KR20090094319A - Orally disintegrating tablet and bitter-blocking preparation each comprising risperidone - Google Patents

Abstract

Disclosed are: an orally disintegrating tablet; and a bitter-blocking preparation, each of which comprises risperidone. It is found that an orally disintegrating table having good disintegration property and ensured hardness can be produced by compressing and shaping a powder comprising risperidone, crystalline cellulose, an inorganic excipient, carmellose, and a lubricating agent in an amount of 0.8 wt% or less, preferably 0.5 wt% or less, more preferably 0.1 wt% or less per one tablet. Specifically disclosed are: a powdery/granular preparation produced by granulating an excipient and/or a disintegrating agent with a solution having a bitter-blocking base material dissolved and/or suspended therein and also having risperidone having a solubility in water of 1 g/mL or less (at 20°C) dissolved or suspended therein; and a tablet produced by tabletting the powdery/granular preparation. The powdery/granule preparation and the tablet can block a bitter taste of risperidone.

Description

Oral disintegrating tablets and anti-inhibiting preparations containing risperidone {ORALLY DISINTEGRATING TABLET AND BITTER-BLOCKING PREPARATION EACH COMPRISING RISPERIDONE}

In recent oral dosages, preparations that are easy to take even for elderly people and children with low swallowing ability are desired, and they collapse quickly in the oral cavity and rarely feel bitter taste. Several formulations have already been developed that can be taken without.

In the field of antipsychotics, oral disintegrating tablets that can be taken without water because they rapidly disintegrate into saliva in the oral cavity, and high antidepressant preparations that rarely feel bitter, go forward one step from `` compliance ''. It is expected that it may lead to participation in active treatment of patient of "drug medication advance" and improvement of medication action. Moreover, since it is a formulation which is easy to accept even in the patient of the acute stage with severe excitement and rejection, it is thought that the therapeutic benefit is also large.

The present invention relates to oral disintegrating tablets and antimicrobial preparations of risperidone already used as antipsychotics.

In the preparation of orally disintegrating tablets, sugars, sugar alcohols and / or disintegrating agents are generally used to ensure the disintegration properties after taking medication. As literature which discloses oral disintegration tablet containing a saccharide | sugar, sugar alcohol, and a disintegrating agent, the following references are mentioned, for example.

Patent Document 1 describes an orally disintegrating tablet containing a pharmaceutical component, erythritol, crystalline cellulose and a disintegrating agent. In addition, Patent Document 2 describes an orally disintegrating tablet containing a pharmaceutical component, D-mannitol, celluloses, and a disintegrating agent. This document is a document which discloses that D-mannitol whose average particle diameter is 30-300 micrometers is preferable. Patent documents 1 and 2 are prescription examples which accelerated disintegration time by mix | blending the sugar, sugar alcohol, and disintegrating agent which are the additives which are used best in the prescription of oral disintegration tablet.

Patent Literature 3 discloses a method for producing an orally disintegrating tablet containing granules obtained by spraying a saccharide with low moldability and a saccharide with high moldability as a binder. Patent document 4 describes that orally disintegrating tablets can be obtained by tableting powders obtained by spray-drying a suspension in which inorganic substances and sugars are uniformly dispersed together with crystalline cellulose and a disintegrating agent. On the other hand, it is described that hardness is bad about the tablet which directly compressed the simple mixture which consists of the same composition. In Patent Document 5, a surface-modifying base such as hard silicic anhydride is mixed with the active ingredient, and surface-modified using a high-speed stirring granulator or the like, and tableting is performed by directly adding a disintegrating agent to the surface-modified powder thus obtained. It is described that orally disintegrating tablets can be obtained. Disintegrants are described as partially alpha starch and crospovidone most suitable. In the formulations of Patent Documents 3, 4, and 5, in order to improve the disintegration property and the hardness of the tablet, the addition of the preparation step is required, and the production efficiency is poor.

Patent document 6 describes that a disintegrating agent may be blended into granules containing a water-soluble drug, and further added to a cellulose powder and / or an inorganic additive, followed by tableting to obtain a tablet having good disintegrability. . This patent document 6 has the disintegration time of a preparation largely over 3 minutes, and does not satisfy the disintegration time as an oral disintegration tablet.

In addition, Non-Patent Document 1 (Kyowa Kagaku Kogyo Co., Ltd. pamphlet (excipient excipient anhydrous calcium hydrogen phosphate GS)) includes crystalline cellulose, anhydrous calcium hydrogen phosphate, carmellose, and Data for formulations containing 1% by weight magnesium stearate are described. In this formulation, the compounding quantity of magnesium stearate which is a lubricant is 1%, and there exists a possibility that the disintegration property of a tablet may fall by heating and humidification.

On the other hand, various agents have been developed as preparations for suppressing bitterness. Specifically, Patent Document 7 describes a formulation in which a bitter substance is added to an ethanol solution in which ethyl cellulose, which is a hydrophobic polymer, and hydroxypropyl cellulose, which is a water-soluble polymer, is added, and the solution is mixed with an excipient. In addition, Patent Document 8 discloses a granule prepared by spraying an ethanol solution of a gas-soluble coating base on a powder mixed with a carbapenem antibiotic and a lactose even when a hydrophobic polymer is not used. Furthermore, it is described about the fine granule which mixed lactose, polyvinylpyrrolidone, etc., sprayed the aqueous solution of hydroxypropyl cellulose, and suppressed bitterness.

However, in the case of high anti-inhibitory preparations such as Patent Literature 7 using a hydrophobic polymer as a base, high odor is also suppressed, but the dissolution rate of risperidone is highly likely to be suppressed. In the case of suppressing the dissolution rate, the dissolution behavior may also vary, and the risperidone dynamic may also fluctuate. In addition, in either case of patent documents 7 and 8, organic solvents, such as ethanol, are used in order to melt | dissolve the base material which suppresses bitterness. In this case, however, it is necessary to install a recovery device for organic solvent in the machine, and also adversely affect the environment.

Risperidone already used as an antipsychotic is a benzoisoxazole derivative represented by the following formula (1) and is used as an atypical antipsychotic that exhibits antagonistic action on both dopamine D2 receptor and serotonin 5-HT2A receptor. . The present invention shows an improvement in both positive and negative symptoms of ataxia, so that weight gain, which is a side effect of atypical antipsychotics, is small, and the risk of developing diabetes is low (see Patent Document 9).

