JP5835875B2 - Method for producing intraorally rapidly disintegrating tablets - Google Patents

Description

  The present invention relates to a process for producing an orally rapidly disintegrating tablet having good disintegration property in the oral cavity and an intraoral rapidly disintegrating tablet obtained by the process.

  Intraorally rapidly disintegrating tablets (OD tablets) have been developed as forms that are easy to be taken by elderly people, children, patients who have difficulty in swallowing drugs, and can be easily taken without water. Intraoral rapidly disintegrating tablets have a disintegration time in the oral cavity of about 60 seconds or less, and have hardness that prevents tablets from being chipped or pulverized during tablet production, transportation, and opening as with normal tablets. There is no disgust in the mouthfeel and taste, and it is necessary to solve more problems than in ordinary tablets. In particular, in the intraoral quick disintegrating tablet, hardness and disintegration time are contradictory elements, and it has been difficult to achieve both.

  As a method for producing an intraoral rapidly disintegrating tablet, various methods have been performed so far, and a method using a specific saccharide, a method of compression molding after wet granulation, and a method of heating or humidification drying after compression molding are known. ing. In particular, the method of processing a tablet after compression molding can further improve performance by combining with a method for producing other intraoral rapidly disintegrating tablets. As a method of compression molding after wet granulation, there is a method (Patent Document 1) using granulated particles obtained by spray drying a saccharide, a disintegrant, and an inorganic excipient.

As a method for increasing the hardness of a tablet after compression molding and producing a rapidly disintegrating tablet in the oral cavity, there is a method in which a saccharide surface is moistened with water and compression molded, followed by drying (Patent Document 2). As a method of heating after compression molding, active ingredient, diluent, saccharide having a low melting point is granulated in a fluidized bed, compression molded, and heated at 80 to 180 ° C. (Patent Document 3), active ingredient, saccharide such as mannitol There are methods (Patent Documents 4 and 5) in which sugars such as xylitol are heated at 90 to 140 ° C. after compression molding. As a method of processing at a low temperature after compression molding, the active ingredient, saccharides such as lactose and sucrose, saccharides such as mannitol and xylitol are compression molded, and then treated at 10 to 40 ° C. for 5 to 72 hours at a humidity of 20 to 75%. To produce a rapidly disintegrating tablet in the oral cavity (Patent Document 6), after fluid bed granulation of active ingredients and highly water-soluble saccharides such as xylitol and compression molding at a low impact pressure of about 300 kg / cm 2 or less There is a method of treating at 30 ° C. or higher (Patent Document 7).

  In the above oral disintegrating tablets, the properties of the active ingredient and the particles containing the active ingredient, as well as the tablet content, disintegration time in the oral cavity, moldability, etc. must be satisfied when the active ingredient content is large. Was not easy. Moreover, it cannot be used for an active ingredient in which heating or water cannot be used in the production process, and it cannot be improved in disintegration / hardness in combination with an existing method for producing a rapidly disintegrating buccal tablet.

JP 2005-139168 A Japanese Patent Laid-Open No. 5-271054 International Publication WO2002 / 92057 Pamphlet International Publication WO2002 / 32403 Pamphlet JP 2006-265242 A Japanese Patent Laid-Open No. 11-12161 JP-A-11-263723

  The present invention is a method for producing an orally rapidly disintegrating tablet having sufficient hardness that does not cause problems during production and transportation and good disintegration property in the oral cavity, and provides a production method excellent in productivity. With the goal. 2. Description of the Related Art Conventionally, there is a demand for a production method that easily imparts higher disintegration in an intraoral quick disintegrating tablet containing main sugars and a disintegrant as main components.

  As a result of intensive research to achieve the above-mentioned object, the present inventors have compression-molded particles and active ingredients obtained by granulating sugars, inorganic powders, and disintegrants in the presence of water, and then added them without humidification. It was found that the disintegration time in the oral cavity was shortened while maintaining the hardness of the tablet by heat treatment.

  The hardness of an orally rapidly disintegrating tablet is obtained by mixing and compressing a saccharide, an inorganic powder, a granulated particle and an active ingredient in the presence of water, followed by compression molding at 30 to 90 ° C. for several hours. The disintegration time can be shortened without affecting other properties. Moreover, since a special apparatus is not required, it can manufacture easily.

It is the graph which showed the change of the disintegration time in the oral cavity of Examples 1-4 by the heating process, and the comparative example 1. FIG.

  The method for producing an intraoral rapidly disintegrating tablet of the present invention comprises granulating a saccharide, an inorganic powder, and a disintegrant in the presence of water, mixing the granulated particles and the active ingredient, and then substantially compressing and molding. It is a method for producing an intraoral quick disintegrating tablet by heating at 30 to 90 ° C. for 1 to 72 hours without humidification. At the time of granulation and mixing, in addition to the aforementioned components, additives that can be blended with pharmaceuticals such as binders, excipients, polymers, disintegration aids, inorganic powders can be blended, disintegration rate, hardness, Formability, humidity stability, etc. can be adjusted in a timely manner.

  The feature of the present invention is that the granulated particles contain an inorganic powder and that no addition or presence of moisture is required during the heating treatment. The reason why the presence of moisture is unnecessary is that the sugar, inorganic powder, and disintegrant are granulated in the presence of water and then dried to remove the moisture. The amount of water contained in the granulated particles may be less than the amount of water contained in the saccharide, inorganic powder, and disintegrant before production. That is, it is a state in which moisture is not substantially present.

  The “orally rapidly disintegrating tablet” in the present invention means a tablet that can disintegrate rapidly in the oral cavity, for example, within 60 seconds, preferably within 40 seconds, more preferably within 30 seconds. The oral disintegration time here is the time obtained by the measurement method described in the examples described later.

  In the present invention, the saccharide is a saccharide and / or a sugar alcohol, and includes one or more of these. Examples of the saccharide include one or more of mannitol, xylitol, erythritol, sorbitol, maltitol, lactose, sucrose, glucose, fructose, maltose, trehalose, palatinit, and palatinose, and two or more thereof may be combined. Preferred are mannitol, xylitol, erythritol, and lactose.

  Two or more of these saccharides are preferable, and in particular, mannitol, xylitol, erythritol, sorbitol, maltitol, lactose, sucrose, glucose, fructose, maltose, trehalose, palatinit, palatinose (hereinafter referred to as “other saccharides”). One or more, more preferably one or more of mannitol, xylitol, erythritol, and sorbitol.

