Method for producing tablet

Abstract

There is provided a method for producing a tablet having high tablet hardness without delaying the disintegration time. More specifically, there is provided a method for producing a tablet, including a granulation step of granulating a powder composition containing one or more selected fi·om the group consisting of an active ingredient, an excipient and a disintegrant, while adding an aqueous composition containing a binder and water to the powder composition, to obtain a granulated product; and a heat treatment and tableting step of subjecting the granulated product to heat treatment and then tableting, or to tableting the granulated product and then heat treatment, to obtain a tablet.

Description

TITLE OF THE INVENTIONMETHOD FOR PRODUCING TABLETBACKGROUND OF THE INVENTION5 1. Field of the InventionThe invention relates to a method for producing a tablet, which is one of thedosage forms of solid preparation in the field of pharmaceuticals or foods.2. Related ArtA tablet, which is one of solid dosage forms of solid preparation in the field of10 pharmaceuticals or foods, is a solid preparation obtained by compression-moldingpowder into a predetermined shape, and has advantages such as easy handling.Especially in the field of pharmaceuticals, the tablets occupy about 50% in all products,and are most widely used.Examples of the method for producing tablets include a direct compression15 method, a dry granulation tableting method, an extrusion granulation tableting method,and a wet granulation tableting method. Above all, the wet granulation tabletingmethod is widely used both in Japan and overseas because the granulation in the methodcan greatly improve binding properties and flowability of powder as well as unifonnityof the active ingredient content in each tablet despite the complication of the method,20 compared with the dry direct tableting method in which an active ingredient, anexcipient and so on are mixed and tableted as they are.The wet granulation tableting method comprises steps of: granulating a mixtureof an active ingredient and an excipient, while spraying or adding a solution of a binderor an appropriate solvent such as water or ethanol to obtain a granulated product; drying25 the granulated product; and tableting the dried granulated product to obtain tablets.1Examples of the wet granulation tableting method include a high shear wet granulationtableting method by using a high shear granulator is used; and a fluidized bedgranulation tableting method using a fluidized bed granulator.When the granulation is carried out using only a solvent such as water or5 ethanol without using a solution of a binder in the wet granulation tableting method, atablet having the desired tablet hardness may not be obtained, or tableting failure suchas capping, laminating or sticking may occur. Hence, the granulation is generallycarried out by using a solution of a binder such as polyvinyl alcohol, hydroxypropylcellulose, polyvinylpyrrolidone, or hydroxypropyl methyl cellulose. However, when10 the amount of the binder added is increased to increase the tablet hardness, there is aproblem that the disintegration of the obtained tablet is deteriorated.Therefore, it is desired to develop a method for producing a tablet having ahigh tablet hardness without increasing the amount of a binder and without using aspecial technique or equipment.15 For example, JPH07-503237A provides a method of producing a tablet withincreased strength, comprising steps of: (a) compressing a mixture of a meltable binder,at least one excipient and a pharmaceutically active agent into a tablet; (b) melting thebinder in the tablet; and (c) solidifying the binder.Furthermore, JP2004-292457 A provides a method for producing a orally20 rapidly disintegrating tablet comprising a drug, a diluent, and erythritol, which is asaccharide having a relatively lower melting point than the drug and the diluent,comprising steps of: (a) compression-molding a statiing material containing the drug,the diluent, the erytln·itol and a binder which is a saccharide having high moldabilityand / or a water-soluble polymer at a low pressure required for maintaining the tablet25 shape, (b) heating the molded product obtained in step (a) to a temperature higher than2or equal to the temperature at which the erythritol melts, and (c) cooling the moldedproduct obtained in step (b) to a temperature lower than or equal to the temperature atwhich the melted erythritol solidifies.5 SUMMARY OF THE INVENTIONHowever, in the method of JPH0?-503237 A, there have been cases in whichthe tablet hardness and disintegration time are changed when the tablet is stored in aroom where the air-conditioning facility is inadequate. It is because the binder isremelted by the increased temperature in the room mainly during summer. In theI 0 method of JP2004-292457 A, there have been cases in which the disintegration time isdelayed despite the attempt to improve the tablet hardness by using dissolution andsolidification of erythritol.The invention has been made in view of the above circumstances, and an objectof the invention is to provide a method for producing a tablet excellent in hardness15 and / or disintegratability without delaying disintegration time of the tablet.As a result of intensive studies to achieve the above object, the inventors havefound that a powder composition containing at least one selected from the groupconsisting of an active ingredient, an excipient and a disintegrant is granulated, whileadding an aqueous composition containing water and a binder selected from the group20 consisting of polyvinyl alcohol, hydroxypropyl cellulose, polyvinylpyrrolidone,hydroxypropyl methyl cellulose, methyl cellulose, sodium carboxymethylcellulose,polyvinyl alcohol / acrylic acid / methyl methacrylate copolymers, andvinylpyrrolidone / vinyl acetate (VPIVA) copolymers thereto to obtain a granulatedproduct; and the granulated product is heat-treated followed by tableting, or is tableted25 followed by heat treatment, to obtain a tablet having excellent hardness and / or3disintegratabililty without delaying the disintegration time.In an aspect of the invention, there is provided a method for producing a tabletcomprising: a granulation step of granulating a powder composition comprising at leastone selected from the group consisting of an active ingredient, an excipient and a5 disintegrant, while adding an aqueous composition comprising a binder and water to thepowder composition, to obtain a granulated product; and a heat treatment and tabletingstep of subjecting the granulated product to heat treatment and then tableting, or totableting and then heat treatment, to obtain a tablet; wherein the binder is selected fromthe group consisting of polyvinyl alcohol, hydroxypropyl cellulose,10 polyvinylpyrrolidone, hydroxypropyl methyl cellulose, methyl cellulose, sodiumcarboxymethylcellulose, polyvinyl alcohol / actylic acid / methyl methacrylatecopolymers, and vinyl pyrro1idone / vinyl acetate copolymers.According to the invention, a high-quality tablet excellent in hardness and / ordisintegration without delaying the disintegration time can be produced, so that the15 occurrence of cracking or chipping in the tablet can be suppressed during packing ortransportation of the tablet, and the medicinal effect can be quickly developed when thetablet is orally administered.20DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTSThe granulation step of granulating a powder composition comprising at leastone selected from the group consisting of an active ingredient, an excipient and adisintegrant, while adding an aqueous composition comprising a binder and water to thepowder composition, to obtain a tablet, will be described.The powder composition contains at least one selected from the group25 consisting of an active ingredient, an excipient and a disintegrant. When the powder4composition does not contain the active ingredient, the aqueous composition maycontain the active ingredient, or a step or substep of mixing the granulated product withthe active ingredient may be provided between the granulation step and the heattreatment and tableting step, or may be provided after the heat treatment and before the5 tableting in the heat treatment and tableting step.The active ingredient is not pmiicularly limited as long as it is an activeingredient that can be orally administered. Exmnples of the active ingredient includedrugs used in phatmaceutical products and active ingredients used in health foods suchas foods with nutrient function claims, foods for specified health use, and foods with1 0 functional claims.Example of the drug used in phmmaceutical