JP6775155B2 - tablet - Google Patents

Description

The present invention relates to tablets having excellent shape stability. More specifically, the present invention relates to a tablet having excellent shape stability, which contains a high proportion of a disintegrant but significantly suppresses appearance changes (swelling, cracking, cracking, etc.) due to moisture absorption.

Ingredients to be added to tablets include excipients added to increase the amount of active ingredient to an appropriate amount for ease of handling, disintegrant added to disintegrate tablets and facilitate release of active ingredient, and raw material powder. There are binders added to bind body particles together, lubricants added to improve the fluidity of the powder particles of the raw material and facilitate compression formation, and the like. Pharmaceutical companies manufacture and sell tablets that exhibit elution and disintegration according to the purpose by examining the types and amounts of additives and the manufacturing methods of formulations.

The disintegrant is an additive useful for adjusting the disintegration property of the tablet and the elution property of the active ingredient, but in the case of the tablet containing a high proportion of the disintegrant, it absorbs the moisture in the air and cracks. There is a problem that the film portion of the film-coated tablet is cracked. Conventionally, problems such as cracking of tablets have been prevented by blending a large amount of other components such as excipients and relatively reducing the content ratio of the disintegrant. However, it has been difficult to miniaturize the tablet because it contains more excipients and the like than necessary.

A first object of the present invention is to provide a tablet having excellent appearance stability in a high humidity environment while containing a relatively large amount of a disintegrant. A second object of the present invention is to provide a small tablet having the above characteristics.

As a result of diligent studies to solve the above problems, the present inventors have specified in the production of tablets containing a disintegrant in a relatively large proportion of 10 to 40% by mass in 100% by mass of uncoated tablets. Sugar alcohol, specifically 350 mg dose is molded with a load of 12 kN (edge diameter: 9.5 mmφ), and by using sugar alcohol that shows strength of 80 N or more as measured by the tablet hardness tester, the outer shape over time We have found that tablets are obtained in which changes are significantly suppressed. Further, such tablets can be suitably produced by a method of compression-molding granules prepared by a wet granule method (wet granule compression method), and in particular, the above-mentioned specific sugar alcohol, disintegrant and pharmaceutically active ingredient as a wet granule compression method. After granulating the powder mixture of, the above-mentioned specific sugar alcohol, disintegrant and lubricant are mixed in the powdered state without granulation, and a manufacturing method having a step of tableting is adopted. It has been found that by doing so, it can be produced more preferably. Furthermore, it has been found that by setting the ratio of the disintegrant in the granulated product to the disintegrant contained in the uncoated tablet to a certain level or more, a tablet in which the change in outer shape over time is significantly suppressed can be obtained.

The present invention has been completed by advancing further research based on these findings, and is characterized by having the following embodiments.

(1) Tablets (1-1) (A) Molded with a mass of 350 mg and 12 kN (pestle diameter: 9.5 mmφ), sugar alcohol showing strength of 80 N or more when measured with a tablet hardness tester, and (B) disintegration Contains the agent,
(B) A tablet having a disintegrant content of 10 to 40% by mass in 100% by mass of the uncoated tablet.

(1-2) The tablet according to (1-1), wherein the content ratio of (A) sugar alcohol in 100% by mass of the uncoated tablet is 20 to 90% by mass.

(1-3) (A) Sugar alcohol is mannitol that is molded with a mass of 350 mg and 12 kN (bare diameter: 9.5 mmφ) and shows a strength of 80 N or more when measured with a tablet hardness tester, (1-1). ) Or the tablet according to (1-2).

(1-4) (B) Disintegrants include croscarmellose, crospovidone, carboxymethyl starch, low degree of substitution hydroxypropyl cellulose, carmellose, crystalline cellulose carmellose, corn starch, potato starch, low degree of substitution hydroxymethyl starch and The tablet according to any one of (1-1) to (1-3), which is at least one selected from the group consisting of those pharmaceutically acceptable salts.

(1-5) (B) The disintegrant is at least one selected from the group consisting of croscarmellose, crospovidone, low-substituted hydroxypropyl cellulose, and pharmaceutically acceptable salts thereof, (1-5). 1-1) The tablet according to any one of (1-3).

(1-6) (B) The tablet according to (1-5), wherein the content ratio of the disintegrant is 10 to 20% by mass in 100% by mass of the uncoated tablet.

(1-7) Further, it is a tablet containing (C) a pharmaceutically active ingredient, and the ratio of the component (C) in 100% by mass of the uncoated tablet is more than 0% by mass and 70% by mass or less (1- 1) The tablet according to any one of (1-6).

(1-8) The tablet according to (1-7), wherein the content of (C) pharmaceutically active ingredient per tablet is 5 to 12 mg.

(1-9) (C) Pharmaceutically active ingredients are procaterol, fenoterol, clenbuterol, salmeterol, theophylline, amlexanox, ibudilast, pemirolast, zafirlukast, ceratrodust, cetirizine, levosetilizine, olopatadine, montelukast, zafirlukast and their pharmaceutically acceptable ingredients. The tablet according to (1-7) or (1-8), which is at least one selected from the group consisting of salmeterol.

(1-10) The tablet according to (1-7), which is a tablet having one of the following characteristics (a) and (b):
(A) Total mass 60 to 80 mg per tablet, content of (C) pharmaceutical active ingredient in one tablet 4.7 to 5.5 mg, side circumference 15 to 22 mm, thickness 2.3 to 3.6 mm, and hardness 35 N or more (b) Total mass 135 to 148 mg per tablet, content of (C) pharmaceutical active ingredient in one tablet 9.9 to 10.9 mg, side circumference 18 to 25 mm, thickness 3.2 to 4.8 mm, And hardness 60 N or more.

(1-11) Granules containing (A) sugar alcohol, (B) disintegrant and (C) pharmaceutical active ingredient, and mixed powder of (A) sugar alcohol, (B) disintegrant and lubricant The tablet according to any one of (1-7) to (1-10) having at least one of the following characteristics:
(I) The ratio of the granulated material to the mixed powder is 2: 1 to 3: 1 in terms of mass ratio.
(Ii) The ratio of the (B) disintegrant in the granules to the (B) disintegrant in the mixed powder is 1: 2 to 2: 1 in terms of mass ratio.

(1-12) The tablet according to any one of (1-1) to (1-11), which is a coated tablet.

(1-13) The tablet according to (1-12), wherein the ratio of the coating layer to 100 parts by mass of the uncoated tablet is 1 to 10 parts by mass.

(1-14) The tablet according to any one of (1-1) to (1-13), which is a tablet having the following characteristics:
(1) When a disintegration test is carried out using water at 37 ° C as the test solution, the disintegration occurs within 10 minutes.

(1-15) The tablet according to (1-14), which further has at least one of the following properties (2) and (3):
(2) When the dissolution test by the paddle method at 37 ° C. and 50 rpm is performed using water as the test solution, the dissolution rate of the pharmaceutically active ingredient after 60 minutes is 60 to 90% (3) Test When the dissolution test by the paddle method at 37 ° C. and 50 rpm rotation was carried out using the second liquid of the Japanese Pharmacopoeia (pH 6.8) as the liquid, the dissolution rate of the medicinal active ingredient after 60 minutes was 10 to 45%. is there.

(2) Method for Producing Tablets (2-1) The method for producing tablets according to any one of (1-1) to (1-15), which comprises a step of producing by using a wet granule compression method.

(2-2) Ingredients containing the component (A) and the component (B) (and, if necessary, the pharmaceutically active ingredient) prepared by the wet granulation method, the component (A), ( B) The method for producing a tablet according to (2-1), which comprises a step of mixing the component and the lubricant in a powder state without granulating and tableting.

(2-3) A step of mixing (I), (A), (B), and (and, if necessary, (C) pharmaceutically active ingredient), and adding a liquid binder to granulate.
(II) The step of drying and sizing the granulated product obtained in the above step, and (III) the sizing product obtained in the above step, at least one of the powdery components (A) and (B). , And the production method according to (2-1) or (2-2), which comprises a step of mixing with a powdery lubricant and tableting the mixture.

(2-4) The component (B) in the granulated product and the powdered component (B) mixed with the component (B) contain a common disintegrant or are the same disintegrant, (2-2) or. The manufacturing method described in (2-3).

(2-5) The ratio of the component (A) in the granulated product to the powdered component (A) mixed with the component (A) is 2: 1 to 4: 1 by mass ratio (2-2) to ( The manufacturing method described in any of 2-4).

(2-6) The ratio of the component (B) in the granulated product to the powdered component (B) mixed with the component (B) is 1: 2 to 2: 1 by mass ratio (2-2) to ( The manufacturing method described in any of 2-5).

(2-7) The ratio of the powder mixture to be blended to 100 parts by mass of the sized product prepared in the steps (II) is 35 to 45 parts by mass, (2-3) to (2-6). The manufacturing method described in any of the above.

(2-8) The production method according to any one of (2-1) to (2-7), which comprises an operation of compression molding at a tableting pressure of 100 to 8,000 kgf / cm ² .

(2-9) The binder is at least one selected from the group consisting of hydroxypropyl cellulose, hypromellose, methyl cellulose, polyvinyl alcohol, gum arabic, pregelatinized starch, dextrin, pullulan, polyvinylpyrrolidone, and macrogol. 2-1) The manufacturing method according to any one of (2-8).

(2-10) The production method according to any one of (2-1) to (2-9), further comprising a coating step of coating the uncoated tablet with a coating agent.

The tablet of the present invention is characterized by being excellent in appearance stability in a high humidity environment, even though it is a tablet containing a disintegrant in a relatively large proportion of 10 to 40% by mass in 100% by mass of the uncoated tablet. And. According to the production method of the present invention, tablets having the above characteristics can be produced. Further, according to the present invention, there is provided a small tablet having the above-mentioned characteristics and a method for producing the same, even though the tablet contains a disintegrant in a relatively large proportion of 10 to 40% by mass in 100% by mass of the uncoated tablet. can do.

(1) Tablets The tablets of the present invention are tablets containing (A) sugar alcohol and (B) disintegrant, and the content of (B) in 100% by mass of the uncoated tablet is 10 to 40% by mass. Yes, and (A) indicates that the 350 mg amount is molded with a load of 12 kN (edge diameter: 9.5 mmφ), and when measured with a tablet hardness meter, the strength is 80 N or more with the tablet hardness meter. It is a feature.

