JPWO2017047586A1 - tablet - Google Patents

Abstract

  The present invention provides a tablet having excellent shape stability and a method for producing the same, wherein the appearance change (swelling, cracking, cracking, etc.) due to moisture absorption is significantly suppressed while containing a disintegrant in a high proportion. . The tablet of the present invention contains (A) a mass of 350 mg, 12 kN (mold diameter: 9.5 mmφ), a sugar alcohol exhibiting a strength of 80 N or more when measured with a tablet hardness meter, and (B) a disintegrant. The content ratio of the component (B) in 100% by mass of the uncoated tablet is 10 to 40% by mass.

Description

  The present invention relates to a tablet excellent in shape stability. More specifically, the present invention relates to a tablet having excellent shape stability, which contains a disintegrant at a high ratio and is significantly suppressed in appearance change (swelling, cracking, cracking, etc.) due to moisture absorption.

  Ingredients to be blended into tablets include excipients added to increase the amount to an appropriate amount for ease of handling when there are few active ingredients, disintegrants added to facilitate tablet release and release of active ingredients, raw material powder There are a binder added to bind body particles, a lubricant added to improve the fluidity of raw material powder particles and to facilitate compression formation. Each pharmaceutical company manufactures and sells tablets that exhibit dissolution and disintegration according to the purpose by examining the types and amounts of additives and the production method of the preparation.

  Disintegrants are useful additives for adjusting the disintegration properties of tablets and the dissolution properties of active ingredients. However, tablets containing a high proportion of disintegrants absorb moisture in the air and cause cracks. There existed a problem that it produced or a crack generate | occur | produced in the film part of a film coat tablet. In the past, problems such as tablet cracking have been prevented by blending a large amount of other components such as excipients and relatively reducing the content of the disintegrant. However, it is difficult to reduce the size of the tablet because it contains more excipient than necessary.

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

  The inventors of the present invention have made extensive studies to solve the above-mentioned problems, and in the manufacture of tablets containing a disintegrant in a relatively large proportion of 10 to 40% by mass in 100% by mass of uncoated tablets, By using a sugar alcohol that shows a strength of 80 N or more measured by a tablet hardness tester when a 350 mg dose is molded at a load of 12 kN (inguinal diameter: 9.5 mmφ). It was found that a tablet in which the change was significantly suppressed was obtained. In addition, such tablets can be preferably produced by a method of compressing granules prepared by a wet granulation method (wet granule compression method), particularly the above-mentioned specific sugar alcohol, disintegrant and pharmaceutically active ingredient as a wet granule compression method. Adopting a production method comprising the steps of granulating the powder mixture and mixing the tablet in the powder state without granulating the specific sugar alcohol, disintegrant and lubricant to the granulated product, and tableting It has been found that it can be more suitably manufactured. Furthermore, it has been found that by making the ratio of the disintegrant in the granulated product with respect to the disintegrant contained in the uncoated tablet more than a certain value, a tablet in which the external shape change with time is significantly suppressed can be obtained.

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

(1) Tablet (1-1) (A) Sugar alcohol showing a strength of 80 N or more when molded with a mass of 350 mg, 12 kN (示 す diameter: 9.5 mmφ) and measured with a tablet hardness meter, and (B) disintegration Containing agents,
(B) A tablet having a disintegrant content of 10 to 40% by mass in 100% by mass of an 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 which is molded at a mass of 350 mg and 12 kN (inguinal diameter: 9.5 mmφ) and has a strength of 80 N or more when measured with a tablet hardness tester. ) Or (1-2).

  (1-4) (B) Disintegrant is croscarmellose, crospovidone, carboxymethyl starch, low-substituted hydroxypropylcellulose, carmellose, crystalline cellulose carmellose, corn starch, potato starch, low-substituted 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 pharmaceutically acceptable salts thereof.

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

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

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

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

  (1-9) (C) The pharmaceutically active ingredient is procaterol, fenoterol, clenbuterol, salmeterol, theophylline, amlexanox, ibudilast, pemirolast, zafirlukast, seratrodast, cetirizine, levocetirizine, olopatadine, montelukast, zafirlukast and pharmaceutically acceptable thereof The tablet according to (1-7) or (1-8), which is at least one selected from the group consisting of:

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

(1-11) Granulated product containing (A) sugar alcohol, (B) disintegrant and (C) pharmaceutically active ingredient, and (A) sugar alcohol, (B) mixed powder of 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 product to the mixed powder is 2: 1 to 3: 1 by mass ratio.
(Ii) The ratio of the (B) disintegrant in the granulated product to the (B) disintegrant in the mixed powder is 1: 2 to 2: 1 by 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 performed using 37 ° C water as a test solution, it disintegrates within 10 minutes.

(1-15) The tablet according to (1-14), further having at least one of the following properties (2) and (3):
(2) When conducting a dissolution test using 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 is 60 to 90% (3) Test When conducting a dissolution test using the paddle method at 37 ° C and rotation at 50 rpm per minute using the JP 2nd liquid (pH 6.8) as the solution, the dissolution rate of the pharmaceutically active ingredient after 60 minutes is 10 to 45%. is there.

(2) Tablet manufacturing method (2-1 ) The tablet manufacturing method according to any one of (1-1) to (1-15), which includes a step of manufacturing using a wet granule compression method.

  (2-2) A granule containing (A) component and (B) component (and (C) pharmaceutically active ingredient as required) prepared by wet granulation method, (A) component, ( B) The method for producing a tablet according to (2-1), comprising a step of mixing the component and the lubricant in a powder state without granulation and tableting.

(2-3) mixing (I) (A) component and (B) component (and (C) pharmaceutically active ingredient as required), adding a liquid binder and granulating;
(II) drying and granulating the granulated product obtained in the above step, and (III) at least one of the powdered (A) component and (B) component of the granulated product obtained in the above step And the production method according to (2-1) or (2-2), which comprises a step of mixing with a powdered lubricant and tableting the mixture.

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

  (2-5) The ratio of the (A) component in the granulated product to the powdered (A) component mixed therewith is 2: 1 to 4: 1 by mass ratio (2-2) to ( The production method according to any one of 2-4).

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

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

(2-8) The production method according to any one of (2-1) to (2-7), which has 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 hydroxypropylcellulose, hypromellose, methylcellulose, polyvinyl alcohol, gum arabic, pregelatinized starch, dextrin, pullulan, polyvinylpyrrolidone, and macrogol. The production method according to any one of 2-1) to (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 a tablet containing a disintegrant in a relatively high proportion of 10 to 40% by mass in 100% by mass of the uncoated tablet, and is excellent in appearance stability in a high humidity environment. And According to the production method of the present invention, a tablet having the above characteristics can be produced. In addition, according to the present invention, there are provided a small tablet having the above characteristics and a method for producing the same, although 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) Tablet The tablet of the present invention is a tablet containing (A) a sugar alcohol and (B) a disintegrant, and the content ratio of (B) in 100% by mass of the uncoated tablet is 10 to 40% by mass. Yes, and (A) shows that the 350 mg amount is molded with a load of 12 kN (diameter: 9.5 mmφ) and shows a strength of 80 N or more with a tablet hardness meter when measured with a tablet hardness meter. Features.

  In the present invention, the “tablet” means a solid preparation having a certain shape for oral administration unless otherwise specified. These include ordinary tablets, orally disintegrating tablets, chewable tablets, troche tablets, Sublingual tablets, foamed tablets, dispersible tablets, dissolving tablets, and sustained release tablets are included. Tablets other than orally disintegrating tablets are preferable, and ordinary tablets are more preferable. The tablets targeted by the present invention include single-layer tablets having a single-layer structure and multilayer tablets having a plurality of layer structures of two or more layers. A monolayer tablet is preferable. Furthermore, the tablets of the present invention include uncoated uncoated tablets (bare tablets), sugar-coated tablets, gelatin-encapsulated tablets, and film-coated tablets (including enteric tablets and gastric tablets) (for uncoated tablets, These are also collectively referred to as “coated tablets”).