products include a drug for thecentral nervous system, a drug for the cardiovascular system, a drug for the respiratorysystem, a drug for the digestive system, an antibiotic, an antitussive and expectorant, anantihistmnine, an antipyretic anti-inflammatory analgesic, a diuretic, an autonomic15 agent, an antimalarial agent, an antidiarrheal agent, a psychotropic, and vitamins andderivatives thereof.2025Examples of the drug for the central nervous system include diazepmn,idebenone, naproxen, piroxicam, indomethacin, sulindac, lorazepam, nitrazepam,phenytoin, acetaminophen, ethenzamide, ketoprofen, and chlordiazepoxide.Examples of the drug for the cm·diovascular system include molsidomine,vinpocetine, propranolol, methyldopa, dipyridamole, furosemide, trimnterene,nifedipine, atenolol, spironolactone, metoprolol, pindolol, captopril, isosorbide dinitrate,delapril hydrochloride, meclofenoxate hydrochloride, diltiazem hydrochloride, etilefrinehydrochloride, digitoxin, and alprenolol hydrochloride.Exmnples of the drug for the respiratory system include mnlexanox,5dextromethorphan, theophylline, pseudoephedrine, salbutamol, and guaifenesin.Examples of the drug for the digestive system include a benzimidazole drughaving antiulcer action, such as 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methy lsulfinyl]benzimidazole and 5-methoxy-2-[ 4-methoxy-3 ,5-dimethyl-2-5 pyridyl)methylsulfinyl]benzimidazole; cimetidine; ranitidine; pirenzepinehydrochloride; pancreatin; bisacodyl; and 5-aminosalicylic acid.Examples of the antibiotic include talampicillin hydrochloride, bacampicillinhydrochloride, cefaclor, and eJytlu·omycin.Examples of the antitussive and expectorant include noscapine hydrochloride,1 0 carbetapentane citrate, isoaminile citrate, and dimemorfan phosphate.Examples of the antihistamine include chlorpheniramine maleate,diphenhydramine hydrochloride, and promethazine hydrochloride.Examples of the antipyretic anti-inflanrmatmy analgesic include ibuprofen,diclofenac sodium, flufenamic acid, sulpyrine, aspirin, and ketoprofen.15 Examples of the diuretic include caffeine.2025Examples of the autonomic agent include dihydrocodeine phosphate, dlmethylephedrinehydrochloride, atropine sulfate, acetylcholine chloride, andneostigmine.Examples of the antimalarial agent include quinine hydrochloride.Examples of the antidiarrheal agent include loperamide hydrochloride.Examples of the psychotropic include chlorpromazine.Examples of the vitamins and derivatives thereof include vitamin A, vitaminB1, fursultiamine, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitaminE, vitamin K, calcium pantothenate, and tranexamic acid.Examples of the active ingredient used in the health food include the above6510vitamins and derivatives thereof, minerals, carotenoids, amino acids and derivativesthereof, plant extracts, and health food materials.Examples of the mineral include calcium, magnesium, manganese, zinc, iron,copper, selenium, chromium, sulfur, and iodine.Examples of the carotenoid include 0-carotene, a-carotene, lutein,c1yptoxanthin, zeaxanthin, lycopene, astaxanthin, and multicarotene.Examples of the amino acid include an acidic amino acid, a basic amino acid, aneutral amino acid, and an acidic amino acid amide.Examples of the acidic amino acid include aspartic acid and glutamic acid.Examples of the basic amino acid include lysine, arginine, and histidine.Examples of the neutral amino acid include linear aliphatic amino acids such asalanine and glycine; branched aliphatic amino acids such as valine, leucine andisoleucine; hydroxyamino acids such as serine and threonine; sulfm-containing aminoacids such as cysteine and methionine; aromatic amino acids such as pheny !alanine and15 tyrosine; heterocyclic amino acids such as tryptophan; and imino acids such as proline.Examples of the acidic amino acid amide include asparagine and glutamine.Examples of the amino acid derivative include acetylglutamine, acetylcysteine,carboxymethylcysteine, acetyltyrosine, acetylhydroxyproline, 5-hydroxyproline,glutathione, creatine, S-adenosylmethionine, glycylglycine, glycylglutamine, dopa,20 alanylglutamine, carnitine and y-aminobutyric acid.Examples of the plant extract include aloe extract, propolis extract, agaricusextract, Panax ginseng extract, ginkgo leaf extract, turmeric extract, em-cumin, sproutedbrown rice extract, shiitake mycelium extract, Rubus suavissimus extract, sweetHydrangea leaf extract, Fomes yucatensis extract, sesame extract, garlic extract, maca25 (Lepidium meyenii) extract, plant worm ( Cordyceps sinensis) extract, camomile extract,7and red pepper extract.Examples of the health food material include royal jelly; dietary fiber; proteins;bifidobacteria; lactic acid bacteria; chitosan; yeast; glucosamine; lecithin; polyphenols;cartilage of animals, fish and shellfish; soft-shelled tmile; lactoferrin; freshwater clams;5 eicosapentaenoic acid; germanium; enzymes; creatine; carnitine; citric acid; raspberryketone; coenzyme Q10; methylsulfonylmethane; and soybean peptides bonded withphospholipids.An amount of the active ingredient may be determined, depending on thecontent of the active ingredient in the tablet described later. If necessary, two or more10 types of active ingredients may be used. A commercially available active ingredientmay be used.Examples of the excipient include sugars such as white soft sugar, lactose,glucose and maltose; sugar alcohols such as D-mannitol, sorbitol and maltitol; starchessuch as wheat starch, rice starch, potato starch and com starch; dextrins; powdered15 cellulose; microcrystalline cellulose; calcium carbonate; calcimn phosphate; andcalcium sulfate.An amount of the excipient may be determined, depending on the content ofthe active ingredient in the tablet described later. If necessary, two or more types ofexcipients may be used. A commercially available excipient may be used.20 Examples of the disintegrant include low-substituted hydroxypropyl cellulose;starches such as wheat starch, rice starch, potato starch and corn starch; partlypregelatinized starch; sodium starch glycolate; carmellose; carmellose calcium;croscannellose sodium; microcrystalline cellulose; and crospovidone.The content ofhydroxypropoxy groups in the low-substituted hydroxypropyl25 cellulose is preferably from 5 to 16% by mass, more preferably from 7 to 15% by mass,85from the viewpoint of disintegration. The content of the hydroxypropoxy groups inthe low-substituted hydroxypropyl cellulose may be determined by the assay describedin the section "Low-substituted hydroxypropyl cellulose" of the JapanesePharmacopoeia Seventeenth Edition.An amount of disintegrant may be detetmined, depending on the content of thedisintegrant in the intended tablet. If necessary, two or more types of disintegrantsmay be used. A commercially available disintegrant may be used.The aqueous composition comprises a binder and water.The binder is selected from the group consisting of polyvinyl alcohol,10 hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol / acrylic acid / methylmethactylate copolymers, and vinyl pyno1idone / vinyl acetate (VPNA) copolymers.The above binder is a solid binder having no melting point preferably in therange of from 25 to 180°C, and the hardness and / or disintegration of the tablet is15 considered to be improved by developing softening or changing the orientation(crystallinity) in the crystal structure of the binder at a temperature of preferably higherthan 80° C.The degree of saponification ofthe polyvinyl alcohol is preferably 78.0 mol%or more, more preferably from 85.0 to 99.5 mol%, fi'Om the viewpoint of solubility in20 water. The degree of saponification of the polyvinyl alcohol may be determined inaccordance with the method of determining the degree of saponification described in JISK6726.The viscosity at 20°C of a 4% by mass aqueous solution of the polyvinylalcohol is preferably from 2.0 to 100.0 mPa·s, more preferably from 3.0 to 50.0 mPa·s,25 from the viewpoint of binding and disintegration. The viscosity at 20°C of a 4% by9mass aqueous solution of the polyvinyl alcohol may be determined in accordance withthe method of determining viscosity described in JIS K6726.The content of hydroxypropoxy groups in the hydroxypropyl cellulose is notparticularly limited. It is preferably from 53.4 to 80.5% by mass, more preferably5 from 55.0 to 75.0% by mass. The content ofhydroxypropoxy groups in thehydroxypropyl cellulose may be determined by the quantitative method described in thesection "Hydroxypropyl cellulose" of the Japanese Pharmacopoeia Seventeenth Edition.The K-value ofpolyvinylpy!Tolidone is not particularly limited. It ispreferably from 10 to 120, more preferably fi·om 15 to 