JP2015078182A - Fast-disintegrating compression molding and producing method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a fast-disintegrating compression molding which has sufficient hardness without producing a chip nor degradation in production or delivery, and has excellent formability, good disintegratability in oral cavity, and together with the stability against humidity.SOLUTION: The invention provides a fast-disintegrating compression molding consisting of (a) an active ingredient, (b) one or more kinds of saccharides selected from mannitol, xylitol, and milk sugar, (c) a disintegrator, (d) an excipient, (e) a lubricant, and optionally (f) inorganic powders. If the active ingredient has a bitter taste, the fast-disintegrating compression molding is provided consisting of masking or coated sustained-release particles, and granulation particles formed from the component selected from (b)-(d) and (f).

Description

  The present invention relates to a disintegrating compression-molded product having rapid disintegration and moderate hardness, and particularly to an intraoral quick disintegrating tablet having rapid disintegration in the oral cavity. Furthermore, the stability of the active ingredient is improved. The collapsible compression molded product of the present invention can be used in fields such as medicine and food.

  There are several known methods for producing an orally rapidly disintegrating tablet, including a wet tableting method, a tableting warming method, and a dry tableting method. 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. In addition to the usual compression molding, the process also involves processes such as humidification, warming, and drying, and thus there is a problem in productivity.

On the other hand, as a method for producing an intraorally rapidly disintegrating tablet by a dry tableting method, an ordinary preparation facility can be used, and several production methods 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 by a binder, and the components of the particles are not uniformly dispersed in the particles, so that the rapidly disintegrating tablet in the oral cavity However, the moldability and disintegration properties suitable for the above have not been fully satisfied.

International Publication No. 00/57857 Pamphlet JP 2001-58944 A

  The present invention is a fast disintegrating compression molding that is easy to manufacture, has sufficient hardness that does not cause problems during manufacturing, transportation, and formulation, good disintegration in the oral cavity, and sufficient hardness and disintegration time under opening. The purpose is to provide goods.

  As a result of researches to achieve the above object, the present inventor has found that (a) an active ingredient, (b) one or more saccharides selected from mannitol, xylitol, and lactose, (c) a disintegrant, (c) an excipient (D) Lubricant, and if necessary, (e) Inorganic powder mixed at a specific ratio and compression molded into a cylindrical shape must have good disintegration, sufficient hardness and moisture resistance I found.

  Furthermore, (a) a granulated product containing an active ingredient, (b) one or more saccharides selected from mannitol, xylitol and lactose, (c) a disintegrant, (c) an excipient, and (e ) A granulated product made of inorganic powder, and a compression molded product obtained by mixing and compression molding a lubricant and compression molding into a cylindrical shape have good disintegration, sufficient hardness and moisture resistance.

  These compression moldings are surprisingly free from problems that occur when the content of the active ingredient is high, have sufficient hardness that does not cause problems during production and transportation, and have good disintegration properties in the oral cavity. At the same time, the inventors have discovered that the production method is highly productive.

  The “fast disintegrating compression molding” in the present invention means a tablet that can disintegrate rapidly in the oral cavity, for example, within 120 seconds, more preferably within 60 seconds, and even more preferably within 30 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 fast-disintegrating compression-molded product of the present invention has a high content of active ingredients as compared with conventional fast-disintegrating tablets, has sufficient hardness that does not cause problems during production and transportation, and decreases hardness under opening. In spite of being small, 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 foods such as pharmaceuticals and supplements that require rapid disintegration in the oral cavity.

  The rapidly disintegrating compression molded product of the present invention comprises (a) an active ingredient, (b) one or more saccharides selected from mannitol, xylitol, and lactose, (c) a disintegrant, (c) an excipient, (d) Lubricant, if necessary (f) A rapidly disintegrating compression molded product made of inorganic powder.

  The rapidly disintegrating compression molded product is preferably composed of granulated particles appropriately formed from each component. The granulated particles include (b) one or more saccharides selected from mannitol, xylitol, and lactose, (c) a disintegrant, (c) an excipient, and (f) an inorganic powder as required. , (A) active ingredient, (b) one or more saccharides selected from mannitol, xylitol, lactose, (c) disintegrant, (c) excipient, and (f) granulated from inorganic powder as required It is preferable to form granulated particles composed of one or more of (g) a binder, (h) a carrier, and (i) a coating agent in the particles and (a) the active ingredient, and then mix them. In particular, when the active ingredient has a bitter taste, the bitter taste can be suppressed or prevented by granulating. In addition, it is possible to prevent the tableting trouble by making it possible to accurately mix the content of the active ingredient by granulation and by making the particle diameters of the ingredients put into the die during compression molding uniform.

  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 saccharide commonly used in pharmaceuticals, such as mannitol, xylitol, sorbitol, erythritol, maltitol, lactose, sucrose, glucose, fructose, maltose, trehalose, and palatinit. And at least one selected from palatinose and the like, and mannitol, xylitol, and lactose are preferable. These saccharides are preferably granulated and should contain an amorphous part. The formability is improved by granulation, and the non-crystalline part imparts bonding properties. What formed the composite particle which consists of the above-mentioned saccharides other than a mannitol in mannitol is preferable. The formation of composite particles can have both an amorphous part and granulation. As sugars combined with mannitol, xylitol and lactose are most preferable. 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 saccharides, those containing amorphous are suitable because the tablet has good moldability, high hardness and short disintegration time, and the proportion of amorphous is 1 to 90%, preferably 5 to 60%. Most preferably, it is 20 to 40%. The ratio of amorphous is determined from X-RD or mass dissolved in water at the time of production.

  As the disintegrant in the present invention, those usually used as disintegrants in pharmaceuticals can be used. For example, adipic acid, alginic acid, sodium alginate, pregelatinized starch, erythritol, fructose, sodium carboxymethyl starch, carmellose, carme Loin calcium, carmellose sodium, hydrous silicon dioxide, agar, xylitol, guar gum, calcium citrate, croscarmellose sodium, crospovidone, synthetic aluminum silicate, magnesium aluminate silicate, crystalline cellulose, crystalline cellulose carmellose sodium, Wheat starch, rice starch, cellulose acetate phthalate, dioctylsodium sulfosuccinate, sucrose fatty acid ester, magnesium alumina hydroxide, steari Calcium stearate, polyoxyl stearate, sorbitan sesquioleate, gelatin, shellac, sorbitol, sorbitan fatty acid ester, talc, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, dextrin, sodium dehydroacetate, corn starch, tragacanth, trehalose, lactose, Maltose, sucrose, hydrotalcite, honey, palatinit, palatinose, potato starch, hydroxyethyl methylcellulose, hydroxypropyl starch, hydroxypropylcellulose, glucose, bentonite, partially pregelatinized starch, monosodium fumarate, polyethylene glycol, polyoxyethylene Hardened castor oil, polyoxyethylene / polyoxypropylene / glycol, polysorbate , Polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, maltitol, D-mannitol, anhydrous citric acid, silicic anhydride, magnesium aluminate metasilicate, methylcellulose, glyceryl monostearate, sodium lauryl sulfate, carmellose, Any of these may be used alone, but two or more of them can be blended.

  More preferably, crystalline cellulose, crystalline cellulose / carmellose sodium, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, magnesium aluminate metasilicate, magnesium aluminate silicate, synthetic aluminum silicate, precipitated calcium carbonate, hydroxylated Alumina magnesium, 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, Palatinite, palatinose, agar, shellac, tragacanth, carmellose.

  Most preferably, it is at least one selected from crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose, crystalline cellulose and carmellose. Any of these may be used alone, but more preferably used 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.

