JPWO2012001977A1 - Disintegrating composition and easily disintegrating compression molding - Google Patents

Abstract

[PROBLEMS] To have a good texture and taste in the oral cavity, excellent tablet formability, sufficient hardness that does not cause problems such as chipping and powdering during the formulation process and distribution, and good disintegration in the oral cavity, There is a need for disintegrating compression moldings that do not contain high-performance disintegrants with limited intake. SOLUTION: A compact with excellent disintegration can be produced by compression molding including starches and, if necessary, crystalline cellulose / inorganic powder. This compression-molded product does not have excellent texture / taste, hardness, disintegration, and intake restriction, and can produce a disintegration compression-molded product for food applications. [Selection] Figure 1

Description

  The present invention relates to starches, which are components that can be used in foods without any restriction on ingestion, as needed, disintegrating compositions for foods made of crystalline cellulose or inorganic substances, and tablet-type compression-molded foods made of these ingredients About.

  In recent years, changes in lifestyle habits, lowering of nutritional components of fresh food, excessive intake of calories, taking necessary nutritional components appropriately, taking natural antioxidant components etc. for high stress society and anti-aging Things are increasing. These nutritional components, antioxidant components, and the like are ingested as foods, and are commercially available as so-called health foods in the form of tablets (tablets), capsules, granules, beverages, and the like. Of these dosage forms, the tablet form is the best in terms of ingestion, production and distribution.

  Health foods in the form of tablets are ingested by so-called super disintegrants such as polyvinylpyrrolidone, croscarmellose sodium and sodium carboxymethyl starch used in pharmaceutical tablets, and disintegrants such as carmellose calcium and low-substituted hydroxypropylcellulose. Because of the limitations, most disintegrants cannot be used, and even if they can be used, the amount is so small that a disintegrant having sufficient disintegration is required. In addition, since tablet-shaped health foods contain naturally derived powders and the like, the compounding amount of the utility component is often 40% or more, and an excellent disintegrant is required without compounding much.

  Furthermore, health foods in the form of chewable or orally disintegrating tablets are desired as forms that can be easily taken by elderly people, children, patients who have difficulty in swallowing drugs, and can be easily taken without water. Health foods of these shapes need to be disintegrated only with saliva in the oral cavity, and an excellent disintegrant is required. Moreover, since it disintegrates in the oral cavity, it is also important that the food texture is good.

  The present inventors have proposed a composite particle composition obtained by spray-drying D-mannitol / erythritol, a super disintegrant, an inorganic substance, and the like as an excipient for a rapidly disintegrating compression molded product of a pharmaceutical (patent) References 1, 2). Super disintegrants such as crospovidone and croscarmellose sodium and disintegrants such as low-substituted hydroxypropylcellulose have limited amounts that can be used in foods and restrictions on their use, making them difficult to use in foods .

  An effervescent intraoral quick disintegrating tablet comprising an organic acid and a carbonate, a network maintaining agent such as corn starch, and a coloring preventing agent such as xylitol and lactose is known (Patent Document 3). Mixing, compression molding, heating and partially reacting organic acids and carbonates to create a porous structure, and improving the solubility in the oral cavity by firing the remaining organic acids and carbonates in the oral cavity Yes. There are problems such as stabilization of the effect ingredient by the blending of the organic acid and a heating step after compression molding are essential.

  There is known an immediate-release compression molding product in which an active ingredient, lactose, corn starch, crystalline cellulose, silicon dioxide, and other pharmaceutical additives are dry-mixed and kneaded and granulated, followed by compression molding (Patent Document 4). There is a description about the release of the active ingredient, but there is no description about the disintegration property in the oral cavity.

  Tablets with a moisture content of 6 to 14% by weight, such as rice starch, cellulose, D-mannitol, etc. (Patent Document 5), starch such as rice starch and cellulose are granulated at a ratio of 90:10 to 50:50. In addition, a solid preparation having a practical hardness and disintegration time in which the amount thereof is 60% or more of a tablet is known (Patent Document 6). In these, comment starch is used as a binder, and there is a description of the general tablet formability and disintegration, pharmacopeia disintegration time. There is no description which has the outstanding performance of an orally quick disintegrating tablet using a specific starch.

JP 2005-139168 A International Publication WO2007 / 29376 Pamphlet JP-A-11-310539 JP 2000-026292 A JP 2006-176696 A JP 2007-332074 A

  Easy-disintegrating compression-molded product that does not contain highly disintegrating disintegrants, has good hardness, disintegration, and texture and can be widely used in the field of foods and pharmaceuticals, and for foods required for its production An object is to provide a disintegrating compressed composition.

  As a result of intensive research to achieve the above object, the present inventors have found that starches with a small particle size and low amylose content, and compression molded products containing crystalline cellulose and inorganic substances as required, have excellent disintegration. It has been found that an easily disintegrating compression-molded product having sufficient properties, sufficient hardness that does not cause problems during production and transportation, and having a mouthfeel and taste without problems in the oral cavity. Further, it has been found that a composition obtained by granulating starch having a small particle size and a low amylose content has good performance for producing a compression-molded product for food.

  The compression molded product of the present invention and containing starches with a low amylose content has sufficient hardness that does not cause sticking or capping during compression molding, does not cause problems during production and transportation, and has a good fast disintegration time. Have Since the intraoral rapidly disintegrating tablet of the present invention is composed of components that are not particularly restricted, it can be used in a wide range of foods and pharmaceuticals.

