JP2011157348A - Disintegrable high-strength spherical particle composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a particle composition as particles to be used for a nucleating agent or the like for producing granules such as in the form of a pharmaceutical, cosmetic or food, having such characteristics as being readily disintegrable on contact with a solvent in the digestive tracts to release an active ingredient, being extremely slight in reactivity with the active ingredient, being high in roundness, being slight in surface unevenness, being easy to form uniform active ingredient laminated layer(s) and/or film layer(s), having well-masking performance, and causing no degeneration on using water in producing the granules. <P>SOLUTION: The disintegrable spherical particles, which are obtained by suspending in water a disintegrant and inorganic particles, and as needed, a water-soluble base agent and/or an active ingredient followed by conducting a spray drying or the like, are readily disintegrable to release the active ingredient, are high in roundness, are slight in surface unevenness, are easy to form uniform active ingredient laminated layer(s) and/or film layer(s), and also have well-masking performance, and cause no degeneration on using water in producing granules; therefore, the disintegrable particles are suitable as particles for a nucleating agent. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to particles that have disintegration and sufficient strength and are used for pharmaceutical applications, a method for producing the same, and a pharmaceutical composition using the particles as a nucleating agent.

  In pharmaceuticals, as a means for controlling release of an active ingredient, enteric dissolution, stability improvement or taste masking, granules having a multilayer structure having an active ingredient-containing layer around a nucleating agent are used. When producing a granule having a multilayer structure, it is preferable to use particles having a uniform particle size and high sphericity as a nucleating agent in order to increase the lamination rate and to uniformly laminate the layer thickness. Further, the properties required for the nucleating agent are required to be strength that does not break due to the load applied during granulation, absorbability to absorb the spray solution, and stability that does not react with the active ingredient. Further, in order to increase the dissolution rate of the active ingredient, there is a demand for particles for nucleating agents in which the particles themselves rapidly disintegrate after dissolution of the coating layer in the digestive tract.

  The spherical particles used as a disintegrating nucleating agent so far contain 95% or more of lactose, the ratio of major axis / minor axis is 1.2 or less, the bulk density is 0.7 g / ml or more, the angle of repose is 35 degrees or less, Contains spherical particles having a friability of 1.0% or less (Patent Document 1), 95% by weight or more of a water-soluble single substance such as sugar alcohol or sodium chloride, the ratio of major axis / minor axis is 1.2 or less, 10% or more of spherical cellulose having a density of 0.65 g / ml or more, an angle of repose of 35 degrees or less and a friability of 1.0% or less and used as a nucleating agent (Patent Document 2), and an average degree of polymerization of 60 to 350 A cellulosic preparation containing a tapping apparent density of 0.60 to 0.95 g / mL, a sphericity of 0.7 or more, a shape factor of 1.10 to 1.50, and an average particle size of 10 to 400 μm Particles for use (Patent Document 3) are known. These are not sufficiently disintegratable in water, and the sphericity of the particle shape is low.In particular, the smaller the particle size, the lower the sphericity. It was unsuitable for use as a nucleating agent for forming a uniform layer.

  Moreover, the present applicant has disclosed a composition for an orally rapidly disintegrating tablet obtained by spray-drying containing an inorganic powder (Patent Documents 4 and 5). Since these are excipients for intraoral rapidly disintegrating tablets, they were excellent in moldability and disintegration, but the strength of the particles was not sufficient to perform a granulation step with an active ingredient. Further, the present applicant has disclosed spherical particles of a high strength nucleating agent for producing a pharmaceutical product, which is obtained by crushing scaly calcium hydrogen phosphate into a nano size and spray drying (Patent Document 6). This is composed of a water-insoluble inorganic substance and has no disintegration property.

  A nucleating agent with high sphericity, sufficient strength in the formulation process, and rapidly disintegrating in the gastrointestinal tract to increase the dissolution rate of the active ingredient, and a disintegrant and inorganic particles, if necessary Spherical particles that contain a water-soluble base and an active ingredient and are used in the preparation are not known.

JP-A-7-173050 JP 2004-066760 A International Publication WO2002 / 036168 Pamphlet JP 2005-139168 A International Publication WO2005 / 037254 Pamphlet JP 2009-120476 A

  Spheroids with high sphericity used for the core of granules and tablets for pharmaceuticals, cosmetics, food, etc. that have sufficient strength for use in the production of granules, etc., and good disintegration in the digestive tract without disintegrating in the oral cavity There is a need for particles.

  The present inventors have found that the disintegrating spherical particle composition obtained by suspending the inorganic particles and the disintegrant in the solvent and spray-drying with respect to the entire spherical particles has a better sphericity than the conventional nucleating agent. The present inventors have found that it has sufficient strength for use in production and the like, and has good disintegration property by contact with a solvent.