Patent Document 1: Japanese Patent Publication 1998-182436

Patent Document 2: Japanese Patent Publication 2001-58944

Patent Document 3: WO95 / 20380

Patent Document 4: Japanese Patent Publication 2000-86537

Patent Document 5: WO00 / 54752

Patent Document 6: Japanese Patent Publication 2002-12540

Patent Document 7: Japanese Patent Publication 2002-363066

Patent Document 8: Japanese Patent Publication 2004-35518

Patent Document 9: Japanese Patent Publication 1986-221186

[Non-Patent Document 1] Kyogawa Chemical Industries, Ltd. Pamphlet (Excipient Anhydrous Calcium Hydrogen Phosphate GS)

Disclosure of Invention

Problems to be Solved by the Invention

In the tablet of risperidone, it has a moderate hardness, rapid disintegration in the mouth and a good feeling of ingestion, and it is a high anti-inhibitory preparation which suppresses the taste of risperidone and the oral disintegration tablet which can be produced by existing equipment without requiring a special preparation machine. To provide.

Means to solve the problem

The inventors have found that powders comprising risperidone, crystalline cellulose, inorganic excipients, disintegrants, in particular carmellose and tablets up to 0.8% by weight, preferably up to 0.5% by weight, more preferably up to 0.1% by weight of lubricant By direct compression molding, it was found that orally disintegrating tablets having good disintegration properties and securing tablet hardness can be obtained. In this case, the compounding quantity of anhydrous calcium hydrogen phosphate as the inorganic excipient and the stearic acid metal salt as the lubricant is 0.8 wt% or less, preferably 0.5 wt% or less, more preferably 0.1 wt% or less per tablet. In particular, by blending risperidone, crystalline cellulose, anhydrous calcium hydrogen phosphate, carmellose and up to 0.1% by weight of magnesium stearate per tablet, and by compression molding by external lubrication, it shows good disintegration properties and purification. Intraoral disintegration tablets with secured hardness were obtained.

In addition, the present inventors have diligently investigated the preparations for improving the defects of the high-inhibiting preparations described above, and susporidon is suspended in high-viscosity liquids, and the obtained liquids are added to excipients and / or disintegrating agents and assembled. In the case of powder and granule preparations (for example, powders, fine granules, granules, and syrups) prepared by virtue of the above, it was possible to suppress bitterness and to complete the high bitterness preparation. On the other hand, the additives described in this specification are described in the pharmaceutical additive dictionary (2005, Yakujinipposha Co., Ltd.).

That is, this invention relates to the following inventions.

(1) tablets characterized by containing risperidone, crystalline cellulose, inorganic excipients, camelos and less than 0.8% by weight of lubricant per tablet;

(2) The tablet according to the above (1), wherein the inorganic excipient is anhydrous calcium hydrogen phosphate,

(3) the tablet according to the above (1) or (2), containing 0.5 wt% or less of a lubricant per tablet;

(4) the tablet according to the above (3), which contains 0.1 wt% or less of a lubricant per tablet;

(5) the tablet according to any one of the above (1) to (4), which contains 1 to 30% by weight of caramel per tablet;

(6) the tablet according to any one of the above (1) to (5), wherein the lubricant is a metal stearate salt;

(7) The tablet according to the above (6), wherein the metal stearate is magnesium stearate,

(8) the tablet according to any one of the above (1) to (7) containing a sweetening agent,

(9) The tablet according to the above (8), wherein the sweetener is a sweetener having a sweetness of 50 times or more when the sweetener of white sugar is 1;

(10) the tablet according to the above (9), wherein the sweetener is acesulfame potassium or sucralose;

(11) The tablet according to any one of the above (1) to (10), wherein the method for adding the lubricant is an external lubricant method;

(12) The tablet according to the above (11), which contains risperidone, crystalline cellulose, anhydrous calcium hydrogen phosphate, carmellose and up to 0.1% by weight of magnesium stearate per tablet, and wherein the method of adding a lubricant is an external lubricant method;

(13) The tablet according to any one of the above (1) to (12), which is an orally disintegrating tablet;

(14) the tablet according to the above (1), which contains risperidone, crystalline cellulose, an inorganic excipient, a caramel, and up to 0.8 wt% of a lubricant per tablet, but does not include sugars and sugar alcohols;

(15) A method for producing a powder and granule preparation containing risperidone, comprising the following steps:

i) a step of suspending risperidone in a liquid having a viscosity (20 占 폚) of 50 to 14000 mPa · s,

ii) adding the solution or suspension obtained in step i) to an excipient and / or disintegrating agent to assemble it,

(16) The manufacturing method of the powder-granule formulation as described in said (15) whose viscosity (20 degreeC) of the said liquid is 100-14000 mPa * s,

(17) The method for producing a powder-part preparation according to (15) or (16), wherein the liquid contains hydroxypropylmethyl cellulose.

(18) powder and granule preparations obtained by the production method according to any one of (15) to (17);

(19) The powder and granule preparation according to the above (18), which is a granule,

(20) the powder and granule preparation according to the above (18) or (19), which has suppressed bitterness;

(21) A method for producing a tablet, which comprises tableting the powder and granule preparation according to (20) above,

(22) A method for producing a tablet, characterized in that an excipient, a lubricant, a disintegrating agent and / or a binder are mixed and compressed into the powder and granule preparation according to (20) above,

(23) tablets obtained by the production method described in (21) or (22) above,

(24) The tablet according to the above (23), which is an orally disintegrating tablet.

Effects of the Invention

The tablet of the present invention can be easily taken without water, rapidly disintegrates in the oral cavity, has an appropriate hardness, and has a good feeling of taking. For this reason, it can be used as an oral disintegration tablet. Moreover, the said tablet is easy to manufacture. In addition, the high anti-inhibitory preparation of the present invention suspends high-risk component risperidone in a highly viscous additive liquid, and adds the obtained solution to an excipient and / or disintegrating agent to achieve high inhibition of risperidone. The high-density inhibitor of the present invention can suppress bitterness without suppressing elution of risperidone.

"Oral disintegrating tablet, characterized in that it contains risperidone, crystalline cellulose, inorganic excipients, carmelose and up to 0.8% by weight of lubricant per tablet," risperidone, crystalline cellulose, inorganic excipients, camelos and tablets 1 By containing 0.8 wt% or less of a lubricant per unit, the agent exhibits the effect of the present invention (good disintegration of tablets and securing appropriate tablet hardness). Risperidone, crystalline cellulose, inorganic excipients, carmelose and up to 0.8 wt.% Of a lubricating agent per tablet may be essential components, and other additives may be included within a range not affecting the effects of the present invention.

