WO2009157214A1 - Spherical non-crystalline magnesium aluminosilicate - Google Patents

Spherical non-crystalline magnesium aluminosilicate Download PDF

Info

Publication number
WO2009157214A1
WO2009157214A1 PCT/JP2009/002972 JP2009002972W WO2009157214A1 WO 2009157214 A1 WO2009157214 A1 WO 2009157214A1 JP 2009002972 W JP2009002972 W JP 2009002972W WO 2009157214 A1 WO2009157214 A1 WO 2009157214A1
Authority
WO
WIPO (PCT)
Prior art keywords
magnesium aluminate
spherical
amorphous magnesium
aluminate silicate
hydrochloride
Prior art date
Application number
PCT/JP2009/002972
Other languages
French (fr)
Japanese (ja)
Inventor
町村等
高堂銀優
大貫哲也
小泉晴佳
Original Assignee
富士化学工業株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 富士化学工業株式会社 filed Critical 富士化学工業株式会社
Priority to JP2010517774A priority Critical patent/JPWO2009157214A1/en
Publication of WO2009157214A1 publication Critical patent/WO2009157214A1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B33/00—Silicon; Compounds thereof
    • C01B33/20—Silicates
    • C01B33/22—Magnesium silicates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/015—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B33/00—Silicon; Compounds thereof
    • C01B33/20—Silicates
    • C01B33/26—Aluminium-containing silicates, i.e. silico-aluminates
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09C—TREATMENT OF INORGANIC MATERIALS, OTHER THAN FIBROUS FILLERS, TO ENHANCE THEIR PIGMENTING OR FILLING PROPERTIES ; PREPARATION OF CARBON BLACK  ; PREPARATION OF INORGANIC MATERIALS WHICH ARE NO SINGLE CHEMICAL COMPOUNDS AND WHICH ARE MAINLY USED AS PIGMENTS OR FILLERS
    • C09C1/00—Treatment of specific inorganic materials other than fibrous fillers; Preparation of carbon black
    • C09C1/40—Compounds of aluminium
    • C09C1/405—Compounds of aluminium containing combined silica, e.g. mica
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/01—Particle morphology depicted by an image
    • C01P2004/03—Particle morphology depicted by an image obtained by SEM
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/30—Particle morphology extending in three dimensions
    • C01P2004/32—Spheres
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2006/00—Physical properties of inorganic compounds
    • C01P2006/12—Surface area
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2006/00—Physical properties of inorganic compounds
    • C01P2006/19—Oil-absorption capacity, e.g. DBP values

