Bepotastine-containing granules as well as manufacturing method and use thereof

Abstract

To provide bepotastine-containing granules that are compact and have excellent bitterness-masking properties.SOLUTION: A spherical granule is formed by a spherical core portion containing bepotastine or a salt thereof as an active ingredient and a coating portion that covers the spherical core portion and contains a masking layer containing a water-insoluble polymer. The volume-based cumulative 50% particle size (D50) of the spherical granule may be 250 μm or less (particularly 200 μm or less). The proportion of the bepotastine or a salt thereof in the spherical granule may be 20 to 80 mass%. The water-insoluble polymer may contain a (meth)acrylic polymer having an ammonio methacrylate unit. The masking layer may further contain an inorganic compound. The proportion of the bepotastine or a salt thereof in the spherical core may be 50 mass% or more. The spherical core portion may be a spherical particle of bepotastine or a salt thereof. An oral preparation (particularly an orally disintegrating tablet) containing the spherical granule may be prepared.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to spherical granules containing bepotastine or a salt thereof as an active ingredient, a method for producing the same, and uses thereof.

Background Art

[0002] Bepotastine besilate is used as a selective histamine H1 receptor antagonist for the treatment of allergic rhinitis, urticaria, cutaneous pruritus, and the like. However, since bepotastine besilate has a strong bitter taste, it is necessary to suppress the elution of the active ingredient in the oral cavity in order to improve the swallowability of a composition (preparation) containing bepotastine besilate. In order to suppress the elution of the active ingredient in the oral cavity, it is necessary to sufficiently coat the active ingredient with a coating film. However, when the thickness of the coating film increases, the preparation becomes larger. That is, there is a trade-off relationship between bitterness masking property and miniaturization, and it has been difficult to achieve both. Therefore, in preparations containing bepotastine besilate, small-sized preparations having a bitterness masking property have been desired.

[0003] Japanese Patent No. 4739340 (Patent Document 1) discloses a method for producing an orally disintegrating tablet, which includes a step of mixing granules containing a bitter drug such as bepotastine besilate and an excipient and having an un-suppressed bitterness, and granules containing a water-soluble saccharide insoluble in an alcoholic solvent and a binder that is water-soluble and soluble in an alcoholic solvent, a step of compression molding the mixture obtained in the above step, and a step of treating the compression molded product obtained in the above step with an alcoholic solvent.

[0004] Japanese Patent No. 6153867 (Patent Document 2) discloses granulated granules containing bepotastine or a pharmaceutically acceptable salt thereof, a water-insoluble polymer selected from hydroxypropyl methylcellulose acetate succinate and carboxymethylcellulose, and an excipient; menthol; and an orally disintegrating tablet containing a disintegrant.

Prior Art Documents

Patent Documents

[0005] [Patent Document 1] Japanese Patent No. 4739340 [Patent Document 2] Japanese Patent No. 6153867 [Summary of the Invention] [Problems to be Solved by the Invention]

[0006] However, in the orally disintegrating tablets of Patent Documents 1 and 2, since the shape of the granules contained in the formulation is non-spherical, it is difficult to form a uniform coating film, and the bitterness masking property is not sufficient. Furthermore, in these orally disintegrating tablets, in order to improve the bitterness masking property, if the thickness of the coating film is increased and the formulation is enlarged, a rough feeling will occur in the mouth, the swallowing feeling will deteriorate, and the elution property of the active ingredient in the body will also decrease.

[0007] Accordingly, an object of the present invention is to provide granules containing bepotastine or a salt thereof, which are excellent in bitterness masking property and miniaturized, and a method for producing the same and uses thereof. [Means for Solving the Problems]

[0008] As a result of intensive studies to achieve the above problems, the present inventors have found that by coating a spherical core portion containing bepotastine or a salt thereof with a coating layer containing a water-insoluble polymer, the bitterness masking property of the spherical granules containing bepotastine can be improved and miniaturized, and thus the present invention has been completed.

[0009] That is, the present invention includes the following aspects.

[0010] Aspect [1]: Spherical granules formed of a spherical core portion containing bepotastine or a salt thereof and a coating portion including a masking layer that coats the spherical core portion and contains a water-insoluble polymer.

[0011] Aspect [2]: The spherical granules of Aspect [1] wherein the cumulative volume-based 50% particle diameter (D 50 ) is 250 μm or less.

[0012] Aspect [3]: The spherical granules of Aspect [1] or [2] wherein the cumulative volume-based 50% particle diameter (D 50 ) is 200 μm or less.

[0013] Aspect [4]: The spherical granules of any one of Aspects [1] to [3] wherein the proportion of the bepotastine or a salt thereof is 20 to 80% by mass in the spherical granules.

[0014] Aspect [5]: The spherical granules of any one of Aspects [1] to [4] wherein the water-insoluble polymer contains at least one selected from the group consisting of (meth)acrylic resins, vinyl resins, and cellulose derivatives.

[0015] Aspect [6]: The spherical granules of any one of Aspects [1] to [5] wherein the water-insoluble polymer contains a (meth)acrylic polymer having an ammoniomethacrylate unit.

[0016] Aspect [7]: The spherical granules of Aspect [6] wherein the (meth)acrylic polymer is a combination of a high water permeability polymer having an ammoniomethacrylate unit proportion of 7.5% by mass or more and a low water permeability polymer having an ammoniomethacrylate unit proportion of less than 7.5% by mass, and the mass ratio of the high water permeability polymer to the low water permeability polymer is former / latter = 10 / 90 to 90 / 10.

[0017] Aspect [8]: The spherical granules of Aspect [6] or [7] wherein the masking layer further contains an inorganic compound, and the proportion of the inorganic compound is 100 parts by mass or less with respect to 100 parts by mass of the (meth)acrylic polymer.

[0018] Aspect [9]: The spherical granules of any one of Aspects [1] to [8] wherein the proportion of the bepotastine or a salt thereof is 50% by mass or more in the spherical core part.

[0019] Aspect

[10] : The spherical granule of any one of the aspects [1] to [9], wherein the spherical nuclear part is spherical particles of bepotastine or a salt thereof.

[0020] Aspect

[11] : The spherical granule of any one of the aspects [1] to

[10] , wherein the sphericity of the spherical nuclear part is 0.6 or more.

[0021] Aspect

[12] : The spherical granule of any one of the aspects [1] to

[11] , wherein the coating part further includes an intermediate layer interposed between the spherical nuclear part and the masking layer.

[0022] Aspect

[13] : A method for producing the spherical granule of any one of the aspects [1] to

[12] , including a nucleation step of forming a spherical nuclear part containing bepotastine or a salt thereof, and a coating step of coating the obtained spherical nuclear part with a coating part including a masking layer containing a water-insoluble polymer to obtain spherical granules.

[0023] Aspect

[14] : An oral preparation containing the spherical granule of any one of the aspects [1] to

[12] .

[0024] Aspect

[15] : The oral preparation of the aspect

[14] , which is an orally disintegrating tablet.

[0025] Aspect

[16] : A method for suppressing bitterness without impairing the swallowability and disintegratability of the oral preparation by forming spherical granules contained in the oral preparation with a spherical nuclear part containing bepotastine or a salt thereof and a coating part that coats the spherical nuclear part and includes a masking layer containing a water-insoluble polymer.

[0026] In the present specification and claims, the "ammonio methacrylate unit" means a unit derived from trimethylammonium ethyl methacrylate chloride as a monomer.

Advantages of the Invention

[0027] In the present invention, since the spherical nucleus containing bepotastine or a salt thereof is coated with a coating portion containing a masking layer containing a water-insoluble polymer, the bitterness masking property of the spherical granules containing bepotastine or a salt thereof can be improved and miniaturized. Therefore, when the obtained spherical granules are used as an oral preparation, bitterness can be suppressed without impairing the swallowability and disintegration property of the oral preparation.

Brief Description of Drawings

[0028]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Modes for Carrying Out the Invention

[0029] [Spherical Granules] The spherical granules of the present invention are formed of a spherical nucleus containing bepotastine or a salt thereof and a coating portion that coats the spherical nucleus and contains a masking layer containing a water-insoluble polymer, and are small spherical granules that can effectively mask bitterness as an oral preparation.

[0030] (Spherical Nucleus) (A)Bepotastine or a salt thereof The spherical nucleus may contain bepotastine as an active ingredient, and bepostastine may be in the form of a salt.

[0031] The salt of bepotastine is not particularly limited as long as it is a pharmaceutically acceptable salt, and it may be a salt with an acid (such as an addition salt) or a salt with a base.

[0032] Examples of the acid for forming the salt include inorganic acids (such as hydrochloric acid, sulfuric acid, phosphoric acid, etc.), organic acids (such as acetic acid, fumaric acid, maleic acid, citric acid, succinic acid, salicylic acid, tartaric acid, besylic acid, theocric acid, tannic acid, pamoic acid, etc.).

[0033] Examples of the base for forming the salt include inorganic bases [such as ammonia; alkali metals (such as lithium, sodium, potassium, etc.), alkaline earth metals (such as calcium, magnesium, etc.), other metals (such as zinc, aluminum, etc.)], organic bases (such as alkylamines such as methylamine, triethylamine; polyamines; alkanolamines such as ethanolamine, triethanolamine; cyclic amines such as morpholine, piperazine, pyrrolidine, picoline, etc.).

