Preparation containing bilastine, and method for producing the same

Abstract

To provide a method for producing a preparation while suppressing transition of a crystal form of bilastine being an active ingredient, a method for suppressing transition of a crystal form of bilastine in producing a preparation containing bilastine anhydride crystals as an active ingredient, and a preparation in which transition of a crystal form of bilastine being an active ingredient is suppressed.SOLUTION: A method for producing a preparation containing bilastine, pharmaceutically acceptable salt thereof, and crystals of active ingredient selected from a solvate thereof includes a step of mixing the crystals and other components under a condition that the whole moisture content is maintained at 5.0 mass% or less.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a formulation while suppressing the crystal form transition of the active ingredient bilastine, a method for suppressing the crystal form transition of bilastine in the production of a formulation containing bilastine as an active ingredient, and a formulation in which the crystal form transition of the active ingredient bilastine is suppressed. [Background technology]

[0002] Bilastine (chemical name: 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoic acid) exhibits histamine H1 receptor antagonistic activity and antiallergic activity. Bilastine also improves indicators of insulin resistance. Therefore, bilastine is used as a therapeutic agent for allergic diseases (Non-Patent Document 1).

[0003] Bilastine is known to have the following crystalline forms: crystalline polymorphs 1 to 3 (Patent Document 1), α to η crystalline forms (Patent Document 2), and polymorphic forms K1 and K2 (Patent Document 3).

[0004] Furthermore, Patent Document 4 describes an orally disintegrating tablet that has high tablet hardness, rapid disintegration properties, and good storage stability, and contains a disintegrant such as bilastine, a specific granulated material, and crospovidone, and a method for producing the same. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special Publication No. 2005-529120 [Patent Document 2] Special Publication No. 2018-522945 [Patent Document 3] International Publication No. 2017 / 167949 Brochure [Patent Document 4] JP 2022-97443 A [Non-patent literature]

[0006] [Non-Patent Document 1] "Bilanoa (registered trademark) Tablets 20 mg" package insert Summary of the Invention [Problem to be solved by the invention]

[0007] As mentioned above, bilastine is known to exist in various crystalline forms. In general, the crystalline form of a drug affects its stability, physical properties such as melting point, and pharmacokinetics, so phase transition in the formulation must be suppressed. However, the present inventors have experimentally found that the crystalline form of bilastine may undergo a phase transition in a formulation. Therefore, the present invention aims to provide a method for producing a formulation while suppressing the crystal form transition of the active ingredient bilastine, a method for suppressing the crystal form transition of bilastine in the production of a formulation containing bilastine anhydrous crystals as the active ingredient, and a formulation in which the crystal form transition of the active ingredient bilastine is suppressed. [Means for solving the problem]

[0008] The present inventors have conducted extensive research to solve the above problems. As a result, they have found that bilastine crystals can be effectively inhibited from transitioning into a crystalline form by using a non-aqueous solvent that does not contain water when the bilastine crystals are mixed with other components, thereby maintaining the total water content at 5.0% by mass or less, thereby completing the present invention. The present invention will now be described.

[0009] [1] A method for producing a formulation containing a crystal of an active ingredient selected from bilastine, a pharma- ceutically acceptable salt thereof, and a solvate thereof, comprising: The method comprises the step of mixing the crystals with other ingredients under conditions that maintain the total moisture content at 5.0% by weight or less. [2] The method according to [1], wherein the crystals and the other components are mixed without using a solvent. [3] When the crystals and the other components are mixed and granulated, the granules are prepared by agitation granulation, fluidized bed granulation, or rolling fluidized bed granulation; The method according to the above [1] or [2], wherein, when the stirring granulation method is used, ethanol with a purity of 90% by mass or more is used as a solvent. [4] The method according to any one of [1] to [3], further comprising a step of compressing a powder for tableting containing the crystals and the other ingredients. [5] The method according to [4], wherein the powder for tableting further contains rapidly disintegrating granules and a lubricant. [6] The method according to [3], wherein the granules contain hydroxypropyl cellulose. [7] The method according to [3], wherein the granules are coated with an aminoalkyl methacrylate copolymer.

[0010] [8] A method for producing a formulation containing a crystal of an active ingredient selected from bilastine, a pharma- ceutically acceptable salt thereof, and a solvate thereof, comprising: The method comprises the step of mixing the crystals with other ingredients without the use of a solvent.

[0011] [9] A method for suppressing transition of the crystalline form of a preparation containing a crystal of an active ingredient selected from bilastine, a pharma- ceutically acceptable salt thereof, and a solvate thereof, comprising: The method comprises the step of mixing the crystals with other ingredients under conditions that maintain the total moisture content at 5.0% by weight or less.

