JP5074190B2 - Orally rapidly disintegrating tablets - Google Patents

Description

  The present invention relates to an orally rapidly disintegrating tablet having rapid disintegration property and appropriate hardness in the oral cavity, and a production method thereof having high productivity. The intraoral rapidly disintegrating tablet of the present invention can be used in the field of medicine.

  The intraoral rapidly disintegrating tablet needs to have a hardness that does not cause tablet chipping or powdering during tablet production or transportation while having a disintegration time of about 60 seconds or less in the oral cavity. Hardness and disintegration time are contradictory elements. When the disintegration time is increased, the hardness is lowered, and when the hardness is increased, the disintegration time is delayed. In order to solve the problem of disintegration time and hardness, several methods are known for producing a rapidly disintegrating tablet in the oral cavity, and there are a wet tableting method, a tableting warming method, a direct tableting method and the like. In the wet tableting method and the tableting warming method, preparation equipment by ordinary compression molding cannot be used, and a heating device, a humidifying device, and a drying device are necessary, and special equipment is required. Further, since the process includes processes such as humidification, warming, and drying in addition to ordinary compression molding, there is a problem in productivity and it is not suitable for a water-soluble active ingredient.

On the other hand, the manufacturing method of the intraoral rapidly disintegrating tablet by the direct tableting method can use a normal formulation equipment. However, in the direct tableting method, it is difficult to have both moldability, moderate hardness and disintegration while increasing the content of the active ingredient, and production methods that improve these are known. For example, there is a method in which an active ingredient, spray-dried mannitol, crospovidone, and an excipient that can be used for pharmaceuticals are mixed in a dry manner and then compression-molded to produce an orally rapidly disintegrating tablet (see Patent Document 1).
Tablets made by using spray-dried mannitol suitable for direct compression and crospovidone, a super disintegrant, have moderate moldability and disintegration, but considering use as a rapidly disintegrating tablet in the oral cavity However, there is a problem that the balance between the disintegration time in the oral cavity and the hardness of the obtained tablet is not always sufficient.

  An orally rapidly disintegrating tablet produced by compression molding after fluidized bed granulation of medicinal ingredients, mannitol having an average particle size of 5 μm to less than 90 μm, mannitol having an average particle size of 90 μm to 500 μm, a disintegrant and crystalline cellulose There is a method to do (see Patent Document 2). This method requires a complicated process in which two types of particles having different particle diameters are fluidized and granulated, and then compression-molded after mixing. In addition, these fluidized bed granulated particles are non-spherical granules in which the particles derived from the raw material are bound together by a binder, and each component of the particles is not uniformly dispersed in the particles, so that the orally rapidly disintegrating tablet However, the moldability and disintegration properties suitable for the above have not been fully satisfied.

In addition, the present inventors previously invented a composition for a rapidly disintegrating tablet in the oral cavity characterized in that a disintegrant and an inorganic substance are homogeneously dispersed in water in saccharide composite particles (Patent Documents 3 and 4). reference). These use spray-dried granulated particles, so they have good meterability and filling properties for compression molding machines, and disintegrants and inorganic particles are homogeneously dispersed. It was. However, tablets obtained by mixing and compressing active ingredients and spray-dried granules in Examples of Patent Documents 3 and 4 have desired disintegration properties but are not sufficiently hard (30-40N). In some cases, problems such as tablet chipping or powdering may occur during transportation. Moreover, when the content rate of the active ingredient was high, the tableting troubles, such as sticking to a ridge, might be caused.
International Publication No. 00/57857 Pamphlet JP 2001-58944 A International Publication No. 2005/037319 Pamphlet International Publication No. 2005/037254 Pamphlet

  The present invention has no problems that occur when the content rate of the active ingredient is high compared to the aforementioned intraoral rapidly disintegrating tablets in the prior art, sufficient hardness that does not cause problems during production and transportation, and in the oral cavity It is an object of the present invention to provide an intraorally rapidly disintegrating tablet having good disintegration and a method for producing an orally rapidly disintegrating tablet having high productivity.

As a result of intensive studies to achieve the above object, the present inventors have (a) spray-dried two or more saccharides, inorganic substances, and disintegrants at a specific ratio, or spray-dried by further adding an active ingredient. There are problems that occur when the tablet containing the granulated particles, (b) lubricant, (c) disintegration aid, and (d) active ingredient is unexpectedly high. In addition, the present inventors have discovered that the production method has sufficient hardness that does not cause problems during production and transportation, good disintegration property in the oral cavity, and high productivity.

  The “orally-fast disintegrating tablet” in the present invention means a tablet that can rapidly disintegrate in the oral cavity, for example, within 40 seconds, more preferably within 30 seconds, and even more preferably within 20 seconds. The oral disintegration time here is the time obtained by the conditions of the intraoral quick disintegrating tablet described later and the method of the examples. The disintegration time in the oral cavity varies depending on the tablet size and tablet shape, and this is also included in the present invention.

  The tablet obtained by using the composition for intraoral rapidly disintegrating tablet of the present invention has a high active ingredient content compared to conventional fast disintegrating tablets and sufficient hardness that does not cause problems during production and transportation. In spite of having, it has the feature of having a good oral disintegration time. Therefore, the intraoral rapidly disintegrating tablet of the present invention obtained by blending a medicinal component with the composition is suitable for a pharmaceutical product that requires rapid disintegration in the oral cavity.

The intraoral quick disintegrating tablet of the present invention comprises (a) a granulated particle in which an inorganic substance and a disintegrant are homogeneously dispersed in composite particles of two or more saccharides, and further contains an active ingredient, ( b) an orally rapidly disintegrating tablet comprising a lubricant, (c) a disintegration aid, and (d) an active ingredient.

  Hereinafter, the granulated particles used in the present invention will be described. The granulated particles used in the present invention are granulated particles in which inorganic substances and disintegrants are uniformly dispersed in composite particles composed of mannitol and other saccharides, or further contain active ingredients. The granulated particles can be obtained by (1) sugars, (2) disintegrants, and (3) inorganic substances dispersed in water followed by spray drying, or further by dispersing active ingredients and spray drying. Specifically, it is a composition for intraorally rapidly disintegrating tablets produced by the method described in International Publication No. 2005/037319 pamphlet or International Publication No. 2005/037254 pamphlet. Several types of these compositions are manufactured and sold by Fuji Chemical Industry Co., Ltd. as F-MELT [trademark], and any of these types can be used.

  In the present invention, saccharide refers to saccharide and sugar alcohol. The saccharide contained in the granulated particles used in the present invention is a combination of mannitol and a saccharide other than mannitol. The saccharide other than mannitol is, for example, at least one selected from xylitol, sorbitol, erythritol, maltitol, lactose, sucrose, glucose, fructose, maltose, trehalose, palatinit, palatinose, and the like. The weight ratio of mannitol to saccharides other than mannitol is mannitol: saccharides other than mannitol = 98 to 67: 2 to 33, preferably mannitol: saccharides other than mannitol = 97 to 87: 3 to 13, more preferably mannitol: mannitol. Saccharides other than 96 = 89: 4-11. Among these saccharides, those having an average particle size can be used as those easily soluble in water.

  As the inorganic substance contained in the granulated particles of the present invention, a pharmaceutically acceptable inorganic oxide containing at least one of aluminum, magnesium and calcium is preferable, for example, magnesium aluminate metasilicate, magnesium aluminate silicate. , Calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, hydrotalcite, aluminum silicate, calcium phosphate, calcium carbonate, calcium silicate, magnesium silicate, magnesium oxide, magnesium hydroxide, water It is at least one selected from alumina magnesium oxide, dry aluminum hydroxide gel, magnesium carbonate and the like. More preferably, magnesium aluminate metasilicate, magnesium aluminate silicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granulation, hydrotalcite, calcium carbonate, calcium silicate and dry hydroxide At least one selected from aluminum gels, and more preferably at least one selected from magnesium aluminate metasilicate, hydrotalcite, anhydrous calcium hydrogen phosphate, and calcium carbonate. The average particle diameter of these inorganic substances is 0.1 to 100 μm, preferably 1 to 60 μm, and more preferably 1 to 40 μm. In order to obtain a desired average particle diameter, a pulverized product by a conventional method can be used.