100. The K-value of10 polyvinylpyrrolidone may be determined by the method for determining K-valuedescribed in the section "Povidone" of the Japanese Phmmacopoeia SeventeenthEdition.The content ofmethoxy groups in the hydroxypropyl methyl cellulose is notpmticularly limited. It is preferably from 16.5 to 30.0% by mass, more preferably15 from 19.0 to 30.0% by mass. The content ofhydroxypropoxy groups in thehydroxypropyl methyl cellulose is not particularly limited. It is preferably from 4.0 to32.0% by mass, more preferably from 4.0 to 12.0% by mass. The content ofmethoxygroups and the content ofhydroxypropoxy groups in the hydroxypropyl methylcellulose may be dete1mined by the assay method described in the section20 "Hypromellose" of the Japanese Pharmacopoeia Seventeenth Edition.The viscosity at 20°C of a 2% by mass aqueous solution ofhydroxypropylmethyl cellulose is preferably from 2.0 to l 00.0 mPa·s, more preferably fi·om 3.0 to 50.0mPa·s, fi·om the viewpoint of binding and disintegration. The viscosity at 20°C of a2% by mass aqueous solution ofhydroxypropyl methyl cellulose may be dete1mined by25 the method for determining viscosity described in the section "Hypromellose" of the10Japanese Pharmacopoeia Seventeenth Edition.The content of the methoxy group in the methyl cellulose is not particularlylimited. It is preferably fi·om 26.0 to 33.0% by mass. The content of the methoxygroup in the methylcellulose may be determined by the quantitative method described in5 the section "Methyl cellulose" of the Japanese Pharmacopoeia Seventeenth Edition.The viscosity at 20°C of a 2% by mass aqueous solution of the methylcelluloseis preferably from 2.0 to 100.0 mPa·s, more preferably from 3.0 to 50.0 mPa·s, from theviewpoint of binding and disintegration. The viscosity at 20°C of a 2% by massaqueous solution of the methyl cellulose may be determined by the method for10 dete1mining viscosity described in the section "Methyl cellulose" of the JapanesePharmacopoeia Seventeenth Edition.The content of sodium in the sodium carboxymethylcellulose is not pmticularlylimited. It is preferably from 6.5 to 8.5% by mass. The content of sodium in thesodium carboxymethy !cellulose may be determined by the quantitative method15 described in the section "sodium carboxymethylcellulose" of the JapanesePharmacopoeia Seventeenth Edition.As the binder, polyvinyl alcohol is preferable from the viewpoint ofimprovement of the disintegration time.If necessary, two or more types of binders may be used. A commercially20 available binder may be used. An amount of the binder is described below as thecontent in the tablet.Examples of the water include purified water.An amount of the water is not particularly limited. It is preferably from 200to 100000 parts by mass, more preferably from 400 to 75000 parts by mass, relative to25 100 pmts by mass of the binder from the viewpoint of productivity and operability.IIThe aqueous composition may optionally contain an active ingredient, anexcipient, a disintegrant, and an additive. The powder composition may alsooptionally contain an additive.Examples of the additive include a flavoring agent, a sweetener, a fluidizing5 agent, and a dissolution aid for the active ingredient.Examples of the flavoring agent include menthol, peppermint oil, and vanillin.Examples of the sweetener include aspartame, acesulfame potassium,sucralose, stevia, and thaumatin.Examples of the fluidizing agent include light anhydrous silicic acid, hydratedI 0 silicon dioxide, and magnesium aluminometasilicate.Examples of the dissolution aid of the active ingredient include organic acidssuch as fumaric acid, succinic acid, malic acid, tmiaric acid and adipic acid; and alkalimetal salts of the organic acids.If necessmy, two or more types of additives may be used. A commercial15 additive may be used. An amount of the additive is described below as the content inthe tablet.20The granulation step may be carried out by using a granulator. Examples ofthe granulator include a fluidized bed granulator, a high shear granulator, a tumblingfluidized bed granulator, and a spray drying granulator.When the granulation operation is explained by using a fluidized bedgranulator as an example, a granulated product may be obtained by placing a powdercomposition containing at least one selected from group consisting of an activeingredient, an excipient and a disintegrant in the fluidized bed granulator, andgranulating the powder composition, while adding (preferably spraying) an aqueous25 composition containing the predetermined binder and water.12In one of examples, a granulated product containing a sugar and / or sugaralcohol as an excipient and low-substituted hydroxypropyl cellulose having ahydroxypropoxy group content of 5 to 16% by mass as a disintegrant may be obtainedin a granulation step of granulating a powder composition containing the sugar and / or5 sngar alcohol, while adding an aqueous composition containing the predeterminedbinder, water, the sugar and / or sugar alcohol and low-substituted hydroxypropylcellulose having a hydroxypropoxy group content of 5 to 16% by mass to the powdercomposition. The sugar and / or sugar alcohol in the aqueous composition is present notonly inside but also on the surface of the granulated product, and the presence on theI 0 surface may contribute to the modification of the surface. In another example, agranulated product may be obtained by a granulation step of granulating a powdercomposition containing a sugar and / or sugar alcohol and low substituted hydroxypropylcellulose, while adding an aqueous composition containing a predetetmined binder andwater.15 The average particle size of the granulated product varies depending ongranulation conditions. It is preferably from 40 to 300 flm, more preferably from 45 to250 flm, from the viewpoint oftabletability and reduced mass deviation between tablets.The average particle size of the granulated product may be determined by using a drymethod based on the Fraunhofer diffraction theory with a laser diffraction type particle20 size distribution measuring apparatus (Master Sizer 3000 produced by Malvern) underthe conditions of dispersion pressure of2 bar and scattering intensity of2 to 10%,where a value corresponding to a 50% cumulative size in the volume-based cumulativepmiicle size distribution curve is used as the average pmiicle size.The obtained granulated product does not need to be further dried when a25 fluidized bed granulator capable of spraying and drying at the same time is used and13drying is actually performed. However, it is preferable to perform drying in a knownmanner when drying is not actually performed or when a granulator incapable of dryingis used.The drying may be performed by using a dryer. Examples of the dryer5 include a fluidized bed chyer, a flash dryer, a box type dryer, a vibration dryer, a naturalconvection type constant temperature d1yer, a forced convection type constanttemperature d1yer, and a forced convection type constant temperature and constanthumidity d1yer. The d1ying temperature is preferably from 40 to 80°C.The water content of the dried granulated product is preferably 5.0% by massI 0 or less, more preferably from 0.0 to 1.0% by mass from the viewpoint of tablet stability.15The water content of the granulated product may be detennined by using a heating anddrying method moisture analyzer (MX-50 produced by A&D Company Ltd.) under theconditions of 5 g of granulated product, a heating temperature of 1 05°C, and a heatingtime of 60 minutes.Next, the heat treatment and tableting step of subjecting the granulated productto heat treatment followed by tableting, or to tableting followed by heat treatment toobtain a tablet will be described.If necessary, the granulated product may be converted to powder for tableting.The powder for tableting may be obtained by a mixing step of mixing the granulated20 product, which may be after or before the heat h·eatment, with at least one selected fromthe group consisting of an active ingredient, an excipient, a disintegrant, a binder, anadditive and a lubricant described later. The addition of a binder to the granulatedproduct is expected to enhance the moldability during tableting. When the granulatedproduct after the heat treatment is used in the mixing step, the subsequent tableting may25 produce a tablet. When the granulated product before the heat treatment is used in the145mixing step, the subsequent tableting followed by the heat treatment may produce atablet. The mixing method is not particularly limited. The mixing may be done byusing a mixer. Examples of the mixer include a V-shape rotating mixer, a ribbonmixer, a container mixer, and a tumbler mixer.When