Chewable tablet manufacturing method

Abstract

To provide chewable tablets that have a refreshing feeling and the like imparted by menthol, are easy to take, and have an excellent appearance due to the suppression of the formation of holes on the surface of the chewable tablets.SOLUTION: Provided is a chewable tablet containing: ingredient (A) menthol; and ingredient (B) at least one inorganic powder selected from the group consisting of synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminometasilicate, calcium silicate, calcium hydrogen phosphate, hydrous silicon dioxide, and light anhydrous silicic acid, the content of ingredient (A) per tablet being 0.01 to 10 mg, and the mass ratio represented by ingredient (B) / ingredient (A) being 0.1 or more.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to chewable tablets, their manufacturing method, co-milled products and tablets. [Background technology]

[0002] Menthol is a volatile component found in plants such as peppermint and mint, and is incorporated into pharmaceuticals and foods such as tablets as a fragrance or cooling agent that imparts a cooling sensation, and as a flavoring agent that masks bitter components (Patent Document 1). Menthol generally exists in the form of large needle-like crystals, and therefore, when blending menthol into tablets or the like, it is sometimes subjected to pretreatment such as crushing (Patent Document 2). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Laid-Open No. 2016-216371 [Patent Document 2] Special Publication No. 2016-540019 Summary of the Invention [Problem to be solved by the invention]

[0004] However, as a result of investigations by the present inventors, it was found that tablets containing menthol, particularly film-coated tablets, have a problem in that menthol particles and the like fall off from the tablet surface during production, causing holes on the tablet surface and resulting in poor appearance.

[0005] An object of one aspect of the present invention is to provide a chewable tablet that has excellent swallowing properties due to the coolness and cooling sensation imparted by menthol, and that has excellent appearance due to the suppression of the formation of holes on the surface of the chewable tablet, and a method for producing the same. Another aspect of the present invention aims to provide a co-ground product that can produce tablets with excellent appearance by suppressing the generation of holes on the tablet surface, and tablets made using the same. [Means for solving the problem]

[0006] The present invention has the following aspects. [1] (A) ingredient: menthol, (B) component: at least one inorganic powder selected from the group consisting of synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminometasilicate, calcium silicate, calcium hydrogen phosphate, hydrous silicon dioxide, and light anhydrous silicic acid; Contains The content of the component (A) per tablet is 0.01 to 10 mg, The mass ratio of the component (B) to the component (A) is 0.1 or more. Chewable tablets. [2] The chewable tablet according to [1] above, which is a coated tablet having a coating layer on the surface of a plain tablet containing the component (A) and the component (B). [3] The chewable tablet of [1] or [2], wherein the mass ratio of the component (B) to the component (A) is 30 or less. [4] The chewable tablet according to any one of the above [1] to [3], wherein the average particle size of the component (B) is 1 to 200 μm. [5] The chewable tablet according to any one of [1] to [4] above, wherein the oil absorption of the component (B) is 0.5 mL / g or more. [6] A method for producing a chewable tablet according to any one of [1] to [5], The method comprises the steps of preparing a powder mixture containing the component (A) and the component (B), and compressing the powder mixture into tablets, A method for producing a chewable tablet, wherein the component (A) and the component (B) are co-ground in the step of preparing the powder mixture. [7] (A) ingredient: menthol, (B) component: at least one inorganic powder selected from the group consisting of synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminometasilicate, calcium silicate, calcium hydrogen phosphate, hydrous silicon dioxide, and light anhydrous silicic acid; and A co-ground product in which the mass ratio of the component (B) to the component (A) is 0.1 or more. [8] The co-ground product of [7] above, having an average particle size of 1 to 200 μm. [9] A tablet containing the co-ground product of [7] or [8].

[10] The tablet according to [9], which is a coated tablet having a coating layer on the surface of a core tablet containing the co-ground product. [Effects of the Invention]

[0007] According to one aspect of the present invention, it is possible to provide a chewable tablet that has excellent swallowing properties due to the cool feeling imparted by menthol, and that has excellent appearance due to the suppression of the formation of holes on the surface of the chewable tablet, and a method for producing the same. According to another aspect of the present invention, it is possible to provide a co-ground product that can suppress the occurrence of holes on the tablet surface and produce tablets with excellent appearance, and tablets made using the same. DETAILED DESCRIPTION OF THE INVENTION

[0008] In this specification and claims, the term "average particle size" refers to the volume average particle size (D50) measured in accordance with a laser diffraction particle size distribution measurement method. "Oil absorption" is measured in accordance with the pigment testing method of the Japanese Industrial Standards (JIS K 5101-13-2). The "specific surface area" is measured by a nitrogen adsorption isotherm according to the known BET method.

[0009] [Chewable tablets] A chewable tablet according to one embodiment of the present invention contains component (A) and component (B), the content of component (A) per tablet is 0.01 to 10 mg, and the mass ratio of component (B) to component (A) (hereinafter also referred to as "B / A ratio") is 0.1 or more. The chewable tablet may further contain other components (hereinafter also referred to as "optional components") other than component (A) and component (B) as needed, provided that the effects of the present invention are not impaired.

[0010] The chewable tablet may be a plain tablet containing component (A) and component (B), or may be a coated tablet having a coating layer on the surface of the plain tablet. Compared to plain tablets, coated tablets are more likely to have holes on the tablet surface due to the heat and impact during the coating process, such as the shedding of component (A) particles.The chewable tablet of this embodiment is preferably a coated tablet, as this significantly improves the appearance by preventing holes from occurring on the surface of the chewable tablet.

[0011] The plain tablet may be a monolayer tablet consisting of a single layer, or a multilayer tablet having two or more layers. A monolayer tablet is composed of a layer containing component (A) and component (B). A multilayer tablet has at least one layer containing component (A) and component (B). The layer containing component (A) and component (B) may further contain optional components. The coating layer will be described in detail later.

[0012] The dimensions of the chewable tablet are not particularly limited, but from the viewpoint of ease of handling and administration, the diameter φ of the chewable tablet is preferably 5 to 14 mm, more preferably 6 to 13 mm, and even more preferably 7 to 12 mm. The mass per chewable tablet is preferably 100 mg to 1000 mg. The shape of the chewable tablet is not particularly limited, but square flat tablets, round flat tablets, rounded R tablets, or two-stage R tablets are preferred.

[0013] The disintegration time of the chewable tablet in the mouth is preferably 60 to 400 seconds, more preferably 60 to 300 seconds. The disintegration time can be measured by the method described in the Examples below.

[0014] The strength of a chewable tablet is set according to the tablet size as a chewable tablet, but for example, in the case of a φ9.5 mm two-stage R tablet, the strength is preferably in the range of 3 to 15 kgf, more preferably 4 to 14 kgf, and even more preferably 5.5 to 13 kgf. The strength of the chewable tablet can be measured, for example, by a tablet hardness tester (PTB111E-500 manufactured by PHARMATEST Co., Ltd.) When the chewable tablet is a coated tablet, the strength is measured on the chewable tablet after coating.

[0015] <Component (A)> Component (A) is menthol. The component (A) may be in the d-, l- or dl-form, but the l- or dl-form is preferred, with the l-form being more preferred.

[0016] The average particle size of component (A) is preferably 1 to 200 μm, more preferably 1 to 150 μm, and even more preferably 1 to 100 μm. If the average particle size of component (A) is at least the lower limit, the handleability of component (A) in the chewable tablet production process (for example, the co-grinding process described below) is improved, and if it is at most the upper limit, the effect of suppressing pitting on the surface of the chewable tablet is improved.

[0017] The content of component (A) per chewable tablet is 0.01 to 10 mg, preferably 0.1 to 10 mg. If the content of component (A) is equal to or greater than the lower limit, a sufficient cooling sensation is imparted and ease of administration is improved, whereas if the content is equal to or less than the upper limit, the irritation and bitterness derived from component (A) are reduced and ease of administration is improved.

[0018] The proportion of component (A) relative to the total mass of the chewable tablet is preferably 0.01 to 10% by mass, more preferably 0.1 to 5% by mass. If the proportion of component (A) is equal to or greater than the lower limit, a sufficient cooling sensation is imparted and ease of administration is improved, whereas if it is equal to or less than the upper limit, the irritation and bitterness derived from component (A) are reduced and ease of administration is improved.

[0019] <(B) component> Component (B) is at least one inorganic powder selected from the group consisting of synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminometasilicate, calcium silicate, calcium hydrogen phosphate, hydrous silicon dioxide, and light anhydrous silicic acid. Calcium hydrogen phosphate may be a hydrate or anhydrous. These inorganic powders may be used alone or in combination of two or more. Among the above, as component (B), synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminometasilicate, calcium silicate, hydrous silicon dioxide, and light anhydrous silicic acid are preferred, with hydrous silicon dioxide and light anhydrous silicic acid being more preferred, in terms of further improving the effect of inhibiting holes from passing through the surface of the chewable tablet. Among the components (B), synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminometasilicate, and calcium hydrogen phosphate also act as physiologically active components. Of the components (B), hydrated silicon dioxide and light anhydrous silicic acid also function as lubricants.