  Hereinafter, each component which comprises the tablet of this invention is demonstrated.

(A) Sugar alcohol The sugar alcohol used as the component (A) in the present invention has a hardness characteristic that exhibits a hardness as high as 80 N or more when compressed by itself. In the present specification, a sugar alcohol having such hardness characteristics may be simply referred to as “component (A)”. Specifically, when the corresponding component 350 mg is compression-molded using a tableting machine having a diameter of 9.5 mmφ at a pressure load of 12 kN and a compression speed of 20 mm / min, the hardness of the resulting compression-molded product (tablet) is The sugar alcohol is characterized by having a tablet hardness meter measured value of 80 N or more. When two or more sugar alcohols are used in combination, when 350 mg of the mixture of sugar alcohols is compression molded under the above conditions, the strength of the resulting compression molded product (tablet) is 80 N or more as measured with a tablet hardness meter. In some cases, a mixture of these excipients also corresponds to the component (A) defined in the present invention.

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

  Here, the sugar alcohol used for the hardness measurement is prepared by adjusting the moisture content so that the moisture content detected at 105 ° C. is 0.5% by mass or less. Moreover, as a tablet hardness meter used for measuring the strength of a compression-molded product of sugar alcohol, a load cell type table hardness meter (PC-30 type, manufactured by Okada Seiko Co., Ltd.) can be exemplified. The measurement conditions are 25 ± 5 ° C. and the breaking operation speed is 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. Preferably, it is a sugar alcohol used in the manufacture of pharmaceuticals or foods, and has the above-mentioned hardness characteristics. Examples of sugar alcohols used in the manufacture of pharmaceuticals or foods include mannitol, erythritol, sorbitol, maltitol, isomalt, lactitol, xylitol, and powdered reduced maltose starch syrup. These sugar alcohols can be used alone or in combination of two or more as long as they have the hardness characteristics described above. Further, as described above, when two or more kinds are combined, the above hardness characteristics may be exhibited. Preferred are mannitol, erythritol, sorbitol, maltitol, isomalt, lactitol, xylitol, and powdered reduced maltose starch syrup. Of these, mannitol, erythritol, isomalt, and maltitol are preferable. Particularly preferred is mannitol.

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

  Although it does not restrict | limit as a mixture ratio of the said (A) component in a tablet, it can select from the range of 10-90 mass% normally as a total amount in 100 mass% of uncoated tablets. Preferably it is 20-90 mass%, More preferably, it is 30-85 mass%, Most preferably, it is 50-85 mass%. When the component (A) is mannitol, the ratio of the mannitol in 100% by mass of the uncoated tablet is usually 10 to 85% by mass, preferably 30 to 85% by mass, more preferably 50 to 85% by mass, although not limited. is there.

(B) Disintegrating agent As the disintegrating agent in the tablet of the present invention, those that are usually used for the production of tablets can be widely used. In this specification, the disintegrant may be simply referred to as “component (B)”. Although not limited, for example, carboxymethylcelluloses (for example, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crystalline cellulose / carmellose sodium, etc.), carboxymethyl starches (for example, carboxymethyl starch, carboxymethyl starch) Sodium), crospovidone, low-substituted hydroxypropylcellulose, low-substituted hydroxymethyl starch sodium, starches (corn starch, potato starch, etc.), alginic acid, bentonite and the like. Preferably, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low substituted hydroxypropylcellulose, carmellose sodium, carmellose calcium, carmellose, crystalline cellulose carmellose sodium, corn starch, potato starch, and low degree of substitution Hydroxymethyl starch sodium. More preferred are low-substituted hydroxypropylcellulose, carmellose calcium, croscarmellose sodium, crospovidone, and sodium carboxymethyl starch. Particularly preferred is croscarmellose sodium.

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

  The mixing ratio of the disintegrant in the tablet of the present invention can be selected from the range of usually 10 to 40% by mass as a total amount in 100% by mass of the uncoated tablet. Preferably 10 to 20% by mass, more preferably 12 to 18% by mass, and still more preferably 13 to 16% by mass. Among the above, carboxymethyl celluloses, carboxymethyl starches, crospovidone, low substitution When using at least one selected from the group consisting of high-degree hydroxypropyl cellulose, low-substituted hydroxymethyl starch sodium, starches, alginic acid, and bentonite, the total amount of these is 10 to 30% in 100% by weight of the uncoated tablet %, 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 the combination of the sugar alcohol as the component (A) and the disintegrant as the component (B). As long as the effect is not hindered, other components can be blended. One of the other components is preferably (C) a pharmaceutically active ingredient.

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

  For example, sleep sedative, antipruritic, antipyretic analgesic or antipyretic analgesic, anti-inflammatory, antiemetic, antitussive, expectorant, antitussive expectorant, antiasthmatic, bronchodilator, antacid or mucosal protective , Antiallergic drugs, sympathomimetic drugs or alpha receptor stimulants, anti-inflammatory enzyme drugs, central nervous system stimulants, antihypertensive drugs, anti-arteriosclerotic drugs, antiarrhythmic drugs, diabetes drugs, antihyperlipidemic drugs, hyperuricemia Therapeutic agents, antibiotics, herbal medicines, stomach medicines, digestives, intestinal regulating agents, nourishing tonics, vitamins, minerals and the like can be exemplified. These pharmaceutically active ingredients may be used alone or in any combination of two or more according to the target disease. For example, cold medicines usually include antipyretic analgesics, anti-inflammatory drugs, antitussives and / or expectorants (or antitussive expectorants), antiasthma drugs, bronchodilators, antiallergic drugs, antacids, mucosal protective drugs, etc. It can be used in combination, and if necessary, a sleep sedative, an antipruritic, etc. may be used in combination.

  Preferred active pharmaceutical ingredients in the tablet of the present invention include antibronchial asthma drugs, bronchodilators, antiallergic drugs and the like.

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

  The blending ratio of the pharmaceutically active ingredient in the tablet of the present invention when blending the pharmaceutically active ingredient varies depending on the target disease and the like, but is usually 80% by weight or less, preferably 0% by weight in 100% by weight of the plain tablet More than 70% by mass can be selected. Preferably it is 0.01-30 mass%, More preferably, it is 0.01-10 mass%. 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. Preferably it is 5-12 mg.

(D) Other components The tablet of this invention may contain the usual carrier component or additive, unless the effect of this invention is impaired. Carrier components or additives include excipients, binders, lubricants, antioxidants, preservatives, solubilizers, surfactants, fluidizers, plasticizers, pH adjusters, colorants, flavoring agents. And sweeteners, flavoring agents, adsorbents, preservatives, wetting agents and the like. These carrier components or additives can be used alone or in combination of two or more.

  Examples of excipients include sugars (lactose, glucose, fructose, sucrose, etc.), crystalline cellulose, powdered cellulose, dextrin, β-cyclodextrin, carmellose sodium, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, sedimentation Examples thereof include basic calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, titanium oxide, calcium lactate, magnesium aluminate metasilicate, synthetic hydrotalcite, talc, and kaolin. In addition, sugar alcohol with different hardness characteristics from component (A) as an excipient, specifically less than 80 N measured by a tablet hardness tester when a 350 mg dose is molded with a load of 12 kN (inguinal diameter: 9.5 mmφ) A sugar alcohol having the following strength (mannitol, D-sorbitol, erythritol, xylitol, powdered 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 mixing ratio of the excipient in the tablet of the present invention is not limited, but can be selected from the range of usually 1 to 40% by mass in 100% by mass of the uncoated tablet. . Preferably it is 10-30 mass%.

