Febuxostat preparations

Abstract

This invention provides a novel formulation that masks the bitterness and pharyngeal irritation of febuxostat while ensuring dissolution and improving disintegration properties. [Solution] Granules characterized by containing febuxostat or a pharmaceutically acceptable salt thereof and an aminoalkyl methacrylate copolymer.

Description

Technical Field

[0001] The present invention relates to granules containing febuxostat or a pharmaceutically acceptable salt thereof. The present invention also relates to tablets containing the above granules. Furthermore, the present invention relates to a method for producing the above granules and a method for improving the dissolution and disintegration properties of a preparation to which the above granules are applied.

Background Art

[0002] Febuxostat has an action of regulating the biosynthesis of uric acid in the living body, and thus is useful in the treatment of gout, hyperuricemia, and the like.

[0003] As a document related to febuxostat, Patent Document 1 is known.

[0004] Patent Document 1 discloses crystal polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid and a method for producing the same. Further, a febuxostat preparation containing the above compound as an active ingredient is currently commercially available.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0006] As a result of the study by the present inventors, it was found that febuxostat has bitterness and pharyngeal irritation.

[0007] Here, it was thought that conventional methods for manufacturing febuxostat tablets, such as those described in Patent Document 2, could not suppress bitterness and pharyngeal irritation, and therefore a technology to mask the bitterness and pharyngeal irritation of febuxostat was needed. However, coating (masking) with polymers had the problem of reducing dissolution. In addition, improvement in the disintegration properties of tablets was desired in order to apply febuxostat to orally disintegrating tablets.

[0008] Therefore, one aspect of the present invention aims to realize a novel formulation that masks the bitterness and pharyngeal irritation of febuxostat while ensuring dissolution and further improving disintegration properties. [Means for solving the problem]

[0009] As a result of diligent research to solve the above problems, the present inventors have discovered for the first time that, in the case of granules containing febuxostat, coating the granules containing febuxostat with a coating layer containing an aminoalkyl methacrylate copolymer improves the disintegration properties of the formulation containing the granules, and that the elution properties of febuxostat from the formulation containing the granules are significantly higher compared to other coating agents, thus completing the present invention. That is, one aspect of the present invention includes the following configuration. <1> Granules characterized in that granules containing febuxostat or a pharmaceutically acceptable salt thereof are coated with a coating layer containing an aminoalkyl methacrylate copolymer. <2> The granules further contain a binder. <1> The granules described above. <3> The binder is hydroxypropyl cellulose. <2> The granules described above. <4> The febuxostat is a G-type crystal. <1> ~ <3> Granules as described in any of the following. <5> A method for producing granules containing febuxostat or a pharmaceutically acceptable salt thereof, A method for producing febuxostat or a pharmaceutically acceptable salt thereof, characterized by comprising the step of coating a granule containing febuxostat or a pharmaceutically acceptable salt thereof with a coating layer containing an aminoalkyl methacrylate copolymer. <6> The process includes a granulation step for granulating the aforementioned granules, The granulation step involves mixing febuxostat or a pharmaceutically acceptable salt thereof with a binder without dissolving or suspending them in a solvent, and then granulating the mixture obtained by the mixing. <5> The manufacturing method described above. <7> A method for improving the dissolution of febuxostat or a pharmaceutically acceptable salt thereof from a formulation containing granules containing febuxostat or a pharmaceutically acceptable salt thereof, A method characterized by coating granules containing febuxostat or a pharmaceutically acceptable salt thereof with a coating layer containing an aminoalkyl methacrylate copolymer. <8> A method for improving the disintegration properties of a formulation containing granules containing febuxostat or a pharmaceutically acceptable salt thereof, A method characterized by coating granules containing febuxostat or a pharmaceutically acceptable salt thereof with a coating layer containing an aminoalkyl methacrylate copolymer. <9> <1> ~ <4> A tablet containing granules as described in any of the following: A tablet characterized by containing 10 mg of febuxostat or a pharmaceutically acceptable salt thereof as febuxostat, and having a tablet diameter of 5.5 mm or less. <10> <1> ~ <4> A tablet containing granules as described in any of the following: A tablet characterized by containing 20 mg of febuxostat or a pharmaceutically acceptable salt thereof as febuxostat, and having a tablet diameter of 7.0 mm or less. <11> <1> ~ <4> A tablet containing granules as described in any of the following: A tablet characterized by containing 40 mg of febuxostat or a pharmaceutically acceptable salt thereof as febuxostat, and having a tablet diameter of 8.5 mm or less. <1a> Granules characterized by comprising febuxostat or a pharmaceutically acceptable salt thereof and an aminoalkyl methacrylate copolymer. <2a> The granules according to <1a>, wherein the tablet further comprises a binder. <3a> The granules according to <2a>, wherein the binder is hydroxypropylcellulose. <4a> The granules according to any one of <1a> to <3a>, wherein the febuxostat is a G-type crystal. <5a> The granules according to any one of <1a> to <4a>, wherein the aminoalkyl methacrylate copolymer E is aminoalkyl methacrylate copolymer E. A tablet characterized by containing granules as described in any of <6a>, <1a>, to <5a>. <7a> A method for producing tablets containing febuxostat or a pharmaceutically acceptable salt thereof, A method for manufacturing a product, characterized by comprising the step of compressing a raw material containing febuxostat or a pharmaceutically acceptable salt thereof and an aminoalkyl methacrylate copolymer into tablets. <8a> A method for improving the dissolution of febuxostat or a pharmaceutically acceptable salt thereof from a tablet containing febuxostat or a pharmaceutically acceptable salt thereof, A method characterized by compressing a raw material containing the aforementioned febuxostat or a pharmaceutically acceptable salt thereof and an aminoalkyl methacrylate copolymer into tablets. <9a> A tablet comprising febuxostat or a pharmaceutically acceptable salt thereof and an aminoalkyl methacrylate copolymer. <10a> The tablet according to <9a>, wherein the aminoalkyl methacrylate copolymer is aminoalkyl methacrylate copolymer E. <11a> A tablet as described in <9a> or <10a>, which is an orally disintegrating tablet. <12> A method for producing tablets containing granules containing febuxostat or a pharmaceutically acceptable salt thereof, A manufacturing method characterized by including a step of tableting granules containing the febuxostat or a pharmaceutically acceptable salt thereof and an aminoalkyl methacrylate copolymer. <13>A method for improving the elution property of febuxostat or a pharmaceutically acceptable salt thereof from tablets containing granules containing the febuxostat or a pharmaceutically acceptable salt thereof, characterized by tableting granules containing the febuxostat or a pharmaceutically acceptable salt thereof and an aminoalkyl methacrylate copolymer. [Advantages of the Invention]