As content of the risperidone which is a chemical | medical agent contained in the tablet of this invention, it is 0.1-6 weight% per tablet, Preferably it is 0.125-4 weight%, More preferably, it is 0.25-2.5 weight%. If it is less than this content, content uniformity may deteriorate, and when there is much, it may become easy to feel a taste.

As crystalline cellulose used in the tablet of this invention, what is necessary is just to be used in the pharmaceutical field, but specifically, CEOLUS PH101, CIOUS PH102, CIOUS PH301, CIOUS PH302, Avicel PH-F20JP, Geolus KG802 (manufactured by Asahi Kasei Kogyo Co., Ltd.), VIVAPUR (grade 105, 101, 103, 301, 102, 112), ARBOCEL (grade M80, P290, A300), PROSOLV SMCC50, PROSOL SMCC90 ( JRS PHARMA company) etc. are mentioned. Although these crystalline celluloses may be individual, you may use 2 or more types together. Preferably the average particle diameter of crystalline cellulose before tablet manufacture is 10-150 micrometers, More preferably, it is 30-130 micrometers, Especially preferably, it is 40-120 micrometers. When larger or smaller than this average particle diameter, the hardness of a tablet may fall or a disintegration time may be delayed. Specifically, the Zeus PH102 (Asahi Kasei Kogyo Co., Ltd. make, average particle diameter about 100 micrometers) is preferable.

The inorganic excipient used in the tablet of the present invention may be any one used in the medical field. Specifically, calcium hydrogen phosphate, anhydrous calcium phosphate, magnesium metaaluminate, synthetic hydrotalcite, precipitated calcium carbonate, magnesium carbonate In particular, as anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate GS (manufactured by Kyowa Chemical Co., Ltd.), Fujikaline (Fuji Chemical Industry Co., Ltd.), anhydrous calcium hydrogen phosphate (() Kyowa Kagaku Kogyo Co., Ltd. make, anhydrous calcium hydrogen phosphate heavy (Kyogawa Kagaku Kogyo Co., Ltd.) etc. are mentioned. Although these inorganic excipients may be individual, they may be used together 2 or more types. Preferably, the bulk density of the inorganic excipient before tablet manufacture is 0.30-1.0 g / mL, More preferably, it is 0.5-1.0 g / mL, Especially preferably, it is 0.6-1.0 g / mL. If it is lower than this volume density or high, the hardness of a tablet may fall or a disintegration time may be delayed. Specifically, anhydrous calcium hydrogen phosphate GS (manufactured by Kyowa Chemical Industry Co., Ltd., volume density 0.71 to 1.0 g / mL) is preferable.

In the tablet of this invention, content of crystalline cellulose and anhydrous calcium hydrogen phosphate which is an inorganic excipient can be easily determined. For example, the appropriate amount can be easily determined by appropriately mixing the desired amount of crystalline cellulose, anhydrous calcium hydrogen phosphate, and camels with the active ingredient, followed by compression molding, and confirming hardness and disintegration.

Since the content of the crystalline cellulose and the inorganic excipient also depends on the physical properties of the active ingredient, it is preferable to determine appropriately as described above. In particular, it is preferable to use 30-99.9 weight% of crystalline cellulose and an inorganic excipient with respect to the tablet total weight. In particular, it is preferable to use 50-99.9 weight% of crystalline cellulose and an inorganic excipient. In these contents, it is hard to be influenced by the physical properties of the active ingredient, and the formulation of the present invention exhibits particularly good disintegration rate and tablet hardness.

Moreover, it is preferable to also determine suitably the weight ratio of crystalline cellulose and anhydrous calcium hydrogen phosphate, and the weight ratio of crystalline cellulose and anhydrous calcium hydrogen phosphate should just be a range of 8: 2-2: 8. Within the above ranges, an intraoral fast disintegrating tablet having a good disintegration rate and tablet hardness can be obtained. If the weight ratio of crystalline cellulose is higher than this, there is a possibility that the texture of the cellulose may be lowered by the odor of crystalline cellulose. If the weight ratio of crystalline cellulose is lower than this, the tablet hardness may be lowered. Preferably, the tablet contains crystalline cellulose and anhydrous calcium hydrogen phosphate in a ratio of 5: 5 to 3: 7 by weight, and more preferably, contains crystalline cellulose and anhydrous calcium hydrogen phosphate in a ratio of about 4: 6 by weight. It is a tablet.

In the tablet of the present invention, the content of crystalline cellulose is 12 to 80% by weight per tablet, preferably 12.5 to 75% by weight, more preferably 15 to 70% by weight. When it is less than this content, tablet hardness may fall, and when there is much, there exists a possibility that a texture may fall by dragging of crystalline cellulose.

In the tablet of this invention, the compounding quantity of anhydrous calcium hydrogen phosphate is 12-80 weight% per tablet, Preferably, it is 12.5-75 weight%, More preferably, it is 15-70 weight%. If it is less than this compounding quantity, there exists a possibility that a tablet may not fully collapse, and when there is much, there exists a possibility that a tablet hardness may fall.

In the tablet of the present invention, as the disintegrating agent used, camelos is preferred. Camelose is a nickname carboxymethyl cellulose. As camelos, what is necessary is just a thing based on the 14th revised standard of Japanese pharmacy room. Specifically, it is NS-300 (Kotoku Yakuhin Co., Ltd.).

As content of a camellose, it is 1-30 weight% per tablet, Preferably it is 5-25 weight%, More preferably, it is 7.5-20 weight%. When less than this content, there exists a possibility that the disintegration time of a tablet may become long, and when there is more than this content, the hardness of a tablet may fall.

In the tablet of the present invention, the lubricant used may be any one used in the medical field, but specific examples thereof include sucrose fatty acid ester, talc, hydrous silicon dioxide, and metal stearate, but are preferably metal stearate. Examples of the metal stearate salt include magnesium stearate and calcium stearate. Preferably, magnesium stearate is magnesium stearate.

As content of a metal stearate, it is 0.8 weight% or less per tablet, Preferably it is 0.5 weight% or less, More preferably, it is 0.1 weight% or less. Specifically, it is 0.001-0.8 weight%, Preferably it is 0.001-0.5 weight%, More preferably, it is 0.001-0.1 weight%. When more than this content, there exists a possibility that the disintegration time of a tablet may become long, and when there is little, there exists a possibility that a tablet may not be formed.