  The disintegrant contained in the granulated particles of the present invention is preferably at least one selected from crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose and crystalline cellulose, and any one of these may be used alone. However, it is more preferable to use it as a mixture. Of these, crospovidone and crystalline cellulose are more preferably used. When using crospovidone and crystalline cellulose, the weight ratio of crospovidone and crystalline cellulose is 5-15: 8-22, preferably 5-14: 10-22, more preferably 6-13: 12-21. The disintegrant preferably has an average particle diameter of 0.1 to 100 μm, more preferably 1 to 60 μm, and more preferably 1 to 60 μm, in order to prevent homogeneous dispersibility in the composition of the present invention and roughness in the oral cavity. Preferably it is 1-40 micrometers. In order to obtain a desired average particle diameter, a pulverized product by a conventional method can be used.

  The blending amount of each component of the granulated particles of the present invention is 40 to 90 parts by weight of saccharide, 1 to 30 parts by weight of an inorganic substance, and 5 to 40 parts by weight of a disintegrant, based on 100 parts by weight of the entire granulated particle. Preferably, it is 50 to 80 parts by weight of saccharide, 2 to 15 parts by weight of an inorganic substance, and 10 to 36 parts by weight of a disintegrant with respect to 100 parts by weight of the whole granulated particles. More preferably, they are 62-78 weight part of saccharides, 3-8 weight part of inorganic substance, and 18-34 weight part of disintegrant with respect to 100 weight part of the whole granulated particle.

  The granulated particles of the present invention have a structure in which a disintegrant and an inorganic substance are uniformly dispersed in composite particles composed of mannitol and a saccharide other than mannitol. By making the saccharide which is a component into composite particles, high moldability, quick disintegration and tablet hardness suitable for a composition for an orally rapidly disintegrating tablet can be provided. Furthermore, by having a structure in which the disintegrant and the inorganic substance are homogeneously dispersed, more minute moisture in the oral cavity can be introduced into the tablet more quickly. In other words, the water-conducting pores of a specific inorganic substance draw minute moisture into the tablet and effectively act on the disintegrant dispersed together, thereby giving good rapid disintegration in the oral cavity. it can.

  The granulated particles used in the present invention can be blended with an active ingredient described later and other ingredients that can be blended in a pharmaceutical within a range not impairing the disintegration shown below. It is 0.01-80 weight part with respect to a total of 100 weight part of an inorganic substance and a disintegrating agent, Preferably it is 0.05-70 weight part, More preferably, it is 0.1-60 weight part. Although described in detail later, the active ingredient is not contained in the granulated particles, and may be mixed with the granulated particles in a dry manner.

  The granulated particles used in the present invention can be produced by a production method capable of obtaining desired physical properties. Commonly used methods such as spray drying, fluidized bed granulation drying, stirring granulation, wet extrusion It can be produced by a wet granulation method such as a granulation method. The spray drying method is preferred from the standpoint of ease of production and easy acquisition of desired physical properties.

  The spray drying method will be specifically described below. It can manufacture by spray-drying the aqueous solution or aqueous dispersion containing saccharides, an inorganic substance, and a disintegrating agent according to a conventional method. More specifically, after the saccharide is previously dissolved or dispersed in an aqueous solvent, a dispersion obtained by uniformly dispersing the disintegrant and the inorganic substance can be produced by spray drying. Moreover, what contains an active ingredient may add an active ingredient arbitrarily other than the said component, and is 1 type of the other component which can be mix | blended with the pharmaceutical shown below in the range which does not impair disintegration property The dispersion liquid added and uniformly dispersed can be produced by spray drying.

  The solvent may be any pharmaceutically acceptable solvent that does not affect the characteristics of the granulated particles, and examples thereof include water, ethanol, and methanol. The dispersion can be prepared by a known method, for example, ordinary stirring, colloid mill, high-pressure homogenizer, ultrasonic irradiation, etc., but any method capable of highly dispersing particles in an aqueous dispersion. That's fine. The concentration in the dispersion may be in a range that can be spray-dried with clay in the dispersion, that is, 5 to 50% by weight, preferably 10 to 45% by weight, more preferably 25 to 45% by weight. .

  The conditions for spray drying are not particularly limited, but it is preferable to use a disk-type or nozzle-type spray dryer as the spray dryer. And as temperature in the case of spray-drying, inlet temperature is about 120-220 degreeC, and outlet temperature is about 80-130 degreeC. The concentration of the solid in the aqueous dispersion when spray-dried may be in a range that allows spray-drying.

  The average particle size of the granulated particles used in the present invention thus obtained can be appropriately adjusted depending on the concentration of the aqueous solution or aqueous dispersion, the spray drying method, the drying conditions, etc., but is preferably 1 to 500 μm, preferably If it is 5-300 micrometers, More preferably, it is 10-200 micrometers, More preferably, if it is 30-200 micrometers, the roughness in an oral cavity can be prevented and it is preferable.

  The static specific volume of the granulated particles is preferably 1.5 to 4.0 g / ml, more preferably 1.5 to 3.5 g / ml, still more preferably 1.5 to 2.5 g / ml. is there. Since the granulated particles have such a static specific volume, they can be easily filled into a mortar when they are formed into tablets, so that the formulation process proceeds smoothly, and the tablets are uniformly compressed. Can show gender. The static specific volume can be measured according to standard methods. Moreover, since it is a particle | grains which has favorable fluidity | liquidity, the tableting property excellent in the formulation process can be shown.

Examples of the lubricant used in the present invention include gum arabic powder, cacao butter, carnauba wax, carmellose calcium, carmellose sodium, caropeptide, hydrous silicon dioxide, dry aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silica. Acid, light liquid paraffin, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, sesame oil, wheat starch, white beeswax, magnesium oxide, dimethylpolysiloxane, potassium sodium tartrate, sucrose fatty acid ester, glycerin fatty acid ester, silicone resin, hydroxylated Aluminum gel, stearyl alcohol, stearic acid, aluminum stearate, calcium stearate, polyoxyl stearate, magnesium stearate, cetanol, gelatin, tar , Magnesium carbonate, precipitated calcium carbonate, corn starch, lactose, hard fat, sucrose, potato tempun, hydroxypropylcellulose, fumaric acid, sodium stearyl fumarate, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, polysorbate, beeswax, metacay Examples include magnesium aluminate, methylcellulose, mole, glyceryl monostearate, sodium lauryl sulfate, calcium sulfate, magnesium sulfate, liquid paraffin, and phosphoric acid.
Preferred are stearic acid, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, sodium stearyl fumarate, and talc.

  The excipient, disintegration aid, and binder in the present invention are components that can enhance the disintegration property and moldability of the intraoral rapidly disintegrating tablet of the present invention, and are generally excipients, disintegrants, and binders. However, it is not particularly limited to these applications.