  The ratio of mannitol to other saccharides may be in a range that enhances moldability while maintaining the disintegration property of mannitol, and is 99 to 65: 1 to 35, preferably 99 to 85: 1 to 15: more preferably 99. ~ 90: 1-10.

  In the present invention, the inorganic powder is a substance that is insoluble and hardly soluble in water and has a high specific surface area, such as magnesium aluminate metasilicate, magnesium aluminate silicate, anhydrous silicic acid, calcium silicate, magnesium silicate. , Aluminum silicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granulation, hydrotalcite, calcium phosphate, calcium carbonate, magnesium oxide, magnesium hydroxide, magnesium alumina hydroxide, dry aluminum hydroxide At least one selected from gel, magnesium carbonate, calcium carbonate, talc and the like.

  Preferably, magnesium carbonate, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, magnesium aluminate metasilicate, magnesium aluminate silicate, hydrotalcite, aluminum silicate, calcium silicate, magnesium silicate, At least one selected from silicic anhydride, silicon dioxide, magnesium oxide, magnesium hydroxide, magnesium alumina hydroxide, dry aluminum hydroxide gel, and talc. Most preferred are magnesium aluminate metasilicate, magnesium aluminate silicate, hydrotalcite, aluminum silicate, calcium silicate, magnesium silicate, anhydrous silicic acid, silicon dioxide and talc.

The inorganic excipient should have a high specific surface area from the viewpoint of water conductivity and dispersibility in the particles. The BET specific surface area is 10 to 500 m 2 / g, and preferably the BET specific surface area is 20 to 500 m 2 / g. is there. Those having a high specific surface area have a structure in which primary particles of several μm or less are aggregated, so that the permeability in the particles can be improved by the water-conducting effect in the granulated particles. It is thought that it is effective in improving the productivity of particles. Moreover, since the aggregation of inorganic powders is loosened by granulation in the presence of water, the structure is dispersed in the particles, which is considered to be more effective than dry mixing.

  In the present invention, the disintegrant is at least one selected from crospovidone, low-substituted hydroxypropylcellulose, microcrystalline cellulose, croscarmellose sodium, carmellose, carmellose calcium, hydroxypropyl starch, pregelatinized starch and starch. It is. Preferably, it is at least one selected from crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, starch, and microcrystalline cellulose, more preferably crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium Any one or more of the above and microcrystalline cellulose. The starch is a naturally derived starch such as corn starch, waxy corn starch, rice starch or waxy rice starch.

  The saccharides used here are those having an average particle size of 0.1 to 500 μm, preferably an average particle size of 0.1 to 200 μm, in order to prevent roughness in the oral cavity. Inorganic powders and disintegrants are used which have an average particle size of 0.1 to 60 μm, preferably an average particle size of 0.1 to 30 μm or less, in order to be insoluble in water and prevent roughness in the oral cavity.

  In the intraoral quick disintegrating tablet of the present invention, the mixing ratio of saccharide, inorganic powder and disintegrant is saccharide: inorganic powder: disintegrant = 40 to 90: 1 to 30: 5 to 40. Preferably, the mixing ratio of saccharide, inorganic powder, and disintegrant is saccharide: inorganic powder: disintegrant = 50-80: 2-15: 10-35. More preferably, the blending ratio of saccharide, inorganic powder, and disintegrant is saccharide: inorganic powder: disintegrant = 60-80: 2-10, 15-35.

  By granulating saccharides, inorganic powder, disintegrant, and if necessary, active ingredients and pharmaceutical additives in the presence of water, particles of structure in which inorganic powder and disintegrant are uniformly dispersed in saccharide Form. Some of the saccharides contained are amorphous due to dissolution in water during granulation in the presence of water and solidification upon drying. Further, it is preferable to form composite particles using two or more kinds of saccharides, and to form particles in which the inorganic powder and the disintegrant are uniformly dispersed (hereinafter referred to as “granulated particles of the present invention”). Such particles are sold as F-MELT (trademark: manufactured by Fuji Chemical Industry Co., Ltd.), an excipient for intraorally rapidly disintegrating tablets.

  The two types of saccharides preferably form “composite particles”. “Composite particles” are formed from two types of saccharides including a solid dispersion state. The composite particles are in a state in which the xylitol molecule is substituted for the mannitol molecule in the mannitol crystal structure, or the xylitol molecule enters the vacancies of the mannitol crystal structure, causing distortion in the mannitol crystal structure. Therefore, the moldability is superior to that of mannitol alone. The composite particles have a high energy state, and the endothermic peak at 167 ° C. is shifted to the low temperature side by 0.5 to 9 ° C. These explanations are described in detail in Japanese Patent Application No. 2004-236573 previously filed by the present applicant.

  The static specific volume of the granulated particles of the present invention is preferably 1.5 to 4.0 ml / g, more preferably 1.5 to 3.5 ml / g, still more preferably 1.5 to 2.5 ml / g. It is. By having such a static specific volume, it is easy to mix with other components, and when it is molded into a tablet, it can be easily filled into the mortar, so that the formulation process can proceed smoothly, and the tablet is compressed evenly and excellent The tableting property can be shown. The static specific volume can be measured according to standard methods.

  The reason why the saccharide and the inorganic powder are used in the present invention is to process the tablet after compression molding at a relatively low temperature of 30 to 90 ° C. to shorten the disintegration time in the oral cavity. This heating treatment essentially does not affect the hardness of the rapidly disintegrating tablet in the oral cavity, and the disintegration time in the oral cavity is dramatically shortened. Particles composed of a saccharide, a disintegrant, and an inorganic powder used in the present invention drastically shorten the disintegration time in the oral cavity by blending the inorganic powder. When particles composed of sugars and disintegrants are compression molded without containing inorganic powder, the disintegration time increases. It is considered that the structure of the granulated particles used in the present invention and the interparticle structure of the saccharide and the inorganic powder and the disintegrant in the granulated particles are reconfigured by heating treatment in the presence of the inorganic powder.

  The change in the particle structure by heating in the present invention is different in behavior from the conventionally known intraoral quick disintegrating tablet by heating and heating treatment. For example, a method in which sugar is dissolved by heating and the components in the tablet are combined (WO 2002/32403), or a saccharide such as mannitol or xylitol and an amorphous saccharide are compressed with low hardness (0.6 to 1.8 kg). After molding, a method for producing a fast-disintegrating tablet in the oral cavity having high hardness (3.2 to 5.8 kg) by treating at 10 to 40 ° C. and humidity of 20 to 75% for 5 to 72 hours (Japanese Patent Laid-Open No. 11-12161) ) Is different.