there is nothing to be added to the granulated product, the granulatedproduct itself may be used as powder for tableting.The heat treatment may be canied out by using a dryer. Examples of thedryer include a fluidized bed dryer, a convection dryer, a box-type dryer, a vibrationdryer, a natural convection type constant temperature dryer, a forced convection type10 constant temperature dryer, and a forced convection type constant temperature andconstant humidity dryer. For example, when the forced convection type constanttemperature dtyer is used, the heat treatment may be carried out by placing a granulatedproduct (including powder for tableting) or tablet in a container such as a vat, andleaving the container in the forced convection type constant temperature dryer having a15 predetermined internal temperature for a predetermined time.The temperature in the heat treatment is preferably higher than 80°C, morepreferably higher than 80°C and not higher than 180°C, still more preferably from 95 to180°C, further still more preferably from 115 to 170°C, and particularly preferably 135to 160°C, from the viewpoint of improvement of tablet hardness and disintegration time.20 The heat treatment time is preferably 5 minutes or more, more preferably from 5 to 120minutes, and still more preferably from I 0 to 90 minutes, from the viewpoint ofimprovement of tablet hardness and disintegration time.When the granulated product is subjected to the heat treatment, the granulatedproduct may be dried in a dtyer and then subjected to the heat treatment in the same25 dryer without being taken out from the dryer, and alternatively, the granulated product15may be subjected to drying and the heat treatment at the same time.After the powder for tableting or a tablet is subjected to the heat treatment, it ispreferably cooled to from 20 to 40°C. The temperature of the granulated product(including the powder for tableting) or tablet subjected to heat treatment may be5 measured by using a pmtable non-contact thetmometer (PT-3LF produced by OPTEXFA Co., Ltd.).The cooling method is not particularly limited. It may be left at roomtemperature or in a low temperature environment such as a refi-igerator. The coolingmay also be carried out in a desiccator or in a sealed container in order to avoid1 0 moisture absorption.The heat treatment is preferably carried out after tableting from the viewpointof improvement of the tablet hardness.The tableting may be carried out by using a tableting machine. Examples ofthe tableting machine include a rotary tableting machine and a single-punch tableting15 machine. The tableting in the heat treatment and tableting step may be canied out inthe presence or absence of a lubricant. It is preferably carried out in the presence of alubricant from the viewpoint of preventing tableting failure.As a method of adding a lubricant (hereinafter also referred to as "lubricationmethod"), an internal lubrication method or an external lubrication method may be20 selected.According to the internal lubrication method, lubricant-containing powder istableted with a tableting machine containing a pestle and a mortar wherein a lubricant isabsent at powder-contact pmts of both of the pestle and the mortar. On the other hand,according to the external lubrication method, lubricant-fi·ee powder or granulated25 product is tableted with a tableting machine containing a pestle and a mortar wherein a16lubricant is present at a powder contact part of the pestle and / or a powder contact part ofthe mortar. The external lubrication method is preferable from the viewpoint ofimprovement of tablet hardness and disintegration time.When a tablet is produced with a rotary tableting machine or a single-punch5 tableting machine in the internal lubrication method, lubricant -containing powder maybe placed in a lubricant-fi·ee mortar and pressed by lubricant-fi·ee upper and lowerpestles at a predetermined pressure.When a tablet is produced with a rotmy tableting machine connected to anexternal lubricant spray system (ELS-Pl, Kikusui Seisakusho Ltd.) in the external10 lubrication method, lubricant-free powder or granulated product may be placed in ammiar and pressed by upper and lower pestles at a predetermined pressure, wherein alubricants is present at each powder or granulated product contact pmi of the mmiar andthe pestle. Examples of a method of placing a lubricant at a powder contact part of apestle and / or a powder contact pmi of mortar include spraying or coating.15 Exmnples of the lubricant include talc; magnesium stemate; calcium stearate;sodium stearyl fumarate; sucrose fatty acid esters; waxes such as paraffin wax andcarnauba wax; and hardened oils such as hardened castor oil, hardened rapeseed oil andhardened beef tallow oil.An amount of the lubricant in the intemallubrication method is preferably20 from 0.2 to 5.0 parts by mass, more preferably from 0.4 to 3.0 parts by mass, relative to100 pmis by mass of the lubricant-free tablet (i.e. granulated product or powder fortableting) from the viewpoint of suppression oftableting failure, disintegration andimprovement of tablet hardness and disintegration time.An amount of the lubricant in the external lubrication method is preferably25 from 0.01 to 2.0 pmis by mass, more preferably from 0.05 to 1.0 pmis by mass, relative17to 100 parts by mass of the lubricant-free tablet (i.e. granulated product or powder fortableting) fi·om the viewpoint of suppression oftableting failure, disintegration, andimprovement of tablet hardness and disintegration time.The tableting pressure is preferably from 20 to 400 MPa fi·om the viewpoint of5 tablet hardness and tableting failure.The content of the active ingredient in the tablet is not patiicularly limited. Itis preferably from 0.01 to 98.90% by mass from the viewpoint of the drug effect orefficacy.The content of the excipient in the tablet is not particularly limited. It is10 preferably from 0.00 to 98.89% by mass, more preferably 0.00 to 95.00% by mass, fromthe viewpoint of controlling the tablet hardness and disintegration time.The content of the disintegrant in the tablet is preferably from 1.0 to 40.0% bymass, more preferably fi·om 2.0 to 30.0% by mass, and still more preferably fi·om 2.0 to20.0% by mass from the viewpoint of disintegration and storage stability.15 The content of the binder in the tablet is preferably from 0.10 to 10.00% bymass, more preferably from 0.10 to 6.00% by mass, and still more preferably from 0.15to 5.00% by mass from the viewpoint of the bindability, disintegration and improvementof tablet hardness and disintegration time.The content of the additive in the tablet is not pmiicularly limited. It is20 preferably from 0 to 10% by mass from the viewpoint of controlling the flavor of thetablet, controlling the fluidity of the powder for tableting or controlling the dissolutionof the active ingredient.An active ingredient, an excipient, a disintegrant, a binder and an additive maybe included in any of the powder composition and the aqueous composition within each25 content range in the tablet as described above. Alternatively, they may optionally be18added to and mixed with the obtained granulated product. The binder may be includednot only in the aqueous composition but also in the powder composition before thegranulation. It is because of the fact that the powder composition may be granulated,while adding an aqueous composition containing a binder and water to the powder5 composition, and the obtained granulated product may be tableted to obtain a tablet.The tablet diameter is preferably from 6 to 12 mm from the viewpoint ofhandling and administration.The mass of tablet is preferably from 70 to 700 mg per tablet.The hardness of the tablet is preferably SON or more, more preferably fro om 80I 0 to 250N, from the viewpoint of preventing cracking, chipping or the like duringpacking, transporting, or removal of the tablet from the PTP sheet. Tablet hardnessmay be measured by using a tablet hardness meter (TBH-125 produced by ERWEKAGmbH) and be obtained as the maximum breaking strength when load is applied to thetablet in the diameter direction at a rate of 1 mm / sec until the tablet breaks.15 The disintegration time of the tablet is preferably within 5 minutes, morepreferably within 3 minutes, and still more preferably within 1 minute, from theviewpoint of the onset of drug efficacy. The disintegration time of tablet may bedetermined by using a disintegration tester (NT-400 produced by Toyama Sangyo Co.,Ltd.) in accordance with to the Disintegration Test (test solution: water, no20 supplementary plate) of the Japanese Pharmacopoeia Seventeenth Edition.25EXAMPLESThe invention will be explained with reference