The tablet of this invention may contain the various additives generally used for manufacture of a tablet as long as it is a range which does not affect disintegrating and compressible formation. For example, an excipient, a sweetening agent, a mating agent, a fragrance | flavor, a lubricant, a binder, a fluidizing agent, a coloring agent, a coating agent, etc. are mentioned. In addition, you may use these substances individually or in mixture at arbitrary ratios.

The sweetener means sugars including sugars and sugar alcohols and other non-sugars. Since the preparation of the present invention does not include sugars and sugar alcohols as excipients, it is difficult to produce sufficient sweetness using sugars and sugar alcohols. Therefore, in tablets of the present invention, particularly orally disintegrating tablets, it is preferable to feel strong sweetness in a small amount compared to sugars and sugar alcohols, and non-sugar natural sweeteners and synthetic sweeteners are preferable. Specifically, when the sweetness of white sugar is 1, it is a sweetener having a sweetness of 50 times or more. Examples include acesulfame potassium, aspartame, saccharin or salts thereof, glycyrrhizin acid or salts thereof, stevia or salts thereof, sucralose, thaumatin and the like. As content of a sweetener, it is 10 weight% or less per tablet, Preferably it is 0.1-10 weight%, More preferably, it is 0.5-7.5 weight%.

As mating agents, for example, ascorbic acid and salts thereof, glycine, sodium chloride, magnesium chloride, hydrochloric acid, dilute hydrochloric acid, citric acid and salts thereof, citric anhydride, L-glutamic acid and salts thereof, succinic acid and salts thereof, acetic acid, tartaric acid and salts thereof Salts, sodium bicarbonate, fumaric acid and salts thereof, malic acid and salts thereof, glacial acetic acid, disodium inosinate, honey and the like.

The fragrance includes those called flavoring agents, for example orange essence, orange oil, caramel, camphor, cinnamon oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, skin oil, pine oil, peppermint oil, vanilla Flavors, bitter essences, fruit flavors, peppermint essences, mix flavors, mint flavors, menthol, lemon powder, lemon oil, rose oil and the like.

Examples of the binder include gum arabic, gum arabic, partially alpha starch, gelatin, agar, dextrin, pullulan, povidone, polyvinyl alcohol, ethyl cellulose, carboxymethylethyl cellulose, camelos, camelos Sodium, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and the like.

Examples of the fluidizing agent include hydrous silicon dioxide, hard silicic anhydride, heavy silicic anhydride, titanium oxide and the like.

Examples of the colorant include food colorings such as edible red No. 3, edible yellow No. 5 and edible blue No. 1, yellow iron 32, iron 32, brown iron oxide, black iron oxide, copper chlorophyll, copper chlorophyll sodium, riboflavin and matcha powder. I) and the like.

Examples of the coating agent include polyvinyl alcohol, ethyl cellulose, carboxymethylethyl cellulose, camelos, carmellose sodium, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, PVA copolymer, and ethyl acrylate. Methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer, Opadry, canava wax, carboxyvinyl polymer, dry methacrylic acid copolymer, dimethylaminoethyl methacrylate methyl methacrylate Copolymer, stearyl alcohol, shellac, cetanol, hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, fumaric acid stearic acid polyvinyl acetal diethylamino acetate hydroxy Propylmethyl Cellulose Mixture, Polybar Carbonyl acetal diethylamino acetate, polyvinyl alcohol, methacrylic acid copolymer, 2-methyl-5-vinyl pyridine, methyl acrylate there may be mentioned methacrylic acid copolymer and the like.

As long as these components are a range which does not impair decayability and moldability in the tablet of this invention, arbitrary amounts can be used individually or in mixture. In the case of a tablet containing risperidone as a medicine, a preferred combination of additives is crystalline cellulose / calcium hydrogen phosphate anhydrous / carmellose / magnesium stearate / acesulfame potassium, crystalline cellulose / calcium hydrogen phosphate anhydrous / carmellose / stearic acid Magnesium / Acesulfame Potassium / Peppermint Oil / Function Silicon Dioxide, Crystalline Cellulose / Anhydrous Calcium Hydrogen Phosphate / Carmellose / Magnesium Stearate / Sucralose, Crystalline Cellulose / Anhydrous Calcium Hydrogen Phosphate / Carmellose / Magnesium Stearate / Sucralose / Mint Oil / Function It is a combination of silicon dioxide. When these knitted additives are used, it is possible to manufacture an orally disintegrating tablet which has a fast disintegration time of tablets, a high hardness of tablets, and furthermore, which can suppress taste.

In oral disintegration tablets, sugars and sugar alcohols are generally used as excipients. On the other hand, the orally disintegrating tablet of the present invention is an orally disintegrating tablet substantially consisting of risperidone, crystalline cellulose and an inorganic excipient. That is, in the oral disintegration tablet, it is characterized by substantially free of saccharides as an excipient which is generally used. In the orally disintegrating tablet of the present invention, sugars such as sucrose, glucose, fructose, starch syrup and lactose are not used as excipients. By using these sugars, the disintegration time of the tablet is extended. In addition, the "sugar" here means a monosaccharide and a disaccharide specifically, according to the nutritional standard (for example, refer to the nutrition labeling standard of the Ministry of Health, Labor and Welfare).

The oral disintegration tablet of the present invention is characterized by substantially free of sugar alcohol as an excipient which is generally used in oral disintegration tablets. In the orally disintegrating tablet of the present invention, sugar alcohols such as erythritol, D-sorbitol, xylitol, D-mannitol and maltitol are not used as excipients. The use of these sugar alcohols increases the decay time. Here, "sugar alcohol" refers to the polyhydric alcohol obtained by reducing the carbonyl group of a saccharide molecule.

As content of the refined sugar of risperidone, crystalline cellulose, anhydrous calcium hydrogen phosphate, carmellose and magnesium stearate, 0.1 to 6 weight% of risperidone, 12 to 80 weight% of crystalline cellulose, and 12 to 80 weight of anhydrous calcium hydrogen phosphate %, Caramels 1-30% and magnesium stearate 0.8% or less, preferably 0.25-5% by weight risperidone, 15-75% by weight crystalline cellulose, 15-75% by weight anhydrous calcium hydrogen phosphate , 2.5-25% by weight of camels and 0.5% by weight or less of magnesium stearate, more preferably 0.5-4.5% by weight of risperidone, 20-70% by weight of crystalline cellulose, 20-70% by weight of anhydrous calcium hydrogen phosphate 5-20 wt% of camelos and 0.1 wt% or less of magnesium stearate.