[0012]

[10] A pharmaceutical composition comprising a crystal of an active ingredient selected from bilastine, a pharma- ceutically acceptable salt thereof, and a solvate thereof, A preparation characterized in that it does not exhibit diffraction peaks at 2θ=5.5±0.2° and 2θ=9.5±0.2° in powder X-ray diffraction using CuKα radiation.

[11] The formulation according to

[10] above, which is an orally disintegrating tablet. Effect of the Invention

[0013] According to the method of the present invention, the phase transition of the crystalline form of the active ingredient bilastine crystals in the preparation can be effectively suppressed. In addition, the bilastine preparation obtained by the method of the present invention does not substantially contain any crystalline form other than the desired crystalline form. Therefore, the bilastine preparation and its manufacturing method according to the present invention are industrially very excellent as one form of the preparation containing bilastine crystals as the medicinal ingredient and its manufacturing method. [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 shows powder X-ray diffraction data for stirred granules of bilastine produced using special-grade ethanol, 80% ethanol in water, or purified water, and for a simple mixed powder. [Diagram 2] Figure 2 shows the powder X-ray diffraction data of the powder for tableting obtained by mixing bilastine crystals with other ingredients without using a solvent. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The formulation according to the present invention contains a crystal of an active ingredient selected from bilastine, a pharma- ceutically acceptable salt thereof, and a solvate thereof.

[0016] The chemical name of bilastine is 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoic acid, and bilastine has the following chemical structure. It is a drug for the treatment of allergies that exhibits histamine H1 receptor antagonistic and antiallergic effects.

[0017] [ka]

[0018] As the active ingredient, a pharma- ceutically acceptable salt of bilastine may be used, such as methanesulfonate, toluenesulfonate, acetate, propionate, succinate, glycolate, stearate, lactate, malate, tartrate, citrate, ascorbate, pamoate, maleate, hydroxymaleate, phenylacetate, glutamate, benzoate, salicylate, sulfanilate, 2-acetoxybenzoate, fumarate, ethanedisulfonate, oxalate, isethionate, and other organic acid salts; and hydrochloride, hydrobromide, sulfate, sulfamate, phosphate, nitrate, and other inorganic acid salts.

[0019] As the active ingredient, bilastine or its pharmaceutically acceptable salt may be used as an anhydride or a solvate thereof. Examples of the solvate include hydrate. Examples of the solvate include monosolvate, 1.5solvate, disolvate, tetrasolvate and pentasolvate.

[0020] Examples of crystalline forms of an active ingredient selected from bilastine, its pharma- ceutically acceptable salts, and solvates thereof include crystalline polymorph 1, crystalline polymorph 2, crystalline polymorph 3, α crystalline form, β crystalline form, γ crystalline form, δ crystalline form, ε crystalline form, ζ crystalline form, η crystalline form, polymorph K1, polymorph K2, solvate crystalline A, and solvate crystalline B.

[0021] The size of the crystals of the active ingredient selected from bilastine, its pharma- ceutically acceptable salts, and solvates thereof is not particularly limited and may be adjusted as appropriate. In the present disclosure, the crystals may be referred to as bilastine crystals. For example, the cumulative 50% particle size (D 50 The cumulative 90% particle diameter (D) on a volume basis can be 0.5 μm or more and 200 μm or less, and preferably 1 μm or more and 100 μm or less. 90The cumulative 10% particle diameter (D) on a volume basis can be 1 μm or more and 500 μm or less, preferably 2 μm or more, more preferably 5 μm or more, and preferably 400 μm or less, more preferably 200 μm or less, and even more preferably 100 μm or less. 10 ) can be 0.1 μm or more and 100 μm or less, preferably 0.5 μm or more, more preferably 1 μm or more, and preferably 50 μm or less, more preferably 20 μm or less. In the present disclosure, the volume-based cumulative 10% particle diameter (D 10 ), cumulative 50% particle diameter (D 50 ), and cumulative 90% particle size (D 90 ) is measured on a volume basis using a laser diffraction particle size distribution measuring device.

[0022] The amount or ratio of bilastine crystals in the preparation of the present invention may be appropriately adjusted within the range in which bilastine crystals can exert their action and effect.For example, the amount of bilastine per preparation, such as one 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, and more preferably 30 mg or less.The ratio of bilastine per preparation can be 1 mass% or more and 30 mass% or less, preferably 2 mass% or more, more preferably 5 mass% or more, even more preferably 10 mass% or more, and preferably 20 mass% or less.For example, the amount of bilastine per tablet can be 20±2 mg.

[0023] The preparation of the present invention may contain, as an ingredient other than bilastine, general additives that are incorporated into pharmaceutical preparations, such as excipients, disintegrants, binders, stabilizers, colorants, lubricants, flow agents, sweeteners, and flavors.

