total formulation. The proportion is preferably 0.1% by mass or more, more preferably 0.5% by mass or more, and is preferably 4% by mass or less, and more preferably 2% by mass or less.

[0045] The fluidizer is a component that increases the fluidity of each component and promotes uniform mixing of the components, and examples thereof include light anhydrous silicic acid. The amount and proportion of the fluidizer may be appropriately adjusted within a range that allows for smooth mixing of the components and tableting, and may be, for example, 0.05% by mass or more and 5% by mass or less of the total formulation. The proportion is preferably 0.1% by mass or more, more preferably 0.5% by mass or more, and is preferably 4% by mass or less, more preferably 2% by mass or less.

[0046] The sweeteners and flavorings may be added in trace amounts within the range in which the effects of each component, particularly the active ingredient apixaban, are not inhibited and the respective effects are exerted.

[0047] The tablet powder can be prepared by mixing at least amorphous apixaban or a solid dispersion containing amorphous apixaban, a first swellable disintegrant, a second swellable disintegrant, and, if necessary, other additives.

[0048] 2.Tableting process In this step, the tableting powder prepared in step 1 is compressed into tablets to obtain tablets containing apixaban.

[0049] The tableting pressure when producing tablets is not particularly limited and can be set appropriately depending on the composition and weight of the tablet. The tableting pressure can be set, for example, to 2 kN or more and 20 kN or less, preferably 3 kN or more, and preferably 18 kN or less, and more preferably 15 kN or less. For example, tableting may be performed at 7 ± 5 kN or 7 ± 3 kN.

[0050] The hardness of the apixaban-containing tablet according to the present invention is not particularly limited, but is preferably, for example, 25 N or more and 200 N or less, and more preferably 30 N or more and 150 N or less. The hardness can be adjusted, for example, by the tableting pressure.

[0051] The moisture content of the apixaban-containing tablet according to the present invention is not particularly limited, but is preferably 2% by mass or less, and more preferably 1% by mass or less. The lower limit of the moisture content is not particularly limited and may be 0% by mass, but the moisture content can be, for example, 0.2% by mass or more. The moisture content can be measured, for example, by the Karl Fischer method.

[0052] The size of the apixaban-containing tablets according to the present invention may be adjusted appropriately, for example, the shape of the tablets may be discoid or lenticular, which is easy to take orally, with a diameter of 4 mm to 10 mm, a thickness of 2 mm to 5 mm, and a weight of 50 mg to 360 mg per tablet.

[0053] 3. Coating process In this step, the tablets obtained in step 2 are coated. This step is optional, and if coating is not required, this step does not have to be performed. When coating is performed, the tablets before coating are sometimes called plain tablets.

[0054] Examples of components of the coating layer include (meth)acrylic acid copolymers such as polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, methacrylic acid copolymer, methyl methacrylate-butyl methacrylate copolymer, methyl methacrylate-dimethylaminoethyl methacrylate copolymer, and aminoalkyl methacrylate copolymer; celluloses such as hypromellose, ethyl cellulose, hydroxypropyl cellulose, cellulose acetate phthalate, and hypromellose phthalate; other polymers such as polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol diethylaminoacetate, and polyvinyl alcohol acetate phthalate; and inorganic compounds such as talc, titanium oxide, and silicic acid. The coating agent may be a single type or a combination of two or more types.

[0055] The coating layer may contain a colorant, such as titanium oxide, yellow ferric oxide, red ferric oxide, black ferric oxide, and tar dyes (red, yellow, or orange).

[0056] The content of the specific colorant relative to the entire tablet of the present invention is not particularly limited as long as it can improve the stability of apixaban, but is preferably 0.01% by mass or more and 1% by mass or less.

[0057] When coating the tablet of the present invention, a known coating method can be used. For example, pan coating, fluidized bed coating, etc. can be used. The coating agent can be appropriately selected from pharmaceutically acceptable agents depending on the application of the coating, and may further contain the above-mentioned colorant.

[0058] To improve identifiability, the surface of the tablet of the present invention may be engraved or printed with a product number, the name of the active ingredient, the content of the active ingredient, the dosage form, the product number, a QR code (registered trademark), a bar code, etc. Engraving or printing may be performed directly on the surface of the plain tablet or the film-coated tablet. As the printing method, an appropriate method can be selected from, for example, ink printing methods using plate-type transfer printing, gravure printing, offset printing, and inkjet printing, and laser printing. The ink used for printing may be an edible ink containing a dye and / or a pigment. The ink color may be one color or may be two or more colors from the viewpoint of distinguishability.

[0059] The apixaban-containing tablet according to the present invention may be packaged in a PTP (Press Through Pack), bottle, aluminum packaging, or the like, as needed.