Definitions

  • the present invention relates to spherical amorphous magnesium aluminate silicate having high sphericity and particle strength, and a pharmaceutical preparation containing them.
  • nucleating agents As a means for controlling the release of long-acting pharmaceuticals, enteric dissolution, improving the stability of medicinal ingredients, or masking tastes, pharmaceuticals use granules having a multilayer structure centering on nucleating agents.
  • spherical particles having a uniform particle diameter and high sphericity As a nucleating agent, it is preferable to use spherical particles having a uniform particle diameter and high sphericity as a nucleating agent in order to increase the lamination rate and to uniformly laminate the thickness of each layer.
  • the properties required of the nucleating agent are required to be strength that does not break from the load applied during granulation, absorbability to absorb the spray solution, and stability that does not react with the drug.
  • spherical particles used as a nucleating agent are known as slightly spherical crystalline cellulose, purified white sugar spherical granules, mixed spherical granules of sugar / starch, lactose / crystalline cellulose spherical granules, and D-mannitol spherical granules. Although these particles had sufficient strength, the sphericity of the particle shape was not high, especially when the particle size was 100 ⁇ m or less, so that a uniform drug layer or coating layer was formed on the surface of the nucleating agent. Was enough performance. Moreover, since it consists of carbohydrates, there existed a problem that water absorption ability was low and granulation time was long.
  • Magnesium aluminate silicate is an amorphous substance represented by the following formula developed and manufactured by the present applicant in the 1955s.
  • Al2O3 ⁇ xMgO ⁇ ySiO2 ⁇ mH2O In the formula, x is 0.3 ⁇ x ⁇ 3.0, y is 1.0 ⁇ y ⁇ 3.0, and m is a number in the range of 0.1 ⁇ m ⁇ 7).
  • These are widely marketed under the name “Neusilin” (trademark, manufactured by Fuji Chemical Industry Co., Ltd., magnesium aluminate silicate).
  • Magnesium aluminate silicate is recorded in an external regulation, and has high antacid activity, moldability and specific surface area, and is used in pharmaceutical preparations as a pharmaceutical antacid, excipient, carrier and fluidizing agent. Further, since the primary particles are fine and the specific surface area is high, anti-caking agents, adsorbent carriers, and pulverized products are often used in the cosmetics and chemical products fields as fluidizing agents. As the form of the product, there are various products having different surface physical properties depending on the shape by a drying method such as an air dryer and a spray dryer and the synthesis method.
  • Spherical types include normal products (alkali type) and neutral products, both of which Al2O3 is 29.1 to 35.5% by weight, MgO is 11.4 to 14.0% by weight, and SiO2 is 29.2 to
  • the primary particles containing 35.6% by weight and having an average particle diameter of 0.01 to 1 ⁇ m are formed into spherical aggregates by spray drying, and the particle size distribution is 44 to 325 ⁇ m (Non-patent Document 1).
  • the pH of the 4 wt% slurry is 8.5 to 10.0 for normal products and 6.0 to 8.0 for neutral products, and the powder powder varies depending on the surface pH.
  • the normal product has a static specific volume of 2.7 to 3.4 ml / g, a specific surface area of 100 to 150 m 2 / g, an angle of repose of 25 to 32 degrees, an oil absorption capacity of 1.3 to 1.4 ml / g,
  • the neutral product has a static specific volume of 4.0 to 7.5 ml / g, a specific surface area of 250 to 300 m 2 / g, an angle of repose of 30 degrees, and an oil absorption capacity of 2.0 to 3.4 ml / g. .
  • This spherical type magnesium aluminate silicate is synthesized by spraying and drying aluminum aluminate, magnesium salt, silicate by adjusting the reaction conditions such as the order of addition in the solvent, pH, temperature, etc.
  • Patent Documents 1, 2, and 3 Conventional magnesium aluminate silicate has been porous and spherical particles by spray drying, but the particle strength is not sufficiently high and the specific volume is relatively large.
  • Patent Document 4 There is also a granule obtained by spray-drying 30% by weight or more of magnesium aluminate metasilicate, silicic anhydride and water insoluble powder. Even when a large amount of moisture is present, the strength is weak enough to maintain the strength and shape. For example, in a shaking test, at least about 20% is destroyed. There is a powder composition obtained by spray drying magnesium aluminate silicate and sugar (Patent Document 5). It is an excipient for intraoral quick disintegrating tablets and its strength is not clarified.
  • the inventors of the present invention smashed amorphous magnesium aluminate silicate to several ⁇ m or less, and spray-dried heavy amorphous spherical magnesium aluminate silicate excellent in particle strength, sphericity, and water absorption ability. It was found that it can be obtained.
  • the present invention has the following configuration. (1) It is composed of amorphous primary particles having an average particle size of 0.01 to 0.5 ⁇ m, a particle strength of 50 to 1000 g / mm 2 , an average particle size of 1 to 500 ⁇ m, and a sphericity of 0.8 or more.
  • the spherical amorphous magnesium aluminate silicate according to (1) having a particle strength of 100 to 1000 g / mm 2 and an average particle size of 5 to 300 ⁇ m, (3) Specific surface area of 10 to 500 m 2 / g, static specific volume of 1.0 to 7.0 ml / g, oil absorption of 0.5 to 5.0 ml / g, water absorption of 0.5 to 5.
  • a granular composition comprising an active ingredient layer around the spherical amorphous magnesium aluminate silicate according to any one of (1) to (5), (7) A pharmaceutical composition comprising the spherical amorphous magnesium aluminate silicate according to any one of (1) to (5).
  • the spherical amorphous magnesium silicate aluminate having high particle strength according to the present invention has high specific surface area and high adsorption performance, and is useful for use in pharmaceutical preparations such as adsorption and mixing of core particles and active substances.
  • FIG. 4 is a SEM photograph (1 memory 5 ⁇ m) of spherical amorphous magnesium aluminate silicate of Example 2.
  • 2 is a SEM photograph (1 memory 5 ⁇ m) of spherical amorphous magnesium aluminate of Comparative Example 1.
  • 4 is a SEM photograph (1 memory 5 ⁇ m) of spherical amorphous magnesium aluminate of Comparative Example 2.
  • 4 is a SEM photograph (1 memory: 10 ⁇ m) of granules of Example 3.
  • FIG. 4 is a SEM photograph (1 memory: 200 ⁇ m) of spherical amorphous magnesium aluminate of Example 4.
  • 6 is a SEM photograph (1 memory: 200 ⁇ m) of crystalline cellulose of Comparative Example 4. It is a table
  • magnesium aluminate silicate is represented by the following composition formula (I).
  • Al 2 O 3 .xMgO.ySiO 2 .mH 2 O (I) (In the formula, 0.1 ⁇ x ⁇ 3.0, y is 0.5 ⁇ y ⁇ 5.0, and m is a number in the range of 0.1 ⁇ m ⁇ 10)
  • the Al 2 O 3 .xMgO.ySiO 2 may be in a range that can maintain a non-crystalline state and form fine primary particles, and 0.1 ⁇ x ⁇ 3.0, y is 0.5 ⁇ y ⁇ 5.0, preferably 0.2 ⁇ x ⁇ 2.0, y is 0.5 ⁇ y ⁇ 3.0, more preferably 0.5 ⁇ x ⁇ 1.5, and y is 1. 4 ⁇ y ⁇ 2.1.
  • the non-crystalline state can be confirmed from the absence of a crystal peak by X-RD.
  • the spherical amorphous magnesium aluminate silicate of the present invention is an aggregate of primary particles of amorphous spherical magnesium aluminate silicate having an irregular shape.
  • the finer the primary particles the more cohesive and the higher the strength. Aggregates are easily formed, and the average particle size is 0.01 to 1.0 ⁇ m, preferably 0.01 to 0.5 ⁇ m.
  • the spherical amorphous magnesium aluminate silicate of the present invention has an average particle size of 1 to 500 ⁇ m, preferably an average particle size of 1 to 300 ⁇ m, more preferably 1 to 200 ⁇ m.
  • the spherical amorphous magnesium aluminate silicate of the present invention has a particle strength of 50 to 1000 g / mm 2 , preferably 100 to 1000 g / mm 2 .
  • commercially available spherical type amorphous magnesium aluminate silicate (Neusilin (trademark) SG1, NS2N, etc.) cannot be measured with a particle hardness measuring device because the particle strength is small (50 g / mm 2 or less).
  • the spherical amorphous magnesium aluminate silicate of the present invention has a sphericity of 0.8 or more, preferably 0.85 or more, more preferably 0.9 or more.
  • Ordinary spherical particles can not reduce the unevenness derived from the raw material, the smaller the particle diameter, the greater the proportion of those unevenness, the shape becomes distorted and the sphericity decreases, the spherical non-crystal of the present invention
  • Magnesium aluminate silicate has a feature that the sphericity does not change even when the particle diameter is reduced.
  • the spherical amorphous magnesium aluminate silicate of the present invention has a particle size as small as nano-order, and the particles themselves are porous agglomerates of porous amorphous magnesium aluminate silicate with small inter-particle voids. It is believed that there is.
  • the sphericity is a value obtained by dividing the minor axis of a spherical particle by an SEM photograph or an optical microscope by the major axis, as will be described later.
  • the spherical amorphous magnesium aluminate silicate of the present invention has a specific surface area equivalent to that of commercially available spherical amorphous magnesium aluminate silicate, and is 20 to 500 m 2 / g, preferably 40 to 400 m 2 / g, more preferably. Is 60 to 300 m 2 / g.
  • the spherical amorphous magnesium aluminate silicate of the present invention has a static specific volume equivalent to that of commercially available spherical amorphous magnesium aluminate silicate, and is 1.0 to 7.0 ml / g, preferably 1.0 to The amount is 5.0 ml / g, more preferably 1.0 to 4.0 ml / g.
  • the spherical amorphous magnesium aluminate silicate of the present invention has an oil absorption equivalent to commercially available spherical amorphous magnesium aluminate silicate, and is 0.5 to 5.0 ml / g, preferably 1.0 to 5. 0 ml / g.
  • the spherical amorphous magnesium aluminate silicate of the present invention has a water absorption equivalent to that of commercially available spherical amorphous magnesium aluminate silicate, and is 0.5 to 5.0 ml / g, preferably 1.0 to 5. 0 ml / g.
  • amorphous spherical magnesium aluminate silicate of the present invention there are two types of amorphous spherical magnesium aluminate silicate of the present invention, a normal product (alkali type) and a neutral product (neutral type), each having different physical properties depending on the surface hydroxide of the primary particles.
  • the alkali type refers to magnesium aluminate silicate having a 4% slurry pH of 8.5 to 11.0, which will be described later
  • the neutral type refers to magnesium aluminate having a 4% slurry pH of 5.5 to 8.5, which will be described later.
  • the 4% slurry pH is a pH value measured by a pH meter after weighing 2 g of a sample and adding water to make a total volume of 50 ml, stirring for 2 minutes.
  • the amorphous spherical magnesium aluminate silicate of the present invention is produced by pulverizing amorphous magnesium aluminate silicate suspended in a solvent into fine particles and spray drying.
  • the amorphous spherical magnesium aluminate silicate of the present invention can be produced commercially or can be produced by a known method disclosed by the present applicant.
  • Japanese Patent Publication No. 34-513, Japanese Patent Publication No. 34-514 And JP-B-34-618, JP-B-36-23163, JP-B-42-7719, JP-B-52-16078, and JP-B-57-17845 can be produced commercially or can be produced by a known method disclosed by the present applicant.
  • Japanese Patent Publication No. 34-513 Japanese Patent Publication No. 34-514 And JP-B-34-618, JP-B-36-23163, JP-B-42-7719, JP-B-52-16078, and JP-B-57-17845.
  • the method for producing amorphous magnesium aluminate silicate has desired physical properties by appropriately selecting mixing conditions such as order of addition of aluminum salt, magnesium salt, and silicate in a solvent, pH, temperature, and the like.
  • the amorphous magnesium aluminate silicate can be produced. These dried products or undried products after wet synthesis are used.
  • pulverization method either wet pulverization or dry pulverization may be used.
  • wet pulverization Nanomizer (product name, manufactured by SGS Engineering Co., Ltd.), Starburst (product name, manufactured by Sugino Machine Co., Ltd.), Ultimateizer (product) Name, Karasawa Fine Co., Ltd.), high-pressure homogenizers such as microfluidizer (product name, manufactured by Mizuho Kogyo Co., Ltd.), bead mill, disk mill, homomixer, etc.
  • the pulverization conditions may be any conditions as long as the desired average particle diameter can be obtained.
  • the slurry concentration that can be pulverized is adjusted, and a plurality of passes at a pressure of 100 MPa or more can be selected as appropriate.
  • the bead mill the bead system, the flow rate, the rotation speed, and the slurry concentration can be appropriately selected so as to obtain a desired average particle size.
  • spherical particles produced by, for example, ordinary spray drying of these secondary agglomerated particles have a large gap with few contact points of constituent particles, a large specific volume, and a low particle strength.
  • the spherical amorphous magnesium aluminate silicate of the present invention is dispersed and pulverized by pulverization of the amorphous magnesium silicate aluminate forming the secondary agglomerated particles to secondary agglomerated particles having small intergranular voids, Adjust to the desired average particle size.
  • the average particle size in the pulverization is 0.01 to 10 ⁇ m, preferably 0.05 to 6 ⁇ m, more preferably 0.01 to 3 ⁇ m.
  • the dry-milled amorphous magnesium aluminate silicate is suspended in a solvent, and the wet-milled amorphous magnesium aluminate silicate is adjusted to adjust the concentration if necessary.
  • the solvent may be any solvent that does not affect the properties of the particles, and examples thereof include hydrophilic solvents such as water, ethanol, methanol, and acetone, preferably water.
  • 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 of the suspension may be in a range that can be sprayed into the air layer, that is, the solid content is 1 to 40% by weight, preferably 5 to 30% by weight.
  • an additive capable of changing physical properties to be described later can be added to adjust the desired physical properties.
  • Drying is performed by spraying the suspension of amorphous magnesium aluminate silicate into the air layer.
  • the drying method by spraying in the gas layer can be performed by any known method for forming spherical particles.
  • spray drying, fluidized bed drying, rolling bed drying, stirring It can be performed by grain drying, freeze drying or the like.
  • spray drying is easy to form the porosity by instantly removing the solvent component, easy to form particles with high sphericity by cohesive drying while maintaining a liquid spherical shape, uniform particle size
  • it is most suitable for the production of spherical particles because the production setting of fine particles is easy.
  • the spray drying conditions are not particularly limited, it is preferable to use a disk-type or nozzle-type spray dryer as the spray device.
  • the inlet temperature is preferably about 120 to 400 ° C.
  • the outlet temperature is preferably about 80 to 300 ° C.
  • Spherical amorphous magnesium aluminate silicate can change or impart particle strength, disintegration, moldability, etc. by blending an additive capable of changing physical properties in addition to amorphous magnesium aluminate silicate.
  • the additive capable of changing the physical properties can be added in the range of 1 to 99% by weight, preferably 10 to 90% by weight, based on the whole spherical particles.
  • the particle strength can be further increased by blending a substance having low melting point or solvent solubility.
  • the pores of amorphous magnesium aluminate silicate are filled, the specific surface area, oil absorption, and water absorption are reduced.
  • a water-soluble additive or disintegrant disintegration can be imparted by contact with water.
  • the additive capable of changing physical properties is a substance generally corresponding to an excipient, a disintegration aid, and a binder in the field of pharmaceutical preparations, but is not particularly limited to these uses. Two or more additives whose physical properties can be changed can be blended in the range of 0 to 89% by weight, respectively.
  • excipient in the present invention examples include starch acrylate, L-aspartic acid, aminoethylsulfonic acid, aminoacetic acid, candy (powder), gum arabic, gum arabic powder, alginic acid, sodium alginate, pregelatinized starch, and inositol.
  • Ethyl cellulose ethylene vinyl acetate copolymer, erythritol, sodium chloride, olive oil, kaolin, cacao butter, casein, fructose, pumice granules, carmellose, carmellose sodium, hydrous silicon dioxide, dry yeast, dry aluminum hydroxide gel, dry sodium sulfate , Dried magnesium sulfate, agar, agar powder, xylitol, citric acid, sodium citrate, disodium citrate, glycerin, calcium glycerophosphate, sodium gluconate, L-glutamine, clay, clay -Grain, croscarmellose sodium, aluminum silicate, synthetic aluminum silicate, hydroxypropyl starch, crystalline cellulose, calcium silicate, magnesium silicate, light anhydrous silicic acid, light liquid paraffin, cinnamon powder, crystalline cellulose, crystalline cellulose Carmellose sodium, microcrystalline cellulose, pearl millet, synthetic aluminum silicate, synthetic hydrotalcite,
  • disintegrant in the present invention examples include adipic acid, alginic acid, sodium alginate, pregelatinized starch, erythritol, fructose, sodium carboxymethyl starch, carmellose, carmellose calcium, carmellose sodium, hydrous silicon dioxide, agar, xylitol, guar gum , Calcium citrate, croscarmellose sodium, crospovidone, synthetic aluminum silicate, low-substituted hydroxypropyl cellulose, crystalline cellulose, crystalline cellulose carmellose sodium, wheat starch, rice starch, cellulose acetate phthalate, dioctyl sodium sulfo Succinate, sucrose fatty acid ester, magnesium magnesium hydroxide, calcium stearate, polyoxyl stearate, sesquiolein Sorbitan, gelatin, shellac, sorbitol, sorbitan fatty acid ester, talc, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate,
  • binder in the present invention examples include, for example, ethyl acrylate / methyl methacrylate copolymer emulsion, acetylglycerin fatty acid ester, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, aminoethylsulfonic acid, candy (powder).
  • Coating agents include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, starch paste, pregelatinized starch, polyvinyl pyrrolidone, gum arabic, sugar syrup, sodium carboxymethylcellulose, pullulan, polyvinyl alcohol, polyethylene glycol, ethylcellulose, acrylic copolymer Examples include coalescence, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, carboxymethylethylcellulose, cellulose acetate, hydroxypropylmethylcellulose acetate succinate, shellac, and silicone resin.
  • Surfactants include sodium lauryl sulfate, lauric acid diethanolamide, sucrose fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, polyethylene glycol fatty acid ester, stearyl alcohol, cetanol, polyoxyethylene polyoxypropylene glycol, polysorbate, polyoxy Examples include ethylene hydrogenated castor oil and phospholipid.
  • the spherical amorphous magnesium aluminate of the present invention can be used as a core particle for producing a granule (granulated particle, fine particle) composition. It is suitable for a controlled-release preparation for gastrointestinal absorption such as bitterness masking for oral disintegrating tablets, sustained release and rapid release.
  • This granular composition consists of an active ingredient layer centering on the spherical amorphous magnesium aluminate of the present invention. If necessary, a coating layer can be formed outside the active ingredient layer.
  • the granular composition comprises 0.01 to 500 parts by weight, preferably 0.1 to 200 parts by weight of the active ingredient per 100 parts by weight of spherical amorphous magnesium aluminate silicate.
  • the active ingredient may be supported on an excipient and granulated with a binder.
  • the blending amount of the coating component is 0.01 to 100 parts by weight with respect to 100 parts by weight of spherical amorphous magnesium aluminate silicate.
  • a binder, a coating agent, an excipient and the like can be blended in the active ingredient layer and / or the coating layer.
  • a water-soluble substance, a plasticizer, a stabilizer, a colorant, a surfactant, a fluidizing agent, etc. for adjusting the dissolution rate may be added as necessary.
  • the active ingredient is not particularly limited, and drugs for central nerves such as agents for peripheral nerves, antipyretic analgesic / anti-inflammatory agents, hypnotic sedatives, and agents for peripheral nerves; drugs for peripheral nerves such as skeletal muscle relaxants and autonomic nerve agents; Cardiovascular agents such as cardiotonic agents, arrhythmic agents, diuretics, vasodilators; respiratory organ agents such as bronchodilators and antitussives; gastrointestinal agents such as digestives, intestines, antacids; hormones, antihistamines, vitamins Metabolic drugs such as drugs; anti-ulcer agents; antibiotics; chemotherapeutic agents; herbal extracts;
  • Examples include active ingredients for cold medicine and active ingredients for rhinitis.
  • active ingredient for cold medicine include antipyretic analgesic / anti-inflammatory agents, bronchodilators, antihistamines, antitussives, antiseptics, antiseptic antiseptics, vitamins, and herbal medicine extracts.
  • active ingredient for rhinitis include sympathomimetic agents, parasympathetic nerve blockers, antiallergic agents and antiinflammatory agents, and the like.
  • Antipyretic analgesic and anti-inflammatory agents include, for example, pranlukast hydrate, acetaminophen, phenacetin, levetamine hydrochloride and other aniline derivatives, etenzamide, sazapyrine, methyl salicylate, phenyl salicylate, sodium salicylate, choline salicylate, aspirin, aspirin aluminum Salicylic acid derivatives, etc., pyrazolo derivatives such as isopropylantipyrine, sulpyrine, phenylbutazone, ketophenylbutazone, antipyrine, aminopyridine, propionic acid derivatives such as ibuprofen, ketoprofen, oxacyprozin, naproxen, fenoprofen calcium, thiaprofenic acid, etc.
  • bronchodilators examples include ephedrine hydrochloride, dl-methyl ephedrine hydrochloride, dl-methyl ephedrine hydrochloride saccharinate, isoprenaline hydrochloride, isoproterenol sulfate, methoxyphenamine hydrochloride, orciprenaline sulfate, chlorprenalin hydrochloride, trimethoxy hydrochloride Ol, salbutamol sulfate, terbutaline sulfate, hexoprenaline sulfate, formoterol fumarate, fenoterol hydrobromide, procaterol hydrochloride, pluterol hydrochloride, clenpterol hydrochloride, mabuterol hydrochloride, aminophylline, theophylline, dibrophyrin, proxyphylline, xanthine derivatives, odor And anticholinergic agents such as flutropium
  • Antihistamines include, for example, ethanolamine antihistamines such as diphenhydramine, propylamine antihistamines such as dl-chlorpheniramine maleate and chlorpheniramine maleate, alimemazine tartrate, isothipentyl hydrochloride, promethazine hydrochloride, and phenothiazine hydrochloride.
  • Examples include antihistamines, diphenylpyralin, carbinoxamine maleate, clemastine fumarate, iproheptin hydrochloride, homochlorcyclidine hydrochloride, cyproheptadine hydrochloride, dimethindene maleate, triprolidine hydrochloride, olopatadine hydrochloride, and the like.
  • Antitussives include, for example, codeines such as codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, cloperastine, noscapine dimethylmorphane, oxerazine, pentoxyberine citrate, eprazinone hydrochloride, clobutinol hydrochloride, citric acid
  • codeines such as codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, cloperastine, noscapine dimethylmorphane, oxerazine, pentoxyberine citrate, eprazinone hydrochloride, clobutinol hydrochloride, citric acid
  • codeines such as codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, cloperastine, noscapine dimethylmorphane, oxerazine, pentoxyberine citrate, eprazinone hydro
  • Examples of the desalting agent include potassium guaiacol sulfonate, carbocysteine, cysteine derivatives such as L-ethylcysteine hydrochloride, L-methylcysteine hydrochloride, acetylcysteine, bromhexine, ambroxol hydrochloride, and the like.
  • Examples of antitussive removers include guaifenesin, tipipedin, oxymethebanol, aroclamide hydrochloride, carbetapentane phenate, trimethquinol hydrochloride, methoxyphenamine hydrochloride, and the like.
  • the medicinal component exemplified as the antitussive agent, antifouling agent, and antitussive exfoliating agent may sometimes exhibit an antitussive action and / or an antifouling action.
  • Examples of psychotropic drugs include chlorpromazine and reserpine.
  • Examples of the anxiolytic drug include tofisopam, zolpidem tartrate, alprazolam, chlordiazepoxide, diazepam and the like.
  • Examples of the antidepressant include tricyclic drugs such as isipran, tetracyclic drugs such as maprotiline hydrochloride, SSRI (selective serotonin reuptake inhibitor) such as sertraline hydrochloride, and SNRI (serotonin noradrenaline such as milnacipran hydrochloride). Reuptake inhibitors).
  • Examples of the hypnotic sedative include estazolam, nitrazepam, diazepam, perlapine, phenobarbital sodium and the like.
  • Examples of antispasmodic agents include scopolamine hydrobromide, papaverine hydrochloride, diphenhydramine hydrochloride, and the like.
  • Examples of central nervous system drugs include citicoline.
  • Examples of the antiepileptic agent include phenytoin and carbamazepine.
  • Examples of the sympathomimetic agent include isoproterenol hydrochloride.
  • Examples of peripheral neuropathy agents include epalrestat and mecobalamin.
  • Gastrointestinal drugs include, for example, healthy gastrointestinals such as diastase, sugar-containing pepsin, funnel extract, cellulase AP3, lipase AP, and cinnamon oil, and intestinals such as berberine chloride, resistant lactic acid bacteria and bifidobacteria.
  • the antacid include magnesium carbonate, sodium hydrogen carbonate, synthetic hydrotalcite, precipitated calcium carbonate, magnesium oxide and the like.
  • the anti-ulcer agent include teprenone, famotidine, lansoprazole, omeprazole, rabeprazole, cimetidine, ranitidine hydrochloride and the like.
  • antihypertensive agents examples include carvedilol, olmesartan medoxomil, benidipine hydrochloride, telmisartan, amlodipine besylate, delapril, captopril, hydralazine hydrochloride, labetalol hydrochloride, manidipine hydrochloride, candesartan cilexetil, methyldopa, perindopril erbumine, etc. It is done.
  • the vasoconstrictor examples include phenylephrine hydrochloride.
  • vasodilator examples include nicorandil, carbochromene hydrochloride, molsidomine, perapamil hydrochloride, cinnarizine and the like.
  • arrhythmic agent examples include procainamide hydrochloride, propranolol hydrochloride, pindolol and the like.
  • cardiotonic agent examples include caffeine and digoxin.
  • diuretic examples include isosorbide, furosemide, hydrochlorothiazide and the like.
  • hyperlipidemia agents examples include ethyl icosapentate, cerivastatin sodium, simvastatin, pravastatin sodium, pitavastatin calcium, atorvastatin calcium hydrate, and the like.
  • Antibiotics include, for example, vancomycin hydrochloride, cefdinir, itraconazole, clarithromycin, cefcapene pivoxil hydrochloride, cephalexin, cefaclor, amoxicillin, pipmecillin hydrochloride, cefotium hexetyl hydrochloride, cefadroxyl, cefixime, cefditren pivoxil, cefterampyrix And cephem compounds such as cefpodoximiproxetil, synthetic antibacterial agents such as ampicillin, cyclacin, nalidixic acid, levofloxacin, enoxacin, monobactams such as carmonam sodium, penems and carbapenems.
  • the chemotherapeutic agent include sulfamethizole.
  • Examples of the agent for diabetes include tolbutamide, voglibose, pioglitazone hydrochloride, glibenclamide, troglidazone and the like.
  • Examples of antispasmodic agents include meclizine hydrochloride and dimenhydrinate.
  • Antirheumatic drugs include methotrexate, bucillamine and the like.
  • Examples of hormone agents include liothyronine sodium, dexamethasone sodium phosphate, prednisolone, oxendron, leuprorelin acetate, and the like.
  • Alkaloid narcotics include opium, morphine hydrochloride, throne, oxycodone hydrochloride, opium alkaloid hydrochloride, ***e hydrochloride, and the like.
  • sulfa drugs include sulfisomidine and sulfamethizole.
  • anti-gout drugs include allopurinol and colchicine.
  • blood coagulation inhibitor include dicumarol.
  • Examples of the antineoplastic agent include 5-fluorouracil, uracil, mitomycin, manidipine hydrochloride, voglibose, candesartan cilexetil, pioglitazone hydrochloride and the like.
  • active ingredients include, for example, tamsulosin hydrochloride, donepezil hydrochloride, oseltamivir, limaprost alphadex, loxoprofen sodium, sarpogrelate hydrochloride, ursodeoxycholic acid, alacepril, brotizolam, berberine hydrochloride or tannate, loperamide hydrochloride, ebastine, etc. Is mentioned.
  • Nutritional ingredients include proteins, carbohydrates, lipids, vitamins, minerals and other beneficial ingredients.
  • vitamins include carotenoids such as astaxanthin, vitamin A, ⁇ -carotene, lutein, zeaxanthin, fursultiamine, fursultiamine hydrochloride, prosultiamine, octothiamine, thiamine disulfide, bisbutyamine, 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 tocop
  • 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 from microorganisms such as foods; extracts from plants such as carrot extract, assembly extract, rosemary extract, buckwheat extract, garlic extract, hinokitiol, cephalanthin; ⁇ - or ⁇ -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 ⁇ -hydroxy acids and derivatives thereof and salts thereof, glycyrrhizic acid, glycyrrhetinic acid, mefenamic acid, phenylbutazone, indomethaci
  • the production of the granular composition using the spherical amorphous magnesium aluminate silicate of the present invention is carried out by using the spherical amorphous magnesium aluminate silicate of the present invention as a nucleating agent, fluidized bed granulation, stirring granulation, rolling layer. It can carry out by well-known wet granulation methods, such as granulation, spray-drying granulation, and extrusion granulation, These conditions can be performed by a conventional method.
  • the binder-containing solution is continuously sprayed, and at the same time, an active ingredient and, if necessary, an excipient. Is supplied, and the powder is coated on spherical amorphous magnesium aluminate silicate and dried to form granules.
  • a solution in which the drug is dissolved or suspended in a binder-containing solution is sprayed, and the drug is applied to spherical amorphous magnesium aluminate silicate.
  • the powder containing is coated and dried to form granules. Subsequently, the coating solution or coating suspension is sprayed while the granules are flowing, and dried to form a film layer for the purpose of moisture proofing, bitterness masking, enteric properties, sustained release, sustainability, etc. Granules. Further, when the powder containing the drug is coated, a coating-containing solution or a coating suspension may be sprayed simultaneously. The order of granulation can be appropriately selected according to the type of drug.
  • the solvent of the above solution may be any pharmaceutically acceptable solvent without affecting these physical properties, and examples thereof include water, ethanol, methanol and the like.
  • the coating agent known excipients and the aforementioned coating agents can be used.
  • the spraying speed can be increased in the granulation process than the conventional organic nucleating agent, and the time required for the layer formation process Can be shortened.
  • the conditions vary depending on the granulator and the like, for example, in the case where an effect component is placed, the time can be shortened by 30 to 80%.
  • the layering can be completed in 10 to 20 hours. If it is light, the number of particles that are not sprayed by the wind is increased. However, since it is heavy, it is easy to apply the spray evenly with little wind.
  • the surface of the spherical amorphous magnesium aluminate of the present invention is a hydroxyl group and is not easily charged. It has better granulation operability than conventional carbohydrate-based organic nucleating agents.
  • the pharmaceutical preparation of the present invention can be in the form of a solid dosage form such as a tablet, a rapidly disintegrating tablet in the oral cavity, a capsule, a granule or a fine granule, or a liquid preparation of a suspension.
  • a solid dosage form such as a tablet, a rapidly disintegrating tablet in the oral cavity, a capsule, a granule or a fine granule, or a liquid preparation of a suspension.
  • the coating for releasability and bitterness masking can be listed uniformly, it is suitable for sustained release agents and oral rapid disintegrating agents that require release control.
  • the tablet is produced by mixing the granular composition of the present invention or the spherical amorphous magnesium aluminate silicate of the present invention with an additive component that can be blended with a pharmaceutical product by a method such as dry mixing or wet mixing, and then compression molding. .
  • a disintegrant such as F-MELT (trademark, manufactured by Fuji Chemical Industry Co., Ltd.), crospovidone, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, croscarmellose sodium, starch, etc. It can be a fast disintegrant.
  • the additive components that can be incorporated into the pharmaceutical preparation of the present invention include lubricants (sucrose fatty acid ester, magnesium stearate, talc , Sodium stearyl fumarate, etc.), acidulants (eg, citric acid, tartaric acid, malic acid, ascorbic acid, etc.), foaming agents (eg, sodium bicarbonate, sodium carbonate, etc.), sweeteners (sodium saccharin, dipotassium glycyrrhizin, aspartame, stevia) , Thaumatin etc.), fragrance (eg lemon oil, orange oil, menthol etc.), colorant (eg edible red No.
  • lubricants sucrose fatty acid ester, magnesium stearate, talc , Sodium stearyl fumarate, etc.
  • acidulants eg, citric acid, tartaric acid, malic acid, ascorbic acid, etc.
  • foaming agents eg, sodium bicarbonate, sodium carbon
  • the granule composition of the present invention and the pharmaceutical composition of the present invention can be used for foods, cosmetics, agricultural chemicals and the like in addition to pharmaceuticals. In particular, it is suitable for controlling the absorbability of functional food in the body.
  • spherical amorphous magnesium aluminate silicate of the present invention include high particle strength, sphericity, and high specific surface area, so column chromatography packing materials, various packing materials, various adsorption carriers, It can be used as a deodorant, a catalyst, a tooth abrasive, a release agent such as a film, a paint adhesion preventive or a matting material.
  • the average particle size of the dry powder was measured with a dry particle size distribution analyzer (LA-920, manufactured by Horiba, Ltd.).
  • a dry particle size distribution analyzer LA-920, manufactured by Horiba, Ltd.
  • the specific surface area was measured using a BET specific surface area measuring device (Monosorb MS-17, manufactured by Yuasa Ionics Co., Ltd.).
  • Water absorption was performed using linseed oil based on JISK5101.
  • Water absorption The amount of water absorption was based on JISK5101, using water instead of linseed oil.
  • Example 1 A suspension of 7.5 kg of amorphous magnesium aluminate silicate (also known as: magnesium aluminate metasilicate, trade name “Neusilin NFL2N”, neutral product, manufactured by Fuji Chemical Industry Co., Ltd.) in 50 L of water with a flow rate of 7 L / min. Then, using an optimizer pulverizer [Starburst Large Machine HJP-25080, manufactured by Sugino Machine Co., Ltd.], the powder was pulverized five times under the condition of a pressure of 245 MPa. The particle size distribution of the slurry after pulverization was 2.9 ⁇ m in terms of average particle size.
  • amorphous magnesium aluminate silicate also known as: magnesium aluminate metasilicate, trade name “Neusilin NFL2N”, neutral product, manufactured by Fuji Chemical Industry Co., Ltd.
  • an optimizer pulverizer Starburst Large Machine HJP-25080, manufactured by Sugino Machine Co., Ltd.
  • this pulverized liquid was prepared to a concentration of 11.6 w / w% and spray-dried using a centrifugal atomizer under the conditions of a rotational speed of 9000 rpm, a heat input temperature of 330 ° C., and an outlet temperature of 160 ° C., and spherical amorphous alumina silicate Magnesium acid was obtained.
  • FIG. 1 shows an SEM photograph
  • FIG. 7 shows an X-RD chart.
  • Example 2 Water is added to 80.4 g of sodium aluminate (Al 2 O 3 : 18.7%) to make a total volume of 500 ml. Water is added to 124.8 g of No. 3 sodium silicate (SiO 2 : 29.5%) to make a total amount of 250 ml. Magnesium chloride hexahydrate (MgO: 19.8%) 41.7 g and aluminum sulfate (Al 2 O 3 : 17.2%) 34.0 g are dissolved in water to make a total amount of 250 ml. Liquid A was placed in the reaction vessel, and liquid B was added at a rate of 10 ml / min with stirring. C solution was then added at approximately 25 ml / min.
  • the mixture was aged for 30 minutes, and then the product was filtered and washed with water.
  • the concentration was adjusted to 19 w / w%, and the mixture was pulverized 5 times under the conditions of a flow rate of 7 L / min and a pressure of 245 MPa using an optimizer pulverizer [Starburst Large Machine HJP-25080, manufactured by Sugino Machine Co., Ltd.].
  • the particle size distribution of the slurry after pulverization was 2.0 ⁇ m in terms of average particle size.
  • this pulverized liquid was prepared to a concentration of 14.9 w / w%, and spray-dried using a centrifugal atomizer under the conditions of a rotation speed of 9000 rpm, a heat input temperature of 330 ° C., and an outlet temperature of 160 ° C., and spherical amorphous alumina silicate Magnesium acid was obtained.
  • FIG. 2 shows an SEM photograph.
  • Example 2 Filtration, water washing, concentration adjustment (19 w / w%) suspension (average particle diameter 14.7 ⁇ m) obtained in Example 2 was rotated at 9000 rpm, heat input temperature 330 ° C., outlet temperature using a centrifugal atomizer. Spray drying was performed at 160 ° C. to obtain spherical amorphous magnesium aluminate silicate.
  • FIG. 4 shows an SEM photograph.
  • the spherical amorphous magnesium aluminate silicate of the present invention has high particle strength, sphericity, low specific volume, and exhibits characteristics not found in conventional spherical amorphous magnesium aluminate silicate. SEM photographs show that the spherical amorphous magnesium aluminate silicate of the present invention has finer particles densely aggregated.
  • Example 3 Manufacture of granules 100 g of spherical amorphous magnesium aluminate silicate of Example 1 was charged into a fluidized granulator / dryer (Freund Sangyo Co., Ltd., Flow Coater Mini FL), and hydroxypropylcellulose 8 367 g of purified water containing 3 g and 41.7 g of ground acetaminophen (200 mesh sieve product) was sprayed at a spraying speed of 1 to 4 g / min to obtain coated granules. The average particle size was 142 ⁇ m.
  • FIG. 5 shows an SEM photograph. A layer of hydroxypropyl cellulose and acetaminophen is uniformly wrapped around the spherical amorphous magnesium aluminate silicate of the present invention to form beautiful granules.
  • Example 3 Manufacture of granules 500 g of spherical amorphous magnesium aluminate silicate of Example 1 was charged into a fluidized granulation dryer (manufactured by Paulex, Multiplex MP-01 type SPC), and 100 g of hydroxypropylcellulose and pulverized 4400 g of purified water containing 500 g of acetaminophen (200 mesh sieve product) was sprayed at a spray rate of 2.2 to 9.6 g / min for 16 hours to obtain coated granules.
  • FIG. 7 shows an SEM photograph
  • FIG. 9 shows the relationship between the spray speed and the spray time.
  • the spherical amorphous magnesium aluminate of the present invention has a finer spherical shape than the nucleating agent made of crystalline cellulose, has a high spray rate, and greatly takes the time required for coating. It can be seen that it has been shortened.
  • Example 5 Manufacture of tablets 300 g of the granules of Example 3 were mixed with 200 g of excipient F-MELT [trademark, manufactured by Fuji Chemical Industry Co., Ltd.] for oral rapid disintegrant, 5 g of magnesium stearate, and 5 g of aspartame.
  • excipient F-MELT trademark, manufactured by Fuji Chemical Industry Co., Ltd.
  • a rotary tableting machine HT-AP18SS-II, manufactured by Hata Iron Works Co., Ltd.
  • a tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was tableted with a set hardness of 50 N to obtain an orally rapidly disintegrating tablet. It was possible to tablet well without capping or peeling.
  • the disintegration time in the pharmacopoeia disintegration test was 16 seconds. The bitterness of acetaminophen was not felt.