  As the excipient of the present invention, those commonly used as excipients in pharmaceuticals can be used, such as starch acrylate, L-aspartic acid, aminoethylsulfonic acid, aminoacetic acid, candy (powder), Gum arabic, gum arabic powder, alginic acid, sodium alginate, pregelatinized starch, inositol, ethyl cellulose, ethylene vinyl acetate copolymer, erythritol, sodium chloride, olive oil, kaolin, cacao butter, casein, fructose, pumice grain, carmellose, carmellose sodium , Hydrous silicon dioxide, dry yeast, dry aluminum hydroxide gel, dry sodium sulfate, dry magnesium sulfate, agar, agar powder, xylitol, citric acid, sodium citrate, disodium citrate, glycerin, glyceroline Calcium, sodium gluconate, L-glutamine, clay, clay granules, croscarmellose sodium, crospovidone, aluminum silicate, synthetic aluminum silicate, hydroxypropyl starch, crystalline cellulose, magnesium aluminate silicate, calcium silicate, silica Magnesium acid, 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 flour, rice (rice flour), rice starch, potassium acetate, calcium acetate, cellulose acetate phthalate, safflower oil, white beeswax, zinc oxide, titanium oxide, magnesium oxide, β-cyclode Xistrin, dihydroxyaluminum aminoacetate, 2,6-di-t-butyl-4-methylphenol, dimethylpolysiloxane, tartaric acid, potassium hydrogen tartrate, baked gypsum, sucrose fatty acid ester, magnesium alumina hydroxide, aluminum hydroxide gel, Coprecipitate of aluminum hydroxide sodium hydrogen carbonate, 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, triphosphate cal Um, soybean oil, soybean oil unsaponifiable, soybean lecithin, skim milk powder, talc, ammonium carbonate, 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, hydrotalcite, maltose, white shellac, white petrolatum, hakudo, sucrose, sucrose starch 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, grape , Glucose hydrate, partially pregelatinized starch, pullulan, propylene glycol, powdered reduced maltose water candy, 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 granulate, Magnesium aluminate metasilicate, Methyl cellulose, Cottonseed powder, Cottonseed oil, Owl, Monosteari Aluminum phosphate, glyceryl monostearate, sorbitan monostearate, silicic anhydride, medicinal charcoal, peanut oil, aluminum sulfate, calcium sulfate, granular limestone, granular corn starch, liquid paraffin, dl-malic acid, calcium monohydrogen phosphate One or more of calcium hydrogen phosphate, potassium hydrogen phosphate, sodium hydrogen phosphate, etc., and any of these may be used alone, but two or more may be blended.

More preferably, crystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, 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, Corn starch, potato starch, partially pregelatinized starch, hydroxypropyl starch, mannitol, xylitol, sorbitol, erythritol, mulch Lumpur, lactose, sucrose, glucose, fructose, maltose, trehalose, palatinit, palatinose, agar, shellac, and tragacanth.
More preferably, crystalline cellulose, croscarmellose sodium, crospovidone, magnesium aluminate metasilicate, magnesium aluminate silicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granule, calcium silicate Aluminum silicate, silicic anhydride, hydrotalcite.

  The inorganic powder of the present invention is preferably a pharmaceutically acceptable inorganic powder having an average pore diameter of 100 nm or less and containing at least one of aluminum, magnesium and calcium, such as magnesium aluminate metasilicate and silica. Magnesium acid aluminate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granulation, hydrotalcite, aluminum silicate, calcium phosphate, calcium carbonate, calcium silicate, magnesium silicate, magnesium oxide, water It is at least one selected from magnesium oxide, alumina magnesium hydroxide, 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, calcium hydrogen phosphate, and calcium carbonate. The average particle diameter of these inorganic powders 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.

(B) One or more saccharides selected from mannitol, xylitol, and lactose, (c) a disintegrant, and (c) the amount of granulated particles comprising an excipient is 100 parts by weight of the entire granulated particles. 40 to 90 parts by weight of sugar, 5 to 40 parts by weight of disintegrant, and 1 to 40 parts by weight of excipient, preferably 50 to 80 parts by weight of sugar and 100 parts by weight of disintegrant with respect to 100 parts by weight of the whole granulated particles. 10 to 36 parts by weight and 2 to 15 parts by weight of excipients. More preferably, they are 62-78 weight part of saccharides, 18-34 weight part of disintegrating agent, and 3-8 weight part of excipient | filler with respect to 100 weight part of the whole granulated particle.
(B) One or more saccharides selected from mannitol, xylitol, and lactose, (c) disintegrant, (c) excipient, (f) The blended amount of granulated particles composed of inorganic powder is For 100 parts by weight, 40 to 90 parts by weight of saccharide, 5 to 40 parts by weight of disintegrant, 1 to 40 parts by weight of excipient, 1 to 30 parts by weight of inorganic powder, and preferably 100 parts by weight of the entire granulated particles The amount of sugar is 50 to 80 parts by weight, the disintegrant is 10 to 36 parts by weight, the excipient is 2 to 15 parts by weight, and the inorganic powder is 2 to 15 parts by weight. More preferably, it is 62 to 78 parts by weight of saccharide, 18 to 34 parts by weight of a disintegrant, 3 to 8 parts by weight of an excipient, and 3 to 8 parts by weight of an inorganic powder with respect to 100 parts by weight of the entire granulated particles.

  The granulated particles mentioned above are (b) one or more saccharides selected from mannitol, xylitol, and lactose, (c) a disintegrant, (d) an excipient, and (g) inorganic powder in the presence of water as required. It is obtained by granulating below. The structure of the granulated particles is as follows: (b) one or more saccharides selected from mannitol, xylitol, and lactose, (c) a disintegrant, (c) an excipient, and (g) inorganic powder as a saccharide as required. A combined structure can be taken. As another structure, (c) a disintegrating agent, and (g) inorganic powder as required may be dispersed in a saccharide matrix.

  Granulated particles having a structure dispersed in a saccharide matrix have a structure in which a disintegrant, an excipient and an inorganic powder are homogeneously dispersed in a matrix containing an saccharide alone or an amorphous substance composed of two or more saccharides. . 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. Further, by having a structure in which the disintegrant and the inorganic powder 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 powder draw minute moisture into the tablet and effectively disintegrate A that is dispersed together to provide good rapid disintegration in the oral cavity. Can do.

  The granulated particles can be blended with an active ingredient described later and other ingredients that can be blended with a pharmaceutical within a range that does not impair the disintegration property described later. It is 0-80 weight part with respect to a total of 100 weight part of a disintegrating agent, Preferably it is 0-70 weight part, More preferably, it is 0-60 weight part.

  The above-mentioned granulated particles can be produced by a production method capable of obtaining desired physical properties, and are generally used methods such as spray drying, fluidized bed granulation drying, stirring granulation, rolling granulation, It can be produced by a wet granulation method such as a wet extrusion 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, inorganic powder, and a disintegrating agent according to a conventional method. More specifically, after the saccharide is previously dissolved or dispersed in an aqueous solvent, the dispersion obtained by uniformly dispersing the disintegrant and the inorganic powder 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 thus obtained can be appropriately adjusted depending on the concentration of the aqueous solution or aqueous dispersion, spray drying method, drying conditions, etc., but is 1 to 500 μm, preferably 5 to 300 μm. More preferably, it is 10 to 200 μm, and more preferably 30 to 200 μm, which can prevent roughness in the oral cavity.

  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. . 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.

The drug can be incorporated into the compression molding composition of the present invention alone or granulated. As the granulation form of the drug, (1) the surface of the drug alone is coated with a coating agent, (2) the drug and other ingredients are granulated, and (3) the drug and other ingredients are granulated, and this surface is coated. (4) The drug can be adsorbed and contained in the carrier.
The drug can be imparted with the performance normally used in pharmaceuticals for imparting sustained release, enteric properties, and rapid release by coating, loading on a carrier, and dispersion in a matrix.