  Examples of the binder include cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, and carxymethyl cellulose; polyvinyl alcohol, polyvinyl pyrrolidone (povidone), vinyl pyrrolidone copolymer (copolyvidone), acrylic acid type high Molecules, gelatin, gum arabic, pullulan, agar, tragacanth, sodium alginate, propylene glycol alginate, pregelatinized starch, dextrin, macrogol, sucrose and the like can be exemplified without limitation. Preferred are hydroxypropylcellulose, hypromellose, methylcellulose, polyvinyl alcohol, gum arabic, pregelatinized starch, dextrin, pullulan, polyvinylpyrrolidone, and macrogol. These binders can be used alone or in combination of two or more. Of these binders, cellulose derivatives such as hydroxypropylcellulose and hypromellose are widely used. When these binders are used, the blending ratio of the binder in the tablet 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. Preferably it is 2-7 mass%.

Examples of lubricants 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 wax it can. These lubricants can be used alone or in combination of two or more. Of these lubricants, stearates such as magnesium stearate are widely used. When these lubricants are used, the blending ratio of the lubricant in the tablet 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 that is preferably 0.5 to 3% by mass include magnesium oxide, calcium oxide, sodium citrate, magnesium chloride, sodium carbonate, sodium bicarbonate, and the like.

  Surfactants include polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene, polyoxyethylene fatty acid ester, glyceryl monostearate, sorbitan fatty acid ester (such as sorbitan monostearate, sorbitan monolaurate), polysorbates, lauryl Nonionic surfactants and anionic surfactants such as sodium sulfate, 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. Examples of the plasticizer include triethyl citrate, polyethylene glycol, triacetin, and cetanol.

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

  Examples of the colorant include water-soluble colorants such as turmeric extract, riboflavin, carotene solution, tar pigment, and caramel, and titanium oxide, iron oxide (yellow iron oxide, iron sesquioxide, yellow iron sesquioxide, bengara, etc.), And water-insoluble colorants such as tar-based pigments (aluminum salts such as lake pigments).

  As sweeteners, sweeteners such as aspartame and stevia, ascorbic acid, menthol, licorice crude extract, simple syrup, etc .; As sweeteners, natural or synthetic sweeteners such as sucrose, D-sorbitol, xylitol, aspartame; Examples of the fragrances include menthol and mint without limitation.

(E) Coating layer As described above, the tablet of the present invention may be an uncoated tablet or a coated tablet (sugar-coated tablet, gelatin-encapsulated tablet, film-coated tablet) having a coating layer (coating layer) on its surface. May be.

  When the tablet of this invention is a coated tablet, the coating agent used for formation of a coating layer can be suitably selected and used based on the technical common sense of this industry according to the objective. For example, sugars such as sucrose, D-mannitol, erythritol, sorbitol, xylitol and trehalose are used for the preparation of sugar-coated tablets. For the preparation of film-coated tablets, hydroxypropylcellulose (HPC) and water-soluble coating agents such as hypromellose, polyvinyl alcohol, pullulan; hypromellose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), carboxy Enteric coating agents such as methyl ethyl cellulose (CMEC), methacrylic acid copolymer, seracephate (cellulose acetate phthalate) and shellac; gastric soluble coating agents such as polyvinyl acetal diethyl amino acetate, aminoalkyl methacrylate copolymer, polyvinyl acetate diethyl amino acetate; ethyl cellulose And polymeric compounds such as sustained-release coatings such as aminoalkyl methacrylate copolymers That.

  In addition, a coloring agent, a corrigent, a sweetener, a flavoring agent, a light-shielding agent, a plasticizer, etc. can also be mix | blended with these coating agents as needed. 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 components forming the coating layer.

  In the coated tablet, the ratio of the coating layer (coating layer, film) 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. Preferably it is 1-8 mass parts, More preferably, it is 2-5 mass parts.

(2) Manufacturing method of tablet The tablet of this invention can be preferably manufactured using the wet granule compression method. Specifically, the binder prepared by mixing the components (A) and (B) and, if necessary, other components (for example, a lubricant and a fluidizing agent) in powder form. And then granulated (wet granulation), dried, sized, and then compression-molded (tablet). In addition, in the above, when a tablet is a pharmaceutical, (C) component can be mix | blended in addition to (A) and (B) component.

This is described as follows for each process.
(I) (A) component and (B) component (in the case of a tablet for pharmaceutical use, (A) component, (B) component and (C) component), and other components as needed And adding a solution 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.

  In addition, the granulated product obtained in the above step (II) is mixed with powder without granulating at least one of the component (A) and the component (B) and the lubricant, and the prepared mixture is ( It can also be subjected to the compression molding process 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 powdery component (A) and the component (B) and a powdery lubricant.

  A production method having steps (I), (II), (III) and (IV) is preferred.

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

Each step will be briefly described below.
(I) Mixing and granulating step At least (A), (B) and (C) components, and (D) other components such as other components used for granulation are pre-pulverized (cutter mill, rotary mill, (Hammer mill, roll mill, shear mill, ball mill, jet mill, etc.) and may be classified as necessary.

  In the step (I) (mixing / granulating step), the components (A), (B) and (C), and other components, if necessary, can be mixed uniformly with the powder of these components. Any method may be used, and the mixing method is not particularly limited. Although not limited, a method of mixing using a mixer such as a rotary mixer (for example, a V-type mixer, a double cone mixer), a fixed mixer (ribbon-type mixer, screw-type mixer), or the like. It can be illustrated.

  In addition, when the tablet of this invention contains (C) component, the said (C) component can mix | blend the whole quantity of (C) component contained in a final uncoated tablet in (I) process. 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 such an amount as 0.01-10% by mass. On the other hand, (A) and (B) component can mix | blend 1 part in the (I) process among (A) and (B) component of the quantity contained in a final uncoated tablet. (I) As a ratio of (A) component mix | blended at a process, 0-100 mass%, Preferably 70-100 mass% can be mentioned among 100 mass% of (A) component whole quantity contained in an uncoated tablet. . Moreover, as a ratio of (B) component mix | blended by (I) process, 0-100 mass%, Preferably 20-80 mass% is mentioned among 100 mass% of (B) component whole quantity contained in an uncoated tablet. it can.

  Granulation can be performed by a method (wet granulation method) in which a powdery mixture prepared above is added with a solution binder, preferably an aqueous binder, and granulated. The aqueous solution concentration of the binder to be used varies depending on the binder to be used and is not limited, but can be appropriately selected from the range of usually 0.5 to 20% by mass. As described above, the amount of the binder is 1 to 10% by mass, preferably 2 to 7% by mass, more preferably 2 in terms of the dry weight of the binder in 100% by mass of the finally produced uncoated tablet. An amount of ˜5% by mass can be mentioned.

  The granulation method may be a wet granulation method generally used in the industry. For example, a raw material powder mixture is kneaded by adding a solution-like binder, and the kneaded product is extruded from a screen and molded. Extrusion granulation method, which is a granulation method; crushing is a method in which a kneaded mass prepared by kneading by the above method is cut with a rotary blade of a granulator, and is ejected from the eyes of the outer screw by centrifugal force Granulation method: Rotating granulation method, which is a method of adding a solution-like binder to a raw material powder mixture and agglomerating it by applying rotational motion or vibration to the moistened powder to obtain particles that are nearly spherical; raw material powder Fluidized bed granulation method in which a mixture is fluidized from below by a hot air stream and sprayed with a solution binder and granulated; the raw material powder is put into a container and stirred with a rotating blade. Or, agitation granulation method that agglomerates raw material granules into a spherical shape by adding granulation liquid Etc. can be exemplified without limitation.

(II) Drying and sizing step For drying the granulated product prepared in the above step (I), a drying method generally used in the industry is adopted, for example, a parallel flow box dryer, aeration flow It can carry out using various drying apparatuses, such as a box-type dryer, a fluidized bed dryer, and a vacuum dryer. Although not limited, it is preferable to dry the granulated product by applying air (hot air) usually heated to about 80 to 90 ° C. in the box type, vent type, and fluidized bed type.

  The sizing is not particularly limited, and a sizing method generally used in the industry can be adopted and is not particularly limited. Preferably, the particles 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 screening method of the powder particle size measurement method No. 2 defined in the General Test Method of the 16th revision Japanese Pharmacopoeia. .