2 is an SEM photograph (1 memory: 10 μm) of spray-dried particles of Example 1.

  The present invention is a starch having a small particle size and a low amylose content (starch of the present invention), a particulate disintegrating composition composed of crystalline cellulose or an inorganic substance, if necessary, and a small particle size, and It is an orally disintegrating compression-molded product containing starches having a low amylose content and, if necessary, crystalline cellulose and inorganic substances.

The particulate disintegrating composition will be described below.
The particulate disintegrating composition of the present invention has a spherical particulate structure in which starches having a small particle diameter and a low amylose content are aggregated and bonded to each other.

  The particulate disintegrating composition of the present invention may have an average particle diameter of 10 to 500 μm, preferably 20 to 300 μm, more preferably 30 to 200 μm, from preventing roughness in the oral cavity and disintegration. An average particle diameter is D50 of the integrated diameter calculated | required by the dry-type laser method mentioned later. From the viewpoint of compression moldability and disintegration, the particle shape is preferably spherical, and the sphericity is 0.7 or more, preferably 0.8 or more. The sphericity is obtained by dividing the minor axis of the particle by the major axis from the SEM photograph. From these, since it is the particle | grains which have favorable fluidity | liquidity, the tableting property excellent in the formulation process can be shown.

  The static specific volume of the particle composition of the present invention is preferably 1.0 to 4.0 ml / g, more preferably 1.5 to 3.5 ml / g, still more preferably 1.5 to 3.0 ml / g. It is. Since the particle composition child has such a static specific volume, it can be easily filled into a mortar when it is formed into a tablet, so that the formulation process proceeds smoothly, and the tablet is uniformly compressed and excellent tableting. Can show gender. The static specific volume can be measured according to standard methods.

  The starch having a low amylose content used in the present invention refers to a starch having a high amylopectin in the ratio of amylopectin to amylose constituting the starch, and amylopectin: amylose = 85: 15 to 100: 0, preferably amylopectin: amylose = 90: 10 to 100: 0, more preferably amylopectin: amylose = 98: 2 to 100: 0. When the average particle size of the starch is large, the compression moldability is poor, and is 1 to 15 μm, preferably 2 to 10 μm, more preferably 3 to 8 μm.

  Starch is divided into amylose and amylopectin depending on its structure. Starches with a low amylose content contain a large amount of amylopectin. Amylopectin has a structure in which sugar chains are separated, and the more amylopectin, the stronger the aggregation of starch particles. Furthermore, the compression moldability is improved by using starches having a small average particle diameter. After drying, since the starch particles contained in the disintegrating composition have many intergranular voids, the effect of water introduction into the composition is high, and the composition disintegrates with a slight amount of water in the oral cavity. In the present invention, low amylose starches have the same meaning as high amylopectin starches.

  Starches having a small particle size and a low amylose content are starches derived from rice, and most preferably starches derived from glutinous rice. Any of the glutinous rice varieties may be used. Starch derived from glutinous rice contains almost no amylose. Within the range of the amylose content and average particle diameter of the starches of the present invention, glutinous rice and other starches may be mixed. As starches to be mixed, rice starch and waxy corn starch are suitable.

  As the crystalline cellulose used in the disintegrating composition of the present invention, those having excellent compression moldability can be used. The average particle size is 10 to 100 μm, the bulk density is 0.1 to 0.5 g / ml, and the shape is A fibrous or nearly spherical particle can be used.

The inorganic substance is a fine inorganic substance having an average particle diameter of 0.1 to 300 μm and a high specific surface area. By including an inorganic substance, there are effects such as a reduction in molding pressure during compression molding of the granulated particles of the present invention, a water-conducting effect in the oral cavity, and an improvement in yield during the production of granulated particles. Among these inorganic substances having physical properties, for example, magnesium carbonate, calcium carbonate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granulated product, magnesium metasilicate aluminate, magnesium aluminate silicate, hydro It is at least one selected from talcite, aluminum silicate, calcium phosphate, calcium carbonate, calcium silicate, magnesium silicate, talc, magnesium oxide, magnesium hydroxide, magnesium alumina hydroxide, dry aluminum hydroxide gel, and the like.
Preferably, it is at least one selected from magnesium carbonate, calcium carbonate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous silicic acid, calcium silicate, and talc.
More preferably, it is at least one selected from calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous silicic acid, calcium silicate, and talc.

  In the case where the suspension of each component of the present invention is sprayed and dried, it is considered that there is an effect in enhancing the productivity of the particles such as the suppression of aggregation between the particles. Moreover, since aggregation is disperse | distributed by making it disperse | distribute to water, it has the structure disperse | distributed in the spherical particle, and it is thought that it is more effective than other manufacturing methods. At the same time, there is a secondary effect of improving moldability.

  The particulate disintegrating composition of the present invention can be mixed with saccharides to adjust the taste and disintegration feeling. The saccharide is a saccharide and / or a sugar alcohol, and includes one or more of these. Examples of the saccharide include one or more of mannitol, xylitol, sorbitol, erythritol, maltitol, lactose, sucrose, glucose, fructose, maltose, trehalose, palatinit, and palatinose. Preferred are erythritol, xylitol, maltitol, and mannitol.