[0010] According to one aspect of the present invention, it is possible to provide a novel preparation that masks the bitterness and pharyngeal irritation of febuxostat or a pharmaceutically acceptable salt thereof, ensures elution property, and further improves disintegration property. Also, according to one aspect of the present invention, it is possible to provide a method for improving the elution property of febuxostat or a pharmaceutically acceptable salt thereof from a preparation and a method for improving the disintegration property of the preparation while masking the bitterness and pharyngeal irritation of febuxostat or a pharmaceutically acceptable salt thereof as compared with other coating agents. [Brief Description of the Drawings]

[0011] [Figure 1] A diagram showing the results of an elution test in examples and comparative examples according to an embodiment of the present invention. [Figure 2] A diagram showing the results of an elution test in examples and comparative examples according to an embodiment of the present invention. [Modes for Carrying Out the Invention]

[0012] Hereinafter, an embodiment of the present invention will be described in detail.

[0013] Unless otherwise specified in this specification, "A~B" indicating a numerical range means "A or more and B or less".

[0014] [1. Outline] A granule according to one embodiment of the present invention (hereinafter referred to as "the granule of the present invention") is a granule characterized in that a granule containing febuxostat or a pharmaceutically acceptable salt thereof (hereinafter sometimes simply referred to as "febuxostat") is coated with a coating layer containing an aminoalkyl methacrylate copolymer. Alternatively, the granule of the present invention can also be described as a granule containing a granule containing febuxostat or a pharmaceutically acceptable salt thereof, characterized in that the aminoalkyl methacrylate copolymer is unevenly distributed on the surface of the granule containing the febuxostat or a pharmaceutically acceptable salt thereof.