Examples of the excipient in the present invention include starch acrylate, L-aspartic acid, aminoethylsulfonic acid, aminoacetic acid, candy (powder), gum arabic, gum arabic powder, alginic acid, sodium alginate, pregelatinized starch, and inositol. , Ethyl cellulose, ethylene vinyl acetate copolymer, erythritol, sodium chloride, olive oil, kaolin, cacao butter, casein, fructose, pumice granules, carmellose, carmellose sodium, hydrous silicon dioxide, dry yeast, dry aluminum hydroxide gel, dry sodium sulfate , Dried magnesium sulfate, agar, agar powder, xylitol, citric acid, sodium citrate, disodium citrate, glycerin, calcium glycerophosphate, sodium gluconate, L-glutamine, clay, clay -Grain, croscarmellose sodium, aluminum silicate, synthetic aluminum silicate, hydroxypropyl starch, crystalline cellulose, magnesium aluminate, calcium silicate, magnesium silicate, light anhydrous silicic acid, light liquid paraffin, cinnamon powder, Crystalline cellulose, crystalline cellulose / carmellose sodium, fine crystalline cellulose, pearl millet, synthetic aluminum silicate, synthetic hydrotalcite, sesame oil, wheat flour, wheat starch, wheat germ powder, riceko (rice flour), rice starch, potassium acetate, acetic acid Calcium, 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 hydroxide magnesium, aluminum hydroxide gel, aluminum hydroxide sodium bicarbonate coprecipitate, 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, skim milk powder, talc, ammonium carbonate Um, calcium carbonate, magnesium carbonate, neutral anhydrous sodium sulfate, low-substituted hydroxypropylcellulose, dextran, dextrin, natural aluminum silicate, corn syrup, corn starch, trehalose, tragacanth, silicon dioxide, calcium lactate, lactose, hydrotal Sight, maltose, white shellac, white petrolatum, white sugar, sucrose, sucrose starch spherical granule, powdered green leaf extract, powdered green leaf 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, propylene glycol, Powdered maltose syrup, powdered cellulose, pectin, bentonite, sodium polyacrylate, polyethylene glycol, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene / polyoxypropylene / glycol, sodium polystyrene sulfonate, 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, magnesium aluminate metasilicate, Methylcellulose, cottonseed powder, cottonseed oil, mole, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, anhydrous Silicic acid, 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, sodium hydrogen phosphate One or more of these may be used alone, but two or more may be blended.
Preferably, crystalline cellulose, powdered cellulose, croscarmellose sodium, magnesium aluminate metasilicate, magnesium aluminate silicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granule, hydrotalcite, Bentonite, aluminum silicate, calcium phosphate, calcium carbonate, calcium silicate, magnesium silicate, magnesium oxide, magnesium hydroxide, magnesium hydroxide alumina, dried aluminum hydroxide gel, magnesium carbonate, wheat starch, rice starch (rice starch), Corn starch (corn starch), potato starch, partially pregelatinized starch, hydroxypropyl starch, mannitol, xylitol, sorbitol, Ellis Torr, maltitol, lactose, sucrose, glucose, fructose, maltose, trehalose, palatinit, palatinose, agar, shellac, and tragacanth.
More preferably, crystalline cellulose, croscarmellose sodium, magnesium aluminate metasilicate, magnesium aluminate silicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granule, calcium silicate, silicic acid Aluminum, silicic anhydride, hydrotalcite.

Examples of the disintegration aid in the present invention include adipic acid, alginic acid, sodium alginate, pregelatinized starch, erythritol, fructose, sodium carboxymethyl starch, carmellose, carmellose 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, phthalate acetate Acid cellulose, dioctyl sodium sulfosuccinate, sucrose fatty acid ester, magnesium alumina hydroxide, calcium stearate, steari Acid polyoxyl, 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, palatinite, palatinose, potato starch, hydroxyethyl methylcellulose, hydroxypropyl starch, hydroxypropylcellulose, glucose, bentonite, partially pregelatinized starch, monosodium fumarate, polyethylene glycol, polyoxyethylene hydrogenated castor oil, Polyoxyethylene, polyoxypropylene, glycol, polysorbate, polyvinyl acetal One or more of ethylaminoacetate, polyvinylpyrrolidone, maltitol, D-mannitol, anhydrous citric acid, anhydrous silicic acid, magnesium aluminate metasilicate, methylcellulose, glyceryl monostearate, sodium lauryl sulfate, etc. May be used alone, but two or more may be blended.
Preferably, low-substituted hydroxypropyl cellulose, crystalline cellulose, carmellose, croscarmellose sodium, sodium carboxymethyl starch, crospovidone, magnesium aluminate metasilicate, magnesium aluminate silicate, synthetic aluminum silicate, precipitated calcium carbonate, water Alumina magnesium oxide, magnesium carbonate, wheat starch, rice starch, corn starch, potato starch, partially pregelatinized starch, hydroxypropyl starch, mannitol, xylitol, sorbitol, erythritol, maltitol, lactose, sucrose, glucose, fructose, maltose, trehalose , Palatinit, palatinose, agar, shellac, tragacanth.
More preferably, low-substituted hydroxypropyl cellulose, crystalline cellulose, carmellose, croscarmellose sodium, sodium carboxymethyl starch, rice starch, corn starch, crospovidone, magnesium metasilicate aluminate, magnesium aluminate silicate, synthetic silicate Aluminum.

  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 used in the present invention is not particularly limited, and is a central nerve agent such as a peripheral nerve agent, antipyretic analgesic / antiinflammatory agent, hypnotic sedative, or neuropsychiatric agent; peripheral agent such as a skeletal muscle relaxant or an autonomic nerve agent. Nervous agents; Cardiovascular agents such as cardiotonic agents, arrhythmic agents, diuretics and vasodilators; Respiratory agents such as bronchodilators and antitussives; Gastrointestinal agents such as digestives, intestinals and antacids; Hormone agents Metabolic drugs such as antihistamines and vitamins; anti-ulcer agents; antibiotics; chemotherapeutic agents; herbal extracts;

As the active ingredient, those processed by a known method such as coating 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 with a pulverized product in order to enhance the feeling of roughness in the mouth and the dosage, and the average particle size is preferably 0.1 to 100 μm.
The active ingredient only needs to be contained in one or both of the inside and outside of the granulated particles. When the active ingredient is not contained in the granulated particles, (a) the granulated particles, (b) the lubricant, and ( c) What is necessary is just to mix | blend at the time of mixing with a disintegration adjuvant.

The intraorally rapidly disintegrating tablet of the present invention is based on (a) 1 to 98 parts by weight of granulated particles, (b) 0.01 to 5 parts by weight of a lubricant, and (c) disintegration aid with respect to 100 parts by weight of the whole tablet. 1 to 98 parts by weight of the agent and (d) 0.01 to 60 parts by weight of the active ingredient. More preferably, (a) 5 to 90 parts by weight of granulated particles, (b) 0.1 to 3 parts by weight of a lubricant, and (c) 5 to 90 parts by weight of a disintegration aid, based on 100 parts by weight of the whole tablet. And (d) 0.1 to 50 parts by weight of the active ingredient.

  The intraoral rapidly disintegrating tablet of the present invention can be blended with other components that can be blended with pharmaceuticals as long as disintegration is not impaired. As a component which does not impair the disintegration property which can be mix | blended with the intraoral quick disintegrating tablet of this invention, surfactant (For example, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan fatty acid ester, polysorbate, glycerin) Fatty acid esters, sodium lauryl sulfate, etc., acidulants (eg, citric acid, tartaric acid, malic acid, ascorbic acid, etc.), foaming agents (eg, sodium bicarbonate, sodium carbonate, etc.), sweeteners (sodium saccharin, dipotassium glycyrrhizinate, aspartame) , Stevia, thaumatin etc.), fragrances (eg lemon oil, orange oil, menthol etc.), colorants (eg edible red No. 2, edible blue No. 2, edible yellow No. 5, edible lake dye, ferric sesquioxide etc.), stable Agent (for example, edetate sodium) Potassium, tocopherol, such as cyclodextrins), flavoring agents, and flavoring agents.