  The compounding ratio of each component of the particulate disintegrating composition of the present invention is, when crystalline cellulose is included, starches: crystalline cellulose = 99: 1 to 70:30, and starches: crystalline cellulose = 95: 5 75:25, most preferably starches: crystalline cellulose = 90: 10 to 80:20. Furthermore, the compounding ratio of each component in the case of containing an inorganic substance is starch: inorganic substance = 99: 1 to 80:20, preferably starch: inorganic substance = 99: 1 to 85:15, most preferably starch: inorganic substance. = 99: 1 to 90:10. When sugars are blended, the blending ratio of starches: saccharides is 99: 1 to 80:20, preferably starches: sugars = 98: 2-85: 15.

  In the particulate disintegrating composition particle composition of the present invention, two or more kinds of effective components described later at the time of production and other components that can be combined within a range not impairing the disintegrating property described later can be blended. The compounding quantity of a component is 0.1-1000 weight part with respect to 100 weight part of starches, or a total of 100 weight part of what added crystalline cellulose, the inorganic substance, etc. as needed, Preferably it is 0.1-1000 weight part. 200 parts by weight, most preferably 0.1 to 100 parts by weight.

  The particle composition of the present invention can be produced by a wet 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. In order to remove the solvent quickly, a method of instantly drying the dispersion using a spray nozzle is preferred, and fluidized bed granulation, stirring granulation, tumbling is performed by spraying the dispersion solution onto the core particles. As a production method, layer drying and spray drying in which granulation is performed only by the spraying step of the dispersion solution are preferable. Spray drying is most preferred from the standpoint of ease of production and ease of obtaining desired physical properties.

  In the wet granulation method, by setting the conditions, the starch composition, and if necessary, each component such as crystalline cellulose and inorganic substance is uniformly dispersed in the solvent, and the particle composition is obtained by quickly removing the solvent. Can be obtained. What is necessary is just to set conditions according to the characteristic of each wet granulation apparatus.

  As a production method of the spray drying method, it can be produced by dispersing starches, if necessary, crystalline cellulose or inorganic substance in a water-soluble solvent and spray-drying the dispersion according to a conventional method. More specifically, a dispersion is prepared by adding a water-soluble binder, starches, a molding agent and an inorganic substance to a water-soluble solvent, but there is no particular order of administration, and there is something that you want to completely dissolve. In particular, it is preferable to prepare a dispersion obtained by dissolving or dispersing a water-soluble binder in an aqueous solvent in advance and then uniformly dispersing hardly soluble substances such as starches, molding agents and inorganic substances. Subsequently, the dispersion can be produced by spray drying. Moreover, it can manufacture by spray-drying the dispersion liquid which added 1 or more types of the other component which can be mix | blended in the range which does not impair an active ingredient and disintegration, and was uniformly disperse | distributed.

  The solvent may be any solvent that does not affect the properties of the particle composition and is acceptable for pharmaceuticals and foods. Examples thereof include water and ethanol, and two or more of them may be used in combination. 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 liquid may be in a range that can be spray-dried depending on the viscosity of the dispersion liquid, that is, 5 to 50% by weight, preferably 10 to 45% by weight.

  Although the conditions of spray drying are not specifically limited, As a spray dryer, it is preferable to use a disk type or nozzle type spray dryer. And as temperature in the case of spray-drying, inlet temperature is about 120-300 degreeC, and outlet temperature is about 80-130 degreeC. The particle size of the particle composition can be appropriately adjusted depending on the concentration of the aqueous solution or aqueous dispersion, the spray drying method, the drying conditions, and the like.

  The fluidized bed granulation, stirring granulation, and rolling bed granulation can be obtained by spraying a solution in which other components are dispersed using starches, crystalline cellulose, or inorganic substances as core particles. Some insoluble components may also be suspended in the dispersion and sprayed. The production conditions may be set so as to have the structure of the particle composition of the present invention described above. For example, the spraying solvent can be increased, the drying rate can be slowed down, for example, the temperature can be lowered, and the suspension can be easily and uniformly dispersed with the core particles.

The collapsible compression molded product of the present invention will be described below.
The “easily disintegrating compression molding” in the present invention can rapidly disintegrate in the oral cavity, for example, within 180 seconds, preferably within 60 seconds, more preferably within 40 seconds, and most preferably within 30 seconds. Means a tablet. The orally disintegrating time here is the time obtained by the conditions of the orally disintegrating tablets described later and the methods 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.

  In the present invention, “texture” that does not cause discomfort in the oral cavity means that it does not feel powdery, mud smell, or the mossiness that increases when the blended raw material absorbs moisture. “Taste” that does not produce a pleasant feeling means that there is no sourness, bitterness, astringency, etc. derived from the raw materials.

  The easily disintegrating compression molded product of the present invention has a good texture, whereas the compression molded product containing starches having a large amount of amylose and starches having an average particle size of 20 μm or more absorbs moisture and increases. It is difficult to drink without water when multiple tablets are included in the oral cavity.

  The collapsible compression-molded product of the present invention comprises an active ingredient, starches with low amylose, and if necessary, crystalline cellulose, an inorganic substance, and a lubricant. As the starch, crystalline cellulose, and inorganic substance having a small amount of amylose, those of the aforementioned disintegrating particle composition can be used.