[0034] Among these, organic acids such as besylic acid, alkali metal salts such as sodium, and alkaline earth metal salts such as calcium are preferred, and besylic acid is particularly preferred.

[0035] Bepotastine or its salt may be in the form of a solvate in the spherical granules. Examples of the solvent for forming the solvate include water, alcohols (such as C of methanol, ethanol, 1-propanol, 2-propanol, etc.) 1-4Alkanols (such as), ketones (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, etc.), nitriles (such as acetonitrile, propionitrile, etc.), esters (such as ethyl acetate, isopropyl acetate, etc.), ethers (such as diethyl ether, t-butyl methyl ether, etc.), aliphatic hydrocarbons (such as normal pentane, normal hexane, cyclohexane, normal heptane, isooctane, etc.), aromatic hydrocarbons (such as toluene, etc.), amides (such as N,N-dimethylformamide, dimethylacetamide, etc.), sulfoxides (dimethyl sulfoxide, etc.) and the like can be mentioned. These solvents can be used alone or in combination of two or more. As the solvate, a hydrate is preferred.

[0036] The proportion of bepostatin or its salt may be 50% by mass or more in the spherical core part, for example, 70% by mass or more, preferably 80% by mass or more, more preferably 90% by mass or more, and most preferably 100% by mass (substantially only bepostatin or its salt). If the proportion of bepostatin or its salt is too small, there is a risk that the particle size of the spherical granules will become large.

[0037] Bepostatin or its salt, which is the main component of the spherical core part, may be an amorphous substance, but a crystal is preferred. Examples of the crystal shape include tabular crystal, needle crystal, columnar crystal, skeletal crystal, symmetric dendritic crystal, asymmetric dendritic crystal, spherulite, etc. Among these, bepostatin or its salt alone can form the spherical core part, and spherulite is preferred from the viewpoint of being easily miniaturized of the spherical granules. That is, when the spherical core part is formed only of bepostatin or its salt, the shape of bepostatin or its salt is preferably a spherulite.

[0038] In the present specification and claims, the term "spherulite" means a crystal aggregate (polycrystalline) having a radial or concentric lamellar structure and a spherical outer shape. Whether the crystal of bepotastine or its salt is a spherulite can be determined, for example, by observing the outer shape of the crystal with a scanning electron microscope (SEM), or by cutting the crystal and observing its internal structure with an SEM.

[0039] The cumulative 50% particle diameter (D 50 ) of the spherulite may be 50 μm or more, and can be selected from the range of about 50 to 230 μm, for example, 60 to 180 μm, preferably 70 to 150 μm, more preferably 80 to 130 μm, still more preferably 90 to 120 μm, and most preferably 100 to 110 μm. If the cumulative 50% particle diameter (central particle diameter) of the spherulite is too small, there is a risk of decreasing productivity, etc. On the contrary, if it is too large, the spherical granules will become larger, and depending on the application, there is a risk of decreasing the feeling of taking.

[0040] In the present specification and claims, the cumulative 50% particle diameter (D 50 ) can be measured by a particle size distribution measuring device, and means the particle diameter of the particle that reaches 50% cumulatively from the small particle side of the particle size distribution based on volume. The cumulative 50% particle diameter (D 50 ) can be measured based on volume using a laser diffraction particle size analyzer, and specifically, it can be measured by the method described in the examples below.

[0041] (B) Binder The spherical core part may further contain a binder (first binder) in addition to bepotastine or a salt thereof. Examples of the binder include synthetic polymers such as polyvinyl pyrrolidones (povidone, vinyl acetate-vinyl pyrrolidone copolymer, etc.), polyvinyl alcohol, carboxyvinyl polymer, polyacrylic acid-based polymers (sodium polyacrylate, acrylic acid copolymer, etc.), polylactic acid, polyethylene glycol, polyvinyl acetate; hydroxyalkyl cellulose ethers such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (hypromellose or HPMC); cellulose esters such as cellulose acetate, and the like.

[0042] These binders can be used alone or in combination of two or more. Among these, hydroxy C 2-4 alkyl cellulose ethers such as HPC are preferred.

[0043] The proportion of the binder may be 30% by mass or less in the spherical core part, preferably 20% by mass or less, more preferably 10% by mass or less, and most preferably 0% by mass. When the spherical core part contains a binder, the proportion of the binder is, for example, 1 to 30 parts by mass, preferably 5 to 20 parts by mass, more preferably 10 to 15 parts by mass with respect to 100 parts by mass of bepotastine or a salt thereof.

[0044] (C) Excipient The spherical core part may further contain an excipient (first excipient) in addition to bepotastine or a salt thereof. Examples of the excipient include saccharides (lactose, glucose, fructose, maltose, sucrose, granulated sugar, powdered reduced maltose syrup, etc.), sugar alcohols (D-mannitol, D-sorbitol, erythritol, xylitol, etc.), celluloses (crystalline cellulose, microcrystalline cellulose, powdered cellulose, etc.), cellulose ethers (methyl cellulose, ethyl cellulose, etc.), and the like.

[0045] These excipients can be used alone or in combination of two or more. Among these, sugar alcohols such as D-mannitol are preferred.

[0046] The proportion of the excipient may be 30% by mass or less in the spherical nucleus, preferably 20% by mass or less, more preferably 15% by mass or less, and most preferably 0% by mass. When the spherical nucleus contains an excipient, the proportion of the excipient is, for example, 0.1 to 30 parts by mass, preferably 0.5 to 20 parts by mass, more preferably 1 to 10 parts by mass with respect to 100 parts by mass of bepotastine or a salt thereof.

[0047] (D) Other additives In addition to bepotastine or a salt thereof, the spherical nucleus may further contain, as other additives, conventional additives formulated in oral preparations. Examples of the conventional additives include disintegrants (first disintegrants), lubricants (first lubricants), plasticizers, surfactants, pH adjusters, colorants, sweeteners or flavoring agents, antioxidants, preservatives or preservatives, wetting agents, antistatic agents, disintegration aids, fluidizing agents and the like. These additives can be used alone or in combination of two or more. The total proportion of these additives may be 30% by mass or less in the spherical nucleus, preferably 20% by mass or less, more preferably 10% by mass or less, and most preferably 0% by mass.

[0048] (E) Shape of the spherical nucleus The shape of the spherical nucleus is not particularly limited as long as it is spherical, and the sphericity (true sphericity) may be 0.6 or more (for example, about 0.6 to 0.99), for example, 0.7 or more (for example, 0.7 to 0.98), preferably 0.75 or more, more preferably 0.8 or more. If the sphericity is too small, it may be difficult to form a smooth coat portion. In particular, the spherical nucleus may be spherical particles (especially spherulites) of bepotastine or a salt thereof, and the sphericity may be the sphericity of the spherulites of bepotastine or a salt thereof.

[0049] In the present specification and the claims, the sphericity means the circularity measured using an industrial microscope (manufactured by Olympus Corporation, model number "BX53M") and the image processing software ImageJ developed by the National Institutes of Health (NIH) in the United States. The circularity can be calculated based on the following formula.

[0050] Circularity = 4π × (area) / [circumference (perimeter length)] 2

[0051] The cumulative 50% particle diameter (D 50 ) of the spherical nucleus part may be 50 μm or more, and can be selected from the range of about 50 to 230 μm, for example, 60 to 200 μm, preferably 70 to 150 μm, more preferably 80 to 130 μm, still more preferably 90 to 120 μm, and most preferably 100 to 110 μm. If the central particle diameter of the spherical nucleus part is too small, there is a risk of reduction in productivity, etc. On the contrary, if it is too large, the spherical granules become larger, and there is a risk of reduction in the feeling of taking depending on the application.

[0052] The sharpness index of the particle size distribution of the spherical nucleus part can be selected from the range of about 1 to 5, for example, 1 to 4, preferably 1 to 3, more preferably 1 to 2.5, still more preferably 1 to 2, and most preferably 1 to 1.5. The sharpness index is an index indicating the uniformity of the particle size, and 1 means the most uniform particle size. If the sharpness index is too large, due to the variation in particle size, the film thickness for each particle after coating becomes non-uniform, and there is a risk that the expression of bitterness becomes faster.

[0053] In the present specification and the claims, the sharpness index can be calculated from the values of D 10 , D 50 , D 90 using the following formula.

[0054] Sharpness index = [(D 90 / D 50 ) + (D50 / D 10 )] / 2

[0055] In addition, in this specification and the claims, the cumulative 10% particle diameter (D 10 ) and the cumulative 90% particle diameter (D 90 ) can be measured in the same manner as the aforementioned cumulative 50% particle diameter (D 50 ).