  (1) In the form of coating the surface of the drug alone with the coating agent, the drug alone is coated with the coating agent or coated with powder. As the coating method, a dry method or a wet method can be used. In the dry method, a drug is mixed with a coating agent or a coating powder, and particles are adhered to the surface of the drug. The wet method is a method in which the drug and the coating agent or coating powder are both suspended in water and dried, or a method in which the coating agent or coating powder is dissolved and suspended in water and mixed, dried, sprayed or dried with the drug. Do.

  (2) The form in which the drug and other components are granulated is a form formed by granulation with the drug and a binder and / or excipient. The granulation method can be performed by a dry method or a wet method. The dry method is a method in which a drug and a binder and / or excipient are mixed and rectified, and a roller compactor or the like can be used. In the wet method, the drug and the binder and / or excipient are both suspended in water and dried, and the binder and / or drug are dissolved and suspended in water and mixed with the drug and / or excipient.・ Use the drying method. Examples thereof include spray drying, fluidized bed granulation drying, stirring granulation, rolling granulation, wet extrusion granulation.

  Examples of the binder include, for example, ethyl acrylate / methyl methacrylate copolymer emulsion, acetylglycerin fatty acid ester, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, aminoethyl sulfonic acid, candy (powder), gum arabic Gum arabic powder, sodium alginate, propylene glycol ester alginate, pregelatinized starch, ester gum H, ethyl cellulose, oat powder, hydrolyzed gelatin powder, sodium caseinate, fructose, caramel, karaya gum powder, carboxyvinyl polymer, carboxymethyl ethyl cellulose, carboxy Methyl starch sodium, carmellose, carmellose sodium, hydrous silicon dioxide, agar, ginger powder, xanthan gum, beef tallow hardened oil, guar gum Glycerin, synthetic aluminum silicate, light anhydrous silicic acid, hydroxypropylcellulose containing light anhydrous silicic acid, crystalline cellulose, hydrogenated oil, copolyvidone, sesame oil, wheat flour, wheat starch, rice (rice flour), rice starch, vinyl acetate resin, phthalate acetate Acid cellulose, honey beeswax, oxidized starch, dioctyl sodium sulfosuccinate, dihydroxyaluminum amino acetate, potassium sodium tartrate, sucrose fatty acid ester, stearyl alcohol, stearic acid, calcium stearate, polyoxyl stearate, sorbitan sesquioleate, cetanol, Gelatin, shellac, sorbitan fatty acid ester, D-sorbitol, soybean lecithin, calcium carbonate, simple syrup, dextrin, starch (soluble), tomato Sorghum starch, tragacanth, paraffin, potato starch, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, piperonyl butoxide, butylphthalyl butanol glycolate, Glucose, partially pregelatinized starch, fumaric acid, pullulan, propylene glycol, pectin, sodium polyacrylate, partially neutralized polyacrylic acid, polyethylene glycol, polyoxyethylene / polyoxypropylene / glycol, polysorbate, polyvinyl acetal diethylaminoacetate, Polyvini One or more of alcohol (completely saponified product), polyvinyl alcohol (partially saponified product), polyvinylpyrrolidone, polybutene, sodium polyphosphate, D-mannitol, water candy, light anhydrous silicic acid, magnesium metasilicate aluminate, Any of these may be used alone, but two or more of them can be blended.

  Preferred are starch, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, crystalline cellulose, gelatin, pullulan, gum arabic powder, and low-substituted hydroxypropylcellulose. When adjusting the aqueous solution of a binder, the concentration of the binder is preferably 0.05 to 20%, more preferably 0.05% to 15%.

  The active ingredient-containing particles obtained here can be coated with a coating agent or the like. The coating method may be performed by forming a continuous layer on the surface of the active ingredient-containing particles, for example, by spraying a solution in which the coating agent is dissolved / suspended in water on the surface of the active ingredient-containing particles. it can. Moreover, you may spray the heat-melted coating agent on the surface of active ingredient containing particle | grains. For example, spray drying method, fluidized bed granulation drying method, stirring granulation method, rolling granulation and the like can be mentioned.

The coating agent of the present invention can be selected from a water-soluble polymer, a water-insoluble polymer, a gastric polymer, and a thermoplastic substance.
Examples of water-soluble polymers include natural polymers such as gum arabic powder, gelatin, pullulan, dextrin, sodium carboxymethyl starch, sodium alginate and polysaccharides and derivatives thereof, carmellose, carmellose sodium, carmellose calcium, Examples thereof include cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose, and carboxymethylcellulose, and water-soluble vinyl derivatives such as polyvinylpyrrolidone and polyvinyl alcohol.

  The water-insoluble polymer is not particularly limited, but water-insoluble cellulose ethers such as ethyl cellulose, ethyl methyl cellulose, ethyl propyl cellulose, isopropyl cellulose, butyl cellulose, benzyl cellulose, cyanoethyl cellulose, ethyl acrylate, methyl methacrylate, methacryl. Examples thereof include water-insoluble acrylic acid copolymers such as trimethylammonium ethyl acrylate copolymer and ethyl acrylate / methyl methacrylate copolymer dispersion. These water-insoluble polymers having an appropriate viscosity are easy to coat. When the viscosity of a 2% by weight aqueous solution is measured at 0 ° C. according to the 14th revision of the Japanese Pharmacopoeia, it is usually 1-100 square mm / Second, preferably 5 to 60 square mm / second, more preferably 10 to 40 square mm / second, more preferably 20 to 30 square mm / second. The blending amount of the water-soluble polymer is usually 3 to 45% by weight, preferably 3 to 40% by weight, based on 100% by weight of the total composition of the drug-containing particles.

  Examples of the gastric polymer include aminoacetal compounds such as polyvinyl acetal and diethylaminoacetate, aminoalkyl methacrylate copolymer E, and mixtures thereof.

  Examples of enteric polymers include enteric cellulose esters such as cellulose acetate propionate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, and methacrylic acid copolymers. Examples thereof include enteric acrylic copolymers such as LD, methacrylic acid copolymer L, and methacrylic acid copolymer S.

  Thermoplastic substances such as hardened castor oil, hardened coconut oil, hardened rapeseed oil, hardened oils such as beef tallow, waxy substances such as paraffin, carnauba wax, beeswax, beeswax, bleached beeswax, paraffin, stearic acid, laurin Higher fatty acids such as acid, myristic acid and palmitic acid, fatty acid esters such as acetyl glycerin fatty acid ester, glycerin fatty acid ester, propylene glycol fatty acid ester and glyceryl monostearate, and higher alcohols such as cetyl alcohol and stearyl alcohol It is done.

  In addition, when an enteric polymer is used, a disintegrant can be added to improve dissolution. As the disintegrant, the disintegrants described above can be used. The content of the disintegrant is 10% to 50%, preferably 15% to 45%, based on the entire active ingredient-containing particles.

  (4) The form in which the drug is adsorbed and included in the carrier is a method in which the drug and the carrier are mechanically strongly mixed (mechanochemical method), a method in which the drug is dissolved in a soluble solvent and adsorbed on the carrier, and the drug is melted. It can be formed from a method of adsorbing on a carrier. The particles may be further coated.

  As the carrier, porous components can be used as described above for the excipients and inorganic powders. Porous means that the BET specific surface area is 1-1000 square m / g, preferably 5-500 square m / g, most preferably 30-400 square m / g. The particle diameter is 20 to 300 μm, preferably 30 to 150 μm.