  The ratio of the starches in the collapsible compression-molded product of the present invention is 1 to 90 parts by weight, preferably 5 to 80 parts by weight, more preferably 20 to 70 parts by weight with respect to 100 parts by weight of the entire collapsible compression-molded product. It is. When the crystalline cellulose is included, the compounding ratio of each component of the disintegrating compression molded product of the present invention is starch: crystalline cellulose = 100: 5 to 25, preferably starch: crystalline cellulose = 100: 5-20. Most preferably, starches: crystalline cellulose = 100: 10-20. Furthermore, the compounding ratio of each component in the case of containing an inorganic substance is starch: inorganic substance = 100: 1 to 10, preferably starch: inorganic substance = 100: 1 to 5, most preferably starch: inorganic substance = 100: 2. ~ 4. When sugars are blended, the blending ratio of starches: saccharides is 100: 2-15, preferably starches: saccharides = 100: 4-11.

  In the collapsible compression-molded product of the present invention, the active ingredient is 0.1 to 500 parts by weight and the lubricant is 0.1 to 20 parts by weight with respect to 100 parts by weight of the starch, crystalline cellulose, and inorganic matter in total. Preferably, the active ingredient is 0.1 to 300 parts by weight and the lubricant is 0.5 to 20 parts by weight with respect to a total of 100 parts by weight of starches, crystalline cellulose and inorganic substances.

  When the disintegrating compression molded product of the present invention contains the particulate disintegrating composition of the present invention, the disintegrating compression molded product may contain the particulate disintegrating composition irrespective of the blending ratio in the previous stage. . In such a case, the disintegrating compression-molded product comprises the particulate disintegrating composition of the present invention, an active ingredient, a lubricant, and a pharmaceutical additive described later. Furthermore, apart from the particulate disintegrating composition of the present invention, starches, crystalline cellulose, and inorganic substances can be added to adjust the moldability and disintegrating property.

  When mix | blending a particulate composition, it is 0.1-500 weight part of active ingredients, and 0.1-20 weight part of lubricant with respect to 100 weight part of particulate disintegrating composition of this invention. Preferably, the active ingredient is 5 to 300 parts by weight and the lubricant is 0.5 to 20 parts by weight with respect to 100 parts by weight of the particulate disintegrating composition of the present invention.

  The disintegrating compression molded product of the present invention may contain an active ingredient, an active ingredient coating or an active ingredient granulated product. Since these moldability and disintegration properties change due to their inherent properties, excipients and binders can be added to adjust the moldability and disintegration properties, and these can be added to the particle composition. You may add to a disintegrating compression molding. The addition to the collapsible compression molded product is mixing and compression molding together with the particle composition and active ingredients. In addition, an excipient | filler and a binder are contained in the other component which can be mix | blended in the range which does not impair disintegration.

  The collapsible compression-molded product of the present invention contains pharmaceutical additives such as active ingredients, excipients, binders, surfactants, acidulants, sweeteners, corrigents, fragrances, colorants, stabilizers as necessary. One or more of these are blended. Each blending ratio is 100 parts by weight of starch, crystalline cellulose, and inorganic substance or 100 parts by weight of the particle composition. The excipient, the disintegration aid, the binding aid, the surfactant, the lubricant, the acidity. 0.01-1000 parts by weight of one or more ingredients of other pharmaceutical additives selected from a fragrance, sweetener, flavoring agent, flavor, colorant, stabilizer, and foaming agent, and 0% active ingredient as necessary. .1 to 500 parts by weight.

  These lubricants, excipients, and / or binders may not be mixed immediately before tablet production, but may be mixed in advance with the particle composition of the present invention. In particular, excipients such as the aforementioned starches are preferably mixed in advance in order to improve the formulation process such as fluidity of the particle composition of the present invention.

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 (corn starch), lactose, hard fat, sucrose, potato tempun, hydroxypropyl cellulose, fumaric acid, sodium stearyl fumarate, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, polysorbate, Examples include beeswax, magnesium aluminate metasilicate, methyl cellulose, 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, glycerin fatty acid ester, polyethylene glycol, sodium stearyl fumarate, talc and hydrogenated oil.

Examples of the excipient in the present invention include the aforementioned starches, adipic acid, pregelatinized starch, erythritol, sodium carboxymethyl starch, carmellose, carmellose calcium, carmellose sodium, hydrous silicon dioxide, agar, xylitol, guar gum, Starch acrylate, L-aspartic acid, aminoethylsulfonic acid, aminoacetic acid, candy (powder), gum arabic, gum arabic powder, alginic acid, sodium alginate, pregelatinized starch, inositol, ethylcellulose, ethylene vinyl acetate copolymer, erythritol, chloride Sodium, olive oil, kaolin, cacao butter, casein, fructose, pumice grains, carmellose, carmellose sodium, hydrous silicon dioxide, dry yeast, dry aluminum hydroxide , Dry sodium sulfate, dry magnesium sulfate, agar, agar powder, xylitol, citric acid, sodium citrate, disodium citrate, glycerin, calcium glycerophosphate, sodium gluconate, L-glutamine, clay, clay granules, croscarmellose sodium , Aluminum silicate, Synthetic aluminum silicate, Hydroxypropyl starch, Crystalline cellulose, Magnesium aluminate, Calcium silicate, Magnesium silicate, Light anhydrous silicic acid, Light liquid paraffin, Powdered cinnamon powder, Crystalline cellulose, Crystalline cellulose, Carme Loin sodium, microcrystalline cellulose, pearl millet, synthetic aluminum silicate, synthetic hydrotalcite, sesame oil, wheat flour, wheat starch, wheat germ, rice (rice flour), rice Pung, potassium acetate, calcium acetate, cellulose acetate phthalate, safflower oil, white beeswax, zinc oxide, titanium oxide, magnesium oxide, β-cyclodextrin, dihydroxyaluminum aminoacetate, 2,6-di-t-butyl-4 -Methylphenol, dimethylpolysiloxane, tartaric acid, potassium hydrogen tartrate, baked gypsum, sucrose fatty acid ester, magnesium 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, sesquiolei Acid sorbitan, 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, calcium carbonate, Magnesium carbonate, neutral anhydrous sodium sulfate, low-substituted hydroxypropyl cellulose, dextran, dextrin, natural aluminum silicate, corn syrup, corn starch, trehalose, tragacanth, silicon dioxide, calcium lactate, lactose, hydrotalcite, maltose, white Shellac, white petrolatum, dried saccharose, white sugar starch spherical granules, green leafy green leaf extract powder, green leafy green leaf juice, honey, palatinit, palatinose, pa Fin, potato starch, semi-digested starch, human serum albumin, hydroxypropyl starch, hydroxypropylcellulose, phytic acid, glucose, 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, polystyrene sulfonate sodium, polysorbate, polyvinyl acetal diethylaminoacetate, polyvinyl Pyrrolidone, maltitol, maltose, D-mannitol, water candy, isopropyl myristate, anhydrous lactose, anhydrous Calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granulated product, magnesium metasilicate aluminate, methylcellulose, cottonseed powder, cottonseed oil, mole, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, 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, etc. These are the above, and any of these may be used alone, but two or more may be blended.
Preferably, crystalline cellulose, croscarmellose sodium, magnesium aluminate metasilicate, magnesium aluminate silicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granulated product, calcium silicate, aluminum silicate Silica, magnesium carbonate.