[0056] (Coating part) The spherical granules of the present invention are coated with the spherical core part by a coating part including a masking layer containing a water-insoluble polymer. In the present invention, the spherical core part containing bepotastine or a salt thereof with strong bitterness is coated with the coating part, whereby the bitterness is masked. The coating part only needs to include a masking layer containing a water-insoluble polymer, and may have a single-layer structure formed of only the masking layer containing a water-insoluble polymer, or may have a laminated structure of the masking layer and other layers. Examples of the laminated structure include a two-layer structure including an intermediate layer interposed between the spherical core part and the masking layer in addition to the masking layer, a two-layer structure including an overcoat layer laminated on the masking layer in addition to the masking layer, and a three-layer structure including the intermediate layer and the overcoat layer in addition to the masking layer.

[0057] (A) Masking layer Since the masking layer, which is an essential component of the coating part, contains a water-insoluble polymer, the bitterness can be masked.

[0058] (a) Water-insoluble polymer Examples of the water-insoluble polymer include (meth)acrylic resins, vinyl resins, cellulose derivatives, and the like.

[0059] (Meth)acrylic resins may be homopolymers or copolymers of (meth)acrylic monomers ((meth)acrylic acid, (meth)acrylic acid ester monomers, N,N-dialkylaminoethyl (meth)acrylate, ammonium (meth)acrylate, etc.), or may be copolymers of (meth)acrylic monomers and copolymerizable monomers (vinyl ester monomers, heterocyclic vinyl monomers, vinyl monomers such as polymerizable unsaturated dicarboxylic acids or their derivatives).

[0060] Examples of homopolymers or copolymers of (meth)acrylic monomers include, for example, methyl methacrylate-ethyl acrylate copolymer (methacrylic acid copolymer LD), methyl methacrylate-n-butyl acrylate copolymer, methyl methacrylate-methyl methacrylate copolymer (methacrylic acid copolymer L,S), methyl methacrylate-dimethylaminoethyl methacrylate copolymer, ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride (ammonio methacrylate) copolymer, methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer, and the like.

[0061] Examples of vinyl resins include, for example, polyvinyl acetate phthalate, polyvinyl acetal diethylaminoacetate, and the like.

[0062] Cellulose derivatives may be any of cellulose ethers, cellulose esters, and cellulose ether esters.

[0063] Examples of cellulose ethers include, for example, cellulose alkyl ethers such as ethyl cellulose, ethyl methyl cellulose, ethyl propyl cellulose, isopropyl cellulose, butyl cellulose; cellulose carboxyalkyl alkyl ethers such as carboxymethyl ethyl cellulose (CMEC); cellulose aralkyl ethers such as benzyl cellulose; cellulose cyanoalkyl ethers such as cyanoethyl cellulose, and the like.

[0064] Examples of the cellulose esters include cellulose acetate butyrate, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose acetate propionate, cellulose phthalate, cellulose acetate phthalate, and the like.

[0065] Examples of the cellulose ether esters include hydroxymethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylcellulose phthalate, hydroxypropylmethylcellulose phthalate (HPMCF), and the like.

[0066] These water-insoluble polymers can be used alone or in combination of two or more.

[0067] As the water-insoluble polymer (a), commercially available products may be used. Examples of the commercially available products include, as pH-independent water-insoluble polymers, "Eudragit RS30D", "Eudragit RSPO", "Eudragit RL30D", "Eudragit RLPO", "Eudragit NE30D" manufactured by Evonik, "Ethocel (registered trademark) Standard 7 Premium", "Ethocel Standard 7FP Premium" manufactured by Nutrition&Biosciences USA1, LLC, "Kollicoat SR30D" manufactured by BASF Japan; as gastric-soluble water-insoluble polymers, "Eudragit E" manufactured by Evonik, "AEA" manufactured by Mitsubishi Chemical, "Kollicoat Smart Seal 30D" manufactured by BASF Japan, and the like. These commercially available products can be used alone or in combination of two or more.

[0068] Among these, at least one selected from the group consisting of (meth)acrylic polymers having ammonio methacrylate units and (meth)acrylic polymers having aminoalkyl methacrylate units is preferable, and (meth)acrylic polymers having ammonio methacrylate units are more preferable.

[0069] (Meth)acrylic polymers having an ammoniomethacrylate unit may have a trimethylammonium ethyl methacrylate unit and may contain copolymerizable units composed of copolymerizable monomers. Examples of the copolymerizable monomers include (meth)acrylic acid, (meth)acrylic acid ester monomers, vinyl ester monomers, N,N-dialkylaminoethyl (meth)acrylate, heterocyclic vinyl monomers, polymerizable unsaturated dicarboxylic acids or their derivatives, and the like. These copolymerizable monomers can be used alone or in combination of two or more.

[0070] As the (meth)acrylic polymer having an ammoniomethacrylate unit, an ethyl acrylate-methyl methacrylate-ammoniomethacrylate copolymer is particularly preferred.

[0071] Furthermore, the (meth)acrylic polymer having an ammoniomethacrylate unit preferably contains at least a high water permeability polymer in which the proportion of the ammoniomethacrylate unit is 7.5% by mass or more. From the viewpoint of being able to adjust the water permeability of the masking layer, a combination of the high water permeability polymer and a low water permeability polymer in which the proportion of the ammoniomethacrylate unit is less than 7.5% by mass is preferred. By combining the two, the lag time can be adjusted, and even if the thickness of the masking layer is small, the lag time can be lengthened, so that the spherical granules can be miniaturized.

[0072] In the high water permeability polymer, the proportion of the ammoniomethacrylate unit may be 7.5% by mass or more, for example, 7.5 to 30% by mass, preferably 7.8 to 20% by mass, more preferably 8 to 15% by mass, still more preferably 8.5 to 13% by mass, and most preferably 8.8 to 12% by mass. If the proportion of the ammoniomethacrylate unit is too small, the water permeability of the masking layer may be low and the elution property of the active ingredient may decrease. As the high water permeability polymer, commercially available products can be used. For example, ammonioalkyl methacrylate copolymer "Eudragit RLPO" manufactured by Evonik can be used.

[0073] In the low water permeability polymer, the proportion of the ammonio methacrylate unit may be less than 7.5% by mass, for example, 1 to 7.4% by mass, preferably 2 to 7.3% by mass, more preferably 3 to 7.2% by mass, still more preferably 4 to 7% by mass, and most preferably 4.3 to 6.8% by mass. If the proportion of the ammonio methacrylate unit is too large, there is a risk that the water permeability to the masking layer will increase and the lag time will be shortened. As the low water permeability polymer, commercially available products can be used. For example, the ammonioalkyl methacrylate copolymer "Eudragit RSPO" manufactured by Evonik can be used.

[0074] The mass ratio of the high water permeability polymer to the low water permeability polymer can be selected from the range of the former / latter = 1 / 99 to 100 / 0, for example, 10 / 90 to 90 / 10, preferably 30 / 70 to 87 / 13, more preferably 50 / 50 to 85 / 15, still more preferably 60 / 40 to 80 / 20, and most preferably 65 / 35 to 75 / 25. From the viewpoint of increasing the elution rate and improving the lag time, the mass ratio of the low water permeability polymer to the high water permeability polymer may be the former / latter = 0 / 100 (that is, the high water permeability polymer alone). If the proportion of the low water permeability polymer is too large, there is a risk that the elution property of the active ingredient will decrease, and if the proportion of the high water permeability polymer is too large, there is a risk that the lag time will be shortened.

[0075] The proportion of the water-insoluble polymer (a) [particularly, a (meth)acrylic polymer having an ammonio methacrylate unit] may be 5% by mass or more in the masking layer, for example, 5 to 90% by mass, preferably 10 to 85% by mass, more preferably 30 to 80% by mass, still more preferably 50 to 75% by mass, and most preferably 60 to 70% by mass. If the proportion of the water-insoluble polymer (a) is too small, there is a risk that it will be difficult to control the lag time. If it is too large, not only will the elution property of the active ingredient decrease, but there is also a risk that the spherical granules will become larger.

[0076] The proportion of the water-insoluble polymer (a) [especially a (meth)acrylic polymer having an ammonio methacrylate unit] may be 10 parts by mass or more with respect to 100 parts by mass of the spherical core part, for example, 10 to 100 parts by mass, preferably 20 to 80 parts by mass, more preferably 30 to 75 parts by mass, still more preferably 40 to 70 parts by mass, and most preferably 60 to 70 parts by mass. If the proportion of the water-insoluble polymer (a) is too small, it may be difficult to control the lag time. If it is too large, the elution property of the active ingredient may decrease and the spherical granules may become larger.

[0077] (b) Inorganic compound In addition to the water-insoluble polymer (a), the masking layer may further contain an inorganic compound (first inorganic compound) (b) in order to adjust the lag time and the elution property of the active ingredient.

[0078] The inorganic compound (b) may be a lubricant. Examples of the lubricant (second lubricant) include silicic acids such as talc, anhydrous silicic acid such as light anhydrous silicic acid, hydrous silicon dioxide (hydrous silicic acid), calcium silicate, magnesium silicate, synthetic aluminum silicate, magnesium aluminometasilicate; metal oxides such as magnesium oxide and titanium oxide; carbonates such as precipitated calcium carbonate and magnesium carbonate; phosphates such as anhydrous calcium hydrogen phosphate and calcium hydrogen monophosphate; minerals such as bentonite, synthetic hydrotalcite, and kaolin.