Unless otherwise specified, the term "tablet" in the present invention means a solid preparation having a certain shape to be orally administered, and includes ordinary tablets, orally disintegrating tablets, chewable tablets, troche tablets, and the like. Includes sublingual tablets, foam tablets, dispersion tablets, dissolution tablets, and sustained release tablets. It is preferably a tablet other than an orally disintegrating tablet, and more preferably a normal tablet. Further, the tablets targeted by the present invention include single-layer tablets having a single-layer structure and multi-layer tablets having a plurality of layers of two or more layers. It is preferably a single layer tablet. Further, the tablets of the present invention include uncoated uncoated tablets (naked tablets), sugar-coated tablets, gelatin-encapsulated tablets, and film-coated tablets (including enteric-coated tablets and gastric-coated tablets) (as opposed to uncoated tablets). These are also collectively referred to as "coated tablets").

Hereinafter, each component constituting the tablet of the present invention will be described.

(A) Sugar alcohol The sugar alcohol used as the component (A) in the present invention has a hardness property of at least 80 N or more when it is compression-molded by itself. In the present specification, a sugar alcohol having such hardness characteristics may be simply referred to as "component (A)". Specifically, when 350 mg of the corresponding component is compression-molded using a tableting machine with a punch diameter of 9.5 mmφ at a pressure load of 12 kN and a compression rate of 20 mm / min, the hardness of the compression-molded product (tablet) obtained is , It is a sugar alcohol characterized by having a measured value of 80 N or more with a tablet hardness tester. When two or more sugar alcohols are used in combination, the strength of the compression molded product (tablet) obtained when 350 mg of the mixture of sugar alcohols used in combination is compression-molded under the above conditions is 80 N or more as measured by a tablet hardness tester. If so, a mixture of these excipients also falls under component (A) as defined in the present invention.

The strength may be 80 N or more as measured by a tablet hardness tester, but is preferably 95 N or more, preferably 120 N or more, more preferably 145 N or more, and particularly more preferably 150 N or more. The upper limit of the measured value with the tablet hardness tester is not limited, but usually 500N, preferably 400N, more preferably 300N, and particularly preferably 250N can be mentioned.

The sugar alcohol used for hardness measurement here has a water content adjusted so that the water content detected under the condition of 105 ° C. is 0.5% by mass or less. Further, as a tablet hardness tester used for measuring the strength of a compression molded product of sugar alcohol, a load cell type desktop hardness tester (PC-30 type, manufactured by Okada Seiko Co., Ltd.) can be mentioned. The measurement conditions are 25 ± 5 ° C and a breaking operation speed of 24 mm / min.

In the present invention, the component (A) can be used without particular limitation as long as it is an edible sugar alcohol having the above hardness characteristics. It is preferably a sugar alcohol used in the production of pharmaceuticals or foods, which has the above-mentioned hardness characteristics. Examples of sugar alcohols used in the production of pharmaceuticals or foods include mannitol, erythritol, sorbitol, maltitol, isomalt, lactitol, xylitol, and powdered reduced maltose sugar candy. These sugar alcohols can be used alone or in combination of two or more as long as they have the above-mentioned hardness characteristics. Further, as described above, the hardness characteristics may be exhibited when two or more kinds are combined. Preferred are mannitol, erythritol, sorbitol, maltitol, isomalt, lactitol, xylitol, and powdered reduced maltose starch syrup. Of these, mannitol, erythritol, isomalt, and maltitol can be preferably mentioned. Particularly preferred is mannitol.

Among the mannitols, D-mannitol having the above-mentioned hardness characteristics, which is preferably sold and used as an excipient for direct tableting, is used. Specifically, among Merck's Pirtek (trade name), Rocket's Pairitol (trade name), and Freund's Granutol (trade name), those satisfying the above-mentioned predetermined requirements are exemplified. be able to.

The blending ratio of the above component (A) in the tablet is not limited, but can be usually selected from the range of 10 to 90% by mass as the total amount in 100% by mass of the uncoated tablet. It is preferably 20 to 90% by mass, more preferably 30 to 85% by mass, and particularly preferably 50 to 85% by mass. When the component (A) is mannitol, the proportion of the mannitol in 100% by mass of the uncoated tablet is usually 10 to 85% by mass, preferably 30 to 85% by mass, and more preferably 50 to 85% by mass, although not limited. is there.

(B) Disintegrant As the disintegrant in the tablets of the present invention, those usually used for producing tablets can be widely used. In the present specification, the disintegrant may be simply referred to as "component (B)". Although not limited, for example, carboxymethyl celluloses (eg, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crystalline cellulose / carmellose sodium, etc.), carboxymethyl starches (eg, carboxymethyl starch, carboxymethyl starch, etc.) (Sodium, etc.), crospovidone, low-substituted hydroxypropyl cellulose, low-substituted hydroxymethyl starch sodium, starches (corn starch, potato starch, etc.), alginic acid, bentonite and the like. Preferably, croscarmellose sodium, crospovidone, carboxymethyl starch sodium, low substitution hydroxypropyl cellulose, carmellose sodium, carmellose calcium, carmellose, crystalline cellulose carmellose sodium, corn starch, potato starch, and low substitution degree. Hydroxymethyl starch sodium. More preferably, it is low-substituted hydroxypropyl cellulose, carmellose calcium, croscarmellose sodium, crospopidone, or carboxymethyl starch sodium. Particularly preferred is croscarmellose sodium.

These disintegrants may be used alone or in any combination of two or more.

The blending ratio of the disintegrant in the tablet of the present invention can be selected from the range of 10 to 40% by mass as a total amount in 100% by mass of the uncoated tablet. It is preferably 10 to 20% by mass, more preferably 12 to 18% by mass, still more preferably 13 to 16% by mass, and the disintegrants include carboxymethyl celluloses, carboxymethyl starches, crospovidone, and low substitutions. When using at least one selected from the group consisting of degree hydroxypropyl cellulose, low degree of substitution hydroxymethyl starch sodium, starches, alginic acid, and bentonite, the total amount of these is 10 to 30% by mass in 100% by mass of the uncoated tablet. It is desirable to adjust the content to%, preferably 10 to 20% by mass, more preferably 12 to 18% by mass, and particularly preferably 14 to 16% by mass.

(C) Pharmaceutically Active Ingredient The tablet of the present invention is characterized by blending a sugar alcohol as the component (A) and a disintegrant as the component (B), and is mainly produced by these components of the present invention. Other ingredients can be blended as long as they do not interfere with the effect. As one of the other ingredients, (C) a pharmaceutically active ingredient can be preferably mentioned.

As described above, the pharmaceutically active ingredient is particularly limited as long as the tablet containing the pharmaceutically active ingredient in addition to the ingredients (A) and (B) has the effect of the present invention. It's not a thing. Within this limit, specifically, it can be selected from various physiologically active ingredients and / or pharmacologically active ingredients.

For example, sleep sedatives, analgesics, antipyretic analgesics or antipyretic analgesics, anti-inflammatory agents, anti-inflammatory agents, antitussives, expectorants, antitussive expectorants, anti-asthmatic agents, bronchial dilators, antacids or mucosal protective agents. , Anti-allergic drug, sympathomimetic or α-receptor stimulant, anti-inflammatory enzyme drug, central nervous system stimulant, antihypertensive drug, antiarteriosclerotic drug, anti-arrhythmic drug, diabetes drug, hyperlipidemia drug Examples thereof include symptom remedies, antibiotics, crude drugs, stomachic drugs, digestive drugs, intestinal regulators, nourishing tonics, vitamins and minerals. These pharmaceutically active ingredients may be used alone, or may be used in any combination of two or more depending on the target disease or the like. For example, cold medicines usually include antipyretic analgesics, anti-inflammatory drugs, antitussives and / or expectorants (or antitussive expectorants), anti-asthmatic drugs, bronchodilators, antiallergic drugs, antacids or mucosal protective drugs. It can be used in combination, and if necessary, a sleep sedative and an antipyretic may be used in combination.

Preferred pharmaceutically active ingredients in the tablets of the present invention include anti-bronchial asthma agents, bronchodilators, antiallergic agents and the like.

More preferred pharmaceutically active ingredients in the tablets of the present invention include procaterol, fenoterol, clenbuterol, salmeterol, theophylline, amlexanox, ibudilast, pemirolast, zafirlukast, ceratrodust, cetirizine, levosetilizine, olopatadine, montelukast, zafirlukast, and pharmaceutically acceptable thereof. Salt.

When the pharmaceutically active ingredient is blended, the blending ratio of the pharmaceutically active ingredient in the tablet of the present invention varies depending on the target disease and the like, but is usually 80% by mass or less, preferably 0% by mass, in 100% by mass of the uncoated tablet. More can be selected from the range of 70% by mass or less. It is preferably 0.01 to 30% by mass, and more preferably 0.01 to 10% by mass. Further, in the tablet of the present invention, the blending amount (absolute weight) of the pharmaceutically active ingredient per tablet is not limited, but can usually be selected from the range of 0.001 to 50 mg. It is preferably 5 to 12 mg.

(D) Other Ingredients The tablets of the present invention may contain conventional carrier components or additives as long as the effects of the present invention are not impaired. Carrier components or additives include excipients, binders, adsorbents, antioxidants, preservatives, solubilizers, surfactants, fluidizers, plasticizers, pH regulators, colorants, and flavoring agents. , Sweeteners, flavoring agents, adsorbents, preservatives, wetting agents and the like can be exemplified. These carrier components or additives can be used alone or in combination of two or more.

Excipients include, for example, sugars (lactose, glucose, fructose, sucrose, etc.), crystalline cellulose, powdered cellulose, dextrin, β-cyclodextrin, carmellose sodium, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, precipitation. Examples thereof include sex calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, titanium oxide, calcium lactose, magnesium aluminometasilicate, synthetic hydrotalcite, talc, and kaolin. In addition, as an excipient, a sugar alcohol having a hardness characteristic different from that of component (A), specifically, when a 350 mg dose is molded under a load of 12 kN (syrup diameter: 9.5 mmφ), the measured value of the tablet hardness meter is less than 80 N. Sugar alcohols having the strength of (mannitol, D-sorbitol, erythritol, xylitol, powder-reduced maltose starch syrup, etc.) can also be used.