  Since the collapsible spherical particle composition of the present invention has a much better sphericity than conventional nucleating agents, the granular composition granulated using this particle has a high lamination rate and good lamination properties. In addition, since it rapidly disintegrates in the digestive tract, granules having good active ingredient release can be produced.

2 is a SEM photograph (1 memory: 5 μm) of spray-dried spherical particles of Example 1. FIG. 2 is a 200 × optical photograph of a water dropping test of Example 1. FIG. 4 is a SEM photograph (1 memory 10 μm) of active ingredient laminated granules of Example 3. FIG.

The disintegrating spherical particle composition of the present invention will be described below.
The collapsible spherical particle composition of the present invention contains inorganic particles and a disintegrant, and if necessary, a water-soluble base, has a sphericity of 0.8 to 1, a particle strength of 100 to 2000 g / mm ² , and an average It is a spherical particle having a particle size of 10 to 500 μm and having good disintegration when contacted with a solvent such as water.

  Good disintegration by contact with a solvent means disintegration in 10 minutes or less, preferably 6 minutes or less, more preferably 3 minutes or less, and most preferably 2 minutes or less. Although the measurement of the disintegration time will be described later, water is dropped on the particles, and the disintegration time is measured with a microscope or the like.

  The disintegrating spherical particle composition of the present invention has an average particle diameter of 10 to 500 μm, preferably 20 to 300 μm, more preferably 30 to 200 μm. If the average particle size is less than 10 μm, it is not preferable because it is difficult to laminate active ingredients and aggregation of particles tends to occur. Further, when the average particle size exceeds 500 μm, the particle size of the laminated granules becomes large, so when applied to an orally disintegrating tablet, it is easy to feel roughness, the dosage is deteriorated, and it is applied to a granule-containing tablet. This is not preferable because it leads to variation in content.

  The collapsible spherical particle composition of the present invention has a sphericity of 0.80 to 1, preferably 0.85 to 1, more preferably 0.90 to 1, and most preferably 0.95. ~ 1. When the sphericity is less than 0.80, the sphericity of the granules after lamination of the active ingredients is low, which is not preferable for coating the active ingredients or forming granules. Another feature is that there are few irregularities on the surface. The sphericity is a value obtained by dividing the minor axis of the sphere by the major axis.

The disintegrating spherical particle composition of the present invention has a particle strength of 100 to 2000 g / mm ² , preferably 200 to 1000 g / mm ² , more preferably 300 to 1000 g / mm ² , and still more preferably 400. ˜1000 g / mm ² . By having these strengths, there is sufficient strength to prevent cracking or chipping when the lamination / coating treatment is performed on the collapsible spherical particle composition of the present invention. When the particle strength is 100 g / mm ² or less, cracking and chipping occur during the granulation step, which is inappropriate as a nucleating agent.
Furthermore, the collapsible spherical particle composition of the present invention rapidly disintegrates when it comes into contact with moisture in the oral cavity or digestive organs, but does not break with moisture sufficient to perform wet granulation as a lamination / coating treatment. It has a feature called.

The BET specific surface area of the collapsible spherical particle composition of the present invention is related to the water supply ability of the particles, and appropriate water absorption is required when coating the spherical particles. The BET specific surface area is 0.15 to 500 m ² / g. , Preferably ² to 400 m ² / g, more preferably 5 to 300 m ² / g. When the BET specific surface area exceeds 500 m ² / g, the water absorption becomes high, which leads to aggregation of the particles and the particle size distribution of the granules becomes wide and non-uniform. Further, if the specific surface area is less than 2 m ² / g, the adhesion force of the solid or liquid to the surface is weakened, which is not preferable.

  The static specific volume of the disintegrating spherical particle composition of the present invention is 1.5 to 5.0 ml / g, preferably 1.5 to 4.0 ml / g. If it is less than 1.5 ml / g, it is heavy, so that the flow in the fluidized bed granulator becomes insufficient, and the active ingredient lamination becomes uneven. If it exceeds 5.0 ml / g, it is not suitable because it is light and the active ingredient lamination is insufficient, and the particles may aggregate in the granulator to form large distorted particles.

  The water absorption amount of the collapsible spherical particle composition of the present invention requires an appropriate amount of solvent or fine powder to adhere to the surface, so the water absorption amount is 0.1 to 3.0 ml / g, preferably 0.3 to 2. 0.0 ml / g, more preferably 0.4 to 1.5 ml. Here, the water absorption is a value indicating absorption of liquids such as organic solvents and oils and fats in addition to water. In liquids other than water, these liquid absorption amounts may cause values outside the stated water absorption range, but such errors are also within the scope of the present invention.