[0020] The average particle size of component (B) is preferably 1 to 200 μm, more preferably 1 to 150 μm, and even more preferably 1 to 100 μm. If the average particle size of component (B) is at least the lower limit, the handleability of component (B) in the chewable tablet production process (for example, the co-grinding process described below) is improved, and if it is at most the upper limit, the chewable tablet will have less roughness when chewed in the oral cavity, improving ease of administration and improving the effect of suppressing holes in the surface of the chewable tablet.

[0021] The oil absorption of component (B) is preferably 0.5 mL / g or more, more preferably 0.8 mL / g or more, and even more preferably 1.2 mL / g or more. When the oil absorption of component (B) is equal to or greater than the lower limit mentioned above, the effect of suppressing the occurrence of holes on the surface of the chewable tablet is more excellent. There is no particular upper limit to the oil absorption of component (B), but it is, for example, 10 mL / g.

[0022] The specific surface area of ​​component (B) is 1m 2 / g or more is preferable, and 30m2 / g or more is more preferable, and 100m 2 When the specific surface area of ​​component (B) is equal to or greater than the lower limit mentioned above, the effect of suppressing the occurrence of holes on the surface of the chewable tablet is more excellent. The upper limit of the specific surface area of ​​component (B) is not particularly limited, but is, for example, 1000 m 2 / g.

[0023] It is preferred that at least a portion of component (B) is co-ground with component (A), which improves the effect of suppressing the occurrence of holes on the surface of the chewable tablet.

[0024] The content of component (B) per chewable tablet is preferably 0.1 to 100 mg, more preferably 0.0.2 to 50 mg, and even more preferably 0.5 to 20 mg. If the content of component (B) is equal to or greater than the lower limit, the effect of suppressing the occurrence of pitting on the surface of the chewable tablet and the effect of suppressing adhesion of component (A) to equipment during the co-grinding process with component (A) are improved, and if the content is equal to or less than the upper limit, the chewable tablet will have less roughness when chewed in the oral cavity and will be easier to take.

[0025] The proportion of component (B) relative to the total mass of the chewable tablet is preferably 0.01 to 50% by mass, more preferably 0.05 to 30% by mass, and even more preferably 0.1 to 20% by mass. If the proportion of component (B) is at least the lower limit, the effect of suppressing the occurrence of pitting on the surface of the chewable tablet and the effect of suppressing adhesion of component (A) to equipment during the co-grinding process with component (A) are improved, while if it is at most the upper limit, the chewable tablet will have less roughness when chewed in the oral cavity and will be easier to take.

[0026] The B / A ratio is 0.1 or more, preferably 0.2 or more, and more preferably 0.5 or more. When the B / A ratio is equal to or greater than the lower limit, the occurrence of holes on the surface of the chewable tablet can be suppressed. Furthermore, the adhesion of component (A) to the equipment during the co-grinding process of component (A) and component (B) can be suppressed. ​Furthermore, the B / A ratio is preferably not more than 50, more preferably not more than 30, even more preferably not more than 20, and even more preferably not more than 10. When the B / A ratio is not more than the upper limit, the chewable tablet becomes less rough when chewed in the oral cavity and taken, improving ease of taking.

[0027] <Optional ingredients> Optional components include known physiologically active ingredients and additives. Examples of additives include binders, excipients, disintegrants, lubricants, acidulants, sweeteners, colorants, flavorings, coating agents, etc. These optional components may be used alone or in combination of two or more. The amount of these optional components can be appropriately determined depending on the purpose, as long as it does not interfere with the effects of the present invention.

[0028] Physiologically active ingredients include loperamide and its pharmaceutically acceptable salts (such as loperamide hydrochloride), berberine tannate, Scopolia extract, acrinol, peony, Corydalis root, licorice, phenyl salicylate, guaiacol, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth subgallate, berberine chloride, creosote, albumin tannate, sodium azulene sulfonate, ursodeoxycholic acid, bile powder, bile extract, and dehydrocholic acid. Examples of suitable herbal extracts include turmeric, Phellodendron bark, Scutellaria root, precipitated calcium carbonate, sodium bicarbonate, calcium lactate, Acacia herb, Ubai, Geranium herb, Chinese gallnut, Hawthorn, Sophora root, Swertia japonica, Chinese laurel, Magnolia bark, Mallotus japonicus, sodium azulene sulfonate, aldioxa, sucralfate hydrate, glycyrrhizic acid and its salts, ibuprofen, aspirin, acetaminophen, loxoprofen sodium hydrate, anhydrous caffeine, live bacterial components, and herbal medicines. The method for extracting herbal medicines is not particularly limited, and they can be used not only as bulk powders but also as processed raw materials such as liquid extracts, dry extracts, and tinctures. The physiologically active ingredients may be granulated using excipients, binders, disintegrants, lubricants, etc. to form active ingredient granules. As the physiologically active ingredient, from the viewpoint of improving the flavor masking property of component (A), preferred are herbal powders, extracts, and dried extracts such as loperamide and pharmaceutically acceptable salts thereof, ursodeoxycholic acid, bile powder, bile extract, anhydrous caffeine, turmeric powder, peony powder, turmeric extract, peony extract, dried peony extract, and dried turmeric extract.

[0029] The content of the physiologically active ingredient per chewable tablet is set according to the type of physiologically active ingredient. For example, the content of loperamide hydrochloride per chewable tablet is preferably 0.1 to 2 mg, more preferably 0.2 to 1 mg. The content of turmeric powder per chewable tablet is preferably 10 to 2,000 mg, more preferably 50 to 700 mg. The content of turmeric extract (equivalent to the crude drug) per chewable tablet is preferably 100 to 6,000 mg, more preferably 200 to 3,000 mg. The content of ursodeoxycholic acid per chewable tablet is preferably 4 mg to 60 mg. The content of bile powder per chewable tablet is preferably 100 mg to 1,500 mg. The content of bile extract (powder) per chewable tablet is preferably 30 mg to 500 mg. The content of anhydrous caffeine per chewable tablet is preferably 5 mg to 500 mg, the content of peony powder per chewable tablet is preferably 60 mg to 2000 mg, and the content of peony extract per chewable tablet (equivalent to the amount of crude drug) is preferably 160 mg to 5000 mg.

[0030] Examples of binders include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, gum arabic, pregelatinized starch, sodium alginate, carboxyvinyl polymer, agar, honey, etc. Among these, polyvinyl alcohol, hydroxypropyl cellulose, and methyl cellulose are preferred from the viewpoints of tablet properties and stability of physiologically active ingredients.

[0031] The proportion of the binder relative to the total mass of the chewable tablet is preferably 0.01 to 30% by mass, more preferably 0.1 to 10% by mass. If the proportion of the binder is equal to or greater than the lower limit, the hardness of the chewable tablet is improved, and the effect of suppressing the occurrence of holes on the surface of the chewable tablet, as well as the chewing comfort and stability, are improved. If the proportion of the binder is equal to or less than the upper limit, the chewable tablet is improved in terms of ease of chewing and disintegration, and the ease of taking it is improved.

[0032] Examples of excipients include crystalline cellulose, lactose, sugar alcohols (mannitol, erythritol, xylitol, lactitol, maltitol, sorbitol, etc.), trehalose, methylethylcellulose, dextrin, cyclodextrin, hydroxypropyl starch, corn starch, potato starch, etc.

[0033] As excipients, sugar alcohols, corn starch, and crystalline cellulose are preferred. These may be used alone or in combination of two or more. From the viewpoint of achieving both ease of administration and tablet strength, it is preferable to use two or more of sugar alcohols, corn starch, and crystalline cellulose in combination, and it is more preferable to use three of them in combination.

[0034] Sugar alcohols are used to provide a cooling sensation when taken, improving ease of administration. The sugar alcohols may be used alone or in combination of two or more. Among sugar alcohols, sorbitol has a lower critical relative humidity and higher hygroscopicity than other sugar alcohols, and when sorbitol is contained in a plain tablet, problems such as adhesion to the mortar and pestle or tablet press and sticking often occur during tableting. Therefore, the sugar alcohol contained in the chewable tablet is preferably a sugar alcohol other than sorbitol, and the proportion of sorbitol relative to the total mass of the chewable tablet is preferably 5% by mass or less, and preferably 0.1% by mass or less, so that it is substantially absent. Preferred sugar alcohols other than sorbitol are mannitol, erythritol, xylitol, and lactitol. The proportion of sugar alcohol to the total mass of the chewable tablet is preferably 5 to 90% by mass, more preferably 10 to 80% by mass. If the proportion of sugar alcohol is equal to or greater than the lower limit, a sufficient cooling sensation can be imparted, and if it is equal to or less than the upper limit, the moldability of the chewable tablet is improved.

[0035] Corn starch is used to reduce adhesion to manufacturing equipment during tableting. The proportion of corn starch relative to the total mass of the chewable tablet is preferably 0.1 to 20% by mass, more preferably 1 to 10% by mass. If the proportion of corn starch is equal to or greater than the lower limit, adhesion to manufacturing equipment during tableting can be sufficiently reduced, and if it is equal to or less than the upper limit, powdery feeling in the mouth when taken can be suppressed.

[0036] Microcrystalline cellulose is used to increase the hardness of chewable tablets. The proportion of crystalline cellulose relative to the total mass of the chewable tablet is preferably 1 to 80% by mass, more preferably 5 to 50% by mass. If the proportion of crystalline cellulose is equal to or greater than the lower limit, the hardness of the chewable tablet is improved and the chewing comfort is improved, while if it is equal to or less than the upper limit, the powdery feeling in the oral cavity when taken can be suppressed.