Abstract

Disclosed is a spherical granular core particle which can be used as a nucleating agent for the production of granules for use in medicinal products, cosmetic products, foods and others, has high particle strength, high water absorbability and high sphericity, is insoluble in water, and has good moldability. Non-crystalline magnesium methaluminosilicate is pulverized and spray-dried, thereby producing non-crystalline spherical magnesium aluminosilicate having improved particle strength and sphericity while keeping good properties of non-crystalline magnesium aluminosilicate for use as an excipient (oil absorbability, water absorbability, a high specific surface area, and antacid properties).

Description

球状非結晶ケイ酸アルミン酸マグネシウムSpherical amorphous magnesium aluminate silicate
　本発明は、真球度・粒子強度の高い球状非結晶ケイ酸アルミン酸マグネシウム、並びそれらを含有する医薬製剤に関する。 The present invention relates to spherical amorphous magnesium aluminate silicate having high sphericity and particle strength, and a pharmaceutical preparation containing them.
　持効性医薬品の放出制御、腸溶化、薬効成分の安定性改善または味のマスキングなど手段として、医薬品では核剤を中心に多層構造を有する顆粒が用いられている。多層構造の顆粒を製造する場合、積層率を高め各層の厚さを均一に積層させるために、粒径が揃っており真球度が高い球形の粒子を核剤として用いることが好ましい。さらに、核剤の要する性質としては、造粒時に掛かる負荷から破損しない強度、噴霧溶液を吸収する吸収能、薬剤と反応しない安定性が求められる。 As a means for controlling the release of long-acting pharmaceuticals, enteric dissolution, improving the stability of medicinal ingredients, or masking tastes, pharmaceuticals use granules having a multilayer structure centering on nucleating agents. When producing granules having a multilayer structure, it is preferable to use spherical particles having a uniform particle diameter and high sphericity as a nucleating agent in order to increase the lamination rate and to uniformly laminate the thickness of each layer. Furthermore, the properties required of the nucleating agent are required to be strength that does not break from the load applied during granulation, absorbability to absorb the spray solution, and stability that does not react with the drug.
　これまで核剤として用いる球状粒子は、やや球状の結晶セルロース、精製白糖球状顆粒、砂糖・澱粉の混合球状顆粒、乳糖・結晶セルロース球状顆粒、Ｄ－マンニトール球状顆粒が知られている。これらは、粒子の強度は十分であったが、粒子形状の真球度が、特に粒径が１００μｍ以下の場合、高くはなく、核剤の表面に均一な薬剤層や被覆層を形成させるには十分な性能ではった。また、炭水化物からなることから吸水能が低く、造粒時間が長いという問題があった。 So far, spherical particles used as a nucleating agent are known as slightly spherical crystalline cellulose, purified white sugar spherical granules, mixed spherical granules of sugar / starch, lactose / crystalline cellulose spherical granules, and D-mannitol spherical granules. Although these particles had sufficient strength, the sphericity of the particle shape was not high, especially when the particle size was 100 μm or less, so that a uniform drug layer or coating layer was formed on the surface of the nucleating agent. Was enough performance. Moreover, since it consists of carbohydrates, there existed a problem that water absorption ability was low and granulation time was long.
　ケイ酸アルミン酸マグネシウムは、本出願人が昭和３０年代に開発・製造した下式で表される非結晶性の物質である。
Ａｌ２Ｏ３・ｘＭｇＯ・ｙＳｉＯ２・ｍＨ２Ｏ
（式中、ｘは０．３≦ｘ≦３．０、ｙは１．０≦ｙ≦３．０、ｍは０．１≦ｍ≦７の範囲の数を示す。）。これらは、「ノイシリン」（商標、富士化学工業（株）製、ケイ酸アルミン酸マグネシウム）の名称で広く市販されている。 Magnesium aluminate silicate is an amorphous substance represented by the following formula developed and manufactured by the present applicant in the 1955s.
Al2O3 · xMgO · ySiO2 · mH2O
(In the formula, x is 0.3 ≦ x ≦ 3.0, y is 1.0 ≦ y ≦ 3.0, and m is a number in the range of 0.1 ≦ m ≦ 7). These are widely marketed under the name “Neusilin” (trademark, manufactured by Fuji Chemical Industry Co., Ltd., magnesium aluminate silicate).
　ケイ酸アルミン酸マグネシウムは、局外規に収録され、制酸活性、成形性、比表面積が高く医薬品の制酸剤、賦形剤、担体、流動化剤として医薬製剤に用いられている。また、一次粒子が微細であり、比表面積が高いことから、固結防止剤や吸着担体、粉砕したものは、流動化剤として化粧品や化成品分野に多く用いられている。製品の形態としては、気流乾燥機、噴霧乾燥機などの乾燥方法による形状、合成方法の違いによる表面物性の異なる種々の製品がある。球状タイプとしては、普通品（アルカリタイプ）と中性品があり、双方ともＡｌ２Ｏ３が２９．１～３５．５重量％、ＭｇＯが１１．４～１４．０重量％、ＳｉＯ２が２９．２～３５．６重量％の成分を含み、平均粒子径が０．０１～１μｍの一次粒子を噴霧乾燥よって球状の凝集体としたものであり、粒度分布は４４～３２５μｍである（非特許文献１）。４重量％スラリーのｐＨが、普通品は８．５～１０．０、中性品は６．０～８．０であり、表面ｐＨの違いにより粉体粉体が異なる。普通品は、静的比容積が２．７～３．４ｍｌ／ｇ、比表面積が１００～１５０ｍ２／ｇ、安息角が２５～３２度、吸油能が１．３～１．４ｍｌ／ｇ、中性品は、静的比容積が４．０～７．５ｍｌ／ｇ、比表面積が２５０～３００ｍ２／ｇ、安息角が３０度、吸油能が２．０～３．４ｍｌ／ｇである。 Magnesium aluminate silicate is recorded in an external regulation, and has high antacid activity, moldability and specific surface area, and is used in pharmaceutical preparations as a pharmaceutical antacid, excipient, carrier and fluidizing agent. Further, since the primary particles are fine and the specific surface area is high, anti-caking agents, adsorbent carriers, and pulverized products are often used in the cosmetics and chemical products fields as fluidizing agents. As the form of the product, there are various products having different surface physical properties depending on the shape by a drying method such as an air dryer and a spray dryer and the synthesis method. Spherical types include normal products (alkali type) and neutral products, both of which Al2O3 is 29.1 to 35.5% by weight, MgO is 11.4 to 14.0% by weight, and SiO2 is 29.2 to The primary particles containing 35.6% by weight and having an average particle diameter of 0.01 to 1 μm are formed into spherical aggregates by spray drying, and the particle size distribution is 44 to 325 μm (Non-patent Document 1). . The pH of the 4 wt% slurry is 8.5 to 10.0 for normal products and 6.0 to 8.0 for neutral products, and the powder powder varies depending on the surface pH. The normal product has a static specific volume of 2.7 to 3.4 ml / g, a specific surface area of 100 to 150 m 2 / g, an angle of repose of 25 to 32 degrees, an oil absorption capacity of 1.3 to 1.4 ml / g, The neutral product has a static specific volume of 4.0 to 7.5 ml / g, a specific surface area of 250 to 300 m 2 / g, an angle of repose of 30 degrees, and an oil absorption capacity of 2.0 to 3.4 ml / g. .
　この球状タイプのケイ酸アルミン酸マグネシウムは、アルミニウム塩、マグネシウム塩、ケイ酸塩を溶媒中での添加順、ｐＨ、温度など反応条件を調整してケイ酸アルミン酸マグネシウムを合成し、噴霧乾燥することによって製造する（特許文献１、２、３）。これまでのケイ酸アルミン酸マグネシウムは、噴霧乾燥することによって多孔質で球状の粒子であったが、粒子強度が十分に高くはなく、また比容積が比較的大きい。 This spherical type magnesium aluminate silicate is synthesized by spraying and drying aluminum aluminate, magnesium salt, silicate by adjusting the reaction conditions such as the order of addition in the solvent, pH, temperature, etc. (Patent Documents 1, 2, and 3). Conventional magnesium aluminate silicate has been porous and spherical particles by spray drying, but the particle strength is not sufficiently high and the specific volume is relatively large.
　また、３０重量％以上のメタケイ酸アルミン酸マグネシウムと無水ケイ酸と水に不溶性の粉体を噴霧乾燥してなる顆粒剤がある（特許文献４）。水分が多量に存在するときでも強度や形状を保持できる程度の弱い強度であり、例えば、振とう試験では少なくとも約２０％が破壊されている。ケイ酸アルミン酸マグネシウムと糖類を噴霧乾燥することによって得られる粉体組成物がある（特許文献５）。口腔内速崩壊錠用の賦形剤であり、強度については明らかにされていない。 There is also a granule obtained by spray-drying 30% by weight or more of magnesium aluminate metasilicate, silicic anhydride and water insoluble powder (Patent Document 4). Even when a large amount of moisture is present, the strength is weak enough to maintain the strength and shape. For example, in a shaking test, at least about 20% is destroyed. There is a powder composition obtained by spray drying magnesium aluminate silicate and sugar (Patent Document 5). It is an excipient for intraoral quick disintegrating tablets and its strength is not clarified.
　以上、これまでのケイ酸アルミン酸マグネシウムは、噴霧乾燥することによって製造しているため、多孔質の球状粒子あり、粒子強度が十分に高くはなく、また比容積が比較的大きいという問題があった。すなわち、製剤工程上で粒子強度を必要とされる用途や、重質成分との混合性が必要とされる用途に関しては必ずしも満足のいく物性ではなかった。
　これまでの球状ケイ酸アルミン酸マグネシウムの多孔性で吸油能が高いなど有用な物性を維持しながら、高い粒子強度とより重質性質を付与し、噴霧乾燥によって粒度分布が狭く、高真球度を有するため顆粒の核粒子などに適している非結晶ケイ酸アルミン酸マグネシウムの球状粒子は知られてはいない。 As described above, since conventional magnesium aluminate silicate is produced by spray drying, there are porous spherical particles, the particle strength is not sufficiently high, and the specific volume is relatively large. It was. That is, the physical properties are not always satisfactory for applications that require particle strength in the formulation process and applications that require mixing with heavy components.
While maintaining useful physical properties such as the porous and high oil absorption capacity of conventional spherical magnesium aluminate silicate, it provides high particle strength and heavier properties, narrow particle size distribution by spray drying, high sphericity Spherical particles of amorphous magnesium aluminate that are suitable for the core particles of granules and the like are not known.
特公昭５２－１６０７８号公報Japanese Examined Patent Publication No. 52-16078 特公昭３６－２３１６３号公報Japanese Patent Publication No. 36-23163 特開昭５５－１４０７１２号公報JP 55-140712 A 特開昭６３－２３９２３６号公報JP-A-63-239236 特開２０００－８６５３７号公報JP 2000-86537 A
　薬物などの活性成分と反応性が少なく、真球度や吸水性が高く、多層構造の粒子製造に有用な粒子強度が高い球状粒子が求められている。 There is a need for spherical particles having low reactivity with active ingredients such as drugs, high sphericity and water absorption, and high particle strength useful for the production of multi-layered particles.
　本発明者らは、非結晶ケイ酸アルミン酸マグネシウムを数μｍ以下に粉砕し、噴霧乾燥することによって重質で粒子強度、真球度、吸水能に優れた球状非結晶ケイ酸アルミン酸マグネシウムが得られることを見出した。 The inventors of the present invention smashed amorphous magnesium aluminate silicate to several μm or less, and spray-dried heavy amorphous spherical magnesium aluminate silicate excellent in particle strength, sphericity, and water absorption ability. It was found that it can be obtained.
　すなわち、本発明は以下の構成よりなる。
（１）　平均粒子径が０.０１～０．５μｍである非結晶一次粒子から構成され、粒子強度が５０～１０００ｇ／ｍｍ２、平均粒子径が１～５００μｍ、真球度が０．８以上であり、下式（Ｉ）で表される球状非結晶ケイ酸アルミン酸マグネシウム、
Ａｌ２Ｏ３・ｘＭｇＯ・ｙＳｉＯ２・ｍＨ２Ｏ　　　（Ｉ）
（式中、ｘは０．１≦ｘ≦３．０、ｙは０．５≦ｙ≦５．０、ｍは０．１≦ｍ≦１０の範囲の数を示す。）、
（２）　粒子強度が１００～１０００ｇ／ｍｍ２、平均粒子径が５～３００μｍである（１）に記載の球状非結晶ケイ酸アルミン酸マグネシウム、
（３）　比表面積が１０～５００ｍ２／ｇ、静的比容積が１．０～７．０ｍｌ／ｇ、吸油量が０．５～５．０ｍｌ／ｇ、吸水量が０．５～５．０ｍｌ／ｇである（１）～（２）のいずれか１項に記載の球状非結晶ケイ酸アルミン酸マグネシウム、
（４）　賦形剤、崩壊剤、結合剤、被覆剤、界面活性剤から選ばれる１種以上の成分を含有してなる（１）～（３）のいずれか１項に記載の球状非結晶ケイ酸アルミン酸マグネシウム、
（５）　非結晶ケイ酸アルミン酸マグネシウムを粉砕し、噴霧乾燥する工程を含む（１）～（４）のいずれかに記載の球状非結晶ケイ酸アルミン酸マグネシウムの製造方法。
（６）　（１）～（５）のいずれか１項に記載の球状非結晶ケイ酸アルミン酸マグネシウムの周囲に活性成分層を有してなる顆粒状組成物、
（７）　（１）～（５）のいずれか１項に記載の球状非結晶ケイ酸アルミン酸マグネシウムを含有してなる医薬組成物。 That is, the present invention has the following configuration.
(1) It is composed of amorphous primary particles having an average particle size of 0.01 to 0.5 μm, a particle strength of 50 to 1000 g / mm 2 , an average particle size of 1 to 500 μm, and a sphericity of 0.8 or more. A spherical amorphous magnesium aluminate represented by the following formula (I):
Al 2 O 3 .xMgO.ySiO 2 .mH 2 O (I)
(Wherein x is 0.1 ≦ x ≦ 3.0, y is 0.5 ≦ y ≦ 5.0, and m is a number in the range of 0.1 ≦ m ≦ 10),
(2) The spherical amorphous magnesium aluminate silicate according to (1), having a particle strength of 100 to 1000 g / mm 2 and an average particle size of 5 to 300 μm,
(3) Specific surface area of 10 to 500 m 2 / g, static specific volume of 1.0 to 7.0 ml / g, oil absorption of 0.5 to 5.0 ml / g, water absorption of 0.5 to 5. The spherical amorphous magnesium aluminate silicate according to any one of (1) to (2), which is 0 ml / g,
(4) The spherical non-crystal according to any one of (1) to (3), comprising at least one component selected from an excipient, a disintegrant, a binder, a coating agent, and a surfactant. Magnesium aluminate silicate,
(5) The method for producing spherical amorphous magnesium aluminate silicate according to any one of (1) to (4), comprising a step of pulverizing and spray-drying amorphous magnesium aluminate silicate.
(6) A granular composition comprising an active ingredient layer around the spherical amorphous magnesium aluminate silicate according to any one of (1) to (5),
(7) A pharmaceutical composition comprising the spherical amorphous magnesium aluminate silicate according to any one of (1) to (5).
　本発明の重質で粒子強度の高い球状非結晶ケイ酸アルミン酸マグネシウムは、比表面積が高く吸着性能が高く、核粒子や活性物質の吸着、混合など医薬製剤の使用に有用である。 The spherical amorphous magnesium silicate aluminate having high particle strength according to the present invention has high specific surface area and high adsorption performance, and is useful for use in pharmaceutical preparations such as adsorption and mixing of core particles and active substances.
実施例１の球状非結晶ケイ酸アルミン酸マグネシウムのＳＥＭ写真（１メモリ５μｍ）である。2 is an SEM photograph (1 memory: 5 μm) of spherical amorphous magnesium aluminate of Example 1. FIG. 実施例２の球状非結晶ケイ酸アルミン酸マグネシウムのＳＥＭ写真（１メモリ５μｍ）である。4 is a SEM photograph (1 memory 5 μm) of spherical amorphous magnesium aluminate silicate of Example 2. 比較例１の球状非結晶ケイ酸アルミン酸マグネシウムのＳＥＭ写真（１メモリ５μｍ）である。2 is a SEM photograph (1 memory 5 μm) of spherical amorphous magnesium aluminate of Comparative Example 1. 比較例２の球状非結晶ケイ酸アルミン酸マグネシウムのＳＥＭ写真（１メモリ５μｍ）である。4 is a SEM photograph (1 memory 5 μm) of spherical amorphous magnesium aluminate of Comparative Example 2. 実施例３の顆粒のＳＥＭ写真（１メモリ１０μｍ）である。4 is a SEM photograph (1 memory: 10 μm) of granules of Example 3. 実施例１の球状非結晶ケイ酸アルミン酸マグネシウムのＸ－ＲＤチャートである。2 is an X-RD chart of spherical amorphous magnesium aluminate silicate of Example 1. FIG. 実施例４の球状非結晶ケイ酸アルミン酸マグネシウムのＳＥＭ写真（１メモリ２００μｍ）である。4 is a SEM photograph (1 memory: 200 μm) of spherical amorphous magnesium aluminate of Example 4. 比較例４の結晶セルロースのＳＥＭ写真（１メモリ２００μｍ）である。6 is a SEM photograph (1 memory: 200 μm) of crystalline cellulose of Comparative Example 4. 実施例４と比較例４の噴霧速度と時間の表である。It is a table | surface of the spraying speed of Example 4 and the comparative example 4, and time.
　本発明において、ケイ酸アルミン酸マグネシウムは次の組成式（Ｉ）によって示される。
Ａｌ２Ｏ３・ｘＭｇＯ・ｙＳｉＯ２・ｍＨ２Ｏ　　　（Ｉ）
（式中、０．１≦ｘ≦３．０、ｙは０．５≦ｙ≦５．０、ｍは０．１≦ｍ≦１０の範囲の数を示す）
　このＡｌ２Ｏ３・ｘＭｇＯ・ｙＳｉＯ２のは、非結晶状態を保ち、微細な一次粒子を形成できる範囲であればよく、０．１≦ｘ≦３．０、ｙは０．５≦ｙ≦５．０であり、好ましくは、０．２≦ｘ≦２．０、ｙは０．５≦ｙ≦３．０であり、より好ましくは０．５≦ｘ≦１．５、ｙは１．４≦ｙ≦２．１である。非結晶の状態はＸ－ＲＤで結晶ピークが無いことから確認できる。 In the present invention, magnesium aluminate silicate is represented by the following composition formula (I).
Al 2 O 3 .xMgO.ySiO 2 .mH 2 O (I)
(In the formula, 0.1 ≦ x ≦ 3.0, y is 0.5 ≦ y ≦ 5.0, and m is a number in the range of 0.1 ≦ m ≦ 10)
The Al 2 O 3 .xMgO.ySiO 2 may be in a range that can maintain a non-crystalline state and form fine primary particles, and 0.1 ≦ x ≦ 3.0, y is 0.5 ≦ y ≦ 5.0, preferably 0.2 ≦ x ≦ 2.0, y is 0.5 ≦ y ≦ 3.0, more preferably 0.5 ≦ x ≦ 1.5, and y is 1. 4 ≦ y ≦ 2.1. The non-crystalline state can be confirmed from the absence of a crystal peak by X-RD.
　本発明の球状非結晶ケイ酸アルミン酸マグネシウムは、不定形状の非結晶の球状ケイ酸アルミン酸マグネシウムの１次粒子の凝集体であり、１次粒子は微細なほど凝集性がよく強度の高い凝集体を形成しやすく、平均粒子径は０．０１～１．０μｍ、好ましくは０．０１～０．５μｍである。 The spherical amorphous magnesium aluminate silicate of the present invention is an aggregate of primary particles of amorphous spherical magnesium aluminate silicate having an irregular shape. The finer the primary particles, the more cohesive and the higher the strength. Aggregates are easily formed, and the average particle size is 0.01 to 1.0 μm, preferably 0.01 to 0.5 μm.
　本発明の球状非結晶ケイ酸アルミン酸マグネシウムは、平均粒子径は１～５００μｍ、好ましくは平均粒子径は１～３００μｍ、より好ましくは１～２００μｍである。 The spherical amorphous magnesium aluminate silicate of the present invention has an average particle size of 1 to 500 μm, preferably an average particle size of 1 to 300 μm, more preferably 1 to 200 μm.
　本発明の球状非結晶ケイ酸アルミン酸マグネシウムは、粒子強度は５０～１０００ｇ／ｍｍ２であり、好ましくは１００～１０００ｇ／ｍｍ２である。なお、市販の球状タイプの非結晶ケイ酸アルミン酸マグネシウム（ノイシリン（商標）　ＳＧ１、ＮＳ２Ｎなど）は、粒子硬度測定装置では粒子強度が小さく測定できない（５０ｇ／ｍｍ２以下）。 The spherical amorphous magnesium aluminate silicate of the present invention has a particle strength of 50 to 1000 g / mm 2 , preferably 100 to 1000 g / mm 2 . In addition, commercially available spherical type amorphous magnesium aluminate silicate (Neusilin (trademark) SG1, NS2N, etc.) cannot be measured with a particle hardness measuring device because the particle strength is small (50 g / mm 2 or less).
　本発明の球状非結晶ケイ酸アルミン酸マグネシウムは、真球度が０．８以上であり、好ましくは０．８５以上であり、より好ましくは０．９以上である。通常の球状粒子は、原料由来の凸凹を小さくすることができず、粒子径が小さくなるほどそれらの凸凹の割合が大きくなり形状が歪になり真球度が低くなるが、本発明の球状非結晶ケイ酸アルミン酸マグネシウムは、粒子径が小さくなっても真球度が変わらないという特徴を持つ。本発明の球状非結晶ケイ酸アルミン酸マグネシウムは、粒子サイズがナノオーダー程度に小さく粒子自体が多孔質の非結晶ケイ酸アルミン酸マグネシウムを粒子間空隙が小さくなって密に凝集しているためであると考えられる。ここで、真球度とは、後述で示す通り、ＳＥＭ写真や光学顕微鏡での球状粒子の短径を長径で割った値である。 The spherical amorphous magnesium aluminate silicate of the present invention has a sphericity of 0.8 or more, preferably 0.85 or more, more preferably 0.9 or more. Ordinary spherical particles can not reduce the unevenness derived from the raw material, the smaller the particle diameter, the greater the proportion of those unevenness, the shape becomes distorted and the sphericity decreases, the spherical non-crystal of the present invention Magnesium aluminate silicate has a feature that the sphericity does not change even when the particle diameter is reduced. The spherical amorphous magnesium aluminate silicate of the present invention has a particle size as small as nano-order, and the particles themselves are porous agglomerates of porous amorphous magnesium aluminate silicate with small inter-particle voids. It is believed that there is. Here, the sphericity is a value obtained by dividing the minor axis of a spherical particle by an SEM photograph or an optical microscope by the major axis, as will be described later.
　本発明の球状非結晶ケイ酸アルミン酸マグネシウムは、市販の球状非結晶ケイ酸アルミン酸マグネシウムと同等の比表面積を有し、２０～５００ｍ２／ｇ、好ましくは４０～４００ｍ２／ｇ、より好ましくは６０～３００ｍ２／ｇである。 The spherical amorphous magnesium aluminate silicate of the present invention has a specific surface area equivalent to that of commercially available spherical amorphous magnesium aluminate silicate, and is 20 to 500 m 2 / g, preferably 40 to 400 m 2 / g, more preferably. Is 60 to 300 m 2 / g.
　本発明の球状非結晶ケイ酸アルミン酸マグネシウムは、市販の球状非結晶ケイ酸アルミン酸マグネシウムと同等の静的比容積を有し、１．０～７．０ｍｌ／ｇ、好ましくは１．０～５．０ｍｌ／ｇ、より好ましくは１．０～４．０ｍｌ／ｇである。 The spherical amorphous magnesium aluminate silicate of the present invention has a static specific volume equivalent to that of commercially available spherical amorphous magnesium aluminate silicate, and is 1.0 to 7.0 ml / g, preferably 1.0 to The amount is 5.0 ml / g, more preferably 1.0 to 4.0 ml / g.
　本発明の球状非結晶ケイ酸アルミン酸マグネシウムは、市販の球状非結晶ケイ酸アルミン酸マグネシウムと同等の吸油量を有し、０．５～５．０ｍｌ／ｇ、好ましくは１．０～５．０ｍｌ／ｇである。 The spherical amorphous magnesium aluminate silicate of the present invention has an oil absorption equivalent to commercially available spherical amorphous magnesium aluminate silicate, and is 0.5 to 5.0 ml / g, preferably 1.0 to 5. 0 ml / g.
　本発明の球状非結晶ケイ酸アルミン酸マグネシウムは、市販の球状非結晶ケイ酸アルミン酸マグネシウムと同等の吸水量を有し、０．５～５．０ｍｌ／ｇ、好ましくは１．０～５．０ｍｌ／ｇである。 The spherical amorphous magnesium aluminate silicate of the present invention has a water absorption equivalent to that of commercially available spherical amorphous magnesium aluminate silicate, and is 0.5 to 5.0 ml / g, preferably 1.0 to 5. 0 ml / g.
　本発明の非結晶球状ケイ酸アルミン酸マグネシウムは、通常品（アルカリタイプ）と中性品（中性タイプ）の２種類があり、一次粒子の表面水酸化物の違いによりそれぞれ物性が異なる。アルカリタイプとは、後述の４％スラリーｐＨが８．５～１１．０、中性タイプとは、後述の４％スラリーｐＨが５．５～８．５のケイ酸アルミン酸マグネシウムを指す。なお、４％スラリーｐＨは、試料２ｇを量り、水を加えて全量を５０ｍｌとし、攪拌後２分放置しｐＨメーターにより測定したｐＨの値である。 There are two types of amorphous spherical magnesium aluminate silicate of the present invention, a normal product (alkali type) and a neutral product (neutral type), each having different physical properties depending on the surface hydroxide of the primary particles. The alkali type refers to magnesium aluminate silicate having a 4% slurry pH of 8.5 to 11.0, which will be described later, and the neutral type refers to magnesium aluminate having a 4% slurry pH of 5.5 to 8.5, which will be described later. The 4% slurry pH is a pH value measured by a pH meter after weighing 2 g of a sample and adding water to make a total volume of 50 ml, stirring for 2 minutes.
　本発明の非結晶球状ケイ酸アルミン酸マグネシウムは、溶媒に懸濁した非結晶ケイ酸アルミン酸マグネシウムを微細な粒子に粉砕し、噴霧乾燥することによって製造する。 The amorphous spherical magnesium aluminate silicate of the present invention is produced by pulverizing amorphous magnesium aluminate silicate suspended in a solvent into fine particles and spray drying.
　本発明の非結晶球状ケイ酸アルミン酸マグネシウムは、市販のもの又は本出願人が公開した公知の方法によって製造することができ、例えば、特公昭３４－５１３号公報、特公昭３４－５１４号公報、特公昭３４－６１８号公報、特公昭３６－２３１６３号公報、特公昭４２－７７１９号公報、特公昭５２－１６０７８号公報、特公昭５７－１７８４５に記載の方法が挙げられる。 The amorphous spherical magnesium aluminate silicate of the present invention can be produced commercially or can be produced by a known method disclosed by the present applicant. For example, Japanese Patent Publication No. 34-513, Japanese Patent Publication No. 34-514 And JP-B-34-618, JP-B-36-23163, JP-B-42-7719, JP-B-52-16078, and JP-B-57-17845.