On the other hand, in order to manufacture a high anti-inhibitory preparation of risperidone, as a liquid in which risperidone is suspended, it is 50-14000 mPa * s as a viscosity of the liquid in 20 degreeC, Preferably it is 100-14000 mPa * s, More preferably, 250-14000 mPa S, Especially preferably, it may adjust so that it may become 500-14000 mPa * s. If it is lower than this viscosity, there exists a possibility that a high uninhibition effect may not fully be exhibited, and if it is higher than this viscosity, there exists a possibility that the compounding liquid of an additive cannot be disperse | distributed in a granulator. This additive needs to be dissolved and / or suspended in water. In this specification, "suspension" means what looks like a solid particle in colloidal particle | grains or the particle | grains to the extent seen with a microscope in a liquid.

As a liquid for suspending the risperidone, an additive must be added to water to adjust the viscosity. Additives (hereinafter sometimes referred to as "highly inhibiting bases") are substances which are dissolved and / or suspended in water and have high viscosity, in particular, a liquid having a viscosity of 50 to 14000 mPa · s at 20 ° C. If it is used in the field. Specifically, hydroxypropyl methyl cellulose, fumaric acid, stearic acid, polyvinyl acetal diethylamino acetate, hydroxypropyl methyl cellulose mixture, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, sodium carmellose, polyvinyl Pyrrolidone K25, Polyvinylpyrrolidone K30, Polyvinylpyrrolidone K90, Polyvinyl alcohol (completely saponified), Polyvinyl alcohol (partly saponified), gum arabic, gum arabic, sodium alginate, propylene alginate Lycol esters, agar, agar powder, gelatin, purified gelatin, tracanth, xanthan gum, alpha starch, partially alpha starch, carboxymethylstarch sodium, pullulan, dextrin and the like. Preferably, hydroxypropylmethyl cellulose, fumaric acid, stearic acid, polyvinyl acetal diethylamino acetate, hydroxypropylmethyl cellulose 2910 mixture, hydroxypropyl cellulose, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30 And polyvinylpyrrolidone K90. More preferably, they are hydroxypropylmethyl cellulose or a fumaric acid, stearic acid, polyvinyl acetal diethylamino acetate and hydroxypropylmethyl cellulose mixture. In addition, an additive "dissolves and suspends" means that one part of an additive melt | dissolves in water, and another part suspends in water. For example, in the case of fumaric acid, stearic acid, polyvinyl acetal diethylamino acetate, hydroxypropylmethyl cellulose mixture, fumaric acid, stearic acid, polyvinyl acetal diethylamino acetate are suspended in water, and hydroxypropylmethyl cellulose is used. Dissolve in water.

In the present invention, as hydroxypropylmethyl cellulose which is a more preferred high anti-suppressive base, it may be one used in the medical field. Specifically, there are hydroxypropylmethyl cellulose 2208, hydroxypropylmethyl cellulose 2906, and hydroxypropylmethyl cellulose 2910 of Japanese Pharmacopoeia, but particularly preferably hydroxypropylmethyl cellulose 2910. Hydroxypropylmethyl cellulose 2910 is a mixed ester of cellulose methyl and hydroxypropyl, and when quantified at drying, 28.0 to 30.0% methoxyl group and 7.0 to 12.0% hydroxypropoxyl group are included. As hydroxypropylmethyl cellulose 2910, more specifically, TC-5E (manufactured by Shin-Etsu Chemical Co., Ltd.), metocell E (Dow Chemical Japan), marpolose (Matsumoto Yushi Seiyaku) There is this.

In particular, in the case where the high inhibitory base is hydroxypropylmethyl cellulose, specifically, when TC-5E (manufactured by Shin-Etsu Chemical Co., Ltd.), which is a type of hydroxypropylmethyl cellulose 2910, is used, the content in the liquid (hereinafter, " "% By weight" may be described as "w / w%"), 6 to 35 w / w%, preferably 6.5 to 32.5 w / w%, and more preferably 7 to 30 w / w%.

As a weight with respect to the preparation whole quantity of the hydroxypropylmethyl cellulose which is a high non-inhibiting base, it is 0.001-50w / w%, Preferably it is 0.01-30w / w%, More preferably, it is 0.1-25w / w%. When it is less than this content, there exists a possibility that it may not fully exhibit a high anti-inhibition effect, and when there is much, there exists a possibility that a formulation may delay collapse.

Risperidone can be used alone or in combination with other medicines. In addition, risperidone is administered a known appropriate amount appropriately determined according to the disease, age, etc. of the patient.

As risperidone content in the hydroxypropyl methyl cellulose liquid which is a highly unrestricted base, it is 0.001-40 w / w%, Preferably it is 1-30 w / w%, More preferably, it is 2-20 w / w%. If it is more than this content, there is a possibility that the taste of risperidone cannot be suppressed.

The weight ratio of hydroxypropylmethyl cellulose and risperidone, which is a high inhibitory base, is 1000: 1 to 0.5: 1, preferably 100: 1 to 0.75: 1, and more preferably 10: 1 to 1: 1. When the weight ratio of hydroxypropylmethyl cellulose and risperidone is greater than 1000: 1, the ratio of hydroxypropylmethyl cellulose may delay the dissolution of risperidone. On the other hand, when the ratio of risperidone is larger than 0.5: 1 by weight of hydroxypropylmethyl cellulose and risperidone, there is a fear that the taste of risperidone may not be suppressed.

It does not specifically limit as a preparation method of a risperidone suspension. For example, a method of suspending a predetermined amount of risperidone in a solution in which a predetermined amount of hydroxypropylmethyl cellulose is dissolved and / or suspended in water, or a predetermined amount of risperidone is suspended in water, and hydroxypropylmethyl cellulose is added to the liquid. There is also a method of dissolving and / or suspending.

In the high inhibitory preparation of the present invention, the excipients to be used may be those used in the medical field. Specifically, either a water-soluble excipient or a water-insoluble excipient can be used. More specific excipients include glucose, fructose, lactose, sucrose, D-mannitol, erythritol, maltitol, trehalose, sorbitol, corn starch, potato starch, wheat starch, rice starch, crystalline cellulose, silicic anhydride, anhydrous calcium hydrogen phosphate, phosphoric acid Calcium hydrogen, calcium carbonate, precipitated calcium carbonate, calcium silicate, hydrous silicon dioxide and the like. Preferably, they are water-insoluble excipients, such as crystalline cellulose, calcium carbonate, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate and calcium hydrogen phosphate.