  The granulated particles of the present invention are mixed with a pharmaceutical additive such as an active ingredient and a disintegration aid, an excipient, a binder, a lubricant, a corrigent, and a fragrance, if necessary, and compression molded. Here, when an active ingredient is contained in the granulated particles of the present invention, the granulated particles of the present invention without an active ingredient can be contained, and other pharmaceutical additives can be blended and compression molded.

The disintegration aid of the present invention corresponds to a disintegrant in the field of pharmaceutical additives, and includes, for example, adipic acid, alginic acid, sodium alginate, pregelatinized starch, erythritol, fructose, sodium carboxymethyl starch, carmellose, carme Loin calcium, carmellose sodium, hydrous silicon dioxide, agar, xylitol, guar gum, calcium citrate, croscarmellose sodium, crospovidone, synthetic aluminum silicate, magnesium aluminate silicate, low substituted hydroxypropylcellulose, crystalline cellulose, Crystalline cellulose / carmellose sodium, wheat starch, rice starch, cellulose acetate phthalate, dioctylsodium sulfosuccinate, sucrose fatty acid ester, alumina hydroxide Gnesium, calcium stearate, polyoxyl stearate, sorbitan sesquioleate, gelatin, shellac, sorbitol, sorbitan fatty acid ester, talc, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, dextrin, sodium dehydroacetate, corn starch, tragacanth, trehalose, Lactose, maltose, sucrose, hydrotalcite, honey, palatinit, palatinose, potato starch, hydroxyethyl methylcellulose, hydroxypropyl starch, hydroxypropylcellulose, glucose, bentonite, partially pregelatinized starch, monosodium fumarate, polyethylene glycol, polyoxy Ethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene g One or more of coal, polysorbate, polyvinyl acetal diethylaminoacetate, polyvinyl pyrrolidone, maltitol, D-mannitol, anhydrous citric acid, anhydrous silicic acid, magnesium metasilicate aluminate, methyl cellulose, glyceryl monostearate, sodium lauryl sulfate, etc. Any of these may be used alone, but two or more of them can be blended.
Preferably, it is selected from the group consisting of crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, hydroxypropylcellulose, crystalline cellulose, carmellose, carmellose sodium, carmellose calcium and starch, more preferably cros Povidone, low substituted hydroxypropylcellulose. These can be used alone or in combination of two or more.

  What is classified into the category as an excipient includes, for example, starch acrylate, L-aspartic acid, aminoethylsulfonic acid, aminoacetic acid, candy (powder), gum arabic, gum arabic powder, alginic acid, sodium alginate , Pregelatinized starch, inositol, ethyl cellulose, ethylene vinyl acetate copolymer, erythritol, sodium chloride, olive oil, kaolin, cocoa butter, casein, fructose, pumice grains, carmellose, carmellose sodium, hydrous silicon dioxide, dry yeast, dry hydroxylation Aluminum gel, dry sodium sulfate, dry magnesium sulfate, agar, agar powder, xylitol, citric acid, sodium citrate, disodium citrate, glycerin, calcium glycerophosphate, sodium gluconate, L- Lutamine, clay, clay grains, croscarmellose sodium, aluminum silicate, synthetic aluminum silicate, hydroxypropyl starch, crystalline cellulose, magnesium silicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, light liquid paraffin , Cinnamon powder, crystalline cellulose, crystalline cellulose / carmellose sodium, microcrystalline crystalline cellulose, pearl millet, synthetic aluminum silicate, synthetic hydrotalcite, sesame oil, wheat flour, wheat starch, wheat germ powder, rice flour (rice flour), rice starch, Potassium acetate, calcium acetate, cellulose acetate phthalate, safflower oil, white beeswax, zinc oxide, titanium oxide, magnesium oxide, β-cyclodextrin, dihydroxyaluminum aminoacetate, 2 , 6-Di-t-butyl-4-methylphenol, dimethylpolysiloxane, tartaric acid, potassium hydrogen tartrate, baked gypsum, sucrose fatty acid ester, magnesium aluminate hydroxide, aluminum hydroxide gel, aluminum hydroxide sodium bicarbonate coprecipitation Product, magnesium hydroxide, squalane, stearyl alcohol, stearic acid, calcium stearate, polyoxyl stearate, magnesium stearate, purified gelatin, purified shellac, purified white sugar, purified white sugar spherical granules, purified montan wax, zein, sorbitan sesquioleate, Cetanol, gypsum, cetostearyl alcohol, shellac, gelatin, sorbitan fatty acid ester, D-sorbitol, tricalcium phosphate, soybean oil, soybean oil unsaponifiable matter, soybean lecithin, defatted powder Talc, ammonium carbonate, calcium carbonate, magnesium carbonate, neutral anhydrous sodium sulfate, low substituted hydroxypropyl cellulose, dextran, dextrin, natural aluminum silicate, corn syrup, corn starch, trehalose, tragacanth, silicon dioxide, calcium lactate, Lactose, hydrotalcite, maltose, white shellac, white petrolatum, sucrose, white sugar, white sugar starch spherical granule, powdered green leaf extract, powdered green leaf green juice, honey, palatinit, palatinose, paraffin, potato starch, semi-digested starch Human serum albumin, hydroxypropyl starch, hydroxypropylcellulose, phytic acid, glucose, glucose hydrate, partially pregelatinized starch, pullulan, Lopylene glycol, powdered reduced maltose water candy, powdered cellulose, pectin, bentonite, sodium polyacrylate, polyethylene glycol, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene, polyoxypropylene, glycol, polystyrene sulfone Sodium acid, polysorbate, polyvinyl acetal diethylaminoacetate, polyvinyl pyrrolidone, maltitol, maltose, D-mannitol, water candy, isopropyl myristate, anhydrous lactose, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granule, aluminum metasilicate Magnesium acid, methylcellulose, cottonseed powder, cottonseed oil, mole, aluminum monostearate, glyceryl monostearate, monostea Sorbitan phosphate, silicic anhydride, medicinal charcoal, peanut oil, aluminum sulfate, calcium sulfate, granular limestone, granular corn starch, liquid paraffin, dl-malic acid, calcium monohydrogen phosphate, calcium hydrogen phosphate, potassium hydrogen phosphate There is sodium hydrogen phosphate, and any of these may be used alone, but two or more of them can be blended.