to Examples and ComparativeExamples. It should not be construed that the invention is limited to or by Examples.19<EXAMPLE 1>An aqueous composition (hereinafter also referred to as "aqueous bindersolution") was prepared by dissolving 6 g of polyvinyl alcohol (PVA) as a binder in 144g of purified water. The polyvinyl alcohol was JF-05 produced by JAPAN VAM &5 POVAL CO., LTD. and had a degree of saponification of98.5 mol% and a viscosity at20°C of 5.0 mPa·s, as determined in a 4% by mass aqueous solution thereof.Next, 60 g of acetaminophen (fine powder grade produced by YamamotoChemical Industry Co., Ltd.) as an active component and 219 g ofD-mannitol(PEARLITOL 25C produced by Raquette Corporation) as an excipient were placed in a10 fluidized bed granulator (MP-0 1 produced by Powrex Corporation) and mixed at an airflow rate of 0.6 to 0.7 m3 / min to obtain a powder composition.In the granulator, the powder composition was granulated, while spraying theaqueous binder solution, under the conditions of a supply air temperature of 80°C, adischarge air temperature of from 35 to 38°C, an air flow rate of from 0.6 to 0.7 m3 / min,15 a spray rate of 10 g / min, and a spray air pressure of 200 kPa to obtain a granulatedproduct. The granulated product has an average particle size of 77 J.Lm and the watercontent of0.3% by mass.Next, 228 g of the obtained granulated product was subjected to addition of 12g of low-substituted hydroxypropyl cellulose (L-HPC) having a hydroxypropoxy group20 content of 11% by mass as a disintegrant and mixed to obtain powder for tableting.Then, using a tabletop tableting machine (single-punch tableting machineHANDTAB-200 produced by Ichihashi Seiki Co., Ltd.) equipped with a pair of pestleshaving a diameter of 8 mm and a curvature radius of 12 mm and a mortar having a holediameter of8 mm, a small amount of magnesium stearate (vegetable grade produced by25 Taihei Chemical Industry Co., Ltd.) as a lubricant was applied to surfaces of the pestles205and the mortar (the surfaces which the powder contacts) by using a cotton swab; 200 mgof the powder for tableting was filled; and the powder was tableted at a pressure of 5.0kN (about 99.5 MPa) to obtain 200.2 mg oftableted product as a result of the externallubrication method.Each tableted product was placed without overlapping each other in a petridish, then subjected to heat treatment at 100°C for 60 minutes in a forced convectionconstant temperature and constant humidity oven (DKN402 produced by YamatoScientific Co., Ltd.), and cooled by being left to stand in a desiccator of roomtemperature until the temperature of the tablet reached 25°C, thereby obtaining a tablet.I 0 The tablet hardness and disintegration time of the tablet was measured. Tabletcomposition, tablet hardness and disintegration time are shown in Tables I and 2. Theratio of with-heat-treatment to without-heat-treatment is a ratio of the measured value inExample I to the measured value in Comparative Example 1.15 <EXAMPLE 2>A tablet was produced in the same manner as in Example I except that thetemperature of the heat treatment of the tableted product was 120°C. The tablethardness and disintegration time of the obtained tablet were measured in the samemanner as in Example 1. The results are shown in Tables I and 2. The ratio ofwith-20 heat-treatment to without-heat-treatment is a ratio of the measured value in Example 2to the measured value in Comparative Example I.<EXAMPLE3>A tablet was produced in the same manner as in Example I except that the25 temperature of the heat treatment of the tableted product was 140°C. The tablet215hardness and disintegration time of the obtained tablet were measured in the samemanner as in Example 1. The results are shown in Tables 1 and 2. The ratio of withheat-treatment to without-heat-treatment is a ratio of the measured value in Example 3to the measured value in Comparative Example 1.<EXAMPLE4>A tablet was prepared in the same manner as in Example 3 except that a periodof time of the heat treatment of the tableted product was 10 minutes. The tablethardness and disintegration time of the obtained tablet were measured in the same10 manner as in Example 1. The results are shown in Tables 1 and 2. The ratio of withheat-treatment to without-heat-treatment is a ratio of the measured value in Example 4to the measured value in Comparative Example 1.<EXAMPLES>15 A tablet was prepared in the same manner as in Example 3 except that a periodof time of the heat treatment of the tableted product was 30 minutes. The tablethardness and disintegration time of the obtained tablet were measured in the samemanner as in Example 1. The results are shown in Tables 1 to 2. The ratio of withheat-treatment to without-heat-treatment is a ratio of the measured value in Example 520 to the measured value in Comparative Example 1.<EXAMPLE6>The granulated product obtained in the same manner as in Example 1 wasspread thinly on a stainless steel vat, then subjected to heat treatment at 140°C for 6025 minutes in a forced convection constant temperature and constant humidity oven22(DKN402 produced by Yamato Scientific Co., Ltd.), and cooled by being left to stand ina desiccator of room temperature until the temperature of the granulated productreached 25°C, thereby obtaining a heat-treated granulated product.The 228 g of the heat-treated granulated product was subjected to addition of5 12 g oflow-substituted hydroxypropyl cellulose having a hyd:roxypropoxy groupcontent of II% by mass as a disintegrant, and mixed to obtain powder for tableting.Then, the powder for tableting was tableted in the same manner as in ExampleI to obtain 200.2 mg oftableted product. The tableted product was used as a tabletwithout subjecting to the heat treatment. The tablet hardness and disintegration timeI 0 of the obtained tablet were measured in the same manner as in Example 1. The resultsare shown in Tables 1 and 2. The ratio of with-heat-treatment to without-heattreatmentis a ratio of the measured value in Example 6 to the measured value inComparative Example 1.15 <EXAMPLE 7>The 228 g of the granulated product obtained in the same manner as inExample 1 was mixed with 12 g oflow-substituted hydroxypropyl cellulose having ahydroxypropoxy group content of 11% by mass as a disintegrant, and then furthermixed with 1.2 g of magnesium stearate (vegetable grade produced by Taihei Chemical20 Industry Co., Ltd.) as a lubricant, thereby obtaining powder for tableting.Then, using a tableting machine (single-punch tableting machine HANDTAB-200 produced by Ichihashi Seiki Co., Ltd.) equipped with a pair of pestles having adiameter of 8 mm, a curvature radius of 12 mm and a mmiar with a hole diameter of 8mm, 201 mg of powder for tableting was filled and tableted at a pressure of 5.0 kN25 (about 99.5 MPa) to obtain 201 mg oftableted product as a result of the inner23lubrication method.Subsequently, the tableted product was subjected to heat treatment at 140°C for60 minutes in a forced convection constant temperature and constant humidity oven(DKN402 produced by Yamato Scientific Co., Ltd.), and then cooled by being left to5 stand in a desiccator of room temperature until the temperature of the tableted productreacOhed 25°C, thereby obtaining a tablet. The tablet hardness and disintegration timeof the obtained tablet were measured in the same manner as in Example 1. The resultsare shown in Tables 1 and 2. The ratio of with-heat-treatment to without-heattreatmentis a ratio of the measured value in Example 7 to the measured value in10 Comparative Example 2.<EXAMPLES>The granulated product obtained in the same manner as in Example 1 was heattreatedat 140°C for 60 minutes in a forced convection constant temperature and15 constant humidity oven (DKN402 produced by Yamato Scientific Co., Ltd.), and thencooled by being left to stand in a desiccator of room temperature until the temperatureof the granulated product reached 25°C, thereby obtaining a heat-treated granulatedproduct.The 228 g of the heat-treated granulated product was mixed with 12 g of Iow-20 substituted hydroxypropyl cellulose having a hydroxypropoxy group content of 11% bymass as a disintegrant, and then mixed with 1.2 g of magnesium stearate (vegetablegrade produced by Taihei Chemical Industry Co., Ltd.) as a lubricant to obtain powderfor tableting.The powder for tableting was tableted in the same manner as in Example 7 to25 obtain 201 mg oftableted product. The 201 mg oftableted product without the heat24treatment was used as a tablet as a result of the internal lubrication method. The tablethardness and disintegration time of the obtained tablet were measured in the samemanner as in Example 1. The results are shown in Tables I and 2. The ratio of withheat-treatment to without-heat-treatment is a ratio of the measured value in Example 85 to the measured value in Comparative Example 2.