As content of the excipient | filler in the highly uninhibited preparation of this invention, it is 0-99.9 w / w% with respect to formulation whole quantity, Preferably it is 5-90 w / w%, More preferably, it is 30-70 w / w%. When it is less than this compounding quantity, there exists a possibility that powder and granule formulation cannot be formed.

In the high inhibitory formulation of the present invention, a disintegrant may be used. Especially in the case of stirring granulation, a disintegrant is required. The disintegrating agent to be used may be any one used in the medical field. Specifically, as a disintegrating agent, specifically, a low-substituted hydroxypropyl cellulose, camelos, camel calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, corn starch, alpha starch, agar powder, etc. to be. Preferably, it is crospovidone.

As content of the disintegrating agent of the highly uninhibited preparation of this invention, it is 0-99.9 w / w% with respect to formulation whole quantity, Preferably it is 5-90 w / w%, More preferably, it is 10-70 w / w%. If there is less than this compounding quantity, there exists a possibility that a collapse property may fall.

In the high inhibitory formulation of the present invention, a binder may be used. What is necessary is just a binder used in the pharmaceutical field as a binder used. Specifically, hydroxypropyl methyl cellulose, fumaric acid, stearic acid, polyvinyl acetal diethylamino acetate, hydroxypropyl methyl cellulose mixture, hydroxypropyl cellulose, camelos, camelodium sodium, carboxymethyl starch sodium, cross camel Loose sodium, crospovidone, hydroxyethylmethyl cellulose, hydroxypropylstarch, hydroxyethyl cellulose and the like. Preferably, they are hydroxypropylmethyl cellulose or a fumaric acid, stearic acid, polyvinyl acetal diethylamino acetate and hydroxypropylmethyl cellulose mixture.

As content of the binder of the highly uninhibited preparation of this invention, it is 0-20 w / w% with respect to preparation whole quantity. If there is more than this compounding quantity, there exists a possibility of delayed collapse.

In the high-inhibiting preparation of this invention, in order to reduce bitterness, a mating agent can also be used. Specifically, such as peppermint oil and citric acid.

TC-5E (Shin-Etsu Chemical Co., Ltd. make) which is a kind of hydroxypropylmethyl cellulose 2910 as liquid content of the hydroxypropyl methyl cellulose and risperidone which are one of the optimal high inhibitory bases in the high inhibitory preparation of this invention. ), 6 to 35 w / w% of hydroxypropylmethyl cellulose, 0.001 to 40 w / w% of risperidone, preferably 6.5 to 32.5 w / w% of hydroxypropylmethyl cellulose, and 1 to 30 w / of risperidone. w%, more preferably hydroxypropylmethyl cellulose is 7-30w / w%, and risperidone is 2-20w / w%.

The powder and granule preparations in the high anti-inhibitory preparation of this invention are a powder, a granule, and a syrup in the formulation general rule of the 14th revision of the Japanese pharmacy room. In particular, the manufacturing method of this invention is a manufacturing method suitable for manufacture of granules, especially the granules which suppressed bitterness.

Best Mode for Carrying Out the Invention

The manufacturing method of the orally disintegrating tablet of this invention is described below.

As a specific manufacturing method, the method of measuring by direct compression tableting using the tableting machine mentioned later and manufacturing the mixing powder for tablets which weighed an active ingredient and an agent raw material, and mixed with suitable mixers, such as a V-type mixer, etc. are mentioned. In addition, in order to obtain a refined mixed powder, a method of vigorously mixing with a stirring granulator, a method of mixing and pulverizing with a pulverizer, a method of compression granulation with a dry granulator, or water, acetone, and ethyl in which a binder is dispersed or dissolved as necessary. A method of wet granulation using alcohol, propyl alcohol or a mixture thereof, or a method of preparing a mixed powder for purification by dividing into two or more separate groups may be used. When manufacturing a tablet powder for mixing, a binder, a copulating agent, a fluidizing agent, a lubricant, a fragrance, a sweetening agent, a coloring agent, etc. may be mixed as needed.

In terms of compression molding, according to the present invention, even if the lubricant is a small amount (0.8 wt% or less per tablet, preferably 0.5 wt% or less, more preferably 0.1 wt% or less), Internal lubricating method) or an external lubricating method for adhering the lubricant to the bottom of the tableting machine. As an apparatus for external lubrication, ELSP1-type III manufactured by Kikusui Seisakusho Co., Ltd., and the like are available.

When the content of the lubricant is reduced, the disintegration rate can be further increased, the tablet hardness can be improved, and the stability of the drug can be further increased. In the conventional method of mixing a lubricant with a tablet powder, a prescription requires 1 to 3 mg of a lubricant per 100 mg of tablets, but in the formulation of the present invention, 0.8 wt% or less per tablet, preferably 0.5 wt% or less More preferably, less than 0.1% by weight of tableting with a small amount of lubricant is possible. In particular, the active ingredient, crystalline cellulose, anhydrous calcium hydrogen phosphate, camelos and magnesium stearate of 0.1% by weight or less per tablet are blended, and the addition method of the lubricant is further preferred.

Among the above, in particular, a powder containing substantially the active ingredient, crystalline cellulose, anhydrous calcium hydrogen phosphate, and camelos (potassium or sucralose when a sweetener is added. It is preferable to shape | mold by an internal mixing method and an external lubrication method. In addition, in this invention, the particle diameter of an active ingredient and an additive is not specifically limited.

The mixed tablet for tablets thus obtained is compression molded at a tablet pressure of 200 kg to 1500 kg using, for example, an external lubricant tableting device, a single tablet press, a rotary tablet press, and the like. If the pressure is lower than this, the tablet hardness is insufficient and sufficient hardness cannot be secured for handling. If the pressure is high, the collapse is delayed, which is not preferable.

Regarding the molding of the buccal disintegrating tablet of the present invention, any shape may be employed, and for example, round, oval, spherical, rod-shaped, donut-shaped and laminated tablets, nucleated tablets, and the like may be further applied to the coating. You can also coat by. Incidentally, marks, letters, and the like for improving the identification may be added, and a dividing line for division may be added.

The tablet of the present invention is useful as an oral disintegrating tablet, and can be taken smoothly without saliva by being rapidly disintegrated in the oral cavity by saliva. The melting time in the mouth of the orally disintegrating tablet of the present invention is usually 1 to 60 seconds, preferably 1 to 40 seconds, and more preferably about 1 to 30 seconds.