[0015] The inventors' research revealed that febuxostat has a bitter taste and causes pharyngeal irritation. While polymer coating is necessary to mask the bitterness and pharyngeal irritation of febuxostat, this coating reduces its elution properties. Therefore, the inventors conducted diligent research and succeeded in obtaining the following findings. In the case of granules containing febuxostat, the disintegration properties of the formulation containing the granules are improved by coating the granules containing febuxostat with a coating layer containing an aminoalkyl methacrylate copolymer. In the case of granules containing febuxostat, coating the granules containing febuxostat with a coating layer containing an aminoalkyl methacrylate copolymer significantly improves the elution of febuxostat from the formulation containing the granules compared to other coating agents.

[0016] The formulation containing the granules of the present invention ensures dissolution despite masking, and furthermore, exhibits good disintegration properties. Moreover, because the masking is applied to the granules, unlike film coating which masks the entire tablet, it has the advantage of minimizing the impact of splitting. Therefore, the granules of the present invention are useful not only for orally disintegrating tablets (hereinafter referred to as "OD tablets") where disintegration is required, but also for ordinary tablets (regular tablets) where dissolution is required.

[0017] Thus, the granules of the present invention exhibit advantageous effects based on the above findings, making it possible to provide a useful novel formulation containing febuxostat or a pharmaceutically acceptable salt thereof.

[0018] [2. Granules of the present invention] The granules of the present invention comprise a granule containing febuxostat or a pharmaceutically acceptable salt thereof. Furthermore, in the granules of the present invention, the granule is coated with a coating layer containing an aminoalkyl methacrylate copolymer.

[0019] (Febuxostat or a pharmaceutically acceptable salt thereof) The granules of the present invention contain febuxostat or a pharmaceutically acceptable salt thereof as an active ingredient. Febuxostat is a compound represented by the following formula (1), and is commonly known as 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid.

[0020] [ka]

[0021] In this specification, “pharmaceutically acceptable salt” means a salt that is medically free from excessive toxicity, irritation, allergic reactions, etc., and suitable for use in contact with human or other mammalian tissues.

[0022] The pharmaceutically acceptable salts of febuxostat are well known in the art and any of them can be used. Examples of pharmaceutically acceptable salts of febuxostat include hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphoric acid, formic acid, acetic acid, propionic acid, 2-hydroxyacetic acid, trifluoroacetic acid, malic acid, butyric acid, benzoic acid, dihydroxybenzoic acid, methyl parahydroxybenzoate, methyl dihydroxybenzoate, ethyl dihydroxybenzoate, trihydroxybenzoic acid, 4-hydroxy-3-methoxybenzoic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, and methanesulfonic acid. Examples include salts with ethanolic acid, ethanesulfonic acid, dodecylsulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid; salts with metals such as lithium, sodium, potassium, cesium, magnesium, calcium, zinc, and aluminum; and salts with amines such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, isopropylamine, butylamine, isobutylamine, tert-butylamine, benzylamine, pyridine, pyrrolidine, and 2,6-lutidine.

[0023] In this specification, febuxostat may be in an anhydrous form, a hydrate form, or an isomer form. Examples of febuxostat hydrates include type A crystals and type G crystals.

[0024] The A-type crystal is the A-type crystal described in Japanese Patent Publication No. 3547707, and exhibits the following physical properties. The X-ray powder diffraction pattern exhibits characteristic peaks at approximately 6.62°, 7.18°, 12.80°, 13.26°, 16.48°, 19.58°, 21.92°, 22.68°, 25.84°, 26.70°, 29.16°, and 36.70°, expressed as a reflection angle 2θ. In infrared spectroscopy, 1678 cm⁻¹ -1 It possesses characteristic absorptions in the vicinity that distinguish it from other crystalline polymorphs.

[0025] The G-type crystal is the G-crystal described in Japanese Patent Publication No. 3547707, and is a crystal that exhibits the following physical properties. The X-ray powder diffraction pattern exhibits characteristic peaks at approximately 6.86°, 8.36°, 9.60°, 11.76°, 13.74°, 14.60°, 15.94°, 16.74°, 17.56°, 20.00°, 21.26°, 23.72°, 24.78°, 25.14°, 25.74°, 26.06°, 26.64°, 27.92°, 28.60°, 29.66°, and 29.98°, expressed as a reflection angle 2θ. In infrared spectroscopy, 1703 cm⁻¹ -1 and 1684cm -1 It possesses characteristic absorptions in the vicinity that distinguish it from other crystalline polymorphs.