[0024] The excipient is an additive that is blended to dilute the medicinal ingredient or increase the amount of the formulation in order to improve the moldability and ease of administration of the formulation. Examples of the excipient include mannitol, ethyl cellulose, lactose, crystalline cellulose, hydroxypropyl cellulose, dextrin, and sucrose. The amount of the excipient may be appropriately adjusted, and may be, for example, 20% by mass or more and 90% by mass or less relative to the entire formulation, preferably 30% by mass or more, more preferably 40% by mass or more, even more preferably 50% by mass or more, and preferably 85% by mass or less, and more preferably 80% by mass or less.

[0025] Disintegrants are ingredients that are added to promote disintegration of tablets and facilitate the release of medicinal ingredients. Disintegrants are not particularly limited, but examples include starch, light anhydrous silicic acid, sodium starch glycolate, partially pregelatinized starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmellose (carboxymethylcellulose), calcium carboxymethylcellulose, crospovidone (crosslinked polyvinylpyrrolidone), corn starch, etc. Disintegrants are preferably sodium starch glycolate, corn starch, crospovidone, and light anhydrous silicic acid, and are available in the grades Primogel (DFE pharma), Cornstarch (W) (Nihon Shokuhin Kako), Polyplasdone INF-10 (ISP), and Adsolider 101 (Fuji Silysia Chemical). The amount of disintegrant may be appropriately adjusted within a range in which the formulation disintegrates well after administration and the medicinal ingredients can be released. For example, it can be 0.5% by mass or more and 40% by mass or less, and preferably 1% by mass or more and 30% by mass or less, based on the total formulation.

[0026] A binder is a component that is added to bind each component and increase the strength of granules or tablets. The binder is not particularly limited, and examples thereof include hypromellose (hydroxypropyl methylcellulose), hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and ethyl cellulose. Hydroxypropyl cellulose is preferred as the binder, and a grade called HPC-SL (Nippon Soda, viscosity: 3.0 to 5.9 mPa·s) is available. The amount and ratio of the binder in the formulation may be appropriately adjusted according to the desired formulation strength and granule strength. For example, the amount of the binder may be 0.1% by mass or more and 10% by mass or less with respect to the entire formulation. The ratio 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.

[0027] The stabilizer is a component that stabilizes the active ingredient bilastine by antioxidant action. The stabilizer is not particularly limited, but examples thereof include anhydrous sodium monohydrogen phosphate, trometamol, calcium gluconate, sodium acetate, ascorbic acid, citric acid, and sodium citrate. The amount and ratio of the stabilizer in the formulation may be appropriately adjusted within a range in which the stabilizing effect of bilastine is exerted. For example, the amount may be 0.005% by mass or more and 5% by mass or less with respect to the entire formulation. The ratio is preferably 0.01% by mass or more, and more preferably 2% by mass or less, and more preferably 1% by mass or less.

[0028] A colorant is an ingredient used for the purpose of beautifying the appearance of a formulation to increase its commercial value, and for the purpose of facilitating identification of the formulation during production or after shipment. The colorant is not particularly limited, but examples thereof include blue colorants such as Blue No. 2 Aluminum Lake, Brilliant Blue, and Indirumin; red colorants such as ferric oxide; and yellow colorants such as yellow ferric oxide. The amount or ratio of the colorant in the formulation may be a small amount as long as it can color the formulation, and may be, for example, 0.005% by mass or more and 5% by mass or less with respect to the entire formulation. The ratio is preferably 0.01% by mass or more, and more preferably 2% by mass or less, and more preferably 1% by mass or less.

[0029] A lubricant is a component that is added to adhere to the surface of each component to increase its fluidity or to suppress adhesion of each component to the device. The lubricant is not particularly limited, but examples thereof include stearic acid, sodium stearate, magnesium stearate, calcium stearate, talc, hydrogenated vegetable oil, glycerin fatty acid ester, sucrose fatty acid ester, etc. The amount and ratio of the lubricant may be appropriately adjusted within a range in which, for example, the mixing and tableting of each component can be performed well. For example, the amount of the lubricant may be 0.05% by mass or more and 5% by mass or less with respect to the entire formulation. The ratio is preferably 0.1% by mass or more, more preferably 0.5% by mass or more, and more preferably 4% by mass or less, and more preferably 2% by mass or less.

[0030] The fluidizing agent is a component that enhances the fluidity of each component and promotes uniform mixing of each component, and examples thereof include light anhydrous silicic acid. The amount and ratio of the fluidizing agent may be appropriately adjusted within a range in which the components can be mixed and compressed well, and may be, for example, 0.05% by mass or more and 5% by mass or less with respect to the entire formulation. The ratio is preferably 0.1% by mass or more, more preferably 0.5% by mass or more, and more preferably 4% by mass or less, and more preferably 2% by mass or less.