[0060] Examples of materials for PTP packaging include resins such as polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, and polycarbonate, as well as metals such as aluminum. These materials may be used alone or in combination. Examples of combinations include laminating polyvinyl chloride and polyvinylidene chloride, or laminating polyvinyl chloride and polychlorotrifluoroethylene. Packaging can be achieved by placing a formulation in a resin sheet formed from the above resins into a pocket shape using a known method, and then covering it with aluminum foil.

[0061] To improve light stability, PTP packaging made of a material capable of blocking or reducing light of specific wavelengths may be used. Examples of light wavelengths for which the transmittance of the PTP packaging material should be suppressed to 90% or less include 390 nm, 480 nm, 550 nm, 560 nm, and 600 nm. Examples of material colors include clear (transparent), persimmon, orange, red, and yellow.

[0062] The PTP package containing the apixaban-containing tablet of the present invention may further be packaged in an aluminum pillow or a packaging bag made of a material capable of blocking or reducing light of a specific wavelength, and may further contain a desiccant or oxygen scavenger. Examples of desiccants include calcium chloride, calcium oxide, magnesium oxide, silica gel, and zeolite. Examples of oxygen scavengers include iron-based desiccant such as iron powder, and organic desiccant such as ascorbic acid, isoascorbic acid, hydroquinone, and catechol. These desiccant and desiccant may be used alone or in combination, or a combination of desiccant and desiccant may be used. An example of a product combining a desiccant and desiccant is "PharmaKeep (registered trademark)" from Mitsubishi Gas Chemical Company, Inc.

[0063] The dosage of the apixaban-containing tablet according to the present invention may be adjusted appropriately depending on the patient's symptoms, severity, age, sex, etc. For example, in terms of the dosage of apixaban, 1 mg to 20 mg may be administered once or more and three or less times per day for five or more days. In particular, for patients aged 80 years or older, patients weighing 60 kg or less, and patients with serum creatinine levels of 1.5 mg / dL or higher, it is preferable to administer a relatively low dosage, for example, 2.5 mg of apixaban twice a day.

[0064] The apixaban-containing tablet according to the present invention contains at least a specific first swellable disintegrant and a specific second swellable disintegrant as disintegrants, and therefore has excellent disintegrability, disintegrates quickly after administration, and allows the active ingredient apixaban to be released. In addition, the variation in tablet disintegration time due to tableting pressure is suppressed, and therefore the tablet can be easily produced with more uniform quality. [Example]

[0065] The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to the following examples, and it is possible to carry out the invention by making appropriate modifications within the scope of the above and below-described aims, and all such modifications are included in the technical scope of the present invention.

[0066] Examples 1 and 2 and Comparative Examples 1 to 3 (1) Amorphization of apixaban The composition is shown in Table 3. 50 :40.2μm,D 90 113.9 μm), hydroxypropyl cellulose ("HPC-SSL" manufactured by Nippon Soda Co., Ltd.), and D-mannitol ("PEARLITOL 50C" manufactured by ROQUETTE) were mixed and placed in an extruder ("Pharma11" manufactured by Thermo Fisher Scientific), melted at 240°C, and then allowed to solidify by naturally cooling to room temperature. The resulting solid dispersion was pulverized using a pin mill and then classified using a 30M sieve to obtain a solid dispersion powder.

[0067] (2) Tablet compression The solid dispersion powder and other ingredients were mixed using a diffusion mixer according to the composition shown in Table 3. Magnesium stearate was then added as a lubricant, and the mixture was mixed using a diffusion mixer to obtain a tableting powder. The obtained tableting powder was compressed using a rotary tableting machine at a tableting pressure of 4 to 12 kN to obtain uncoated tablets. However, in Comparative Examples 1 and 2, the tableting pressure was set to 4 to 6 kN so that the disintegration time was approximately the same as that of the other uncoated tablets. The swelling degree of croscarmellose sodium is about 180% and the wetting time is about 500 seconds, while the swelling degree of crospovidone is about 80% and the wetting time is about 20 seconds.

[0068] (3) Film coating On the uncoated tablets of Comparative Example 1, a film coating (FC) layer was formed with the composition shown in Table 3. Talc was dispersed in a solution obtained by dissolving polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer in purified water. Separately, titanium dioxide and ferric oxide or yellow ferric oxide were dispersed in purified water. A colorant dispersion was added to the talc dispersion and mixed. Anhydrous ethanol was added to the resulting dispersion to create a film coating solution. The uncoated tablets were placed in a film coating pan machine, coated with the film coating solution, and dried.