[0026] In one embodiment of the present invention, febuxostat is preferably in the form of a hydrate, and more preferably in the form of a G-type crystal of a hydrate.

[0027] (Granulated material) In this specification, "granules" means in the sense commonly used in the art, and refers to a mixture of powdered components formed into granules. The granules in the present invention contain febuxostat or a pharmaceutically acceptable salt thereof.

[0028] In one embodiment of the present invention, the granules in the granules of the present invention may further contain a binder.

[0029] The binder is not particularly limited, but examples include hydroxypropyl cellulose, hypromellose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl acetate, or combinations thereof, pregelatinized starch, gelatin, agar, and gum arabic. Hydroxypropyl cellulose is preferably used.

[0030] In one embodiment of the present invention, the amount of binder (e.g., hydroxypropyl cellulose) contained in the granules is, for example, 0.01 to 30.0% by mass, preferably 0.10 to 20.0% by mass, and more preferably 1.0 to 10.0% by mass, based on the mass of the granules.

[0031] In one embodiment of the present invention, the granules in the granules of the present invention may contain excipients, disintegrants, and the like as components other than those mentioned above.

[0032] Excipients are not particularly limited, but examples include D-mannitol, lactose, sucrose, corn starch, calcium phosphate, sorbitol, and crystalline cellulose. D-mannitol is preferably used.

[0033] The disintegrant is not particularly limited, but examples include crospovidone, low-substituted hydroxypropylcellulose, sodium starch glycolate, croscarmellose sodium, and potato starch. Croscarmellose sodium is preferably used.

[0034] The content of each additive in the granules is not particularly limited and can be set appropriately based on conventionally known techniques.

[0035] (Coating layer) The coating layer in the granules of the present invention contains an aminoalkyl methacrylate copolymer. By including an aminoalkyl methacrylate copolymer in the coating layer of the granules of the present invention, the disintegration time of the formulation to which the granules are applied is shortened, and the dissolution of febuxostat is improved compared to other coating agents.

[0036] The aminoalkyl methacrylate copolymer contained in the granules of the present invention is not particularly limited as long as it is of a grade suitable for use in pharmaceuticals, but aminoalkyl methacrylate copolymer E ("Eudragit® E100" manufactured by Evonik Japan Co., Ltd.) is preferred.

[0037] In one embodiment of the present invention, the amount of aminoalkyl methacrylate copolymer contained in the coating layer is, for example, 0.01 to 30.0% by mass, preferably 0.5 to 15.0% by mass, and more preferably 1.0 to 10.0% by mass, based on the mass of the granules.

[0038] In one embodiment of the present invention, the coating layer in the granules of the present invention may contain components other than those described above. Such components are not particularly limited, but examples include titanium dioxide, talc, silicic acid, hydroxypropyl cellulose, hypromellose, ethyl cellulose, polyvinyl alcohol, and copolymers of polyvinyl alcohol, acrylic acid, and methyl methacrylate. Talc is preferably used.

[0039] The content of the component in the coating layer is not particularly limited and can be set appropriately based on conventionally known techniques.

[0040] [3. Formulation of the present invention] In one embodiment of the present invention, a formulation (hereinafter referred to as "the formulation of the present invention") is provided, characterized by containing the granules described in [2. Granules of the present invention].

[0041] The formulation of the present invention is characterized by comprising granules containing febuxostat, wherein the granules are coated with a coating layer containing an aminoalkyl methacrylate copolymer. Therefore, compared to other coating agents, the elution of febuxostat from the formulation is improved, and the disintegration properties of the formulation are also improved.

[0042] In this specification, the formulation is not particularly limited as long as it is a drug formed for oral administration, but examples include tablets (including orally disintegrating tablets), capsules, granules, powders, dry syrups, etc. The formulation of the present invention is preferably a tablet.

[0043] In one embodiment of the present invention, the amount of febuxostat contained in the formulation of the present invention is not particularly limited and can be appropriately set based on conventionally known techniques. The amount of febuxostat contained in the granules of the present invention is preferably 40 mg, 20 mg, or 10 mg.

[0044] In addition to the granules described above, the formulation of the present invention may contain various other components depending on the type and form of the formulation. Examples of such components include excipients, binders, disintegrants, lubricants, and colorants.

[0045] For example, those described in [2. Granules of the present invention] can be used as excipients, binders, and disintegrants.