[0031] The sweeteners and flavors may be added in small amounts as long as the effects of each component, especially the active ingredient bilastine, are not inhibited, and each component exerts its effect as necessary. Examples of sweeteners include aspartame, white sugar, acesulfame K, sucralose, stevia, thaumatin, erythritol, etc., and aspartame is particularly suitable for bilastine.

[0032] The dosage form of the preparation of the present invention is not particularly limited, and may be, for example, a tablet. Examples of the tablet include general tablets produced by mixing the active ingredient bilastine crystals or granules containing bilastine crystals with other ingredients and tableting them, as well as granules containing bilastine crystals, fast disintegrating granules, and orally disintegrating tablets which are compression molded products containing a lubricant or a fluidizer.

[0033] Granules containing bilastine crystals may contain excipients, disintegrants, binders, stabilizers, colorants, etc. in addition to the active ingredient bilastine. The size of the granules may be adjusted appropriately. For example, the cumulative 50% particle diameter (D 50 ) can be 30 μm or more and 300 μm or less, and preferably 50 μm or more and 200 μm or less.

[0034] The rapidly disintegrating granules contained in the orally disintegrating tablet of the present invention are granules that absorb moisture in the oral cavity to rapidly promote disintegration of the orally disintegrating tablet of the present invention and accelerate the release of the active ingredient bilastine or a salt thereof. The rapidly disintegrating granules contain at least an excipient and a disintegrant.

[0035] The water content of the preparation of the present invention is not particularly limited, but is preferably 3% by mass or less, more preferably 2% by mass or less. The lower limit of the water content is not particularly limited, and may be 0% by mass, but the water content can be, for example, 0.2% by mass or more. The water content can be measured, for example, by the Karl Fischer method.

[0036] When the preparation of the present invention is a tablet such as an orally disintegrating tablet, its hardness is not particularly limited, but is preferably from 25 N to 200 N, more preferably from 30 N to 150 N. The hardness can be adjusted, for example, by the tableting pressure.

[0037] When the preparation of the present invention is an orally disintegrating tablet, the disintegration time is not particularly limited, but is preferably, for example, 90 seconds or less, more preferably 60 seconds or less.

[0038] The shape of the tablet according to the present invention is not particularly limited, and can be appropriately selected from circular, elliptical, spherical, rod-shaped, donut-shaped, etc. When the tablet is a circular tablet, the diameter is not particularly limited, but is, for example, 4 mm or more and 12 mm or less, preferably 6 mm or more and 10 mm or less. The thickness of the tablet is not particularly limited, but is, for example, 3 mm or more and 12 mm or less, preferably 4 mm or more and 10 mm or less. When the tablet is an oval tablet, the size is not particularly limited, but is, for example, a major axis of 10 mm or more and 15 mm or less, a minor axis of 4 mm or more and 8 mm or less, and a thickness of 3 mm or more and 10 mm or less.

[0039] The preparation of the present invention may be packaged, as necessary, in a PTP (press through pack), bottle, aluminum package, or the like.

[0040] Examples of materials for PTP packaging include resins such as polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, and polycarbonate, and metals such as aluminum. These materials may be used alone or in combination. Examples of combinations include laminating polyvinyl chloride and polyvinylidene chloride, and laminating polyvinyl chloride and polychlorotrifluoroethylene. The above resins are molded into a pocket-shaped resin sheet by a known method, and the formulation is placed in the resin sheet, which is then covered with aluminum foil to complete packaging.

[0041] From the viewpoint of improving light stability, PTP packaging using a material capable of blocking or reducing light of a specific wavelength may be used. Examples of wavelengths of light that should be suppressed to 90% or less of transmittance through the PTP packaging material include 390 nm, 480 nm, 550 nm, 560 nm, and 600 nm. Examples of the color of the material include clear (transparent color), persimmon, orange, red, and yellow.

[0042] The PTP package containing the formulation 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, such as calcium chloride, calcium oxide, magnesium oxide, silica gel, or zeolite.

[0043] The preparation of the present invention can be produced by a method including a step of obtaining a mixture as a powder for tableting by mixing bilastine crystals and other ingredients under conditions that maintain the total moisture content at 5.0% by mass or less. Preferably, the total moisture content of the active ingredient crystals and the composition containing them is maintained at 5.0% by mass or less throughout the process from the active ingredient crystals as raw materials to the mixing of the active ingredient crystals and the composition containing them with other ingredients. The total moisture content refers to the moisture content of the composition containing the bilastine crystals and other ingredients to be mixed.