  Those classified in the category as the binder include, for example, ethyl acrylate / methyl methacrylate copolymer emulsion, acetylglycerin fatty acid ester, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, aminoethylsulfonic acid. , Candy (powder), gum arabic, gum arabic powder, sodium alginate, propylene glycol alginate, pregelatinized starch, ester gum H, ethyl cellulose, agate powder, hydrolyzed gelatin powder, sodium caseinate, fructose, caramel, karaya gum powder, carboxy Vinyl polymer, carboxymethyl ethyl cellulose, carboxymethyl starch sodium, carmellose, carmellose sodium, hydrous silicon dioxide, agar, ume powder, oxa Tan gum, beef tallow hardened oil, guar gum, glycerin, synthetic aluminum silicate, light anhydrous silicic acid, light anhydrous silicic acid-containing hydroxypropylcellulose, crystalline cellulose, hardened oil, copolyvidone, sesame oil, wheat flour, wheat starch, rice (rice flour), rice Starch, vinyl acetate resin, cellulose acetate phthalate, honey beeswax, oxidized starch, dioctyl sodium sulfosuccinate, dihydroxyaluminum amino acetate, sodium potassium tartrate, sucrose fatty acid ester, stearyl alcohol, stearic acid, calcium stearate, polyoxyl stearate Sorbitan sesquioleate, cetanol, gelatin, shellac, sorbitan fatty acid ester, D-sorbitol, soybean lecithin, calcium carbonate, simple syrup, Xistrin, starch (soluble), corn starch, tragacanth, paraffin, potato starch, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, piperonyl butoxide, Butylphthalyl bunal glycolate, glucose, partially pregelatinized starch, fumaric acid, pullulan, propylene glycol, pectin, sodium polyacrylate, partially neutralized polyacrylic acid, polyethylene glycol, polyoxyethylene / polyoxypropylene glycol, Polysorbate, polyvinyl acetal Diethylaminoacetate, polyvinyl alcohol (completely saponified product), polyvinyl alcohol (partially saponified product), polyvinylpyrrolidone, polybutene, sodium polyphosphate, D-mannitol, water candy, light anhydrous silicic acid, magnesium metasilicate aluminate, these Any one of them may be used alone, but two or more kinds can be blended.

Preferably, sugars such as mannitol, xylitol, sorbitol, erythritol, maltitol, lactose, glucose, fructose, maltose, trehalose, palatinit, palatinose, glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, One or more amino acids such as methionine, asparagine, glutamine, proline, phenylalanine, tyrosine, tryptophan, and salts thereof, any of which may be used alone, but two or more may be blended .

  Examples of the binder in the present invention include, for example, ethyl acrylate / methyl methacrylate copolymer emulsion, acetylglycerin fatty acid ester, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, aminoethylsulfonic acid, candy (powder). , Gum arabic, gum arabic powder, sodium alginate, propylene glycol alginate, pregelatinized starch, ester gum H, ethyl cellulose, buckwheat powder, hydrolyzed gelatin powder, sodium caseinate, fructose, caramel, caraya gum powder, carboxyvinyl polymer, carboxymethyl Ethylcellulose, sodium carboxymethyl starch, carmellose, carmellose sodium, hydrous silicon dioxide, agar, agar powder, xanthan gum, cured beef tallow , Guar gum, glycerin, synthetic aluminum silicate, light anhydrous silicic acid, light anhydrous silicic acid-containing hydroxypropyl cellulose, crystalline cellulose, hardened oil, copolyvidone, sesame oil, wheat flour, wheat starch, rice flour (rice flour), rice starch, vinyl acetate resin , Cellulose acetate phthalate, honey beeswax, oxidized starch, dioctyl sodium sulfosuccinate, dihydroxyaluminum amino acetate, sodium potassium tartrate, sucrose fatty acid ester, stearyl alcohol, stearic acid, calcium stearate, polyoxyl stearate, sorbitan sesquioleate , Cetanol, gelatin, shellac, sorbitan fatty acid ester, D-sorbitol, soy lecithin, calcium carbonate, simple syrup, dextrin, demp (Soluble), corn starch, tragacanth, paraffin, potato starch, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, piperonyl butoxide, butylphthalyl Nalglycolate, glucose, partially pregelatinized starch, fumaric acid, pullulan, propylene glycol, pectin, sodium polyacrylate, partially neutralized polyacrylic acid, polyethylene glycol, polyoxyethylene / polyoxypropylene / glycol, polysorbate, polyvinyl Acetal diethylaminoacete 1 type or more of a salt, polyvinyl alcohol (completely saponified product), polyvinyl alcohol (partially saponified product), polyvinylpyrrolidone, polybutene, sodium polyphosphate, D-mannitol, water candy, light anhydrous silicic acid, magnesium metasilicate aluminate, etc. Any of these may be used alone, but two or more of them can be blended.

  The active ingredient is not particularly limited, and is a central nerve agent such as a peripheral nerve agent, an antipyretic analgesic / antiinflammatory agent, a hypnotic sedative, or a neuropsychiatric agent; a peripheral nerve agent such as a skeletal muscle relaxant or an autonomic nerve agent; Cardiovascular agents such as cardiotonic agents, arrhythmic agents, diuretics, vasodilators; respiratory organ agents such as bronchodilators and antitussives; gastrointestinal agents such as digestives, intestines, antacids; hormones, antihistamines, vitamins Metabolic drugs such as drugs; anti-ulcer agents; antibiotics; chemotherapeutic agents; herbal extracts;