<EXAMPLE9>A tablet was produced in the same manner as in Example 3 except that 3 g ofpolyvinyl alcohol having a degree of saponification of98.5 mol% and a viscosity at10 20°C of 5.0 mPa·s, as determined in a 4% by mass aqueous solution thereof, wasdissolved in 147 g of purified water to obtain an aqueous binder solution, and 222 g ofD-mannitol was placed in the fluidized bed granulator. The obtained granulatedproduct had an average particle size of 57 J.Lm, and a water content of 0.3% by mass.The tablet hardness and disintegration time of the obtained tablet were measured in the15 same manner as in Example I. The results are shown in Tables I and 2. The ratio ofwith-heat-treatment to without-heat-treatment is a ratio of the measured value inExample 9 to the measured value in Comparative Example 3.20<EXAMPLE 1 0>A tablet was produced in the same manner as in Example 3 except that 9 g ofpolyvinyl alcohol having a degree of saponification of98.5 mol% and a viscosity at20°C of 5.0 mPa·s, as determined in a 4% by mass aqueous solution thereof, wasdissolved in 141 g of purified water to obtain an aqueous binder solution, and 216 g ofD-mannitol was placed in the fluidized bed granulator. The obtained granulated25 product had an average particle size of 106 J.Lm, and a water content of0.3% by mass.255The tablet hardness and disintegration time of the obtained tablet were measured in thesame manner as in Example 1. The results are shown in Tables 1 and 2. The ratio ofwith-heat-treatment to without-heat-treatment is a ratio of the measured value inExample 10 to the measured value in Comparative Example 4.<EXAMPLE 11>A tablet was produced in the same manner as in Example 3 except that 6 g ofpolyvinyl alcohol (JP-05 produced by Japan YAM & POVAL Co., Ltd.) having a degreeof saponification of 88.0 mol% and a viscosity at 20°C of 5.0 mPa·s, as determined in a10 4% by mass aqueous solution thereof, was used as the aqueous binder solution. Theobtained granulated product had an average particle size of 83 J-Ill, and the watercontent was 0.3% by mass. The tablet hardness and disintegration time of the obtainedtablet were measured in the same manner as in Example 1. The results are shown inTables 1 and 2. The ratio of with-heat-treatment to without-heat-treatment is a ratio of15 the measured value in Example 11 to the measured value in Comparative Example 5.<EXAMPLE 12>A tablet was produced in the same manner as in Example 3 except that the Dmannitolwas not used and the mixing at an air flow rate of 0.6 to 0. 7m3 / min was not20 carried out. The obtained granulated product had an average particle size of 87 J-Ill,and a water content of 0.2% by mass. The tablet hardness and disintegration time of theobtained tablet were measured in the same manner as in Example 1. The results areshown in Tables 1 and 2. The ratio of with-heat-treatment to without-heat-treatment isa ratio of the measured value in Example 12 to the measured value in Comparative25 Example 6.26<EXAMPLE 13>A tablet was produced in the same manner as in Example 3 except that 60 g oftheophylline (produced by SHIRATORI Pharmaceutical Co., Ltd.) was used as an active5 ingredient and 219 g of D-mannitol was placed. The obtained granulated product hadan average particle size of 79 J.lm, and a water content of 0.2% by mass. The tablethardness and disintegration time of the obtained tablet were measured in the samemanner as in Example 1. The results are shown in Tables 1 and 2. The ratio of withheat-treatment to without-heat-treatment is a ratio of the measured value in Example 1310 to the measured value in Comparative Example 7.<EXAMPLE 14>A tablet was produced in the same manner as in Example 3 except that 228 g ofthe obtained granulated product was subjected to mixing with 12 g of sodium starch15 glycolate (Primojel produced by the DFE Pharma) as a disintegrant. The tablethardness and disintegration time of the obtained tablet were measured in the samemanner as in Example 1. The results are shown in Tables 1 and 2. The ratio of withheat-treatment to without-heat-treatment is a ratio of the measured value in Example 14to the measured value in Comparative Example 8.20<EXAMPLE 15>A tablet was produced in the same manner as in Example 3 except that 228 g ofthe obtained granulated product was mixed with 12 g of croscarmellose sodium (Ac-DiSolproduced by FMC Corporation). The tablet hardness and disintegration time of the25 obtained tablet were measured in the same manner as in Example 1. The results are27shown in Tables 1 and 2. The ratio of with-heat-treatment to without-heat-treatment isa ratio of the measured value in Example 15 to the measured value in ComparativeExample 9.5 <EXAMPLE 16>A tablet was produced in the same manner as in Example 3 except that 6 g ofhydroxypropyl methyl cellulose having a methoxy group content of29.0% by mass anda hydroxypropoxy group content of9.0% by mass, and a viscosity at 20°C of6.0 mPa·s,as determined in a 2% by mass aqueous solution thereof, was used as a binder to form10 an aqueous binder solution. The obtained granulated product had an average pmiiclesize of 58 flm, and a water content of 0.3% by mass. The tablet hardness anddisintegration time of the obtained table was measured by the same manner as inExample 1. The results are shown in Tables 1 and 2. The ratio of with-heattreatmentto without-heat-treatment is a ratio of the measured value in Example 16 to15 the measured value in Comparative Example 10.<EXAMPLE 17>A tablet was produced in the same manner as in Example 3 except that 6 g ofhydroxypropyl cellulose (HPC-SL produced by Nippon Soda Co., Ltd.) having a20 hydroxypropoxy group content of 64% by mass was used as a binder to form anaqueous binder solution. The obtained granulated product had an average particle sizeof 63 flm, and a water content of 0.2% by mass. The tablet hardness and disintegrationtime of the obtained tablet were measured in the same marmer as in Example 1. Theresults are shown in Tables 1 and 2. The ratio of with-heat-treatment to without-heat-25 treatment is a ratio of the measured value in Example 17 to the measured value in28Comparative Example II.<EXAMPLE 18>A tablet was produced in the same manner as in Example 3 except that 6 g of5 polyvinylpyrrolidone (K30 produced by Wako Pure Chemical Industries, Ltd.) having aK-value of30 was used as a binder to form an aqueous binder solution. The obtainedgranulated product had an average particle size of 48 f1m, and a water content of 0.2%.The tablet hardness and disintegration time of the obtained tablet were measured in thesame manner as in Example I. The results are shown in Tables I and 2. The ratio of10 with-heat-treatment to without-heat-treatment is a ratio of the measured value inExample 18 to the measured value in Comparative Example 12.<EXAMPLE 19>The 0.8g of polyvinyl alcohol (JF-10 produced by Japan VAM & POVAL Co.,15 Ltd.), as a binder, having a degree of saponification of98.5 mol% and a viscosity at20°C of30.0 mPa·s, as determined in a 4% by mass aqueous solution thereof, and 60 gofD-mannitol (PEARLITOL 25C produced by Raquette Corporation) as an excipientwere dissolved in 499.2 g of purified water, and then mixed with 40 g of low-substitutedhydroxypropyl cellulose having a hydroxypropoxy group content of 8%as a disintegrant20 to obtain an aqueous composition which was an aqueous dispersion.Then, 299.2 g ofD-mannitol (PEARLITOL 25C produced by RaquetteCorporation) as an excipient was placed in a fluidized bed granulator, and granulated,while spraying the aqueous dispersion thereto, tmder the conditions of a supply airtemperature of 60°C, a discharge air temperature of 25 to 28°C, an air flow rate of 0.6 to25 0.7 m3 / min, a spray rate of 12 g / min, and a spray air pressure of 150 !cPa to obtain a29granulated product. The obtained granulated product had an average particle size of 61ftm, and a water content of 0.5% by mass.Next, 192 g of the obtained granulated product was mixed with 48 g ofacetaminophen (fine powder grade produced by Yamamoto Chemical Industry Co.,5 Ltd.) as an active ingredient to obtain powder for tableting. The powder was tabletedin the same manner as in Example 1 to produce 200.2 mg oftableted product to be heattreated.Subsequently, the tableted product was heat-treated at 140°C for 60 minutes ina forced convection constant temperature and constant humidity oven (DKN402I 0 produced by Yamato Scientific Co., Ltd.), and then cooled by being left to stand in adesiccator until the temperature of the tableted product reached 25°C, thereby obtaininga tablet. The tablet hardness and disintegration time of the obtained tablet weremeasured in the same manner as in Example I. The results are shown in Tables I and2. The ratio of with-heat-treatment to without-heat-treatment is a ratio of the measured15 value in Example 19 to the measured value in Comparative Example 13.