[0044] 1. How to measure moisture content In the present invention, the moisture content is maintained at 5.0% by mass or less when bilastine crystals are mixed with other components. The conditions for measuring the moisture content are not particularly limited, but samples may be taken from the mixture at appropriate times and measured. The moisture content between measurements can be estimated from the moisture content measured at both times. More specifically, for example, the moisture content between measurements can be estimated by creating a graph showing the relationship between time and the measured moisture content.

[0045] The method for measuring the moisture content is not particularly limited, and for example, the moisture content can be measured using a heat-drying moisture meter, a Karl Fischer moisture meter, etc. As the heat-drying moisture meter, for example, MOC-120H manufactured by Shimadzu Corporation can be used, and as the Karl Fischer moisture meter, for example, AQ-2200 manufactured by Hiranuma Corporation can be used.

[0046] The water content is preferably 4.0% by mass or less or 3.0% by mass or less, more preferably 2.0% by mass or less or 1.5% by mass or less. The lower limit of the water content is preferably below the detection limit, that is, 0% by mass.

[0047] 2.Mixing method Possible methods for mixing bilastine crystals with other ingredients while maintaining the total moisture content at 5.0% by mass or less include the following.

[0048] 2-1. Direct mixing When bilastine crystals are mixed directly with other components, no solvent is used. When mixed directly, there is no need to use a solvent, and by not using a solvent, it is possible to suppress the transition of the crystal form of bilastine crystals caused by the moisture from the solvent.

[0049] 2-2. Preparation of granulated material When preparing a granulated product of bilastine crystals, the granulated product is prepared by agitation granulation, fluidized bed granulation, or tumbling fluidized bed granulation, and when agitation granulation is used, ethanol with a purity of 90% by mass or more is used as a solvent. In these methods, the solvent is distilled off while granulation is performed, so that the total moisture content can be maintained at 5.0% by mass or less.

[0050] The stirring granulation method is a method of granulation in which a solvent, binder solution or binder dispersion is sprayed as a binding liquid while rotating a stirring blade at high speed. In the production of a preparation containing bilastine crystals, if the binding liquid contains water as a solvent, the crystal form of the bilastine crystals may be transformed. Therefore, in the method of the present invention, when the stirring granulation method is used, ethanol with a purity of 90% by mass or more is used as the solvent. The purity is preferably 95% by mass or more, more preferably 98% by mass or more or 99% by mass or more, and even more preferably 99.5% by mass or more or 99.8% by mass or more. The upper limit of the purity is preferably 100% by mass.

[0051] The fluidized bed granulation method is a method of granulating powder by spraying a solvent and a binder solution or binder dispersion while fluidizing the powder with hot air. The tumbling fluidized bed granulation method is a method of granulating particles in a fluidized bed while applying fluidizing motion by fluidizing gas and tumbling compaction motion by rotating agitator blades. In these methods, the particles are blown up into the air current and dried, and the solvent attached to the particles is efficiently and quickly distilled off. Therefore, even if the solvent contained in the binder liquid is 100% water by mass, the bilastine crystals are not easily affected by the solvent, and it is considered that the transition of the crystal form of the bilastine crystals is suppressed.

[0052] 2-3.Coating Bilastine crystals or granulated materials containing bilastine crystals may be coated. Known coating methods can be used as coating methods. Also, granulation can be performed while coating by appropriately adjusting coating conditions. Examples of coating methods that can be used include pan coating, fluidized bed granulation (fluidized bed coating), rolling fluidized bed granulation (rolling fluidized bed coating), and stirring granulation (stirring coating).

[0053] The coating agent can be appropriately selected from pharma- ceutically acceptable ones depending on the application of the coating. Examples of the coating agent include hypromellose, ethyl cellulose, talc, titanium oxide, silicic acid, hydroxypropyl cellulose, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer, polyvinyl alcohol, polyvinyl alcohol diethylaminoacetate, polyvinyl alcohol acetate phthalate, cellulose acetate phthalate, hypromellose phthalate, methacrylic acid copolymer, copolymer of methyl methacrylate and butyl methacrylate or dimethylaminoethyl methacrylate, etc. The coating agent may be one kind or two or more kinds in combination.

[0054] When coating, the transition of the crystal form of bilastine crystals can be suppressed by using fluidized bed granulation or tumbling fluidized bed granulation, or by using ethanol with a purity of 90% by mass or more as the solvent when using agitation granulation.

[0055] The active ingredient, bilastine crystals and / or granulated products thereof, are preferably crushed or sieved, which breaks down agglomerates of bilastine crystals and improves the disintegration and dissolution properties of the preparation.

[0056] 3.Tableting process When the preparation of the present invention is a tablet, in this step, a powder for tableting containing bilastine crystals and other ingredients is tableted. The tableting machine used in the tableting step is not particularly limited, but for example, a single punch tableting machine or a rotary tableting machine can be used.