　より具体的には、非結晶ケイ酸アルミン酸マグネシウムの製造方法は、アルミニウム塩、マグネシウム塩、ケイ酸塩を溶媒中での添加順、ｐＨ、温度など混合条件を適宜選ぶことによって所望の物性を有する非結晶ケイ酸アルミン酸マグネシウムを製造することができる。これらの乾燥品、又は湿式合成した後の未乾燥品を用いる。 More specifically, the method for producing amorphous magnesium aluminate silicate has desired physical properties by appropriately selecting mixing conditions such as order of addition of aluminum salt, magnesium salt, and silicate in a solvent, pH, temperature, and the like. The amorphous magnesium aluminate silicate can be produced. These dried products or undried products after wet synthesis are used.
　粉砕方法としては、湿式粉砕や乾式粉砕のいずれでもよく、湿式粉砕としてはナノマイザー（製品名、エス・ジーエンジニアリング株式会社製）、スターバースト（製品名、株式会社スギノマシン製）、アルティマイザー（製品名、株式会社カラサワファイン）、マイクロフルイダイザー（製品名、みづほ工業株式会社製）などの高圧ホモジナイザー、ビーズミル、ディスクミル、ホモミキサーなど、乾式粉砕としてはピンミル、ジェットミル、ボールミル、ハンマーミル、カッターミルなどで行うことができるが、好ましくは高圧ホモジナイザー、ビーズミル、カッターミル、ハンマーミルであり、スラリーの取り扱いのしやすさから最も好ましくは高圧ホモジナイザーやビーズミルである。 As the pulverization method, either wet pulverization or dry pulverization may be used. As wet pulverization, Nanomizer (product name, manufactured by SGS Engineering Co., Ltd.), Starburst (product name, manufactured by Sugino Machine Co., Ltd.), Ultimateizer (product) Name, Karasawa Fine Co., Ltd.), high-pressure homogenizers such as microfluidizer (product name, manufactured by Mizuho Kogyo Co., Ltd.), bead mill, disk mill, homomixer, etc. For dry grinding, pin mill, jet mill, ball mill, hammer mill, cutter A high-pressure homogenizer, a bead mill, a cutter mill, and a hammer mill are preferable, and a high-pressure homogenizer and a bead mill are most preferable because of easy handling of the slurry.
　粉砕条件としては、所望の平均粒子径にできる条件であれば良く、例えば、高圧ホモジナイザーにおいては、粉砕可能なスラリー濃度を調整し、圧力１００ＭＰａ以上で複数回パスするなど、適宜選ぶことができる。同様に、ビーズミルにおいても、所望の平均粒子径となるように、ビーズ系、流速、回転速度、スラリー濃度を適宜選ぶことができる。 The pulverization conditions may be any conditions as long as the desired average particle diameter can be obtained. For example, in a high-pressure homogenizer, the slurry concentration that can be pulverized is adjusted, and a plurality of passes at a pressure of 100 MPa or more can be selected as appropriate. Similarly, in the bead mill, the bead system, the flow rate, the rotation speed, and the slurry concentration can be appropriately selected so as to obtain a desired average particle size.
　市販品及び合成した非結晶ケイ酸アルミン酸マグネシウムは、１次粒子が大きな粒間空隙を持った２次凝集粒子を形成している。このため、それら２次凝集粒子を例えば通常の噴霧乾燥で製造した球状粒子は構成粒子の接点が少なく大きな空隙を形成しており、比容積が大きく、粒子強度も弱い。対して本発明の球状非結晶ケイ酸アルミン酸マグネシウムは、粉砕によって、２次凝集粒子を形成している非結晶ケイ酸アルミン酸マグネシウムを粒間空隙の小さい２次凝集粒子まで分散・粉砕し、所望の平均粒子径に調整する。粉砕での平均粒子径は、０．０１～１０μｍ、好ましくは０．０５～６μｍ、より好ましくは０．０１～３μｍである。粉砕によって所望の平均粒子径とすることで、乾燥時に空隙の小さい、重質で球形度の高い粒子を形成することができる。また、構成粒子の接点も多くなるため、粒子強度の高い球状非結晶ケイ酸アルミン酸マグネシウムとすることができる。 Commercial products and synthesized amorphous magnesium aluminate silicate form secondary agglomerated particles in which the primary particles have large intergranular voids. For this reason, spherical particles produced by, for example, ordinary spray drying of these secondary agglomerated particles have a large gap with few contact points of constituent particles, a large specific volume, and a low particle strength. On the other hand, the spherical amorphous magnesium aluminate silicate of the present invention is dispersed and pulverized by pulverization of the amorphous magnesium silicate aluminate forming the secondary agglomerated particles to secondary agglomerated particles having small intergranular voids, Adjust to the desired average particle size. The average particle size in the pulverization is 0.01 to 10 μm, preferably 0.05 to 6 μm, more preferably 0.01 to 3 μm. By setting the desired average particle size by pulverization, it is possible to form heavy and highly spherical particles with small voids during drying. In addition, since the number of contact points of the constituent particles is increased, spherical amorphous magnesium aluminate silicate having high particle strength can be obtained.
　乾式粉砕した非結晶ケイ酸アルミン酸マグネシウムを溶媒に懸濁させ、また湿式粉砕した非結晶ケイ酸アルミン酸マグネシウムは必要有れば濃度を調節して懸濁液を調整する。溶媒としては、粒子の特性に影響を及ぼさない溶媒であればよく、例えば水、エタノール、メタノール、アセトンなどの親水性溶媒が挙げられ、好ましくは水である。分散液は、公知の方法により調製することができ、例えば、通常の撹拌、コロイドミル、高圧ホモジナイザー、超音波照射などが挙げられるが、水性分散液中で粒子を高度に分散させ得る方法であればよい。懸濁液の濃度としては、気層中に噴霧できる範囲であればよく、すなわち固形分は１～４０重量％であり、好ましくは５～３０重量％である。この時、後述する物性変更可能な添加物を加え、所望の物性に調整することができる。 The dry-milled amorphous magnesium aluminate silicate is suspended in a solvent, and the wet-milled amorphous magnesium aluminate silicate is adjusted to adjust the concentration if necessary. The solvent may be any solvent that does not affect the properties of the particles, and examples thereof include hydrophilic solvents such as water, ethanol, methanol, and acetone, preferably water. 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 of the suspension may be in a range that can be sprayed into the air layer, that is, the solid content is 1 to 40% by weight, preferably 5 to 30% by weight. At this time, an additive capable of changing physical properties to be described later can be added to adjust the desired physical properties.
　この非結晶ケイ酸アルミン酸マグネシウムの懸濁液を気層中に噴霧することによって乾燥を行う。気層中で噴霧して乾燥を行う方法は、球状の粒子を形成する公知の方法であればいずれの方法でも行うことができ、例えば、噴霧乾燥、流動層乾燥、転動層乾燥、攪拌造粒乾燥、凍結乾燥などで行うことができる。中でも、噴霧乾燥が、溶媒成分を瞬時に除去し多孔性を形成しやすいこと、液的の球形を保ちながら凝集乾燥することにより真球度の高い粒子を形成しやすいこと、粒度が揃っていること、微少な粒子の製造設定が容易であることなどにより、球状粒子の製造に最も適している。噴霧乾燥の条件は特に限定されないが、噴霧装置としては、円盤式またはノズル式の噴霧乾燥機を用いるのが好ましい。噴霧乾燥の際の温度としては、入口温度が約１２０～４００℃であり、出口温度が約８０～３００℃が好ましい。噴霧乾燥の温度、風量、噴霧などの条件を選ぶことによって、粒子径や粒度分布、粒子の強度を適宜調整することができる。 Drying is performed by spraying the suspension of amorphous magnesium aluminate silicate into the air layer. The drying method by spraying in the gas layer can be performed by any known method for forming spherical particles. For example, spray drying, fluidized bed drying, rolling bed drying, stirring It can be performed by grain drying, freeze drying or the like. Above all, spray drying is easy to form the porosity by instantly removing the solvent component, easy to form particles with high sphericity by cohesive drying while maintaining a liquid spherical shape, uniform particle size In addition, it is most suitable for the production of spherical particles because the production setting of fine particles is easy. Although the spray drying conditions are not particularly limited, it is preferable to use a disk-type or nozzle-type spray dryer as the spray device. As the temperature at the time of spray drying, the inlet temperature is preferably about 120 to 400 ° C., and the outlet temperature is preferably about 80 to 300 ° C. By selecting conditions such as spray drying temperature, air volume, and spraying, the particle size, particle size distribution, and particle strength can be appropriately adjusted.
　本発明の球状非結晶ケイ酸アルミン酸マグネシウムが、通常の噴霧乾燥させた球状非結晶ケイ酸アルミン酸マグネシウムよりも、粒子強度が高く、静的嵩密度が低い理由としては、粉砕工程によって凝集した粒子が粉砕・解砕されて、粒間空隙の小さい２次凝集粒子又に分散し、噴霧乾燥で再凝集させることによって再凝集時に粒子間の接点が多くなり粒子間空隙がより密になって分子間力が強く働くためである。重質で球形度の高い物性が得られるのも同様の理由である。 The reason why the spherical amorphous magnesium aluminate silicate of the present invention has higher particle strength and lower static bulk density than ordinary spray-dried spherical amorphous magnesium aluminate silicate is agglomerated by the pulverization process. Particles are pulverized and pulverized, dispersed into secondary agglomerated particles with small intergranular voids, and reaggregated by spray drying to increase the number of contacts between particles during reaggregation and make intergranular voids denser. This is because the intermolecular force works strongly. For the same reason, it is possible to obtain heavy physical properties with high sphericity.
　球状非結晶ケイ酸アルミン酸マグネシウムは、非結晶ケイ酸アルミン酸マグネシウムの他に物性変更可能な添加物を配合することによって、粒子強度、崩壊性、成形性などを変更又は付与することができる。物性変更可能な添加物は、球状粒子全体に対して１～９９重量％、好ましくは１０～９０重量％の範囲で添加することができる。例えば、低融点性や溶媒溶解性を有する物質を配合させることにより、粒子強度をより高めることができる。しかし、非結晶ケイ酸アルミン酸マグネシウムの細孔を埋めるため、比表面積や吸油量、吸水量が小さくなる。水溶性の添加剤や崩壊剤を添加することにより、水と接触することにより崩壊性を付与することができる。物性変更可能な添加物とは、医薬製剤の分野で一般に賦形剤、崩壊助剤、結合剤に該当する物質であるが、ここではそれら用途に特に限定されるものではない。物性変更可能な添加物は、それぞれ０～８９重量％の範囲で２種以上配合することができる。 Spherical amorphous magnesium aluminate silicate can change or impart particle strength, disintegration, moldability, etc. by blending an additive capable of changing physical properties in addition to amorphous magnesium aluminate silicate. The additive capable of changing the physical properties can be added in the range of 1 to 99% by weight, preferably 10 to 90% by weight, based on the whole spherical particles. For example, the particle strength can be further increased by blending a substance having low melting point or solvent solubility. However, since the pores of amorphous magnesium aluminate silicate are filled, the specific surface area, oil absorption, and water absorption are reduced. By adding a water-soluble additive or disintegrant, disintegration can be imparted by contact with water. The additive capable of changing physical properties is a substance generally corresponding to an excipient, a disintegration aid, and a binder in the field of pharmaceutical preparations, but is not particularly limited to these uses. Two or more additives whose physical properties can be changed can be blended in the range of 0 to 89% by weight, respectively.
　本発明における賦形剤とは、例えば、アクリル酸デンプン、Ｌ－アスパラギン酸、アミノエチルスルホン酸、アミノ酢酸、あめ（粉）、アラビアゴム、アラビアゴム末、アルギン酸、アルギン酸ナトリウム、アルファー化デンプン、イノシトール、エチルセルロース、エチレン酢酸ビニルコポリマー、エリスリトール、塩化ナトリウム、オリブ油、カオリン、カカオ脂、カゼイン、果糖、軽石粒、カルメロース、カルメロースナトリウム、含水二酸化ケイ素、乾燥酵母、乾燥水酸化アルミニウムゲル、乾燥硫酸ナトリウム、乾燥硫酸マグネシウム、カンテン、カンテン末、キシリトール、クエン酸、クエン酸ナトリウム、クエン酸ニナトリウム、グリセリン、グリセロリン酸カルシウム、グルコン酸ナトリウム、Ｌ－グルタミン、クレー、クレー粒、クロスカルメロースナトリウム、ケイ酸アルミニウム、合成ケイ酸アルミニウム・ヒドロキシプロピルスターチ・結晶セルロース、ケイ酸カルシウム、ケイ酸マグネシウム、軽質無水ケイ酸、軽質流動パラフィン、ケイヒ末、結晶セルロース、結晶セルロース・カルメロースナトリウム、微粒子結晶セルロース、ゲンマイコウジ、合成ケイ酸アルミニウム、合成ヒドロタルサイト、ゴマ油、小麦粉、コムギデンプン、小麦胚芽粉、コメコ（米粉）、コメデンプン、酢酸カリウム、酢酸カルシウム、酢酸フタル酸セルロース、サフラワー油、サラシミツロウ、酸化亜鉛、酸化チタン、酸化マグネシウム、β－シクロデキストリン、ジヒドロキシアルミニウムアミノアセテート、２，６－ジ－ｔ－ブチル－４－メチルフェノール、ジメチルポリシロキサン、酒石酸、酒石酸水素カリウム、焼セッコウ、ショ糖脂肪酸エステル、水酸化アルミナマグネシウム、水酸化アルミニウムゲル、水酸化アルミニウム炭酸水素ナトリウム共沈物、水酸化マグネシウム、スクワラン、ステアリルアルコール、ステアリン酸、ステアリン酸カルシウム、ステアリン酸ポリオキシル、ステアリン酸マグネシウム、精製ゼラチン、精製セラック、精製白糖、精製白糖球状顆粒、精製モンタンワックス、ゼイン、セスキオレイン酸ソルビタン、セタノール、セッコウ、セトステアリルアルコール、セラック、ゼラチン、ソルビタン脂肪酸エステル、Ｄ－ソルビトール、第三リン酸カルシウム、ダイズ油、大豆油不けん化物、大豆レシチン、脱脂粉乳、タルク、炭酸アンモニウム、炭酸カルシウム、炭酸マグネシウム、中性無水硫酸ナトリウム、低置換度ヒドロキシプロピルセルロース、デキストラン、デキストリン、天然ケイ酸アルミニウム、トウモロコシシロップ、トウモロコシデンプン、トレハロース、トラガント、二酸化ケイ素、乳酸カルシウム、乳糖、ハイドロタルサイト、麦芽糖、白色セラック、白色ワセリン、ハクド、白糖、白糖デンプン球状顆粒、ハダカムギ緑葉エキス末、ハダカムギ緑葉青汁乾燥粉末、ハチミツ、パラチニット、パラチノース、パラフィン、バレイショデンプン、半消化体デンプン、人血清アルブミン、ヒドロキシプロピルスターチ、ヒドロキシプロピルセルロース、フィチン酸、ブドウ糖、ブドウ糖水和物、部分アルファー化デンプン、プルラン、プロピレングリコール、粉末還元麦芽糖水アメ、粉末セルロース、ペクチン、ベントナイト、ポリアクリル酸ナトリウム、ポリエチレングリコール、ポリオキシエチレンアルキルエーテル、ポリオキシエチレン硬化ヒマシ油類、ポリオキシエチレン・ポリオキシプロピレン・グリコール、ポリスチレンスルホン酸ナトリウム、ポリソルベート、ポリビニルアセタールジエチルアミノアセテート、ポリビニルピロリドン、マルチトール、マルトース、Ｄ－マンニトール、水アメ、ミリスチン酸イソプロピル、無水乳糖、無水リン酸水素カルシウム、無水リン酸水素カルシウム造粒物、メチルセルロース、綿実粉、綿実油、モクロウ、モノステアリン酸アルミニウム、モノステアリン酸グリセリン、モノステアリン酸ソルビタン、無水ケイ酸、薬用炭、ラッカセイ油、硫酸アルミニウム、硫酸カルシウム、粒状石灰石、粒状トウモロコシデンプン、流動パラフィン、ｄｌ－リンゴ酸、リン酸一水素カルシウム、リン酸水素カルシウム、リン酸水素カリウム、リン酸水素ナトリウムなどの１種以上であり、これらのいずれかを単独で用いてもよいが、２種以上を配合することができる。
好ましくは、結晶セルロース、粉末セルロース、クロスカルメロースナトリウム、リン酸水素カルシウム、無水リン酸水素カルシウム、無水リン酸水素カルシウム造粒物、ハイドロタルサイト、ベントナイト、ケイ酸アルミニウム、リン酸カルシウム、炭酸カルシウム、ケイ酸カルシウム、ケイ酸マグネシウム、酸化マグネシウム、水酸化マグネシウム、水酸化アルミナマグネシウム、乾燥水酸化アルミニウムゲル、炭酸マグネシウム、コムギデンプン、コメデンプン（ライススターチ）、トウモロコシデンプン（コーンスターチ）、バレイショデンプン、部分アルファー化デンプン、ヒドロキシプロピルスターチ、マンニトール、キシリトール、ソルビトール、エリスリトール、マルチトール、乳糖、白糖、ブドウ糖、果糖、麦芽糖、トレハロース、パラチニット、パラチノース、カンテン、セラック、トラガントである。 Examples of the excipient in the present invention include starch acrylate, L-aspartic acid, aminoethylsulfonic acid, aminoacetic acid, candy (powder), gum arabic, gum arabic powder, alginic acid, sodium alginate, pregelatinized starch, and inositol. , Ethyl cellulose, ethylene vinyl acetate copolymer, erythritol, sodium chloride, olive oil, kaolin, cacao butter, casein, fructose, pumice granules, carmellose, carmellose sodium, hydrous silicon dioxide, dry yeast, dry aluminum hydroxide gel, dry sodium sulfate , Dried magnesium sulfate, agar, agar powder, xylitol, citric acid, sodium citrate, disodium citrate, glycerin, calcium glycerophosphate, sodium gluconate, L-glutamine, clay, clay -Grain, croscarmellose sodium, aluminum silicate, synthetic aluminum silicate, hydroxypropyl starch, crystalline cellulose, calcium silicate, magnesium silicate, light anhydrous silicic acid, light liquid paraffin, cinnamon powder, crystalline cellulose, crystalline cellulose Carmellose sodium, microcrystalline cellulose, pearl millet, synthetic aluminum silicate, synthetic hydrotalcite, sesame oil, wheat flour, wheat starch, wheat germ powder, rice (rice flour), rice starch, potassium acetate, calcium acetate, cellulose acetate phthalate , Safflower oil, white beeswax, zinc oxide, titanium oxide, magnesium oxide, β-cyclodextrin, dihydroxyaluminum aminoacetate, 2,6-di-t-butyl-4-methylphenol, dimethyl Polysiloxane, tartaric acid, potassium hydrogen tartrate, baked gypsum, sucrose fatty acid ester, magnesium hydroxide alumina, aluminum hydroxide gel, aluminum hydroxide sodium bicarbonate coprecipitate, magnesium hydroxide, squalane, stearyl alcohol, stearic acid, stear Calcium phosphate, 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, tribasic calcium phosphate, soybean oil, soybean oil unsaponifiable matter, soybean lecithin, skim milk powder, talc, ammonium carbonate, calcium carbonate, maize carbonate Nesium, 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, dried sucrose, sucrose starch spherical granule, powdered green leaf extract, powdered green leaf juice, honey, palatinit, palatinose, paraffin, potato starch, semi-digested starch, human serum albumin, hydroxypropyl starch, hydroxy Propylcellulose, phytic acid, glucose, glucose hydrate, partially pregelatinized starch, pullulan, propylene glycol, powdered reduced maltose water candy, powder cell , 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 granulated product, methylcellulose, cottonseed powder, cottonseed oil, molasses, monostearin Aluminum acid, glyceryl monostearate, sorbitan monostearate, silicic anhydride, medicinal charcoal, peanut oil, aluminum sulfate, calcium sulfate, One or more of granular limestone, granular corn starch, liquid paraffin, dl-malic acid, calcium monohydrogen phosphate, calcium hydrogen phosphate, potassium hydrogen phosphate, sodium hydrogen phosphate, etc. Although you may use, 2 or more types can be mix | blended.
Preferably, crystalline cellulose, powdered cellulose, croscarmellose sodium, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granulated product, hydrotalcite, bentonite, aluminum silicate, calcium phosphate, calcium carbonate, silica Calcium oxide, magnesium silicate, magnesium oxide, magnesium hydroxide, magnesium hydroxide magnesium, dried aluminum hydroxide gel, magnesium carbonate, wheat starch, rice starch (rice starch), corn starch (corn starch), potato starch, partially pregelatinized Starch, hydroxypropyl starch, mannitol, xylitol, sorbitol, erythritol, maltitol, lactose, sucrose, glucose, fructose, maltose, tre Loin, Palatinit, Palatinose, agar, shellac, a tragacanth.
　本発明における崩壊剤とは、例えば、アジピン酸、アルギン酸、アルギン酸ナトリウム、アルファー化デンプン、エリスリトール、果糖、カルボキシメチルスターチナトリウム、カルメロース、カルメロースカルシウム、カルメロースナトリウム、含水二酸化ケイ素、カンテン、キシリトール、グァーガム、クエン酸カルシウム、クロスカルメロースナトリウム、クロスポビドン、合成ケイ酸アルミニウム、低置換度ヒドロキシプロピルセルロース、結晶セルロース、結晶セルロース・カルメロースナトリウム、コムギデンプン、コメデンプン、酢酸フタル酸セルロース、ジオクチルソジウムスルホサクシネート、ショ糖脂肪酸エステル、水酸化アルミナマグネシウム、ステアリン酸カルシウム、ステアリン酸ポリオキシル、セスキオレイン酸ソルビタン、ゼラチン、セラック、ソルビトール、ソルビタン脂肪酸エステル、タルク、炭酸水素ナトリウム、炭酸マグネシウム、沈降炭酸カルシウム、デキストリン、デヒドロ酢酸ナトリウム、トウモロコシデンプン、トラガント、トレハロース、乳糖、麦芽糖、白糖、ハイドロタルサイト、ハチミツ、パラチニット、パラチノース、バレイショデンプン、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルスターチ、ヒドロキシプロピルセルロース、ブドウ糖、ベントナイト、部分アルファー化デンプン、フマル酸一ナトリウム、ポリエチレングルコール、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレン・ポリオキシプロピレン・グリコール、ポリソルベート、ポリビニルアセタールジエチルアミノアセテート、ポリビニルピロリドン、マルチトール、Ｄ－マンニトール、無水クエン酸、無水ケイ酸、メチルセルロース、モノステアリン酸グリセリン、ラウリル硫酸ナトリウム、アラニン、アルギニン、アスパラギン、アスパラギン酸、システイン、グルタミン、グルタミン酸、グリシン、ヒスチジン、イソロイシン、ロイシン、リシン、メチオニン、フェニルアラニン、プロリン、セリン、トレオニン、トリプトファン、チロシン、バリンなどの１種以上であり、これらのいずれかを単独で用いてもよいが、２種以上を配合することができる。
好ましくは、低置換度ヒドロキシプロピルセルロース、結晶セルロース、カルメロース、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、クロスポビドン、メタケイ酸アルミン酸マグネシウム、ケイ酸アルミン酸マグネシウム、合成ケイ酸アルミニウム、沈降炭酸カルシウム、水酸化アルミナマグネシウム、炭酸マグネシウム、コムギデンプン、コメデンプン、トウモロコシデンプン、バレイショデンプン、部分アルファー化デンプン、ヒドロキシプロピルスターチ、マンニトール、キシリトール、ソルビトール、エリスリトール、マルチトール、乳糖、白糖、ブドウ糖、果糖、麦芽糖、トレハロース、パラチニット、パラチノース、カンテン、セラック、トラガントである。 Examples of the disintegrant in the present invention include adipic acid, alginic acid, sodium alginate, pregelatinized starch, erythritol, fructose, sodium carboxymethyl starch, carmellose, carmellose calcium, carmellose sodium, hydrous silicon dioxide, agar, xylitol, guar gum , Calcium citrate, croscarmellose sodium, crospovidone, synthetic aluminum silicate, low-substituted hydroxypropyl cellulose, crystalline cellulose, crystalline cellulose carmellose sodium, wheat starch, rice starch, cellulose acetate phthalate, dioctyl sodium sulfo Succinate, sucrose fatty acid ester, magnesium magnesium hydroxide, calcium stearate, polyoxyl stearate, sesquiolein Sorbitan, gelatin, shellac, sorbitol, sorbitan fatty acid ester, talc, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, dextrin, sodium dehydroacetate, corn starch, tragacanth, trehalose, lactose, maltose, sucrose, hydrotalcite, honey, Palatinite, palatinose, potato starch, hydroxyethyl methylcellulose, hydroxypropyl starch, hydroxypropylcellulose, glucose, bentonite, partially pregelatinized starch, monosodium fumarate, polyethylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxy Propylene glycol, polysorbate, polyvinyl acetal diethylaminoacetate, polyvinyl chloride Lupyrrolidone, maltitol, D-mannitol, anhydrous citric acid, silicic anhydride, methylcellulose, glyceryl monostearate, sodium lauryl sulfate, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, One or more of leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, etc., any of which may be used alone, but two or more may be blended.
Preferably, low-substituted hydroxypropyl cellulose, crystalline cellulose, carmellose, croscarmellose sodium, sodium carboxymethyl starch, crospovidone, magnesium aluminate metasilicate, magnesium aluminate silicate, synthetic aluminum silicate, precipitated calcium carbonate, water Alumina magnesium oxide, magnesium carbonate, wheat starch, rice starch, corn starch, potato starch, partially pregelatinized starch, hydroxypropyl starch, mannitol, xylitol, sorbitol, erythritol, maltitol, lactose, sucrose, glucose, fructose, maltose, trehalose , Palatinit, palatinose, agar, shellac, tragacanth.
　本発明における結合剤とは、例えば、アクリル酸エチル・メタクリル酸メチル共重合体乳濁液、アセチルグリセリン脂肪酸エステル、アミノアルキルメタクリレートコポリマーＥ、アミノアルキルメタクリレートコポリマーＲＳ、アミノエチルスルホン酸、あめ（粉）、アラビアゴム、アラビアゴム末、アルギン酸ナトリウム、アルギン酸プロピレングリコールエステル、アルファー化デンプン、エステルガムＨ、エチルセルロース、オウバク末、加水分解ゼラチン末、カゼインナトリウム、果糖、カラメル、カラヤガム末、カルボキシビニルポリマー、カルボキシメチルエチルセルロース、カルボキシメチルスターチナトリウム、カルメロース、カルメロースナトリウム、含水二酸化ケイ素、カンテン、寒梅粉、キサンタンガム、牛脂硬化油、グァーガム、グリセリン、合成ケイ酸アルミニウム、軽質無水ケイ酸、軽質無水ケイ酸含有ヒドロキシプロピルセルロース、結晶セルロース、硬化油、コポリビドン、ゴマ油、小麦粉、コムギデンプン、コメコ（米粉）、コメデンプン、酢酸ビニル樹脂、酢酸フタル酸セルロース、サラシミツロウ、酸化デンプン、ジオクチルソジウムスルホサクシネート、ジヒドロキシアルミニウムアミノアセテート、酒石酸ナトリウムカリウム、ショ糖脂肪酸エステル、ステアリルアルコール、ステアリン酸、ステアリン酸カルシウム、ステアリン酸ポリオキシル、セスキオレイン酸ソルビタン、セタノール、ゼラチン、セラック、ソルビタン脂肪酸エステル、Ｄ－ソルビトール、大豆レシチン、炭酸カルシウム、単シロップ、デキストリン、デンプン（溶性）、トウモロコシデンプン、トラガント、パラフィン、バレイショデンプン、ヒドロキシエチルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルスターチ、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート、ピペロニルブトキシド、ブチルフタリルブナルグリコレート、ブドウ糖、部分アルファー化デンプン、フマル酸、プルラン、プロピレングリコール、ペクチン、ポリアクリル酸ナトリウム、ポリアクリル酸部分中和物、ポリエチレングリコール、ポリオキシエチレン・ポリオキシプロピレン・グリコール、ポリソルベート、ポリビニルアセタールジエチルアミノアセテート、ポリビニルアルコール（完全けん化物）、ポリビニルアルコール（部分けん化物）、ポリビニルピロリドン、ポリブテン、ポリリン酸ナトリウム、Ｄ－マンニトール、水アメ、軽質無水ケイ酸などの１種以上であり、これらのいずれかを単独で用いてもよいが、２種以上を配合することができる。 Examples of the binder in the present invention include, for example, ethyl acrylate / methyl methacrylate copolymer emulsion, acetylglycerin fatty acid ester, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, aminoethylsulfonic acid, candy (powder). , Gum arabic, gum arabic powder, sodium alginate, propylene glycol alginate, pregelatinized starch, ester gum H, ethyl cellulose, buckwheat powder, hydrolyzed gelatin powder, sodium caseinate, fructose, caramel, caraya gum powder, carboxyvinyl polymer, carboxymethyl Ethylcellulose, sodium carboxymethyl starch, carmellose, carmellose sodium, hydrous silicon dioxide, agar, agar powder, xanthan gum, beef tallow Oil, Guar gum, Glycerin, Synthetic aluminum silicate, Light anhydrous silicic acid, Light anhydrous silicic acid-containing hydroxypropylcellulose, Crystalline cellulose, Hardened oil, Copolyvidone, Sesame oil, Flour, Wheat starch, Rice (rice flour), Rice starch, Vinyl acetate Resin, cellulose acetate phthalate, honey beeswax, oxidized starch, dioctyl sodium sulfosuccinate, dihydroxyaluminum amino acetate, sodium potassium tartrate, sucrose fatty acid ester, stearyl alcohol, stearic acid, calcium stearate, polyoxyl stearate, sesquioleic acid Sorbitan, cetanol, gelatin, shellac, sorbitan fatty acid ester, D-sorbitol, soybean lecithin, calcium carbonate, simple syrup, dextrin, den (Soluble), corn starch, tragacanth, paraffin, potato starch, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, piperonyl butoxide, butylphthalic Rubunal 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 One or more of tate, polyvinyl alcohol (completely saponified product), polyvinyl alcohol (partially saponified product), polyvinylpyrrolidone, polybutene, sodium polyphosphate, D-mannitol, water candy, light anhydrous silicic acid, etc. May be used alone, but two or more may be blended.