  Examples of the binder in the present invention include alginic acid, 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, alum powder, hydrolyzed gelatin powder, sodium caseinate, fructose, caramel, karaya gum powder, carboxyvinyl polymer, Carboxymethyl ethyl cellulose, sodium carboxymethyl starch, carmellose, carmellose sodium, hydrous silicon dioxide, agar, agar powder, xanthan , Beef tallow oil, guar gum, glycerin, synthetic aluminum silicate, light anhydrous silicic acid, light silicic acid-containing hydroxypropylcellulose, crystalline cellulose, hardened oil, copolyvidone, sesame oil, wheat flour, wheat starch, rice flour (rice flour), rice starch , Vinyl acetate resin, cellulose acetate phthalate, white beeswax, oxidized starch, dioctylsodium sulfosuccinate, dihydroxyaluminum aminoacetate, sodium potassium tartrate, sucrose fatty acid ester, stearyl alcohol, stearic acid, calcium stearate, polyoxyl stearate, Sorbitan sesquioleate, cetanol, gelatin, shellac, sorbitan fatty acid ester, D-sorbitol, soybean lecithin, calcium carbonate, simple syrup, dextst , Starch (soluble), corn starch, tragacanth, paraffin, potato starch, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, piperonyl butoxide, Butylphthalyl bunal glycolate, glucose, partially pregelatinized starch, fumaric acid, pullulan, propylene glycol, pectin, sodium polyacrylate, partially neutralized polyacrylic acid, polyethylene glycol, polyoxyethylene / polyoxypropylene glycol, Polysorbate, polyvinyl acetal diethyl One or more of aminoacetate, polyvinyl alcohol (completely saponified product), polyvinyl alcohol (partially saponified product), polyvinylpyrrolidone, polybutene, sodium polyphosphate, D-mannitol, water candy, light anhydrous silicic acid, magnesium metasilicate aluminate, etc. Any of these may be used alone, but two or more of them can be blended.

  The active ingredient is not particularly limited, but it is a nutritional ingredient, so-called health food material, vitamins, peripheral nerve agent, antipyretic analgesic / anti-inflammatory agent, hypnotic sedative, neuropsychiatric agent, etc .; skeletal muscle relaxant Drugs for peripheral nerves such as cardiotonic agents, cardiovascular agents such as cardiotonic agents, arrhythmic agents, diuretics, and vasodilators; drugs for respiratory organs such as bronchodilators and antitussives; digestive agents, intestinal regulating agents, antacids, etc. Gastrointestinal drugs; metabolic drugs such as hormones and antihistamines; anti-ulcer agents; antibiotics; chemotherapeutic agents; herbal extracts;

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

  Examples of so-called health food materials include deoxyribonucleic acid and salts thereof, adenylic acid derivatives such as adenosine triphosphate and adenosine monophosphate and salts thereof, ribonucleic acid and salts thereof, guanine, xanthine and derivatives thereof and 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, Eicosapentaenoic acid and their derivatives, succinic acid and its derivatives and their salts, estradiol And derivatives thereof, and salts thereof, glycolic acid, lactic acid, malic acid, citric acid, salicylic acid and other α-hydroxy acids and derivatives thereof and salts thereof, 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, glucosamine, chondroitin, collagen, aloe extract, salvia extract, arnica extract , Chamomile extract, birch extract, hypericum extract, eucalyptus extract and mugwort extract, tyrosinase activity inhibitor is cysteine and its derivatives and salts thereof, Sempukuka extract, Kettou extract, Sunpens extract, Sohakuhi extract, Toki extract, Ibukitorano extract, Clara extract, Hawthorn extract, Shirayuri extract, Hop extract, Neubara extract and Yokuinin extract, Hyaluronic acid, Chondroitin sulfate , Dermatan sulfate, heparan sulfate, heparin and keratan sulfate and their salts, collagen, elastin, keratin and their derivatives and their salts, yeast, deep sea water, loofah extract, papaya extract, papaya powder, zinc, ginseng Select one or more from the group consisting of extract, bullberry extract, DHA, ginkgo biloba extract, glutathione, flavonoid, tannin, ellagic acid, nucleic acids, herbal medicines, seaweeds, minerals, etc., and mixtures thereof be able to.