[0079] These inorganic compounds can be used alone or in combination of two or more. Among these, one or more selected from the group consisting of talc, magnesium aluminometasilicate, and synthetic hydrotalcite are preferable, and talc is particularly preferable.

[0080] The shape of the inorganic compound (b) (especially talc) is not particularly limited, and may be amorphous, fibrous, ellipsoidal, spherical, plate-like, powder-like, etc., and is usually amorphous, powder-like, etc.

[0081] The volume-based cumulative 50% particle diameter (D of the inorganic compound (b) (especially talc)50 ) is, for example, 0.3 to 10 μm, preferably 0.5 to 8 μm, more preferably 1 to 7 μm, still more preferably 1.5 to 6 μm, and most preferably 2 to 6 μm.

[0082] The proportion of the inorganic compound (b) (especially talc) may be 100 parts by mass or less with respect to 100 parts by mass of the water-insoluble polymer (a) (especially a (meth)acrylic polymer having an ammoniomethacrylate unit), for example, 1 to 100 parts by mass, preferably 5 to 90 parts by mass, more preferably 10 to 80 parts by mass, still more preferably 30 to 70 parts by mass, and most preferably 40 to 60 parts by mass. If the proportion of the inorganic compound (b) is too large, there is a risk that the elution property of the active ingredient will decrease.

[0083] (c) Binder In addition to the water-insoluble polymer (a), the masking layer may further contain a binder (second binder) (c) in order to improve the mechanical properties and interlayer adhesion of the masking layer. Examples of the second binder include the binders exemplified as the first binder. The binder can be used alone or in combination of two or more. Among the binders, hydroxy C such as HPC 2-4 alkyl cellulose ether is preferred.

[0084] In the second binder (c), the viscosity of an aqueous 2 mass% solution (20 °C) of hydroxy C 2-4 alkyl cellulose ether (especially HPC) is, for example, 2 to 20 mPa·s, preferably 5 to 15 mPa·s, and more preferably 6 to 10 mPa·s.

[0085] In the present specification and claims, the viscosity can be measured by a conventional method, for example, the capillary viscometer method.

[0086] The proportion of the second binder (c) may be 100 parts by mass or less with respect to 100 parts by mass of the water-insoluble polymer (a) (particularly, a (meth)acrylic polymer having an ammoniomethacrylate unit), for example, 1 to 30 parts by mass, preferably 3 to 20 parts by mass, more preferably 2 to 10 parts by mass, still more preferably 3 to 8 parts by mass, and most preferably 4 to 6 parts by mass. If the proportion of the second binder (c) is too small, the effect of improving the mechanical properties and the interlayer adhesion of the masking layer may not be exhibited. If it is too large, there is a possibility that the lag time may not be formed.

[0087] (d) Other additives (additives for the masking layer) In addition to the water-insoluble polymer (a), the masking layer may further contain, as other additives (additives for the masking layer), conventional additives formulated in oral preparations. Examples of the conventional additives include excipients (second excipients), disintegrants (second disintegrants), plasticizers, surfactants, pH adjusters, colorants, sweeteners or flavoring agents, antioxidants, preservatives or preservatives, wetting agents, antistatic agents, disintegration aids, fluidizing agents, and the like. These additives can be used alone or in combination of two or more. The total proportion of the additives for the masking layer may be 30% by mass or less in the masking layer, preferably 20% by mass or less, more preferably 10% by mass or less, still more preferably 5% by mass or less, and most preferably 1% by mass or less.

[0088] (e) Characteristics of the masking layer The proportion of the masking layer can be selected from the range of about 10 to 150 parts by mass with respect to 100 parts by mass of the spherical core part, for example, 20 to 130 parts by mass, preferably 30 to 110 parts by mass, more preferably 40 to 100 parts by mass, still more preferably 50 to 90 parts by mass, and most preferably 60 to 80 parts by mass. If the proportion of the masking layer is too small, it may be difficult to mask the bitterness. On the contrary, if it is too large, the elution property of the active ingredient may decrease and it may also be difficult to miniaturize the spherical granules.

[0089] The average thickness of the masking layer is, for example, 1 to 30 μm, preferably 2 to 25 μm, more preferably 3 to 20 μm, still more preferably 4 to 17 μm, and most preferably 5 to 13 μm. If the thickness is too thin, it may be difficult to mask bitterness. Conversely, if it is too thick, the elution property of the active ingredient may decrease and it may also be difficult to miniaturize the spherical granules.

[0090] (B) Intermediate layer The coating portion may have an intermediate layer interposed between the spherical core portion and the masking layer. In the present invention, by interposing an intermediate layer between the spherical core portion and the masking layer, it is possible to achieve both bitterness masking property and miniaturization.

[0091] The intermediate layer may contain an inorganic compound (second inorganic compound). The second inorganic compound may be a lubricant (third lubricant). The third lubricant can be selected from the lubricants exemplified as the second lubricant.

[0092] The inorganic compound can be used alone or in combination of two or more. Among the inorganic compounds, one or more selected from the group consisting of talc, magnesium aluminometasilicate, and synthetic hydrotalcite are preferred, and talc is particularly preferred.

[0093] The shape of the second inorganic compound (particularly, talc) is not particularly limited and may be amorphous, fibrous, ellipsoidal, spherical, flat plate-like, powdery granular, etc., and is usually amorphous, powdery granular, etc.

[0094] The volume-based cumulative 50% particle size (D 50 ) of the second inorganic compound (particularly, talc) is, for example, 0.3 to 10 μm, preferably 0.5 to 8 μm, more preferably 1 to 7 μm, still more preferably 1.5 to 6 μm, and most preferably 2 to 6 μm.

[0095] The proportion of the second inorganic compound (in particular, talc) may be 10% by mass or more in the intermediate layer, for example, 10 to 95% by mass, preferably 30 to 90% by mass, more preferably 50 to 85% by mass, still more preferably 60 to 80% by mass, and most preferably 70 to 75% by mass. If the proportion of the inorganic compound is too large, the effect of improving adhesion may be reduced.

[0096] In addition to the second inorganic compound, the intermediate layer may further contain a binder (third binder). Examples of the third binder include the binders exemplified as the first binder. The binder can be used alone or in combination of two or more. Among the binders, hydroxy C 2-4 alkyl cellulose ether is preferred.

[0097] In the third binder, the viscosity of the 2% by mass aqueous solution (20 °C) of hydroxy C 2-4 alkyl cellulose ether (especially HPC) is, for example, 1 to 10 mPa·s, preferably 2 to 8 mPa·s, and more preferably 3 to 6 mPa·s.

[0098] The proportion of the third binder may be 1000 parts by mass or less with respect to 100 parts by mass of the second inorganic compound, for example, 5 to 300 parts by mass, preferably 10 to 100 parts by mass, more preferably 20 to 80 parts by mass, still more preferably 30 to 50 parts by mass, and most preferably 35 to 45 parts by mass. If the proportion of the third binder is too large, the effect of adjusting the lag time and the elution property of the active ingredient may be reduced.

[0099] In addition to the second inorganic compound and the third binder, the intermediate layer may further contain, as other additives (additives for the intermediate layer), conventional additives formulated in oral preparations. Examples of the conventional additives include excipients (third excipients), disintegrants (third disintegrants), plasticizers, surfactants, pH adjusters, colorants, sweeteners or flavoring agents, antioxidants, preservatives or storage agents, wetting agents, antistatic agents, disintegration aids, fluidizing agents, and the like. These additives can be used alone or in combination of two or more. The total proportion of the additives for the intermediate layer may be 30% by mass or less in the intermediate layer, preferably 20% by mass or less, more preferably 10% by mass or less, still more preferably 5% by mass or less, and most preferably 1% by mass or less.

[0100] The proportion of the intermediate layer can be selected from the range of about 5 to 100 parts by mass with respect to 100 parts by mass of the spherical core part, for example, 10 to 95 parts by mass, preferably 15 to 90 parts by mass, more preferably 20 to 80 parts by mass, still more preferably 30 to 70 parts by mass, and most preferably 40 to 60 parts by mass. If the proportion of the intermediate layer is too small, the effect of improving the adhesion between the spherical parts and the coating part may be reduced. Conversely, if it is too large, the elution property of the active ingredient may be reduced and it may be difficult to miniaturize the spherical granules.

[0101] The average thickness of the intermediate layer is, for example, 0.1 to 15 μm, preferably 1 to 9 μm, more preferably 2 to 8 μm, still more preferably 3 to 7 μm, and most preferably 4 to 6 μm. If the thickness is too thin, the effect of improving the adhesion between the spherical core part and the coating part may be reduced. If it is too thick, the elution property of the active ingredient may be reduced and it may be difficult to miniaturize the spherical granules.

[0102] (C) Overcoat layer The coating part may further cover the surface of the masking layer with an overcoat layer. In the present invention, by laminating an overcoat layer on the masking layer, the handleability of the spherical granules can be improved.

[0103] The overcoat layer may contain an excipient. Examples of the excipient (the fourth excipient) include the excipients exemplified as the first excipient. The excipient can be used alone or in combination of two or more. Among the excipients, sugar alcohols such as D-mannitol are preferred.