[0069] Test Example 1: Tablet disintegration test The disintegration times of the tablets of Examples 1 and 2 and Comparative Examples 1 to 3 were measured in accordance with the disintegration test method of Japanese Pharmacopoeia 6.09. One tablet was placed in each of the six glass tubes of the disintegration tester, and the tester was operated at 37±2°C using water as the test liquid. The tablet was judged to have disintegrated when no tablet residue was found in the glass tube, or when any residue was found that was a soft substance that had clearly lost its original shape. The tableting pressure (kN) was plotted on the horizontal axis and the disintegration time (min) on the vertical axis, and the approximate formula and its coefficient of determination R 2 Representative graphs for the tablets of Example 1 and Comparative Example 1 are shown in Figure 1, and the slopes of the respective approximation equations are shown in Table 3.

[0070] [Table 3]

[0071] As shown in Table 3, the tablets of Comparative Examples 1 to 3, which did not contain either croscarmellose sodium, which has a swelling degree of more than 100%, or crospovidone, which has a shorter wetting time than croscarmellose sodium, showed a large change in disintegration time depending on the tableting pressure. This shows that the tableting conditions must be controlled relatively strictly to obtain tablets that exhibit the desired disintegrability.

[0072] Furthermore, although the change in disintegration time according to the tableting pressure of the tablet of Comparative Example 3 was relatively small, small lumps that could not pass through the mesh remained on the mesh of the disintegration tester. It is unlikely that the active ingredient apixaban would be released well from such small lumps, and if the disintegration time of the tablet is defined as the time until all the small lumps on the mesh disappear, the disintegration time should be longer and the slope of the approximation equation should also be greater. In contrast, the tablets of Examples 1 and 2 containing both croscarmellose sodium and crospovidone rapidly disintegrated regardless of the tableting pressure, the slope of the approximation equation was small, and the change in disintegration time depending on the tableting pressure was small. Therefore, the tablet according to the present invention has a wide tolerance range for the tableting pressure according to a predetermined disintegration time, and the manufacturing conditions can be set relatively loosely.

[0073] Examples 3 and 4: Preparation of film-coated tablets Film-coated tablets were produced using the compositions shown in Table 4 in the same manner as in Comparative Example 1 above.

[0074] [Table 4]

[0075] Test Example 2: Examination of the effects of sugar alcohols Apixaban drug substance (43.7 g) and hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) (525.0 g) were mixed together, followed by 1 to 20% by mass of D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE). Each mixture was placed in an extruder ("Pharma11" manufactured by Thermo Fisher Scientific) and melt-extruded at 240°C. However, when D-mannitol was not added or when the D-mannitol content was 3% by mass or less, the melt viscosity of the mixture was high, the torque value of the extruder used exceeded the recommended upper limit, and melt extrusion became difficult. On the other hand, when the D-mannitol content was 20% by mass, the viscosity of the molten material was too low, and the molten material leaked from the extruder before extrusion. The results are shown in Figure 2. As shown in Figure 2, it was revealed that when apixaban drug substance is converted into a solid dispersion to make it amorphous, an appropriate amount of sugar alcohol with a relatively low melting point should be added to reduce the viscosity of the molten product to a certain extent.

[0076] Examples 5 and 6: Preparation of film-coated tablets Film-coated tablets were produced using the compositions shown in Table 5 in the same manner as in Comparative Example 1 above.

[0077] [Table 5]

Claims

1. A method for suppressing variation in disintegration time of an apixaban-containing tablet due to tableting pressure, comprising: A method for preparing tableted powder containing amorphous apixaban, comprising blending a first swellable disintegrant having a swelling degree of more than 100% and a second swellable disintegrant having a wetting time shorter than that of the first swellable disintegrant.

2. 2. The method according to claim 1, wherein the first swelling disintegrant is at least one swelling disintegrant selected from croscarmellose sodium and sodium starch glycolate.

3. The method of claim 1, wherein crospovidone is used as the second swellable disintegrant.

4. 2. The method of claim 1, wherein the amorphous apixaban is contained in a solid dispersion, the solid dispersion containing a sugar alcohol in addition to the amorphous apixaban.

5. The method according to claim 4, wherein the content of the sugar alcohol in the solid dispersion is 4% by mass or more and 10% by mass or less.

6. 1. A method for producing a tablet containing apixaban as an active ingredient, comprising: preparing a powder for tableting containing amorphous apixaban, a first swellable disintegrant having a swelling degree of more than 100%, and a second swellable disintegrant having a wetting time shorter than that of the first swellable disintegrant; and The method comprises a step of compressing the tablet powder into tablets.

7. A tablet comprising amorphous apixaban, a first swellable disintegrant having a swelling degree of more than 100%, and a second swellable disintegrant having a wetting time shorter than that of the first swellable disintegrant.

8. 8. The tablet of claim 7, wherein the amorphous apixaban is contained in a solid dispersion, and the solid dispersion contains a sugar alcohol in addition to the amorphous apixaban.

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