  As the active ingredients, those having a bitter taste or those that release in the digestive tract can be processed by a known method such as coating. For example, the method described in JP-A No. 11-263723, that is, an active ingredient, a readily soluble substance such as xylitol, sorbitol, and sucrose, and a water-soluble binder such as polyvinylpyrrolidone, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, gum arabic, and gelatin , And mannitol, lactose, and mannose can be coated with an active ingredient by spray drying, fluidized bed granulation, stirring granulation, kneading granulation, or the like.

  As long as the astringency, sourness, and bitterness derived from the ingredients can be suppressed by flavoring and flavoring, acidulants (for example, citric acid, tartaric acid, malic acid, ascorbic acid, etc.), sweeteners (sodium saccharin, diglycyrrhizic acid) Potassium, aspartame, stevia, thaumatin, etc.), flavoring agents, flavors (for example, various fruit flavors including lemon oil, orange oil, strawberry and yogurt, mint, menthol, etc.). These flavoring agents and flavoring agents can be blended in an amount of 0.01 to 0.5 parts by weight with respect to 100 parts by weight of the whole tablet.

  The disintegrating compression-molded product of the present invention can be blended with other components that can be blended with food as long as the disintegrating property is not impaired. As a component which does not impair the disintegration property which can be mix | blended with the disintegration compression molding 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.), foaming agents (eg, sodium bicarbonate, sodium carbonate, etc.), colorants (eg, edible red No. 2, edible blue No. 2, edible yellow No. 5, edible lake pigment, iron sesquioxide, carmine, etc. ), Stabilizers (for example, sodium edetate, tocopherol, cyclodextrin, etc.).

  The collapsible compression-molded product of the present invention comprises an active ingredient, starches, lubricants, at least one selected from crystalline cellulose, inorganic substances, and other additives, and an active ingredient and other ingredients that can be blended with other pharmaceuticals. After mixing, it can be manufactured by compression molding. The starches, if necessary, crystalline cellulose, and inorganic substances can be added after producing the rare particles composition as described above. Since uniformity, texture, disintegration, and compression moldability are more excellent, it is preferable to granulate in advance rather than dry mixing.

  The compression molding is preferably performed by the direct tableting method, and the molding pressure at that time varies depending on the size of the tablet, but is usually 200 to 2000 kgf, preferably 250 to 1600 kgf, more preferably 250 to 1200 kgf. is there.

  The collapsible compression-molded product of the present invention has a hardness of usually 20 to 150N, preferably 30 to 120N, more preferably 40 to 100N. The disintegrating compression molded product of the present invention is also characterized by good moldability, and does not cause tableting troubles such as sticking and capping during compression molding of tablets. On the other hand, a compression molded product comprising starches having a large amount of amylose or starches having an average particle diameter of 20 μm or more has poor moldability. For example, a molding pressure of 1500 kg or more is required to set a hardness of 50 N, Prone to sticking and capping.

  As other manufacturing methods, after active ingredients, starches, crystalline cellulose, and inorganic substances are wet-granulated, 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 the collapsible compression molded product in the present invention, as described above, the lubricant may be mixed with other components and then mixed with other compounding components and then compression molded. It is possible to manufacture by compression method (external lubrication method) and apply desired hardness and disintegration to the surface of the punch and the surface of the mortar of the compression molding machine. Can do. The method of applying the lubricant to the mortar can be performed by a conventionally known method or machine.

The disintegrating compression-molded product of the present invention can be used as other solid preparations such as those that are not intended for disintegrating tablets in the mouth, such as chewable tablets or tablets that disintegrate in the digestive tract. Can do. In the case of a chewable tablet type or a general tablet, the hardness may be higher than the above-mentioned hardness.
The disintegrating compression-molded product of the present invention can be used for foods that disintegrate in the oral cavity because it disintegrates immediately with a small amount of water.

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 required for 3 to 5 subjects to put tablets (each tablet n = 6) on the tongue in the oral cavity and completely disintegrate was measured, and the average value was defined as the oral disintegration time.
[Sensory test]
The tablets were naturally disintegrated by 3-5 subjects on the tongue in the oral cavity. After confirming the texture, those that felt that the majority were good were judged as “good”, and those that felt that the majority were bad as “bad”.
[Tablet hardness]
It measured using the load cell type tablet hardness meter (PC-30, Okada Seiko Co., Ltd. product).
[Tabletability]
The mortar of the tableting machine and the tablet after tableting were observed to evaluate sticking and capping.
[Average particle size]
It measured using the dry-type particle size measuring device (LA-920, Horiba, Ltd. make). The integrated diameter D50 was defined as the average particle diameter.