  The active ingredient for cold medicine, the active ingredient for rhinitis, etc. can be mentioned. Examples of the active ingredient for cold medicine include antipyretic analgesic / anti-inflammatory agents, bronchodilators, antihistamines, antitussives, antiseptics, antiseptic antiseptics, vitamins, and herbal medicine extracts. Examples of the active ingredient for rhinitis include sympathomimetic agents, parasympathetic nerve blockers, antiallergic agents and antiinflammatory agents, and the like. Antipyretic analgesic and anti-inflammatory agents include, for example, pranlukast hydrate, acetaminophen, phenacetin, levetamine hydrochloride and other aniline derivatives, etenzamide, sazapyrine, methyl salicylate, phenyl salicylate, sodium salicylate, choline salicylate, aspirin, aspirin aluminum, etc. Salicylic acid derivatives, etc., pyrazolo derivatives such as isopropylantipyrine, sulpyrine, phenylbutazone, ketophenylbutazone, antipyrine, and aminopyridine, propionic acid derivatives such as ibuprofen, ketoprofen, oxacyprozin, naproxen, fenoprofen calcium, thiaprofenic acid, etc. , Phenbufen, diclofenac sodium, amphenac sodium and other phenylacetic acid derivatives, indomethacin, indomethacin Insole acetic acid derivatives such as Nesyl, Progouritacin maleate, Tolmetine sodium, Anthranilacetic acid derivatives such as Mefenamic acid, Flufenamic acid, Tolfenamic acid, Oxicum derivatives such as Piroxicam, Ampiroxicam, Tenoxicam, Benzydamine hydrochloride, Epirizole (Mepyrizole), Examples thereof include tinolidine hydrochloride, tiaramid hydrochloride, anti-inflammatory enzyme agents, serrapeptidase (trade name), lysozyme chloride, and the like. These antipyretic analgesic / anti-inflammatory agents can be used alone or in combination of two or more.

  Examples of bronchodilators include ephedrine hydrochloride, dl-methyl ephedrine hydrochloride, dl-methyl ephedrine hydrochloride saccharinate, isoprenaline hydrochloride, isoproterenol sulfate, methoxyphenamine hydrochloride, orciprenaline sulfate, chlorprenalin hydrochloride, trimethoxy hydrochloride. Ol, salbutamol sulfate, terbutaline sulfate, hexoprenaline sulfate, formoterol fumarate, fenoterol hydrobromide, procaterol hydrochloride, pluterol hydrochloride, clenpterol hydrochloride, mabuterol hydrochloride, aminophylline, theophylline, dibrophyrin, proxyphylline, xanthine derivatives, odor And anticholinergic agents such as flutropium iodide and oxitropium bromide. Examples of the antihistamine include ethanolamine antihistamines such as diphenhydramine, propylamine antihistamines such as dl-chlorpheniramine maleate and chlorpheniramine maleate, alimemazine tartrate, isothipentyl hydrochloride, promethazine hydrochloride, and phenothiazine hydrochloride. Examples include antihistamines, diphenylpyralin, carbinoxamine maleate, clemastine fumarate, iproheptin hydrochloride, homochlorcyclidine hydrochloride, cyproheptadine hydrochloride, dimethindene maleate, triprolidine hydrochloride, olopatadine hydrochloride, and the like.

  Antitussives include, for example, codeines such as codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, cloperastine, noscapine dimethylmorphane, oxerazine, pentoxyberine citrate, eprazinone hydrochloride, clobutinol hydrochloride, citric acid Examples include isoaminyl, fominoben hydrochloride, clofedanol hydrochloride, benproperin phosphate, hydrocotarnine, dibutate sodium and the like.

  Examples of the desquamating agent include potassium guaiacol sulfonate, carbocysteine, L-ethylcysteine hydrochloride, L-methylcysteine hydrochloride, cysteine derivatives such as acetylcysteine, bromhexine, ambroxol hydrochloride, and the like. Examples of antitussive removers include guaifenesin, tipipedin, oxymethebanol, aroclamide hydrochloride, carbetapentane phenate, trimethquinol hydrochloride, methoxyphenamine hydrochloride, and the like. In addition, the active ingredient illustrated as the said antitussive, an antifouling agent, and an antitussive exfoliating agent may show an antitussive action and / or an antifouling action in combination.

  Examples of psychotropic drugs include chlorpromazine, reserpine and the like. Examples of the anxiolytic drug include tofisopam, zolpidem tartrate, alprazolam, chlordiazepoxide, diazepam and the like. Examples of the antidepressant include maprotiline hydrochloride, imipramine, amphetamine, metafetan and the like. Examples of the hypnotic sedative include estazolam, nitrazepam, diazepam, perlapine, phenobarbital sodium and the like. Examples of antispasmodic agents include scopolamine hydrobromide, papaverine hydrochloride, diphenhydramine hydrochloride, and the like. Examples of central nervous system drugs include citicoline. Examples of the antiepileptic agent include phenytoin and carbamazepine. Examples of the sympathomimetic agent include isoproterenol hydrochloride. Examples of peripheral neuropathy agents include epalrestat and mecobalamin.

  The gastrointestinal drugs include, for example, gastrointestinal agents such as diastase, sugar-containing pepsin, funnel extract, cellulase AP3, lipase AP, cinnamon oil, etc., berberine chloride, resistant lactic acid bacteria, bifidobacteria and the like. Examples of the antacid include magnesium carbonate, sodium bicarbonate, magnesium aluminate metasilicate, magnesium aluminate silicate, synthetic hydrotalcite, precipitated calcium carbonate, magnesium oxide and the like. Examples of the anti-ulcer agent include teprenone, famotidine, lansoprazole, omeprazole, rabeprazole, cimetidine, ranitidine hydrochloride and the like. Examples of digestive organ drugs include mosapride citrate.

Examples of antihypertensive agents include carvedilol, olmesartan medoxomil, benidipine hydrochloride, telmisartan, amlodipine besylate, delapril, captopril, hydralazine hydrochloride, labetalol hydrochloride, manidipine hydrochloride, candesartan cilexetil, methyldopa, perindopril erbumine, etc. It is done. Examples of the vasoconstrictor include phenylephrine hydrochloride. Examples of the vasodilator include nicorandil, carbochromene hydrochloride, molsidomine, perapamil hydrochloride, cinnarizine and the like. Examples of the arrhythmic agent include procainamide hydrochloride, propranolol hydrochloride, pindolol and the like. Examples of the cardiotonic agent include caffeine and digoxin.
Examples of the diuretic include isosorbide, furosemide, hydrochlorothiazide and the like.
Examples of the hyperlipidemia agent include ethyl icosapentate, cerivastatin sodium, simvastatin, pravastatin sodium, atorvastatin calcium hydrate and the like.

Antibiotics include, for example, vancomycin hydrochloride, cefdinir, itraconazole, clarithromycin, cefcapene pivoxil hydrochloride, cephalexin, cefaclor, amoxicillin, pipmecillin hydrochloride, cefotium hexetyl hydrochloride, cefadroxyl, cefixime, cefditren pivoxil, cefterampyrix And cephem compounds such as cefpodoximiproxetil, synthetic antibacterial agents such as ampicillin, cyclacin, nalidixic acid, levofloxacin, enoxacin, monobactams such as carmonam sodium, penems and carbapenem antibiotics.
Examples of the chemotherapeutic agent include sulfamethizole.