[0037] Examples of disintegrants include low-substituted hydroxypropyl cellulose, carmellose, carmellose sodium, carmellose calcium, crospovidone, croscarmellose sodium, partially pregelatinized starch, sodium starch glycolate, etc. Among these, crospovidone is preferred in terms of its non-runny feel in the oral cavity when taken and its disintegrating properties. The proportion of the disintegrant relative to the total mass of the chewable tablet is preferably 0.1 to 30% by mass, more preferably 0.2 to 20% by mass. If the proportion of the disintegrant is equal to or greater than the lower limit, the tablet will not feel runny in the oral cavity when taken and disintegration properties will be improved, while if the proportion is equal to or less than the upper limit, a hardness that allows for good chewability will be ensured.

[0038] Examples of lubricants include magnesium stearate, calcium stearate, sodium stearyl fumarate, sucrose fatty acid esters, talc, etc. Among these, magnesium stearate and calcium stearate are preferred in terms of improving the fluidity of the powder mixture before tableting. The proportion of the lubricant relative to the total mass of the chewable tablet is preferably 0.01 to 5% by mass, more preferably 0.05 to 2% by mass. If the proportion of the lubricant is equal to or greater than the lower limit, the fluidity of the powder mixture to be compressed into tablets is improved, and if it is equal to or less than the upper limit, a hardness that allows for good chewability can be ensured.

[0039] Examples of the acidulant include organic acids such as citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, and salts thereof. Among these, citric acid (hydrate), tartaric acid, and malic acid are preferred because they improve the stability of physiologically active ingredients such as loperamide hydrochloride. The proportion of the acidulant relative to the total mass of the chewable tablet is preferably 0.01 to 10% by mass, more preferably 0.05 to 8% by mass. When the proportion of the acidulant is equal to or greater than the lower limit, the stability of physiologically active ingredients such as loperamide hydrochloride is improved. Furthermore, when the proportion of the acidulant is within the above range, a moderate sour taste is felt, improving ease of administration.

[0040] Examples of sweeteners include aspartame, sucralose, acesulfame potassium, stevia, refined white sugar, saccharin, glycyrrhizin, etc. Among these, aspartame, sucralose, and acesulfame potassium are preferred because they can mask the bitterness of physiologically active ingredients (bitter drugs) that have a bitter taste, such as turmeric dried extract. The ratio of the sweetener to the total mass of the chewable tablet is preferably 0.01 to 20% by mass, more preferably 0.1 to 10% by mass. If the ratio of the sweetener is equal to or greater than the lower limit, the bitter-tasting drug is masked, improving ease of administration. If the ratio is equal to or less than the upper limit, there is no unpleasant aftertaste of sweetness.

[0041] Examples of coloring agents include titanium oxide, iron sesquioxide, yellow iron sesquioxide, Yellow No. 5, Yellow No. 4, and the like. The proportion of the colorant relative to the total mass of the chewable tablet is, for example, 0.1 to 5% by mass.

[0042] As the fragrance, powdered fragrances can be suitably used, and examples thereof include powdered fragrances obtained by triturating limonene and plant essential oils (peppermint oil, mint oil, lychee oil, orange oil, lemon oil, etc.) with gum arabic, dextrin, etc. The proportion of the flavoring agent relative to the total mass of the chewable tablet is, for example, 0.1 to 3% by mass.

[0043] <Coating layer> The coating layer is a layer formed from a constituent material containing a coating agent. The coating agent is not particularly limited as long as it does not impair the ease of taking the chewable tablet, and examples thereof include water-soluble polymer compounds, plasticizers, colorants, and flavoring agents.

[0044] Examples of water-soluble polymer compounds include celluloses such as carmellose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxymethyl cellulose, methyl cellulose, and ethyl cellulose; gum arabic, carboxyvinyl polymer, povidone, crospovidone, polyvinyl alcohol, polyacrylic acid, monosaccharides, disaccharides or higher polysaccharides (lactose, maltose, xylose, isomerized lactose, alginic acid and its salts, pectin, etc.), sugar alcohols (palatinite, lactitol, erythritol, xylitol, reduced starch hydrolyzates, maltitol, mannitol, lactitol, etc.), starch syrup, isomerized sugars, oligosaccharides, sucrose, and trehalose.

[0045] Examples of plasticizers include macrogol, glycerin, triethyl citrate, triacetin, sucrose fatty acid esters, and the like, which are listed in official compendia such as the Japanese Pharmacopoeia (Hirokawa Shoten) and the Pharmaceutical Additives Standards (Yakuji Nipposha Co., Ltd.). Examples of coloring agents include titanium oxide, talc, iron sesquioxide, yellow iron sesquioxide, Yellow No. 5, Yellow No. 4 (or aluminum lake), and the like. Examples of flavoring agents include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid and salts thereof, aspartame, sucralose, acesulfame potassium, stevia, refined white sugar, saccharin, glycyrrhizin, and the like. The component (A) may be contained in the coating layer as a flavoring agent.

[0046] The coating agent can be used alone or in combination of two or more. Alternatively, commercially available premixed products such as Opadry (manufactured by Colorcon Japan LLC) may be used. The coating agent preferably contains a water-soluble polymer compound, and more preferably contains hydroxypropylmethylcellulose, in that the coating layer is less likely to remain in the oral cavity when taken.

[0047] The content of the coating agent is preferably 0.1 to 20% by mass, more preferably 0.2 to 10% by mass, relative to the total mass of the chewable tablet. When the content of the coating agent is equal to or greater than the lower limit, a chewable tablet with a chewable feel can be obtained. In addition, the stability of the active ingredient and the masking effect of bitter-tasting drugs are improved. When the content of the coating agent is equal to or less than the upper limit, the coating process time is shortened, thereby further suppressing the formation of holes on the surface of the chewable tablet.

[0048] <Chewable tablet manufacturing method> The chewable tablet described above can be produced, for example, by a manufacturing method including a step of preparing a powder mixture containing component (A) and component (B) (powder preparation step) and a step of tableting the powder mixture obtained in the powder preparation step (tabletting step). The powder mixture may further contain optional components, if necessary. After the tableting step, if necessary, a step of forming a coating layer on the surface of the uncoated tablets obtained in the tableting step (coating step) may be further included.

[0049] <Powder preparation process> The components (A), (B), and optional components may be obtained by known production methods or may be commercially available. Furthermore, each component may be used as a bulk powder or may be granulated. When granulated components are used, known granulation methods, such as fluidized bed granulation, agitation granulation, and extrusion granulation, can be used.

[0050] In the powder preparation step, the components can be mixed together or sequentially to form a powder mixture. From the viewpoint of more effective prevention of hole formation on the surface of the chewable tablet, it is preferable that at least component (A) is pulverized, and it is more preferable that components (A) and (B) are pulverized. It is even more preferable that the powder mixture contains a co-pulverized product of components (A) and (B). If necessary, optional components may be pulverized together with components (A) and (B). If necessary, the ground product or co-ground product may be mixed with optional ingredients.

[0051] Methods for co-pulverizing component (A) and component (B), and optional components as needed, include conventionally known pulverization methods, but pulverization methods using a fine pulverizer or agitator granulator are preferred, and pulverization methods that apply shear force to the powder or that allow heating are more preferred. Examples include pulverization methods using a fine pulverizer such as a stone mill (manufactured by West Co., Ltd.), a pin mill (manufactured by Powrex Corporation), an atomizer (Dalton Co., Ltd.), or a Wonder Crusher (Osaka Chemical Co., Ltd.), and pulverization methods using a pulverizer (Vertical Granulator VG-25, Powrex Corporation) while heating externally using a jacket or the like.

[0052] In a fine pulverization method in which shearing force is applied to the powder, heat is generated during pulverization. The temperature of the powder during pulverization may rise above the melting point of component (A) (42 to 44°C), for example, to about 45 to 60°C. Pulverization conditions using a stone mill include, for example, a grinding mill rotation speed of 50 rpm or more. Pulverization conditions using a pin mill include, for example, a disk rotation speed of 3000 rpm or more. Pulverization conditions using an atomizer include, for example, a disk rotation speed of 4000 rpm or more. The upper limit of these rotation speeds may be the upper limit allowed for manufacturing each device. The pulverization speed is, for example, 2 to 400 g / min. When component (A) and component (B) are co-milled, the temperature of the powder during milling is preferably set to the melting point of component (A) (42 to 44°C) or higher, and the temperature when heated externally is preferably, for example, 45 to 60°C. By maintaining the temperature within this range, the effect of suppressing the occurrence of holes on the surface of the chewable tablet and the effect of suppressing adhesion of component (A) to the equipment during the co-milling process with component (A) are improved. Examples of milling conditions (stirring conditions) include a stirring blade rotation speed of 100 rpm or more and a crushing blade rotation speed of 500 rpm or more. The milling time is, for example, 3 to 60 minutes.

[0053] When mixing the co-ground product with optional components, the mixing method is not particularly limited, and includes conventionally known powder mixing methods. For example, mixing can be performed using a commonly used mixer. Examples of mixers include a Bohle Container Mixer (manufactured by Kotobuki Industries Co., Ltd.), a V-type mixer (manufactured by Dalton Co., Ltd.), and a ribbon mixer (manufactured by Dalton Co., Ltd.). All components can be charged into a mixing container and mixed, or some components can be mixed and then the other components can be sequentially charged and mixed.