[0057] The tableting pressure may be appropriately adjusted depending on the desired tablet hardness, and may be, for example, 800 kgf or more and 1100 kgf or less. The tableting pressure is preferably 850 kgf or more, more preferably 900 kgf or more, and is preferably 1050 kgf or less, more preferably 1000 kgf or less.

[0058] The bilastine crystals contained in the preparation produced by the method of the present invention have suppressed crystal form transition compared to the raw bilastine crystals.For example, specifically, when raw bilastine crystals that do not show diffraction peaks at 2θ=5.5±0.2° and 2θ=9.5±0.2° in powder X-ray diffraction using CuKα rays are used, the bilastine crystals contained in the preparation of the present invention do not show diffraction peaks at 2θ=5.5±0.2° and 2θ=9.5±0.2°.In addition, in the present disclosure, not showing diffraction peaks means that the intensity ratio to the highest diffraction peak is 5 or less, with the intensity of the highest diffraction peak being 100.The intensity ratio is preferably 3 or less, more preferably 2 or less, and even more preferably 1 or less.

[0059] The dosage of the formulation of the present invention may be adjusted as appropriate depending on the patient's symptoms, severity, age, etc., but for example, in terms of the dosage of bilastine, 5 mg or more and 30 mg or less may be administered at least 0.5 times and no more than 2 times per day on an empty stomach. EXAMPLES

[0060] 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 present invention by making appropriate modifications within the scope of the above and below-mentioned aims, and all of these modifications are included in the technical scope of the present invention.

[0061] Example 1: Preparation of bilastine orally disintegrating tablets (1) Manufacturing of uncoated and coated granules of bilastine Bilastine orally disintegrating tablets having the composition shown in Table 1 were manufactured. Specifically, bilastine anhydrous type 1 crystals, D-mannitol, sodium starch glycolate, and hydroxypropyl cellulose ("HPC-SL", Nippon Soda Co., Ltd.) were fed to an agitation granulator ("Vertical Granulator FM-VG-05", Powrex Corporation) and mixed. Separately, hydroxypropyl cellulose was dissolved in special grade ethanol (Konishi Co., Ltd., purity: 99.5% or higher) to prepare a 7.41% by mass solution, which was fed to the agitation granulator and granulated at 8°C. The obtained granules were fed to a fluidized bed granulation dryer ("FD-MP-01D / SPC / SFP", Powrex Corporation), dried at 60°C, and dried using a Comil. 50 : Particle size adjusted to 100~150μm. Separately, purified water and special grade ethanol (Konishi, purity: 99.5% or more) were mixed at a ratio of 30:70 (mass ratio) to obtain 70% by mass ethanol water. Aminoalkyl methacrylate copolymer (Eudragit (registered trademark) E, EVONIK) was dissolved in 70% by mass ethanol water to prepare a 9.09% by mass solution, and talc was further added for dispersion. The granules and the dispersion were fed into a fluidized bed granulation dryer (Flow Coater FL-LABO, Freund), and the granules were coated. The obtained coated granules were dried at 65°C and dried using a Comil. 50 : Particle size adjusted to 100~150μm. Although special grade ethanol with a purity of 99.5% or more was used as the solvent during granulation, and 70% by mass ethanol water was used during coating, since the fluidized bed coating method was used for coating, the moisture content of the final coated granules was thought to be 5.0% by mass or less.

[0062] (2) Manufacturing of fast-disintegrating granules D-mannitol, ethyl cellulose, light anhydrous silicic acid, corn starch, and crospovidone were mixed in a fluidized bed granulator and granulated using purified water. The resulting granules were thoroughly dried and sized to produce rapidly disintegrating granules.

[0063] (3) Tablet compression The bilastine-coated granules, the rapidly disintegrating granules, aspartame, and magnesium stearate were placed in a PE bag and mixed non-mechanically to obtain a powder for tableting. The obtained powder for tableting was compressed by a rotary tableting machine to obtain tablets. The bilastine-coated granules are considered to have a low moisture content, and the rapidly disintegrating granules were also sufficiently dried. Since these were mixed without using a solvent, the moisture content of the powder for tableting is considered to be 5.0% by mass or less.

[0064] [Table 1]

[0065] Comparative Example 1: Production of bilastine granules A bilastine granule was produced in the same manner as in Example 1(1), except that the solvent for stirring granulation was changed from special grade ethanol to 80% by mass ethanol in water, and the granule was not coated.

[0066] Comparative Example 2: Production of bilastine granules A bilastine granule was produced in the same manner as in Example 1(1), except that the solvent for stirring granulation was changed from special grade ethanol to purified water and the granule was not coated.