Examples of the agent for diabetes include tolbutamide, voglibose, pioglitazone hydrochloride, glibenclamide, troglidazone and the like.
Examples of antispasmodic agents include meclizine hydrochloride and dimenhydrinate.
Antirheumatic drugs include methotrexate, bucillamine and the like.
Examples of hormone agents include liothyronine sodium, dexamethasone sodium phosphate, prednisolone, oxendron, leuprorelin acetate, and the like.
Alkaloid narcotics include opium, morphine hydrochloride, throne, oxycodone hydrochloride, opium alkaloid hydrochloride, cocaine hydrochloride, and the like.
Examples of the sulfa drugs include sulfisomidine and sulfamethizole.
Examples of anti-gout drugs include allopurinol and colchicine.
Examples of the blood coagulation inhibitor include dicumarol.
Examples of the antineoplastic agent include 5-fluorouracil, uracil, mitomycin, manidipine hydrochloride, voglibose, candesartan cilexetil, pioglitazone hydrochloride and the like.

  Other active ingredients include, for example, tamsulosin hydrochloride, donepezil hydrochloride, oseltamivir, limaprost alphadex, loxoprofen sodium, sarpogrelate hydrochloride, ursodeoxycholic acid, alacepril, brotizolam, berberine hydrochloride or tannate, loperamide hydrochloride, ebastine, etc. Is mentioned.

Nutritional ingredients include proteins, carbohydrates, lipids, vitamins, minerals and other beneficial ingredients.
Examples of vitamins include carotenoids such as astaxanthin, vitamin A, β-carotene, lutein, zeaxanthin, fursultiamine, fursultiamine hydrochloride, prosultiamine, octothiamine, thiamine disulfide, bisbutaminamine, bisbuthiamine Vitamin B1 such as bisibutiamine, benfotiamine, cetotiamine hydrochloride or a derivative thereof or a salt thereof, riboflavin, sodium riboflavin phosphate, sodium flavin adenine dinucleotide, a riboflavin vitamin B2 or a derivative thereof, or a salt thereof, Vitamin C derivatives such as ascorbic acid, ascorbic acid glucoside, L-ascorbyl palmitate, L-ascorbic acid phosphate, tocopherol, tocopherol acetate, co Click tocopherol, tocopherol nicotinate, vitamin E such as tocotrienol or the like.

  Other useful ingredients include, for example, deoxyribonucleic acid and its salts, adenylic acid derivatives such as adenosine triphosphate, adenosine monophosphate and their salts, ribonucleic acid and its salts, guanine, xanthine and their derivatives and their derivatives. Nucleic acid-related substances such as salt; Serum deproteinized extract, spleen extract, placenta extract, chicken crown extract, royal jelly extract, etc .; yeast extract, lactic acid bacteria extract, bifidobacteria extract, ganoderma extract Extracts derived from microorganisms such as foods; extracts derived from plants such as carrot extract, assembly extract, rosemary extract, agaric extract, garlic extract, hinokitiol, cephalanthin; α- or γ-linolenic acid, Icosapentaenoic acid and their derivatives, succinic acid and its derivatives and their salts, estradiol and Derivatives thereof and salts thereof, α-hydroxy acids such as glycolic acid, lactic acid, malic acid, citric acid, salicylic acid and their derivatives and their salts, glycyrrhizic acid, glycyrrhetinic acid, mefenamic acid, phenylbutazone, indomethacin, ibuprofen , Ketoprofen, allantoin, guaiazulene and their derivatives and their salts, ε-aminocaproic acid, zinc oxide, diclofenac sodium, hyaluronic acid, chondroitin, collagen, aloe extract, salvia extract, arnica extract, chamomile extract, birch Extract, hypericum extract, eucalyptus extract and mukuroji extract, tyrosinase activity inhibitor is cysteine and its derivatives and salts thereof, Sempokka extract, keiketou extract, sun penz extract, Sakuhakuhi extract, Toki extract, Ibukitorano extract, Clara extract, Hawthorn extract, Shirayuri extract, Hops extract, Neubara extract and Yokuinin extract, Hyaluronic acid, Chondroitin sulfate, Dermatan sulfate, Heparan sulfate, Heparin And keratan sulfate and salts thereof, collagen, elastin, keratin and derivatives thereof, and salts thereof, deep ocean water, loofah extract, gypsum extract, papaya powder, zinc, ginseng extract, bullberry extract, DHA, ginkgo One or more kinds can be selected from the group consisting of leaf extract, glutathione, flavonoid, tannin, ellagic acid, nucleic acids, herbal medicines, seaweeds, inorganic substances and the like, and mixtures thereof.

  As the active ingredient, those processed by a known method such as coating or spray drying can be used for the purpose of concealing bitterness and controlling release. Moreover, in order to release in the digestive tract, the release may be controlled by a known method. The active ingredient can be blended in order to improve the feeling of roughness in the oral cavity and the feeling of administration, and the average particle size is preferably from 0.1 to 100 μm. The active ingredient may be added simultaneously with the masking during the production of the granulated particles of the present invention.

  The intraoral quick disintegrating tablet of the present invention is a total of 1 to 98 parts by weight of (a) saccharide, inorganic powder and disintegrant, and (b) 0.01 to 60 active ingredient powders based on 100 parts by weight of the whole tablet. It comprises at least one or more selected from 1 part by weight, (c) an excipient, a disintegration aid and / or a binder, and (d) 0.01 to 5 parts by weight of a lubricant.

  As an additional component that can be blended in the pharmaceutical preparation of the present invention, a binder (for example, carmellose, hydroxypropylcellulose, alginic acid, gelatin, partially pregelatinized starch, popidone, gum arabic, pullulan, dextrin, etc.), excipient (for example, Corn starch, potato starch, rice starch, powdered sugar, lactose, D-mannitol, trehalose, crystalline cellulose, crystalline cellulose / carmellose sodium, magnesium aluminate metasilicate, calcium hydrogen phosphate, hydrotalcite, silicic anhydride, etc.) , Surfactant (for example, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan fatty acid ester, polysorbate, fatty acid glycerin ester, sodium lauryl sulfate, etc.), lubricant (sucrose fatty acid ester) , Magnesium stearate, talc, sodium stearyl fumarate, etc.), acidulants (eg, citric acid, tartaric acid, malic acid, ascorbic acid, etc.), foaming agents (eg, sodium bicarbonate, sodium carbonate, etc.), sweeteners (sodium saccharin, Glycyrrhizin dipotassium, aspartame, stevia, thaumatin, acesulfame potassium, etc.), fragrance (eg lemon oil, orange oil, menthol, etc.), colorant (eg edible red No. 2, edible blue No. 2, edible yellow No. 5, edible lake Pigments, iron sesquioxide, etc.), stabilizers (for example, sodium edetate, tocopherol, cyclodextrin, etc.), flavoring agents, flavoring agents and the like.