[0046] The coloring agent is not particularly limited, but examples include yellow coloring agents (e.g., yellow iron(III) oxide, yellow iron oxide, food yellow No. 4 aluminum lake, red iron oxide, etc.), red coloring agents (e.g., iron(III) oxide, food red No. 2, food red No. 3, food red No. 102, etc.), black coloring agents (e.g., black iron oxide, carbon black, medicinal charcoal, etc.), and caramel. Preferably, iron oxide and caramel are used, and more preferably, yellow iron(III) oxide is used.

[0047] The lubricant is not particularly limited, but examples include carnauba wax, hydrated silicon dioxide, hydrated amorphous silicon dioxide, dried aluminum hydroxide gel, magnesium silicate, light anhydrous silicic acid, synthetic aluminum silicate, magnesium oxide, heavy anhydrous silicic acid, sucrose fatty acid ester, aluminum hydroxide gel, stearyl alcohol, stearic acid, calcium stearate, magnesium stearate, cetanol, magnesium carbonate, precipitated calcium carbonate, sodium stearyl fumarate, talc, anhydrous silicic acid hydrate, magnesium aluminometasilicate, etc. Magnesium stearate is preferably used.

[0048] The content of the aforementioned additive is not particularly limited and can be appropriately determined based on conventionally known techniques.

[0049] In one embodiment of the present invention, if the formulation of the present invention is a tablet, granule, etc., a film coating may be further provided on the outside of the tablet, granule, etc. The coating agent used for the film coating is not particularly limited, but examples include talc, silicic acid, hydroxypropyl cellulose, hypromellose, ethyl cellulose, polyvinyl alcohol, a copolymer of polyvinyl alcohol, acrylic acid, and methyl methacrylate, etc. Preferably, polyvinyl alcohol, hydroxypropyl cellulose, hypromellose, talc, etc. are used.

[0050] In one embodiment of the present invention, the formulation of the present invention is a formulation comprising granules in which a granule containing febuxostat or a pharmaceutically acceptable salt thereof is coated with a coating layer containing an aminoalkyl methacrylate copolymer, wherein the formulation contains 10 mg of febuxostat or a pharmaceutically acceptable salt thereof as febuxostat, and the tablet has a diameter of 5.5 mm or less.

[0051] Furthermore, in one embodiment of the present invention, the formulation of the present invention is a formulation comprising granules in which granules containing febuxostat or a pharmaceutically acceptable salt thereof are coated with a coating layer containing an aminoalkyl methacrylate copolymer, characterized in that the formulation contains 20 mg of febuxostat or a pharmaceutically acceptable salt thereof as febuxostat, and the diameter of the tablet is 7.0 mm or less.

[0052] Furthermore, in one embodiment of the present invention, the formulation of the present invention is a formulation comprising granules in which granules containing febuxostat or a pharmaceutically acceptable salt thereof are coated with a coating layer containing an aminoalkyl methacrylate copolymer, characterized in that the formulation contains 40 mg of febuxostat or a pharmaceutically acceptable salt thereof as febuxostat, and the tablet has a diameter of 8.5 mm or less.

[0053] The formulation of the present invention is not particularly limited, and any shape can be used. If the formulation of the present invention is a tablet, it may be, for example, round, oval, spherical, rod-shaped, or donut-shaped. Furthermore, if the formulation of the present invention is a tablet, it may be a single-layer tablet, a laminated tablet, a core-containing tablet, or the like.

[0054] The moisture content (loss on drying) in the formulation of the present invention is not particularly limited, but is preferably 10% or less, more preferably 5% or less, and even more preferably 3% or less.

[0055] Furthermore, if the formulation of the present invention is in tablet form, its hardness is not particularly limited, but is preferably about 20 to 200 N, and more preferably about 50 to 150 N.

[0056] [4. Other] The present invention provides a method for producing granules containing febuxostat or a pharmaceutically acceptable salt thereof, characterized by comprising the step of coating the granules containing febuxostat or a pharmaceutically acceptable salt thereof with a coating layer containing an aminoalkyl methacrylate copolymer (hereinafter referred to as "the production method of the present invention").

[0057] The manufacturing method of the present invention may include, for example, a granule manufacturing step, a coating layer coating step, and a mixed tableting step. For example, granules containing febuxostat are manufactured by the method described in the examples. The obtained granules are then coated with a coating layer (granule A). Separately, granules B that do not contain febuxostat are manufactured. Subsequently, the obtained granules A and B are mixed, a lubricant is added, and the mixture is compressed to obtain the formulation (tablet) of the present invention.