  In order to improve the elution of the active ingredient at a desired site, a solubility improving ingredient such as a surfactant can be added to the active ingredient-containing particles. Examples of the surfactant include polysorbate, sorbitan ester, poloxamer block copolymer, PEG-35 castor oil, PEG-40 hydrogenated castor oil, caprylcaproyl macrogol-8 glyceride, PEG-8 caprylic acid / capric acid glyceride, Sodium lauryl sulfate, dioctyl sulfate oxalate, polyethylene lauryl ether, ethoxydiglycol, propylene glycol mono-dicaprylate, glycerol monocaprylate; glyceryl ethoxylated fatty acid (C8-C18), glyceryl oleate, glyceryl linoleate, caprylic acid / Glyceryl caprate, glyceryl monooleate, glyceryl monolaurate, caprylic / capric triglyceride, ethoxylated nonylphenol, PEG-stearate 8-50), olive oil PEG-6 esters, triolein PEG-6 esters, lecithin, and a d-alpha tocopheryl polyethylene glycol succinate.

  The amount of the active ingredient in the active ingredient-containing particles is 1 to 30% by weight, preferably 4 to 25% by weight, based on 100% by weight of the total composition of the particles. The amount of other components / carriers such as excipients in the active ingredient-containing particles is 40 to 90% by weight, preferably 60 to 90% by weight with respect to 100% by weight of the total composition. The average particle diameter of the active ingredient-containing particles is 10 to 300 μm, preferably 50 to 200 μm.

  In the production of the rapidly disintegrating compression molded product in the present invention, the lubricant may be mixed with the other components and then compression molded, but the lubricant is mixed with the other components. Without being applied, it can be manufactured by a method (external lubrication method) in which the material is applied in advance to the surface of the punch and the wall of the die and compression molded (external lubrication method), and desired hardness and disintegration can be imparted. The method of applying the lubricant to the mortar can be performed by a conventionally known method or machine.

  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 active ingredient is not particularly limited, and is a central nervous system drug, peripheral nervous system drug, sensory organ drug, cardiovascular drug, respiratory organ drug, gastrointestinal drug, hormone drug, urogenital drug, etc. Individual organ system drugs, vitamins, nourishing tonics, blood and body fluids, other metabolic drugs, cell activating drugs, tumor drugs, radiopharmaceuticals, allergic drugs, and other tissue cell functional drugs , Herbal medicines, Kampo medicines, other medicines based on herbal medicines and Kampo medicines, antibiotics, chemotherapeutics, biologicals, drugs against parasites, drugs against other pathogenic organisms, pharmaceuticals for dispensing, diagnostics, public Examples include hygiene drugs, in-vitro diagnostic drugs, other drugs not intended for treatment, alkaloid narcotics (natural narcotics), and non-alkaloid narcotics. .

  Among the drugs for central nervous system, hypnotic sedatives / anti-anxiety drugs include alprazolam, estazolam, dexmedetomidine hydrochloride, rilmazafone hydrochloride, oxazolam, quazepam, tandospirone citrate, cloxazolam, dipotassium chlorazepate, chlordiazepoxide, diazepam, potassium bromide , Calcium bromide, sodium bromide, zolpidem tartrate, sodium secobarbital, zopiclone, tofisopam, triazolam, triclofos sodium, nitrazepam, nimetazepam, pasciflora extract, barbital, haloxazolam, phenobarbital, prazepam, fludiazepam, flutazolam, flutopram Flunitrazepam, flurazepam hydrochloride, brotizolam, bromazepam, bromovaleryl urea, pentobarbital Chloral hydrate, midazolam, mexazolam, medazepam, ethyl loflazepate, lorazepam, and the like lormetazepam.

Examples of antiepileptic agents include acetylphenetride, gabapentin, carbamazepine, clonazepam, clobazam, sultiam, zonisamide, trimetadione, sodium valproate, phenytoin, and primidone.
Antipyretic analgesic and anti-inflammatory agents include actarit, aspirin, acetaminophen, ampiroxicam, ibuprofen, indomethacin, indomethacin farnesyl, etenzamide, etodolac, epilysole, emorphazone, tramadol, buprenorphine hydrochloride, oxaprozin, ketoprofen, sodium salicylate, zaltoprofen sodium, zaltoprofen sodium Sulindac, sulpyrine hydrate, celecoxib, thiaprofenic acid, thiaramide hydrochloride, tenoxicam, naproxen, bucolome, pentazocine, mefenamic acid, meloxicam, mofezolac, loxoprofen sodium hydrate and the like.

  Antiparkinson agents include amantadine hydrochloride, selegiline hydrochloride, talipexol hydrochloride, proheptin hydrochloride, pramipexole hydrochloride hydrate, masaticol hydrochloride, methixene hydrochloride, entacapone, cabergoline, trihexyphenidyl hydrochloride, droxidopa, biperidene, bromocriptine mesylate, Examples include pergolide mesylate and levodopa.

As neuropsychiatric agents, amitriptyline hydrochloride, amoxan, aripiprazole, imipramine hydrochloride, etizolam, sultopride hydrochloride, sertraline hydrochloride, trazodone hydrochloride, paroxetine hydrochloride hydrate, flolopipamide hydrochloride, perospirone hydrochloride hydrate, mianserin hydrochloride, milnaci hydrochloride Plan, methylphenidate hydrochloride, mosapramine hydrochloride, moperon hydrochloride, lofepramine hydrochloride, oxypertin, olanzapine, carpipramine, clocapramine hydrochloride hydrate, clothiazepam, clomipramine hydrochloride, chlorpromazine, spiperone, sulpiride, zotepine, lithium carbonate, timiperone, haloperidol decanoate , Nemonapride, nortriptyline hydrochloride, haloperidol, hydroxyzine hydrochloride, hydroxyzine pamoate, pimozide, Quetiapine oxalate, fluphenazine, prochlorperazine, propericazine, bromperidol, perphenazine, maprotiline hydrochloride, stipiline maleate, trifloperazine maleate, trimipramine maleate, fluvoxamine maleate, modafinil, risperidone, levomepromazine Etc.
Other drugs for the central nervous system include thioprid hydrochloride, donepezil hydrochloride, tartilelin hydrate, terguride, mazindol, riluzole and the like.

Among the peripheral nervous system drugs, examples of the local anesthetic include ethyl aminobenzoate, bupivacaine hydrochloride, ropivacaine hydrochloride hydrate, oxesazein, procaine hydrochloride, mepivacaine hydrochloride, lidocaine and the like.
Examples of the autonomic nerve agent include ambenonium chloride, oxapium iodide, distigmine bromide, propantheline bromide, and mepenzolate bromide.
Antispasmodic agents include afroqualone, eperisone hydrochloride, piperidyl hydrochloride, tizanidine hydrochloride, timepidium bromide hydrate, tolperisone hydrochloride, baclofen, papaverine hydrochloride, butyl scopolamine bromide, butropium bromide, furopropion, N-methyl sulfate Examples include scopolamine.

  Examples of otolaryngological agents for sensory organs include amlexanox, lomefloxacin hydrochloride, ofloxacin, chloramphenicol and the like. Examples of the antipruritic agent include isoproterenol hydrochloride, diphenidol hydrochloride, betahistine mesylate and the like.

Among cardiovascular drugs, examples of the cardiotonic agent include aminophylline hydrate, ethylephrine hydrochloride, isoproterenol hydrochloride, corintheophylline, digitoxin, digoxin, denopamine, pimobendan, proxyphylline, vesnarinone, methyldigoxin, ubidecalenone and the like.
As an arrhythmia agent, ajmaline, acebutolol hydrochloride, atenolol, alprenolol hydrochloride, arotinolol hydrochloride, aprindine hydrochloride, amiodarone hydrochloride, sotalol hydrochloride, pilcainide hydrochloride, propafenone hydrochloride, bepridil hydrochloride, oxprenolol hydrochloride, Carteolol hydrochloride, quinidine sulfate hydrate, cibenzoline succinate, flecainide acetate, disopyramide, nadolol, pindolol, bufetrol hydrochloride, bisoprolol fumarate, procainamide hydrochloride, propranolol hydrochloride, verapamil hydrochloride, mexiletine hydrochloride, etc. Is mentioned.