These excipients can be used alone or in combination of two or more. When these excipients are used, the blending ratio of the excipient in the tablet of the present invention is not limited, but can be usually selected from the range of 1 to 40% by mass in 100% by mass of the uncoated tablet. .. It is preferably 10 to 30% by mass.

Examples of the binder include cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, and calximethyl cellulose; polyvinyl alcohol, polyvinylpyrrolidone (povidone), vinylpyrrolidone copolymer (copolyvidone), and acrylic acid-based high molecular weight. Examples of molecules, gelatin, gum arabic, purulan, canten, tragant, sodium alginate, propylene glycol alginate, pregelatinized starch, dextrin, macrogol, sucrose and the like can be exemplified without limitation. Preferred are hydroxypropyl cellulose, hypromellose, methyl cellulose, polyvinyl alcohol, gum arabic, pregelatinized starch, dextrin, pullulan, polyvinylpyrrolidone, and macrogol. These binders can be used alone or in combination of two or more. Among these binders, cellulose derivatives such as hydroxypropyl cellulose and hypromellose are widely used. When these binders are used, the blending ratio of the binder in the tablets of the present invention can be selected from the range of usually 1 to 10% by mass in 100% by mass of the uncoated tablet. It is preferably 2 to 7% by mass.

Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, hydrogenated oil, polyethylene glycol, dimethylpolysiloxane, carnauba wax, sodium lauryl sulfate, beeswax, and beeswax. it can. These lubricants can be used alone or in combination of two or more. Among these lubricants, stearate such as magnesium stearate is widely used. When these lubricants are used, the blending ratio of the lubricant in the tablets of the present invention can be selected from the range of usually 0.01 to 30% by mass in 100% by mass of the uncoated tablet. Examples of the solubilizing agent, which is preferably 0.5 to 3% by mass, include magnesium oxide, calcium oxide, sodium citrate, magnesium chloride, sodium carbonate, and sodium hydrogen carbonate.

Surfactants include polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene, polyoxyethylene fatty acid ester, glycerin monostearate, sorbitan fatty acid ester (sorbitan monostearate, sorbitan monolaurate, etc.), polysorbates, lauryl. Nonionic surfactants such as sodium alkyl sulfate and anionic surfactants such as sodium sulfate, macrogol, and sucrose fatty acid ester can be exemplified.

Examples of the fluidizing agent include light anhydrous silicic acid, talc, hydrous silicon dioxide and the like; and examples of the plasticizer include triethyl citrate, polyethylene glycol, triacetin and cetanol.

Examples of the pH adjuster include organic acids such as glycine, sodium hydrogen carbonate, calcium hydrogen phosphate, sodium hydrogen phosphate, acetic acid, succinic acid, tartaric acid, fumaric acid and citric acid, or salts thereof.

Colorants include water-soluble colorants such as turmeric extract, riboflavin, carotene solution, tar pigment, and caramel, as well as titanium oxide, iron oxide (yellow iron oxide, iron sesquioxide, yellow sesquioxide, red iron oxide, etc.). And water-insoluble colorants such as tar-based pigments (aluminum salts such as lake pigments) can be mentioned.

Sweeteners such as aspartame and stevia, ascorbic acid, menthol, crude kanzo extract, simple syrup, etc. as sweeteners; natural or synthetic sweeteners such as sucrose, D-sorbitol, xylitol, aspartame; As the fragrance, menthol, mint and the like can be exemplified without limitation.

(E) Coating layer As described above, the tablet of the present invention is a coating tablet (sugar-coated tablet, gelatin-encapsulated tablet, film-coated tablet) having a coating layer (coating layer) on its surface even if it is an uncoated tablet. You may.

When the tablet of the present invention is a coated tablet, the coating agent used for forming the coating layer can be appropriately selected and used according to the purpose based on the common general technical knowledge in the art. For example, sugars such as sucrose, D-mannitol, erythritol, sorbitol, xylitol, and trehalose are used in the preparation of sugar-coated tablets. For the preparation of film-coated tablets, hydroxypropyl cellulose (HPC) and water-soluble coating agents such as hypromellose, polyvinyl alcohol, and purulan; hypromellose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and carboxy Enteric coating agents such as methyl ethyl cellulose (CMEC), methacrylic acid copolymer, ceracefate (cellulose phthalate acetate) and cellac; gastrosoluble coating agents such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, polyvinyl acetate diethyl amino acetate; ethyl cellulose And high molecular weight compounds such as sustained release coatings such as aminoalkyl methacrylate copolymers are used.

If necessary, these coating agents may be blended with one or a combination of two or more colorants, flavoring agents, sweetening agents, flavoring agents, light-shielding agents, plasticizers and the like. The blending ratio of these colorants and the like in the coating layer is not limited, but is appropriately adjusted so as to be in the range of 0.0001 to 20% by mass in 100% by mass of the total amount of the components forming the coating layer.

In the coated lock, the ratio of the coating layer (coating layer, coating) is not limited, but can be appropriately selected from the range of usually 1 to 10 parts by mass with respect to 100 parts by mass of the uncoated tablet. It is preferably 1 to 8 parts by mass, and more preferably 2 to 5 parts by mass.

(2) Method for Producing Tablets The tablets of the present invention can preferably be produced by using a wet granule compression method. Specifically, a binder prepared by powder-mixing the components (A) and (B) and, if necessary, other components (for example, a lubricant, a fluidizing agent, etc.) and preparing a solution thereof. It can be produced by adding granulation (wet granulation), drying, sizing, and then compression molding (locking). In the above, when the tablet is a pharmaceutical product, the component (C) can be blended in addition to the components (A) and (B).

This is described for each process as follows.
(I) Ingredients (A) and (B) (in the case of tablets for pharmaceutical use, ingredients (A), (B) and (C)), and if necessary, other ingredients are powder-mixed. And the process of adding a solution-like binder to granulate,
(II) A step of drying and sizing the granulated product obtained in the above step, and (IV) a step of compression molding the product obtained in the above step.

The sizing product obtained in the above step (II) is mixed with at least one of the components (A) and (B) and a lubricant as a powder without granulation, and the prepared mixture is mixed ( It can also be used in the compression molding step of IV). That is, the following step (III) may be further provided between the steps (II) and (IV).

(III) A step of mixing the sized product obtained in the step (II) with at least one of the powdered components (A) and (B) and a powdered lubricant.

It is preferably a production method having steps (I), (II), (III) and (IV).

In the tablet of the present invention, swelling of the tablet can be suppressed and cracks and cracks can be prevented without coating, but coating may be applied if necessary. When the tablet of the present invention is a coated tablet having a coating layer, the coated tablet can be produced by further subjecting the tablet (uncoated tablet) obtained in the above step (IV) to the (V) coating step. ..

Each process will be briefly described below.
(I) Mixing / granulating process At least the components (A), (B) and (C), and (D) other components used for granulation are previously crushed by a crusher (cutter mill, rotary mill, etc.). It may be crushed with a hammer mill, a roll mill, a shear mill, a ball mill, a jet mill, etc., and may be classified as necessary.

In the step (I) (mixing / granulating step), the components (A), (B) and (C) and, if necessary, other components can be mixed so that the powders of these components can be uniformly mixed. Any method may be used, and the mixing method is not particularly limited. A method of mixing using a mixer such as a rotary mixer (for example, a V-type mixer, a bicone-type mixer), a fixed-type mixer (ribbon-type mixer, a screw-type mixer), etc., without limitation. It can be exemplified.

When the tablet of the present invention contains the component (C), the component (C) can be blended in the step (I) with the entire amount of the component (C) contained in the final uncoated tablet. Specifically, as described above, the proportion of the component (C) in 100% by mass of the uncoated tablet is usually 80% by mass or less, preferably more than 0 and 70% by mass, preferably 0.01 to 30% by mass, more preferably. Is an amount such that it is 0.01 to 10% by mass. On the other hand, as the components (A) and (B), one part of the components (A) and (B) contained in the final uncoated tablet can be blended in the step (I). The ratio of the component (A) to be blended in the step (I) may be 0 to 100% by mass, preferably 70 to 100% by mass, out of 100% by mass of the total amount of the component (A) contained in the uncoated tablet. .. Further, as the ratio of the component (B) to be blended in the step (I), 0 to 100% by mass, preferably 20 to 80% by mass, out of 100% by mass of the total amount of the component (B) contained in the uncoated tablet. it can.

Granulation can be carried out by a method (wet granulation method) in which a solution binder, preferably an aqueous binder is added to the powder mixture prepared above to granulate. The concentration of the aqueous solution of the binder to be used is not limited depending on the binder to be used, but can be appropriately selected from the range of 0.5 to 20% by mass. As described above, the proportion of the binder in 100% by mass of the uncoated tablet finally produced is 1 to 10% by mass, preferably 2 to 7% by mass, more preferably 2 by weight of the binder. An amount such as ~ 5% by mass can be mentioned.

The granulation method may be a wet granulation method generally used in the art. For example, a solution-like binder is added to a raw material powder mixture and kneaded, and the kneaded product is extruded from a screen for molding. Extrusion granulation method, which is a method of granulating; crushing, which is a method of cutting a kneaded mass prepared by kneading by the above method with a rotary blade of a granulator and ejecting it from the outer screw eyes by centrifugal force. Granulation method; Rolling granulation method, which is a method of adding a liquid binder to a mixture of raw material powders and applying rotational motion or vibration to the humidified powder to agglomerate them to obtain particles that are close to spherical. A fluid layer granulation method in which a mixture is flowed from below by a hot air stream and sprayed with a solution-like binder to granulate the mixture; raw material powder is put into a container and water is stirred with a rotating blade. Alternatively, a stirring granulation method in which a raw material powder or granular material is agglomerated into a spherical shape by adding a granulation liquid can be exemplified without limitation.

(II) Drying / sizing process For drying the granules prepared in the above step (I), a drying method generally used in the industry is adopted, for example, a parallel flow box type dryer, a ventilation flow. This can be performed using various drying devices such as a box-type dryer, a fluidized bed dryer, and a vacuum-type dryer. Although not limited, in the box type, ventilation type, and fluidized bed type, it is preferable to blow the granulated product with air (hot air) usually heated to about 80 to 90 ° C. to dry it.