[0054] Methods for grinding only component (A) and methods for co-grinding component (A) and optional components include methods similar to the co-grinding described above, but it is preferable to keep the powder temperature below the melting point of component (A) during grinding, for example, by cooling from the outside to keep the product temperature at 40°C or less during grinding. Grinding conditions (stirring conditions) include, for example, a stirring blade rotation speed of 100 rpm or more and a crushing blade rotation speed of 500 rpm or more. The grinding time is, for example, 3 to 60 minutes. The average particle size of component (A) after pulverization is preferably 1 to 150 μm, more preferably 1 to 100 μm. If the average particle size of the pulverized product of component (A) is at least the lower limit, the pulverized product will be easier to handle in the tablet production process, and if it is at most the upper limit, the effect of suppressing pitting on the tablet surface will be improved.

[0055] <Tableting process> In the tableting step, the powder mixture obtained in the powder preparation step is tableted to obtain uncoated tablets. A known tablet press can be used for tableting, such as a rotary tablet press ("Libra 2" manufactured by Kikusui Seisakusho Co., Ltd.) Tableting conditions such as tableting pressure and rotation speed of the turntable are set appropriately.

[0056] As described above, the uncoated tablet may be a single-layer tablet consisting of a single layer, or a multi-layer tablet having two or more layers. When the uncoated tablet is a single-layer tablet, it can be produced by compressing the above-mentioned powder mixture. When the uncoated tablet is a multi-layer tablet, it can be produced, for example, by stacking the first layer with either the above-mentioned powder mixture or other powders (for example, powders of one or more optional ingredients) as the first layer and the other as the second layer, and then compressing and molding the first and second layers between an upper punch and a lower punch.

[0057] <Coating process> In the coating step, a coating layer is formed on the surface of the uncoated tablets obtained in the above-mentioned tabletting step. The coating step is a step that is carried out as needed for the purposes of improving the ease of administration and stability of the chewable tablet (suppressing the decomposition of physiologically active ingredients and maintaining the physical properties of the chewable tablet), imparting chewiness, etc. The coating layer can be formed by subjecting the uncoated tablets to a coating treatment with a coating agent. Conventional methods can be used to prepare the coating agent and perform the coating treatment, and for example, a pan-type coating device such as HC-FZ-LABO (manufactured by Freund Corporation) or Aquacoater (manufactured by Freund Corporation) can be used. First, the coating agent is dispersed in a solvent such as water, and a colorant or the like is added as needed to obtain a coating liquid. The coating liquid is then applied to the uncoated tablets by spraying or the like so as to coat them. The solvent components of the coating liquid are then dried to obtain coated tablets.

[0058] <Action and effect> In the chewable tablet of this embodiment, by containing component (A) and component (B) in the chewable tablet, the occurrence of holes on the surface of the chewable tablet is suppressed, resulting in an excellent appearance. In particular, by including a powder mixture in which component (A) and component (B) are co-ground in a chewable tablet, the occurrence of holes on the surface of the chewable tablet is further suppressed. For example, component (A) in a crystalline state may be crushed to be incorporated into a chewable tablet. If component (B) is not present, it is assumed that the crushed particles of component (A) present on the surface of the chewable tablet may be dislodged by impact, particularly the impact and heat during the coating process, resulting in holes. In this embodiment, the chewable tablet contains component (A) and component (B), and preferably, component (A) is adsorbed and supported by component (B) by co-grinding component (A) and component (B), which is presumably why the falling off of particles of component (A) etc. due to the effects of impact or heat is suppressed.

[0059] [Co-pulverized product] The co-ground product according to one embodiment of the present invention is a co-ground product of component (A) and component (B), and has a B / A ratio of 0.1 or more. The co-ground product of this embodiment may be a co-ground product of component (A), component (B), and an optional component. The component (A), the component (B), and the optional components are as described above.

[0060] The B / A ratio of the co-ground product is 0.1 or more, preferably 0.2 or more, and more preferably 0.5 or more. When the B / A ratio is equal to or greater than the lower limit, the occurrence of holes on the surface of tablets containing the co-ground product can be suppressed. Furthermore, adhesion of component (A) to equipment during the co-grounding process of component (A) and component (B) can be suppressed. The B / A ratio is preferably not more than 30, more preferably not more than 20, and even more preferably not more than 10. When the B / A ratio is not more than the upper limit, the amount of material to be processed during co-grinding is reduced, shortening the production time and improving productivity.

[0061] The content of the optional components in the co-ground product is, for example, 0 to 1000 parts by mass per 100 parts by mass of the total of the components (A) and (B).

[0062] The average particle size of the co-ground product is preferably 1 to 200 μm, more preferably 1 to 150 μm, and even more preferably 1 to 100 μm. If the average particle size of the co-ground product is at least the lower limit, the handleability of the co-ground product in the tablet production process (for example, the co-ground process described below) is improved, and if it is at most the upper limit, the effect of suppressing pitting on the tablet surface is improved.

[0063] The co-ground product of this embodiment can be produced by a method of co-grounding component (A) and component (B), and, if necessary, optional components. The co-grinding method may be the same as that described above.

[0064] 〔tablet〕 A tablet according to one embodiment of the present invention contains the co-ground product. If necessary, the tablet may further contain component (A) that has not been co-ground with component (B), component (B) that has not been co-ground with component (A), and optional components, within the scope that does not impair the effects of the present invention. The component (A), the component (B), and the optional components are as described above. The proportion of component (A) that is not co-milled with component (B) relative to the total mass of component (A) is preferably 20% by mass or less, more preferably 10% by mass or less, and may even be 0% by mass, in terms of the effect of suppressing pitting on the tablet surface. This does not apply when component (A) that is not co-milled with component (B) is milled separately.

[0065] The tablet may be a plain tablet containing the co-milled product, or a coated tablet having a coating layer on the surface of the plain tablet. Compared to plain tablets, coated tablets tend to be more susceptible to the occurrence of holes on the tablet surface due to the shedding of component (A) particles, etc., caused by heat and impact during the coating process. In view of the significant effect of improving the appearance by suppressing the occurrence of holes on the tablet surface, the tablet of this embodiment is preferably a coated tablet.

[0066] The plain tablet may be a single-layer tablet consisting of a single layer, or a multi-layer tablet having two or more layers. A single-layer tablet is composed of a layer containing a co-milled substance. A multi-layer tablet has at least one layer containing a co-milled substance. The coating layer is as described above.

[0067] The type of tablet is not particularly limited, and examples include chewable tablets, orally disintegrating tablets, effervescent tablets, etc. Chewable tablets and orally disintegrating tablets are preferred, with chewable tablets being particularly preferred, since component (A) can provide a refreshing feeling, a masking effect for bitter drugs, etc.

[0068] The dimensions of the tablet are not particularly limited in terms of the effects of the present invention and are appropriately selected depending on the type of tablet. For example, when the tablet is a chewable tablet, the preferred ranges of the tablet diameter φ and the mass per tablet are the same as those described above. The shape of the tablets is not particularly limited, but square flat tablets, round flat tablets, rounded R tablets, or two-stage R tablets are preferred.

[0069] The content of the co-ground material in the tablet is set so that the content of component (A) in the tablet is the desired value. The preferred content of component (A) is the same as that for chewable tablets. The preferred content of component (B), the preferred B / A ratio, and the preferred content of optional components are also the same as those for chewable tablets.

[0070] The tablet of this embodiment can be produced in the same manner as the chewable tablet described above.

[0071] <Action and effect> In the tablet of this embodiment, the occurrence of holes on the surface of the tablet is suppressed, resulting in an excellent appearance. The reason for this effect is not clear, but it is presumed that this is because component (A) is adsorbed to and supported by component (B) when components (A) and (B) are co-ground. For example, component (A) that exists in a crystalline state may be crushed to be incorporated into tablets. If component (B) is not present, it is assumed that the crushed particles of component (A) present on the tablet surface may be dislodged by impact, particularly the impact and heat applied during the coating process, causing holes. In this embodiment, by co-grinding the components (A) and (B), the component (A) is atomized and the component (A) is adsorbed and supported by the component (B), which is thought to have suppressed the falling off of particles of the component (A) and other components due to the effects of impact or heat. [Example]

[0072] The present invention will be described in detail below with reference to examples, but the present invention is not limited to the following description. Examples 1 and 18 are reference examples.

[0073] (Materials used) <Component (A)> l-Menthol, product name "Super Menthol 3003", manufactured by Nagaoka Jitsugyo Co., Ltd., in flake form of a few millimeters to a few centimeters.

[0074] <(B) component> Hydrous silicon dioxide (Fujisil): Product name "Fujisil", manufactured by Fuji Chemical Industry Co., Ltd. Hydrous silicon dioxide (Adsolider 102): Product name "Adsolider 102", manufactured by Freund Corporation. Light anhydrous silicic acid: Product name "Silysia 350", manufactured by Fuji Silysia Chemical Ltd. Magnesium aluminometasilicate: Product name "Neusilin UFL2", manufactured by Fuji Chemical Industry Co., Ltd. Synthetic aluminum silicate: Product name: "Synthetic aluminum silicate (S)", manufactured by Kyowa Chemical Industry Co., Ltd. Synthetic hydrotalcite: Product name "Alcamac SH", manufactured by Fuji Chemical Industry Co., Ltd. Calcium silicate: Product name "Fluorite R", manufactured by Tomita Pharmaceutical Co., Ltd. Anhydrous calcium hydrogen phosphate: Product name "Fujicalin SG", manufactured by Fuji Chemical Industry Co., Ltd. Calcium hydrogen phosphate hydrate: Grade "FF-100", manufactured by Kyowa Chemical Industry Co., Ltd. Table 1 shows the oil absorption, specific surface area, and average particle size of these components (B).