[0058] Furthermore, the manufacturing method of the present invention may include a step of mixing febuxostat or a pharmaceutically acceptable salt thereof with a binder without dissolving or suspending them in a solvent, and granulating the mixture obtained by the mixing. In the granulation step, if febuxostat and the binder are mixed without dissolving or suspending them in a solvent (in other words, if febuxostat and the binder are mixed in a powder state), it is thought that the binder will not be uniformly distributed throughout the granules. As a result, the binding force between the powder particles decreases, creating weak areas in the intergranular binding within the tablet, and consequently, an improvement in disintegration can be expected.

[0059] In other words, the present invention provides a method for producing granules containing febuxostat or a pharmaceutically acceptable salt thereof, comprising the steps of: mixing febuxostat or a pharmaceutically acceptable salt thereof and a binder without dissolving or suspending them in a solvent; granulating the mixture obtained by the mixing (granulation step); and coating the granules containing febuxostat or a pharmaceutically acceptable salt thereof with a coating layer containing an aminoalkyl methacrylate copolymer.

[0060] Furthermore, in one embodiment of the present invention, a method is provided for improving the elution properties of febuxostat or a pharmaceutically acceptable salt thereof from a formulation comprising granules containing febuxostat or a pharmaceutically acceptable salt thereof, compared to other coating agents, characterized in that the granules are coated with a coating layer containing an aminoalkyl methacrylate copolymer (hereinafter referred to as "the elution property improvement method of the present invention").

[0061] As described above, the dissolution improvement method of the present invention can improve the dissolution of febuxostat formulations compared to other coating agents while masking the bitterness and pharyngeal irritation of febuxostat. Therefore, the dissolution improvement method of the present invention is extremely useful in designing stable febuxostat formulations.

[0062] Furthermore, in one embodiment of the present invention, a method is provided for improving the disintegration properties of a formulation comprising granules containing febuxostat or a pharmaceutically acceptable salt thereof, characterized in that the granules are coated with a coating layer containing an aminoalkyl methacrylate copolymer (hereinafter referred to as "the disintegration property improvement method of the present invention").

[0063] As described above, the disintegration improvement method of the present invention can improve the disintegration properties of febuxostat preparations. Therefore, the disintegration improvement method of the present invention is extremely useful, for example, in designing febuxostat preparations such as orally disintegrating tablets.

[0064] In the manufacturing method, dissolution improvement method, and disintegration improvement method of the present invention described above, the descriptions of each component (for example, "febuxostat or a pharmaceutically acceptable salt thereof," "granules," "coating layer," etc.) are referenced from those described in [2. Granules of the present invention] and [3. Formulations of the present invention].

[0065] The present invention is not limited to the embodiments described above, and various modifications are possible within the scope of the claims. Embodiments obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention. [Examples]

[0066] One embodiment of the present invention is described below.

[0067] [Measurement and evaluation methods] The evaluations in the examples and comparative examples were carried out using the following method.

[0068] (1. Dissolution test) Dissolution tests were conducted in accordance with the dissolution test method (paddle method / immediate-release formulation) of the 17th revised Japanese Pharmacopoeia, using 900 mL of test solutions with pH 1.2 (0.5% polysorbate, Figure 1) and pH 6.8 (1% polysorbate, Figure 2). Details are as follows.

[0069] After setting the container containing the above-mentioned test solution into the dissolution test apparatus, the sample was added, and the apparatus was operated at a rotation speed of 50 rpm. The test solution was then collected at specified intervals (5 minutes, 15 minutes, 30 minutes, 60 minutes, and 120 minutes).

[0070] The amount of febuxostat in the collected test solution was measured by ultraviolet-visible spectrophotometry (UV), and the dissolution rate (%) was determined as the percentage relative to 40 mg of febuxostat.

[0071] (2. Collapse Test) In accordance with the disintegration test method (immediately disintegrating preparations) of the 17th revised Japanese Pharmacopoeia, a disintegration test was conducted without an auxiliary disc, and the disintegration time when the tablets disintegrated was measured.

[0072] (3. Measuring the thickness of the lock) The tablet thickness was measured using a thickness gauge. The tablet diameter can be measured using, for example, a thickness gauge or calipers.