  The intraoral quick disintegrating tablet of the present invention comprises (a) granulated particles, (b) a lubricant, (c) an excipient, a disintegration aid and / or a binder, and ( d) It can be produced by mixing the active ingredient and other ingredients that can be blended with pharmaceuticals and then compression molding. 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 and can be selected within the range of tableting pressure that can be formulated.

  Other production methods include (a) granulated particles, (b) lubricant, (c) at least one selected from excipients, disintegration aids and / or binders, and (d) active ingredients. After wet granulation, compression molding may be performed. Examples of the wet granulation method include a spray drying method, a fluidized bed granulation drying method, a stirring granulation method, and a wet extrusion granulation method. In addition, after compression molding, aging such as heating and humidification can be performed according to a conventional method to impart desired hardness and disintegration.

  In the production of an orally rapidly disintegrating tablet according to the present invention, as described above, the lubricant may be mixed with other ingredients together with other ingredients and then compression molded. Without mixing with the ingredients, it can be manufactured by the method of applying to the surface of the punch and the wall of the die in advance and compression molding (external lubrication method), giving the desired hardness and disintegration be able to. The method of applying the lubricant to the mortar can be performed by a conventionally known method or machine.

  The intraoral rapidly disintegrating tablet of the present invention has a hardness of usually 40 to 200N, preferably 40 to 150N, more preferably 40 to 120N. Further, since the tableting pressure varies depending on the size of the tablet, the tableting pressure can be adjusted as appropriate so as to achieve the above-mentioned hardness. When a 200 mg tablet is pressed using a 8 mm diameter punch, the tablet has a hardness of 40 to 70 N when the tableting pressure is 300 to 2400 kgf.

  In the present invention, the drug content is high, and sufficient hardness, good disintegration and good moldability are unknown in detail, but the properties (structure and shape) of the granulated particles are maintained. And because of the synergistic effect with the granulated particles due to the properties of certain excipients, disintegration aids and / or binders themselves.

The intraoral rapidly disintegrating tablet of the present invention can also be used as other solid preparations such as molding into tablets (for example, chewable tablets) other than those intended for rapid disintegration.
Since the rapidly disintegrating tablet in the oral cavity of the present invention disintegrates immediately with a small amount of water, it can be used not only for pharmaceuticals but also for foods, health foods, specific function foods, pet foods, feeds and agricultural chemicals.

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 from when 3 to 8 subjects put tablets (n = 6 each) into the oral cavity until they completely disintegrated was measured, and the average value was defined 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.

[Comparative Example 1] Tableting after dry mixing Spray-dried granulated D-mannitol (Pearlitol 200 SD, manufactured by Roquette) 51.2 parts by weight, Xylitol [Xylit XC, manufactured by Towa Kasei Kogyo Co., Ltd.] 3.2 parts by weight Crospovidone [Collidon CL, manufactured by BASF Takeda Vitamin Co., Ltd.] 7.2 parts by weight, crystalline cellulose [Theolas PH-101, manufactured by Asahi Kasei Co., Ltd.] 13.6 parts by weight, magnesium aluminate metasilicate [Neucillin UFL2, FUJI CHEMICAL CO., LTD.] 4.8 parts by weight, 20 parts by weight of aspirin added and mixed, and then mixed with an appropriate amount of magnesium stearate, and then a rotary tableting machine [HT-AP18SS-II, Inc. ) Made by Hata Iron Works], a tablet having a weight of 200 mg, a diameter of 8 mm, and a 9R was tableted with a set hardness of 50 N. However, sticking occurred during tableting, and the tablet Rukoto could not.

[Reference Example 1] Production of granulated particles Mannitol [Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd.] 64 parts by weight, 4 parts by weight of xylitol, 9 parts by weight of crospovidone, 17 parts by weight of crystalline cellulose, magnesium aluminate metasilicate After 6 parts by weight of water is uniformly dispersed in water, it is spray-dried at an outlet temperature of 90 ° C. using a spray dryer (L-8 type, manufactured by Okawahara Chemical Co., Ltd.), and has a white sphere with good fluidity. Of granulated particles were obtained.

[Comparative Example 2]
After mixing 5 parts by weight of aspirin with 95 parts by weight of the granulated particles obtained in Reference Example 1 and mixing an appropriate amount of magnesium stearate, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine, weight 200 mg, diameter 8 mm 9R tablets were obtained.

[Example 1]
88 parts by weight of the granulated particles obtained in Reference Example 1, 5 parts by weight of aspirin, 1 part by weight of low-substituted hydroxypropyl cellulose [LH-B1, manufactured by Shin-Etsu Chemical Co., Ltd.], 1 part by weight of magnesium aluminate metasilicate And 5 parts by weight of croscarmellose sodium (Kiccolate ND200, manufactured by Asahi Kasei), after mixing an appropriate amount of magnesium stearate, tableted with a rotary tableting machine with a set hardness of 50N, weight 200mg, diameter 8mm, 9R Tablets were obtained.

[Example 2]
88 parts by weight of the granulated particles obtained in Reference Example 1, 5 parts by weight of aspirin, 1 part by weight of polyvinylpyrrolidone [Collidon 30, manufactured by BASF Takeda Vitamin Co., Ltd.], 1 part by weight of magnesium aluminate metasilicate and 5 parts by weight of crospovidone The parts were mixed and an appropriate amount of magnesium stearate was mixed, and then tableted with a rotary tableting machine with a set hardness of 50 N to obtain tablets with a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 3]
88 parts by weight of the granulated particles obtained in Reference Example 1, 5 parts by weight of aspirin, 1 part by weight of hydroxypropylmethylcellulose [TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.], 1 part by weight of magnesium aluminate metasilicate and crospovidone After mixing 5 parts by weight and mixing an appropriate amount of magnesium stearate, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine to obtain tablets with a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 4]
88 parts by weight of the granulated particles obtained in Reference Example 1 and 5 parts by weight of aspirin, 1 part by weight of hydroxypropylcellulose [HPC SL, Nippon Soda Co., Ltd.], calcium silicate [FLORITE RE, Eisai Food Chemical Co., Ltd. )] 1 part by weight and 5 parts by weight of croscarmellose sodium were mixed, and after mixing an appropriate amount of magnesium stearate, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine, and was tableted with a weight of 200 mg, diameter 8 mm, 9R Got.

[Comparative Example 3]
After mixing 20 parts by weight of aspirin with 80 parts by weight of the granulated particles obtained in Reference Example 1 and mixing an appropriate amount of magnesium stearate, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine, weight 200 mg, diameter 8 mm 9R tablets were obtained.

[Example 5]
60 parts by weight of the granulated particles obtained in Reference Example 1 were mixed with 20 parts by weight of aspirin and 20 parts by weight of crystalline cellulose, mixed with an appropriate amount of magnesium stearate, and then tableted with a rotary tableting machine with a set hardness of 50N. A tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Example 6]
After mixing 20 parts by weight of aspirin and 20 parts by weight of corn starch (manufactured by Nippon Corn Starch Co., Ltd.) with 60 parts by weight of the granulated particles obtained in Reference Example 1, an appropriate amount of magnesium stearate is mixed, and then a rotary tableting machine. Was tableted with a set hardness of 50 N to obtain tablets with a weight of 200 mg, a diameter of 8 mm, and 9R.

[Comparative Example 4]
After mixing 40 parts by weight of aspirin with 60 parts by weight of the granulated particles obtained in Reference Example 1 and mixing an appropriate amount of magnesium stearate, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine, weight 200 mg, diameter 8 mm 9R tablets were obtained.

[Example 7]
After mixing 50 parts by weight of the granulated particles obtained in Reference Example 1 with 40 parts by weight of aspirin and 10 parts by weight of crystalline cellulose, and mixing an appropriate amount of magnesium stearate, the tablet is tableted with a set hardness of 50 N using a rotary tableting machine. A tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

  Since Comparative Example 1 caused tableting failure and a tablet could not be obtained, it can be seen that the granulated particles used in the present invention play an important role. From Examples 1-7 and Comparative Examples 2-4, by adding at least one selected from the excipients, disintegration aids and / or binders in the present invention, good disintegration and good moldability It can be seen that higher hardness is obtained.