[0075] [Table 1]

[0076] <(B') component, optional component> Corn starch: Product name: "Pharmacopoeial Matsutani Dried Cornstarch", manufactured by Matsutani Chemical Industry Co., Ltd., average particle size: 18 μm. Loperamide hydrochloride: Product name: "Loperamide hydrochloride", manufactured by Shiono Chemical Co., Ltd. Erythritol: Product name: "Erythritol 50M", manufactured by Bussan Food Science Co., Ltd. D-Mannitol: Product name "Pearitol 200SD", manufactured by Rocket Japan Co., Ltd. D-Mannitol (2): Product name: "Pearitol 50C", manufactured by Rocket Japan Co., Ltd. Polyvinyl alcohol: Partially saponified, used in uncoated tablets, product name "GOHSENOL EG-05(P)", manufactured by Mitsubishi Chemical Corporation. Polyvinyl alcohol (2): Partially saponified, used in coating agents, product name "GOHSENOL EG-05 (PW)", manufactured by Mitsubishi Chemical Corporation. Hydroxypropyl cellulose, product name "HPC-L", manufactured by Nippon Soda Co., Ltd. Turmeric dried extract: Product name: "Turmeric dried extract", manufactured by Matsuura Pharmaceutical Co., Ltd. Turmeric powder: Product name: "Turmeric Powder", manufactured by Nippon Powder Pharmaceutical Co., Ltd. Turmeric extract: Product name: "Turmeric Extract-A", manufactured by Nippon Powder Pharmaceutical Co., Ltd. Ursodeoxycholic acid: Product name: "Ursodeoxycholic acid", manufactured by Zhongshan Belling Biotechnology Co., Ltd. Berberine tannate: Product name: "Berberine tannate", manufactured by Alps Pharmaceutical Industries Co., Ltd. Scopolia Extract Triple Powder: Product name: "Scoliosis Extract Triple Powder C", manufactured by Alps Pharmaceutical Industries Co., Ltd. Peony dried extract: Product name: "Peony dried extract", manufactured by Nippon Powder Pharmaceutical Co., Ltd. Anhydrous caffeine: Product name: "Anhydrous Caffeine 0.2 / 0.5", manufactured by Shiratori Pharmaceutical Co., Ltd. Irofecoxib sodium dihydrate: Product name: "Irofecoxib sodium dihydrate", manufactured by Yamato Pharmaceutical Industry Co., Ltd. Acetaminophen: Product name: Piretinol, manufactured by Iwaki Pharmaceutical Co., Ltd. Light anhydrous silicic acid: Product name "Silysia 350", manufactured by Fuji Silysia Chemical Ltd. Crospovidone: Product name "Kollidon CL-SF", manufactured by BASF Japan Ltd. Citric acid hydrate: Product name: "Purified Citric Acid (Crystal) L", manufactured by Fuso Chemical Co., Ltd. Crystalline cellulose: Product name "Ceolas UF-711", manufactured by Asahi Kasei Corporation. Crystalline cellulose (2): Product name "Ceolas KG-1000", manufactured by Asahi Kasei Corporation. Aspartame: Product name: "Ajinomoto KK Aspartame", manufactured by Ajinomoto Co., Inc. Lemon flavoring: Product name: "Ever Fresh 100 Lemon Flavor", manufactured by Givaudan Japan Co., Ltd. Apple flavoring: Product name: "Apple Flavor GIVO 55772", manufactured by Givaudan Japan Co., Ltd. Magnesium stearate: Product name: "Magnesium stearate (light) vegetable-based", manufactured by Taihei Chemical Industry Co., Ltd. Fructose: Product name: "Japanese Pharmacopoeia Fructose", manufactured by Kato Chemical Co., Ltd. Ethyl cellulose aqueous dispersion (30% solids): Product name "Aquacoat", manufactured by DuPont. Triacetin: Product name: "Triacetin", manufactured by Daihachi Chemical Industry Co., Ltd. Hypromellose: Product name "TC-5", manufactured by Shin-Etsu Chemical Co., Ltd. Macrogol 6000: Product name "Macrogol 6000", manufactured by Sanyo Chemical Industries, Ltd. Macrogol 4000: Product name "Macrogol 4000", manufactured by Sanyo Chemical Industries, Ltd. Talc: Product name: "Crown Talc Official PP", manufactured by Matsumura Sangyo Co., Ltd. Titanium oxide: Product name: "Titanium oxide FG", manufactured by Freund Corporation. Yellow ferric oxide: Product name: "Yellow ferric oxide", manufactured by Kishi Chemical Co., Ltd. Yellow No. 4 Aluminum Rake: Product name: "Yellow No. 4 Aluminum Rake", manufactured by Kishi Kasei Co., Ltd. Sucralose: Product name: "Sucralose (P)", manufactured by San-Ei Gen F.F.I. Co., Ltd.

[0077] (Manufacturing of tablets (chewable tablets)) <1. Grinding of ingredients (A) and (B)> In Examples 1 to 6, co-ground products were obtained by the following grinding method (1). In Examples 7, 8, and 10 to 17, co-ground products of component (A) and component (B) were obtained by the following grinding method (2). In Example 9, a co-ground product was obtained by the following grinding method (3). In Example 18, a ground product of component (A) alone (average particle size 62 μm) was obtained by the following grinding method (4). In Comparative Examples 1 and 2, a co-ground product of component (A) and component (B') was obtained by the grinding method (2). In Comparative Example 3, a ground product of component (A) alone (average particle size 98 μm) was obtained by the grinding method (4). In Comparative Example 4, a co-ground product of component (A) and component (B) was obtained by the grinding method (4). The average particle sizes of the resulting co-ground products (or ground products of component (A) alone) are shown in Tables 2 to 5. The average particle size of component (B) before co-milling was almost the same as that of the co-milled product, suggesting that the average particle size of component (B) remained almost unchanged before and after co-milling.

[0078] "Crushing method (1): Agitation granulator" The components (A) and (B) were placed in a stirring granulator (Vertical Granulator VG-25, manufactured by Powrex Corporation) in the ratios shown in Tables 2 and 3, the blade rotation speed was set to 220 rpm, and the chopper rotation speed was set to 2000 rpm. The jacket was heated to 60°C, and once the product temperature reached 44°C (the melting point of l-menthol), stirring was continued for 10 minutes to obtain a co-ground product.

[0079] "Crushing method (2): Tabletop fine grinder" Components (A) and (B) (or (B')) were placed in a benchtop grinder (Wonder Crusher WC-3, manufactured by Osaka Chemical Co., Ltd.) in the ratios shown in Tables 3 to 5 and ground at 20,000 rpm for a given number of seconds until the mixture was granulated. The resulting mixture was passed through a sieve with 500 μm openings to obtain a co-ground product.

[0080] "Crushing method (3): Fine grinder" Component (A) and component (B) were placed in a fine grinding mill (Labo Mill, manufactured by Dalton Co., Ltd.) so as to obtain the ratio of components shown in Table 3, and ground at 12,000 rpm to obtain a co-ground product.

[0081] "Crushing Method (4): Mortar" Component (A) alone, or component (A) and component (B) were placed in a mortar in the amount ratio shown in Table 5, and ground with a pestle to prevent component (A) from sticking, to obtain a pulverized product.

[0082] <2. Production of granulated active ingredient> The amounts of loperamide hydrochloride, erythritol, and corn starch listed in the columns for active ingredient granules in Tables 2 to 5, each amounting to 20,000 tablets, were placed in a fluidized bed granulator (FLO-5, Freund Corporation), and a previously prepared 8% by mass binding solution (aqueous polyvinyl alcohol solution) was sprayed onto the mixture until the amount reached the specified amount listed in the tables. The mixture was then spun at an inlet air temperature of 90°C and an exhaust air volume of 2.0 m. 3 Fluidized bed granulation was carried out at a rate of 1 / min. After spraying was completed, the mixture was dried until the exhaust temperature reached 65°C, yielding a granular dried product. The resulting granular dried product was passed through a sieve with 850 µm openings, yielding a granulated product of the active ingredient.