Example 1 Production of Particle Disintegrating Composition Waxy Rice Starch (Motil B: manufactured by Joetsu Starch Co., Ltd., amylopectin: amylose = 99.5: 0.5, average particle size 6.1 μm) 82 parts by weight, crystalline cellulose ( Theolas FD101: Asahi Kasei Chemicals Co., Ltd. 15 parts by weight, anhydrous calcium hydrogen phosphate (Fujicalin SG, Fuji Chemical Industry Co., Ltd., average particle size 120 μm, bulk density 0.46 g / mL, BET specific surface area 40 m ² / g) 3 weights After the part is uniformly dispersed in water, it is spray-dried at an outlet temperature of 90 to 100 ° C. using a spray dryer (S-50N / R, manufactured by Niro Co., Ltd.), and a white spherical particle composition having good fluidity. I got a thing. The average particle size was 105.8 μm. A SEM photograph is shown in FIG.

Example 2 Production of Particle Disintegrating Composition 80 parts by weight of waxy rice starch, 15 parts by weight of crystalline cellulose, and 5 parts by weight of magnesium carbonate (magnesium carbonate light (food additive): manufactured by Kamishima Chemical Co., Ltd.) are uniformly added to water. After the dispersion, the mixture was spray-dried at an outlet temperature of 90 to 100 ° C. using a spray dryer to obtain a white spherical particle composition having good fluidity.

Example 3 Production of Particle Disintegrating Composition 50 parts by weight of waxy rice starch, rice starch (Fine Snow: manufactured by Joetsu Starch Co., Ltd., amylopectin: amylose = 83.0: 17.0, average particle size: 4.5 μm) 32 Part by weight, 15 parts by weight of crystalline cellulose, and 3 parts by weight of anhydrous calcium hydrogen phosphate (Fujicalin SG, manufactured by Fuji Chemical Industry Co., Ltd.) are uniformly dispersed in water, and then the outlet temperature is 90 to 100 ° C. using a spray dryer. Was spray-dried to obtain a white spherical particle composition having good fluidity.

Example 4 Production of Particle Composition Erythritol (erythritol: manufactured by Mitsubishi Chemical Foods) 5 parts by weight, waxy rice starch 77 parts by weight, crystalline cellulose 15 parts by weight, anhydrous calcium hydrogen phosphate 3 parts by weight uniformly in water After the dispersion, the mixture was spray-dried at an outlet temperature of 90 to 100 ° C. using a spray dryer to obtain a white spherical particle composition having good fluidity.

Example 5 Production of Particle Composition Maltose (Sanmalto S, Hayashibara Co., Ltd.) 10 parts by weight, waxy rice starch (72 parts by weight, microcrystalline cellulose 15 parts by weight, anhydrous calcium hydrogen phosphate 3 parts by weight in water Then, using a spray dryer, it was spray dried at an outlet temperature of 90 to 100 ° C. to obtain a white spherical particle composition having good fluidity.

[Example 6] Manufacture of disintegrating compression molded product After mixing 99 parts by weight of the granulated product prepared in Example 1 and 1 part by weight of sucrose stearate (Ryoto Sugar Ester S370, manufactured by Mitsubishi Chemical Foods) Then, 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, a diameter of 8 mm, and 9R.

[Example 7] Manufacture of disintegrating compression-molded product After mixing 99 parts by weight of the granulated product prepared in Example 2 and 1 part by weight of sucrose stearate, tableting was performed with a rotary tableting machine at a set hardness of 50 N. A tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Example 8] Production of disintegrating compression molded product After mixing 99 parts by weight of the granulated product produced in Example 3 and 1 part by weight of sucrose stearate, tableting was performed using a rotary tableting machine with a set hardness of 50 N. A tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Example 9] Manufacture of disintegrating compression-molded product After mixing 99 parts by weight of the granulated product prepared in Example 4 and 1 part by weight of sucrose stearate, tableting was performed with a rotary tableting machine at a set hardness of 50N. A tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Example 10] Manufacture of disintegrating compression-molded product After mixing 99 parts by weight of the granulated product prepared in Example 5 and 1 part by weight of sucrose stearate, tableting was performed with a rotary tableting machine at a set hardness of 50N. A tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was obtained.

[Comparative Example 1] Manufacture of a disintegrating compression molded product Cornstarch (eclipse cornstarch IP (W): manufactured by Nippon Shokuhin Kako Co., Ltd., amylopectin: amylose = 75.0: 25.0, average particle size 15.0 μm) 79 parts by weight , 8.5 parts by weight of crystalline cellulose, 5 parts by weight of xylitol (Xilisolv 700: made by Rocket Japan), 5 parts by weight of magnesium carbonate, 2.5 parts by weight of calcium carbonate (Kalmigen A: made by Bihoku Flour Industries) And then spray-dried at an outlet temperature of 90 to 100 ° C. using a spray dryer (L-8 type, manufactured by Okawara Chemical Co., Ltd.) to obtain a white spherical particle composition with good fluidity. Obtained.
After mixing 99 parts by weight of the granulated product and 1 part by weight of sucrose 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, a diameter of 8 mm, and 9R.

[Table 1] Test results

  From the results of Examples 6 to 11, the compression-molded product containing the low amylose starches of the present invention is excellent in moldability, disintegration time, and texture, and is excellent as an intraoral quick disintegrating tablet. On the other hand, the compression-molded product containing the high amylose starches of Comparative Example 1 causes sticking due to high molding pressure and the like, and because it has a powdery property derived from starch in the oral cavity, as an orally disintegrating tablet Is not suitable.

[Examples 11-15, Comparative Example 1] Effect of blending amount The granulated product produced in Example 1 is lactose blending amount of Table 2, citric acid 2 parts by weight, aspartame 0.9 part by weight, lemon flavor 1 After mixing 4 parts by weight and 0.5 parts by weight of sucrose stearate, tableting was performed with a rotary 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.