(III) Mixing step The mixing step mixes the sized product prepared in the above step (II) with at least one of the powdery component (A) and the component (B) and a powdery lubricant. It is a process to do. As in the step (I), the mixing may be any method that can uniformly mix the sized product, the component (A) and / or the component (B), and a powder such as a lubricant. For example, a rotary mixer Or by using a mixer such as a stationary mixer.

  The proportion of the powdery component (A) to be blended here is 0 to 100% by mass, preferably 0 to 30% by mass, out of 100% by mass of the total amount of component (A) contained in the uncoated tablet. The component (A) used in the step (III) may be the same as the component (A) used in the granulation in the step (I), but is different as long as it has the characteristics described above. It may be a sugar alcohol. It is preferable to use sugar alcohols that are not identical or completely identical but have some common components. More preferably, the same kind 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.

  Moreover, the ratio of the powdery (B) component mix | blended here is 0-100 mass% among 100 mass% of (B) component whole quantity contained in an uncoated tablet, Preferably it mentions 20-80 mass%. 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 disintegrants that are not identical or completely identical but have some common components. 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, preferably 2: 3 to 3: 2 by mass ratio. be able to.

  The blending ratio of the lubricant is preferably 0.5 to 3% by weight, more preferably 0.5 to 1.5% by weight so that the ratio of the lubricant in 100% by weight of the uncoated tablet is in the range of 0.01 to 30% by weight. An example of such a ratio is%.

(IV) Compression molding (tablet) process For tableting, a tableting method generally used in the industry is employed. Specifically, it can be performed using a conventional tableting machine such as a single tableting machine or a rotary tableting machine.

  Here, the tableting pressure and other tableting conditions are not limited as long as the tablet 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 The coating method generally used in this industry is employ | adopted for coating. Specific examples include a pan coating method, a fluidized bed coating method, and an air-drying pan coating method, and coating can be performed using a coating apparatus corresponding to these methods.

  For coating, the surface of the uncoated tablet produced in steps (I) to (IV) is coated with a coating solution containing the above-mentioned coating agent and, if necessary, a colorant, a corrigent, a sweetener, and a flavoring agent. Can be done.

  The coating is prepared such 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. Preferably it is 1-8 mass parts, More preferably, it is 2-5 mass parts. 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, more preferably 0.08 to 0.12 mm.

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

(A) Disintegration property Specifically, the tablet of the present invention is characterized in that the uncoated tablet has the following disintegration characteristics.
Disintegrates within 10 minutes in the disintegration test prescribed by the Japanese Pharmacopoeia using 37 ° C water as the test solution (without use of auxiliary panel). Here, “disintegrate” (adapted) means that all six test tablets disintegrate in one disintegration test, or if one or two disintegrate did not disintegrate, an additional 12 test tablets could be disintegrated. It is possible to determine that “adapted (disintegrates)” when 16 or more test tablets of a total of 18 test tablets 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 abnormalities in shape such as cracks and cracks are observed when visually inspected after leaving for 24 hours under open conditions at 40 ° C and 75% RH. Preferably, even after being left for 48 hours under the same conditions, no cracks or cracks are visually observed. More preferably, no cracks or cracks are visually observed even after being left for 10 days under the same conditions. Here, “40 ° C., 75% RH open condition” means that the tablet is placed in a container without a lid and the specimen is exposed under the conditions of 40 ° C., 75% RH.

  Furthermore, the tablet of the present invention may have at least one of the following properties (c) and (d).

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

(D) Swelling inhibitory property 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, the expansion rate (%) of tablets after 24 hours under the condition of 40 ° C. and 75% RH release [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%).

  Although the characteristics of (b) and (d) are not limited, it is considered that the tablet of the present invention has 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 table hardness tester, PC-30 type, manufactured by Okada Seiko) (breaking 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 relatively small and small tablet having a total mass of about 50 to 150 mg per tablet. Such tablets include, for example, a total mass of 60 to 80 mg per tablet, a content of component (C) in the tablet of 4.9 to 5.5 mg, a side circumference of 15 to 22 mm, and a thickness of 2.3 to 3.6 mm. And tablets characterized by a hardness of 35 N or more. In another embodiment, the total mass per tablet is 135 to 148 mg, the content of component (C) in the 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, the hardness Tablets that are 60 N or more are also included.

  In the tablet of the present invention, the shape is not particularly limited, and examples include tablets having an arbitrary shape such as a circle, an ellipse, and a rhombus when viewed from the front (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 tablet of the present invention may be administered once or 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, for tablets, one tablet or multiple tablets (for example, 2 to 6 tablets) ) May be administered.

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

Test Method The following experimental methods were employed for evaluating 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 16th revised Japanese Pharmacopoeia general test method [Disintegration test method].

(2) Shape stability test The tablet is left for 24 hours under an open condition of 40 ° C. and 75% RH, and then the appearance is visually observed to evaluate cracks such as cracks and cracks in the tablet appearance.

(3) Swelling inhibition test (variation rate of tablet thickness with respect to the following initial stage)
The thickness of the tablet is measured with a thickness meter (Dial Thickness Gauge [SM-112], manufactured by Teclock Co., Ltd.). The tablet thickness is measured at the start of the test and at each time point after storage at 40 ° C. and 75% RH for 24 hours (after the test), and the rate of change of the tablet thickness after the test relative to the start of the test is calculated.

(4) Tablet hardness Using the load cell type tablet hardness tester (load cell type table hardness tester, PC-30 type, manufactured by Okada Seiko Co., Ltd.), the prepared tablet was subjected to a breaking operation speed of 24 mm / min and a temperature of 25 ± 5. It measured on the conditions of (degreeC).

Reference Example Table 1 below shows physical properties 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 is 0.5 mass% or less under the condition of 105 ° C, and the 350 mg dose is adjusted to a tableting machine with a tablet diameter of 9.5 mmφ. 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 speed of 20 mm / min. The hardness was measured using a load cell type tablet hardness tester (load cell type table hardness tester, PC-30 type, manufactured by Okada Seiko Co., Ltd.) at 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 a fluid BET single point method using Macsorb HM-model 1220 (manufactured by Mountec Co., Ltd.). The angle of repose (°) below is a value measured using an angle of repose measuring instrument (FK type, Konishi Medical Instrument Co., Ltd.). Furthermore, the bulk density (g / mL) described in Table 1 means the ratio between the mass of the powder sample in a non-tapped (loosened) state and the volume of the powder including the interparticle void volume factor. The sample was sieved with a sieve having an opening of 1,000 μm and weighed 25 g, and the volume when the sample was put into a graduated cylinder through a funnel was 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 tap until no change in volume is observed. The volume at that time was measured and calculated.

Example 1
The tablet of this invention was prepared through the following process.

(1) Preparation of core granules (granulation, drying, and sizing)
Montelukast sodium 1260 g, D-mannitol (Partec M100) 9490 g, and croscarmellose sodium 1200 g were added to a high-speed agitation granulator (VG-FM50 type, manufactured by Paulek Co., Ltd .: blade 180 rpm, cross screw 3578 rpm). Add 4830 g of 1 wt% hydroxypropylcellulose solution and granulate, then fluidized bed granulator (WSG15, manufactured by POWREC Co., Ltd .: supply temperature 85 ° C (80-90 ° C), air volume: 4 -12 m ³ / min) until the granule moisture was 2% or less. Next, the dried granule was sized with a screen granulator (Comil QC-197S, manufactured by POWREC Co., Ltd .: screen size 991 μm, rotation speed 25 Hz) to prepare a nuclear granule.

(2) Preparation of uncoated tablets (mixing with extragranular additives, tableting)
10000 g of core granules prepared in (1) above, 2770 g of D-mannitol (Pearitol 200SD), 1100 g of croscarmellose sodium, and 130 g of magnesium stearate are mixed in a container-rotating mixer (Bore container mixer manufactured by Matsubo Co., Ltd.) MC100 / PM-100, rotating at 10 rpm) for 20 minutes to obtain granules for tableting. Here, D-mannitol, croscarmellose sodium, and magnesium stearate were all in powder form. Next, using a rotary tableting machine (Collect 12HUK, manufactured by Kikusui Seisakusho), mass 140 mg / tablet with a tableting load of 900 kgf using a 7 mm diameter circular tablet die. Molded to obtain an uncoated tablet.