　被覆剤としては、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、澱粉糊、アルファー化澱粉、ポリビニルピロリドン、アラビアガム、糖シロップ、カルボキシメチルセルロース・ナトリウム、プルラン、ポリビニルアルコール、ポリエチレングリコール、エチルセルロース、アクリル系共重合体、ヒドロキシプロピルメチルセルロースフタレート、セルロースアセテートフタレート、カルボキシメチルエチルセルロース、セルロースアセテート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、シェラック、シリコン樹脂などが挙げられる。 Coating agents include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, starch paste, pregelatinized starch, polyvinyl pyrrolidone, gum arabic, sugar syrup, sodium carboxymethylcellulose, pullulan, polyvinyl alcohol, polyethylene glycol, ethylcellulose, acrylic copolymer Examples include coalescence, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, carboxymethylethylcellulose, cellulose acetate, hydroxypropylmethylcellulose acetate succinate, shellac, and silicone resin.
　界面活性剤としては、ラウリル硫酸ナトリウム、ラウリン酸ジエタノールアミド、ショ糖脂肪酸エステル、グリセリン脂肪酸エステル、ソルビタン脂肪酸エステル、ポリエチレングリコール脂肪酸エステル、ステアリルアルコール、セタノール、ポリオキシエチレンポリオキシプロピレングリコール、ポリソルベート、ポリオキシエチレン硬化ヒマシ油、リン脂質等が挙げられる。 Surfactants include sodium lauryl sulfate, lauric acid diethanolamide, sucrose fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, polyethylene glycol fatty acid ester, stearyl alcohol, cetanol, polyoxyethylene polyoxypropylene glycol, polysorbate, polyoxy Examples include ethylene hydrogenated castor oil and phospholipid.
　本発明の球状非結晶ケイ酸アルミン酸マグネシウムを顆粒（造粒粒子、細粒）組成物製造用の核粒子として用いることができる。口腔内速崩壊錠用の苦味マスキング、徐放性や速放性など胃腸吸収用の放出制御製剤に好適である。 The spherical amorphous magnesium aluminate of the present invention can be used as a core particle for producing a granule (granulated particle, fine particle) composition. It is suitable for a controlled-release preparation for gastrointestinal absorption such as bitterness masking for oral disintegrating tablets, sustained release and rapid release.
　この顆粒状組成物は、本発明の球状非結晶ケイ酸アルミン酸マグネシウムを中心に活性成分層よりなる。必要に応じて、活性成分層の外側に被覆層を作ることができる。顆粒状組成物は、球状非結晶ケイ酸アルミン酸マグネシウム１００重量部に対して、活性成分０．０１～５００重量部、好ましくは０．１～２００重量部からなる。活性成分は、賦形剤などに担持、結合剤などで造粒したものでもよい。被覆成分の配合量は、球状非結晶ケイ酸アルミン酸マグネシウム１００重量部に対して、被覆成分０．０１～１００重量部である。活性成分層および／または被覆層には、結合剤、被覆剤、賦形剤などを配合することができる。また、溶出速度調節のための水溶性物質、可塑剤、安定化剤、着色料、界面活性剤、流動化剤などを必要に応じて加えてもよい。 This granular composition consists of an active ingredient layer centering on the spherical amorphous magnesium aluminate of the present invention. If necessary, a coating layer can be formed outside the active ingredient layer. The granular composition comprises 0.01 to 500 parts by weight, preferably 0.1 to 200 parts by weight of the active ingredient per 100 parts by weight of spherical amorphous magnesium aluminate silicate. The active ingredient may be supported on an excipient and granulated with a binder. The blending amount of the coating component is 0.01 to 100 parts by weight with respect to 100 parts by weight of spherical amorphous magnesium aluminate silicate. A binder, a coating agent, an excipient and the like can be blended in the active ingredient layer and / or the coating layer. In addition, a water-soluble substance, a plasticizer, a stabilizer, a colorant, a surfactant, a fluidizing agent, etc. for adjusting the dissolution rate may be added as necessary.
　活性成分としては、特に限定されず、末梢神経用剤、解熱鎮痛消炎剤、催眠鎮静剤、精神神経用剤などの中枢神経用薬剤；骨格筋弛緩剤、自律神経剤などの末梢神経用薬剤；強心剤、不整脈用剤、利尿剤、血管拡張剤などの循環器用薬剤；気管支拡張剤、鎮咳剤などの呼吸器官用薬剤；消化剤、整腸剤、制酸剤などの消化管用薬剤；ホルモン剤、抗ヒスタミン剤、ビタミン剤などの代謝性薬剤；抗潰瘍剤；抗生物質；化学療法剤；生薬エキス剤；微生物類などが挙げられる。 The active ingredient is not particularly limited, and drugs for central nerves such as agents for peripheral nerves, antipyretic analgesic / anti-inflammatory agents, hypnotic sedatives, and agents for peripheral nerves; drugs for peripheral nerves such as skeletal muscle relaxants and autonomic nerve agents; Cardiovascular agents such as cardiotonic agents, arrhythmic agents, diuretics, vasodilators; respiratory organ agents such as bronchodilators and antitussives; gastrointestinal agents such as digestives, intestines, antacids; hormones, antihistamines, vitamins Metabolic drugs such as drugs; anti-ulcer agents; antibiotics; chemotherapeutic agents; herbal extracts;
　かぜ薬用活性成分や鼻炎用活性成分等をあげることができる。かぜ薬用活性成分としては、例えば、解熱鎮痛消炎剤、気管支拡張剤、抗ヒスタミン剤、鎮咳剤、去淡剤、鎮咳去淡剤、ビタミン剤、漢方薬エキス等が挙げられる。鼻炎用活性成分としては、例えば、交感神経興奮剤、副交感神経遮断剤、抗アレルギー剤・抗炎症薬等が挙げられる。解熱鎮痛消炎剤としては、例えば、プランルカスト水和物、アセトアミノフェン、フェナセチン、塩酸レフェタミン等のアニリン誘導体、エテンザミド、サザピリン、サリチル酸メチル、サリチル酸フェニル、サリチル酸ナトリウム、サリチル酸コリン、アスピリン、アスピリンアルミニウム等のサリチル酸誘導体等、イソプロピルアンチピリン、スルピリン、フェニルブタゾン、ケトフェニルブタゾン、アンチピリン、アミノピリジン等のピラゾロ誘導体、イブプロフェン、ケトプロフェン、オキサシプロジン、ナプロキセン、フェノプロフェンカルシウム、チアプロフェン酸等のプロピオン酸誘導体、フェンブフェン、ジクロフェナクナトリウム、アンフェナクナトリウム等のフェニル酢酸誘導体、インドメタシン、インドメタシンファルネシル、マレイン酸プログルメタシン、トルメチンナトリウム等のインドール酢酸誘導体、メフェナム酸、フルフェナム酸、トルフェナム酸等のアントラニル酢酸誘導体、ピロキシカム、アンピロキシカム、テノキシカム等のオキシカム誘導体、塩酸ベンジダミン、エピリゾール（メピリゾール）、塩酸チノリジン、塩酸チアラミド等、消炎酵素剤、セラペプチダーゼ（商品名）、塩化リゾチーム等が挙げられる。これらの解熱鎮痛消炎剤は、１種又は２種以上併用することもできる。 Examples include active ingredients for cold medicine and active ingredients for rhinitis. Examples of the active ingredient for cold medicine include antipyretic analgesic / anti-inflammatory agents, bronchodilators, antihistamines, antitussives, antiseptics, antiseptic antiseptics, vitamins, and herbal medicine extracts. Examples of the active ingredient for rhinitis include sympathomimetic agents, parasympathetic nerve blockers, antiallergic agents and antiinflammatory agents, and the like. Antipyretic analgesic and anti-inflammatory agents include, for example, pranlukast hydrate, acetaminophen, phenacetin, levetamine hydrochloride and other aniline derivatives, etenzamide, sazapyrine, methyl salicylate, phenyl salicylate, sodium salicylate, choline salicylate, aspirin, aspirin aluminum Salicylic acid derivatives, etc., pyrazolo derivatives such as isopropylantipyrine, sulpyrine, phenylbutazone, ketophenylbutazone, antipyrine, aminopyridine, propionic acid derivatives such as ibuprofen, ketoprofen, oxacyprozin, naproxen, fenoprofen calcium, thiaprofenic acid, etc. , Phenbufen, diclofenac sodium, amphenac sodium and other phenylacetic acid derivatives, indomethacin, indomethacin Insole acetic acid derivatives such as Nesyl, Progouritacin maleate, Tolmethine sodium, Anthranilacetic acid derivatives such as Mefenamic acid, Flufenamic acid, Tolfenamic acid, Oxicic derivatives such as Piroxicam, Ampiroxicam, Tenoxicam, Benzydamine hydrochloride, Epirizole (Mepyrizole), Examples thereof include tinolidine hydrochloride, tiaramid hydrochloride, anti-inflammatory enzyme agents, serrapeptidase (trade name), lysozyme chloride and the like. These antipyretic analgesic / anti-inflammatory agents can be used alone or in combination of two or more.
　気管支拡張剤としては、例えば、塩酸エフェドリン、ｄｌ－塩酸メチルエフェドリン、ｄｌ－塩酸メチルエフェドリンサッカリネート、塩酸イソプレナリン、硫酸イソプロテレノール、塩酸メトキシフェナミン、硫酸オルシプレナリン、塩酸クロルプレナリン、塩酸トリメトキノール、硫酸サルブタモール、硫酸テルブタリン、硫酸ヘキソプレナリン、フマル酸フォルモテロール、臭化水素酸フェノテロール、塩酸プロカテロール、塩酸プルテロール、塩酸クレンプテロール、塩酸マブテロール、アミノフィリン、テオフィリン、ジブロフィリン、プロキシフィリン等のキサンチン誘導体、臭化フルトロピウム、臭化オキシトロピウム等の抗コリン剤等が挙げられる。抗ヒスタミン剤としては、例えば、ジフェンヒドラミン等のエタノールアミン系抗ヒスタミン剤、ｄｌ－マレイン酸クロルフェニラミン、ｄ－マレイン酸クロルフェニラミン等のプロピルアミン系抗ヒスタミン剤、酒石酸アリメマジン、塩酸イソチペンジル、塩酸プロメタジン、メキタジン等のフェノチアジン系抗ヒスタミン剤、ジフェニルピラリン、マレイン酸カルビノキサミン、フマル酸クレマスチン、塩酸イプロヘプチン、塩酸ホモクロルシクリジン、塩酸シプロヘプタジン、マレイン酸ジメチンデン、塩酸トリプロリジン、塩酸オロパタジン等が挙げられる。 Examples of bronchodilators include ephedrine hydrochloride, dl-methyl ephedrine hydrochloride, dl-methyl ephedrine hydrochloride saccharinate, isoprenaline hydrochloride, isoproterenol sulfate, methoxyphenamine hydrochloride, orciprenaline sulfate, chlorprenalin hydrochloride, trimethoxy hydrochloride Ol, salbutamol sulfate, terbutaline sulfate, hexoprenaline sulfate, formoterol fumarate, fenoterol hydrobromide, procaterol hydrochloride, pluterol hydrochloride, clenpterol hydrochloride, mabuterol hydrochloride, aminophylline, theophylline, dibrophyrin, proxyphylline, xanthine derivatives, odor And anticholinergic agents such as flutropium iodide and oxitropium bromide. Antihistamines include, for example, ethanolamine antihistamines such as diphenhydramine, propylamine antihistamines such as dl-chlorpheniramine maleate and chlorpheniramine maleate, alimemazine tartrate, isothipentyl hydrochloride, promethazine hydrochloride, and phenothiazine hydrochloride. Examples include antihistamines, diphenylpyralin, carbinoxamine maleate, clemastine fumarate, iproheptin hydrochloride, homochlorcyclidine hydrochloride, cyproheptadine hydrochloride, dimethindene maleate, triprolidine hydrochloride, olopatadine hydrochloride, and the like.
　鎮咳剤としては、例えば、リン酸コデイン、リン酸ジヒドロコデイン等のコデイン類、臭化水素酸デキストロメトルファン、クロペラスチン、ノスカピンジメモルファン、オキセラジン、クエン酸ペントキシベリン、塩酸エプラジノン、塩酸クロブチノール、クエン酸イソアミニル、塩酸ホミノベン、塩酸クロフェダノール、リン酸ベンプロペリン、ヒドロコタルニン、ジブナートナトリウム等が挙げられる。 Antitussives include, for example, codeines such as codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, cloperastine, noscapine dimethylmorphane, oxerazine, pentoxyberine citrate, eprazinone hydrochloride, clobutinol hydrochloride, citric acid Examples include isoaminyl, fominoben hydrochloride, clofedanol hydrochloride, benproperin phosphate, hydrocotarnine, dibutate sodium and the like.
　去淡剤としては、例えば、グアヤコールスルホン酸カリウム、カルボシステイン、塩酸Ｌ－エチルシステイン、塩酸Ｌ－メチルシステイン、アセチルシステイン等のシステイン誘導体、ブロムヘキシン、塩酸アンブロキソール等が挙げられる。鎮咳去淡剤として、例えば、グアイフェネシン、チペピジン、オキシメテバノール、塩酸アロクラミド、フェン酸カルベタペンタン、塩酸トリメトキノール、塩酸メトキシフェナミン等が含まれる。なお、上記鎮咳剤、去淡剤、鎮咳去淡剤として例示した薬効成分は、鎮咳作用及び／又は去淡作用を複合的に示す場合がある。 　 Examples of the desalting agent include potassium guaiacol sulfonate, carbocysteine, cysteine derivatives such as L-ethylcysteine hydrochloride, L-methylcysteine hydrochloride, acetylcysteine, bromhexine, ambroxol hydrochloride, and the like. Examples of antitussive removers include guaifenesin, tipipedin, oxymethebanol, aroclamide hydrochloride, carbetapentane phenate, trimethquinol hydrochloride, methoxyphenamine hydrochloride, and the like. In addition, the medicinal component exemplified as the antitussive agent, antifouling agent, and antitussive exfoliating agent may sometimes exhibit an antitussive action and / or an antifouling action.
　向精神薬としては、例えばクロルプロマジン、レセルピンなどが挙げられる。抗不安薬としては、例えば、トフィソパム、酒石酸ゾルピデム、アルプラゾラム、クロルジアゼポキシド、ジアゼパムなどが挙げられる。抗うつ剤としては、例えばイシプランなどの三環系薬剤、塩酸マプロチリンなどの四環系薬剤、塩酸セルトラリンなどのＳＳＲＩ（選択的セロトニン再取り込み阻害薬）、塩酸ミルナシプランなどのＳＮＲＩ（セロトニン・ノルアドレナリン再取り込み阻害薬）などが挙げられる。催眠鎮静剤としては、例えばエスタゾラム、ニトラゼパム、ジアゼパム、ペルラピン、フェノバルビタールナトリウムなどが例示される。鎮痙剤には、例えば臭化水素酸スコポラミン、塩酸パパベリン、塩酸ジフェンヒドラミンなどが挙げられる。中枢神経作用薬としては、例えばシチコリンなどが挙げられる。抗てんかん剤としては、例えばフェニトイン、カルバマゼピン等が挙げられる。交感神経興奮剤としては、例えば塩酸イソプロテレノール等が挙げられる。末梢性神経障害剤としては、例えば、エパルレスタット、メコバラミン等が挙げられる。 Examples of psychotropic drugs include chlorpromazine and reserpine. Examples of the anxiolytic drug include tofisopam, zolpidem tartrate, alprazolam, chlordiazepoxide, diazepam and the like. Examples of the antidepressant include tricyclic drugs such as isipran, tetracyclic drugs such as maprotiline hydrochloride, SSRI (selective serotonin reuptake inhibitor) such as sertraline hydrochloride, and SNRI (serotonin noradrenaline such as milnacipran hydrochloride). Reuptake inhibitors). Examples of the hypnotic sedative include estazolam, nitrazepam, diazepam, perlapine, phenobarbital sodium and the like. Examples of antispasmodic agents include scopolamine hydrobromide, papaverine hydrochloride, diphenhydramine hydrochloride, and the like. Examples of central nervous system drugs include citicoline. Examples of the antiepileptic agent include phenytoin and carbamazepine. Examples of the sympathomimetic agent include isoproterenol hydrochloride. Examples of peripheral neuropathy agents include epalrestat and mecobalamin.
　胃腸薬には、例えばジアスターゼ、含糖ペプシン、ロートエキス、セルラーゼＡＰ３、リパーゼＡＰ、ケイヒ油などの健胃消化剤、塩化ベルベリン、耐性乳酸菌、ビフィズス菌などの整腸剤などが含まれる。制酸剤としては、例えば炭酸マグネシウム、炭酸水素ナトリウム、合成ヒドロタルサイト、沈降炭酸カルシウム、酸化マグネシウムなどが挙げられる。抗潰瘍剤としては、例えば、テプレノン、ファモチジン、ランソプラゾール、オメプラゾール、ラベプラゾール、シメチジン、塩酸ラニチジンなどが挙げられる。 Gastrointestinal drugs include, for example, healthy gastrointestinals such as diastase, sugar-containing pepsin, funnel extract, cellulase AP3, lipase AP, and cinnamon oil, and intestinals such as berberine chloride, resistant lactic acid bacteria and bifidobacteria. Examples of the antacid include magnesium carbonate, sodium hydrogen carbonate, synthetic hydrotalcite, precipitated calcium carbonate, magnesium oxide and the like. Examples of the anti-ulcer agent include teprenone, famotidine, lansoprazole, omeprazole, rabeprazole, cimetidine, ranitidine hydrochloride and the like.
　血圧降下剤としては、例えば、カルベジロール、オルメサルタンメドキソミル、ベニジピン塩酸塩、テルミサルタン、ベシル酸アムロジピン、塩酸デラプリル、カプトプリル、塩酸ヒドララジン、塩酸ラベタロール、塩酸マニジピン、カンデサルタンシレキセチル、メチルドパ、ペリンドプリルエルブミンなどが挙げられる。血管収縮剤としては、例えば塩酸フェニレフリンなどが挙げられる。血管拡張剤としては、例えばニコランジル、塩酸カルボクロメン、モルシドミン、塩酸ペラパミル、シンナリジン等が挙げられる。不整脈用剤としては、例えば塩酸プロカインアミド、塩酸プロプラノロール、ピンドロールなどが挙げられる。強心剤としては、例えばカフェイン、ジゴキシンなどが挙げられる。
利尿薬としては、例えばイソソルピド、フロセミド、ヒドロクロロチアジドなどが挙げられる。 Examples of antihypertensive agents include carvedilol, olmesartan medoxomil, benidipine hydrochloride, telmisartan, amlodipine besylate, delapril, captopril, hydralazine hydrochloride, labetalol hydrochloride, manidipine hydrochloride, candesartan cilexetil, methyldopa, perindopril erbumine, etc. It is done. Examples of the vasoconstrictor include phenylephrine hydrochloride. Examples of the vasodilator include nicorandil, carbochromene hydrochloride, molsidomine, perapamil hydrochloride, cinnarizine and the like. Examples of the arrhythmic agent include procainamide hydrochloride, propranolol hydrochloride, pindolol and the like. Examples of the cardiotonic agent include caffeine and digoxin.
Examples of the diuretic include isosorbide, furosemide, hydrochlorothiazide and the like.
　高脂血症用剤としては、例えば、イコサペント酸エチル、セリバスタチンナトリウム、シンバスタチン、プラバスタチンナトリウム、ピタバスタチンカルシウム、アトルバスタチンカルシウム水和物等が挙げられる。 Examples of hyperlipidemia agents include ethyl icosapentate, cerivastatin sodium, simvastatin, pravastatin sodium, pitavastatin calcium, atorvastatin calcium hydrate, and the like.
　抗生物質には、例えば、塩酸バンコマイシン、セフジニル、イトラコナゾール、クラリスロマイシン、塩酸セフカペンピボキシル、セファレキシン、セファクロル、アモキシシリン、塩酸ピプメシリナム、塩酸セフォチアムヘキセチル、セファドロキシル、セフィキシム、セフジトレンピボキシル、セフテラムピボキシル、セフポドキシミプロキセチルなどのセフェム系、アンピシリン、シクラシン、ナリジクス酸、レボフロキサシン、エノキサシンなどの合成抗菌剤、カルモナムナトリウムなどのモノバクタム系、ペネム系及びカルバペネム系抗生物質などが挙げられる。
化学療法剤としては、例えばスルファメチゾールなどが挙げられる。 Antibiotics include, for example, vancomycin hydrochloride, cefdinir, itraconazole, clarithromycin, cefcapene pivoxil hydrochloride, cephalexin, cefaclor, amoxicillin, pipmecillin hydrochloride, cefotium hexetyl hydrochloride, cefadroxyl, cefixime, cefditren pivoxil, cefterampyrix And cephem compounds such as cefpodoximiproxetil, synthetic antibacterial agents such as ampicillin, cyclacin, nalidixic acid, levofloxacin, enoxacin, monobactams such as carmonam sodium, penems and carbapenems.
Examples of the chemotherapeutic agent include sulfamethizole.
　糖尿病用剤としては、例えばトルブタミド、ボグリボース、塩酸ピオグリタゾン、グリベンクラミド、トログリダゾンなどが挙げられる。
鎮けい剤としては、塩酸メクリジン、ジメンヒドリナートなどが挙げられる。
抗リウマチ薬としては、メソトレキセート、ブシラミンなどが挙げられる。
ホルモン剤としては、例えばリオチロニンナトリウム、リン酸デキメタゾンナトリウム、プレドニゾロン、オキセンドロン、酢酸リュープロレリンなどが挙げられる。
アルカロイド系麻薬として、アヘン、塩酸モルヒネ、トロン、塩酸オキシコドン、塩酸アヘンアルカロイド、塩酸コカインなどが挙げられる。
サルファ剤としては、例えばスルフィソミジン、スルファメチゾールなどが挙げられる。
痛風治療薬としては、例えばアロプリノール、コルヒチンなどが挙げられる。
血液凝固阻止剤としては、例えばジクマロールが挙げられる。
抗悪性腫瘍剤としては、例えば５－フルオロウラシル、ウラシル、マイトマイシン、塩酸マニジピン、ボグリボース、カンデサルタンシレキセチル、塩酸ピオグリタゾンなどが挙げられる。 Examples of the agent for diabetes include tolbutamide, voglibose, pioglitazone hydrochloride, glibenclamide, troglidazone and the like.
Examples of antispasmodic agents include meclizine hydrochloride and dimenhydrinate.
Antirheumatic drugs include methotrexate, bucillamine and the like.
Examples of hormone agents include liothyronine sodium, dexamethasone sodium phosphate, prednisolone, oxendron, leuprorelin acetate, and the like.
Alkaloid narcotics include opium, morphine hydrochloride, throne, oxycodone hydrochloride, opium alkaloid hydrochloride, ***e hydrochloride, and the like.
Examples of the sulfa drugs include sulfisomidine and sulfamethizole.
Examples of anti-gout drugs include allopurinol and colchicine.
Examples of the blood coagulation inhibitor include dicumarol.
Examples of the antineoplastic agent include 5-fluorouracil, uracil, mitomycin, manidipine hydrochloride, voglibose, candesartan cilexetil, pioglitazone hydrochloride and the like.
　その他の活性成分としては、例えば、塩酸タムスロシン、塩酸ドネペジル、オセルタミビル、リマプロストアルファデクス、ロキソプロフェンナトリウム、塩酸サルポグレラート、ウルソデオキシコール酸、アラセプリル、ブロチゾラム、ベルベリンの塩酸塩又はタンニン酸塩、塩酸ロペラミド、エバスチンなどが挙げられる。 Other active ingredients include, for example, tamsulosin hydrochloride, donepezil hydrochloride, oseltamivir, limaprost alphadex, loxoprofen sodium, sarpogrelate hydrochloride, ursodeoxycholic acid, alacepril, brotizolam, berberine hydrochloride or tannate, loperamide hydrochloride, ebastine, etc. Is mentioned.
　栄養成分としては、タンパク質、糖質、脂質、ビタミン、ミネラル、その他の効用成分などである。
　ビタミン類としては、例えば、アスタキサンチン、ビタミンＡ、β－カロチン、ルテイン、ゼアキサンチン等のカロチノイド類、フルスルチアミン、塩酸フルスルチアミン、プロスルチアミン、オクトチアミン、チアミンジスルフィド、ビスベンチアミン、ビスブチチアミン、ビスイブチアミン、ベンフォチアミン、塩酸セトチアミン等のビタミンＢ１もしくはその誘導体又はそれらの塩、リボフラビン、リン酸リボフラビンナトリウム、フラビンアデニンジヌクレオチドナトリウム、酪酸リボフラビン等のビタミンＢ２もしくはその誘導体又はそれらの塩、アスコルビン酸やアスコルビン酸グルコシド、パルミチン酸Ｌ－アスコルビル、Ｌ－アスコルビン酸リン酸エステル等のビタミンＣ誘導体、トコフェロール、酢酸トコフェロール、コハク酸トコフェロール、ニコチン酸トコフェロール、トコトリエノール等のビタミンＥ類等が挙げられる。 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, bisbutyamine, 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.
　その他の効用成分としては、例えば、デオキシリボ核酸及びその塩、アデノシン三リン酸、アデノシン一リン酸などのアデニル酸誘導体及びそれらの塩、リボ核酸及びその塩、グアニン、キサンチン及びそれらの誘導体並びにそれらの塩などの核酸関連物質；血清除蛋白抽出物、脾臓抽出物、胎盤抽出物、鶏冠抽出物、ローヤルゼリーなどの動物由来の抽出物；酵母抽出物、乳酸菌抽出物、ビフィズス菌抽出物、霊芝抽出物などの微生物由来の抽出物；ニンジン抽出物、センブリ抽出物、ローズマリー抽出物、オウバク抽出物、ニンニク抽出物、ヒノキチオール、セファランチンなどの植物由来の抽出物；α－またはγ－リノレイン酸、エイコサペンタエン酸及びそれらの誘導体、コハク酸及びその誘導体並びにそれらの塩、エストラジオール及びその誘導体並びにそれらの塩、グリコール酸、乳酸、リンゴ酸、クエン酸、サリチル酸などのα－ヒドロキシ酸及びそれらの誘導体並びにそれらの塩、グリチルリチン酸、グリチルレチン酸、メフェナム酸、フェニルブタゾン、インドメタシン、イブプロフェン、ケトプロフェン、アラントイン、グアイアズレン及びそれらの誘導体並びにそれらの塩、ε－アミノカプロン酸、酸化亜鉛、ジクロフェナクナトリウム、ヒアルロン酸、コンドロイチン、コラーゲン、アロエ抽出物、サルビア抽出物、アルニカ抽出物、カミツレ抽出物、シラカバ抽出物、オトギリソウ抽出物、ユーカリ抽出物及びムクロジ抽出、チロシナーゼ活性阻害剤が、システイン及びその誘導体並びにその塩、センプクカ抽出物、ケイケットウ抽出物、サンペンズ抽出物、ソウハクヒ抽出物、トウキ抽出物、イブキトラノオ抽出物、クララ抽出物、サンザシ抽出物、シラユリ抽出物、ホップ抽出物、ノイバラ抽出物及びヨクイニン抽出物、ヒアルロン酸、コンドロイチン硫酸、デルマタン硫酸、ヘパラン硫酸、ヘパリン及びケラタン硫酸並びにこれらの塩類、コラーゲン、エラスチン、ケラチン及びこれらの誘導体並びにその塩類、海洋深層水、ヘチマ抽出物、センキュウ抽出物、パパイヤ末、亜鉛、高麗人参抽出物、ブルベリー抽出物、ＤＨＡ、イチョウ葉抽出物、グルタチオン、フラボノイド、タンニン、エラグ酸、核酸類、漢方薬類、海草類、無機物など、並びにそれらの混合物からなる群から１種または２種以上選択することができる。 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 from microorganisms such as foods; extracts from plants such as carrot extract, assembly extract, rosemary extract, buckwheat 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, 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, keiketto extract, sun penz extract , Sakuhakuhi 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 salts thereof, collagen, elastin, keratin and derivatives thereof and salts thereof, deep ocean water, loofah extract, papaya extract, papaya powder, zinc, ginseng extract, bulberry extract, DHA , Ginkgo biloba leaf extract, glutathione, flavonoid, tannin, ellagic acid, nucleic acids, herbal medicines, seaweeds, inorganic substances, etc., and mixtures thereof can be selected from one or more.