[0067] Test Example 1: Measurement of moisture content The moisture content of the uncoated and coated bilastine granules produced in Example 1(1) was measured using a heat-dry moisture meter ("MOC-120H", Shimadzu Corporation). Approximately 5 g of granules was used for the measurement, and the mass of the granules was measured every 30 seconds while heating at 80.0°C. The measurement was continued until the change in mass over 30 seconds was less than 0.05%, and the moisture content in the granules was calculated from the change in mass. The measurement results (LOD: loss on drying) are shown in Table 2.

[0068] [Table 2]

[0069] Test Example 2: X-ray diffraction The uncoated bilastine granules prepared in Example 1(1) were analyzed using a powder X-ray diffractometer ("D8 ADVANCE" manufactured by Bruker). For comparison, uncoated granulated bilastine produced in the same manner except that 80% by mass ethanol water (Comparative Example 1) or purified water (Comparative Example 2) was used instead of special grade ethanol was also analyzed in the same manner. Furthermore, a mixed powder made by simply mixing the components was also analyzed in the same manner. The results are shown in Figure 1.

[0070] As shown in FIG. 1, the bilastine contained in the uncoated granules of Example 1(1) that were granulated by stirring using special-grade ethanol showed the same X-ray diffraction pattern as the bilastine contained in the simply mixed powder, indicating that the crystal form had not changed. In contrast, the uncoated granules granulated by stirring using 80% by mass ethanol water (Comparative Example 1) and the uncoated granules granulated by stirring using only purified water (Comparative Example 2) showed X-ray diffraction peaks that were not seen in the bilastine contained in the simply mixed powder, revealing that at least a portion of the crystal form had changed.

[0071] Example 2: Preparation of bilastine orally disintegrating tablets (1) Manufacturing of bilastine-coated granules Bilastine orally disintegrating tablets with the composition shown in Table 3 were manufactured. Specifically, special grade ethanol (Konishi, purity: 99.5% or more) and purified water were mixed to prepare 70% by mass ethanol water. Bilastine anhydrous, 70% by mass ethanol water, aminoalkyl methacrylate copolymer E, and talc were fed to a fluidized bed granulation dryer ("Flow Coater FL-LABO", Freund) in the ratios shown in Table 3 and mixed at 65°C, and granulated while coating with bilastine. The obtained bilastine-coated granules were dried at 65°C and then sized using a sieve with 30 mesh openings. Although 70% by mass ethanol in water was used as the solvent, the particles were heated while being fluidized in a fluidized bed granulation dryer, so the moisture content of the obtained granules is thought to be 5.0% by mass or less.

[0072] (2) Manufacturing of fast-disintegrating granules D-mannitol, ethyl cellulose, light anhydrous silicic acid, corn starch, and crospovidone were mixed and granulated with purified water. The resulting granules were thoroughly dried and sized to produce rapidly disintegrating granules.

[0073] (3) Tablet compression The bilastine-coated granules, the rapidly disintegrating granules, D-mannitol, aspartame, and magnesium stearate were placed in a PE bag and mixed non-mechanically to obtain a powder for tableting. The obtained powder for tableting was compressed by a rotary tableting machine to obtain tablets. The bilastine-coated granules are considered to have a low moisture content, and the rapidly disintegrating granules were also sufficiently dried. Since these were mixed without using a solvent, the moisture content of the powder for tableting is considered to be 5.0% by mass or less.

[0074] [Table 3]

[0075] Example 3: Preparation of bilastine orally disintegrating tablets (1) Manufacturing of fast-disintegrating granules D-mannitol, ethyl cellulose, light anhydrous silicic acid, sodium starch glycolate, and corn starch were mixed and granulated using purified water. The resulting granules were thoroughly dried and sized to produce rapidly disintegrating granules.

[0076] (2) Tablet compression Bilastine anhydrous, rapidly disintegrating granules, D-mannitol, aspartame, light anhydrous silicic acid, flavoring, and magnesium stearate were fed into a diffusion mixer ("Bohle Container Mixer PM-100" manufactured by Hiroshima Metal & Machinery Co., Ltd.) and mixed to obtain a powder for tableting. The rapidly disintegrating granules were thoroughly dried and mixed with other ingredients such as bilastine anhydrous without the use of a solvent, so the moisture content of the powder for tableting is considered to be 5.0% by mass or less. The obtained powder for tableting was tableted by a rotary tableting machine to obtain tablets.

[0077] [Table 4]

[0078] Example 4: Preparation of bilastine orally disintegrating tablets Bilastine orally disintegrating tablets were produced by direct compression in the same manner as in Example 3, except that the composition was changed to that shown in Table 5.

[0079] [Table 5]

[0080] Examples 5 to 9: Preparation of bilastine orally disintegrating tablets Bilastine orally disintegrating tablets were produced by direct compression in the same manner as in Example 3, except that the composition was changed to that shown in Table 6.