  Examples of the diuretic include azosemide, chlorthalidone, spironolactone, torasemide, triamterene, trichlormethiazide, hydrochlorothiazide, pyrethanide, bumetanide, furosemide, benzylhydrochlorothiazide, mefluside, mozabaptan hydrochloride and the like.

Examples of blood lowering agents include azelnidipine, alacepril, alanidipine, indapamide, amosulalol hydrochloride, imidapril hydrochloride, efonidipine hydrochloride, quinapril hydrochloride, seriprolol hydrochloride, tirisolol hydrochloride, temocapril hydrochloride, terazosin hydrochloride, delapril hydrochloride, varnidipine hydrochloride, prazosin hydrochloride, hydrochloric acid Betaxolol, benazepril hydrochloride, bevantolol hydrochloride, manidipine hydrochloride, labetalol hydrochloride, olmesartan medoxomil, cadralazine, captopril, carteolol hydrochloride, carbendilol, candesartan cilexetil, guanabenz acetate, clonidine hydrochloride, cilazapril, cilnidipine hydrochloride, ternidipine hydrochloride, Salt hydrate, trandolapril, tripamide, nicardipine hydrochloride, nipyrazilol, nil Dipine, valsartan, hydralazine hydrochloride, pindolol, felodipine, budralazine, bunazosin hydrochloride, propranolol hydrochloride, perindopril erbumine, benbutrol sulfate, enalapril maleate, bopindolol malonate, doxazosin mesylate, meticrane, methyldopa hydrate, metoprolol Examples thereof include tartrate, lisinopril hydrate, resinamine, reserpine, and losartan potassium.
Examples of the vasoconstrictor include rizatriptan benzoate, midodrine hydrochloride, dihydroergotamine mesylate, eletriptan hydrobromide, sumatriptan, zolmitriptan, and the like.

As vasodilators, isosorbide mononitrate, inositol hexanicotinate, isoxsuprine hydrochloride, dipyridamole, isosorbide nitrate, dilazep hydrochloride hydrate, diltiazem hydrochloride, trapidil, trimetazidine hydrochloride, nicorandil, nisoldipine, nitrendipine, nitroglycerin, nifedipine, Examples include amlodipine besylate, benidipine hydrochloride, hepronicart, verapamil hydrochloride, and the like.
Examples of drugs for hyperlipidemia include atorvastatin calcium hydrate, ezemitib, elastase ES, clinofibrate, clofibrate, colestimide, simvastatin, soysterol, sodium dextran sulfate, nicomol, niceritrol, pivastatin calcium, fenofibrate, Examples include pravastatin sodium, fluvastatin sodium, probucol, bezafibrate, polyenephosphatidylcholine, rosuvastatin calcium and the like.

  Other cardiovascular drugs include ifenprodil tartrate, indomethacin, sevelamer hydrochloride, fasudil hydrochloride hydrate, lomerizine hydrochloride, gamma-aminobutyric acid, dihydroergotoxin mesylate, tocopherol nicotinate, nicergoline, bosentan hydrate, Examples include meclofenoxate hydrochloride and amethinium methylsulfate.

Among the respiratory drugs, antitussives include ephedrine hydrochloride, clofedanol hydrochloride, cloperastine, dimemorphan phosphate, dextromethorphan hydrobromide hydrate, pentoxyberine citrate, benproperine phosphate Etc.
Examples of the leavening agent include L-ethylcysteine hydrochloride, L-methylcysteine hydrochloride, L-carbocysteine, ambroxol hydrochloride, fudostein, bromohexine hydrochloride and the like.
Examples of the antitussive expectorant include eprazinone hydrochloride, guaifenesin, codeine phosphate hydrate, and tipepidine hibenzate.

Bronchodilators include aminophylline hydrate, isoproterenol hydrochloride, clenbuterol hydrochloride, mabuterol hydrochloride, methoxyphenamine hydrochloride, orciprenaline sulfate, salbutamol sulfate, fenoterol hydrobromide, tubuterol, theophylline, terbutaline sulfate, triflate. Metoquinol hydrochloride hydrate, procaterol hydrochloride hydrate, formoterol fumarate hydrate and the like.
Examples of the gargle include sodium azulene sulfonate.

  Among the drugs for digestive organs, examples of the antidiarrheal agent / intestinal adjuster include loperamide hydrochloride, dimethicone, resistant lactic acid bacteria preparation, bifidobacteria preparation, berberine chloride hydrate, butyric acid bacteria preparation and the like.

Peptic ulcer agents include sodium azulene sulfonate, aldioxa, bexinate hydrochloride betadex, omeprazole, ornoprostil, gefarnate, cimetidine, sucralfate hydrate, sulpiride, cetraxate hydrochloride, sofalcone, teprenone, troxipide, Nizatidine, pirenzepine hydrochloride hydrate, famotidine, plaunotol, proglumide, polaprezinc, irsogladine maleate, misoprostol, methylmethionine sulfonium chloride, ranitidine hydrochloride, lafutidine, rabeprazole sodium, lansoprazole, clevopride malate, rebamipide hydrochloride Examples include salt.
Examples of the antacid include magnesium oxide, magnesium hydroxide, sodium hydrogen carbonate, precipitated calcium carbonate, magnesium metasilicate aluminate, and the like.

Laxatives include senna extract, sennoside, picosulfate sodium hydrate and the like.
Examples of the astringent include anethole trithione, ursodeoxycholic acid, trepibutone, nicotinic acid / naphthyl acetic acid, and the like.
Other drugs for digestive organs include acamegasiwa extract, sodium azulenesulfonate, cetylpyridinium chloride, decalinium chloride, azacetron hydrochloride, itopride hydrochloride, indisetron hydrochloride, granisetron hydrochloride, cevimeline hydrochloride hydrate, tropisetron hydrochloride, ramosetron hydrochloride, ondansetron , Kitasamycin acetate, mosapride citrate, domifene bromide, dexamethasone, trimebutine maleate, domperidone, pilocarpine hydrochloride, polycarbophil calcium, mesalazine, metoclopramide and the like.

Examples of salivary gland hormone preparations, thyroid and parathyroid hormone agents include dry thyroid, thiamazole, propylthiouracil, liothyronine sodium, levothyroxine sodium hydrate and the like.
Examples of protein anabolic steroids include mestanolone and methenolone.

Examples of adrenal hormone agents include cortisone acetate, fludrocortisone acetate, dexamethasone, triamcinolone, hydrocortisone, prednisolone, betamazone, methylprednisolone, and the like.
Examples of male hormone agents include methyl testosterone.
Examples of follicular hormones and yellow hormone agents include allylestrenol, estriol, ethinyl estradiol, chlormadinone acetate, conjugated estrogens, medroxyprogesterone acetate, didrogesterone, norethisterone, pregnanediol, phosfestol, and the like.
Other hormonal agents include kallidinogenase, clomiphene citrate, cyclophenyl, danazol, trilostane, finasteride and the like.

Among the drugs for genitourinary organs, reproductive organ agents include estriol, clotrimazole, chloramphenicol, tinidazole, metronidazole and the like.
Examples of the uterine contractor include methyl ergometrimalenate.
Examples of contraceptives include ethinyl estradiol norethisterone, ethinyl estradiol levonorgestrail, desogestrel ethinyl estradiol, and the like.