　本発明の球状非結晶ケイ酸アルミン酸マグネシウムを用いた顆粒状組成物の製造は、本発明の球状非結晶ケイ酸アルミン酸マグネシウムを核剤として、流動層造粒、攪拌造粒、転動層造粒、噴霧乾燥造粒、押出造粒など公知の湿式造粒方法で行うことができ、これらの条件は常法によって行うことができる。 The production of the granular composition using the spherical amorphous magnesium aluminate silicate of the present invention is carried out by using the spherical amorphous magnesium aluminate silicate of the present invention as a nucleating agent, fluidized bed granulation, stirring granulation, rolling layer. It can carry out by well-known wet granulation methods, such as granulation, spray-drying granulation, and extrusion granulation, These conditions can be performed by a conventional method.
　具体的には、本発明の球状非結晶ケイ酸アルミン酸マグネシウムを湿式造粒装置中で転動させながら、結合剤含有溶液を連続的に噴霧し、同時に活性成分と必要ならば賦形剤とから成る粉体を供給し、球状非結晶ケイ酸アルミン酸マグネシウムに粉体を被覆し、乾燥して顆粒とする。あるいは球状非結晶ケイ酸アルミン酸マグネシウムを湿式造粒機中で流動させながら、結合剤含有溶液中に薬物を溶解あるいは懸濁させた液を噴霧し、球状非結晶ケイ酸アルミン酸マグネシウムに薬物を含む粉体を被覆し、乾燥して顆粒とする。続いて顆粒を流動させながら被覆剤の溶液または被覆剤の懸濁液を噴霧し、乾燥させて防湿、苦味マスキング、腸溶性、徐放性、持続性などを目的とした皮膜層を形成させ、顆粒とする。また、薬物を含む粉体を被覆する際、被覆剤含有溶液あるいは被覆剤の懸濁液を同時に噴霧してもよい。これらの造粒順番は、薬剤の種類などに応じて適宜選ぶことができる。 Specifically, while rolling the spherical amorphous magnesium aluminate silicate of the present invention in a wet granulator, the binder-containing solution is continuously sprayed, and at the same time, an active ingredient and, if necessary, an excipient. Is supplied, and the powder is coated on spherical amorphous magnesium aluminate silicate and dried to form granules. Alternatively, while flowing spherical amorphous magnesium aluminate silicate in a wet granulator, a solution in which the drug is dissolved or suspended in a binder-containing solution is sprayed, and the drug is applied to spherical amorphous magnesium aluminate silicate. The powder containing is coated and dried to form granules. Subsequently, the coating solution or coating suspension is sprayed while the granules are flowing, and dried to form a film layer for the purpose of moisture proofing, bitterness masking, enteric properties, sustained release, sustainability, etc. Granules. Further, when the powder containing the drug is coated, a coating-containing solution or a coating suspension may be sprayed simultaneously. The order of granulation can be appropriately selected according to the type of drug.
　上記溶液の溶媒としては、これらの物性に影響を及ぼさず、医薬的に許容される溶媒であればよく、例えば水、エタノール、メタノールなどが挙げられる。被覆剤としては、公知の賦形剤や前述の被覆剤を用いることができる。 The solvent of the above solution may be any pharmaceutically acceptable solvent without affecting these physical properties, and examples thereof include water, ethanol, methanol and the like. As the coating agent, known excipients and the aforementioned coating agents can be used.
　本発明の球状非結晶ケイ酸アルミン酸マグネシウムは、吸水性・吸油性が高いため、従来の有機系の核剤より造粒工程で、噴霧速度を大きくすることができ、層形成工程に要する時間を短縮することができる。造粒装置などによって条件が異なるが、例えば、効用成分を乗せる場合、３０～８０％ほど時間を短縮することができる。具体的には、本発明の核剤に同量の効用成分などをレイヤリングする場合、１０～２０時間でレイヤリングを完了することができる。軽質であると風の巻き上げによる噴霧液のかからない粒子が多くなるが、重質であるため風の巻き上げが少なく均一に噴霧液がかかりやすい。有機物は流動させると摩擦により静電気を帯び装置壁面への付着が大井が、本発明の球状非結晶ケイ酸アルミン酸マグネシウムの表面は水酸基であり帯電しにくい。従来の炭水化物系の有機核剤よりも造粒操作性に優れている。 Since the spherical amorphous magnesium aluminate of the present invention has high water absorption and oil absorption, the spraying speed can be increased in the granulation process than the conventional organic nucleating agent, and the time required for the layer formation process Can be shortened. Although the conditions vary depending on the granulator and the like, for example, in the case where an effect component is placed, the time can be shortened by 30 to 80%. Specifically, in the case where the same amount of a benefit ingredient is layered on the nucleating agent of the present invention, the layering can be completed in 10 to 20 hours. If it is light, the number of particles that are not sprayed by the wind is increased. However, since it is heavy, it is easy to apply the spray evenly with little wind. When the organic substance is flowed, it is electrostatically charged due to friction and adheres to the wall surface of the device, but the surface of the spherical amorphous magnesium aluminate of the present invention is a hydroxyl group and is not easily charged. It has better granulation operability than conventional carbohydrate-based organic nucleating agents.
　本発明の医薬製剤は、錠剤、口腔内速崩壊錠、カプセル、顆粒、細粒などの固形投薬形態、懸濁液の液状製剤などの製剤形状とすることができる。特に、放出性や苦味マスキングのためのコーティングが均一で掲載できるため、放出制御が必要な徐放剤や口腔内速崩壊剤に適している。 The pharmaceutical preparation of the present invention can be in the form of a solid dosage form such as a tablet, a rapidly disintegrating tablet in the oral cavity, a capsule, a granule or a fine granule, or a liquid preparation of a suspension. In particular, since the coating for releasability and bitterness masking can be listed uniformly, it is suitable for sustained release agents and oral rapid disintegrating agents that require release control.
　錠剤の製造方法は、本発明の顆粒状組成物や本発明の球状非結晶ケイ酸アルミン酸マグネシウムを医薬品に配合可能な添加成分と乾式混合や湿式混合などの方法で混合したのち、圧縮成型する。このとき、Ｆ－ＭＥＬＴ〔商標　富士化学工業（株）製〕、クロスポビドン、低置換度ヒドロキシプロピルセルロース、カルボキシメチルスターチナトリウム、クロスカルメロースナトリウム、澱粉などの崩壊剤を添加することによって、口腔内速崩壊剤とすることができる。 The tablet is produced by mixing the granular composition of the present invention or the spherical amorphous magnesium aluminate silicate of the present invention with an additive component that can be blended with a pharmaceutical product by a method such as dry mixing or wet mixing, and then compression molding. . At this time, by adding a disintegrant such as F-MELT (trademark, manufactured by Fuji Chemical Industry Co., Ltd.), crospovidone, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, croscarmellose sodium, starch, etc. It can be a fast disintegrant.
　本発明の医薬製剤に配合可能な添加成分としては、前述の賦形剤、結合剤、崩壊剤、界面活性剤、被覆剤に加えて、滑沢剤（ショ糖脂肪酸エステル、ステアリン酸マグネシウム、タルク、フマル酸ステアリルナトリウムなど）、酸味料（例えばクエン酸、酒石酸、リンゴ酸、アスコルビン酸など）、発泡剤（例えば炭酸水素ナトリウム、炭酸ナトリウムなど）、甘味剤（サッカリンナトリウム、グリチルリチン二カリウム、アスパルテーム、ステビア、ソーマチンなど）、香料（例えばレモン油、オレンジ油、メントールなど）、着色剤（例えば食用赤色２号、食用青色２号、食用黄色５号、食用レーキ色素、三二酸化鉄など）、安定化剤（例えばエデト酸ナトリウム、トコフェロール、シクロデキストリンなど）、矯味剤、着香剤など医薬品添加物辞典などに記載されている通常の医薬品添加物が挙げられる。 In addition to the excipients, binders, disintegrants, surfactants, and coating agents described above, the additive components that can be incorporated into the pharmaceutical preparation of the present invention include lubricants (sucrose fatty acid ester, magnesium stearate, talc , Sodium stearyl fumarate, etc.), acidulants (eg, citric acid, tartaric acid, malic acid, ascorbic acid, etc.), foaming agents (eg, sodium bicarbonate, sodium carbonate, etc.), sweeteners (sodium saccharin, dipotassium glycyrrhizin, aspartame, stevia) , Thaumatin etc.), fragrance (eg lemon oil, orange oil, menthol etc.), colorant (eg edible red No. 2, edible blue No. 2, edible yellow No. 5, edible lake dye, ferric sesquioxide etc.), stabilizer (For example, sodium edetate, tocopherol, cyclodextrin, etc.), flavoring agents, flavoring agents, etc. Conventional excipients listed like goods additives dictionary and the like.
　本発明の顆粒組成物及び本発明の医薬組成物は、医薬品の他に食品、化粧、農薬、などに使用することができる。特に、機能性食品の体内吸収性を制御するのに好適である。 The granule composition of the present invention and the pharmaceutical composition of the present invention can be used for foods, cosmetics, agricultural chemicals and the like in addition to pharmaceuticals. In particular, it is suitable for controlling the absorbability of functional food in the body.
　本発明の球状非結晶ケイ酸アルミン酸マグネシウムの医薬製剤以外のその他の用途としては、粒子強度、球状度、比表面積が高いことからカラムクロマトグラフィーの充填剤、各種充填材、各種の吸着担体、消臭剤、触媒、歯の研磨剤、フィルムなどの離型剤、塗料の付着防止剤やつや消し材として用いることができる。 Other uses other than the pharmaceutical preparation of spherical amorphous magnesium aluminate silicate of the present invention include high particle strength, sphericity, and high specific surface area, so column chromatography packing materials, various packing materials, various adsorption carriers, It can be used as a deodorant, a catalyst, a tooth abrasive, a release agent such as a film, a paint adhesion preventive or a matting material.
　以下に、本発明を実施例により説明するが、これらの実施例は本発明の範囲を限定するものではない。
　［粒子強度］
　粒子硬度測定装置（グラノ、岡田精工（株）製）を用いて測定した。
　［真球度］
　ＳＥＭ（走査型顕微鏡）（日立製作所（株）、Ｓ－３０００Ｎ）を用いて撮影した映像から、各粒子の短径と長径を測定し、短径／長径の比より数値を導いた。
　［粒子径測定方法］
　懸濁液中の粒子の平均粒子径は、湿式粒度分布測定器（ＳＡＬＤ－２０００Ｊ、島津製作所(株)製）で屈折率１．７－０．２０ｉの条件で平均粒子径を測定した。
　乾式粉末の平均粒子径は、乾式粒度分布測定器（ＬＡ－９２０、（株）堀場製作所製）で平均粒子径を測定した。
　［比表面積］
　比表面積は、ＢＥＴ比表面積測定装置（モノソーブＭＳ－１７、ユアサアイオニクス（株）製）を用いて測定した。
　［吸油量］
　吸水量はＪＩＳＫ５１０１に基づき、アマニ油を用いて行った。
　［吸水量］
　吸水量はＪＩＳＫ５１０１に基づき、アマニ油の代わりに水を用いて行った。
　［静的比容積］
　静的比容積は１００ｍｌのメスシリンダーにガラス管を挿入し、９０～１００ｍｌの容量となるようにロートで試料をガラス管内に入れ、ガラス管を静かに引き抜き、試料の表面を平らにしたときの容積（Ｖｍｌ）と試料の重量（Ｗｇ）をＶ／Ｗにより求めた。
　［４重量％スラリーｐＨ］
　４重量％スラリーｐＨは、試料２ｇを量り、水を加えて全量を５０ｍｌとし攪拌後２分間放置しｐＨメーターにより測定した。 EXAMPLES The present invention will be described below with reference to examples, but these examples do not limit the scope of the present invention.
[Particle strength]
It measured using the particle hardness measuring apparatus (Grano, Okada Seiko Co., Ltd. product).
[Sphericity]
The short diameter and long diameter of each particle were measured from an image taken using an SEM (scanning microscope) (Hitachi, Ltd., S-3000N), and a numerical value was derived from the ratio of the short diameter / long diameter.
[Particle size measurement method]
The average particle size of the particles in the suspension was measured with a wet particle size distribution analyzer (SALD-2000J, manufactured by Shimadzu Corporation) under the condition of a refractive index of 1.7-0.20i.
The average particle size of the dry powder was measured with a dry particle size distribution analyzer (LA-920, manufactured by Horiba, Ltd.).
[Specific surface area]
The specific surface area was measured using a BET specific surface area measuring device (Monosorb MS-17, manufactured by Yuasa Ionics Co., Ltd.).
[Oil absorption]
Water absorption was performed using linseed oil based on JISK5101.
[Water absorption]
The amount of water absorption was based on JISK5101, using water instead of linseed oil.
[Static specific volume]
The static specific volume is obtained when a glass tube is inserted into a 100 ml measuring cylinder, the sample is put into the glass tube with a funnel so that the volume becomes 90 to 100 ml, the glass tube is gently pulled out, and the surface of the sample is flattened. Volume (Vml) and sample weight (Wg) were determined by V / W.
[4 wt% slurry pH]
The 4 wt% slurry pH was measured with a pH meter after weighing 2 g of sample and adding water to make a total volume of 50 ml, stirring for 2 minutes.
　［実施例１］　
　非結晶ケイ酸アルミン酸マグネシウム（別名：メタケイ酸アルミン酸マグネシウム、商品名「ノイシリンＮＦＬ２Ｎ」、中性品、富士化学工業株式会社製）７．５ｋｇを水５０Ｌに懸濁し、流速７Ｌ／ｍｉｎの条件でアルティマイザー粉砕器〔スターバースト大型機　ＨＪＰ－２５０８０、スギノマシン（株）製〕を用い、圧力２４５ＭＰａの条件で５回粉砕した。粉砕後スラリーの粒度分布は平均粒子径で２．９μｍであった。ついでこの粉砕液を１１．６ｗ／ｗ％濃度に調製し、遠心式アトマイザーを用いて、回転数９０００ｒｐｍ、入熱温度３３０℃、出口温度１６０℃の条件で噴霧乾燥し、球状非結晶ケイ酸アルミン酸マグネシウムを得た。図１にＳＥＭ写真を、図７にＸ－ＲＤチャートを示す。 [Example 1]
A suspension of 7.5 kg of amorphous magnesium aluminate silicate (also known as: magnesium aluminate metasilicate, trade name “Neusilin NFL2N”, neutral product, manufactured by Fuji Chemical Industry Co., Ltd.) in 50 L of water with a flow rate of 7 L / min. Then, using an optimizer pulverizer [Starburst Large Machine HJP-25080, manufactured by Sugino Machine Co., Ltd.], the powder was pulverized five times under the condition of a pressure of 245 MPa. The particle size distribution of the slurry after pulverization was 2.9 μm in terms of average particle size. Next, this pulverized liquid was prepared to a concentration of 11.6 w / w% and spray-dried using a centrifugal atomizer under the conditions of a rotational speed of 9000 rpm, a heat input temperature of 330 ° C., and an outlet temperature of 160 ° C., and spherical amorphous alumina silicate Magnesium acid was obtained. FIG. 1 shows an SEM photograph, and FIG. 7 shows an X-RD chart.
　［実施例２］
　アルミン酸ソーダ（Ａｌ２Ｏ３：１８．７％）８０．４ｇに水を加えて全量５００ｍｌとし、これをＡ液とする。３号ケイ酸ソーダ（ＳｉＯ２：２９．５％）１２４．８ｇに水を加えて全量２５０ｍｌとし、これをＢ液とする。塩化マグネシウム六水塩（ＭｇＯ：１９．８％）４１．７ｇと硫酸アルミニウム（Ａｌ２Ｏ３：１７．２％）３４．０ｇを水に溶解させ全量２５０ｍｌとし、これをＣ液とする。反応槽にＡ液を入れ、攪水拌しながらＢ液を１０ｍｌ／毎分の速度で添加した。次いでＣ液を約２５ｍｌ／毎分で添加した。Ｃ液添加後、３０分間熟成させた後、生成物をろ過し、水洗した。
　濃度１９ｗ／ｗ％に調製し、アルティマイザー粉砕器〔スターバースト大型機　ＨＪＰ－２５０８０、スギノマシン（株）製〕を用い、流速７Ｌ／ｍｉｎ、圧力２４５ＭＰａの条件で５回粉砕した。粉砕後スラリーの粒度分布は平均粒子径で２．０μｍであった。ついでこの粉砕液を１４．９ｗ／ｗ％濃度に調製し、遠心式アトマイザーを用いて、回転数９０００ｒｐｍ、入熱温度３３０℃、出口温度１６０℃の条件で噴霧乾燥し、球状非結晶ケイ酸アルミン酸マグネシウムを得た。図２にＳＥＭ写真を示す。 [Example 2]
Water is added to 80.4 g of sodium aluminate (Al 2 O 3 : 18.7%) to make a total volume of 500 ml. Water is added to 124.8 g of No. 3 sodium silicate (SiO 2 : 29.5%) to make a total amount of 250 ml. Magnesium chloride hexahydrate (MgO: 19.8%) 41.7 g and aluminum sulfate (Al 2 O 3 : 17.2%) 34.0 g are dissolved in water to make a total amount of 250 ml. Liquid A was placed in the reaction vessel, and liquid B was added at a rate of 10 ml / min with stirring. C solution was then added at approximately 25 ml / min. After addition of solution C, the mixture was aged for 30 minutes, and then the product was filtered and washed with water.
The concentration was adjusted to 19 w / w%, and the mixture was pulverized 5 times under the conditions of a flow rate of 7 L / min and a pressure of 245 MPa using an optimizer pulverizer [Starburst Large Machine HJP-25080, manufactured by Sugino Machine Co., Ltd.]. The particle size distribution of the slurry after pulverization was 2.0 μm in terms of average particle size. Next, this pulverized liquid was prepared to a concentration of 14.9 w / w%, and spray-dried using a centrifugal atomizer under the conditions of a rotation speed of 9000 rpm, a heat input temperature of 330 ° C., and an outlet temperature of 160 ° C., and spherical amorphous alumina silicate Magnesium acid was obtained. FIG. 2 shows an SEM photograph.
　［比較例１］　
　非結晶ケイ酸アルミン酸マグネシウム（別名：メタケイ酸アルミン酸マグネシウム、商品名「ノイシリンＮＦＬ２Ｎ」、通常品、富士化学工業株式会社製）７．５ｋｇを水５０Ｌに懸濁し、ついでこの懸濁液（平均粒子径１１．５μｍ）を遠心式アトマイザーを用いて、回転数９０００ｒｐｍ、入熱温度３３０℃、出口温度１６０℃の条件で噴霧乾燥し、球状非結晶ケイ酸アルミン酸マグネシウムを得た。図３にＳＥＭ写真を示す。 [Comparative Example 1]
A suspension of 7.5 kg of amorphous magnesium aluminate silicate (also known as magnesium aluminate metasilicate, trade name “Neusilin NFL2N”, regular product, manufactured by Fuji Chemical Industry Co., Ltd.) in 50 L of water, then this suspension (average A particle size of 11.5 μm was spray-dried using a centrifugal atomizer under the conditions of a rotation speed of 9000 rpm, a heat input temperature of 330 ° C., and an outlet temperature of 160 ° C. to obtain spherical amorphous magnesium aluminate silicate. FIG. 3 shows an SEM photograph.
　［比較例２］
　実施例２で得られた濾過・水洗、濃度調製（１９ｗ／ｗ％）懸濁液（平均粒子径１４．７μｍ）を遠心式アトマイザーを用いて、回転数９０００ｒｐｍ、入熱温度３３０℃、出口温度１６０℃の条件で噴霧乾燥し、球状非結晶ケイ酸アルミン酸マグネシウムを得た。図４にＳＥＭ写真を示す。 [Comparative Example 2]
Filtration, water washing, concentration adjustment (19 w / w%) suspension (average particle diameter 14.7 μm) obtained in Example 2 was rotated at 9000 rpm, heat input temperature 330 ° C., outlet temperature using a centrifugal atomizer. Spray drying was performed at 160 ° C. to obtain spherical amorphous magnesium aluminate silicate. FIG. 4 shows an SEM photograph.
　［表１］測定値
Figure JPOXMLDOC01-appb-I000001
注）粒子強度において測定不可とは、粒子強度が小さく最大荷重値が読みとれないことを示す。粒径が１００μｍ程度では５０ｇ／ｍｍ２が測定の下限である。 [Table 1] Measurement values
Figure JPOXMLDOC01-appb-I000001
Note) Inability to measure particle strength means that particle strength is small and the maximum load value cannot be read. When the particle size is about 100 μm, 50 g / mm 2 is the lower limit of the measurement.
　本発明の球状非結晶ケイ酸アルミン酸マグネシウムは、粒子強度、真球度が高く、比容積も低く従来の球状非結晶ケイ酸アルミン酸マグネシウムにはない特性を示している。ＳＥＭ写真より、本発明の球状非結晶ケイ酸アルミン酸マグネシウムは、より微細な粒子が密に凝集していることが示されている。 The spherical amorphous magnesium aluminate silicate of the present invention has high particle strength, sphericity, low specific volume, and exhibits characteristics not found in conventional spherical amorphous magnesium aluminate silicate. SEM photographs show that the spherical amorphous magnesium aluminate silicate of the present invention has finer particles densely aggregated.
　［実施例３］　顆粒の製造
　実施例１の球状非結晶ケイ酸アルミン酸マグネシウム１００ｇを流動造粒乾燥機〔フロイント産業（株）製、フロー・コーター・ミニ　ＦＬ〕に仕込み、ヒドキシプロピルセルロース８．３ｇおよび粉砕アセトアミノフェン（２００ｍｅｓｈ篩過品）４１．７ｇを含む精製水３６７ｇを噴霧速度１～４ｇ／ｍｉｎで噴霧し、コーティング顆粒を得た。平均粒子径は１４２μｍであった。図５にＳＥＭ写真を示す。本発明の球状非結晶ケイ酸アルミン酸マグネシウムの周りに、ヒドキシプロピルセルロースとアセトアミノフェンの層が均一に取り巻き綺麗な顆粒となっている。 [Example 3] Manufacture of granules 100 g of spherical amorphous magnesium aluminate silicate of Example 1 was charged into a fluidized granulator / dryer (Freund Sangyo Co., Ltd., Flow Coater Mini FL), and hydroxypropylcellulose 8 367 g of purified water containing 3 g and 41.7 g of ground acetaminophen (200 mesh sieve product) was sprayed at a spraying speed of 1 to 4 g / min to obtain coated granules. The average particle size was 142 μm. FIG. 5 shows an SEM photograph. A layer of hydroxypropyl cellulose and acetaminophen is uniformly wrapped around the spherical amorphous magnesium aluminate silicate of the present invention to form beautiful granules.
　［比較例３］　顆粒の製造
　比較例１の球状非結晶ケイ酸アルミン酸マグネシウムを実施例１と同様の条件で、コーティング顆粒を作ろうとした。しかし、球状非結晶ケイ酸アルミン酸マグネシウムの強度が弱く、破壊されコーティング顆粒を作ることはできなかった。 [Comparative Example 3] Manufacture of granules Coated granules were prepared using the spherical amorphous magnesium aluminate of Comparative Example 1 under the same conditions as in Example 1. However, the strength of spherical amorphous magnesium aluminate silicate was so weak that it was broken and could not produce coated granules.
　［実施例３］　顆粒の製造
　実施例１の球状非結晶ケイ酸アルミン酸マグネシウム５００ｇを流動造粒乾燥機〔パウレッックス社製、マルチプレックスＭＰ－０１　ｔｙｐｅ　ＳＰＣ〕に仕込み、ヒドキシプロピルセルロース１００ｇおよび粉砕アセトアミノフェン（２００ｍｅｓｈ篩過品）５００ｇを含む精製水４４００ｇを噴霧速度２．２～９．６ｇ／ｍｉｎで噴霧を１６時間行い、コーティング顆粒を得た。図７にＳＥＭ写真を、図９に噴霧速度と噴霧時間の関係を示す。 [Example 3] Manufacture of granules 500 g of spherical amorphous magnesium aluminate silicate of Example 1 was charged into a fluidized granulation dryer (manufactured by Paulex, Multiplex MP-01 type SPC), and 100 g of hydroxypropylcellulose and pulverized 4400 g of purified water containing 500 g of acetaminophen (200 mesh sieve product) was sprayed at a spray rate of 2.2 to 9.6 g / min for 16 hours to obtain coated granules. FIG. 7 shows an SEM photograph, and FIG. 9 shows the relationship between the spray speed and the spray time.
　［比較例４］　顆粒の製造
　結晶セルロース製の核剤（セルフィア　ＳＣＰ－１００（商標　旭化成ケミカルズ社製））を流動造粒乾燥機〔パウレッックス社製、マルチプレックスＭＰ－０１　ｔｙｐｅ　ＳＰＣ〕に仕込み、ヒドキシプロピルセルロース１００ｇおよび粉砕アセトアミノフェン（２００ｍｅｓｈ篩過品）５００ｇを含む精製水４４００ｇを噴霧速度約２．５～５．６ｇ／ｍｉｎで噴霧を２７時間行い、コーティング顆粒を得た。図８にＳＥＭ写真を、図９に噴霧速度と噴霧時間の関係を示す。 Comparative Example 4 Production of Granules Nucleating agent made of crystalline cellulose (Selfia SCP-100 (trade name, manufactured by Asahi Kasei Chemicals Co., Ltd.)) was charged into a fluidized granulator / dryer (manufactured by Paulex, multiplex MP-01 type SPC). 4400 g of purified water containing 100 g of xylpropylcellulose and 500 g of pulverized acetaminophen (200 mesh sieve product) was sprayed at a spray rate of about 2.5 to 5.6 g / min for 27 hours to obtain coated granules. FIG. 8 shows an SEM photograph, and FIG. 9 shows the relationship between the spraying speed and the spraying time.
　実施例４と比較例４の結果より、本発明の球状非結晶ケイ酸アルミン酸マグネシウムは、結晶セルロース製核剤よりも綺麗な球状であり、また、噴霧速度が大きく、コーティングに要する時間が大幅に短縮されていることが分かる。 From the results of Example 4 and Comparative Example 4, the spherical amorphous magnesium aluminate of the present invention has a finer spherical shape than the nucleating agent made of crystalline cellulose, has a high spray rate, and greatly takes the time required for coating. It can be seen that it has been shortened.
　［実施例５］　錠剤の製造
　実施例３の顆粒３００ｇを口腔内速崩壊剤用賦形剤Ｆ－ＭＥＬＴ〔商標、富士化学工業（株）製〕２００ｇ、ステアリン酸マグネシウム５ｇ、アスパルテーム５ｇと混合し、ロータリー打錠機〔（株）畑鉄工所製、ＨＴ－ＡＰ１８ＳＳ－ＩＩ〕により、重量２００ｍｇ、直径８ｍｍ、９Ｒの錠剤を設定硬度５０Ｎとして打錠し口腔内速崩壊錠を得た。キャッピングやハリツキもなく良好に打錠することができた。局方の崩壊試験での崩壊時間は１６秒であった。アセトアミノフェンの苦みは感じられなかった。 [Example 5] Manufacture of tablets 300 g of the granules of Example 3 were mixed with 200 g of excipient F-MELT [trademark, manufactured by Fuji Chemical Industry Co., Ltd.] for oral rapid disintegrant, 5 g of magnesium stearate, and 5 g of aspartame. Using a rotary tableting machine (HT-AP18SS-II, manufactured by Hata Iron Works Co., Ltd.), a tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was tableted with a set hardness of 50 N to obtain an orally rapidly disintegrating tablet. It was possible to tablet well without capping or peeling. The disintegration time in the pharmacopoeia disintegration test was 16 seconds. The bitterness of acetaminophen was not felt.