[0083] <3. Manufacturing of chewable tablets> Chewable tablets (plain or coated tablets) were manufactured according to the following procedure. The co-ground product (or ground product of component (A) only, or ground product of component (A) only and component (B)), active ingredient granules, and optional externally added ingredients were mixed to obtain the ratios shown in Tables 2 to 5, and then compressed using a rotary tablet press (LIBRA2, manufactured by Kikusui Seisakusho Co., Ltd.) or a single-punch tablet press (manufactured by Kikusui Seisakusho Co., Ltd.) equipped with a 9.5 mm diameter (two-stage R) mortar and pestle to obtain uncoated tablets. The tableting pressure was adjusted so that the hardness was 7 kgf to 8 kgf using a tablet hardness tester (manufactured by Yamato Scientific Co., Ltd.). In Examples 2 to 18 and Comparative Examples 2 to 4, the obtained uncoated tablets were coated with a Hicoater FZ-LABO 20 model (manufactured by Freund Corporation) at an intake air temperature of 65°C and an intake air volume of 0.8 m 3The coating solution was sprayed onto the uncoated tablets under conditions of a flow rate of 1 / min and an exhaust temperature of 42±5°C so that the amount of coating agent per tablet was the value shown in Tables 2 to 5. The coating solution was prepared in advance by dispersing each component in purified water to a concentration of 15% by mass and the blending ratio shown in the table. Then, the inlet air temperature was 65°C and the inlet air volume was 0.8 m. 3 / min for 7 minutes to obtain coated tablets with a coating layer on the surface of the uncoated tablets.

[0084] (Appearance evaluation) Of the chewable tablets obtained in each example, 100 tablets were randomly selected, and the tablet surfaces were thoroughly inspected visually. The percentage of chewable tablets with holes out of the 100 tablets (rate of holes) was evaluated according to the following criteria. The results are shown in Tables 2 to 5. AA: The rate of hole penetration is less than 5%. A: The rate of hole penetration is between 5% and 10%. B: The rate of hole penetration is 10% or more but less than 30%. C: The rate of hole penetration is 30% or more but less than 50%. D: The rate of hole penetration is 50% or more but less than 70%. E: The rate of hole penetration is 70% or more.

[0085] (Evaluation of disintegration in the mouth) One chewable tablet was placed in the mouth and gently rolled around on the tongue without chewing, allowing the tablet to disintegrate in saliva. The time it took for the tablet to completely disintegrate was measured. The test was conducted on five adults, and the average values ​​(rounded down to the nearest whole number) are shown. The results are shown in Tables 2 to 5.

[0086] (Roughness evaluation) The chewable tablets of Examples 14 to 16 were evaluated for roughness in the mouth when taken by the following procedure. One chewable tablet was placed in the mouth, chewed, and completely disintegrated. The lack of roughness in the mouth was evaluated using the following three-point scale. The test was conducted on five adults, and the most common score is shown. The results are shown in Table 6. A: Good; no roughness felt in the mouth. B: Normal; slight roughness in the mouth. C: Poor; rough feeling in the mouth.

[0087] [Table 2]

[0088] [Table 3]

[0089] [Table 4]

[0090] [Table 5]

[0091] [Table 6]

[0092] In Examples 1 to 18, the occurrence of surface pitting was suppressed, and an effect of suppressing poor appearance was observed. In contrast, in Comparative Examples 1 and 2, in which component (B') was used instead of component (B), Comparative Example 3, which did not contain component (B), and Comparative Example 4, in which the B / A ratio was less than 0.1, an effect of suppressing poor appearance was not observed. Comparing Examples 14 to 16, Examples 14 and 15, which had a B / A ratio of 30 or less, caused little or no roughness in the mouth when taken, and were easy to take.

[0093] (Production Example 1) Film-coated chewable tablets (single dose: 1 tablet) were manufactured according to the following formulation (B / A ratio = 6, 2 mg of (B) was co-ground with (A)). The formulation below shows the content of each ingredient per tablet. (A): l-menthol 2mg (B): Light anhydrous silicic acid 12 mg Loperamide hydrochloride 0.5mg D-mannitol (2) 200mg Corn starch 10mg Hydroxypropyl cellulose 4.4mg Turmeric dry extract 20mg Crospovidone 1.5mg Citric acid hydrate 1mg Crystalline cellulose 138.6mg Aspartame 6mg Lemon flavoring 2mg Magnesium stearate 2mg (Uncoated tablets total 400mg) Hypromellose 5.4mg D-mannitol (2) 0.9mg Macrogol 6000 1mg Talc 2.4mg Titanium oxide 2mg Yellow ferric oxide 0.2mg Yellow No. 4 Aluminum Lake 0.1mg (Film-coated chewable tablets total 412 mg)

[0094] <Co-grinding of component (A) and component (B)> Component (A) in an amount sufficient for 25,000 tablets and the same amount of component (B) were placed in a fine grinding mill (Labo Mill, manufactured by Dalton Co., Ltd.) and ground at 12,000 rpm to obtain a co-ground product.

[0095] <Production of active ingredient granules (1)> Loperamide hydrochloride, D-mannitol (2), and corn starch in an amount equivalent to 20,000 tablets were placed in a fluidized bed granulator (FLO-5, manufactured by Freund Corporation), and then a 6% by mass binder solution (aqueous hydroxypropyl cellulose solution) prepared in advance was sprayed onto the mixture until the amount of hydroxypropyl cellulose per tablet reached a predetermined amount, followed by fluidized bed granulation. After spraying, the mixture was dried to obtain a granular dried product, which was then passed through a sieve with an opening of 850 μm to obtain the active ingredient granulated product (1).

[0096] <Production of active ingredient granules (2)> 500 g of light anhydrous silicic acid (50,000 tablets) was placed in a stirring granulator (Vertical Granulator VG-25, manufactured by Powrex Corporation), and while stirring (blade rotation speed: 300 rpm, chopper rotation speed: 2500 rpm), 700 g of purified water was added dropwise over 3 minutes, followed by stirring for 6 minutes. Turmeric dry extract and crospovidone (50,000 tablets) were then added, followed by stirring for 4 minutes. 700 g of purified water was added dropwise over 3 minutes, and the mixture was stirred until the blade current value reached 8.2 A. The resulting granules were mixed in a 1000-well flask with an inlet air temperature of 80°C and an exhaust air volume of 2.0 m. 3 Fluidized bed drying (Spiraflow SFC-5, Freund Corporation) was carried out at 1000 kJ / min until the exhaust temperature reached 53° C. After drying, the mixture was pulverized using a Comil (Powrex Corporation) to obtain active ingredient granules (2).

[0097] <Tablet manufacturing> The co-ground product of components (A) and (B) prepared in the above steps, active ingredient granules (1) and (2), D-mannitol, crystalline cellulose, citric acid hydrate, aspartame, flavoring, and magnesium stearate were mixed in the amounts described in the formulation examples, and then compressed using a rotary tablet press (LIBRA2, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain uncoated tablets with a diameter of 9.5 mm (two-stage R). The tableting pressure was adjusted so that the hardness was approximately 7 to 8 kgf, as measured using a tablet hardness tester (manufactured by Yamato Scientific Co., Ltd.). The coating liquid was sprayed onto the obtained uncoated tablets using a Hicoater FZ-LABO 20 model (Freund Corporation) under conditions of an inlet air temperature of 65°C and an inlet air volume of 0.8 m3 / min so that the amount of coating agent per tablet was 12 mg. The coating liquid was prepared in advance by dispersing the tablets in purified water to a concentration of 15% by mass and in the blending ratio described in the formulation example. Thereafter, the tablets were sprayed under conditions of an inlet air temperature of 65°C and an inlet air volume of 0.8 m3 / min so that the amount of coating agent per tablet was 12 mg. 3 / min to obtain film-coated chewable tablets with a coating layer on the surface of the uncoated tablets.

[0098] (Production Example 2) Film-coated chewable tablets (single dose: 1 tablet) were manufactured according to the following formulation, which shows the content of each ingredient per tablet. (A): l-menthol 1.5mg (B): Hydrous silicon dioxide 6 mg (B / A=4) Loperamide hydrochloride 0.5mg Erythritol 200mg Corn starch 20mg Polyvinyl alcohol 8.8mg Turmeric powder 100mg Crospovidone 10mg Citric acid hydrate 3mg Crystalline cellulose 40.2mg Aspartame 6mg Lemon flavoring 2mg Magnesium stearate 2mg (Uncoated tablets total 400mg) Hypromellose 7mg D-mannitol (2) 4mg Macrogol 6000 1.1mg Talc 1.5mg Titanium oxide 3.6mg Yellow ferric oxide 0.45mg Yellow No. 4 Aluminum Lake 0.25mg Sucralose 0.1mg (Film-coated chewable tablets total 418mg)

[0099] <Co-grinding of component (A) and component (B)> Component (A) and component (B) in amounts sufficient for 100,000 tablets were placed in a stirring granulator (Vertical Granulator VG-25, manufactured by Powrex Corporation), the rotation speed was set to 200 rpm for the blade and 2,000 rpm for the chopper, the jacket was heated to 60°C, and once the product temperature reached 44°C (the melting point of l-menthol), stirring was continued for 10 minutes to obtain a co-ground product.

[0100] <Production of granulated active ingredients> Loperamide hydrochloride, erythritol, and corn starch in amounts equivalent to 20,000 tablets were placed in a fluidized bed granulator (FLO-5, manufactured by Freund Corporation), and then a previously prepared 8% by weight binder solution (aqueous polyvinyl alcohol solution) was sprayed onto the mixture until the amount of polyvinyl alcohol per tablet reached a predetermined amount, followed by fluidized bed granulation. After spraying, the mixture was dried to obtain a granular dried product, which was then passed through a sieve with an opening of 850 μm to obtain active ingredient granules (1).

[0101] <Tablet manufacturing> The other ingredients and the active ingredient granules were mixed and compressed in the same manner as in Production Example 1 to obtain uncoated tablets with a diameter of 9.5 mm (two-stage R). A coating solution was sprayed onto the obtained uncoated tablets so that the amount of coating agent per tablet was 18 mg, and the tablets were dried to obtain film-coated chewable tablets with a coating layer on the surface of the uncoated tablets.