<Comparative Example 1>A tablet was produced in the same manner as in Example 1 except that thetableted product was not heat-treated. The tablet hardness and disintegration time of20 the produced table were measured in the same manner as in Example I. The resultsare shown in Tables 1 and 2.<Comparative Example 2>A tablet was produced in the same manner as in Example 7 except that the25 tableted product was not heat-treated. The tablet hmdness and disintegration time of305the produced tablet were measured in the same manner as in Example 7. The resultsare shown in Tables 1 and 2.<Comparative Example 3>A tablet was produced in the same mmmer as in Example 9 except that thetableted product was not heat-treated. The tablet hardness and disintegration time ofthe produced tablet were measured in the same manner as in Example 9. The resultsm·e shown in Tables 1 and 2.10 <Comparative Example 4>15A tablet was produced in the same manner as in Example I 0 except that thetableted product was not heat-treated. The tablet hardness and disintegration time ofthe produced tablet were measured in the same manner as in Example 10. The resultsare shown in Tables 1 and 2.<Comparative Example 5>A tablet was produced in the same manner as in Example 11 except that thetableted product was not heat-treated. The tablet hardness and disintegration time ofthe produced tablet were measured in the same manner as in Example 11. The results20 are shown in Tables 1 and 2.<Comparative Example 6>A tablet was produced in the same manner as in Example 12 except that thetableted product was not heat treated. The tablet hardness and disintegration time of25 the produced tablet was measured in the same manner as in Example 12. The results31are shown in Tables 1 and 2.<Comparative Example 7>A tablet was produced in the same manner as in Example 13 except that the5 tableted product was not heat-treated. The tablet hardness and disintegration time ofthe produced table were measured in the same manner as in Example 13. The resultsare shown in Tables 1 and 2.10<Comparative Example 8>A tablet was produced in the same manner as in Example 14 except that thetableted product was not heat-treated. The tablet hardness and disintegration time ofthe produced tablet were measured in the same manner as in Example 14. The resultsare shown in Tables 1 and 2.15 <Comparative Example 9>20A tablet was produced in the same manner as in Example 15 except that thetableted product was not heat-treated. The tablet hardness and disintegration time ofthe produced tablet were measured in the same manner as in Example 15. The resultsare shown in Tables 1 and 2.<Comparative Example 10>A tablet was produced in the same manner as in Example 16 except that thetableted product was not heat-treated. The tablet hardness and disintegration time ofthe produced tablet were measured in the same manner as in Example 16. The results25 are shown in Tables 1 and 2.32<Comparative Example 11>A tablet was produced in the same manner as in Example 17 except that thetableted product was not heat-treated. The tablet hardness and disintegration time of5 the produced tablet were measured in the same manner as in Example 17. The resultsare shown in Tables 1 and 2.<Comparative Example 12>A tablet was produced in the same manner as in Example 18 except that the10 tableted product was not heat -treated. The tablet hardness and disintegration time ofthe produced tablet were measured in the same manner as in Example 18. The resultsare shown in Tables 1 and 2.15Comparative Example 13A tablet was produced in the same manner as in Example 19 except that thetableted product was not heat-treated. The tablet hardness and disintegration time ofthe produced tablet were measured in the same manner as in Example 19. The resultsare shown in Tables 1 and 2.33Table 1active ingredient excipient disintegrant binderacetaminophen theophylline mannitol L-HPC sodium eros- PVA PVA hydroxy- hydroxy- polyvinylstarchcarmel!ose degree of degree of propyl propyl pyrrolidoneglycolate sodium saponification saponification methyl ce!!uloseof98.5 mol% of88.0 mol% cellulose(mass%) {mass%) (mass%) (mass%) {mass%) (mass%) (mass%) (mass%) (mass%) (mass%) (mass%)Example1 20.00 0.00 73.00 5.0 0.0 0.0 2.00 0.00 0.00 0.00 0.00Example2 20.00 0.00 73.00 5.0 0.0 0.0 2.00 0.00 0.00 0.00 0.00Example3 20.00 0.00 73.00 5.0 0.0 0.0 2.00 0.00 0.00 0.00 0.00Example4 20.00 0.00 73.00 5.0 0.0 0.0 2.00 0.00 0.00 0.00 0.00ExampleS 20.00 0.00 73.00 5.0 0.0 0.0 2.00 0.00 0.00 0.00 0.00ExampleS 20.00 0.00 73.00 5.0 0.0 0.0 2.00 0.00 0.00 0.00 0.00Example? 20.00 0.00 73.00 5.0 0.0 0.0 2.00 0.00 0.00 0.00 0.00ExampleS 20.00 0.00 73.00 5.0 0.0 0.0 2.00 0.00 0.00 0.00 0.00Example9 20.00 0.00 74.00 5.0 0.0 0.0 1.00 0.00 0.00 0.00 0.00Example10 20.00 0.00 72.00 5.0 0.0 0.0 3.00 0.00 0.00 0.00 0.00Example11 20.00 0.00 73.00 5.0 0.0 0.0 0.00 2.00 0.00 0.00 0.00Example12 93.00 0.00 0.00 5.0 0.0 0.0 2.00 0.00 0.00 0.00 0.00Example13 0.00 20.00 73.00 5.0 0.0 0.0 2.00 0.00 0.00 0.00 0.00Example14 20.00 0.00 73.00 0.0 5.0 0.0 2.00 0.00 0.00 0.00 0.00Example15 20.00 0.00 73.00 0.0 0.0 5.0 2.00 0.00 0.00 0.00 0.00Example16 20.00 0.00 73.00 5.0 0.0 0.0 0.00 0.00 2.00 0.00 0.00Example17 20.00 0.00 73.00 5.0 0.0 0.0 0.00 0.00 0.00 2.00 0.00Example18 20.00 0.00 73.00 5.0 0.0 0.0 0.00 0.00 0.00 0.00 2.00Example19 20.00 0.00 71.84 8.0 0.0 0.0 0.16 0.00 0.00 0.00 0.00* D-mannitol was used as "Mannitol".34Table 1 (Continued)active ingredient excipient disintegrant binderacetaminophen theophylline mannitol L-HPC sodium eros- PVA PVA hydroxy- hydroxy- polyvinylstarchcarmel lose degree of degree of propyl propyl pyrrolidoneglycolate sodium saponification saponification methyl ce!!uloseof 98.5 mol% of 88.0 mol% cellulose(mass%) (mass%) (mass%) (mass%) (mass%) (mass%) (mass%) (mass%) (mass%) (mass%) (mass%)Comp.Ex.1 20.00 0.00 73.00 5.0 0.0 0.0 2.00 0.00 0.00 0.00 0.00Comp.Ex.2 20.00 0.00 75.00 5.0 0.0 0.0 2.00 0.00 0.00 0.00 0.00Comp.Ex.3 20.00 0.00 74.00 5.0 0.0 0.0 1.00 0.00 0.00 0.00 0.00Comp.Ex.4 20.00 0.00 72.00 5.0 0.0 0.0 3.00 0.00 0.00 0.00 0.00Comp.Ex.5 20.00 0.00 73.00 5.0 0.0 0.0 0.00 2.00 0.00 0.00 0.00Comp.Ex.6 93.00 0.00 0.00 5.0 0.0 0.0 2.00 0.00 0.00 0.00 0.00Comp.Ex.7 0.00 20.00 73.00 5.0 0.0 0.0 2.00 0.00 0.00 0.00 0.00Comp.Ex.S 20.00 0.00 73.00 0.0 5.0 0.0 2.00 0.00 0.00 0.00 0.00Comp.Ex.9 20.00 0.00 73.00 0.0 0.0 5.0 2.00 0.00 0.00 0.00 0.00Comp.Ex.10 20.00 0.00 73.00 5.0 0.0 0.0 0.00 0.00 2.00 0.00 0.00Comp.Ex.11 20.00 0.00 73.00 5.0 0.0 0.0 0.00 0.00 0.00 2.00 0.00Comp.Ex.12 20.00 0.00 73.00 5.0 0.0 0.0 0.00 0.00 0.00 0.00 2.00Comp.Ex.13 20.00 0.00 76.64 3.2 0.0 0.0 0.16 0.00 0.00 0.00 0.00* D-mannitol was used as "Mannitol".35Table 2heat treatment lubrication amount of tablet properties ratio of with-heatMtreatmenttarget temperature time lubricant to without-heat-treatmenttablet disintegration tablet disintegrationhardness time hardness time('C) (min) - (parts by mass) (N) (sec) (%) (%)Example1 tableted product 100 60 external 0.1 115 97 134 84Examp!e2 tableted product 120 60 external 0.1 122 68 142 59Example3 tableted product 140 60 external 0.1 141 42 164 36Example4 tableted product 140 10 external 0.1 119 41 138 35Example5 tableted product 140 30 external 0.1 138 41 160 35ExampleS granulated product 140 60 external 0.1 88 31 102 27Example? tab!eted product 140 60 internal 0.5 122 128 151 89ExampleS granulated product 140 60 internal 0.5 87 35 107 24Example9 tableted product 140 60 external 0.1 97 20 152 37Example10 tableted product 140 60 external 0.1 158 187 174 37Example11 tableted product 140 60 external 0.1 167 43 186 36Exampe12 tableted product 140 60 external 0.1 99 29 157 71Exampe13 tableted product 140 60 external 0.1 131 30 138 15Example14 tableted product 140 60 external 0.1 132 101 165 80Example15 tableted product 140 60 external 0.1 129 12 161 29Example16 tableted product 140 60 external 0.1 118 32 159 94Example17 tableted product 140 60 external 0.1 188 26 251 90Example18 tableted product 140 60 external 0.1 201 33 226 100Example19 tableted product 140 60 external 0.1 82 13 152 81* The amount of the lubricant is expressed as parts by mass relative to 100 parts by mass of the power for tableting containing nolubricant.36Table 2 (Continued)heat treatment lubrication amount of tablet properties ratio of with-heat-treatmenttarget temperature time lubricant to without-heat-treatmenttablet disintegration tablet