[0073] (4. Measurement of hardness) The hardness of the tablets was measured using a hardness tester (manufactured by ERWEKA).

[0074] (5. Measurement of Tablet Moisture Content) The moisture content of tablets is measured using a Karl Fischer moisture meter.

[0075] [Example 1] (Manufacturing of A-grain) Febuxostat hydrate G-type crystals, D-mannitol (PEARLITOL 50C from ROQUETTE), hydroxypropyl cellulose (HPC-L fine powder from Nippon Soda Co., Ltd.), and croscarmellose sodium (Acdisol® from FMC Health & Nutrition) were mixed with purified water and granulated. The resulting granules were wet-sizing, dried, and then sizing again to obtain granulated powder. Separately, aminoalkyl methacrylate copolymer E (Eudragit® E100 from Evonik Japan Co., Ltd.) was dissolved in anhydrous ethanol, and then purified water and talc were dispersed to prepare a coating solution. The granulated powder was coated with the coating solution, dried, and then sizing to obtain granules A.

[0076] (Manufacturing of B-grade granules) D-mannitol (PEARLITOL 50C from ROQUETTE), corn starch (Corn Starch (W) from Nippon Shokuhin Kako Co., Ltd.), ethylcellulose (Etocell Standard 7FP Premium from THE DOW CHEMICAL), light anhydrous silicic acid (Adsolider-101 from Fuji Silysia Chemical Co., Ltd.), and crospovidone (Polyplasdon INF-10 from ISP) were mixed with purified water, granulated, dried, and then sized to produce B granules.

[0077] (mixing / tableting) The above-mentioned A granules, B granules, D-mannitol (Merck's "Parteck M100"), aspartame (Ajinomoto Co., Inc.), light anhydrous silicic acid (Fuji Silysia Chemical's "Adsolider-101"), and peppermint micron (Takasago International Corporation's "Peppermint Micron H-81550") were mixed. Magnesium stearate (Taihei Chemical Industry Co., Ltd.) was added to the resulting mixture and mixed to form a tablet powder. The tablet powder was compressed using a rotary tablet press to obtain tablets.

[0078] [Comparative Example 1] (Manufacturing of A-grain) Febuxostat hydrate G-type crystals, D-mannitol (ROQUETTE's "PEARLITOL 50C"), hydroxypropyl cellulose (Nippon Soda Co., Ltd.'s "HPC-L fine powder"), and croscarmellose sodium (FMC Health & Nutrition's "Acdisol®") were mixed with purified water and granulated. The resulting granules were wet-sizing, dried, and then sizing again to obtain granule A.

[0079] (Manufacturing of B-grade granules) D-mannitol (PEARLITOL 50C from ROQUETTE), corn starch (Corn Starch (W) from Nippon Shokuhin Kako Co., Ltd.), ethylcellulose (Etocell Standard 7FP Premium from THE DOW CHEMICAL), light anhydrous silicic acid (Adsolider-101 from Fuji Silysia Chemical Co., Ltd.), and crospovidone (Polyplasdon INF-10 from ISP) were mixed with purified water, granulated, dried, and then sized to produce B granules.

[0080] (mixing / tableting) The above-mentioned granules A and B, aspartame (manufactured by Ajinomoto Co., Inc.), light anhydrous silicic acid ("Adsolider-101" manufactured by Fuji Silysia Chemical Co., Ltd.), and peppermint micron ("Peppermint Micron H-81550" manufactured by Takasago International Corporation) were mixed. Magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) was added to the resulting mixture and mixed to form a tablet powder. The tablet powder was compressed using a rotary tablet press to obtain tablets.

[0081] [Comparative Example 2] Tablets were obtained in the same manner as in Example 1, except that aminoalkyl methacrylate copolymer E was replaced with ethylcellulose ("Etocell Standard 7 Premium" manufactured by THE DOW CHEMICAL).

[0082] For the amounts of each component in Example 1 and Comparative Examples 1-2, please refer to Table 1. In Table 1, 41.14 mg of febuxostat hydrate G-type crystals corresponds to 40 mg of febuxostat.

[0083] [Table 1]

[0084] [Result-1] The hardness and disintegration time of the tablets produced in Example 1 and Comparative Examples 1-2 were measured and evaluated using the method described in [Measurement and Evaluation Method] above. The results are shown in Table 2.