(3) Preparation of coated tablets (coating)
Using the tablet coating machine (Paulec Co., Ltd., ventilated coating machine DRC650, air supply temperature 50-60 ℃, air volume 4 m ³ / min) to the plain tablet prepared in (2) above, 9% by weight 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 coating was performed until the film weight per tablet (uncoated tablet 140 mg) was 8 mg.

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

(4) Tablet characteristics As a result of the disintegration test, the tablet of Example 1 (coated tablet) showed disintegration within 10 minutes, and the hardness was 192N. As a result of the shape stability test, the tablet was allowed to stand for 24 hours at 40 ° C. and 75% RH, and the appearance was visually observed. As a result, the tablet appearance was not cracked or cracked. Further, as a result of the swelling inhibition test, the variation rate of the tablet thickness was 3.3%, and it was confirmed that the swelling rate was suppressed as compared with the same variation rate (7.3%) of Comparative Example 1 described later.

Example 2
(1) Preparation of core granules (granulation, drying, and sizing)
Montelukast sodium 1260 g, D-mannitol (Partec M100) 9490 g, and croscarmellose sodium 1200 g were added to a high-speed agitation granulator (VG-FM50 type, manufactured by Paulek Co., Ltd .: blade 180 rpm, cross screw 3578 rpm). Add 4830 g of 1% by weight hydroxypropylcellulose solution and granulate, then fluidized bed granulator / dryer (WSG15, manufactured by POWREC Co., Ltd .: supply temperature 85 ° C (80-90 ° C), air volume: 3- 11 m ³ / min) until the granule moisture was 2% or less. The dried granules were sized with a screen type particle sizer (Comm QC-197S, manufactured by POWREC Co., Ltd .: screen size 991 μm, rotation speed 25 Hz) to prepare core granules.

(2) Preparation of uncoated tablets (mixing with extragranular additives, tableting)
The nuclear granule 1500 g prepared in the above (1), 420 g of D-mannitol (Pairitol 200SD), 165 g of croscarmellose sodium, and 20 g of magnesium stearate (all in powder form) are mixed in a container rotary mixer (( The mixture was mixed for 20 minutes with Matsubo Boule Container Mixer MC10 / LM-20 (rotation speed: 14 rpm) to obtain granules for tableting. Next, using a rotary tableting machine (Collect 12HUK, manufactured by Kikusui Seisakusho), a mass of 70 mg / tablet was tableted with a tableting load of 1000 kgf using a 6 mm diameter circular tablet die. And obtained an uncoated tablet.

(3) Preparation of coated tablets (coating)
9% by weight using the tablet coating machine (Pauleck Co., Ltd., ventilated coating machine DRC350, air supply temperature 45-55 ° C, air flow 100 m ³ / min) to the plain 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 coating was carried out until the film weight per tablet (70 mg uncoated tablet) was 5 mg.

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

(4) Tablet characteristics As a result of the disintegration test, the tablet (coated tablet) prepared above showed disintegration within 10 minutes and the hardness was 99N. As a result of the shape stability test, the tablet was allowed to stand for 24 hours at 40 ° C. and 75% RH, and the appearance was visually observed. As a result, the tablet appearance was not cracked or cracked. Further, as a result of the swelling inhibition test, the variation rate of the tablet thickness was 3.8%, and it was confirmed that the swelling rate was suppressed as compared with the same variation rate (7.3%) of Comparative Example 1 described later.

Example 3
(1) Preparation of core granules (granulation, drying, and sizing)
Montelukast sodium (3.0 g), D-mannitol (Partec M100) (20.0 g), and croscarmellose sodium (2.5 g) were granulated by adding 9.0 g of 1% by weight hydroxypropylcellulose solution in a mortar (Yamato Scientific Co., Ltd.) Drying Oven DV600: air supply temperature 60 ° C.) and dried until the moisture content of the granules was 2% or less. The dried granule was pulverized in a mortar, and the dried product that passed through a 500 μm screen (sieve) was used as the core granule.

(2) Preparation of uncoated tablets (mixing with extragranular additives, tableting)
25.0 g of the nuclear granules prepared in (1), 7.0 g of D-mannitol (Pearritol 200SD), 3.0 g of croscarmellose sodium, and 0.5 g of magnesium stearate (all in powder form) are placed in a vinyl bag. The mixture was shaken for minutes to obtain granules for tableting. Using a one-shot tableting machine (AUTOGRAPH AG-X manufactured by Shimadzu Corporation), this was tableted with a mass of 140 mg / tablet with a tableting load of 800 kgf using a 7 mm diameter circular locking die. , Got an uncoated tablet.

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

(3) Tablet characteristics As a result of the disintegration test, the tablet prepared above showed disintegration within 10 minutes and the hardness was 120N. As a result of the shape stability test, the tablet was allowed to stand for 24 hours at 40 ° C. and 75% RH, and the appearance was visually observed. As a result, the tablet appearance was not cracked or cracked.

Example 4
(1) Preparation of uncoated tablets (granulation, drying, granulation, and tableting)
620 g of D-mannitol (Partec M100) and 115 g of croscarmellose sodium are weighed and 4 weights using a high-speed agitation granulator (VG-FM05 type, manufactured by POWREC Co., Ltd .: blade 380 rpm, cross screw 3585 rpm) 100 g of hydroxypropylcellulose solution is added and granulated, fluidized bed dryer (WSG15, manufactured by POWREC Co., Ltd .: supply temperature 85 ° C (80-90 ° C), air volume: 3-11 m ³ / min) And dried until the granule moisture was 2% or less. The dried granule was sized using a screen sizing machine (Comek QC-197S, manufactured by POWREC Co., Ltd .: screen size 991 μm, rotation speed 25 Hz). Next, the sized product and 4 g of magnesium stearate are placed in a vinyl bag and mixed by shaking for 1 minute to form granules for tableting. A rotary tableting machine (Collect 12HUK, manufactured by Kikusui Seisakusho: 40 rpm) Was used, and a tablet with a tableting load of 1400 kgf was molded at a weight of 250 mg / tablet with a circular tablet mold having a diameter of 9 mm to obtain an uncoated tablet. In addition, the above-mentioned various pharmaceutically active ingredients are blended in the uncoated tablet as (C) the pharmaceutically active ingredient at a ratio of 80% by mass or less, preferably 0.01 to 30% by mass in 100% by mass of the uncoated tablet. Can do.

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

  The total mass of the coated tablets obtained was 255 mg, the side circumference was 28.9 mm, and the thickness was 3.85 mm.

(3) Tablet characteristics As a result of the disintegration test, the tablet prepared above showed disintegration within 10 minutes and the hardness was 143N. As a result of the shape stability test, the tablet was allowed to stand for 24 hours at 40 ° C. and 75% RH, and the appearance was visually observed. As a result, the tablet appearance was not cracked or cracked. Further, as a result of the swelling inhibition test, the variation rate of the tablet thickness was 2.9%, and it was confirmed that the swelling rate was suppressed as compared with the same variation rate (7.3%) of Comparative Example 1 described later.

Example 5
(1) Preparation of core granules (granulation, drying, and sizing)
400 g of D-mannitol (Pearitol 100SD), 100 g of corn starch, and 100 g of low-substituted hydroxypropylcellulose were added to a fluidized bed granulator / dryer (MP-01 manufactured by POWREC Co., Ltd., supply air temperature 85 ° C (80- And dried with spraying 400 g of 3% 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% by weight or less. In addition, in the core granule, (C) various pharmaceutically active ingredients described above as a pharmaceutically active ingredient, such that the ratio in 100% by mass of the uncoated tablet is 80% by mass or less, preferably 0.01 to 30% by mass. Can be blended.