[Reference Example 2] Production of granulated particles After 65 parts by weight of mannitol, 4 parts by weight of xylitol, 9 parts by weight of crospovidone, 17 parts by weight of crystalline cellulose and 5 parts by weight of anhydrous calcium hydrogen phosphate were uniformly dispersed in water. Using a spray dryer (L-8 type, manufactured by Okawara Chemical Industries Co., Ltd.), spray drying was performed at an outlet temperature of 90 ° C. to obtain white spherical granulated particles having good fluidity.

[Comparative Example 5]
After 90 parts by weight of the granulated particles obtained in Reference Example 2 were mixed with 10 parts by weight of aspirin and mixed with an appropriate amount of magnesium stearate, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine, weight 200 mg, diameter 8 mm 9R tablets were obtained.

[Example 8]
After mixing 70 parts by weight of the granulated particles obtained in Reference Example 2 with 10 parts by weight of aspirin and 20 parts by weight of low-substituted hydroxypropylcellulose, and mixing an appropriate amount of magnesium stearate, a setting hardness of 50 N using a rotary tableting machine. As a result, tablets having a weight of 200 mg, a diameter of 8 mm, and 9R were obtained.

[Example 9]
50 g of croscarmellose sodium [Ac-Di-Sol, manufactured by Asahi Kasei Co., Ltd.] and 50 g of light anhydrous silicic acid [Adsolider-101, Freund Sangyo Co., Ltd.] were kneaded in a mortar while adding an appropriate amount of water. This was granulated with a 22 mesh sieve, dried at 60 ° C. for 18 hours, and then granulated with a 22 mesh sieve to obtain granules A.
After mixing 10 parts by weight of aspirin and 10 parts by weight of granule A with 80 parts by weight of the granulated particles obtained in Reference Example 2, and mixing an appropriate amount of magnesium stearate, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine, A tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Comparative Example 6]
After mixing 20 parts by weight of aspirin with 80 parts by weight of the granulated particles obtained in Reference Example 2 and mixing an appropriate amount of magnesium stearate, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine, weight 200 mg, diameter 8 mm 9R tablets were obtained.

[Example 10]
70 parts by weight of the granulated particles obtained in Reference Example 2 were mixed with 20 parts by weight of aspirin and 10 parts by weight of croscarmellose sodium, and after mixing an appropriate amount of magnesium stearate, the mixture was punched at a set hardness of 50 N using a rotary tableting machine. Tablets were obtained having a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 11]
60 parts by weight of the granulated particles obtained in Reference Example 2 are mixed with 20 parts by weight of aspirin and 20 parts by weight of carmellose [NS-300, manufactured by Gotoku Pharmaceutical] and mixed with an appropriate amount of magnesium stearate. Was tableted with a set hardness of 50 N to obtain tablets with a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 12]
After mixing 60 parts by weight of the granulated particles obtained in Reference Example 2 with 20 parts by weight of aspirin and 20 parts by weight of crystalline cellulose, and mixing an appropriate amount of magnesium stearate, the tablet is tableted with a set hardness of 50 N using a rotary tableting machine. A tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Example 13]
After mixing 32 parts by weight of the granulated particles obtained in Reference Example 2 with 20 parts by weight of aspirin and 48 parts by weight of crystalline cellulose, an appropriate amount of magnesium stearate is mixed, and then tableted with a rotary tableting machine with a set hardness of 50N. A tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Example 14]
70 parts by weight of the granulated particles obtained in Reference Example 2 were mixed with 20 parts by weight of aspirin and 10 parts by weight of corn starch, mixed with an appropriate amount of magnesium stearate, and then tableted with a rotary tableting machine with a set hardness of 50N. A tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Comparative Example 7]
After mixing 30 parts by weight of aspirin with 70 parts by weight of the granulated particles obtained in Reference Example 2 and mixing an appropriate amount of magnesium stearate, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine, weight 200 mg, diameter 8 mm 9R tablets were obtained.

[Example 15]
60 parts by weight of the granulated particles obtained in Reference Example 2 were mixed with 30 parts by weight of aspirin and 10 parts by weight of crospovidone, mixed with an appropriate amount of magnesium stearate, and then tableted with a rotary tableting machine with a set hardness of 50N. A tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Comparative Example 8]
After mixing 40 parts by weight of aspirin with 60 parts by weight of the granulated particles obtained in Reference Example 2 and mixing an appropriate amount of magnesium stearate, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine, weight 200 mg, diameter 8 mm 9R tablets were obtained.

[Example 16]
After mixing 50 parts by weight of the granulated particles obtained in Reference Example 2 with 40 parts by weight of aspirin and 10 parts by weight of carmellose and mixing an appropriate amount of magnesium stearate, the tablet is tableted with a set hardness of 50 N using a rotary tableting machine, A tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Example 17]
After mixing 40 parts by weight of the granulated particles obtained in Reference Example 2 with 40 parts by weight of aspirin and 20 parts by weight of corn starch, an appropriate amount of magnesium stearate is mixed, and then tableted with a rotary tableting machine with a set hardness of 50N. A tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Example 18]
After mixing 40 parts by weight of the granulated particles obtained in Reference Example 2 with 40 parts by weight of aspirin and 20 parts by weight of rice starch (Micropearl, manufactured by Shimada Chemical Co., Ltd.), and mixing an appropriate amount of magnesium stearate, Tableting was performed using a rotary tableting machine with a set hardness of 50 N to obtain tablets having a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 19]
50 parts by weight of the granulated particles obtained in Reference Example 2 are mixed with 40 parts by weight of aspirin and 10 parts by weight of crospovidone, mixed with an appropriate amount of magnesium stearate, and then tableted with a rotary tableting machine with a set hardness of 50N. A tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

  From the results of Table 2, the hardness is increased even if the content of the drug is increased by adding at least one selected from excipients, disintegration aids and / or binders to the granulated particles in the present invention. It can be seen that good disintegration and good moldability can be obtained.

[Reference Example 3] Manufacture of granulated particles Mannitol [Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd.] 65 parts by weight, 5 parts by weight of xylitol, 8 parts by weight of crospovidone, 15 parts by weight of crystalline cellulose, magnesium aluminate metasilicate After 7 parts by weight of water is homogeneously dispersed in water, it is spray-dried at an outlet temperature of 80 ° C. using a spray dryer (L-8 type, manufactured by Okawara Kako Co., Ltd.), and has a white sphere with good fluidity. Of granulated particles were obtained.

[Comparative Example 9]
After mixing 30 parts by weight of acetaminophen with 70 parts by weight of the granulated particles obtained in Reference Example 3 and mixing an appropriate amount of magnesium stearate, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine, and the weight was 200 mg. A tablet with a diameter of 8 mm and 9R was obtained.

[Example 20]
After mixing 65 parts by weight of the granulated particles obtained in Reference Example 3 with 30 parts by weight of acetaminophen and 5 parts by weight of carmellose, and mixing with an appropriate amount of magnesium stearate, tableting with a rotary tableting machine with a set hardness of 50N is performed. As a result, a tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Example 21]
After mixing 50 parts by weight of the granulated particles obtained in Reference Example 3 with 30 parts by weight of acetaminophen and 20 parts by weight of hydroxypropyl cellulose, and mixing an appropriate amount of magnesium stearate, the hardness is set to 50 N with a rotary tableting machine. Tableting was performed to obtain tablets having a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 22]
50 parts by weight of the granulated particles obtained in Reference Example 3 were mixed with 30 parts by weight of acetaminophen and 20 parts by weight of carmellose, mixed with an appropriate amount of magnesium stearate, and then tableted with a rotary tableting machine with a set hardness of 50N. As a result, a tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Comparative Example 10]
After mixing 50 parts by weight of acetaminophen with 50 parts by weight of the granulated particles obtained in Reference Example 3 and mixing an appropriate amount of magnesium stearate, the setting hardness 50N, weight 200 mg, diameter 8 mm, 9R with a rotary tableting machine. Tableting was attempted, but the upper limit pressure of the tableting machine exceeded 2400 kgf, and the apparatus was stopped, so that tablets could not be obtained.