In addition, although hardness (measured value by a tablet hardness tester) is known as a value normally if it is about 30-70N, the oral disintegration tablet of this invention is 10-200N, Preferably it is about 30-150N.

On the other hand, the preparation can be taken without disintegration in the oral cavity or with water.

As a manufacturing method of the powder-granule preparation of the high-inhibition preparation in this invention, what is necessary is just to be usable pharmaceutical form, but wet granulation method, Preferably fluidized bed granulation method, stirring granulation method, extrusion granulation method, rolling granulation method, More preferably, Is a stirring granulation method. The fluidized bed granulation method is a method in which a binder is sprayed onto powder fluidized in a bed to obtain a granulated product. A stirring granulation method is a method of obtaining the target granulated material by adding a binder liquid to the target substance charged in the tank, and applying a shear, electric motor, a consolidation effect, etc. by rotating the stirring blade which made various shapes. The extrusion granulation method is a method of obtaining a granulated material by forcibly pushing out a wet mass associated with kneading from a screen of a suitable size. In addition, the rolling granulation method is a method in which the raw material powder pushed to the outer wall portion by the centrifugal force of the rotating rotor is rolled by air blown from the slit, and at this time, the binder is sprayed to obtain a granulated product. On the other hand, with the spray drying method, manufacturing time becomes longer than the said manufacturing method and it is difficult also to suppress the taste of risperidone.

When the preparation of the present invention is prepared by the fluidized bed granulation method, the above-mentioned liquid is sprayed while preparing a dissolution and / or suspension of a high-inhibitory base in which risperidone is dissolved or suspended in advance, and the excipient and / or disintegrating agent is flowed in the fluidized bed. To assemble.

When the preparation of the present invention is prepared by the stirring granulation method, the dissolution and / or suspension of the high-inhibitory base in which the risperidone is dissolved or suspended in advance is prepared, and the excipient and / or disintegrating agent are stirred in the bath of the stirring granulator, The liquid is added and granulated.

When the preparation of the present invention is prepared by extrusion granulation, a dissolution and / or suspension of a high-inhibitory base in which risperidone has been dissolved or suspended in advance is prepared, and the liquid is mixed and associated with an excipient and / or a disintegrating agent and the combination The granulation is assembled by an extrusion granulator.

When the preparation of the present invention is prepared by a rolling granulation method, a dissolution and / or suspension of a high-inhibitory base in which risperidone is dissolved or suspended in advance is prepared, and the excipient and / or disintegrating agent is rolled in the tank of the centrifugal electric assembly device. The above-mentioned liquid is added and granulated.

The powder and granule preparation of the present invention can be used as it is, for example, as granules or fine granules with reduced bitterness. In that case, no particular deterioration is recognized in the blood dynamics of risperidone.

In addition, together with the powder and granule preparation of the present invention, an excipient, a disintegrating agent, a binder, and a lubricant may be mixed and compressed to form a tablet. As the excipient, the disintegrating agent, and the binder, those mentioned above can be used. Examples of the lubricant include magnesium stearate, sucrose fatty acid ester, magnesium carbonate and the like.

In addition, together with the powder and granule formulation of the present invention, an excipient, a disintegrating agent, and a binder are mixed, and a small amount of lubricant is attached to the tablets and tablets of the tableting machine, and the external lubricant is compressed into the mixture. According to the conventional method, a tablet can be manufactured. The tableting method is a tableting method that is useful for risperidone that can be tableted with a small amount of lubricant and is easily changed into the lubricant.

In addition to the usual tablets, the powder-granule preparation of the present invention is formulated into an oral disintegrating tablet which is instantaneously disintegrated in the oral cavity. It can manufacture. In the case of oral disintegrating tablets, excipients, disintegrants, binders, lubricants may use the general additives described above. In addition, in order to improve the feeling of taking, it is also possible to add a copulating agent such as peppermint oil and citric acid in the tablet.

Risperidone is known to have a very bitter taste. As mentioned above, after preparing the powder and granules which suppressed the bitter rice of this invention containing risperidone beforehand (for example, refer to 1 of a later Example 1), if the said powder and granule preparation is contained in a tablet, It is possible to produce the tablet which was suppressed. In addition, when the powder and granules which suppressed bitterness mentioned above are contained in the above-mentioned oral disintegrating tablet, it is also possible to manufacture the oral disintegrating tablet which suppressed bitterness.

On the other hand, the blood dynamics of the orally disintegrating tablet of the present invention was inferior to the conventional risperidone tablet.

Hereinafter, although an Example and a comparative example are given and this invention is demonstrated in detail, these do not limit this invention.

The tablet obtained in the Example measured the tablet hardness and disintegration time by the following test method, and tested the function of bitter rice.

(1) hardness test

It measured using the hardness measuring machine (made by ERWEKA International AG). The test is carried out with 10 tablets and the average value is shown. (Based on 30N or more)

(2) collapse test

The collapse time of 6 tablets is measured based on the 14th Japanese Pharmacopoeia Disintegration Test Method, and the maximum value is shown. (We assume within 20 seconds)

(3) working test

The prepared formulations were placed in the mouth of five healthy adults and tested for action for about 5 seconds on the tongue.

Example 1

Preparation of risperidone oral disintegration tablet (1, external lubrication method)

1) Preparation of high inhibitory formulation (granule) containing risperidone

According to the amount shown in Table 1, on the scale of 10,000 tablets, hydroxypropylmethyl cellulose 2910 was dissolved in purified water, and then risperidone was suspended to obtain a granulated solution. In addition, the viscosity of the granulation liquid at 20 degreeC was 100-14000 mPa * s.

Anhydrous calcium hydrogen phosphate and camelos calcium were added to a Type 2 high speed mixer and mixed. Subsequently, the granulation liquid was poured and granulated, to obtain granules.

The granulated product was dried with a FL-MINI fluid bed granulator to obtain dry granules. Dry granules were sized with a P-3 type power mill to obtain risperidone granules.

On the other hand, although the function test of bitterness was performed with respect to the said granule, bitterness was not felt.

2) Manufacture of peppermint powder

According to the compounding quantity of Table 1, peppermint oil was added to the hydrous silicon dioxide in a plastic bag on the scale of 100,000 tablets, the plastic bag was mixed, and the mixed powder was obtained. The mixed horses were sieved with a wire mesh, filtered and mixed with a plastic bag to obtain peppermint oil.