[Table 2] Test results

  The disintegration time of the tablet mainly composed of lactose of Comparative Example 1 was 300 seconds or more. On the other hand, the compression-molded product containing the low amylose starches of the present invention has an extremely excellent disintegration property with a disintegration time of 30 seconds or less even if the blending amount is between 10 and 95.2 parts by weight. ing.

[Example 16]
20 parts by weight of the granulated product produced in Example 1, 21.1 parts by weight of lactose, 5 parts by weight of crystalline cellulose, 50 parts by weight of N-acetylglucosamine, 2 parts by weight of citric acid, 0.9 part by weight of aspartame, orange flavor 1 After mixing 4 parts by weight and 0.7 parts by weight of calcium stearate, the tablet was tableted with a setting hardness of 50 N using a rotary tableting machine to obtain tablets having a weight of 200 mg, a diameter of 8 mm, and 9R. The decay time was 22 seconds.

[Example 17]
82 parts by weight of waxy rice starch, 3 parts by weight of crystalline cellulose and anhydrous calcium hydrogen phosphate were placed in a mortar, and water was added and kneaded to such an extent that the powder became wet. The mixture was sieved with a 150 mesh sieve and dried overnight at 80 ° C. to obtain a white powder. After 99 parts by weight of this powder was mixed with 1 part by weight of sucrose 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, a diameter of 8 mm, and 9R. The decay time was 38 seconds.

[Formulation Example 1]
After mixing 50 parts by weight of the granulated product produced in Example 1, 15.6 parts by weight of lactose, 30 parts by weight of ascorbic acid, 1 part by weight of aspartame, 1.4 parts by weight of lemon flavor, 2 parts by weight of calcium stearate, 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.

[Formulation Example 2]
82.8 parts by weight of the granulated product produced in Example 1, 11.7 parts by weight of zinc gluconate, 2.5 parts by weight of selenium yeast, 2.5 parts by weight of chrome yeast, and 0.5 parts by weight of magnesium stearate are mixed. After that, 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, a diameter of 8 mm, and 9R.

Claims (16)

A particulate disintegrating composition having an average particle diameter of 1 to 15 μm and a starch having an amylopectin and amylose mixing ratio of 85:15 to 100: 0 and having an average particle diameter of 10 to 500 μm. The disintegrating composition according to claim 1, wherein the starch comprises one or more starches. The disintegrating composition according to claim 1, comprising an inorganic substance. The disintegrating composition according to claim 3, wherein the compounding ratio of the starch and the inorganic substance is 100: 1 to 100: 20. Magnesium carbonate, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, magnesium aluminate metasilicate, magnesium aluminate silicate, hydrotalcite, silica, with an average particle size of 0.1 to 300 μm 5. The composition according to claim 3, comprising at least one selected from the group consisting of aluminum silicate, calcium silicate, magnesium silicate, anhydrous silicic acid, silicon dioxide, magnesium oxide, magnesium hydroxide, magnesium alumina hydroxide, and dry aluminum hydroxide gel. The disintegrating particle composition according to any one of the above. The disintegrating composition according to any one of claims 1 to 5, comprising crystalline cellulose. The disintegrating composition according to claim 6, wherein the compounding ratio of starches and crystalline cellulose is 100: 1 to 100: 30. The disintegrating composition according to any one of claims 1 to 7, comprising a saccharide. The disintegrating composition according to claim 8, wherein the compounding ratio of starch and saccharide is 99: 1 to 80:20. It is a manufacturing method of the disintegrating composition of any one of Claims 1-9, Comprising: Any one or more types of starches, crystalline cellulose, inorganic powder, and saccharides are used for water. A method for producing a disintegrating composition for granulation. It is a manufacturing method of the disintegrating composition of any one of Claims 1-9, Comprising: One or more types of starches, crystalline cellulose, inorganic powder, and saccharides were disperse | distributed to water as needed. The manufacturing method of the disintegrating composition including the process of spraying and drying after that. An orally disintegrating compression-molded product containing 0.1 to 500 parts by weight of an active ingredient and 0.1 to 20 parts by weight of a lubricant with respect to 100 parts by weight of the disintegrating composition according to claim 1. An orally disintegrating compression-molded article containing starches having an average particle diameter of 1 to 15 μm and a blending ratio of amylopectin and amylose of 85:15 to 100: 0, an active ingredient and a lubricant. The orally disintegrating compression-molded product according to claim 13, comprising 0.1 to 500 parts by weight of an active ingredient and 0.1 to 20 parts by weight of a lubricant with respect to 100 parts by weight of the starch. Consisting of starches, inorganic substances and crystalline cellulose,
The compounding ratio of starches and crystalline cellulose is starches: crystalline cellulose = 100: 5 to 100: 25,
The compounding ratio of starches and inorganic substances is starches: inorganic substances = 100: 1 to 100: 10,
The orally disintegrating compression-molded product according to claim 14. 0.1 to 500 parts by weight of the active ingredient and 0.01 to 1000 parts by weight of other pharmaceutical additives as necessary with respect to a total of 100 parts by weight of the starch, crystalline cellulose and / or inorganic powder as required It is an orally disintegrating compression molding product,
The other pharmaceutical additives are excipients, disintegrants, binders, surfactants, acidulants, sweeteners, corrigents, fragrances, colorants, and stabilizers. Orally disintegrating compression-molded article according to item.

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