The manufacturing method of the intraoral quick disintegrating tablet of this invention is described below.
The saccharide, inorganic powder, and disintegrant are granulated in the presence of water, and if necessary, active ingredients and pharmaceutical additives are mixed and compression molded, and then held at a temperature of 30 to 90 ° C. for 1 to 72 hours.

  Granulation in the presence of water refers to general wet granulation and may be any ordinary wet granulation, for example, spray drying, fluidized bed granulation, rolling bed granulation, stirring granulation Kneading granulation is preferred, but spray drying, fluidized bed granulation, rolling bed granulation, and stirring granulation are preferred, and continuous production is possible. Spray drying is most preferred. A method for producing the granulated particles of the present invention by spray drying is described in JP-A-2005-139168.

The compression molding is preferably performed by a direct tableting method, and the tableting pressure at that time varies depending on the size of the tablet, but is usually 200 to 2000 kgf, preferably 250 to 1600 kgf, more preferably 250 to 1200 kgf. It is. In the manufacturing method of the present invention, compression molding can be performed with sufficient hardness in such a manufacturing process, and compression molding with low hardness is not necessary.
The intraoral quick disintegrating tablet of the present invention usually has a hardness of 30 to 200N, preferably 40 to 100N. The tableting pressure varies depending on the size and shape of the tablet. For example, when a 200 mg tablet is compressed using a 8 mm diameter punch, the tablet has a hardness of 30 to 150 N when the tableting pressure is 100 to 1200 kgf. When the tableting pressure is 100 to 1000 kgf, it has a hardness of 30 to 100N.

  In the production of the rapidly disintegrating tablet in the oral cavity according to the present invention, as described above, the lubricant may be mixed with other ingredients and then mixed with other ingredients and then compression molded. It is possible to manufacture by compression method (external lubrication method) and apply desired hardness and disintegration in advance to the surface of the punch and the wall of the mortar without mixing. Can do. The method of applying the lubricant to the mortar can be performed by a conventionally known method or machine.

In the heating process, temperature is an important condition, but humidity is not important.
The temperature of the heating treatment is 30 to 90 ° C, preferably 40 to 80 ° C, more preferably 40 to 70 ° C. When the temperature is higher than 90 ° C., the saccharide is melted, which is not preferable, and when the temperature is low, it takes time to reduce the disintegration time, which is not industrial. The processing time varies depending on the heating temperature. For example, the processing time decreases as the heating temperature increases. The heating time is 1 to 72 hours, preferably 2 to 48 hours, and most preferably 2 to 24 hours. The effect of the heating treatment can be seen by shortening the oral disintegration time of the tablet or slightly changing the tablet hardness.

  Regarding the change in the disintegration time of the tablet, the disintegration time after the heating treatment is shortened by 15% or more, preferably 20% or more, more preferably 25% or more with respect to the disintegration time before the heating treatment. The longer the disintegration time is, the greater the disintegration time shortening effect is. For example, those having a disintegration time in the oral cavity of about 20 seconds can be shortened by 3 seconds or more, and those having a disintegration time of about 40 seconds can be shortened by 10 seconds or more.

  The present invention is characterized in that no substantial decrease in hardness occurs. The fact that the hardness does not substantially decrease means that the change in tablet hardness due to the heating treatment holds the hardness after the heating treatment to 85% or more, preferably 90% or more compared to before the heating treatment. is there.

  During the heating process of the present invention, it is not necessary to perform humidification, and heating is performed by sealing. At the time of the heating treatment, it is not necessary to increase the humidity such as application of water to the tablet or humidification in advance, and an open system may be used. The apparatus used for heating may be any apparatus that can perform normal heating.

EXAMPLES The present invention will be described below with reference to examples, but these examples do not limit the scope of the present invention.
Evaluation about each tablet obtained in the Example was performed by the following method.
[Oral disintegration time]
The time taken for 5 subjects to put tablets (n = 5 each) on the tongue in the oral cavity and completely disintegrate was measured, and the average value was taken as the oral disintegration time.
[Tablet hardness]
It measured using the load cell type tablet hardness meter [PC-30, Okada Seiko Co., Ltd. product].
[Tabletting disorder]
The mortar of the tableting machine and the tablet after tableting were observed to evaluate sticking and capping.

[Example 1]
After uniformly dispersing 40 parts by weight of mannitol, 3 parts by weight of xylitol, 5 parts by weight of magnesium aluminate metasilicate, 2 parts by weight of hydroxypropylmethylcellulose, 5 parts by weight of crospovidone and 45 parts by weight of acetaminophen, spraying Using a drier (L-8 type, manufactured by Okawara Chemical Co., Ltd.), spray drying was performed at an outlet temperature of 100 ° C. to obtain white spherical granulated particles having good fluidity.
83 parts by weight of the granulated particles, 8.5 parts by weight of microcrystalline cellulose, 4 parts by weight of crospovidone, 1.5 parts by weight of sucralose, 0.5 parts by weight of acesulfame potassium, 2 parts by weight of citric acid, 0. After mixing 5 parts by weight, it was compression molded with a rotary tableting machine (manufactured by Hata Iron Works Co., Ltd., HT-AP18SS-II) with a set hardness of 50 N to obtain 300 mg tablets. The tablets were sealed and placed in a blowing constant temperature dryer (FC-610 manufactured by ADVANTEC) and held at a temperature of 60 ° C. for 16 hours.

[Example 2]
After uniformly dispersing 65 parts by weight of mannitol, 5 parts by weight of xylitol, 7 parts by weight of magnesium aluminate metasilicate, 15 parts by weight of microcrystalline cellulose, and 8 parts by weight of crospovidone, spray drying at an outlet temperature of 100 ° C., White spherical granulated particles having good fluidity were obtained.
After mixing 55 parts by weight of the granulated particles, 40 parts by weight of acetaminophen, 1.5 parts by weight of sucralose, 1 part by weight of acesulfame potassium, 2 parts by weight of citric acid and 0.5 parts by weight of magnesium stearate, the set hardness A 300 mg tablet was obtained by compression molding with a rotary tableting machine as 50N. This tablet was sealed and placed in an air-cooled constant temperature dryer and kept at a temperature of 60 ° C. for 16 hours.