[Example 23]
After mixing 50 parts by weight of the granulated particles obtained in Reference Example 3 with 40 parts by weight of acetaminophen and 10 parts by weight of crospovidone and mixing an appropriate amount of sodium stearyl fumarate, the rotary tableting machine sets the hardness to 50 N. Tableting was performed to obtain tablets having a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 24]
After mixing 20 parts by weight of the granulated particles obtained in Reference Example 3 with 50 parts by weight of acetaminophen and 30 parts by weight of carmellose and mixing an appropriate amount of magnesium stearate, the tableting is performed with a rotary tableting machine with a set hardness of 50N. As a result, a tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Example 25]
After mixing 50 parts by weight of acetaminophen and 30 parts by weight of rice starch with 20 parts by weight of the granulated particles obtained in Reference Example 3, and mixing an appropriate amount of magnesium stearate, the mixture was pressed with a rotary tableting machine to a set hardness of 50N. Tablets were obtained having a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 26]
20 parts by weight of the granulated particles obtained in Reference Example 3 are mixed with 50 parts by weight of acetaminophen and 30 parts by weight of corn starch, mixed with an appropriate amount of magnesium stearate, and then pressed with a rotary tableting machine with a set hardness of 50N. Tablets were obtained having a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 27]
After mixing 50 parts by weight of acetaminophen, 20 parts by weight of rice starch, and 10 parts by weight of corn starch with 20 parts by weight of the granulated particles obtained in Reference Example 3, and then mixing an appropriate amount of magnesium stearate, a rotary tableting machine. Was tableted with a set hardness of 50 N to obtain tablets with a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 28]
After mixing 60 parts by weight of acetaminophen and 30 parts by weight of crystalline cellulose with 10 parts by weight of the granulated particles obtained in Reference Example 3, and mixing an appropriate amount of magnesium stearate, the mixture is punched at a set hardness of 50 N using a rotary tableting machine. Tablets were obtained having a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 29]
After mixing 60 parts by weight of acetaminophen, 10 parts by weight of carmellose and 20 parts by weight of rice starch with 10 parts by weight of the granulated particles obtained in Reference Example 3, and mixing an appropriate amount of magnesium stearate, a rotary tableting machine is used. Tableting was performed with a set hardness of 50 N to obtain tablets having a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 30]
After mixing 60 parts by weight of acetaminophen, 25 parts by weight of crospovidone and 5 parts by weight of crystalline cellulose with 10 parts by weight of the granulated particles obtained in Reference Example 3, a suitable amount of magnesium stearate is mixed, and then a rotary tableting machine. Was tableted with a set hardness of 50 N to obtain tablets with a weight of 200 mg, a diameter of 8 mm, and 9R.

  From the results of Table 3, the hardness is increased even if the content of the drug is increased by adding at least one selected from excipients, disintegration aids and / or binders to the granulated particles in the present invention. It can be seen that good disintegration and good moldability can be obtained.

[Reference Example 4] Production of granulated particles After 65 parts by weight of mannitol, 5 parts by weight of xylitol, 8 parts by weight of crospovidone, 18 parts by weight of crystalline cellulose, and 4 parts by weight of anhydrous calcium hydrogen phosphate were uniformly dispersed in water. Using a spray dryer [L-8 type, manufactured by Okawahara Chemical Co., Ltd.], spray drying was performed at an outlet temperature of 80 ° C. to obtain white spherical granulated particles having good fluidity.

[Comparative Example 11]
After mixing 20 parts by weight of acetaminophen with 80 parts by weight of the granulated particles obtained in Reference Example 4 and mixing an appropriate amount of magnesium stearate, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine, and the weight was 200 mg. A tablet with a diameter of 8 mm and 9R was obtained.

[Example 31]
After mixing 64 parts by weight of the granulated particles obtained in Reference Example 4 with 20 parts by weight of acetaminophen and 16 parts by weight of crystalline cellulose, and mixing an appropriate amount of magnesium stearate, the mixture is punched to a set hardness of 50 N using a rotary tableting machine. Tablets were obtained having a weight of 200 mg, a diameter of 8 mm, and 9R.

[Comparative Example 12]
After mixing 30 parts by weight of acetaminophen with 70 parts by weight of the granulated particles obtained in Reference Example 4 and mixing an appropriate amount of magnesium stearate, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine, and the weight was 200 mg. A tablet with a diameter of 8 mm and 9R was obtained.

[Example 32]
After mixing 65 parts by weight of the granulated particles obtained in Reference Example 4 with 30 parts by weight of acetaminophen and 5 parts by weight of crospovidone, and mixing an appropriate amount of sodium stearyl fumarate, the setting hardness is set to 50 N using a rotary tableting machine. Tableting was performed to obtain tablets having a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 33]
50 parts by weight of the granulated particles obtained in Reference Example 4 were mixed with 30 parts by weight of acetaminophen and 20 parts by weight of carmellose, mixed with an appropriate amount of magnesium stearate, and then tableted using a rotary tableting machine with a set hardness of 50N. As a result, a tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Comparative Example 13]
After mixing 40 parts by weight of acetaminophen with 60 parts by weight of the granulated particles obtained in Reference Example 4 and mixing an appropriate amount of magnesium stearate, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine, and the weight was 200 mg. A tablet with a diameter of 8 mm and 9R was obtained.

[Example 34]
After mixing 40 parts by weight of acetaminophen and 25 parts by weight of crystalline cellulose with 35 parts by weight of the granulated particles obtained in Reference Example 4, and mixing an appropriate amount of magnesium stearate, the mixture is punched to a set hardness of 50 N using a rotary tableting machine. Tablets were obtained having a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 35]
After mixing 40 parts by weight of acetaminophen and 25 parts by weight of rice starch with 35 parts by weight of the granulated particles obtained in Reference Example 4, and mixing an appropriate amount of magnesium stearate, the mixture was pressed with a set hardness of 50 N using a rotary tableting machine. Tablets were obtained having a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 36]
After mixing 40 parts by weight of acetaminophen, 20 parts by weight of rice starch and 5 parts by weight of crystalline cellulose with 35 parts by weight of the granulated particles obtained in Reference Example 4, a suitable amount of magnesium stearate is mixed, and then a rotary tableting machine. Was tableted with a set hardness of 50 N to obtain tablets with a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 37]
After mixing 40 parts by weight of acetaminophen, 20 parts by weight of rice starch and 5 parts by weight of carmellose with 35 parts by weight of the granulated particles obtained in Reference Example 4, and mixing an appropriate amount of magnesium stearate, a rotary tableting machine is used. Tableting was performed with a set hardness of 50 N to obtain tablets having a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 38]
40 parts by weight of acetaminophen and 25 parts by weight of carmellose are mixed with 35 parts by weight of the granulated particles obtained in Reference Example 4, and after mixing an appropriate amount of magnesium stearate, the tablet is tableted with a set hardness of 50 N using a rotary tableting machine. As a result, a tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Comparative Example 14]
After mixing 50 parts by weight of acetaminophen with 50 parts by weight of the granulated particles obtained in Reference Example 4 and mixing an appropriate amount of magnesium stearate, the setting hardness 50N, weight 200 mg, diameter 8 mm, 9R with a rotary tableting machine. However, the tablet was not able to be obtained because the device was stopped exceeding the upper limit of 2400 kgf of the tableting machine.