Examples of the agent for hemorrhoid diseases include venous vascular plexus extract, tribenoside, bromelain / tocopherol acetate, and merirot extract.
Other urogenital drugs include imidafenacin, vulgari extract, oxybutynin hydrochloride, vardenafil hydrochloride hydrate, propiverine hydrochloride, sildenafil citrate, solifenacin succinate, tolterodine tartrate, silodosin, cernitine pollen extract, tamsulosin hydrochloride, naphthopidyl , Flavoxate hydrochloride, ritodrine hydrochloride and the like.

  Other individual organ drugs include gamma-oryzanol, cephalatin and the like.

Among the vitamin preparations, examples of vitamin A and D preparations include alphacalcidol, calcitriol, vitamin A, and fare calcitriol.
Examples of the vitamin B1 agent include diceamine hydrochloride, octothiamine, thiamine disulfide, bisbenchamine, fursultiamine, and benfotiamine.

Examples of the vitamin B agent include cobamide, nicotinic acid, pantethine, hydroxocobalamin acetate, pyridoxine hydrochloride, flavin adenine dinucleotide, mecobalamin, folic acid, riboflavin butyrate, pyridoxal phosphate, and the like.
Examples of the vitamin C agent include ascorbic acid, and examples of the vitamin E agent include tocopherol succinate calcium and tocopherol acetate.
Examples of vitamin K agents include phytonadione and menatetrenone.
Examples of other vitamin agents include astaxanthin, fucoxanthin, lutein and the like.

Among the nutritional tonics, examples of calcium agents include calcium L-aspartate and calcium lactate hydrate.
Examples of the inorganic preparation include potassium L-aspartate, potassium chloride, sodium ferrous citrate, potassium gluconate, iodine lecithin, iron sulfate hydrate and the like.

Among the blood / body fluid drugs, hemostatic agents include sodium carbazochrome sulfonate hydrate, tranexamic acid, adrenochrome monoaminoguanidine mesylate and the like.
Examples of the blood coagulation inhibitor include warfarin potassium.
Other drugs for blood and body fluids include aspirin, ethyl icosapentate, sarpogrelate hydrochloride, cilostazol, ticlopidine hydrochloride, beraprost sodium, limaprost alphadex, clopidogrel sulfate, and the like.

Among the other metabolic drugs, examples of the liver disease agent include liver hydrolyzate, dichloroacetate diisopyramine, thiopronin, disodium protoporphyrin, malotilate and the like.
Examples of the antidote include disodium calcium edetate, glutathione, sodium hydrogen carbonate, and folinate calcium.

Examples of therapeutic agents for gout include allopurinol, colchicine, probenecid, and benzbromarone.
Examples of the enzyme preparation include semi-alkaline proteinase, serrapeptase, pronase, bromelain, lysozyme hydrochloride and the like.

Diabetes agents include acarbose, acetohexamide, pioglitazone hydrochloride, buformin hydrochloride, gliclazide, glyclopyramide, glibutol, glibenclamide, glimepiride, chlorpropamide, tolbutamide, nateglinide, voglibose, miglitol, mitiglinide calcium hydrate, metformin hydrochloride Etc.
Other metabolic drugs include azathioprine, adenosine triphosphate disodium, alendronate sodium hydrate, inosine pranobex, ipriflavone, etidronate disodium, epalrestat, everolimus, L-cysteine, levocarnitine chloride, hydrochloric acid Raloxifene, camostat mesylate, cyclosporine, tacrolimus, mizoribine, methotrexate, risedronate sodium hydrate, leflunomide and the like.

Examples of cell stimulants include adenine.
Tumor drugs include cyclophosphamide hydrate, melphalan, estramustine phosphate sodium, capecitabine, carmofur, tegafur, fluorouracil, methotrexate, fludarabine phosphate, etoposide, acegraton, anastrozole, exemestane, fadrazole hydrochloride Examples include hydrate, tamoxifen citrate, toremifene citrate, tamibarotene, gefitinib, tamibarotene, bicalutamide, flutamide, procarbazine hydrochloride, imatinib mesylate, letrozole and the like.

  Allergic drugs include alimemazine, triprolidine hydrochloride, clemastine fumarate, chlorpheniramine maleate, diphenhydramine hydrochloride, cycloheptazine hydrochloride hydrate, promethazine hydrochloride, homochlorcyclidine hydrochloride, mequitazine, aura Nophine, bucillamine, amlexanox, ibudilast, ebastine, azelastine hydrochloride, epinastine hydrochloride, ozagrel hydrochloride, olopatadine hydrochloride, cetirizine hydrochloride, fexofenadine hydrochloride, oxatomide, ketotifen fumarate, zafirlukast, seratrodast, suplatast tosilate, tranilast, tranilast, tranilast Emedastine acid, pranlukast hydrate, bepotastine besylate, pemirolast potassium, montelukast sodium, ramatroban, repirinast, ro Tagine and the like.

  Antibiotic preparations include vancomycin hydrochloride, amoxicillin hydrate, cephalexin, cefaclor, cefixime, cefcapene pivoxil hydrochloride hydrate, cefdinir, cefteram pivoxil, cefpodoxime proxetil, azithromycin, enoxacin, clarithromycin Cyclacillin, josamycin, roxithromycin, levofloxacin and the like.

  Examples of the synthetic antibacterial agent include moxifloxacin hydrochloride, lomefloxacin hydrochloride, ofloxacin, cipolofloxacin, nalidixic acid, norfloxacin, pipemidic acid hydrate, fleroxacin and the like.

Antiviral agents include acyclovir, adefovir pivoxil, efavirenz, emtricitabine, valacyclovir hydrochloride, entecavir hydrate, zanamivir hydrate, sanylvudine, didanosine, zidovudine, nevirapine, palivizumab, phosamprenavir calcium, saquinavir mesilate, Lamivudine, ritonavir, ribavirin, abacavir sulfate, oseltamivir phosphate, lopinavir ritonavir and the like.
Other chemotherapeutic agents include itraconazole, terbinafine hydrochloride, fluconazole and the like.

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

  Other ingredients that can be blended within the range that does not impair disintegration are usually blended in pharmaceuticals such as excipients, surfactants, lubricants, acidulants, sweeteners, corrigents, fragrances, colorants, and stabilizers. One or more of these can be blended. For example, surfactant (for example, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan fatty acid ester, polysorbate, glycerin fatty acid ester, sodium lauryl sulfate, etc.), foaming agent (for example, sodium bicarbonate, sodium carbonate, etc.) ), Coloring agents (eg, edible red No. 2, edible blue No. 2, edible yellow No. 5, edible lake pigment, iron sesquioxide, carmine, etc.), stabilizers (eg, sodium edetate, tocopherol, cyclodextrin, etc.) Etc. As these components, the corresponding components described in the Pharmaceutical Additives Dictionary (Pharmaceutical Daily) and the Japanese Pharmacopoeia can be used.

  In order to suppress astringency, sourness or bitterness derived from raw materials such as active substances, acidulants (eg, citric acid, tartaric acid, malic acid, ascorbic acid, etc.), sweeteners (eg, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, Acesulfame K, thaumatin, etc.), flavoring agents, flavors (for example, various fruit flavors including lemon oil, orange oil, strawberry and yogurt, mint, menthol, etc.). In addition, to suppress bitterness, lactic acid, gluconic acid, glycerophosphoric acid, citric acid, acetic acid, benzoic acid, formic acid, fumaric acid, butyric acid, isobutyric acid, malic acid, propionic acid and other organic acids and calcium salts Can do.