[Example 3]
After uniformly dispersing 65 parts by weight of mannitol, 5 parts by weight of xylitol, 7 parts by weight of magnesium aluminate metasilicate, 15 parts by weight of microcrystalline cellulose, and 8 parts by weight of crospovidone, spray drying at an outlet temperature of 100 ° C. White spherical granulated particles having good fluidity were obtained. After mixing 99.5 parts by weight of the granulated particles and 0.5 parts by weight of magnesium stearate, a 300 mg tablet was obtained by compression molding with a rotary tableting machine with a set hardness of 50N. This tablet was sealed and placed in an air blowing constant temperature dryer and kept at a temperature of 40 ° C. for 16 hours.

[Example 4]
After uniformly dispersing 65 parts by weight of mannitol, 5 parts by weight of xylitol, 4 parts by weight of anhydrous calcium hydrogen phosphate, 18 parts by weight of microcrystalline cellulose, and 8 parts by weight of crospovidone, spray drying at an outlet temperature of 100 ° C. White spherical granulated particles having good fluidity were obtained.
After mixing 99.5 parts by weight of the granulated particles and 0.5 parts by weight of magnesium stearate, a 300 mg tablet was obtained by compression molding with a rotary tableting machine with a set hardness of 50N. This tablet was sealed and placed in an air blowing constant temperature dryer and kept at a temperature of 40 ° C. for 16 hours.

[Comparative Example 1]
70 parts by weight of mannitol, 5.4 parts by weight of xylitol, 16 parts by weight of microcrystalline cellulose, and 8.6 parts by weight of crospovidone are uniformly dispersed in water, and then spray-dried at an outlet temperature of 100 ° C. Of spherical granulated particles were obtained.
After mixing 99.5 parts by weight of the granulated particles and 0.5 parts by weight of magnesium stearate, a 300 mg tablet was obtained by compression molding with a rotary tableting machine with a set hardness of 50N. This tablet was sealed and placed in an air blowing constant temperature dryer and kept at a temperature of 40 ° C. for 16 hours.

[Table 1] Measured values of intraorally rapidly disintegrating tablets

  The rate of change in hardness is a percentage obtained by dividing the hardness before the heating treatment by the hardness after the heating treatment. The disintegration time rate is a percentage obtained by dividing the disintegration time before the heat treatment by the disintegration time after the heat treatment.

  The intraoral quick disintegrating tablet containing the granulated particles to which the inorganic powders of Examples 1 to 4 are added has a disintegration time shortened by 20% or more by the heating treatment. On the other hand, it is understood that the intraoral quick disintegrating tablet containing granulated particles not blended with the inorganic powder of Comparative Example 1 has a hardness reduced by 30% or more and a disintegration time is delayed by 35% or more.

Claims (12)

The saccharides, inorganic powder, particles obtained by granulating and drying the disintegrant in the presence of water, and active ingredients are compression-molded, and the resulting compression-molded product is 1 at a temperature of 40 to 90 ° C. without substantially humidifying. A method for producing an intraorally rapidly disintegrating tablet, characterized by treating for 72 hours and shortening the disintegration time,
Substantially not humidified means that there is no humidification / water addition step after granulation of saccharides, inorganic powders and disintegrant in the presence of water, or no humidification or water addition step after compression molding The manufacturing method of the intraoral quick disintegrating tablet which is. Particles obtained by granulating and drying saccharides, inorganic powder, disintegrant and active ingredient in the presence of water are compression-molded, and the obtained compression-molded product is 1 to 1 at a temperature of 40 to 80 ° C. without substantially humidifying. It is a method for producing an orally rapidly disintegrating tablet characterized by treating for 72 hours and shortening the disintegration time,
Substantially not humidified means that there is no humidification / water addition step after granulation of saccharides, inorganic powders and disintegrant in the presence of water, or no humidification or water addition step after compression molding The manufacturing method of the intraoral quick disintegrating tablet which is. The production according to any one of claims 1 to 2, wherein the saccharide is any two or more of mannitol, xylitol, sorbitol, erythritol, maltitol, lactose, sucrose, glucose, fructose, maltose, trehalose, palatinit and palatinose. Method. The saccharide comprises xylitol, sorbitol, erythritol, maltitol, lactose, sucrose, glucose, fructose, maltose, trehalose, palatinit and palatinose, and mannitol. Manufacturing method. The disintegrant is crospovidone, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, croscarmellose sodium, carmellose, carmellose calcium, hydroxypropyl starch, starch, and pregelatinized starch. The manufacturing method as described in. Inorganic powder is magnesium aluminate metasilicate, magnesium aluminate silicate, hydrotalcite, aluminum silicate, calcium silicate, magnesium silicate, anhydrous silicic acid, silicon dioxide, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate It is a calcium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, talc, and dry aluminum hydroxide gel, The manufacturing method of any one of Claims 1-5. The method according to any one of claims 1 to 6, wherein the granulated particles are granulated particles having two or more sugars to form composite particles. The production method according to any one of claims 1 to 7, wherein a blending ratio of the saccharide, the inorganic powder, and the disintegrant of the granulated particles is 40 to 90: 1 to 30: 5 to 40. The production method according to any one of claims 1 to 8, wherein a blending ratio of the saccharide, the inorganic powder, and the disintegrant of the granulated particles is 50 to 80: 2 to 15:10 to 35. The method according to any one of claims 1 to 9, wherein the saccharide comprises mannitol and other saccharides, and a ratio of mannitol to other saccharides is 99 to 67: 1 to 33. The manufacturing method according to any one of claims 1 to 10, wherein the heating temperature is 40 to 80 ° C. 0.01 to 200 parts by weight of an active ingredient and 0.01 to 1000 parts by weight of a pharmaceutical additive component as required, based on a total of 100 parts by weight of a saccharide, an inorganic powder, and a disintegrant. A manufacturing method, wherein the pharmaceutical additive component is selected from the group consisting of an excipient, a disintegrant, a binder, a surfactant, a sour agent, a sweetener, a corrigent, a fragrance, a colorant, and a stabilizer. The manufacturing method of any one of claim | item 1 -11.

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