The sizing is not particularly limited, and a sizing method generally used in the art can be adopted and is not particularly limited. Preferably, the granules are sized so that there are no coarse particles of 1000 μm or more and the average particle size of the granules is in the range of 100 to 400 μm. Here, the "average particle size" means the average particle size calculated from the result of the sieving method of the second method of powder particle size measurement method specified in the general test method of the 16th revised Japanese Pharmacy Law. ..

(III) Mixing Step In the mixing step, the sized product prepared in the above step (II) is mixed with at least one of the powdered components (A) and (B) and a powdered lubricant. It is a process to do. As in the step (I), the mixing may be performed by a method capable of uniformly mixing the sized product, the component (A) and / or the component (B), and a powder such as a lubricant, for example, a rotary mixer. It can be carried out by mixing using a mixer such as a fixed mixer or a fixed mixer.

The ratio of the powdered component (A) to be blended here may be 0 to 100% by mass, preferably 0 to 30% by mass, out of 100% by mass of the total amount of the component (A) contained in the uncoated tablet. The component (A) used in the step (III) may be the same as the component (A) used for granulation in the step (I), but it is different as long as it has the above-mentioned characteristics. It may be a sugar alcohol. It is preferable to use sugar alcohols that are the same or have some components in common even if they are not completely the same. More preferably, the same type of mannitol is used. The ratio of the component (A) contained in the granulated product to the component (A) used in the step (III) is 2: 1 to 4: 1, preferably 5: 2 to 3: 1 in terms of mass ratio. be able to.

The ratio of the powdered component (B) to be blended here may be 0 to 100% by mass, preferably 20 to 80% by mass, out of 100% by mass of the total amount of the component (B) contained in the uncoated tablet. it can. Here, the disintegrant used in the step (III) may be the same as the disintegrant used for granulation in the step (I), but may be a different disintegrant. It is preferable to use a disintegrant that is the same or has some components in common even if they are not completely the same. The ratio of the component (B) contained in the granulated product to the component (B) used in the step (III) is 1: 2 to 2: 1 in terms of mass ratio, preferably 2: 3 to 3: 2. be able to.

The blending ratio of the lubricant is preferably 0.5 to 3% by mass, more preferably 0.5 to 1.5% by mass so that the ratio of the lubricant in 100% by mass of the uncoated tablet is in the range of 0.01 to 30% by mass. It is possible to exemplify the ratio such that it becomes%.

(IV) Compression molding (locking) process For tableting, a tableting method generally used in the art is adopted. Specifically, it can be performed by using a conventional locking machine such as a single-shot locking machine and a rotary locking machine.

Here, the tableting pressure and other tableting conditions are not limited as long as tablets having the effects of the present invention can be produced, but the following conditions can be mentioned.

The tableting pressure, there may be mentioned normal 100~8,000kgf / cm ^2, preferably 1,000~3,500kgf / cm ^2. More preferably, it is 1,500 to 2,500 kgf / cm ² .

(V) Coating process For coating, a coating method generally used in the art is adopted. Specific examples thereof include a pan coating method, a fluidized bed coating method, a breathable dry pan coating method, and the like, and coating can be performed using a coating device corresponding to these methods.

The coating is performed by coating the surface of the uncoated tablets produced in the steps (I) to (IV) with a coating liquid obtained by blending the above-mentioned coating agent with a colorant, a flavoring agent, a sweetening agent, a flavoring agent, etc. as necessary. It can be done by doing.

The coating is prepared so that the ratio of the coating layer to 100 parts by mass of the uncoated tablet is usually 1 to 10 parts by mass by dry weight. It is preferably 1 to 8 parts by mass, more preferably 2 to 5 parts by mass. The thickness of the coating layer covering the surface of the uncoated tablet is not limited, but can be appropriately adjusted in the range of usually 0.05 to 0.2 mm, preferably 0.06 to 0.15 mm, and more preferably 0.08 to 0.12 mm.

(3) Characteristics of Tablets The tablets of the present invention are characterized by having at least the following characteristics (a) and (b).

(A) Disintegration Specifically, the tablet of the present invention is characterized in that the uncoated tablet has the following disintegrating characteristics.
It disintegrates within 10 minutes in a disintegration test (without an auxiliary panel) specified by the Japanese Pharmacopoeia using water at 37 ° C as the test solution. Here, "disintegrate" (conformity) means that if all 6 test tablets disintegrate in one disintegration test, or 1 or 2 do not disintegrate, a disintegration test is performed with 12 more test tablets. When 16 or more test tablets out of a total of 18 test tablets are disintegrated, it can be judged to be "fit (disintegrate)".

(B) Good shape stability Specifically, the tablet of the present invention is characterized in that the uncoated tablet has the following shape stability.

No shape abnormality such as cracks or cracks is observed when visually inspected after leaving for 24 hours under the conditions of 40 ° C and 75% RH open. Preferably, no cracks or cracks are visually observed even after being left for 48 hours under the same conditions. More preferably, no cracks or cracks are visually observed even after being left under the same conditions for 10 days. Here, "40 ° C., 75% RH open condition" means that the tablet is placed in a container without a lid and the sample is exposed under the condition of 40 ° C. and 75% RH.

Furthermore, the tablets of the present invention can also have at least one of the following properties (c) and (d).

(C) Dissolution Specifically, the tablet of the present invention is characterized in that the uncoated tablet has the following dissolution characteristics.
(C-1) In the dissolution test by the paddle method at 37 ° C. and 50 rpm rotation using water as the test solution, the dissolution rate of the pharmaceutically active ingredient after 60 minutes was 60 to 90%.
(C-2) In the dissolution test by the paddle method at 37 ° C. and 50 rpm rotation using the second solution (pH 6.8) of the Japanese Pharmacopoeia as the test solution, the dissolution rate of the pharmaceutical active ingredient after 60 minutes was 10. ~ 45%.

(D) Inhibitory swelling Specifically, the tablet of the present invention is characterized in that the uncoated tablet has the following expansion rate (swelling rate) (variation rate of tablet thickness with respect to the initial stage).

For example, under the conditions of 40 ° C. and 75% RH opening, the expansion rate (%) of the tablet after 24 hours [100 × (tablet thickness after expansion / initial tablet thickness)] is 106% or less (about 100 to 106%). ), Preferably 105% or less (about 100 to 105%), more preferably 104% or less (about 100 to 104%).

The properties (b) and (d) above are not limited, but are considered to be due to the tablets of the present invention having a relatively high hardness. The tablet of the present invention has a hardness of 35 N or more when measured with a load cell type tablet hardness tester (for example, load cell type tabletop hardness tester, PC-30 type, manufactured by Okada Seiko) (breaking operation speed: 24 mm / min). It is characterized by being. Although the upper limit is not particularly limited, 300N can be exemplified.

The tablet provided by the present invention is preferably a small tablet having a total mass of about 50 to 150 mg per tablet in a relatively small amount. Such tablets have, for example, a total mass of 60 to 80 mg per tablet, a content of component (C) in one tablet of 4.9 to 5.5 mg, a lateral circumference of 15 to 22 mm, and a thickness of 2.3 to 3.6 mm. Includes tablets characterized by a hardness of 35 N or higher. In other embodiments, the total mass per tablet is 135 to 148 mg, the content of the component (C) in one tablet is 9.9 to 10.9 mg, the side circumference is 18 to 25 mm, the thickness is 3.2 to 4.8 mm, and the hardness. Also includes tablets that are 60 N or higher.

The shape of the tablet of the present invention is not particularly limited, and includes, for example, a tablet having an arbitrary shape such as a circular shape, an elliptical shape, and a rhombus shape when viewed from the front surface (upper surface). A tablet having a circular front shape is preferable. In this case, the diameter of the former tablet is preferably in the range of 5.9 to 6.3 mm, and the diameter of the latter tablet is preferably in the range of 6.9 to 7.3 mm.

The tablets of the present invention may be administered once or in a plurality of times (for example, 2 to 6 times) per day. The dose per dose (single dose) can be selected according to gender, age, degree of illness, etc. For example, in the case of tablets, one tablet or a plurality of tablets (for example, 2 to 6 tablets) can be selected. ) May be administered.

Hereinafter, the present invention will be described in more detail based on Examples. However, these examples are examples, and the present invention is not limited to these examples.

Test Method The following experimental method was adopted for the evaluation of the tablet characteristics of Examples 1 to 12 and Comparative Examples 1 to 8 below.

(1) Disintegration test test solution Using water heated to 37 ° C, conduct an experiment according to the general test method [disintegration test method] of the 16th revised Japanese Pharmacopoeia.

(2) Shape stability test After the tablet is left at 40 ° C. and 75% RH open condition for 24 hours, the appearance is visually observed and cracks such as cracks and cracks in the appearance of the tablet are evaluated.

(3) Swelling inhibitory test (rate of change in tablet thickness with respect to the initial stage below)
Measure the thickness of the tablet with a thickness gauge (dial thickness gauge [SM-112], manufactured by Teclock Co., Ltd.). The tablet thickness is measured at the start of the test and after storage at 40 ° C. and 75% RH for 24 hours (after the test), and the rate of change in the tablet thickness after the test is calculated from the start of the test.

(4) Tablet hardness The prepared tablet is subjected to a breaking operation speed of 24 mm / min and a temperature of 25 ± 5 using a load cell type tablet hardness tester (load cell type desktop hardness tester, PC-30 type, manufactured by Okada Seiko Co., Ltd.). It was measured under the condition of ℃.

Reference Examples Table 1 below shows the physical property values of D-mannitol, crystalline cellulose, lactose hydrate, and purified sucrose used in Examples and Comparative Examples.

The tablet hardness (N) below is adjusted so that the water content of the target ingredient is 0.5% by mass or less under the condition of 105 ° C, and then the 350 mg dose is applied to a tableting machine with a tablet diameter of 9.5 mmφ. It is the hardness measured for a compression molded product (tablet) produced by compression molding under the conditions of a tableting load of 12 kN and a compression rate of 20 mm / min. The hardness was measured using a load cell type tablet hardness tester (load cell type desktop hardness tester, PC-30 type, manufactured by Okada Seiko Co., Ltd.) under the conditions of a breaking operation speed of 24 mm / min and a temperature of 25 ± 5 ° C.