  The rapidly disintegrating compression-molded product of the present invention comprises one or more saccharides 70 selected from (a) 0.01 to 60 parts by weight of an active ingredient, (b) mannitol, xylitol, and lactose with respect to 100 parts by weight of the whole tablet. -90 parts by weight, (c) 1-25 parts by weight of disintegrant, (c) 1-25 parts by weight of excipient, (d) 0.01-5 parts by weight of lubricant, (f) inorganic powder 0 Consists of 25 parts by weight.

  The rapidly disintegrating compression molded product of the present invention preferably has a hardness of 40 to 200 N, more preferably 40 to 150 N, and still more preferably 40 to 120 N. The tableting pressure varies depending on the size of the tablet. For example, when a 200 mg tablet is tableted using a 8 mm diameter punch, the tablet has a hardness of 40 to 150 N when the tableting pressure is 100 to 1200 kgf. When the tableting pressure is 100 to 800 kgf, it has a hardness of 40 to 80N.

The rapidly disintegrating compression-molded product 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 disintegrating properties.
Since the rapidly disintegrating compression molded product 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 (Okada Seiko Co., Ltd. product).
[Tabletting disorder]
The mortar of the tableting machine and the tablet after tableting were observed to evaluate sticking and capping.

[Example 1]
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, and then spray dryer (L-8 type, Okawara) (Kako Koki Co., Ltd.) was used and spray dried at an outlet temperature of 80 ° C. to obtain white spherical granulated particles having good fluidity.
After mixing 32 parts by weight of the granulated particles with 20 parts by weight of aspirin and 48 parts by weight of crystalline cellulose, a suitable amount of magnesium stearate is mixed, and then tableted with a rotary tableting machine with a set hardness of 50 N, and a tablet having a weight of 200 mg and a diameter of 8 mm Got. The tablet hardness was 44.4 N, and the oral disintegration time was 22.3 seconds.

[Example 2]
After uniformly dispersing 65 parts by weight of mannitol, 5 parts by weight of xylitol, 8 parts by weight of crospovidone, 15 parts by weight of crystalline cellulose, and 7 parts by weight of magnesium aluminate metasilicate, a spray dryer (L-8 type, Okawara) (Kako Koki Co., Ltd.) was used and spray dried at an outlet temperature of 80 ° C. to obtain white spherical granulated particles having good fluidity.
After mixing 32 parts by weight of the granulated particles with 20 parts by weight of aspirin and 48 parts by weight of crystalline cellulose, a suitable amount of magnesium stearate is mixed, and then tableted with a rotary tableting machine with a set hardness of 50 N, and a tablet having a weight of 200 mg and a diameter of 8 mm Got. Tablet hardness was 46.5 N and oral disintegration time was 24.2 seconds.

[Example 3]
After uniformly dispersing 65 parts by weight of mannitol, 5 parts by weight of xylitol, 8 parts by weight of crospovidone, 15 parts by weight of crystalline cellulose, and 7 parts by weight of magnesium aluminate metasilicate, a spray dryer (L-8 type, Okawara) (Kako Koki Co., Ltd.) was used and spray dried at an outlet temperature of 80 ° C. to obtain white spherical granulated particles having good fluidity.
After mixing 32 parts by weight of the granulated particles with 20 parts by weight of aspirin and 48 parts by weight of crystalline cellulose, a suitable amount of magnesium stearate is mixed, and then tableted with a rotary tableting machine with a set hardness of 50 N, and a tablet having a weight of 200 mg and a diameter of 8 mm Got. The tablet hardness was 50.8 N, and the oral disintegration time was 26.5 seconds.

[Example 4]
After uniformly dispersing 65 parts by weight of mannitol, 5 parts by weight of xylitol, 8 parts by weight of crospovidone, 15 parts by weight of crystalline cellulose, and 7 parts by weight of magnesium aluminate metasilicate, a spray dryer (L-8 type, Okawara) (Kako Koki Co., Ltd.) was used and spray dried at an outlet temperature of 80 ° C. to obtain white spherical granulated particles having good fluidity.
After mixing 12 parts by weight of acetaminophen and 0.4 parts by weight of light anhydrous silicic acid, 77.6 parts by weight of granulated particles and an appropriate amount of magnesium stearate are mixed, and then tableting is performed with a setting hardness of 50 N using a rotary tableting machine. As a result, a tablet having a weight of 200 mg and a diameter of 8 mm was obtained. Tablet hardness was 48.7 N and oral disintegration time was 29.2 seconds.

[Example 5]
After uniformly dispersing 65 parts by weight of mannitol, 5 parts by weight of xylitol, 8 parts by weight of crospovidone, 15 parts by weight of crystalline cellulose, and 7 parts by weight of magnesium aluminate metasilicate, a spray dryer (L-8 type, Okawara) (Kako Koki Co., Ltd.) was used and spray dried at an outlet temperature of 80 ° C. to obtain white spherical granulated particles having good fluidity.
4 parts by weight of tocopherol is absorbed into 20 parts by weight of magnesium aluminate metasilicate and powdered. After mixing 46 parts by weight of granulated particles, 30 parts by weight of carmellose and an appropriate amount of magnesium stearate, a set hardness of 50 N is obtained using a rotary tableting machine. As a result, tablets with a weight of 200 mg and a diameter of 8 mm were obtained. The tablet hardness was 50.7 N and the oral disintegration time was 28.8 seconds.

[Example 6]
After uniformly dispersing 65 parts by weight of mannitol, 5 parts by weight of xylitol, 8 parts by weight of crospovidone, 15 parts by weight of crystalline cellulose, and 7 parts by weight of magnesium aluminate metasilicate, a spray dryer (L-8 type, Okawara) (Kako Koki Co., Ltd.) was used and spray dried at an outlet temperature of 80 ° C. to obtain white spherical granulated particles having good fluidity.
Spray 21 parts by weight of cilostazol, 20 parts by weight of methylcellulose and 59 parts by weight of D-mannitol with 10 parts by weight of water, granulate with a stirring granulator, dry at 80 ° C. overnight, and sieve with a 32 mesh sieve, Masking particles were created.
After mixing 57 parts by weight of granulated particles, 20 parts by weight of masking particles, 10 parts by weight of corn starch, 10 parts by weight of crystalline cellulose, 3 parts by weight of crospovidone, and an appropriate amount of magnesium stearate, the mixture was punched with a set hardness of 50 N using a rotary tableting machine. Tablets were obtained having a weight of 200 mg and a diameter of 8 mm. The tablet hardness was 52.7 N and the oral disintegration time was 26.2 seconds.

[Example 7]
In a fluidized bed granulator, 320 g of mannitol was flowed, and an aqueous solution in which 200 g of mannitol, 40 g of xylitol, 64 g of crospovidone, 144 g of crystalline cellulose, and 32 g of calcium hydrogen phosphate were suspended in 1200 g of water was sprayed. Granulation was performed at an exhaust temperature of 30 ° C. to obtain white spherical granulated particles.
Spray 10 parts by weight of water on 21 parts by weight of amlodipine, 20 parts by weight of methylcellulose and 59 parts by weight of D-mannitol, granulate with a stirring granulator, dry at 80 ° C. overnight, and sieve through a 32 mesh sieve, Masking particles were created.
After mixing 57 parts by weight of granulated particles, 20 parts by weight of masking particles, 10 parts by weight of corn starch, 10 parts by weight of crystalline cellulose, 3 parts by weight of crospovidone, and an appropriate amount of magnesium stearate, the mixture was punched with a set hardness of 50 N using a rotary tableting machine. Tablets were obtained having a weight of 200 mg and a diameter of 8 mm. Tablet hardness was 54.7 N and oral disintegration time was 26.8 seconds.