[Example 39]
After mixing 50 parts by weight of acetaminophen and 30 parts by weight of rice starch with 20 parts by weight of the granulated particles obtained in Reference Example 4, and mixing an appropriate amount of magnesium stearate, the mixture was punched at a set hardness of 50 N using a rotary tableting machine. Tablets were obtained having a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 40]
After mixing 20 parts by weight of the granulated particles obtained in Reference Example 4 with 50 parts by weight of acetaminophen and 30 parts by weight of carmellose, and mixing an appropriate amount of magnesium stearate, tableting with a rotary tableting machine with a set hardness of 50N is performed. As a result, a tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Example 41]
After mixing 60 parts by weight of acetaminophen, 10 parts by weight of carmellose and 20 parts by weight of rice starch with 10 parts by weight of the granulated particles obtained in Reference Example 4, and mixing an appropriate amount of magnesium stearate, a rotary tableting machine is used. Tableting was performed with a set hardness of 50 N to obtain tablets having a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 42]
After mixing 60 parts by weight of acetaminophen and 30 parts by weight of carmellose with 10 parts by weight of the granulated particles obtained in Reference Example 4, and mixing a suitable amount of magnesium stearate, the tableting is performed with a set hardness of 50 N using a rotary tableting machine. As a result, a tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

  From the results in Table 4, the hardness is increased even if the content of the drug is increased by adding at least one selected from excipients, disintegration aids and / or binders to the granulated particles in the present invention. However, it can be seen that very good disintegration and good moldability can be obtained.

[Reference Example 5] Production of granulated particles containing a drug 64.5 parts by weight of mannitol, 5 parts by weight of xylitol, 8 parts by weight of crospovidone, 18 parts by weight of crystalline cellulose, 4 parts by weight of anhydrous calcium hydrogen phosphate, loperamide hydrochloride (Japan) Pharmacopoeia Pharmaceutical Standards) 0.5 parts by weight are uniformly dispersed in water, and then spray-dried at an outlet temperature of 90 ° C. using a spray dryer (L-8, manufactured by Okawahara Koki Co., Ltd.). Good white spherical granulated particles were obtained.

[Comparative Example 15]
An appropriate amount of magnesium stearate was mixed with the granulated particles obtained in Reference Example 5, and then tableted with a rotary tableting machine with a set hardness of 50 N to obtain tablets having a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 43]
After mixing 20 parts by weight of hydroxypropyl starch with 80 parts by weight of the granulated particles obtained in Reference Example 5, and mixing an appropriate amount of magnesium stearate, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine, and the weight was 200 mg. A tablet with a diameter of 8 mm and 9R was obtained.

[Example 44]
After mixing 93 parts by weight of the granulated particles obtained in Reference Example 1 with 1 part by weight of hydroxypropyl cellulose, 1 part by weight of magnesium aluminate metasilicate and 5 parts by weight of crospovidone, and mixing an appropriate amount of magnesium stearate, a rotary Tableting was performed with a tableting machine with a set hardness of 50 N, and tablets with a weight of 200 mg, a diameter of 8 mm, and 9R were obtained.

[Example 45]
5 g of crospovidone, 10 g of trehalose [Asahi Kasei Co., Ltd.] and 85 g of the granulated particles obtained in Reference Example 5 were kneaded in a mortar while adding an appropriate amount of ethanol (99.5%). This was granulated with a 22 mesh sieve, dried at 60 ° C. for 18 hours, and then granulated with a 22 mesh sieve to obtain granules B.
After mixing an appropriate amount of magnesium stearate with granule B, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine to obtain tablets of weight 200 mg, diameter 8 mm, 9R.

[Example 46]
50 g of crospovidone and 10 g of maltitol (manufactured by Towa Kasei Kogyo Co., Ltd.) were kneaded in a mortar while adding an appropriate amount of ethanol (99.5%). This was granulated with a 22 mesh sieve, dried at 60 ° C. for 18 hours, and then granulated with a 22 mesh sieve to obtain granules C.
After mixing 12 parts by weight of granule C with 88 parts by weight of the granulated particles obtained in Reference Example 5 and mixing an appropriate amount of magnesium stearate, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine, weight 200 mg, diameter 8 mm 9R tablets were obtained.

[Example 47]
10 g of crospovidone and 90 g of the granulated particles obtained in Reference Example 5 were kneaded in a mortar while adding an appropriate amount of ethanol (99.5%). This was granulated with a 22 mesh sieve, dried at 60 ° C. for 18 hours, and then granulated with a 22 mesh sieve to obtain granules D.
After mixing an appropriate amount of magnesium stearate with granule D, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine to obtain tablets of weight 200 mg, diameter 8 mm, 9R.

[Example 48]
Crospovidone 50 g, maltitol 50 g, and magnesium aluminate metasilicate 10 g were kneaded in a mortar while adding an appropriate amount of ethanol (99.5%). This was granulated with a 22 mesh sieve, dried at 60 ° C. for 18 hours, and then granulated with a 22 mesh sieve to obtain granules E.
After mixing 11 parts by weight of granule E with 89 parts by weight of the granulated particles obtained in Reference Example 5 and mixing an appropriate amount of magnesium stearate, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine, weight 200 mg, diameter 8 mm 9R tablets were obtained.

[Example 49]
Crospovidone 5 g, maltitol 20 g, magnesium metasilicate aluminate 5 g and hydroxypropyl starch 70 g were kneaded in a mortar while adding an appropriate amount of ethanol (99.5%). This was granulated with a 22 mesh sieve, dried at 60 ° C. for 18 hours, and then granulated with a 22 mesh sieve to obtain granules F.
After 90 parts by weight of the granulated particles obtained in Reference Example 5 were mixed with 10 parts by weight of granule F and mixed with an appropriate amount of magnesium stearate, the tablet was tableted with a rotary tableting machine with a set hardness of 50 N, weight 200 mg, diameter 8 mm 9R tablets were obtained.

  From the results in Table 5, by adding at least one selected from excipients, disintegration aids and / or binders to the granulated particles in the present invention, good disintegration is obtained while achieving higher hardness. I understand that

[Reference Example 6] Production of granulated particles Mannitol [Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd.] 63 parts by weight, xylitol 6 parts by weight, crospovidone 7 parts by weight, crystalline cellulose 19 parts by weight, magnesium aluminate metasilicate After 5 parts by weight of water is uniformly dispersed in water, it is spray-dried at an outlet temperature of 90 ° C. using a spray dryer (L-8 type, manufactured by Okawahara Chemical Co., Ltd.), and has a white spherical shape with good fluidity. Of granulated particles were obtained.

[Comparative Example 16]
After mixing 30 parts by weight of ascorbic acid with 70 parts by weight of the granulated particles obtained in Reference Example 6 and mixing an appropriate amount of magnesium stearate, the tablet was tableted with a set hardness of 50 N using a rotary tableting machine, weight 200 mg, diameter An 8 mm, 9R tablet was obtained.

[Example 50]
40 parts by weight of the granulated particles obtained in Reference Example 6 were mixed with 30 parts by weight of ascorbic acid and 30 parts by weight of rice starch, mixed with an appropriate amount of magnesium stearate, and then tableted with a setting hardness of 50 N using a rotary tableting machine. As a result, a tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Example 51]
After mixing 40 parts by weight of the granulated particles obtained in Reference Example 6 with 30 parts by weight of ascorbic acid, 20 parts by weight of rice starch and 10 parts by weight of corn starch, and mixing an appropriate amount of magnesium stearate, a rotary tableting machine is used. Tableting was performed with a set hardness of 50 N to obtain tablets having a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 52]
After mixing 40 parts by weight of the granulated particles obtained in Reference Example 6 with 30 parts by weight of ascorbic acid, 20 parts by weight of rice starch and 10 parts by weight of crystalline cellulose, and mixing an appropriate amount of magnesium stearate, a rotary tableting machine is used. Tableting was performed with a set hardness of 50 N to obtain tablets having a weight of 200 mg, a diameter of 8 mm, and 9R.