The specific surface area (m ² / g) shown in Table 1 is a value measured by the fluid BET one-point method using Macsorb HM-model 1220 (manufactured by Mountech Co., Ltd.). The angle of repose (°) below is a value measured using an angle of repose measuring device (FK type, Konishi Medical Instrument Co., Ltd.). Further, the bulk density (g / mL) shown in Table 1 means the ratio between the mass of the powder sample in the untapped (loose) state and the volume of the powder containing the factor of the interparticle void volume, and is defined in advance. The sample was sieved with a mesh of 1,000 μm and weighed 25 g, and the volume when the sample was put into a measuring cylinder via a filter was measured and calculated. The tap density (g / mL) shown in Table 1 is the bulk density obtained by mechanically tapping the container containing the powder sample, and specifically, tapping until no change in volume is observed. Then, the volume at that time was measured and calculated.

Example 1
The tablets of the present invention were prepared through the following steps.

(1) Preparation of nuclear granules (granulation, drying, and sizing)
Montercasto sodium 1260 g, D-mannitol (Pertec M100) 9490 g, and croscarmellose sodium 1200 g to a high-speed stirring granulator (VG-FM50 type manufactured by Paulek Co., Ltd .: blade 180 rpm, cross screw 3578 rpm) Add 4830 g of 1 wt% hydroxypropyl cellulose solution for granulation, then fluidized bed granulator / dryer (WSG15 manufactured by Paulek Co., Ltd .: air supply temperature 85 ° C (80-90 ° C), air volume: 4 It was dried at -12 m ³ / min) until the water content of the granules became 2% or less. Next, the dried granules were sized with a screen type sizing machine (Comil QC-197S type manufactured by Paulek Co., Ltd .: screen size 991 μm, rotation speed 25 Hz) to prepare nuclear granules.

(2) Preparation of uncoated tablets (mixing with extragranular additives, tableting)
10000 g of nuclear granules, 2770 g of D-mannitol (Pearitol 200SD), 1100 g of croscarmellose sodium, and 130 g of magnesium stearate prepared in (1) above are mixed in a container rotary mixer (Matsubo Co., Ltd. Bole container mixer). MC100 / PM-100, rotation speed 10 rpm) was mixed for 20 minutes to prepare granules for tableting. Here, D-mannitol, sodium croscarmellose, and magnesium stearate were all in powder form. Next, using a rotary type locking machine (Kikusui Seisakusho collect 12HUK: rotation speed 40 rpm), a mass of 140 mg / tablet is locked with a circular lock mold having a diameter of 7 mm with a locking load of 900 kgf. It was molded to obtain an uncoated tablet.

(3) Preparation of coated lock (coating)
9% by weight using a tablet coating machine (manufactured by Paulek Co., Ltd., ventilation type coating machine DRC650 type, air supply temperature 50-60 ° C, air volume 4 m ³ / min) to the uncoated tablet prepared in (2) above. A coating solution consisting of 7940 g of hypromellose solution, 110 g of titanium oxide, 0.5 g of iron sesquioxide, and 2.5 g of yellow iron sesquioxide was sprayed and coated until the film weight for one tablet (140 mg of uncoated tablet) was 8 mg.

The total mass of each of the obtained coated tablets was 148 mg, of which the content of sodium montelukast corresponding to the component (C) was 10.4 mg, the peripheral length of the side surface was 22.6 mm, and the thickness was 3.6 mm.

(4) Tablet characteristics As a result of the disintegration test, the tablet (coated tablet) of Example 1 showed disintegration within 10 minutes, and the hardness was 192N. As a result of the shape stability test, after the tablet was left at 40 ° C. and 75% RH open condition for 24 hours, when the appearance was visually observed, no cracks such as cracks and cracks were observed in the appearance of the tablet. Furthermore, as a result of the swelling inhibitory test, the fluctuation rate of the tablet thickness was 3.3%, and it was confirmed that the swelling rate was suppressed as compared with the fluctuation rate (7.3%) of Comparative Example 1 described later.

Example 2
(1) Preparation of nuclear granules (granulation, drying, and sizing)
Montercasto sodium 1260 g, D-mannitol (Pertec M100) 9490 g, and croscarmellose sodium 1200 g to a high-speed stirring granulator (VG-FM50 type manufactured by Paulek Co., Ltd .: blade 180 rpm, cross screw 3578 rpm) Add 4830 g of 1 wt% hydroxypropyl cellulose solution to granulate, then fluidized bed granulator / dryer (WSG15 manufactured by Paulek Co., Ltd .: air supply temperature 85 ° C (80-90 ° C), air volume: 3- It was dried at 11 m ³ / min) until the water content of the granules became 2% or less. The dried granules were sized with a screen type sizing machine (Comil QC-197S type manufactured by Paulek Co., Ltd .: screen size 991 μm, rotation speed 25 Hz) to prepare nuclear granules.

(2) Preparation of uncoated tablets (mixing with extragranular additives, tableting)
1500 g of nuclear granules prepared in (1) above, 420 g of D-mannitol (Pearitol 200SD), 165 g of croscarmellose sodium, and 20 g of magnesium stearate (all in powder form) were placed in a container rotary mixer (((1)). Bole container mixer MC10 / LM-20 manufactured by Matsubo Co., Ltd., rotating speed 14 rpm) was mixed for 20 minutes to obtain granules for tableting. Next, using a rotary locking machine (Kikusui Seisakusho collect 12HUK: rotation speed 40 rpm), a mass of 70 mg / tablet was tableted with a circular tablet mold with a diameter of 6 mm at a tableting load of 1000 kgf. And got an uncoated tablet.

(3) Preparation of coated lock (coating)
9% by weight using a tablet coating machine (manufactured by Paulek Co., Ltd., ventilation type coating machine DRC350 type, air supply temperature 45-55 ° C, air volume 100 m ³ / min) to the uncoated tablet prepared in (2) above. A coating solution consisting of 6880 g of hypromellose solution, 170 g of titanium oxide, 0.8 g of iron sesquioxide, and 3.6 g of yellow iron sesquioxide was sprayed and coated until the film weight for one tablet (70 mg uncoated tablet) was 5 mg.

The total mass of each of the obtained coated tablets was 75 mg, of which the content of sodium montelukast corresponding to the component (C) was 5.2 mg, the peripheral length of the side surface was 19.5 mm, and the thickness was 2.6 mm.

(4) Tablet characteristics As a result of the disintegration test, the tablets (coated tablets) prepared above showed disintegration within 10 minutes, and the hardness was 99N. As a result of the shape stability test, after the tablet was left at 40 ° C. and 75% RH open condition for 24 hours, when the appearance was visually observed, no cracks such as cracks and cracks were observed in the appearance of the tablet. Furthermore, as a result of the swelling inhibitory test, the fluctuation rate of the tablet thickness was 3.8%, and it was confirmed that the swelling rate was suppressed as compared with the fluctuation rate (7.3%) of Comparative Example 1 described later.

Example 3
(1) Preparation of nuclear granules (granulation, drying, and sizing)
Montercasto sodium 3.0 g, D-mannitol (Pertec M100) 20.0 g, and croscarmellose sodium 2.5 g are granulated in a dairy pot by adding 9.0 g of 1 wt% hydroxypropyl cellulose solution, and a ventilation dryer (Yamato Scientific Co., Ltd.) ) Drying Oven DV600: Air supply temperature 60 ° C) dried until the granule moisture content was 2% or less. The dried granules were crushed in a mortar, and the dried product passed through a 500 μm mesh screen (sieve) was used as nuclear granules.

(2) Preparation of uncoated tablets (mixing with extragranular additives, tableting)
Put 25.0 g of nuclear granules prepared in (1), 7.0 g of D-mannitol (Pearitol 200SD), 3.0 g of croscarmellose sodium, and 0.5 g of magnesium stearate (all in powder form) in a vinyl bag. The granules were mixed by shaking for a minute to obtain granules for tableting. Using a single-shot tableting machine (AUTOGRAPH AG-X manufactured by Shimadzu Corporation), a mass of 140 mg / tablet was tableted with a circular tablet mold with a diameter of 7 mm at a tableting load of 800 kgf. , I got an uncoated tablet.

The total mass of the obtained uncoated tablets was 140 mg, of which the content of montelukast sodium corresponding to the component (C) was 11.6 mg, the lateral circumference was 22 mm, and the thickness was 3.5 mm.

(3) Tablet characteristics As a result of the disintegration test, the tablets prepared above showed disintegration within 10 minutes, and the hardness was 120 N. As a result of the shape stability test, after the tablet was left at 40 ° C. and 75% RH open condition for 24 hours, when the appearance was visually observed, no cracks such as cracks and cracks were observed in the appearance of the tablet.

Example 4
(1) Preparation of uncoated tablets (granulation, drying, sizing, and tableting)
Weigh 620 g of D-mannitol (Pertec M100) and 115 g of croscarmellose sodium, and weigh 4 weights with a high-speed stirring granulator (VG-FM05 type manufactured by Paulek Co., Ltd .: blade 380 rpm, cross screw 3585 rpm). Granulate by adding 100 g of% hydroxypropyl cellulose solution, fluidized bed dryer (WSG15 type manufactured by Paulek Co., Ltd .: Air supply temperature 85 ° C (80-90 ° C), air volume: 3-11 m ³ / min) The granules were dried until the water content of the granules became 2% or less. The dried granules were sized with a screen type sizing machine (Comill QC-197S type manufactured by Paulek Co., Ltd .: screen size 991 μm, rotation speed 25 Hz). Next, the sized product and 4 g of magnesium stearate were placed in a vinyl bag and shaken for 1 minute to mix them into granules for tableting, and a rotary tableting machine (Kikusui Seisakusho Collect 12HUK: rotation speed 40 rpm). A tablet having a mass of 250 mg / tablet was tablet-molded with a circular tablet mold having a diameter of 9 mm at a tableting load of 1400 kgf to obtain an uncoated tablet. In addition, as the (C) medicinal active ingredient, the above-mentioned various medicinal active ingredients shall be blended in the uncoated tablet in a proportion of 80% by mass or less, preferably 0.01 to 30% by mass, based on 100% by mass of the uncoated tablet. Can be done.

(2) Preparation of coated lock (coating)
A 10 wt% hypromellose solution was applied to the uncoated tablet prepared in (1) above using a tablet coating machine (manufactured by Paulek Co., Ltd., ventilation type coating machine DRC200 type, air supply temperature 55 ° C, air volume 38 m ³ / min). A coating solution consisting of 800 g, 20 g of titanium oxide, and 0.5 g of iron sesquioxide was sprayed, and the spraying was terminated when the film weight per tablet (250 mg) became 5 mg.