[Example 8]
In a fluidized bed granulator, 320 g of mannitol was flowed, and an aqueous solution in which 200 g of mannitol, 40 g of xylitol, 64 g of crospovidone, 144 g of crystalline cellulose, and 32 g of calcium hydrogen phosphate were suspended in 1200 g of water was sprayed. Granulation was performed at an exhaust temperature of 30 ° C. to obtain white spherical granulated particles.
Spray 10 parts by weight of water on 21 parts by weight of amlodipine, 20 parts by weight of methylcellulose and 59 parts by weight of D-mannitol, granulate with a stirring granulator, dry at 80 ° C. overnight, and sieve through a 32 mesh sieve, Masking particles were created.
57 parts by weight of granulated particles, 20 parts by weight of masking particles, 10 parts by weight of corn starch, 10 parts by weight of crystalline cellulose, 3 parts by weight of crospovidone, and an appropriate amount of magnesium stearate before filling the mortar of the tableting machine And a tableting machine with an external lubrication device equipped with a device for applying to the mortar wall (manufactured by Kikusui Seisakusho, small high-speed rotary tableting machine VIRGO) to produce tablets having a tablet weight of 200 mg and a diameter of 8 mm. . Tablet hardness was 55.7 N and oral disintegration time was 21.8 seconds.

[Comparative Example 1] Tableting after dry blending 61.6 parts by weight of granulated D-mannitol, 6.4 parts by weight of crospovidone, 12 parts by weight of crystalline cellulose are mixed, 20 parts by weight of aspirin is added and mixed, and then After mixing an appropriate amount of magnesium stearate, tablets with a weight of 200 mg and a diameter of 8 mm were set at a set hardness of 50 N using a rotary tableting machine (manufactured by Hata Iron Works, HT-AP18SS-II). And a tablet could not be obtained.

[Example 2]
After 70 parts by weight of erythritol, 8 parts by weight of crospovidone, 18 parts by weight of crystalline cellulose, and 4 parts by weight of anhydrous calcium hydrogen phosphate are uniformly dispersed in water, a spray dryer (L-8 type, manufactured by Okawara Kako Co., Ltd.) Was spray-dried at an outlet temperature of 80 ° C. to obtain white spherical granulated particles having good fluidity.
After mixing 32 parts by weight of the granulated particles with 20 parts by weight of aspirin and 48 parts by weight of crystalline cellulose, a suitable amount of magnesium stearate is mixed, and then tableted with a rotary tableting machine with a set hardness of 50 N, and a tablet having a weight of 200 mg and a diameter of 8 mm Got. Tablet hardness was 52.3N and oral disintegration time was 124 seconds.

[Comparative Example 3]
After uniformly dispersing 74 parts by weight of mannitol, 8 parts by weight of crospovidone and 18 parts by weight of crystalline cellulose in water, using a spray dryer (L-8 type, manufactured by Okawara Chemical Co., Ltd.) at an outlet temperature of 80 ° C. Spray drying was performed to obtain white spherical granulated particles having good fluidity.
After mixing 20 parts by weight of aspirin with 80 parts by weight of the granulated particles 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 having a weight of 200 mg and a diameter of 8 mm. The tablet hardness was 25.3 N and the oral disintegration time was 108 seconds.

  Comparative Example 1 caused tableting failure and could not obtain tablets, Comparative Examples 2-3 did not show the desired hardness and disintegration time, and Examples 1-8 were excellent in both hardness and disintegration time It turns out that the effect is demonstrated.

Claims (18)

(A) active ingredient, (b) one or more saccharides selected from mannitol, xylitol, lactose, (c) disintegrant, (d) excipient, (e) fast disintegrating compression molded product comprising lubricant . (F) The rapidly disintegrating compression-molded product according to claim 1, wherein inorganic powder is mixed. The rapidly disintegrating compression-molded product according to claim 1, comprising (b) a granulated product formed from one or more saccharides selected from mannitol, xylitol, and lactose, and (c) a disintegrant. 3. The granulated product formed from (b) one or more saccharides selected from mannitol, xylitol, and lactose, (c) a disintegrant, (c) an excipient, and (g) an inorganic powder. Fast disintegrating compression molding. 5. The composition according to claim 1, comprising (a) an active ingredient, (b) one or more saccharides selected from mannitol, xylitol, and lactose, and (c) a granulated product formed from a disintegrant. Fast disintegrating compression molding. The rapidly disintegrating compression according to any one of claims 1 to 4, wherein (a) the active ingredient is granulated with one or more of (h) a binder, (i) a carrier, and (j) a coating agent. Molded product. The rapidly disintegrating compression molded product according to any one of claims 2 to 6, wherein the granulation method is fluidized bed granulation, rolling granulation, stirring granulation, spray drying granulation, or kneading granulation. The shape of the rapidly disintegrating compression molding is a cylindrical shape having a height of 3 to 15 mm and a diameter of 5 to 20 mm, and the end of the cylindrical shape is a curved surface having a radius of 0.2 to 2 mm as necessary. The rapidly disintegrating compression molding of any one of these. The excipient is powdered cellulose, magnesium aluminate metasilicate, magnesium aluminate silicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granulation, hydrotalcite, bentonite, aluminum silicate, Synthetic aluminum silicate, hydroxypropyl starch, crystalline cellulose, calcium phosphate, calcium carbonate, calcium silicate, magnesium silicate, magnesium oxide, magnesium hydroxide, magnesium alumina hydroxide, dry aluminum hydroxide gel, magnesium carbonate, mannitol, xylitol, Selected from sorbitol, erythritol, maltitol, lactose, sucrose, glucose, fructose, maltose, trehalose, palatinit, palatinose, agar, shellac, tragacanth Rapidly disintegrating compression-molded article according to any one of claims 1 to 9 at least one. The lubricant according to any one of claims 1 to 10, wherein the lubricant is at least one selected from stearic acid, magnesium stearate, calcium stearate, sucrose fatty acid ester, glycerin fatty acid ester, polyethylene glycol, sodium stearyl fumarate, and talc. 2. A rapidly disintegrating compression molded product according to item 1. Inorganic powder is magnesium aluminate metasilicate, magnesium aluminate silicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granulation, hydrotalcite, aluminum silicate, calcium phosphate, calcium carbonate, silica It consists of at least one selected from calcium acid, magnesium silicate, magnesium oxide, magnesium hydroxide, magnesium hydroxide alumina, dried aluminum hydroxide gel, magnesium carbonate, hydrous silicon dioxide, and light anhydrous silicic acid. 11. The rapidly disintegrating compression molded product according to any one of 11 above. The rapid disintegration according to any one of claims 1 to 12, wherein the binder is at least one selected from carmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gum arabic powder, gelatin, and pullulan. Compression molding. The carrier is at least one selected from mannitol, lactose, starch, dextrin, crystalline cellulose, calcium hydrogen phosphate, magnesium aluminate metasilicate, or one or more granules thereof. The rapidly disintegrating compression molding of any one of Claims 1. The carrier is at least one selected from mannitol, lactose, starch, dextrin, crystalline cellulose, calcium hydrogen phosphate, magnesium aluminate metasilicate, or one or more granules thereof. The rapidly disintegrating compression molding of any one of Claims 1. The amount of each component is 1 to 50% by weight of the active ingredient, one or more saccharides consisting of mannitol, xylitol and lactose, 10 to 90% by weight, 1 to 30% by weight of disintegrant, 10 to 90% by weight of excipient, The rapidly disintegrating compression-molded product according to claim 1-123, wherein the content is 0.1 to 2 wt%. The fast-disintegrating compression-molded product according to any one of claims 1 to 15, wherein the lubricant is added by spraying the lubricant onto a die. The rapidly disintegrating compression molded product according to any one of claims 1 to 16, wherein the saccharide has an amorphous ratio of 1 to 90%. The fast-disintegrating compression molded product according to any one of claims 1 to 17, wherein the binder is substantially free of crystals.