[0085] [Table 2]

[0086] Table 2 shows that in Example 1, the disintegration time was faster compared to Comparative Examples 1 and 2. Furthermore, there was no significant difference in tablet hardness between Example 1 and Comparative Examples 1 and 2.

[0087] From this, it was found that the disintegration properties of the tablet were improved by making the febuxostat into a tablet containing granules coated with a coating layer containing an aminoalkyl methacrylate copolymer.

[0088] [Result-2] The dissolution tests of the tablets produced in Example 1 and Comparative Example 2 were measured and evaluated using the method described in [Measurement and Evaluation Method] above. The results are shown in Figures 1 and 2.

[0089] As shown in Figures 1 and 2, Example 1 showed a higher elution rate in strongly acidic solvents and near-neutral solvents compared to Comparative Example 2.

[0090] This indicates that the dissolution of febuxostat from the tablet is improved by forming a tablet containing granules coated with a coating layer containing an aminoalkyl methacrylate copolymer.

[0091] [Prescription Example 1] Febuxostat hydrate G-type crystals, D-mannitol (ROQUETTE's "PEARLITOL 50C"), hydroxypropyl cellulose (Nippon Soda Co., Ltd.'s "HPC-L"), and croscarmellose sodium (FMC Health & Nutrition's "Acdisol®") are mixed with purified water and granulated. The resulting granules are wet-sizing, dried, and then dry-sizing to obtain granulated powder. The obtained granulated powder is preheated. Separately, aminoalkyl methacrylate copolymer E (Evonik Japan Co., Ltd.'s "Eudragit® E100") is dissolved in anhydrous ethanol, and then purified water and talc (Hayashi Chemical Co., Ltd.'s "Talkan Hayashi") are dispersed to make a coating solution. The granulated powder is coated with the coating solution, dried, and then sized to obtain A-granules.

[0092] (mixing / tableting) The above A granules, D-mannitol (Merck's "Parteck M100"), and croscarmellose sodium (FMC Health & Nutrition's "Acdisol®") are mixed. Magnesium stearate (Taihei Chemical Industry Co., Ltd.) is added to the resulting mixture and mixed to form a tablet powder. The tablet powder is compressed using a rotary tablet press to obtain tablets with a diameter of 8.5 mm and a thickness of 3.9 mm.

[0093] [Prescription Example 2] Except for changing the amounts of each ingredient to those listed in Table 3, tablets with a diameter of 7.0 mm and a thickness of 3.4 mm were obtained using the same method as in Prescription Example 1.

[0094] [Prescription Example 3] Except for changing the amounts of each ingredient to those listed in Table 3, tablets with a diameter of 5.5 mm and a thickness of 2.9 mm were obtained using the same method as in Prescription Example 1.

[0095] For the quantities of each component, please refer to Table 3. In Table 3, 41.14 mg of febuxostat hydrate G-type crystals is equivalent to 40 mg of febuxostat, 20.57 mg of febuxostat hydrate G-type crystals is equivalent to 20 mg of febuxostat, and 10.28 mg of febuxostat hydrate G-type crystals is equivalent to 10 mg of febuxostat. The tablet moisture content for each prescription example is shown in Table 4.

[0096] [Table 3]

[0097] [Table 4] [Industrial applicability]

[0098] According to the present invention, a novel formulation of febuxostat with improved dissolution and disintegration properties can be realized. Therefore, the present invention can be suitably used in the field of manufacturing pharmaceuticals containing febuxostat, and in the field of treating gout, hyperuricemia, and the like.

Claims

1. A tablet comprising febuxostat or a pharmaceutically acceptable salt thereof and aminoalkyl methacrylate copolymer E.

2. The tablet according to claim 1, wherein the febuxostat or a pharmaceutically acceptable salt thereof and the aminoalkyl methacrylate copolymer E are contained in granules.

3. A tablet according to claim 1 or 2, which does not contain organic acids and methylcellulose.

4. The tablet according to claim 1 or 2, wherein the febuxostat is a G-type crystal.

5. A method for producing tablets containing febuxostat or a pharmaceutically acceptable salt thereof, A method for producing a product, characterized by comprising the step of compressing a raw material containing febuxostat or a pharmaceutically acceptable salt thereof and aminoalkyl methacrylate copolymer E into tablets.

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