3) Preparation of oral disintegrating tablets

According to the compounding quantity of Table 1, in a 50-capacity scale, anhydrous calcium hydrogen phosphate, said risperidone granules, said acesulpam potassium, peppermint oil, crystalline cellulose, and camellos were thrown in a plastic bag, and the mixed bag was mixed, Obtained. This mixed horse was hand sifted with a wire mesh, filtered, and mixed with a plastic bag to obtain a finished horse. Magnesium stearate was purified by 0.1% of the tablet mass with a cotton swab in a dry mouth (use: 0.5 mg tablet φ = 5.0 mm, 1 mg tablet φ = 6.5 mm, 2 mg tablet φ = 7 mm, 3 mg tablet φ = 8.0 mm). The following amounts were attached and compressed into a static compression tester to obtain risperidone oral disintegration tablets.

(Test of the function of tablet hardness, disintegration time and taste)

By the method described above, the hardness and disintegration time of the obtained risperidone orally disintegrating tablets were tested. The results are shown in Table 2. On the other hand, in the action test of bitter gourd, neither type of sweetener was felt.

For reference, the measurement results of the hardness and disintegration time of tablets (1 mg) of risperidone currently on the market are shown below.

Example 2

Preparation of risperidone oral disintegration tablet (2, internal mixing method)

(Production method of tablet)

The risperidone granules, carmellose, crystalline cellulose, anhydrous calcium hydrogen phosphate and acesulfam potassium prepared in Example 1 were weighed according to the blending amounts shown in Table 4, mixed in a plastic bag, magnesium stearate was added and mixed, Obtained a genuine. The obtained powder was compressed into a static compression tester (use: φ = 6.5 mm) to obtain risperidone oral disintegration tablets.

(Test of the function of tablet hardness, disintegration time and taste)

By the method described above, the hardness and disintegration time of the obtained risperidone orally disintegrating tablets were tested. The results are shown in Table 5. On the other hand, in the working test of bitter gourd, no bitter gourd was felt.

Oral Disintegration Tablets Tablet Hardness (N) Decay time (sec) Example 2 59.4 16

Example 3

Preparation of risperidone oral disintegration tablet (3, external glidant method)

(Production method of tablet)

Risperidone, carmellose, crystalline cellulose, anhydrous calcium hydrogen phosphate, and acesulfame potassium were weighed according to the blending amounts shown in Table 5, and mixed in a plastic bag to obtain a crude product. The obtained tablet was attached with magnesium stearate to an amount of 0.1% or less of the tablet mass with a cotton swab to a spherical sphere (use: φ = 6.5 mm), and compressed into a static compression tester to obtain risperidone orally disintegrating tablets.

(Test of the function of tablet hardness, disintegration time and taste)

By the method described above, the hardness and disintegration time of the obtained risperidone orally disintegrating tablets were tested. The results are shown in Table 7. On the other hand, in the action test of bitter gourd, although some bitter gourd was felt, it was the level which can be taken.

Oral Disintegration Tablets Tablet Hardness (N) Decay time (sec) Example 3 60.4 8

The tablet of this invention is easy to manufacture, has the strength at the time of manufacture and storage, and is excellent also in long-term storage and stability. In addition, since it rapidly disintegrates in the oral cavity, it is considered to have a large therapeutic benefit since it is a formulation that is easy to be accepted even in acutely ill patients with severe excitement or rejection. In addition, since this invention can suppress bitterness only by the base material melt | dissolved or suspended in water, Moreover, since only water is used as a solvent, it is highly practical. Moreover, the formulation of this invention can also be mix | blended with oral disintegration tablet, and can manufacture the tablet which can suppress bitterness, disintegrating in oral cavity in an instant.

Claims (24)

A tablet comprising risperidone, crystalline cellulose, an inorganic excipient, a carmelose and up to 0.8% by weight of a lubricant per tablet. The method of claim 1, The inorganic excipient is anhydrous calcium hydrogen phosphate. The method according to claim 1 or 2, A tablet containing up to 0.5% by weight of lubricant per tablet. The method of claim 3, wherein A tablet containing up to 0.1% by weight of lubricant per tablet. The method according to any one of claims 1 to 4, A tablet containing 1-30% by weight of camelos per tablet. The method according to any one of claims 1 to 5, A tablet wherein the lubricant is a metal stearate salt. The method of claim 6, A tablet wherein the stearic acid metal salt is magnesium stearate. The method according to any one of claims 1 to 7, Tablets containing sweeteners. The method of claim 8, The sweetener is a sweetener which has a sweetness of 50 times or more when the sweetener of white sugar is 1. The method of claim 9, A tablet wherein the sweetener is acesulfame potassium or sucralose. The method according to any one of claims 1 to 10, The refinement | purification method of adding a lubricant is an external lubricant method. The method of claim 11, A tablet containing risperidone, crystalline cellulose, anhydrous calcium hydrogen phosphate, carmellose and up to 0.1% by weight of magnesium stearate per tablet, and the method of adding a lubricant is an external lubricant method. The method according to any one of claims 1 to 12, Tablets that are oral disintegrating tablets. The method of claim 1, Tablets containing risperidone, crystalline cellulose, inorganic excipients, carmellose and up to 0.8% by weight of lubricant per tablet, but no sugars and sugar alcohols. A process for producing a powder granule preparation containing risperidone, comprising the following steps: i) the process of suspending risperidone in the liquid whose viscosity (20 degreeC) is 50-14000 mPa * s, ii) a step of granulating the solution or suspension obtained in step i) by adding the excipient and / or disintegrant. The method of claim 15, The manufacturing method of the powder formulation of said liquid whose viscosity (20 degreeC) is 100-14000 mPa * s. The method according to claim 15 or 16, A method for producing a powder and granule formulation containing hydroxypropylmethyl cellulose in the liquid. Powder formulation obtained by the manufacturing method in any one of Claims 15-17. The method of claim 18, Powder granule preparation which is granule. The method of claim 18 or 19, Powder and granule preparation which suppressed bitterness. The tablet manufacturing method of Claim 20 is tableted, The manufacturing method of the tablet characterized by the above-mentioned. An excipient, a lubricant, a disintegrating agent and / or a binder are mixed and compressed into the powder and granule preparation according to claim 20, and the tablet manufacturing method is characterized by the above-mentioned. The tablet obtained by the manufacturing method of Claim 21 or 22. The method of claim 23, Tablets that are oral disintegrating tablets.