[0104] The proportion of the fourth excipient may be 10% by mass or more in the overcoat layer, for example, 10 to 100% by mass, preferably 30 to 100% by mass, more preferably 50 to 100% by mass, still more preferably 70 to 100% by mass, and most preferably 75 to 100% by mass. If the proportion of the excipient is too small, the mechanical properties of the overcoat layer may deteriorate.

[0105] In addition to the excipient, the overcoat layer may further contain, as other additives (additives for the overcoat layer), conventional additives formulated in oral preparations. Examples of the conventional additives include, for example, a binder (the fourth binder), a disintegrant (the fourth disintegrant), a plasticizer, a surfactant, a pH adjuster, a coloring agent, a sweetening agent or a flavoring agent, an antioxidant, a preservative or a preservative, a wetting agent, an antistatic agent, a disintegration aid, a fluidizing agent and the like. These additives can be used alone or in combination of two or more. The total proportion of the additives for the overcoat layer may be 30% by mass or less in the overcoat layer, preferably 20% by mass or less, more preferably 10% by mass or less, still more preferably 5% by mass or less, and most preferably 1% by mass or less.

[0106] The proportion of the overcoat layer can be selected from the range of about 5 to 100 parts by mass with respect to 100 parts by mass of the spherical core part, for example, 10 to 80 parts by mass, preferably 15 to 70 parts by mass, more preferably 20 to 50 parts by mass, still more preferably 25 to 40 parts by mass, and most preferably 30 to 35 parts by mass. If the proportion of the overcoat layer is too small, the effect of improving the handleability may be reduced. On the contrary, if it is too large, the elution property of the active ingredient may be reduced and it may be difficult to miniaturize the spherical granules.

[0107] In the specification and claims of the present application, the lubricant adhered to the surface of the overcoat layer shall not be a component of the overcoat layer.

[0108] The average thickness of the overcoat layer is, for example, 0.1 to 20 μm, preferably 0.3 to 15 μm, more preferably 0.5 to 10 μm, still more preferably 0.8 to 8 μm, and most preferably 1 to 5 μm. If the thickness is too thin, the effect of improving handleability may be reduced. If the thickness is too thick, the elution property of the active ingredient may be reduced, and it may be difficult to miniaturize the spherical granules.

[0109] In the specification and claims of the present application, the average thickness of the overcoat layer means the average thickness in a state where the lubricant is not adhered to the surface.

[0110] A lubricant (fourth lubricant) may be adhered to the surface of the overcoat layer. Examples of the fourth lubricant include the lubricants exemplified as the second lubricant. The lubricant can be used alone or in combination of two or more. Among the lubricants, one or more selected from the group consisting of talc, magnesium aluminometasilicate, light anhydrous silicic acid, and synthetic hydrotalcite are preferable, and talc is particularly preferable.

[0111] The shape of the fourth lubricant is not particularly limited, and may be amorphous, fibrous, ellipsoidal, spherical, flat plate-like, powder-like, etc., and is usually amorphous, powder-like, etc.

[0112] The volume-based cumulative 50% particle diameter (D50) of the fourth lubricant is, for example, 0.3 to 10 μm, preferably 0.5 to 8 μm, more preferably 1 to 7 μm, still more preferably 1.5 to 6 μm, and most preferably 2 to 6 μm.

[0113] The proportion of the fourth lubricant is 0.1 to 10% by mass, preferably 1 to 8% by mass, more preferably 1.5 to 5% by mass, still more preferably 2 to 4% by mass, and most preferably 2.5 to 3.5% by mass in the spherical granules. If the proportion of the fourth lubricant is too small, the effect of improving handleability may be reduced. On the contrary, if it is too large, the elution property of the active ingredient may be reduced.

[0114] [Properties of Spherical Granules] In the spherical granules of the present invention, since the spherical core portion containing bepotastine or a salt thereof is coated with a coating portion containing a water-insoluble polymer, small spherical granules with the bitterness of bepotastine or a salt thereof masked can be prepared.

[0115] The volume-based cumulative 50% particle diameter (D 50 ) of the spherical granules of the present invention may be 250 μm or less (particularly 200 μm or less), and can be selected from the range of about 70 to 250 μm, for example, 80 to 200 μm, preferably 100 to 180 μm, more preferably 110 to 170 μm, still more preferably 120 to 160 μm, and most preferably 125 to 155 μm. If the cumulative 50% particle diameter (central particle diameter) of the spherical granules is too small, there is a risk that the medicinal effects such as productivity may decrease. On the contrary, if it is too large, the size will increase, and depending on the use, there is a risk that the feeling of taking the medicine may decrease.

[0116] The sphericity (true sphericity) of the spherical granules of the present invention may be 0.6 or more (for example, about 0.6 to 0.99), for example, 0.7 or more (for example, 0.7 to 0.98), preferably 0.75 or more, and more preferably 0.8 or more.

[0117] The proportion of bepotastine or a salt thereof may be 10 to 80% by mass in the spherical granules, preferably 15 to 60% by mass, more preferably 25 to 57% by mass, still more preferably 30 to 55% by mass, and most preferably 30 to 40% by mass. If the proportion of bepotastine or a salt thereof is too small, there is a risk that the elution property of the active ingredient may decrease. On the contrary, if it is too large, there is a risk that the bitterness masking property may decrease.

[0118] [Method for Producing Spherical Granules] The spherical granules of the present invention can be produced by undergoing a nucleation step of forming a spherical core portion containing bepotastine or a salt thereof, and a coating step of coating the obtained spherical core portion with a coating portion containing a masking layer to obtain spherical granules.

[0119] In the nucleation step, as a method for forming the spherical core portion, conventional granulation methods such as a spray granulation method, a rolling granulation method, a fluidized bed granulation method, a stirring granulation method, and an in-liquid granulation method can be used. Among these granulation methods, the stirring granulation method is preferred. When the spherical core portion is spherulites of bepotastine or a salt thereof, as a method for producing the spherulites, for example, the production method described in WO 2020 / 040233 pamphlet can be used.

[0120] In the coating step (the first coating step), the spherical core portion (when the coating portion includes an intermediate layer, the intermediate layer) may be coated with a masking composition for forming a masking layer by a conventional coating method. Examples of the conventional coating method include coating, spraying, impregnation / dipping, pan coating, fluidized bed coating, rolling coating, and rolling fluidized coating. Among these, fluidized bed coating and rolling fluidized coating are preferred, and rolling fluidized coating is particularly preferred.

[0121] The masking composition preferably contains a solvent in addition to the above components for forming the masking layer. The solvent is not particularly limited, but from the viewpoint of safety, water, an aqueous solvent, etc. can be used. Examples of the aqueous solvent include lower alcohols (such as C 2-4 alkanols such as ethanol and isopropanol), aliphatic ketones (such as acetone), etc. These solvents can be used alone or in combination of two or more.

[0122] Among these solvents, water alone, an aqueous solvent alone, and a mixed solvent of water and an aqueous solvent are preferred, and water alone, water and C 2-4A mixed solvent of alkanol is more preferable, and a mixed solvent of water and ethanol is most preferable. These solvents can be selected according to the types of components contained, and water and C 2-4 In the mixed solvent of alkanol, the proportion of water is C 2-4 For 100 parts by mass of alkanol, for example, it is 1 to 100 parts by mass, preferably 3 to 50 parts by mass, more preferably 5 to 30 parts by mass, and still more preferably 8 to 20 parts by mass.

[0123] In the masking composition, the proportion of the solvent is, for example, 50 to 3000 parts by mass, preferably 100 to 2500 parts by mass, more preferably 500 to 2000 parts by mass, still more preferably 800 to 1500 parts by mass, and most preferably 1000 to 1200 parts by mass with respect to 100 parts by mass of bepotastine or its salt.

[0124] When the coating part includes an intermediate layer, as a pre-step for subjecting to the first coating step for forming the masking layer, it is subjected to a coating step (second coating step) of coating the spherical core part with the intermediate layer. Also in the second coating step, the intermediate composition for forming the intermediate layer may be coated on the spherical core part by a conventional coating method. Examples of the conventional coating method include the coating methods exemplified in the first coating step. Among the above methods, fluidized bed coating and rolling fluidized coating are preferable, and rolling fluidized coating is particularly preferable.

[0125] The intermediate composition preferably contains a solvent in addition to the above components for forming the intermediate layer. Examples of the solvent include the solvents exemplified in the first coating step. The above solvents can be used alone or in combination of two or more. Among the above solvents, water alone is preferable.

[0126] In the intermediate composition, the proportion of the solvent is, for example, 50 to 1000 parts by mass, preferably 100 to 700 parts by mass, more preferably 150 to 500 parts by mass, still more preferably 200 to 400 parts by mass, and most preferably 250 to 300 parts by mass with respect to 100 parts by mass of bepotastine or its salt.

[0127] When the coating part includes an overcoat layer, spherical particles are obtained through a third coating step of further coating the coating layer of the first spherical particles obtained in the first coating step with the overcoat layer to obtain second spherical particles. Also in the third coating step, the first spherical particles may be coated with an overcoat composition for forming the overcoat layer by a conventional coating method. Examples of the conventional coating method include the coating methods exemplified in the first coating step. Among the above methods, fluidized bed coating and rolling fluidized coating are preferred, and rolling fluidized coating is particularly preferred.