[0102] (Production Example 3) Film-coated chewable tablets (single dose: 1 tablet) were manufactured according to the following formulation, which shows the content of each ingredient per tablet. (A): l-menthol 1mg (B)-1: Calcium silicate 3 mg (B-1 / A=3) (B)-2: Light anhydrous silicic acid 20 mg (total B / A = 23, B-2 is not ground together with A) Loperamide hydrochloride 0.5mg Erythritol 100mg Corn starch 10mg Polyvinyl alcohol 2.2mg Turmeric extract 30mg Crospovidone 10mg D-mannitol 150mg Crystalline cellulose 65.3mg Aspartame 4mg Lemon flavoring 2mg Magnesium stearate 2mg (Uncoated tablets total 400mg) Polyvinyl alcohol (2) 8mg Macrogol 4000 3mg Talc 3mg Titanium oxide 5.3mg Yellow ferric oxide 0.4mg Yellow No. 4 Aluminum Lake 0.25mg Aspartame 0.1mg (film-coated tablets total 420mg)

[0103] <Co-grinding of component (A) and component (B)> Component (A) and component (B)-1 in an amount sufficient to produce 5,000 tablets were crushed at 20,000 rpm for an arbitrary number of seconds using a benchtop crusher (Wonder Crusher WC-3, manufactured by Osaka Chemical Co., Ltd.) until the mixture was granulated. The entire mixture was passed through a sieve with 500 μm openings to obtain a co-crushed product.

[0104] <Production of active ingredient granules (1)> Loperamide hydrochloride, erythritol, and corn starch in amounts sufficient for 50,000 tablets were placed in a fluidized bed granulator (FLO-5, manufactured by Freund Corporation), and a 6% by mass binder solution (aqueous polyvinyl alcohol solution) was sprayed onto the mixture until the amount of polyvinyl alcohol per tablet reached a predetermined amount, followed by fluidized bed granulation. After spraying, the mixture was dried to obtain a granular dried product, which was then passed through a sieve with an opening of 850 μm to obtain active ingredient granules (1).

[0105] <Production of active ingredient granules (2)> A 50,000-tablet amount of component (B)-2 was placed in a stirring granulator (Vertical Granulator VG-25, manufactured by Powrex Corporation), and a predetermined amount of turmeric extract was added dropwise and stirred under stirring (blade rotation speed: 300 rpm, chopper rotation speed: 2500 rpm). After that, a predetermined amount of crospovidone was added and stirred, and the resulting granules were heated at an inlet air temperature of 80°C and an exhaust air volume of 2.0 m. 3 Fluidized bed drying (Spiraflow SFC-5, Freund Corporation) was carried out at 1000 kJ / min until the exhaust temperature reached 53° C. After drying, the mixture was pulverized using a Comil (Powrex Corporation) to obtain active ingredient granules (2).

[0106] <Tablet manufacturing> The ingredients were mixed and compressed in the same manner as in Production Example 1 to obtain uncoated tablets with a diameter of 9.5 mm (two-stage R). The coating solution was sprayed onto the obtained uncoated tablets so that the amount of coating agent per tablet was 20 mg, and the tablets were dried to obtain film-coated chewable tablets with a coating layer provided on the surface of the uncoated tablets.

[0107] (Production Example 4) Film-coated chewable tablets (single dose: 1 tablet) were manufactured according to the following formulation, which shows the content of each ingredient per tablet. (A): l-menthol 2mg (B)-1: Hydrous silicon dioxide 5 mg (B-1 / A=2.5) (B)-2: Light anhydrous silicic acid 10 mg (B / A=7.5, B-2 is not ground together with A) Loperamide hydrochloride 0.5mg Erythritol 200mg Corn starch 20mg Polyvinyl alcohol 8.8mg Turmeric dry extract 20mg Crospovidone 5mg Citric acid hydrate 3mg Crystalline cellulose 118mg Aspartame 4mg Lemon flavoring 2mg Magnesium stearate 2mg (Uncoated tablets total 400mg) Hypromellose 7.2mg D-mannitol (2) 3mg Macrogol 6000 1mg Talc 1.2mg Titanium oxide 3mg Yellow ferric oxide 0.4mg Yellow No. 4 Aluminum Lake 0.1mg Sucralose 0.1mg (film-coated tablets total 416mg)

[0108] <Co-grinding of component (A) and component (B)> Component (A) and component (B)-1 in an amount sufficient to produce 5,000 tablets were crushed at 20,000 rpm for an arbitrary number of seconds using a benchtop crusher (Wonder Crusher WC-3, manufactured by Osaka Chemical Co., Ltd.) until the mixture was granulated. The entire mixture was passed through a sieve with 500 μm openings to obtain a co-crushed product.

[0109] <Production of active ingredient granules (1)> Loperamide hydrochloride, erythritol, and corn starch in amounts sufficient for 20,000 tablets were placed in a fluidized-bed granulator (FLO-5, manufactured by Freund Corporation), and then a previously prepared 8% by mass binder (aqueous polyvinyl alcohol solution) was sprayed onto the mixture until the amount of polyvinyl alcohol per tablet reached a predetermined amount, followed by fluidized-bed granulation. After spraying, the mixture was dried to obtain a granular dried product, which was then passed through a sieve with an opening of 850 μm to obtain active ingredient granules (1).

[0110] <Production of active ingredient granules (2)> A 50,000-tablet amount of (B)-2 component was placed in a stirring granulator (Vertical Granulator VG-25, manufactured by Powrex Corporation) and dispersed (blade rotation speed: 300 rpm, chopper rotation speed: 2500 rpm). Then, 800 g of a citric acid aqueous solution containing a predetermined amount of citric acid hydrate was added dropwise over 3 minutes and stirred for 5 minutes. A predetermined amount of turmeric dry extract was then added and stirred, followed by the addition of a predetermined amount of crospovidone. 700 g of purified water was added dropwise over 2 minutes and stirred. The resulting granules were then transferred to a centrifuge at an intake air temperature of 80°C and an exhaust air volume of 2.0 m. 3 Fluidized bed drying (Spiraflow SFC-5, Freund Corporation) was carried out at 1000 kJ / min until the exhaust temperature reached 53° C. After drying, the mixture was pulverized using a Comil (Powrex Corporation) to obtain active ingredient granules (2).

[0111] <Tablet manufacturing> The other ingredients and the active ingredient granules (1) and (2) were mixed and compressed in the same manner as in Production Example 1 to obtain uncoated tablets with a diameter of 9.5 mm (two-stage R). A coating solution was sprayed onto the obtained uncoated tablets so that the amount of coating agent per tablet was 16 mg, and the tablets were dried to obtain film-coated chewable tablets with a coating layer on the surface of the uncoated tablets.

[0112] (Production Example 5) Film-coated chewable tablets (single dose: 1 tablet) were manufactured according to the following formulation, which shows the content of each ingredient per tablet. (A): l-menthol 0.5mg (B): Magnesium aluminometasilicate 2 mg (B / A=4) Loperamide hydrochloride 0.5mg Erythritol 150mg Corn starch 15mg Polyvinyl alcohol 6.6mg Ursodeoxycholic acid 30mg Crospovidone 5mg Citric acid hydrate 3mg Crystalline cellulose 77.4mg D-mannitol 100mg Aspartame 6mg Lemon flavoring 2mg Magnesium stearate 2mg (Uncoated tablets total 400mg) Hypromellose 8mg Macrogol 6000 1.6mg Talc 2.4mg Titanium dioxide 3.5mg Yellow ferric oxide 0.4mg Aspartame 0.1mg (Film-coated chewable tablets total 416 mg)

[0113] <Co-grinding of component (A) and component (B)> Component (A) and component (B) in an amount equivalent to 5,000 tablets were crushed at 20,000 rpm for an arbitrary number of seconds using a benchtop crusher (Wonder Crusher WC-3, manufactured by Osaka Chemical Co., Ltd.) until the mixture was granulated. The entire mixture was passed through a sieve with 500 μm openings to obtain a co-crushed product.

[0114] <Production of granulated active ingredients> Loperamide hydrochloride, erythritol, and corn starch in amounts sufficient for 30,000 tablets were placed in a fluidized-bed granulator (FLO-5, Freund Corporation), and then a 6% by mass binder solution (aqueous polyvinyl alcohol solution) prepared in advance was sprayed onto the mixture until the amount of polyvinyl alcohol per tablet reached a predetermined amount, followed by fluidized-bed granulation. After spraying, the mixture was dried to obtain a granular dried product, which was then passed through a sieve with an opening of 850 μm to obtain a granulated product of the active ingredient.

[0115] <Tablet manufacturing> The other ingredients and the active ingredient granules were mixed and compressed in the same manner as in Production Example 1 to obtain uncoated tablets with a diameter of 9.5 mm (two-stage R). A coating solution was sprayed onto the obtained uncoated tablets so that the amount of coating agent per tablet was 16 mg, and the tablets were dried to obtain film-coated chewable tablets with a coating layer on the surface of the uncoated tablets.