disintegrationhardness time hardness time('C) (min) - (parts by mass) (N) (sec) (%) (%)Comp.Ex.1 no treatment - - external 0.1 86 116Comp.Ex.2 no treatment - - internal 0.5 81 144 - -Comp.Ex.3 no treatment - - external 0.1 64 54 - -Comp.Ex.4 no treatment - - external 0.1 91 510 - -Comp.Ex.S no treatment - - external 0.1 90 120 - -Comp.Ex.6 no treatment - - external 0.1 63 41 - -Comp.Ex.7 no treatment - - external 0.1 95 198 - -Comp.Ex.8 no treatment - - external 0.1 80 127 - -Comp.Ex.9 no treatment - - external 0.1 80 41 - -Comp.Ex.10 no treatment - - external 0.1 74 34 - -Comp.Ex.11 no treatment - - external 0.1 75 29 - -Comp.Ex.12 no treatment - - external 0.1 89 33 - -Comp.Ex.13 no treatment - - external 0.1 54 16 - -*The amount of the lubricant is expressed as parts by mass relative to 100 parts by mass of the power for tableting containing nolubricant.37In Examples I to 5 where a tableted product produced in the presence oflubricant in the extemallubrication method was heat-treated to obtain a tablet, the tablethardness increased and the disintegration time decreased. Thus, both of the tablethardness and the disintegration time were improved in Examples I to 5, compared with5 those in Comparative Example I, where a tableted product produced in the presence oflubricant in the external lubrication method was not heat-treated and was used as atablet. It is evident from the results of Examples I to 3 that the improvement of thetablet hardness and the disintegration time is greater as the temperature of the heattreatment is higher. It is evident from the results of Examples 3 to 5 that theI 0 improvement of the tablet hardness is greater as the period of time for the heat treatmentis longer.Further, in Example 7, where a tableted product produced by tabletinglubricant-containing powder obtained in the internal lubrication method was heattreatedto obtain a tablet, both of the tablet hardness and the disintegration time were15 improved.It is evident from the results of Examples 3 and 7 that when the tabletedproduct is heat-treated, the external lubrication method provides higher improvement inboth of tablet hardness and disintegration time than the internal lubrication method.Further, in Example 6, where a tableted product produced by tableting the heat-20 treated granulated product in the presence of lubricant in the external lubrication methodwas not heat-treated and was used as a tablet, and in Example 8, where a tabletedproduct produced by tableting after addition of a lubricant to the heat-treated granulatedproduct in the internal lubrication method was not heat-treated and used as a tablet, thedisintegration time could be improved, while maintaining the tablet hardness.25 A tableted product is in the state where a predetermined binder and powders38such as an active ingredient, an excipient and a disintegrant are compacted andcontacted each other. When the tableted product is heat-treated, it is considered thatthe predetermined binder becomes softened to increase the contact area with thepowders for stronger binding, thereby resulting in the increased tablet hardness (see5 Examples I to 5, 7, and 9 to 19). On the other hand, when the granulated product isheated, it is considered that a strong binding cannot not be formed because there aremany voids between the predetermined binder and the powders, thereby resulting in noincrease of the tablet hardness (see Examples 6 and 8).In general, when a tablet absorbs water, a predetermined binder dissolves to1 0 develop viscosity, thereby deteriorating water conduction and delaying disintegrationtime. In Examples 1 to 15 and 19, where polyvinyl alcohol was used as a binder, it isconsidered that the development of viscosity was suppressed and the disintegration timewas shortened because of increased crystallinity and lowered solubility in water aftersoftening the polyvinyl alcohol in the heat treatment oftableted or granulated product.15 On the other hand, in Examples 16, 17, and 18, where a binder other than polyvinylalcohol was used, it is considered that the solubility in water and the disintegration timewere maintained because of no change in the crystallinity after softening thepredetermined binder in the heat treatment of table ted product.When a tableted product produced by tableting after addition of a lubricant by20 the internal lubrication method is heat -treated, it is considered that the lubricant iscontained inside the tableted product and spreads widely inside the tableted productduring the heat treatment, so that the hydrophobicity of the tableted product increases,thereby inhibiting improvement of the disintegration time (Example 7). On the otherhand, when a tableted product produced by tableting in the extemallubrication method25 is heat-treated, it is considered that the above-described inhibiting effect does not occur39because oflack of the lubricant inside of the tableted product (Example 3).When tableting is carried out after the heat treatment of the granulated product,the lubricant added in either the intemallubrication method or the external lubricationmethod is not heat-treated, so that the above-mentioned inhibiting effect is not5 generated (Examples 6 and 8).It is evident from the results of Examples 9 to 11 that both of tablet hardnessand disintegration time are improved regardless of the amount of binder added and thedegree of saponification of polyvinyl alcohol. In Example 12 in the absence of anexcipient, Example 13 with the use of a different type of active ingredient, andI 0 Examples 14 and 15 with the use of a different type of disintegrant, the tablet hardnessand disintegration time were improved. It is considered that none of the excipient, theactive ingredient and the disintegrant brings the improvement, but the heat treatment ofgranulated product or tableted product, each containing a predetermined binder, bringsthe improvement.15 In Example 16 with the use ofhydroxypropyl methyl cellulose, Example 1720with the use of hydroxypropyl cellulose, and Example 18 with the use ofpolyvinylpyrrolidone, each as the predetermined binder, the tablet hardness increases,while maintaining the disintegration time. The polyvinyl alcohol is excellent inimprovements of both of the tablet hardness and the disintegration time.It is evident from the results of Example 19 that even addition of activeingredient to the composite granulated product containing an excipient, a predeterminedbinder and a disintegrant improves the tablet hardness and disintegration time.

Claims

CLAIMS1. A method for producing a tablet, comprising:a granulation step of granulating a powder composition comprising at least oneselected from the group consisting of an active ingredient, an excipient and adisintegrant, while adding an aqueous composition comprising a binder and water to thepowder composition, to obtain a granulated product; anda heat treatment and tableting step of subjecting the granulated product to heattreatment and then tableting, or to tableting and then heat treatment, to obtain a tablet;wherein the binder is selected from the group consisting of polyvinyl alcohol,hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol / acrylic acid / methylmethactylate copolymers, and vinylpylTolidone / vinyl acetate copolymers.

2. The method for producing a tablet according to claim 1, wherein thepolyvinyl alcohol has a degree of saponification of78.0 mol% or more.

3. The method for producing a tablet according to claim 1 or 2, wherein theexcipient is selected from the group consisting of sugars, sugar alcohols, starches,dextrins, powdered cellulose, microcrystalline cellulose, calcium carbonate, calciumphosphate, and calcium sulfate.

4. The method for producing a tablet according to any one of claims 1 to 3,wherein the disintegrant is selected from the group consisting of low-substitutedhydroxypropyl cellulose, starches, pmily pregelatinized starch, sodium starch glycolate,41carmellose, carmellose calciwn, croscarmellose sodium, microcrystalline cellulose, andcrospovidone.

5. The method for producing a tablet according to any one of claims 1 to 4,wherein the tableting in the heat treatment and tableting step is canied out in an externallubricating method in which a lubricant is applied to a pestle surface and / or a mortarsurface of a tableting machine.

6. The method for producing a tablet according to any one of claims 1 to 5,wherein the excipient is sugar and / or sugar alcohol, and the disintegrant is lowsubstitutedhydroxypropyl cellulose having a hydroxypropoxy group content of 5 to16% by mass.

7. The method for producing a tablet according to any one of claims I to 6,wherein a temperature in the heat treatment is higher than 80°C.