The total mass of each of the obtained coated tablets was 255 mg, the peripheral length of the side surface was 28.9 mm, and the thickness was 3.85 mm.

(3) Tablet characteristics As a result of the disintegration test, the tablets prepared above showed disintegration within 10 minutes, and the hardness was 143N. As a result of the shape stability test, after the tablet was left at 40 ° C. and 75% RH open condition for 24 hours, when the appearance was visually observed, no cracks such as cracks and cracks were observed in the appearance of the tablet. Furthermore, as a result of the swelling inhibitory test, the fluctuation rate of the tablet thickness was 2.9%, and it was confirmed that the swelling rate was suppressed as compared with the fluctuation rate (7.3%) of Comparative Example 1 described later.

Example 5
(1) Preparation of nuclear granules (granulation, drying, and sizing)
D-mannitol (Pearitol 100SD) 400 g, corn starch 100 g, and low-substituted hydroxypropyl cellulose 100 g, fluidized bed granulation dryer (MP-01 manufactured by Paulec Co., Ltd.), air supply temperature 85 ° C (80-) It was dried while spraying 400 g of 3 wt% polyvinyl alcohol at 90 ° C.) and an air volume of 3-11 m ³ / min) to obtain granulated granules having a water content of 2.5 wt% or less. In addition, in the nuclear granules, as (C) the pharmaceutical active ingredient, the ratio of the above-mentioned various pharmaceutical active ingredients in 100% by mass of the uncoated tablet is 80% by mass or less, preferably 0.01 to 30% by mass. Can be blended with.

(2) Preparation of uncoated tablets (mixing with extragranular additives, tableting)
The dried granulated granules prepared in (1) were sized with a screen type sizing machine (Comil QC-197S type manufactured by Paulek Co., Ltd .: screen size 991 μm, rotation speed 25 Hz). Next, put the sized product and 4 g of magnesium stearate in a vinyl bag and shake for 1 minute to mix them into granules for tableting, and use a rotary tableting machine (Kikusui Seisakusho Collect 12HUK: rotation speed 40 rpm). Then, a tablet having a mass of 180 mg / tablet was tablet-molded with a circular tablet mold having a diameter of 8 mm at a tableting load of 1000 kgf to obtain an uncoated tablet.

(3) Preparation of coated lock (coating)
Using a tablet coating machine (manufactured by Paulek Co., Ltd., ventilation type coating machine DRC200 type, air supply temperature 55 ° C, air volume 38 m ³ / min) on the uncoated tablets prepared in (2), a 10 wt% hypromellose solution 800 g The coating solution consisting of the above was sprayed, and the spraying was terminated when the film weight per tablet (180 mg) became 5 mg.

The total mass of each of the obtained coated tablets was 185 mg, the peripheral length of the side surface was 25.8 mm, and the thickness was 3.9 mm.

(4) Tablet characteristics As a result of the disintegration test, the tablets prepared above showed disintegration within 10 minutes, and the hardness was 152N. As a result of the shape stability test, after the tablet was left at 40 ° C. and 75% RH open condition for 24 hours, when the appearance was visually observed, no cracks such as cracks and cracks were observed in the appearance of the tablet.

Example 6
(1) Preparation of uncoated tablets (granulation, drying, sizing, and tableting)
D-mannitol (Pearitol 200SD) 400 g, crystalline cellulose 50 g, corn starch 50 g, low-substituted hydroxypropyl cellulose 90 g, and magnesium stearate 4 g in a container rotary mixer (Matsubo Co., Ltd. Bole container mixer) MC10 / LM-20: Mix at 14 rpm for 20 minutes to make starch for tableting. Using a rotary type tableting machine (Kikusui Seisakusho collect 12HUK: rotation speed 40 rpm) for tableting granules, a mass of 180 mg / tablet is used in a circular tablet mold with a diameter of 8 mm at a tableting load of 1200 kgf. It was molded into a lock to obtain an uncoated tablet. In addition, as the (C) medicinal active ingredient, the above-mentioned various medicinal active ingredients shall be blended in the uncoated tablet in a proportion of 80% by mass or less, preferably 0.01 to 30% by mass, based on 100% by mass of the uncoated tablet. Can be done.

(2) Preparation of coated lock (coating)
10 wt% hypromellose solution 800 using a tablet coating machine (manufactured by Paulek Co., Ltd., ventilation type coating machine DRC200 type, air supply temperature 55 ° C, air volume 38 m ³ / min) to the uncoated tablets prepared in (1). The coating solution consisting of g and 20 g of titanium oxide was sprayed, and the spraying was terminated when the film weight per tablet (180 mg) became 5 mg.

The total mass of each of the obtained coated tablets was 185 mg, the peripheral length of the side surface was 25.8 mm, and the thickness was 3.80 mm.

(3) Tablet characteristics As a result of the disintegration test, the tablets prepared above showed disintegration within 10 minutes, and the hardness was 103N. As a result of the shape stability test, after the tablet was left at 40 ° C. and 75% RH open condition for 24 hours, when the appearance was visually observed, no cracks such as cracks and cracks were observed in the appearance of the tablet.

Example 7
(1) Preparation of uncoated tablets (drying, granulation, and tableting)
122 g of D-mannitol (Pertec M100), 60 g of potato starch, 100 g of crystalline cellulose, 15 g of crospovidone, and 3 g of magnesium stearate in a container rotary mixer (Matsubo Co., Ltd. Bole container mixer MC5 / LM- 20: Mixing at 20 rpm) for 20 minutes to obtain granules for tableting. Using a rotary type tableting machine (Kikusui Seisakusho collect 12HUK: rotation speed 40 rpm) for tableting granules, a mass of 300 mg / tablet is used in a circular tablet mold with a diameter of 9 mm at a tableting load of 1200 kgf. It was molded into a lock to obtain an uncoated tablet.

The total mass of each of the obtained coated tablets was 300 mg, the peripheral length of the side surface was 28.3 mm, and the thickness was 4.2 mm.

Example 8
(1) Preparation of nuclear granules (granulation, drying, and sizing)
Montercasto sodium 1260 g, D-mannitol (Pertec DeltaM) 9490 g, and croscarmellose sodium 1200 g to a high-speed stirring granulator (VG-FM50 type manufactured by Paulek Co., Ltd .: blade 180 rpm, cross screw 3578 rpm) Add 4830 g of 1 wt% hydroxypropyl cellulose solution to granulate, then fluidized bed granulator / dryer (WSG15 manufactured by Paulek Co., Ltd .: air supply temperature 85 ° C (80-90 ° C), air volume: 4 -12 m ³ / min) to dry the granules until the water content is 2% or less. Next, the dried granules are sized with a screen type sizing machine (Comil QC-197S type manufactured by Paulek Co., Ltd .: screen size 991 μm, rotation speed 25 Hz) to prepare nuclear granules.

(2) Preparation of uncoated tablets (mixing with extragranular additives, tableting)
10000 g of nuclear granules prepared in (1) above, 2770 g of D-mannitol (Pearitol 200SD), 1100 g of croscarmellose sodium, and 130 g of magnesium stearate (all in powder form) are placed in a container rotary mixer. (Matsubo Co., Ltd. Bole container mixer MC100 / PM-100, rotation speed 10 rpm) was mixed for 20 minutes to obtain granules for tableting. Next, using a rotary type locking machine (Kikusui Seisakusho collect 12HUK: rotation speed 40 rpm), a mass of 140 mg / tablet is locked with a circular lock mold having a diameter of 7 mm with a locking load of 900 kgf. Mold and obtain uncoated tablets.

(3) Preparation of coated lock (coating)
Using a tablet coating machine (manufactured by Paulek Co., Ltd., ventilation type coating machine DRC650 type, air supply temperature 50-60 ° C, air volume 4 m ³ / min), 9% by weight of the uncoated tablet prepared in (2) above. A coating solution consisting of 7940 g of hypromellose solution, 110 g of titanium oxide, 0.5 g of iron sesquioxide, and 2.5 g of yellow iron sesquioxide is sprayed and coated until the film weight per tablet (140 mg of uncoated tablet) is 8 mg.

Example 9
(1) Preparation of nuclear granules (granulation, drying, and sizing)
1260 g of Montercast sodium, 9490 g of D-mannitol (Pertec DeltaM), and 1200 g of croscarmellose sodium were added to a high-speed stirring granulator (VG-FM50 type manufactured by Paulek Co., Ltd .: blade 180 rpm, cross screw 3578 rpm). Add 4830 g of 1 wt% hydroxypropyl cellulose solution for granulation, then fluidized bed granulation dryer (WSG15 type manufactured by Paulek Co., Ltd .: air supply temperature 85 ° C (80-90 ° C), air volume: 3- Dry at 11 m ³ / min) until the water content of the granules is 2% or less. The dried granules are sized with a screen type sizing machine (Comil QC-197S type manufactured by Paulek Co., Ltd .: screen size 991 μm, rotation speed 25 Hz) to prepare nuclear granules.

(2) Preparation of uncoated tablets (mixing with extragranular additives, tableting)
1500 g of nuclear granules prepared in (1) above, 420 g of D-mannitol (Pearitol 200SD), 165 g of croscarmellose sodium, and 20 g of magnesium stearate (all in powder form) are placed in a container rotary mixer. (Matsubo Co., Ltd. Bole container mixer MC10 / LM-20, rotation speed 14 rpm) was mixed for 20 minutes to obtain granules for tableting. Next, using a rotary locking machine (Kikusui Seisakusho collect 12HUK: rotation speed 40 rpm), a mass of 70 mg / tablet was tableted with a circular tablet mold with a diameter of 6 mm at a tableting load of 1000 kgf. And get an uncoated tablet.

(3) Preparation of coated lock (coating)
9% by weight using a tablet coating machine (manufactured by Paulec Co., Ltd., ventilation type coating machine DRC350 type, air supply temperature 45-55 ° C, air volume 100 m ³ / min) to the uncoated tablet prepared in (2) above. Spray a coating solution consisting of 6880 g of hypromellose solution, 170 g of titanium oxide, 0.8 g of iron sesquioxide, and 3.6 g of yellow iron sesquioxide, and coat until the film weight per tablet (70 mg of uncoated tablet) is 5 mg. ..