[0128] The overcoat composition preferably contains a solvent in addition to the above components for forming the overcoat layer. Examples of the solvent include the solvents exemplified in the first coating step. The solvents can be used alone or in combination of two or more. Among the above solvents, water alone is preferred.

[0129] In the overcoat composition, the proportion of the solvent is, for example, 50 to 1000 parts by mass, preferably 80 to 700 parts by mass, more preferably 100 to 500 parts by mass, still more preferably 150 to 300 parts by mass, and most preferably 200 to 250 parts by mass with respect to 100 parts by mass of the above components for forming the overcoat layer.

[0130] When attaching a fourth lubricant to the surface of the overcoat layer, after coating the overcoat composition, the fourth lubricant may be attached to the surface of the spherical particles by mixing the obtained spherical particles and the fourth lubricant (mixing treatment or film-forming step).

[0131] [Formulation] The formulation of the present invention only needs to contain the above spherical particles, and among them, it can be preferably used as various oral formulations.

[0132] The oral preparation of the present invention can be miniaturized while suppressing the bitterness of bepotastine or its salt with strong bitterness. That is, in the oral preparation of the present invention, it is possible to achieve both suppression of bitterness, which was a trade-off relationship in conventional preparations, and the elution property of bepotastine or its salt. In particular, in the oral preparation of the present invention, the elution of the active ingredient in the oral cavity is suppressed, not only can the bitterness be suppressed, but also the spherical granules are miniaturized, so that in addition to improving the elution property, the feel in the oral cavity is smooth and the swallowability can be improved. Furthermore, by forming the coating part with a specific component, the elution of the active ingredient can be suppressed at the target lag time, and since it is miniaturized, the elution property can also be improved. On the other hand, in conventional preparations, in order to suppress bitterness, when the thickness of the coating part was increased, the preparation became larger, the swallowability and the elution property of the active ingredient decreased, and it was impossible to achieve both suppression of bitterness and miniaturization.

[0133] Examples of oral preparations include pills, powders, troches, dry syrups, tablets, capsules, suspensions, and the like. Among these, it is effective for oral preparations in which the active ingredient is easily eluted in the oral cavity, such as powders, troches, dry syrups, tablets, suspensions, etc., particularly effective for tablets, and most effective for orally disintegrating tablets (OD tablets). In the present invention, since the spherical granules are miniaturized, tablets such as OD tablets can also be miniaturized.

[0134] (OD tablet) The orally disintegrating tablet (OD tablet) of the present invention only needs to contain the above-mentioned spherical granules. The proportion of the spherical granules may be 1% by mass or more in the OD tablet, for example, 1 to 90% by mass, preferably 3 to 70% by mass, more preferably 5 to 50% by mass, still more preferably 10 to 30% by mass, and most preferably 12 to 25% by mass.

[0135] The OD tablet of the present invention may further contain fast-disintegrating granules in addition to the above-mentioned spherical granules. The fast-disintegrating granules preferably contain an excipient (fifth excipient) and a disintegrant (fifth disintegrant).

[0136] Examples of the fifth excipient include the excipients exemplified as the first excipient. The excipients can be used alone or in combination of two or more. Among the excipients, sugar alcohols such as D-mannitol, celluloses such as crystalline cellulose, and cellulose ethers such as ethyl cellulose are preferred.

[0137] The fifth excipient may be a combination of a sugar alcohol and cellulose ethers. When the fifth excipient is the combination, the proportion of the cellulose ethers is, for example, 0.1 to 30 parts by mass, preferably 0.5 to 10 parts by mass, more preferably 1 to 5 parts by mass with respect to 100 parts by mass of the sugar alcohol.

[0138] The proportion of the fifth excipient may be 30% by mass or more in the rapidly disintegrating granules, for example, 30 to 95% by mass, preferably 50 to 90% by mass, more preferably 60 to 85% by mass, still more preferably 65 to 80% by mass, most preferably 70 to 75% by mass.

[0139] Examples of the fifth disintegrant include polysaccharides [starches such as corn starch, potato starch, pregelatinized starch, partially pregelatinized starch, oxidized starch, dextrin, cyclodextrin, hydroxypropyl starch, carboxymethyl starch, sodium carboxymethyl starch, etc.; cellulose ethers such as carmellose, sodium carmellose, calcium carmellose, croscarmellose sodium, low-substituted hydroxypropyl cellulose (L-HPC), etc.; agar, carrageenan, gum arabic, alginic acid, sodium alginate, propylene glycol alginate, guar gum, locust bean gum, tragacanth gum, pullulan, xanthan gum, hyaluronic acid, pectin, sodium chondroitin sulfate, etc.], proteins (such as gelatin, casein, soybean protein, etc.), polyvinylpyrrolidones [polyvinylpyrrolidone (povidone), vinylpyrrolidone copolymer (copovidone), crospovidone, etc.], silicas (such as talc, light anhydrous silica, calcium silicate, magnesium silicate, synthetic aluminum silicate, magnesium aluminometasilicate, etc.), minerals (such as bentonite, synthetic hydrotalcite, kaolin, etc.). These disintegrants can be used alone or in combination of two or more. Among these disintegrants, starches such as corn starch and partially pregelatinized starch, polyvinylpyrrolidones such as crospovidone, and silicas such as light anhydrous silica are preferred, and starches and silicas are particularly preferred.

[0140] The fifth disintegrant may be a combination of starches and silicas. When the fifth disintegrant is the above combination, the proportion of silicas is, for example, 0.1 to 30 parts by mass, preferably 1 to 10 parts by mass, more preferably 3 to 7 parts by mass, based on 100 parts by mass of starches.

[0141] The proportion of the fifth disintegrant is, for example, 5 to 100 parts by mass, preferably 10 to 70 parts by mass, more preferably 20 to 50 parts by mass, and most preferably 30 to 40 parts by mass with respect to 100 parts by mass of the fifth excipient. If the proportion of the fifth disintegrant is too small, the disintegration property of the OD tablets may decrease. Conversely, if it is too large, the mechanical properties may decrease.

[0142] The rapidly disintegrating granules may further contain conventional additives formulated in oral preparations as other additives (additives for rapidly disintegrating granules). Examples of conventional additives include, for example, the fifth binder, the fifth lubricant, a plasticizer, a surfactant, a pH adjuster, a coloring agent, a sweetening agent or a flavoring agent, an antioxidant, a preservative or a storage agent, a wetting agent, an antistatic agent, a disintegration aid, a fluidizing agent, and the like. These additives can be used alone or in combination of two or more. The total proportion of the additives for rapidly disintegrating granules may be 30% by mass or less in the rapidly disintegrating granules, preferably 20% by mass or less, more preferably 10% by mass or less, still more preferably 5% by mass or less, and most preferably 1% by mass or less.

[0143] The volume-based cumulative 50% particle diameter (D 50 ) of the rapidly disintegrating granules is, for example, 10 to 200 μm, preferably 20 to 150 μm, more preferably 30 to 100 μm, still more preferably 40 to 70 μm, and most preferably 45 to 60 μm.

[0144] The proportion of the rapidly disintegrating granules is, for example, 10 to 3000 parts by mass, preferably 50 to 1000 parts by mass, more preferably 100 to 800 parts by mass, and most preferably 300 to 600 parts by mass with respect to 100 parts by mass of the spherical granules.

[0145] In addition to the spherical granules and the rapid disintegrating granules, the OD tablets of the present invention may further contain conventional additives (additives for OD tablets) formulated in the OD tablets. Examples of additives for OD tablets include a sixth excipient (sugar alcohols such as D-mannitol), a fluidizing agent (silicic acids such as light anhydrous silicic acid), a sixth lubricant (fatty acids such as magnesium stearate or metal salts thereof), a sweetening agent or a flavoring agent (aspartame, acesulfame potassium, sucralose, ascorbic acid, stevia, menthol, crude licorice extract, simple syrup, etc.), a flavoring agent or a fragrance (menthol, ginger oil, etc.), a cooling agent, and the like.

[0146] The ratio of the additives for OD tablets is, for example, 0.1 to 100 parts by mass, preferably 1 to 70 parts by mass, more preferably 5 to 50 parts by mass, and most preferably 10 to 30 parts by mass with respect to 100 parts by mass of the spherical granules.

[0147] The method for producing the OD tablets of the present invention may be any method of tableting using a composition containing spherical granules, and may be a conventional method.

Examples

[0148] Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited by these examples. The raw materials and evaluation methods used in the following examples are shown below. Also, all the masses of the raw materials used are solid content masses.