[0116] (Production Example 6) Film-coated chewable tablets (single dose: 1 tablet) were manufactured according to the following formulation, which shows the content of each ingredient per tablet. (A): l-menthol 1mg (B)-1: Hydrous silicon dioxide 1 mg (B-1 / A=1) (B)-2: Light anhydrous silicic acid 12 mg (total B / A = 13, B-2 is not ground together with A) Berberine tannate 100mg Scopolia extract triple powder 60mg Fructose 6.35mg Peony dry extract 24mg Crospovidone 4.5mg Microcrystalline cellulose (2) 45mg D-mannitol 187.6mg Aspartame 6mg Apple flavor 1.1mg Magnesium stearate 1.8mg (Uncoated tablets total 450mg) Hypromellose 9mg Macrogol 6000 1.8mg Talc 2.7mg Titanium dioxide 3.5mg Yellow ferric oxide 0.9mg Sucralose 0.1mg (Film-coated chewable tablets total 468mg)

[0117] <Co-grinding of component (A) and component (B)> Component (A) and component (B)-1 in an amount sufficient to produce 5,000 tablets were crushed at 20,000 rpm for an arbitrary number of seconds using a benchtop crusher (Wonder Crusher WC-3, manufactured by Osaka Chemical Co., Ltd.) until the mixture was granulated. The entire mixture was passed through a sieve with 500 μm openings to obtain a co-crushed product.

[0118] <Production of active ingredient granules (1)> Berberine tannate and triple triturated Scopolia extract in an amount sufficient to produce 15,000 tablets were placed in a stirring granulator (Vertical Granulator VG-25, manufactured by Powrex Corporation), and a predetermined amount of 7% fructose aqueous solution was added dropwise over 1 minute while stirring (blade rotation speed: 400 rpm, chopper rotation speed: 2500 rpm), followed by stirring for 10 minutes. The resulting granules were then heated in a 80°C inlet air chamber with an exhaust air volume of 2.5 m. 3 Fluidized bed drying (Spiraflow SFC-5, Freund Corporation) was carried out at a rate of 1 / min until the exhaust temperature reached 60° C. After drying was completed, the entire amount was passed through a sieve with an opening of 850 μm to obtain active ingredient granules (1).

[0119] <Production of active ingredient granules (2)> A 40,000-tablet amount of (B)-2 component was placed in a stirring granulator (Vertical Granulator VG-25, manufactured by Powrex Corporation), and 720 g of purified water was added dropwise over 3 minutes while stirring (blade rotation speed: 300 rpm, chopper rotation speed: 2500 rpm), followed by stirring for 10 minutes. Thereafter, a 40,000-tablet amount of peony root extract and crospovidone were added and stirred, and the resulting granules were heated at an inlet air temperature of 80°C and an exhaust air volume of 2.0 m. 3 Fluidized bed drying (Spiraflow SFC-5, Freund Corporation) was carried out at 1000 kJ / min until the exhaust temperature reached 53° C. After drying, the mixture was pulverized using a Comil (Powrex Corporation) to obtain active ingredient granules (2).

[0120] <Tablet manufacturing> The ingredients were mixed and compressed in the same manner as in Production Example 1 to obtain uncoated tablets with a diameter of 9.5 mm (two-stage R). The coating solution was sprayed onto the obtained uncoated tablets so that the amount of coating agent per tablet was 18 mg, and the tablets were dried to obtain film-coated chewable tablets with a coating layer provided on the surface of the uncoated tablets.

[0121] (Production Example 7) Film-coated chewable tablets (single dose: 1 tablet) were manufactured according to the following formulation, which shows the content of each ingredient per tablet. (A): l-menthol 4mg (B): Light anhydrous silicic acid 8 mg (B / A=2) Caffeine anhydrous 167mg Ethyl cellulose aqueous dispersion (solid content 30%) 100mg D-mannitol 215mg (15mg is contained in the active ingredient granules, 200mg is added externally) Triacetin 7.5mg Crospovidone 20mg Crystalline cellulose 34.5mg Aspartame 10mg Lemon flavoring 2mg Magnesium stearate 2mg (Uncoated tablets total 500mg) Hypromellose 7.5mg Macrogol 6000 1.5mg D-mannitol (2) 1mg Talc 1.8mg Titanium oxide 3.1mg Sucralose 0.1mg (Film-coated chewable tablets total 515mg)

[0122] <Co-grinding of component (A) and component (B)> Component (A) and component (B) in an amount equivalent to 5,000 tablets were crushed at 20,000 rpm for an arbitrary number of seconds using a benchtop crusher (Wonder Crusher WC-3, manufactured by Osaka Chemical Co., Ltd.) until the mixture was granulated. The entire mixture was passed through a sieve with 500 μm openings to obtain a co-crushed product.

[0123] <Production of granulated active ingredients> 1000 g of anhydrous caffeine was coated by spraying a coating solution prepared with a mass ratio of 100% ethyl cellulose aqueous dispersion, 15% D-mannitol, and 7.5% triacetin at a rate of 20 g / min at an air volume that gave an inlet air temperature of 80°C and an exhaust air temperature of 35 to 45°C onto the anhydrous caffeine, followed by drying to obtain a granulated product of the active ingredient.

[0124] <Tablet manufacturing> The other ingredients and the active ingredient granules were mixed and compressed in the same manner as in Production Example 1 to obtain uncoated tablets with a diameter of 10 mm (two-stage R). A coating solution was sprayed onto the obtained uncoated tablets so that the amount of coating agent per tablet was 15 mg, and the tablets were dried to obtain film-coated chewable tablets with a coating layer on the surface of the uncoated tablets.

[0125] (Production Example 8) Film-coated chewable tablets (single dose: 1 tablet) were manufactured according to the following formulation, which shows the content of each ingredient per tablet. (A): l-menthol 1mg (B): Magnesium aluminometasilicate 5 mg (B / A=5) Loxoprofen sodium dihydrate 68.1mg Acetaminophen 150mg Corn starch 20mg Hydroxypropyl cellulose 5mg D-mannitol 100mg Crospovidone 5mg Crystalline cellulose 34.9mg Citric acid hydrate 1mg Aspartame 6mg Lemon flavoring 2mg Magnesium stearate 2mg (Uncoated tablets total 400mg) Polyvinyl alcohol (2) 7mg Macrogol 4000 2mg D-mannitol (2) 2mg Talc 1.8mg Titanium oxide 3mg Iron oxide 0.1mg Aspartame 0.1mg (film-coated tablets total 416mg)

[0126] <Co-grinding of component (A) and component (B)> Component (A) and component (B) in an amount equivalent to 5,000 tablets were crushed at 20,000 rpm for an arbitrary number of seconds using a benchtop crusher (Wonder Crusher WC-3, manufactured by Osaka Chemical Co., Ltd.) until the mixture was granulated. The entire mixture was passed through a sieve with 500 μm openings to obtain a co-crushed product.

[0127] <Production of granulated active ingredients> Loxoprofen sodium, acetaminophen, and corn starch in amounts sufficient for 20,000 tablets were placed in a fluidized bed granulator (FLO-5, Freund Corporation), and a 5% by mass binder solution (aqueous hydroxypropyl cellulose solution) prepared in advance was sprayed onto the mixture until the required amount was reached, followed by fluidized bed granulation. After spraying, the mixture was dried to obtain a dried granular product, which was then passed through a sieve with an opening of 850 μm to obtain a granulated product of the active ingredient.

[0128] <Tablet manufacturing> The other ingredients and the active ingredient granules were mixed and compressed in the same manner as in Production Example 1 to obtain uncoated tablets with a diameter of 9 mm (two-stage R). A coating solution was sprayed onto the obtained uncoated tablets so that the amount of coating agent per tablet was 16 mg, and the tablets were dried to obtain film-coated chewable tablets with a coating layer on the surface of the uncoated tablets.

Claims

1. A method for producing a chewable tablet, comprising: The chewable tablet comprises: (A) component: menthol, (B) component: at least one inorganic powder selected from the group consisting of synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminometasilicate, calcium silicate, calcium hydrogen phosphate, hydrous silicon dioxide, and light anhydrous silicic acid; Contains The content of the component (A) per tablet is 0.01 to 10 mg, the mass ratio of the component (B) to the component (A) is 0.1 or more, The average particle size of the component (B) is 1 to 200 μm, the component (A) is adsorbed and supported on the component (B), A coated tablet having a coating layer on the surface of a plain tablet containing the component (A) and the component (B), the content of the coating agent forming the coating layer is 0.1 to 20% by mass relative to the total mass of the chewable tablet; The method comprises the steps of preparing a powder mixture containing the component (A) and the component (B), and compressing the powder mixture into tablets, The step of preparing the powder mixture includes a step of co-grinding the component (A) and the component (B), The co-grinding step is a step of pulverizing the powder by a fine pulverization method that applies shear force to the powder or a pulverization method that allows heating, and raising the temperature of the powder during pulverization to a temperature equal to or higher than the melting point of the component (A). Manufacturing method for chewable tablets.

2. the component (B) is at least one inorganic powder selected from the group consisting of synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminometasilicate, calcium silicate, hydrous silicon dioxide, and light anhydrous silicic acid; The method for producing a chewable tablet according to claim 1, wherein the mass ratio of the component (B) to the component (A) is 0.5 or more and 30 or less.

3. The method for producing a chewable tablet according to claim 1 or 2, wherein the oil absorption of the component (B) is 0.5 mL / g or more.

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