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

(3) Preparation of coated tablets (coating)
Using the tablet coating machine (Pauleck Co., Ltd., ventilated coating machine DRC200, air supply temperature 55 ° C, air flow 38 m ³ / min) on the plain tablets prepared in (2), 800 g of 10 wt% hypromellose solution When the coating weight per tablet (180 mg) reached 5 mg, the spraying was terminated.

  The total mass of the coated tablets obtained was 185 mg, the side circumference was 25.8 mm, and the thickness was 3.9 mm.

(4) Tablet characteristics As a result of the disintegration test, the tablet prepared above showed disintegration within 10 minutes and the hardness was 152N. As a result of the shape stability test, the tablet was allowed to stand for 24 hours at 40 ° C. and 75% RH, and the appearance was visually observed. As a result, the tablet appearance was not cracked or cracked.

Example 6
(1) Preparation of uncoated tablets (granulation, drying, granulation, and tableting)
D-mannitol (Pearitol 200SD) 400 g, crystalline cellulose 50 g, corn starch 50 g, low-substituted hydroxypropylcellulose 90 g, and magnesium stearate 4 g MC10 / LM-20: Mix at 20 rpm for 20 minutes to make granules for tableting. Using a rotary tableting machine (Collect 12HUK manufactured by Kikusui Seisakusho: Rotation speed: 40 rpm), the granules for tableting were weighed 180 mg / tablet in a round tablet mold with a diameter of 8 mm at a tableting load of 1200 kgf. Tableting was performed to obtain an uncoated tablet. In addition, the above-mentioned various pharmaceutically active ingredients are blended in the uncoated tablet as (C) the pharmaceutically active ingredient at a ratio of 80% by mass or less, preferably 0.01 to 30% by mass in 100% by mass of the uncoated tablet. Can do.

(2) Preparation of coated tablets (coating)
Use the tablet coating machine (Pauleck Co., Ltd., ventilated coating machine DRC200, air supply temperature 55 ° C, air volume 38 m ³ / min) on the uncoated tablets prepared in (1) to obtain a 10 wt% hypromellose solution 800 The coating liquid consisting of g and titanium oxide 20 g was sprayed, and the spraying was terminated when the film weight per tablet (180 mg) reached 5 mg.

  The total mass of the coated tablets obtained was 185 mg, the side circumference 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, the tablet was allowed to stand for 24 hours at 40 ° C. and 75% RH, and the appearance was visually observed. As a result, the tablet appearance was not cracked or cracked.

Example 7
(1) Preparation of uncoated tablets (drying, sizing and tableting)
D-mannitol (Partec M100) 122 g, potato starch 60 g, crystalline cellulose 100 g, crospovidone 15 g, and magnesium stearate 3 g are mixed in a container-rotating mixer (Matsubo Boule Container Mixer MC5 / LM- 20: The mixture was mixed at a rotation speed of 20 rpm for 20 minutes to obtain granules for tableting. Using a rotary tableting machine (Collect 12HUK, manufactured by Kikusui Seisakusho, rotation speed: 40 rpm), the granules for tableting were weighed 300 mg / tablet with a tableting load of 1200 kgf in a 9 mm diameter circular tablet die. Tableting was performed to obtain an uncoated tablet.

  The total mass of the coated tablets obtained was 300 mg, the side circumference was 28.3 mm, and the thickness was 4.2 mm.

Example 8
(1) Preparation of core granules (granulation, drying, and sizing)
Montelukast sodium 1260 g, D-mannitol (Partec DeltaM) 9490 g, and croscarmellose sodium 1200 g were added to a high-speed agitation granulator (VG-FM50 type, manufactured by Paulek Co., Ltd .: blade 180 rpm, cross screw 3578 rpm). Add 4830 g of 1% by weight hydroxypropylcellulose solution and granulate, then fluidized bed granulator (WSG15, manufactured by POWREC Co., Ltd .: supply temperature 85 ° C (80-90 ° C), air volume: 4 -12 m ³ / min) until the granule moisture is 2% or less. Next, the dried granule is sized with a screen-type granulator (Comm QC-197S, manufactured by POWREC Co., Ltd .: screen size 991 μm, rotation speed 25 Hz) to prepare a nuclear granule.

(2) Preparation of uncoated tablets (mixing with extragranular additives, tableting)
10000 g of core 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) (Matsubo Co., Ltd. Boule container mixer MC100 / PM-100, rotation speed 10 rpm) was mixed for 20 minutes to obtain granules for tableting. Next, using a rotary tableting machine (Collect 12HUK, manufactured by Kikusui Seisakusho), mass 140 mg / tablet with a tableting load of 900 kgf using a 7 mm diameter circular tablet die. Mold to obtain uncoated tablets.

(3) Preparation of coated tablets (coating)
9% by weight using the tablet coating machine (Pauleck Co., Ltd., ventilated coating machine DRC650, air supply temperature 50-60 ° C, air volume 4 m ³ / min) on the plain 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 uncoated tablet) is 8 mg.

Example 9
(1) Preparation of core granules (granulation, drying, and sizing)
Montelukast sodium 1260 g, D-mannitol (Partec DeltaM) 9490 g, and croscarmellose sodium 1200 g were added to a high-speed agitation granulator (VG-FM50 type, manufactured by Paulek Co., Ltd .: blade 180 rpm, cross screw 3578 rpm). Add 4830 g of 1 wt% hydroxypropylcellulose solution and granulate, then fluidized bed granulator / dryer (WSG15, manufactured by POWREC Co., Ltd .: supply temperature 85 ° C (80-90 ° C), air volume: 3- 11 m ³ / min) until the granule moisture is 2% or less. The dried granule is sized by a screen-type granulator (Comm QC-197S, manufactured by POWREC Co., Ltd .: screen size 991 μm, rotation speed 25 Hz) to prepare a nuclear granule.

(2) Preparation of uncoated tablets (mixing with extragranular additives, tableting)
A container-rotating mixer with 1500 g of the core 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) (Matsubo Co., Ltd. Bore container mixer MC10 / LM-20, rotating at 14 rpm) was mixed for 20 minutes to obtain granules for tableting. Next, using a rotary tableting machine (Collect 12HUK, manufactured by Kikusui Seisakusho), a mass of 70 mg / tablet was tableted with a tableting load of 1000 kgf using a 6 mm diameter circular tablet die. And get an uncoated tablet.

(3) Preparation of coated tablets (coating)
9% by weight using the tablet coating machine (Paulec Co., Ltd., ventilated coating machine DRC350, air supply temperature 45-55 ° C, air flow 100 m ³ / min) to the plain 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 1 mg (70 mg uncoated tablet) has a coating weight of 5 mg. .

Example 10
(1) Preparation of core granules (granulation, drying, and sizing)
Montelukast sodium 1260 g, D-mannitol (Granitol S) 9490 g, and croscarmellose sodium 1200 g are mixed with a high-speed agitation granulator (VG-FM50, manufactured by POWREC Co., Ltd .: blade 180 rpm, cross screw 3578 rpm) And then granulated by adding 4830 g of 1% by weight hydroxypropylcellulose solution, then fluidized bed granulator / dryer (WSG15 type, manufactured by POWREC Co., Ltd .: supply temperature 85 ° C (80-90 ° C), air volume: 4-12 m ³ / min) until the granule moisture is 2% or less. Next, the dried granule is sized with a screen-type granulator (Comm QC-197S, manufactured by POWREC Co., Ltd .: screen size 991 μm, rotation speed 25 Hz) to prepare a nuclear granule.

(2) Preparation of uncoated tablets (mixing with extragranular additives, tableting)
10000 g of core 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) (Matsubo Co., Ltd. Boule container mixer MC100 / PM-100, rotation speed 10 rpm) was mixed for 20 minutes to obtain granules for tableting. Next, using a rotary tableting machine (Collect 12HUK, manufactured by Kikusui Seisakusho), mass 140 mg / tablet with a tableting load of 900 kgf using a 7 mm diameter circular tablet die. Mold to obtain uncoated tablets.