[0149] [Raw materials] Bepotastine drug substance: Bepotastine besilate Hydroxypropyl cellulose a: Trade name "HPC-SL", 2% (20 °C) aqueous solution viscosity 3 to 6 mPa·s Hydroxypropyl cellulose b: Trade name "HPC-L", 2% (20 °C) aqueous solution viscosity 6 to 10 mPa·s High water permeability polymer: Ammonioalkyl methacrylate copolymer, trade name "Eudragit RLPO" Low water permeability polymer: Ammonioalkyl methacrylate copolymer, trade name "Eudragit RSPO" D-Mannitol a: Trade name "PEARLITOL 50C" D-Mannitol b: Trade name "Parteck M100" Ethyl cellulose a: Trade name "Ethocel Standard 7FP Premium" Ethyl cellulose b: Trade name "Ethocel Standard 7 Premium" Polyvinyl alcohol: Trade name "Gosenol EG-05PW" Corn starch: Trade name "Corn Starch (W)" Partial pregelatinized starch: Trade name "PCS[PC-10]" Crospovidone: Trade name "Polyplasdone INF-10" Talc a: Trade name "MICRO ACE P-3" Talc b: Trade name "Talkan Hayashi" Light anhydrous silicic acid: Trade name "Adsorider 101" Corn starch Partial alpha pregelatinized starch: Trade name "PCS[PC-10]" Magnesium stearate: Trade name "Vegetable (Taiping)" L-Menthol Aspartame.

[0150] [Particle size distribution] Particle size distribution (D 50 ) was measured based on volume in dry state using a laser diffraction particle size distribution analyzer (manufactured by Malvern Instruments Ltd., trade name "Mastersizer 3000") to obtain the cumulative 50% particle size (D 50 ) and the sharpness index.

[0151] [SEM image] The SEM image was observed using a scanning electron microscope (manufactured by Keyence Corporation, trade name "E-7800").

[0152] [Average thickness of each layer] It was calculated from the particle size distribution (D 50 ) before and after coating.

[0153] [Bitter taste evaluation method of OD tablets] Before the test, rinse the mouth with water. Hold the sample in the mouth for 1 minute and then spit it out after 1 minute. Thereafter, the presence or absence of bitterness was evaluated for 4 minutes (total 5 minutes).

[0154] As a result of the evaluation, when no bitter taste was felt for 5 minutes, the presence or absence of bitterness was continuously evaluated up to 10 minutes.

[0155] The intensity of bitterness was recorded as shown in the entry example in Figure 1. Also, the time when the bitter taste began to be felt was separately recorded in the upper column.

[0156] In addition, the subjects were obliged to spit out saliva generated during the evaluation at any time until 2 minutes. After that, the evaluation was carried out without spitting it out.

[0157] Also, subjects who disliked swallowing saliva were permitted to spit it out during the evaluation. After the test, the subjects were obliged to rinse their mouths with water.

[0158] Furthermore, when testing the next lot, the subjects were required to leave an interval of more than 1 hour and conduct the test in a state where there was no bitterness or discomfort in the oral cavity.

[0159] [Hardness of OD tablets] For the measurement of hardness, a hardness tester (manufactured by ERWEKA, product name "TBH425") was used.

[0160] [Disintegration time (18th revised Japanese Pharmacopoeia)] A disintegration tester (conforming to the Japanese Pharmacopoeia) was used. 900 mL of water at 37 °C was placed in a glass container, and a basket (with a net-like bottom) containing the tablets was moved up and down in the water of the container, and the time until the tablets disintegrated completely was measured.

[0161] Example 1 [Preparation of spherical nucleus part] Using the bepotastine bulk drug, spherical particles of the bepotastine bulk drug were produced according to the production method of Example 30 described in Pamphlet of International Publication No. 2020 / 040233. The obtained spherical particles were classified using a 100-mesh (100M, 150 μm) sieve and a 200M sieve (75 μm), and the spherical particles that passed through the 100M sieve and remained on the 200M sieve were used as spherical bulk drug of bepotastine besilate (hereinafter referred to as "spherical bulk drug of bepotastine"). An SEM photograph of the spherical bulk drug of bepotastine (spherical core part) is shown in Figure 2. The cumulative 10% particle size (D 10 ), median diameter (D 50 ), cumulative 90% particle size (D 90 ) and sharpness index of the spherical core part were 93 μm, 110 μm, 129 μm and 1.18, respectively.

[0162] [Coating Step of Masking Layer] The spherical bulk drug of bepotastine (drug core) was charged into a fluidized bed granulation dryer. A dispersion obtained by dissolving 14 parts by mass of a high water-permeable polymer and 32.67 parts by mass of a low water-permeable polymer in a mixed solution of purified water and ethanol and dispersing 23.33 parts by mass of talc a was sprayed in its entirety for coating, followed by drying and classification using a 30M sieve to obtain bitter taste masking particles with a median diameter (D 50 ) of 128 μm. The average thickness of the masking layer was 9 μm. Table 1 shows the actual amounts charged to obtain the bitter taste masking particles.

[0163] [Table 1]

[0164] [Coating Step of Overcoat Layer] The bitter taste masking particles were charged into a fluidized bed granulation dryer. A solution obtained by dissolving 15 parts by mass of D-mannitol a in purified water was sprayed in its entirety for coating on 100 parts by mass of the bitter taste masking particles, followed by drying and classification using a 30M sieve to obtain overcoat particles. The cumulative 10% particle size (D 10 ) of the obtained overcoat particles, median diameter (D50 ) The cumulative 90% particle diameter (D 90 ) and the sharpness index were 103 μm, 131 μm, 163 μm, and 1.26, respectively. The average thickness of the overcoat layer was 1.5 μm. Table 2 shows the actual charge amount for obtaining the overcoat particles.

[0165]

Table 2

[0166] [Film-forming process (mixing process)] As the film-forming process, 3 parts by mass of talc a was mixed with 100 parts by mass of the classified overcoat particles and charged into a shelf-type constant temperature and humidity chamber. It was heated at 60 °C and 45% RH for about 480 minutes, classified with a 30M sieve, and drug particles (spherical granules) were obtained. An SEM photograph (50 times) of the drug particles (spherical granules) is shown in Figure 3, and an SEM photograph (300 times) of the drug particles (spherical granules) is shown in Figure 4. Table 3 shows the actual charge amount in the mixing process with talc a (for obtaining the drug particles).

[0167]

Table 3

[0168] [Granulation process of fast-disintegrating particles] 49.7 parts by mass of D-mannitol a, 21.3 parts by mass of D-mannitol b, 2 parts by mass of ethyl cellulose a, and 1 part by mass of light anhydrous silicic acid were charged into a fluidized bed granulator dryer. 20 parts by mass of corn starch and 6 parts by mass of partially pregelatinized starch were dispersed in purified water, and this solution was sprayed for granulation, then dried, classified with a 30M sieve, and fast-disintegrating particles with a central particle diameter (D 50 ) of 59 μm were obtained. Table 4 shows the actual charge amount for obtaining the fast-disintegrating particles.

[0169]

Table 4

[0170] [Mixing and Tableting Process] In addition to the drug particles and rapidly disintegrating particles obtained in the above process, aspartame, D-mannitol b, light anhydrous silicic acid, and magnesium stearate were mixed and rotary tableted to obtain orally disintegrating tablets (OD tablets). The hardness of the obtained OD tablets (tablet diameter 7.0 mm, tablet weight 135 mg) was 58 N, and the disintegration time was 15 seconds. The actual charge amounts for obtaining the OD tablets are shown in Table 5.

[0171]

Table 5

[0172] Example 2 [Coating Process of Intermediate Layer] The bepotastine spherical drug substance (drug core) obtained in Example 1 was charged into a fluidized bed granulator / dryer. With respect to 100 parts by mass of the drug core part, 13.9 parts by mass of hydroxypropyl cellulose a was dissolved in purified water, and a dispersion liquid in which 36.1 parts by mass of talc a was dispersed was spray-coated in its entirety, followed by drying and classification through a 30M sieve to obtain intermediate layer-coated particles. The cumulative 10% particle diameter (D 10 ), median particle diameter (D 50 ), cumulative 90% particle diameter (D 90 ), and sharpness index of the intermediate layer-coated particles were 101 μm, 119 μm, 140 μm, and 1.18, respectively. The average thickness of the intermediate layer was 4.5 μm. The actual charge amounts for obtaining the intermediate layer-coated particles are shown in Table 6.

[0173]

Table 6

[0174] [Coating Process of Masking Layer] The intermediate layer coating particles were charged into a tumbling fluidized bed granulation dryer. With respect to 100 parts by mass of the intermediate layer coating particles, 12.88 parts by mass of a highly water-permeable polymer, 30.05 parts by mass of a low water-permeable polymer, and 2.26 parts by mass of hydroxypropyl cellulose b were dissolved in a mixed solution of purified water and ethanol, and the entire amount of a dispersion liquid in which 21.47 parts by mass of talc a was dispersed was spray-coated. After drying and classification with a 30M sieve, bitter taste masking particles were obtained. The cumulative 10% particle size (D 10 ), the median particle size (D 50 ), the cumulative 90% particle size (D 90 ) and the sharpness index of the bitter taste masking particles were 122 μm, 139 μm, 160 μm and 1.15, respectively. The average thickness of the masking layer was 10 μm. Table 7 shows the actual amounts charged for obtaining the bitter taste masking particles.