[0081] [Table 6]

[0082] Example 10: Preparation of bilastine orally disintegrating tablets The particle size of bilastine anhydrous was measured by the cumulative 50% particle size (D 50 ) was adjusted to be 34 μm or more and 95 μm or less. Rapidly disintegrating granules were prepared in the same manner as in Example 3(1). Bilastine anhydrous and the fast-disintegrating granules were fed into a diffusion mixer ("Bole Container Mixer PM-100" manufactured by Hiroshima Metal & Machinery Co., Ltd.) and mixed, and then sieved using a dry granulator ("Comil QC-197S" manufactured by Powrex Corporation, screen diameter: 457 μm) to obtain a primary mixed powder. The primary mixed powder, D-mannitol, aspartame, light anhydrous silicic acid, crospovidone, flavor and magnesium stearate were triturated and mixed to obtain a powder for tableting according to the composition shown in Table 7. The rapidly disintegrating granules were thoroughly dried and mixed with other ingredients such as bilastine anhydrous without the use of a solvent, so the moisture content of the powder for tableting is considered to be 5.0% by mass or less. The obtained powder for tableting was tableted at a tableting pressure of 10 kN using a rotary tableting machine while spraying a small amount of magnesium stearate onto the punch to obtain tablets. In Table 7, the "small amount" in Example 10 indicates that 0.1% by mass or less was added by spraying onto the punch using the external lubrication method. In this tableting process, no tableting problems such as sticking, cracking, binding, or capping were observed. The obtained tablets were circular tablets with a hardness of 54 N, a tablet diameter of 7.5 mm and a tablet thickness of 3.4 mm, and had a moisture content of 2.4% by mass.

[0083] [Table 7]

[0084] The disintegration time of the manufactured tablets was evaluated according to the disintegration test method of the 18th revision of the Japanese Pharmacopoeia, and the disintegration time was 19 to 22 seconds, showing good disintegrability. This is thought to be because the agglomerations of bilastine anhydrous were broken down by sieving during the primary mixed powder manufacturing process.

[0085] In addition, a powder for tableting obtained by mixing bilastine anhydrous crystals with other ingredients without using a solvent was analyzed by X-ray diffraction in the same manner as in Test Example 2. The results are shown in Figure 2. As shown in the results in Figure 2, the powder for tableting obtained by mixing bilastine anhydrous crystals with other ingredients without using a solvent does not show the characteristic peaks observed in the X-ray diffraction patterns of the granulated products of Comparative Examples 1 and 2, which used 80% by mass ethanol water or purified water, confirming that the crystal form of the bilastine contained in the powder for tableting of this Example 10 has not changed.

Claims

1. A method for producing a formulation containing a crystal of an active ingredient selected from bilastine, a pharma- ceutically acceptable salt thereof, and a solvate thereof, comprising the steps of: The method comprises the step of mixing the crystals with other ingredients under conditions that maintain a total moisture content of 5.0% by weight or less.

2. 10. The method of claim 1, wherein the crystals and the other ingredients are mixed without the use of a solvent.

3. When the crystals and the other components are mixed and granulated, the granules are prepared by agitation granulation, fluidized bed granulation, or tumbling fluidized bed granulation; The method according to claim 1, wherein, when the stirring granulation method is used, ethanol with a purity of 90% by mass or more is used as a solvent.

4. 2. The method of claim 1, further comprising compressing the tableting powder containing said crystals and said other ingredients.

5. The method according to claim 4, wherein the tableting powder further comprises rapidly disintegrating granules and a lubricant.

6. The method of claim 3, wherein the granulation comprises hydroxypropyl cellulose.

7. The method of claim 3, wherein the granules are coated with an aminoalkyl methacrylate copolymer.

8. A method for producing a formulation containing a crystal of an active ingredient selected from bilastine, a pharma- ceutically acceptable salt thereof, and a solvate thereof, comprising the steps of: The method comprises the step of mixing the crystals with other ingredients without the use of a solvent.

9. A method for suppressing transition of a crystalline form of a crystal in the production of a preparation containing a crystal of an active ingredient selected from bilastine, a pharma- ceutically acceptable salt thereof, and a solvate thereof, comprising: The method comprises the step of mixing the crystals with other ingredients under conditions that maintain a total moisture content of 5.0% by weight or less.

10. The present invention relates to a pharmaceutical composition comprising a crystalline form of an active ingredient selected from bilastine, a pharma- ceutically acceptable salt thereof, and a solvate thereof, A preparation characterized in that it does not exhibit diffraction peaks at 2θ=5.5±0.2° and 2θ=9.5±0.2° in powder X-ray diffraction using CuKα radiation.

11. The formulation according to claim 10, which is an orally disintegrating tablet.

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