(3) Preparation of coated tablets (coating)
9% by weight using the tablet coating machine (Pauleck Co., Ltd., ventilated coating machine DRC650, air supply temperature 50-60 ° C, air volume 4 m ³ / min) on the plain 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 uncoated tablet) is 8 mg.

Example 11
(1) Preparation of core granules (granulation, drying, and sizing)
Montelukast sodium 1260 g, D-mannitol (Granitol S) 9490 g, and croscarmellose sodium 1200 g are mixed with a high-speed agitation granulator (VG-FM50, manufactured by POWREC Co., Ltd .: blade 180 rpm, cross screw 3578 rpm) And then granulated by adding 4830 g of 1% by weight hydroxypropylcellulose solution at the same time, then fluidized bed granulator / dryer (WSG15, manufactured by POWREC Co., Ltd .: supply temperature 85 ° C (80-90 ° C), air volume: 3 -11 m ³ / min) until the granule moisture is 2% or less. The dried granule is sized by a screen-type granulator (Comm QC-197S, manufactured by POWREC Co., Ltd .: screen size 991 μm, rotation speed 25 Hz) to prepare a nuclear granule.

(2) Preparation of uncoated tablets (mixing with extragranular additives, tableting)
A container-rotating mixer with 1500 g of the core 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) (Matsubo Co., Ltd. Bore container mixer MC10 / LM-20, rotating at 14 rpm) was mixed for 20 minutes to obtain granules for tableting. Next, using a rotary tableting machine (Collect 12HUK, manufactured by Kikusui Seisakusho), a mass of 70 mg / tablet was tableted with a tableting load of 1000 kgf using a 6 mm diameter circular tablet die. And get an uncoated tablet.

(3) Preparation of coated tablets (coating)
9% by weight using the tablet coating machine (Paulec Co., Ltd., ventilated coating machine DRC350, air supply temperature 45-55 ° C, air flow 100 m ³ / min) to the plain 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 1 mg (70 mg uncoated tablet) has a coating weight of 5 mg. .

Example 12
(1) Preparation of uncoated tablets (drying, sizing and tableting)
D-mannitol (granitol S) 122 g, potato starch 60 g, crystalline cellulose 100 g, crospovidone 15 g, and magnesium stearate 3 g are mixed in a container-rotating mixer (Matsubo Bore Container Mixer MC5 / LM) -20: mixing at 20 rpm) for 20 minutes to form granules for tableting. Using a rotary tableting machine (Collect 12HUK, manufactured by Kikusui Seisakusho, rotation speed: 40 rpm), the granules for tableting were weighed 300 mg / tablet with a tableting load of 1200 kgf in a 9 mm diameter circular tablet die. Tableting molding to obtain uncoated tablets.

Comparative Example 1
(1) Preparation of uncoated tablets (granulation, drying, granulation, and tableting)
620 g of D-mannitol (Mannit P) and 115 g of croscarmellose sodium were weighed and 4 weights were obtained using a high-speed agitation granulator (VG-FM05 type, manufactured by POWREC Co., Ltd .: blade 380 rpm, cross screw 3585 rpm) Add 100 g of% hydroxypropylcellulose solution and granulate, fluidized bed dryer (MP-01, manufactured by POWREC Co., Ltd., supply air temperature 85 ° C (80-90 ° C), air volume 3-11 m ³ / min) And dried until the water content is 2% by weight or less. The dried granule is sized with a screen sizing machine (Comm QC-197S, manufactured by POWREC Co., Ltd .: screen size 991 μm, rotation speed 25 Hz), and then the sized product and magnesium stearate 4 g In a plastic bag and mixed by shaking for 1 minute to form granules for tableting. Using a rotary tableting machine (Collect 12HUK, manufactured by Kikusui Seisakusho, rotation speed 40 rpm), weigh 250 mg / tablet in diameter. An uncoated tablet was obtained by tableting with a tableting load of 1400 kgf using a 9 mm circular tablet die.

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

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

(3) Tablet characteristics As a result of the disintegration test, the tablet prepared above showed disintegration within 10 minutes and the hardness was 67 N. However, as a result of the shape stability test, the tablet was allowed to stand for 24 hours at 40 ° C. and 75% RH, and the appearance was visually observed. Cracks such as cracks and cracks were observed in the tablet appearance. Furthermore, as a result of the swelling inhibition test, the variation rate of the tablet thickness was 7.3%.

Comparative Example 2
(1) Preparation of uncoated tablets (drying, sizing and tableting)
D-mannitol (Mannit P) 400 g, crystalline cellulose 50 g, corn starch 50 g, low-substituted hydroxypropylcellulose 90 g, and magnesium stearate 4 g Container rotating mixer (Matsubo Bore Container) (Mixer MC5 / LM-20: rotation speed 20 rpm) was mixed for 20 minutes to obtain granules for tableting. Using a rotary tableting machine (Collect 12HUK manufactured by Kikusui Seisakusho: Rotation speed 40 rpm), the granules for tableting were weighed 250 mg / tablet with a tableting load of 1200 kgf in a 9 mm diameter circular tablet die. Tableting was performed to obtain an uncoated tablet.

Comparative Example 3
(1) Preparation of uncoated tablets (drying, sizing and tableting)
D-mannitol (Mannit P) 122 g, Potato starch 60 g, Crystalline cellulose 100 g, Crospovidone 15 g, and Magnesium stearate 3 g Container rotating mixer (Matsubo Co., Ltd. Bore container mixer MC5 / LM) -20: mixing at 20 rpm) for 20 minutes to obtain granules for tableting. Using a rotary tableting machine (Collect 12HUK, manufactured by Kikusui Seisakusho, rotation speed: 40 rpm), the granules for tableting were weighed 300 mg / tablet with a tableting load of 1200 kgf in a 9 mm diameter circular tablet die. Tableting was performed to obtain an uncoated tablet.

Comparative Example 4
(1) Preparation of uncoated tablets (granulation, drying, granulation, and tableting)
Lactose hydrate (DMV200M) 620 g and croscarmellose sodium 115 g were weighed and 4% by weight with a high-speed agitation granulator (VG-FM05 type, manufactured by POWREC Co., Ltd .: blade 380 rpm, cross screw 3585 rpm) Add 100 g of hydroxypropylcellulose solution, granulate, and add to fluidized bed dryer (MP-01 manufactured by POWREC Co., Ltd., supply air temperature 85 ° C (80-90 ° C), air flow 3-11 m ³ / min) And dried until the water content was 2% by weight or less. The dried granule is sized with a screen sizing machine (Comm QC-197S, manufactured by POWREC Co., Ltd .: screen size 991 μm, rotation speed 25 Hz), and then the sized product and magnesium stearate 4 g Into a plastic bag and mixed by shaking for 1 minute to form granules for tableting. Using a rotary tableting machine (Collect 12HUK, manufactured by Kikusui Seisakusho, rotation speed: 40 rpm), the mass is 245 mg / tablet. An uncoated tablet was obtained by tableting with a tableting load of 1400 kgf using a 9 mm circular tablet die.

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

Comparative Example 5
(1) Preparation of uncoated tablets (granulation, drying, granulation, and tableting)
620 g of crystalline cellulose (PH-101) and 115 g of croscarmellose sodium are weighed and 4% by weight with a high-speed stirring granulator (VG-FM05 type, manufactured by POWREC Co., Ltd .: blade 380 rpm, cross screw 3585 rpm) Add 100 g of hydroxypropylcellulose solution, granulate, and add to fluidized bed dryer (MP-01 manufactured by POWREC Co., Ltd., supply air temperature 85 ° C (80-90 ° C), air flow 3-11 m ³ / min) And dried until the water content was 2% by weight or less. The dried granule is sized with a screen sizing machine (Comm QC-197S, manufactured by POWREC Co., Ltd .: screen size 991 μm, rotation speed 25 Hz), and then the sized product and magnesium stearate 4 g Into a plastic bag and mixed by shaking for 1 minute to form granules for tableting. Using a rotary tableting machine (Collect 12HUK, manufactured by Kikusui Seisakusho, rotation speed: 40 rpm), the mass is 245 mg / tablet. An uncoated tablet was obtained by tableting with a tableting load of 1400 kgf using a 9 mm circular tablet die.