Example 10
(1) Preparation of nuclear granules (granulation, drying, and sizing)
1260 g of Montercast sodium, 9490 g of D-mannitol (granutol S), and 1200 g of croscarmellose sodium, high-speed stirring granulator (VG-FM50 type manufactured by Paulek Co., Ltd .: blade 180 rpm, cross screw 3578 rpm) To granulate by adding 4830 g of 1 wt% hydroxypropyl cellulose solution, then a fluidized bed granulator / dryer (WSG15 manufactured by Paulek Co., Ltd .: air supply temperature 85 ° C (80-90 ° C), air volume: Dry at 4-12 m ³ / min) until the water content of the granules is 2% or less. Next, the dried granules are sized with a screen type sizing machine (Comil QC-197S type manufactured by Paulek Co., Ltd .: screen size 991 μm, rotation speed 25 Hz) to prepare nuclear granules.

(2) Preparation of uncoated tablets (mixing with extragranular additives, tableting)
10000 g of nuclear granules prepared in (1) above, 2770 g of D-mannitol (Pearitol 200SD), 1100 g of croscarmellose sodium, and 130 g of magnesium stearate (all in powder form) are placed in a container rotary mixer. (Matsubo Co., Ltd. Bole container mixer MC100 / PM-100, rotation speed 10 rpm) was mixed for 20 minutes to obtain granules for tableting. Next, using a rotary type locking machine (Kikusui Seisakusho collect 12HUK: rotation speed 40 rpm), a mass of 140 mg / tablet is locked with a circular lock mold having a diameter of 7 mm with a locking load of 900 kgf. Mold and obtain uncoated tablets.

(3) Preparation of coated lock (coating)
Using a tablet coating machine (manufactured by Paulek Co., Ltd., ventilation type coating machine DRC650 type, air supply temperature 50-60 ° C, air volume 4 m ³ / min), 9% by weight of the uncoated tablet prepared in (2) above. A coating solution consisting of 7940 g of hypromellose solution, 110 g of titanium oxide, 0.5 g of iron sesquioxide, and 2.5 g of yellow iron sesquioxide is sprayed and coated until the film weight per tablet (140 mg of uncoated tablet) is 8 mg.

Example 11
(1) Preparation of nuclear granules (granulation, drying, and sizing)
1260 g of Montercast sodium, 9490 g of D-mannitol (granutol S), and 1200 g of croscarmellose sodium, high-speed stirring granulator (VG-FM50 type manufactured by Paulek Co., Ltd .: blade 180 rpm, cross screw 3578 rpm) Granules were made by adding 4830 g of 1 wt% hydroxypropyl cellulose solution, and then a fluidized bed granulation dryer (WSG15 type manufactured by Paulek Co., Ltd .: air supply temperature 85 ° C (80-90 ° C), air volume: 3 -11 m ³ / min) to dry the granules until the water content is 2% or less. The dried granules are sized with a screen type sizing machine (Comil QC-197S type manufactured by Paulek Co., Ltd .: screen size 991 μm, rotation speed 25 Hz) to prepare nuclear granules.

(2) Preparation of uncoated tablets (mixing with extragranular additives, tableting)
1500 g of nuclear granules prepared in (1) above, 420 g of D-mannitol (Pearitol 200SD), 165 g of croscarmellose sodium, and 20 g of magnesium stearate (all in powder form) are placed in a container rotary mixer. (Matsubo Co., Ltd. Bole container mixer MC10 / LM-20, rotation speed 14 rpm) was mixed for 20 minutes to obtain granules for tableting. Next, using a rotary locking machine (Kikusui Seisakusho collect 12HUK: rotation speed 40 rpm), a mass of 70 mg / tablet was tableted with a circular tablet mold with a diameter of 6 mm at a tableting load of 1000 kgf. And get an uncoated tablet.

(3) Preparation of coated lock (coating)
9% by weight using a tablet coating machine (manufactured by Paulec Co., Ltd., ventilation type coating machine DRC350 type, air supply temperature 45-55 ° C, air volume 100 m ³ / min) to the uncoated tablet prepared in (2) above. Spray a coating solution consisting of 6880 g of hypromellose solution, 170 g of titanium oxide, 0.8 g of iron sesquioxide, and 3.6 g of yellow iron sesquioxide, and coat until the film weight per tablet (70 mg of uncoated tablet) is 5 mg. ..

Example 12
(1) Preparation of uncoated tablets (drying, granulation, and tableting)
122 g of D-mannitol (granutol S), 60 g of potato starch, 100 g of crystalline cellulose, 15 g of crospovidone, and 3 g of magnesium stearate in a container rotary mixer (Matsubo Co., Ltd. Bole container mixer MC5 / LM -20: Mix at 20 rpm) for 20 minutes to make granules for tableting. Using a rotary type tableting machine (Kikusui Seisakusho collect 12HUK: rotation speed 40 rpm) for tableting granules, a mass of 300 mg / tablet is used in a circular tablet mold with a diameter of 9 mm at a tableting load of 1200 kgf. It is molded into a lock to obtain an uncoated tablet.

Comparative Example 1
(1) Preparation of uncoated tablets (granulation, drying, sizing, and tableting)
Weighing 620 g of D-mannitol (Mannit P) and 115 g of croscarmellose sodium, 4 weights with a high-speed stirring granulator (VG-FM05 type manufactured by Paulek Co., Ltd .: blade 380 rpm, cross screw 3585 rpm) Granulate by adding 100 g of% hydroxypropyl cellulose solution, fluidized bed dryer (MP-01 manufactured by Paulek Co., Ltd., air supply temperature 85 ° C (80-90 ° C), air volume 3-11 m ³ / min) The mixture was dried until the water content was 2% by weight or less. The dried granules are sized with a screen sizing machine (Coul QC-197S type manufactured by Paulek Co., Ltd .: screen size 991 μm, rotation speed 25 Hz), and then the sized product and magnesium stearate 4 g. In a vinyl bag, shake for 1 minute to mix to form granules for tableting, and use a rotary tableting machine (Kikusui Seisakusho collect 12HUK: rotation speed 40 rpm) to measure 250 mg / tablet in diameter. An uncoated tablet was obtained by tableting with a 9 mm circular tablet mold with a tableting load of 1400 kgf.

(2) Preparation of coated lock (coating)
A 10 wt% hypromellose solution was applied to the uncoated tablet prepared in (1) above using a tablet coating machine (manufactured by Paulek Co., Ltd., ventilation type coating machine DRC200 type, air supply temperature 55 ° C, air volume 38 m ³ / min). A coating solution consisting of 800 g, 20 g of titanium oxide, and 0.5 g of iron sesquioxide was sprayed, and the spraying was terminated when the film weight per tablet (250 mg) became 5 mg.

The total mass of each of the obtained coated tablets was 255 mg, the circumference of the side surface was 28.9 mm, and the thickness was 3.8 mm.

(3) Tablet characteristics As a result of the disintegration test, the tablets prepared above showed disintegration within 10 minutes, and the hardness was 67 N. However, as a result of the shape stability test, after the tablet was left at 40 ° C. and 75% RH open condition for 24 hours, when the appearance was visually observed, cracks such as cracks and cracks were observed in the appearance of the tablet. Furthermore, as a result of the swelling inhibitory test, the fluctuation rate of the tablet thickness was 7.3%.

Comparative Example 2
(1) Preparation of uncoated tablets (drying, granulation, and tableting)
D-mannitol (Mannit P) 400 g, crystalline cellulose 50 g, corn starch 50 g, low-substituted hydroxypropyl cellulose 90 g, and magnesium stearate 4 g container rotary mixer (Matsubo Co., Ltd. Bole container) Mixing with a mixer MC5 / LM-20 (rotation speed 20 rpm) for 20 minutes to obtain granules for tableting. Using a rotary type tableting machine (Kikusui Seisakusho collect 12HUK: rotation speed 40 rpm) for tableting granules, a mass of 250 mg / tablet is used in a circular tablet mold with a diameter of 9 mm at a tableting load of 1200 kgf. It was molded into a lock to obtain an uncoated tablet.

Comparative Example 3
(1) Preparation of uncoated tablets (drying, granulation, and tableting)
122 g of D-mannitol (Mannit P), 60 g of potato starch, 100 g of crystalline cellulose, 15 g of crospovidone, and 3 g of magnesium stearate in a container rotary mixer (Matsubo Co., Ltd. Bole container mixer MC5 / LM) -20: Mixing at 20 rpm) for 20 minutes to obtain granules for tableting. Using a rotary type tableting machine (Kikusui Seisakusho collect 12HUK: rotation speed 40 rpm) for tableting granules, a mass of 300 mg / tablet is used in a circular tablet mold with a diameter of 9 mm at a tableting load of 1200 kgf. It was molded into a lock to obtain an uncoated tablet.

Comparative Example 4
(1) Preparation of uncoated tablets (granulation, drying, sizing, and tableting)
Weigh 620 g of lactose hydrate (DMV200M) and 115 g of croscarmellose sodium, and use a high-speed stirring granulator (VG-FM05 type manufactured by Paulek Co., Ltd .: blade 380 rpm, cross screw 3585 rpm) to 4% by weight. Granulate by adding 100 g of hydroxypropyl cellulose solution to a fluidized bed dryer (MP-01 manufactured by Paulek Co., Ltd., air supply temperature 85 ° C (80-90 ° C), air volume 3-11 m ³ / min). Then, it was dried until the water content became 2% by weight or less. The dried granules are sized with a screen sizing machine (Coul QC-197S type manufactured by Paulek Co., Ltd .: screen size 991 μm, rotation speed 25 Hz), and then the sized product and magnesium stearate 4 g. In a vinyl bag and shake for 1 minute to mix to form granules for tableting. Using a rotary tableting machine (Kikusui Seisakusho collect 12HUK: rotation speed 40 rpm), weigh 245 mg / tablet in diameter. An uncoated tablet was obtained by tableting with a 9 mm circular tablet mold with a tableting load of 1400 kgf.

(2) Preparation of coated lock (coating)
A 10 wt% hypromellose solution was applied to the uncoated tablet prepared in (1) above using a tablet coating machine (manufactured by Paulek Co., Ltd., ventilation type coating machine DRC200 type, air supply temperature 55 ° C, air volume 38 m ³ / min). A coating solution consisting of 800 g, 20 g of titanium oxide, and 0.5 g of iron sesquioxide was sprayed, and the spraying was terminated when the film weight per tablet (250 mg) became 5 mg.