Claims (7)

  1. 平均粒子径が０.０１～０．５μｍである非結晶一次粒子から構成され、粒子強度が５０～１０００ｇ／ｍｍ２、平均粒子径が１～５００μｍ、真球度が０．８以上であり、下式（Ｉ）で表される球状非結晶ケイ酸アルミン酸マグネシウム。
    Ａｌ２Ｏ３・ｘＭｇＯ・ｙＳｉＯ２・ｍＨ２Ｏ　　　（Ｉ）
    （式中、ｘは０．１≦ｘ≦３．０、ｙは０．５≦ｙ≦５．０、ｍは０．１≦ｍ≦１０の範囲の数を示す。）     Composed of amorphous primary particles having an average particle size of 0.01 to 0.5 μm, a particle strength of 50 to 1000 g / mm 2 , an average particle size of 1 to 500 μm, and a sphericity of 0.8 or more, Spherical amorphous magnesium aluminate silicate represented by the following formula (I):
    Al 2 O 3 .xMgO.ySiO 2 .mH 2 O (I)
    (In the formula, x is 0.1 ≦ x ≦ 3.0, y is 0.5 ≦ y ≦ 5.0, and m is a number in the range of 0.1 ≦ m ≦ 10.)
  2. 粒子強度が１００～１０００ｇ／ｍｍ２、平均粒子径が５～３００μｍである請求項１に記載の球状非結晶ケイ酸アルミン酸マグネシウム。 2. The spherical amorphous magnesium aluminate silicate according to claim 1, having a particle strength of 100 to 1000 g / mm 2 and an average particle size of 5 to 300 μm.
  3. 比表面積が１０～５００ｍ２／ｇ、静的比容積が１．０～７．０ｍｌ／ｇ、吸油量が０．５～５．０ｍｌ／ｇ、吸水量が０．５～５．０ｍｌ／ｇである請求項１～２のいずれかに記載の球状非結晶ケイ酸アルミン酸マグネシウム。 Specific surface area of 10 to 500 m 2 / g, static specific volume of 1.0 to 7.0 ml / g, oil absorption of 0.5 to 5.0 ml / g, water absorption of 0.5 to 5.0 ml / g The spherical amorphous magnesium aluminate silicate according to any one of claims 1 and 2.
  4. 賦形剤、崩壊剤、結合剤、被覆剤、界面活性剤から選ばれる１種以上の成分を含有してなる請求項１～３のいずれか１項に記載の球状非結晶ケイ酸アルミン酸マグネシウム。 The spherical amorphous magnesium aluminate silicate according to any one of claims 1 to 3, comprising at least one component selected from an excipient, a disintegrant, a binder, a coating agent, and a surfactant. .
  5. 非結晶ケイ酸アルミン酸マグネシウムを粉砕し、噴霧乾燥する工程を含む請求項１～４のいずれか１項に記載の球状非結晶ケイ酸アルミン酸マグネシウムの製造方法。 The method for producing spherical amorphous magnesium aluminate silicate according to any one of claims 1 to 4, comprising a step of pulverizing and spray-drying amorphous magnesium aluminate silicate.
  6. 請求項１～５のいずれか１項に記載の球状非結晶ケイ酸アルミン酸マグネシウムの周囲に活性成分層を有してなる顆粒状組成物。 A granular composition comprising an active ingredient layer around the spherical amorphous magnesium aluminate according to any one of claims 1 to 5.
  7. 請求項１～５のいずれか１項に記載の球状非結晶ケイ酸アルミン酸マグネシウムを含有してなる医薬組成物。 A pharmaceutical composition comprising the spherical amorphous magnesium aluminate silicate according to any one of claims 1 to 5.
PCT/JP2009/002972 2008-06-27 2009-06-26 Spherical non-crystalline magnesium aluminosilicate WO2009157214A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2010517774A JPWO2009157214A1 (en) 2008-06-27 2009-06-26 Spherical amorphous magnesium aluminate silicate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2008169020 2008-06-27
JP2008-169020 2008-06-27