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

Comparative Example 6
(1) Preparation of uncoated tablets (granulation, drying, granulation, and tableting)
620 g of D-mannitol (Pearlitol 35 micron) and 115 g of croscarmellose sodium were weighed, and 4 weights were obtained using a high-speed agitation granulator (VG-FM05 type, manufactured by Paulec Co., Ltd .: blade 380 rpm, cross screw 3585 rpm) Add 100 g of% hydroxypropylcellulose solution and granulate, fluidized bed dryer (MP-01, manufactured by POWREC Co., Ltd., supply air temperature 85 ° C (80-90 ° C), air volume 3-11 m ³ / min) And dried until the water content is 2% by weight or less. The dried granule is sized with a screen sizing machine (Comm QC-197S, manufactured by POWREC Co., Ltd .: screen size 991 μm, rotation speed 25 Hz), and then the sized product and magnesium stearate 4 g Into a plastic bag and mixed by shaking for 1 minute to form granules for tableting. Using a rotary tableting machine (Collect 12HUK, manufactured by Kikusui Seisakusho, rotation speed: 40 rpm), the mass is 245 mg / tablet. An uncoated tablet was obtained by tableting with a tableting load of 1400 kgf using a 9 mm circular tablet die.

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

Comparative Example 7
(1) Preparation of uncoated tablets (granulation, drying, granulation, and tableting)
620 g of D-mannitol (Pearlitol 160C) and 115 g of croscarmellose sodium were weighed and 4% by weight with a high-speed agitation granulator (VG-FM05 type, manufactured by POWREC Co., Ltd .: blade 380 rpm, cross screw 3585 rpm) Add 100 g of hydroxypropylcellulose solution, granulate, and add to fluidized bed dryer (MP-01 manufactured by POWREC Co., Ltd., supply air temperature 85 ° C (80-90 ° C), air flow 3-11 m ³ / min) And dried until the water content was 2% by weight or less. The dried granule is sized with a screen sizing machine (Comm QC-197S, manufactured by POWREC Co., Ltd .: screen size 991 μm, rotation speed 25 Hz), and then the sized product and magnesium stearate 4 g Into a plastic bag and mixed by shaking for 1 minute to form granules for tableting. Using a rotary tableting machine (Collect 12HUK, manufactured by Kikusui Seisakusho, rotation speed: 40 rpm), the mass is 245 mg / tablet. An uncoated tablet was obtained by tableting with a tableting load of 1400 kgf using a 9 mm circular tablet die.

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

Comparative Example 8
(1) Preparation of uncoated tablets (granulation, drying, granulation, and tableting)
620 g of refined sucrose (nonparel 103) and 115 g of croscarmellose sodium were weighed and 4% by weight hydroxy using a high-speed stirring granulator (VG-FM05 type, manufactured by Paulec Co., Ltd .: blade 380 rpm, cross screw 3585 rpm) Add 100 g of propylcellulose solution and granulate, using a fluidized bed dryer (MP-01 manufactured by POWREC Co., Ltd., supply air temperature 85 ° C (80-90 ° C), air volume 3-11 m ³ / min) And dried until the water content was 2% by weight or less. The dried granule is sized with a screen sizing machine (Comm QC-197S, manufactured by POWREC Co., Ltd .: screen size 991 μm, rotation speed 25 Hz), and then the sized product and magnesium stearate 4 g Into a plastic bag and mixed by shaking for 1 minute to form granules for tableting. Using a rotary tableting machine (Collect 12HUK, manufactured by Kikusui Seisakusho, rotation speed: 40 rpm), the mass is 245 mg / tablet. An uncoated tablet was obtained by tableting with a tableting load of 1400 kgf using a 9 mm circular tablet die.

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

Claims (15)

(A) Mass 350 mg, molded at 12 kN (杵 diameter: 9.5 mmφ), containing sugar alcohol showing strength of 80 N or more when measured with a tablet hardness meter, and (B) a disintegrant,
(B) A tablet having a disintegrant content of 10 to 40% by mass in 100% by mass of an uncoated tablet. The tablet according to claim 1, wherein the content ratio of (A) sugar alcohol in 100% by mass of the uncoated tablet is 20 to 90% by mass. The tablet according to claim 1 or 2, wherein (A) the sugar alcohol is mannitol molded at a mass of 350 mg and 12 kN (inguinal diameter: 9.5 mmφ) and having a strength of 80 N or more when measured with a tablet hardness meter. . (B) disintegrant is croscarmellose, crospovidone, carboxymethyl starch, low-substituted hydroxypropyl cellulose, carmellose, crystalline cellulose carmellose, corn starch, potato starch, low-substituted hydroxymethyl starch and their pharmaceutically The tablet according to any one of claims 1 to 3, which is at least one selected from the group consisting of acceptable salts. (B) The disintegrant is at least one selected from the group consisting of croscarmellose, crospovidone, low-substituted hydroxypropylcellulose, and pharmaceutically acceptable salts thereof. A tablet according to any one of the above. (B) The tablet according to claim 5, wherein the content of the disintegrant is 10 to 20% by mass in 100% by mass of the uncoated tablet. Furthermore, (C) It is a tablet containing a pharmaceutically active ingredient, Comprising: The ratio of the said (C) component in 100 mass% of uncoated tablets is more than 0 mass% and 70 mass% or less, Any one of Claims 1-6 Tablets described in 1. The tablet according to claim 7, wherein the content of the pharmaceutically active ingredient (C) per tablet is 5 to 12 mg. (C) The pharmaceutically active ingredient is a group consisting of procaterol, fenoterol, clenbuterol, salmeterol, theophylline, amlexanox, ibudilast, pemirolast, zafilcaste, seratrodast, cetirizine, levocetirizine, olopatadine, montelukast, zafirlukast and pharmaceutically acceptable salts thereof The tablet according to claim 7 or 8, which is at least one selected from the group. The tablet according to claim 7, which is a tablet having any one of the following characteristics (a) and (b):
(A) Total weight 60 to 80 mg per tablet, content of 4.7 to 5.5 mg of (C) pharmaceutically active ingredient in one tablet, side circumference 15 to 22 mm, thickness 2.3 to 3.6 mm, and hardness 35 N or more,
(B) Total mass of 135 to 148 mg per tablet, (C) pharmaceutically active ingredient content of 9.9 to 10.9 mg in one tablet, side circumference of 18 to 25 mm, thickness of 3.2 to 4.8 mm, and hardness 60 N or more. A tablet comprising (A) a sugar alcohol, (B) a disintegrant and (C) a granulated product containing a pharmaceutically active ingredient, and (A) a mixture powder of sugar alcohol, (B) disintegrant and lubricant. The tablet according to any one of claims 7 to 10, which has at least one of the following characteristics:
(I) The ratio of the granulated product to the mixed powder is 2: 1 to 3: 1 by mass ratio.
(Ii) The ratio of the (B) disintegrant in the granulated product to the (B) disintegrant in the mixed powder is 1: 2 to 2: 1 by mass ratio. The tablet according to any one of claims 1 to 11, which is a coated tablet. The tablet according to claim 12, 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 13, which is a tablet having the following characteristics:
(1) When a disintegration test is performed using 37 ° C water as a test solution, it disintegrates within 10 minutes. The tablet according to claim 14, further having at least one of the following properties (2) and (3):
(2) When performing a dissolution test by the paddle method using water as a test solution at 37 ° C. and rotating at 50 rpm per minute, the dissolution rate of the pharmaceutically active ingredient after 60 minutes is 60 to 90%.
(3) When conducting a dissolution test by the paddle method at 37 ° C and rotation at 50 rpm per minute using the JP 2nd liquid (pH 6.8) as the test solution, the dissolution rate of the pharmaceutically active ingredient after 10 minutes is 10 ~ 45%.