Comparative Example 5
(1) Preparation of uncoated tablets (granulation, drying, sizing, and tableting)
Weigh 620 g of crystalline cellulose (PH-101) and 115 g of croscarmellose sodium, and use a high-speed stirring granulator (VG-FM05 type manufactured by Paulek Co., Ltd .: blade 380 rpm, cross screw 3585 rpm) to 4% by weight. Granulate by adding 100 g of hydroxypropyl cellulose solution to a fluidized bed dryer (MP-01 manufactured by Paulek Co., Ltd., air supply temperature 85 ° C (80-90 ° C), air volume 3-11 m ³ / min). Then, it was dried until the water content became 2% by weight or less. The dried granules are sized with a screen sizing machine (Coul QC-197S type manufactured by Paulek Co., Ltd .: screen size 991 μm, rotation speed 25 Hz), and then the sized product and magnesium stearate 4 g. In a vinyl bag and shake for 1 minute to mix to form granules for tableting. Using a rotary tableting machine (Kikusui Seisakusho collect 12HUK: rotation speed 40 rpm), weigh 245 mg / tablet in diameter. An uncoated tablet was obtained by tableting with a 9 mm circular tablet mold with a tableting load of 1400 kgf.

(2) Preparation of coated lock (coating)
A 10 wt% hypromellose solution was applied to the uncoated tablet prepared in (1) above using a tablet coating machine (manufactured by Paulek Co., Ltd., ventilation type coating machine DRC200 type, air supply temperature 55 ° C, air volume 38 m ³ / min). A coating solution consisting of 800 g, 20 g of titanium oxide, and 0.5 g of iron sesquioxide was sprayed, and the spraying was terminated when the film weight per tablet (250 mg) became 5 mg.

Comparative Example 6
(1) Preparation of uncoated tablets (granulation, drying, sizing, and tableting)
Weighing 620 g of D-mannitol (Pearitol 35 micron) and 115 g of croscarmellose sodium, 4 weights with a high-speed stirring granulator (VG-FM05 type manufactured by Paulek Co., Ltd .: blade 380 rpm, cross screw 3585 rpm) Granulate by adding 100 g of% hydroxypropyl cellulose solution, fluidized bed dryer (MP-01 manufactured by Paulek Co., Ltd., air supply temperature 85 ° C (80-90 ° C), air volume 3-11 m ³ / min) The mixture was dried until the water content was 2% by weight or less. The dried granules are sized with a screen sizing machine (Coul QC-197S type manufactured by Paulek Co., Ltd .: screen size 991 μm, rotation speed 25 Hz), and then the sized product and magnesium stearate 4 g. In a vinyl bag and shake for 1 minute to mix to form granules for tableting. Using a rotary tableting machine (Kikusui Seisakusho collect 12HUK: rotation speed 40 rpm), weigh 245 mg / tablet in diameter. An uncoated tablet was obtained by tableting with a 9 mm circular tablet mold with a tableting load of 1400 kgf.

(2) Preparation of coated lock (coating)
A 10 wt% hypromellose solution was applied to the uncoated tablet prepared in (1) above using a tablet coating machine (manufactured by Paulek Co., Ltd., ventilation type coating machine DRC200 type, air supply temperature 55 ° C, air volume 38 m ³ / min). A coating solution consisting of 800 g, 20 g of titanium oxide, and 0.5 g of iron sesquioxide was sprayed, and the spraying was terminated when the film weight per tablet (250 mg) became 5 mg.

Comparative Example 7
(1) Preparation of uncoated tablets (granulation, drying, sizing, and tableting)
Weigh 620 g of D-mannitol (Pearitol 160C) and 115 g of croscarmellose sodium, and use a high-speed stirring granulator (VG-FM05 type manufactured by Paulek Co., Ltd .: blade 380 rpm, cross screw 3585 rpm) to 4% by weight. Granulate by adding 100 g of hydroxypropyl cellulose solution to a fluidized bed dryer (MP-01 manufactured by Paulek Co., Ltd., air supply temperature 85 ° C (80-90 ° C), air volume 3-11 m ³ / min). Then, it was dried until the water content became 2% by weight or less. The dried granules are sized with a screen sizing machine (Coul QC-197S type manufactured by Paulek Co., Ltd .: screen size 991 μm, rotation speed 25 Hz), and then the sized product and magnesium stearate 4 g. In a vinyl bag and shake for 1 minute to mix to form granules for tableting. Using a rotary tableting machine (Kikusui Seisakusho collect 12HUK: rotation speed 40 rpm), weigh 245 mg / tablet in diameter. An uncoated tablet was obtained by tableting with a 9 mm circular tablet mold with a tableting load of 1400 kgf.

(2) Preparation of coated lock (coating)
A 10 wt% hypromellose solution was applied to the uncoated tablet prepared in (1) above using a tablet coating machine (manufactured by Paulek Co., Ltd., ventilation type coating machine DRC200 type, air supply temperature 55 ° C, air volume 38 m ³ / min). A coating solution consisting of 800 g, 20 g of titanium oxide, and 0.5 g of iron sesquioxide was sprayed, and the spraying was terminated when the film weight per tablet (250 mg) became 5 mg.

Comparative Example 8
(1) Preparation of uncoated tablets (granulation, drying, sizing, and tableting)
Weigh 620 g of refined sucrose (non-parel 103) and 115 g of croscarmellose sodium, and use a high-speed stirring granulator (VG-FM05 type manufactured by Paulec Co., Ltd .: blade 380 rpm, cross screw 3585 rpm) to 4% by weight hydroxy Granulate by adding 100 g of propyl cellulose solution, and use a fluidized bed dryer (MP-01 manufactured by Paulek Co., Ltd., air supply temperature 85 ° C (80-90 ° C), air volume 3-11 m ³ / min). , Dryed until the water content was 2% by weight or less. The dried granules are sized with a screen sizing machine (Coul QC-197S type manufactured by Paulek Co., Ltd .: screen size 991 μm, rotation speed 25 Hz), and then the sized product and magnesium stearate 4 g. In a vinyl bag and shake for 1 minute to mix to form granules for tableting. Using a rotary tableting machine (Kikusui Seisakusho collect 12HUK: rotation speed 40 rpm), weigh 245 mg / tablet in diameter. An uncoated tablet was obtained by tableting with a 9 mm circular tablet mold with a tableting load of 1400 kgf.

(2) Preparation of coated lock (coating)
A 10 wt% hypromellose solution was applied to the uncoated tablet prepared in (1) above using a tablet coating machine (manufactured by Paulek Co., Ltd., ventilation type coating machine DRC200 type, air supply temperature 55 ° C, air volume 38 m ³ / min). A coating solution consisting of 800 g, 20 g of titanium oxide, and 0.5 g of iron sesquioxide was sprayed, and the spraying was terminated when the film weight per tablet (250 mg) became 5 mg.

Claims (14)

A tablet containing (A) sugar alcohol, (B) disintegrant and (C) granules containing a pharmaceutical active ingredient, and (A) sugar alcohol, (B) disintegrant and lubricant mixed powder. hand,
The content of (A) is sugar alcohol which is molded with a mass of 350 mg and 12 kN (bare diameter: 9.5 mmφ) and shows a strength of 80 N or more when measured with a tablet hardness tester, and the content ratio of the disintegrant (B). , 10-40% by mass in 100% by mass of uncoated tablets,
Tablets with at least one of the following properties:
(I) The ratio of the granulated material to the mixed powder is 2: 1 to 3: 1 in terms of mass ratio.
(Iii) The ratio of the (A) sugar alcohol in the granulated material to the (A) sugar alcohol in the mixed powder is 2: 1 to 4: 1 in terms of mass ratio. The tablet according to claim 1, which is a coated tablet. The tablet according to claim 2, wherein the ratio of the coating layer to 100 parts by mass of the uncoated tablet is 1 to 10 parts by mass. The tablet according to any one of claims 1 to 3, wherein the content ratio of the sugar alcohol (A) in 100% by mass of the uncoated tablet is 20 to 90% by mass. (A) Any of claims 1 to 4, wherein the sugar alcohol is mannitol which is molded with a mass of 350 mg and 12 kN (bare diameter: 9.5 mmφ) and shows a strength of 80 N or more when measured with a tablet hardness tester. Tablets to describe. (B) Disintegrants are croscarmellose, crospovidone, carboxymethyl starch, low-degree-of-substitution hydroxypropyl cellulose, carmellose, crystalline cellulose-carmellose, corn starch, potato starch, low-degree-of-substitution hydroxymethyl starch and their pharmaceuticals. The tablet according to any one of claims 1 to 5, which is at least one selected from the group consisting of acceptable salts. (B) The tablet according to any one of claims 1 to 6, wherein the content ratio of the disintegrant is 10 to 20% by mass in 100% by mass of the uncoated tablet. (C) The tablet according to any one of claims 1 to 7, wherein the pharmaceutically active ingredient is more than 0% by mass and 70% by mass or less in 100% by mass of the uncoated tablet. The tablet according to any one of claims 1 to 8, wherein the content of the (C) pharmaceutically active ingredient per tablet is 5 to 12 mg. (C) The pharmaceutically active ingredient comprises procaterol, fenoterol, clenbuterol, salmeterol, theophylline, amlexanox, ibudilast, pemirolast, zafirlukast, ceratrodust, cetirizine, levosetilizine, olopatadine, montelukast, zafirlukast and pharmaceutically acceptable salts thereof. The tablet according to any one of claims 1 to 9, which is at least one selected from the above. The tablet according to any one of claims 1 to 10, wherein the total mass per tablet is 50 to 150 mg. Granules containing (A) sugar alcohol, (B) disintegrant and (C) pharmaceutical active ingredient prepared by the wet granulation method, (A) sugar alcohol, (B) disintegrant, and lubricant. The method for producing a tablet according to any one of claims 1 to 11, further comprising a step of mixing and tableting in a powder state without granulating. The production method according to claim 12, wherein the ratio of the powder mixture to be blended with respect to 100 parts by mass of the granulated product is 35 to 45 parts by mass. The production method according to claim 12 or 13, further comprising a coating step of coating the uncoated tablet with a coating agent.