Publications (1)

Publication Number Publication Date
WO2009157214A1 true WO2009157214A1 (en) 2009-12-30

Family

ID=41444286

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2009/002972 WO2009157214A1 (en) 2008-06-27 2009-06-26 Spherical non-crystalline magnesium aluminosilicate

Country Status (2)

Country Link
JP (1) JPWO2009157214A1 (en)
WO (1) WO2009157214A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011184328A (en) * 2010-03-05 2011-09-22 Fuji Silysia Chemical Ltd Powder-compressed molded product for medicine or food, and method for producing the same
JP2012025711A (en) * 2010-07-27 2012-02-09 Ohara Yakuhin Kogyo Kk Method for producing physiologically active substance-containing particle
WO2012091040A1 (en) * 2010-12-27 2012-07-05 富田製薬株式会社 Decay-type nuclear particle for pharmaceutical formulation
JP2013056791A (en) * 2011-09-07 2013-03-28 Fuji Kagaku Kk Amorphous sodium aluminum silicate and manufacturing method therefor
JP2013241451A (en) * 2013-08-05 2013-12-05 Ohara Yakuhin Kogyo Kk Production method of physiologically active substance-containing particle
JP2015048352A (en) * 2014-01-08 2015-03-16 旭化成ケミカルズ株式会社 Cellulose nuclear particle and production method thereof
WO2017204142A1 (en) * 2016-05-23 2017-11-30 沢井製薬株式会社 Intraorally disintegrable tablet containing olmesartan medoxomil
JPWO2018087870A1 (en) * 2016-11-10 2019-09-26 日本たばこ産業株式会社 Spherical powder aggregate and method for producing the same
JPWO2020071539A1 (en) * 2018-10-05 2021-09-02 富士化学工業株式会社 Porous silica particle composition
CN114149011A (en) * 2020-09-08 2022-03-08 浙江丰虹新材料股份有限公司 Pharmaceutic adjuvant magnesium aluminum silicate and synthesis method thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5216078B2 (en) * 1971-10-25 1977-05-06
JPS55140712A (en) * 1979-04-20 1980-11-04 Fuji Kagaku Kogyo Kk Manufacture of neutral magnesium silicoaluminate for medical treatment
JPH01151939A (en) * 1987-12-09 1989-06-14 Mizusawa Ind Chem Ltd White spherical adsorbent and its production
JP2000086537A (en) * 1998-09-11 2000-03-28 Fuji Chem Ind Co Ltd Inorganic compound saccharide composition, vehicle, rapidly disintegrating compression molded product, and their production

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5216078B2 (en) * 1971-10-25 1977-05-06
JPS55140712A (en) * 1979-04-20 1980-11-04 Fuji Kagaku Kogyo Kk Manufacture of neutral magnesium silicoaluminate for medical treatment
JPH01151939A (en) * 1987-12-09 1989-06-14 Mizusawa Ind Chem Ltd White spherical adsorbent and its production
JP2000086537A (en) * 1998-09-11 2000-03-28 Fuji Chem Ind Co Ltd Inorganic compound saccharide composition, vehicle, rapidly disintegrating compression molded product, and their production

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011184328A (en) * 2010-03-05 2011-09-22 Fuji Silysia Chemical Ltd Powder-compressed molded product for medicine or food, and method for producing the same
JP2012025711A (en) * 2010-07-27 2012-02-09 Ohara Yakuhin Kogyo Kk Method for producing physiologically active substance-containing particle
JP5578534B2 (en) * 2010-12-27 2014-08-27 富田製薬株式会社 Disintegrating core particles for pharmaceutical products
WO2012091040A1 (en) * 2010-12-27 2012-07-05 富田製薬株式会社 Decay-type nuclear particle for pharmaceutical formulation
JP2014169318A (en) * 2010-12-27 2014-09-18 Tomita Pharmaceutical Co Ltd Decay-type nuclear particle for pharmaceutical formulation
JP2013056791A (en) * 2011-09-07 2013-03-28 Fuji Kagaku Kk Amorphous sodium aluminum silicate and manufacturing method therefor
JP2013241451A (en) * 2013-08-05 2013-12-05 Ohara Yakuhin Kogyo Kk Production method of physiologically active substance-containing particle
JP2015048352A (en) * 2014-01-08 2015-03-16 旭化成ケミカルズ株式会社 Cellulose nuclear particle and production method thereof
WO2017204142A1 (en) * 2016-05-23 2017-11-30 沢井製薬株式会社 Intraorally disintegrable tablet containing olmesartan medoxomil
JPWO2018087870A1 (en) * 2016-11-10 2019-09-26 日本たばこ産業株式会社 Spherical powder aggregate and method for producing the same
JPWO2020071539A1 (en) * 2018-10-05 2021-09-02 富士化学工業株式会社 Porous silica particle composition
JP7124107B2 (en) 2018-10-05 2022-08-23 富士化学工業株式会社 Porous silica particle composition
JP7471675B2 (en) 2018-10-05 2024-04-22 富士化学工業株式会社 Porous silica particle composition
CN114149011A (en) * 2020-09-08 2022-03-08 浙江丰虹新材料股份有限公司 Pharmaceutic adjuvant magnesium aluminum silicate and synthesis method thereof

Also Published As

Publication number Publication date
JPWO2009157214A1 (en) 2011-12-08

Similar Documents

Publication Publication Date Title
WO2009157214A1 (en) Spherical non-crystalline magnesium aluminosilicate
EP1523974B1 (en) Composition for rapid disintegrating tablet in oral cavity
JP5637624B2 (en) Disintegrating particle composition and fast disintegrating compression molding using the same
EP1674083B1 (en) Tablet quickly disintegrating in oral cavity
JP7124107B2 (en) Porous silica particle composition
CN101227894B (en) Rapidly disintegratable oral tablet
JP5956475B2 (en) Orally disintegrating tablets containing bitter mask granules
JP5835875B2 (en) Method for producing intraorally rapidly disintegrating tablets
US8349361B2 (en) Composition for rapid disintegrating tablet in oral cavity
JP2011157348A (en) Disintegrable high-strength spherical particle composition
JP5392892B2 (en) Spherical particles made of calcium hydrogen phosphate
WO2012001977A1 (en) Disintegrating composition and easily disintegrating compression molded article
JP4691925B2 (en) Production method of compression molding
JP2011046750A (en) Quickly disintegrating tablet in oral cavity
JP6104038B2 (en) Composite composition of crystalline cellulose

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09769924

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2010517774

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09769924

Country of ref document: EP

Kind code of ref document: A1