[0175] [Table 7]

[0176] [Coating process of overcoat layer] The bitter taste masking particles were charged into a tumbling fluidized bed granulation dryer. With respect to 100 parts by mass of the bitter taste masking particles, a solution in which 15 parts by mass of D-mannitol a was dissolved in purified water was spray-coated in its entirety. After drying and classification with a 30M sieve, overcoat particles were obtained. The cumulative 10% particle size (D 10 ), the median particle size (D 50 ), the cumulative 90% particle size (D 90 ) and the sharpness index of the obtained overcoat particles were 128 μm, 147 μm, 171 μm and 1.16, respectively. The average thickness of the overcoat layer was 4 μm. Table 8 shows the actual amounts charged for obtaining the overcoat particles.

[0177] [Table 8]

[0178] [Film-forming process (mixing process)] As a film-forming process, 3 parts by mass of talc a was mixed with 100 parts by mass of classified overcoat particles and charged into a shelf-type thermo-hygrostat. It was heated at 60 °C and 45% RH for about 480 minutes, classified with a 30M sieve, and drug particles (spherical granules) were obtained. Table 9 shows the actual charged amounts in the mixing treatment with talc a (for obtaining drug particles).

[0179]

Table 9

[0180] [Mixing and tableting process] In addition to the drug particles obtained in the above process and the rapidly disintegrating particles obtained in Example 1, aspartame, D-mannitol b, light anhydrous silicic acid, and magnesium stearate were mixed and rotary tableted to obtain orally disintegrating tablets (OD tablets). The hardness of the obtained OD tablets (tablet diameter 7.0 mm, tablet weight 135 mg) was 50 N, and the disintegration time was 17 seconds. Table 10 shows the actual charged amounts for obtaining OD tablets.

[0181]

Table 10

[0182] Comparative Example 1 [Granulation process of spherical core part] Vepotastine raw drug (central particle diameter 19 μm, sharpness index 2.36) and D-mannitol a were charged into a fluidized bed granulator dryer. A solution prepared by dissolving polyvinyl alcohol and D-mannitol a in purified water was sprayed in its entirety for granulation, followed by drying and classification with a 30M sieve to obtain non-spherical granulated powder (drug nuclei). The cumulative 10% particle diameter (D 10 ), central particle diameter (D 50 ), cumulative 90% particle diameter (D 90) And the sharpness index was 17 μm, 40 μm, 77 μm, and 2.14, respectively. For the measurement of the median particle diameter of the raw drug and granulated powder, a laser diffraction particle size distribution analyzer (manufactured by Nikkiso Co., Ltd., trade name "AEROTRAC SPR Model 7340") was used instead of the laser diffraction particle size distribution analyzer (manufactured by Malvern Panalytical, trade name "Mastersizer 3000"). Table 11 shows the actual amounts charged to obtain the granulated powder.

[0183]

Table 11

[0184] [Coating process of the masking layer] The granulated powder was put into a fluidized bed granulator / dryer. 16 parts by mass of ethylcellulose b was dissolved in a mixed solution of purified water and ethanol, and a dispersion liquid in which 8 parts by mass of talc b was dispersed was sprayed in its entirety for coating. After that, it was dried and classified with a 30M sieve to obtain bitter taste masking particles (spherical granules). The cumulative 10% particle diameter (D 10 ), median particle diameter (D 50 ), cumulative 90% particle diameter (D 90 ) and sharpness index of the obtained bitter taste masking particles were 28 μm, 80 μm, 144 μm, and 2.33, respectively. For the measurement of the median particle diameter of the bitter taste masking particles, a laser diffraction particle size distribution analyzer (manufactured by Nikkiso Co., Ltd., trade name "AEROTRAC SPR Model 7340") was used instead of the laser diffraction particle size distribution analyzer (manufactured by Malvern Panalytical, trade name "Mastersizer 3000"). Fig. 5 shows an SEM photograph (50 times) of the bitter taste masking particles (non-spherical granules), and Fig. 6 shows an SEM photograph (300 times) of the bitter taste masking particles (non-spherical granules). Table 12 shows the actual amounts charged to obtain the bitter taste masking particles.

[0185]

Table 12

[0186] [Granulation process of fast-disintegrating particles] 34.2 parts by mass of D-mannitol a, 35 parts by mass of D-mannitol b, and 4 parts by mass of ethylcellulose a were charged into a fluidized bed granulation dryer. 24 parts by mass of corn starch and 2.8 parts by mass of crospovidone were dispersed in purified water, and this solution was sprayed for granulation, followed by drying and classification at 30M to obtain fast-disintegrating particles. Then, this operation was repeated twice to obtain fast-disintegrating particles with a median particle diameter (D 50 ) of 102 μm. For the measurement of the median particle diameter of the fast-disintegrating particles, a continuous fully automatic dry sonic sieve shaker (manufactured by Seishin Enterprise Co., Ltd., trade name "Robot Shifter RPS-205") was used instead of a laser diffraction particle size distribution analyzer (manufactured by Malvern, trade name "MasterSizer 3000"). Table 13 shows the actual amounts charged for obtaining the fast-disintegrating particles.

[0187] [Table 13]

[0188] [Preparation of menthol powder for dilution] D-mannitol a and L-menthol were pulverized in a dry granulator (screen diameter 1016 μm), and then further pulverized in a dry granulator (screen diameter 457 μm) to obtain a powder for dilution of menthol. Table 14 shows the actual amounts charged for obtaining the powder for dilution of menthol.

[0189] [Table 14]

[0190] [Mixing and tableting process] In addition to the bitter masking particles, fast-disintegrating particles, and menthol powder for dilution obtained in the above process, aspartame, D-mannitol a, light anhydrous silicic acid, and magnesium stearate were mixed and tabletted to obtain OD tablets. The hardness of the obtained OD tablets (tablet diameter 9.0 mm, tablet weight 270 mg) was 62 N, and the disintegration time was 25 seconds. Table 15 shows the actual amounts charged for obtaining the OD tablets.

[0191]

Table 15

[0192] The bitterness of the OD tablets obtained in Example 1 and the OD tablets obtained in Comparative Example 1 was evaluated and compared, and the results are shown in Fig. 7. As is clear from Fig. 7, while the OD tablets obtained in Comparative Example 1 immediately felt bitterness after administration, the OD tablets obtained in Example 1 did not feel bitterness for at least 10 minutes.

Industrial Applicability

[0193] Since the spherical granules of the present invention contain bepotastine or a salt thereof as an active ingredient, they can be effectively used as a therapeutic agent for allergic rhinitis, urticaria, cutaneous pruritus and the like.

Claims

1. A spherical granule formed of a spherical nucleus portion containing bepotastine or a salt thereof, and a coating portion covering the spherical nucleus portion and containing a water-insoluble polymer.

2. The cumulative 50% particle diameter (D ５０ ) of the spherical granules according to claim 1 is 250 μm or less.

3. The cumulative 50% particle size (D ５０ ) of the spherical granules according to claim 1 is 200 μm or less.

4. The spherical granule according to any one of Claims 1 to 3, wherein the proportion of the bepotastine or a salt thereof is 20 to 80% by mass in the spherical granule.

5. The spherical granule according to any one of Claims 1 to 3, wherein the water-insoluble polymer contains at least one selected from the group consisting of (meth)acrylic resins, vinyl resins, and cellulose derivatives.

6. The spherical granule according to any one of Claims 1 to 3, wherein the water-insoluble polymer contains a (meth)acrylic polymer having an ammoniomethacrylate unit.

7. The spherical granule according to Claim 6, wherein the (meth)acrylic polymer is a combination of a high water permeability polymer having an ammoniomethacrylate unit proportion of 7.5% by mass or more and a low water permeability polymer having an ammoniomethacrylate unit proportion of less than 7.5% by mass, and the mass ratio of the high water permeability polymer to the low water permeability polymer is former / latter = 10 / 90 to 90 / 10.

8. The spherical granule according to Claim 6, wherein the masking layer further contains an inorganic compound, and the proportion of the inorganic compound is 100 parts by mass or less with respect to 100 parts by mass of the (meth)acrylic polymer.

9. The spherical granule according to any one of Claims 1 to 3, wherein the proportion of the bepotastine or a salt thereof is 50% by mass or more in the spherical nucleus portion.

10. The spherical granule according to any one of Claims 1 to 3, wherein the spherical nucleus portion is spherical particles of bepotastine or a salt thereof.

11. The spherical granule according to Claim 9, wherein the sphericity of the spherical nucleus portion is 0.6 or more.

12. The spherical granule according to any one of Claims 1 to 3, wherein the coating portion further includes an intermediate layer interposed between the spherical nucleus portion and the masking layer.

13. A method for producing a spherical granule containing bepotastine or a salt thereof, the method including a nucleus formation step of forming a spherical nucleus portion containing bepotastine or a salt thereof, and a coating step of coating the obtained spherical nucleus portion with a coating portion including a masking layer containing a water-insoluble polymer to obtain a spherical granule.

14. An oral preparation containing the spherical granule according to Claim 1.

15. The oral preparation according to Claim 14, which is an orally disintegrating tablet.

16. A method for suppressing bitterness by forming spherical granules contained in an oral preparation with a globus pallidus part containing bepotastine or a salt thereof and a coating part covering the globus pallidus part and containing a water-insoluble polymer, without impairing the swallowability and disintegrability of the oral preparation.

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