[Example 53]
40 parts by weight of the granulated particles obtained in Reference Example 6 were mixed with 30 parts by weight of ascorbic acid and 30 parts by weight of crystalline back cellulose, mixed with an appropriate amount of magnesium stearate, and then pressed with a rotary tableting machine to a set hardness of 50N. Tablets were obtained having a weight of 200 mg, a diameter of 8 mm, and 9R.

  From the results in Table 6, by adding at least one selected from excipients, disintegration aids and / or binders to the granulated particles in the present invention, good disintegration is obtained while achieving higher hardness. I understand that

[Reference Example 7] Manufacture of granulated particles 65 parts by weight of mannitol, 5 parts by weight of lactose, 8 parts by weight of crospovidone, 18 parts by weight of crystalline cellulose, and 4 parts by weight of calcium hydrogen phosphate are uniformly dispersed in water and sprayed. Using a dryer [L-8 type, manufactured by Okawahara Chemical Co., Ltd.], spray drying was performed at an outlet temperature of 90 ° C. to obtain white spherical particles having good fluidity.

[Comparative Example 17]
After mixing 80 parts by weight of the granulated particles obtained in Reference Example 7, 20 parts by weight of aspirin and an appropriate amount of magnesium stearate, a tableting machine [compact high-speed rotary tableting machine VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.] ] Was used to obtain tablets having a tablet weight of 200 mg, a diameter of 8 mm, and a flat corner angle.

[Example 54]
20 parts by weight of aspirin is mixed with 80 parts by weight of the granulated particles obtained in Reference Example 7, and an appropriate amount of magnesium stearate is applied to the surface of the punch and the mortar wall before filling the granules into the mortar of the tableting machine. Tablet using an external lubrication device (compact high-speed rotary tableting machine VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.) equipped with a device to perform tablet weight 200 mg, diameter 8 mm, flat sum angle tablet Manufactured.

  From the results of Table 7, oral disintegrating tablets that were tableted by the external lubrication method obtained good moldability and disintegration, and compared to oral disintegrating tablets that were previously mixed with a lubricant and tableted. It can be seen that the disintegration time is short and the disintegration is excellent.

It can be provided as a tablet having sufficient hardness and good disintegration property in the oral cavity.
There is no problem that occurs when the content of the active ingredient is high, and there is sufficient disintegration in the oral cavity while it has sufficient hardness and high formability that does not cause problems such as chipping and powdering in manufacturing and transportation. It is possible to provide a method for producing a rapidly disintegrating oral disintegrating tablet having properties and an intraoral quick disintegrating tablet obtained by compression molding using a normal preparation facility.

Claims (13)

(A) 1 to 98 parts by weight of granulated particles, (b) 0.01 to 5 parts by weight of a lubricant, (c) 1 to 98 parts by weight of a disintegration aid, (d) Ri Do the active ingredient from 0.01 to 60 parts by weight, hardness is an oral rapidly disintegrating tablet Ru 40~200N der,
(A) granulated particles (i) granulated particles in which (b) inorganic substance and (c) disintegrant are uniformly dispersed in composite particles of two or more saccharides,
Disintegration aids are crystalline cellulose, crystalline cellulose carmellose sodium, carmellose, croscarmellose sodium, sodium carboxymethyl starch, crospovidone, low-substituted hydroxypropylcellulose, hydrous silicon dioxide, light anhydrous silicic acid, wheat starch, rice An orally rapidly disintegrating tablet that is at least one selected from starch, corn starch, potato starch, partially pregelatinized starch, and hydroxypropyl starch . The intraoral rapidly disintegrating tablet according to claim 1 , wherein the saccharide of the granulated particles is a composite particle composed of mannitol and at least one selected from the following group;
Xylitol, sorbitol, erythritol, maltitol, lactose, sucrose, glucose, fructose, maltose, trehalose, palatinit and palatinose. Granulated particles are inorganic magnesium metasilicate, magnesium aluminate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granulation, hydrotalcite, aluminum silicate, calcium phosphate, carbonic acid The oral cavity according to claim 1 or 2 , comprising at least one selected from calcium, calcium silicate, magnesium silicate, magnesium oxide, magnesium hydroxide, magnesium hydroxide alumina, dried aluminum hydroxide gel, and magnesium carbonate. Fast disintegrating tablet. The intraorally rapidly disintegrating tablet according to claim 1 , wherein the disintegrant for the granulated particles comprises at least one selected from crospovidone, low-substituted hydroxypropylcellulose, crystalline cellulose, and croscarmellose sodium. Each component of the granulated particles of claims 1 to 4 is (i) 40 to 90 parts by weight of a saccharide, (b) 1 to 30 parts by weight of an inorganic substance, and (c) 5 to 40 parts by weight of a disintegrant. the total amount of a) to (c) is from 100 parts by weight, (a) the saccharide is mannitol: mannitol other sugars = 98 to 67: to claims 1-4 comprising the granulated particles made of the proportion of 2 to 33 The intraoral rapidly disintegrating tablet as described . Each component of the granulated particles according to claims 1 to 4 is (i) 50 to 80 parts by weight of a saccharide, (b) 2 to 15 parts by weight of an inorganic substance, and (c) 10 to 36 parts by weight of a disintegrant. the total amount of a) to (c) is from 100 parts by weight, (a) the saccharide is mannitol: mannitol other sugars = 97 to 87: to claims 1-4 comprising the granulated particles made of the proportion of 3 to 13 The intraoral rapidly disintegrating tablet as described . Each component of the granulated particles of claims 1 to 4 is (i) 62 to 78 parts by weight of a saccharide, (b) 3 to 8 parts by weight of an inorganic substance, and (c) 18 to 34 parts by weight of a disintegrant. the total amount of a) to (c) is from 100 parts by weight, (a) the saccharide is mannitol: mannitol other sugars = 96 to 89: to claims 1-4 comprising the granulated particles made of the proportion of 4 to 11 The intraoral rapidly disintegrating tablet as described . The granulated particles according to claims 1 to 7 are granulated particles obtained by suspending (a) two or more kinds of sugars, (b) inorganic substances, and (c) disintegrants in water and then spray drying. orally rapidly disintegrating tablet according to claims 1-7. The intraoral rapidly disintegrating tablet according to claim 1 , wherein the granulated particles according to claim 1 are granulated particles containing an active ingredient. Lubricant is stearic acid, magnesium stearate, calcium stearate, sucrose fatty acid esters, glycerin fatty acid ester, polyethylene glycol, sodium stearyl fumarate, according to claims 1 to 9 at least one selected from talc Orally rapidly disintegrating tablet. (A) 5 to 90 parts by weight of granulated particles, (b) 0.01 to 3 parts by weight of a lubricant, (c) 5 to 90 parts by weight of a disintegration aid, and (d) orally rapidly disintegrating tablet according to claim 10 consisting of the active ingredient 0.1 to 50 parts by weight. The intraoral rapidly disintegrating tablet according to claim 1 , which is obtained by compression molding after mixing (a) granulated particles, (b) lubricant, (c) disintegration aid, and (d) active ingredient. The manufacturing method. (B) Lubricant is applied in advance to the ridge surface and mortar wall of the compression molding machine, and (a) granulated particles, (c) disintegration aid, and (d) active ingredients are mixed and filled and compression molded. The manufacturing method of the intraoral rapidly disintegrating broken tablet of Claim 1-11 which becomes.