  The angle of repose of the collapsible spherical particle composition of the present invention is good because of its high sphericity, and is 20 to 45 degrees, preferably 20 to 40 degrees, and more preferably 20 to 35 degrees. By having such an angle of repose, excellent fluidity is exhibited, and active ingredient lamination and coating can be easily and uniformly operated. The angle of repose is based on the measurement method of JIS (Japanese Industrial Standard).

In the disintegrating spherical particle composition of the present invention, the mixing ratio of the disintegrant is 1 to 50% by weight, preferably 2 to 40% by weight, more preferably 5 to 30% by weight, based on the entire disintegrating spherical particle composition. %.
The blending ratio of the inorganic particles is 5 to 95% by weight, preferably 10 to 90% by weight, more preferably 20 to 80% by weight, and most preferably 30 to 70% by weight based on the entire disintegrating spherical particle composition. %.
Further, if necessary, when a water-soluble base is blended, the blending ratio of the water-soluble base is 5 to 85% by weight, preferably 10 to 80% by weight, based on the entire disintegrating spherical particle composition. Preferably it is 20 to 75% by weight.

  As the inorganic particles of the present invention, pharmaceutically acceptable inorganic particles comprising at least one of aluminum, magnesium and calcium are used. For example, magnesium aluminate metasilicate, magnesium aluminate silicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, calcium phosphate, hydroxyapatite, hydrotalcite, aluminum silicate, zeolite, anhydrous It is at least one selected from silicic acid, hydrous silicic acid, calcium carbonate, calcium silicate, magnesium silicate, magnesium oxide, magnesium hydroxide, magnesium alumina hydroxide, dry aluminum hydroxide gel, magnesium carbonate and the like. More preferably, magnesium aluminate metasilicate, magnesium aluminate silicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granule, hydrotalcite, calcium carbonate, calcium silicate and dry hydroxylation At least one selected from aluminum gels, and more preferably at least one selected from magnesium aluminate metasilicate and calcium hydrogen phosphate. Among the above calcium hydrogen phosphates, the scaly calcium hydrogen phosphate disclosed in Patent 2700141 is suitable.

  The average particle diameter of these inorganic particles is 0.01 to 20 μm, preferably 0.01 to 10 μm, more preferably 0.01 to 5 μm. The smaller the particle size, the stronger the contact force between the particles, which is preferable for increasing the strength of the composition of the present invention and further increasing the sphericity. In order to obtain a desired average particle diameter, a pulverized product by a conventional method can be used.

The disintegrant of the present invention corresponds to a disintegrant in the field of pharmaceutical additives. For example, adipic acid, alginic acid, sodium alginate, pregelatinized starch, erythritol, fructose, sodium carboxymethyl starch, carmellose, carmellose Calcium, carmellose sodium, hydrous silicon dioxide, agar, xylitol, guar gum, calcium citrate, croscarmellose sodium, crospovidone, synthetic aluminum silicate, magnesium aluminate silicate, low substituted hydroxypropylcellulose, crystalline cellulose, crystals Cellulose and carmellose sodium, wheat starch, rice starch, cellulose acetate phthalate, dioctylsodium sulfosuccinate, sucrose fatty acid ester, hydroxyalumina hydroxide Nesium, calcium stearate, polyoxyl stearate, sorbitan sesquioleate, gelatin, shellac, sorbitol, sorbitan fatty acid ester, talc, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, dextrin, sodium dehydroacetate, corn starch, tragacanth, trehalose, Lactose, maltose, sucrose, hydrotalcite, honey, palatinit, palatinose, potato starch, hydroxyethyl methylcellulose, hydroxypropyl starch, hydroxypropylcellulose, glucose, bentonite, partially pregelatinized starch, monosodium fumarate, polyethylene glycol, poly Oxyethylene hydrogenated castor oil, polyoxyethylene, polyoxypropylene, grease 1 type or more of alcohol, polysorbate, polyvinyl acetal diethylaminoacetate, polyvinyl pyrrolidone, maltitol, D-mannitol, anhydrous citric acid, anhydrous silicic acid, magnesium metasilicate aluminate, methyl cellulose, glyceryl monostearate, sodium lauryl sulfate, etc. Yes, any of these may be used alone, but two or more of them may be blended.
Preferably, it is selected from the group consisting of crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, hydroxypropylcellulose, crystalline cellulose, carmellose, carmellose sodium, carmellose calcium and starch, more preferably cros Povidone, low substituted hydroxypropylcellulose. These can be used alone or in combination of two or more.

  These disintegrants preferably have a smaller particle diameter in order to increase the sphericity and particle strength of the composition of the present invention. The average particle diameter is 0.1 to 40 μm, preferably 0.1 to 20 μm, more preferably 0.1 to 10 μm.

The water-soluble base of the present invention generally corresponds to those that are water-soluble among those classified as excipients and binders in the field of pharmaceutical additives.
What is classified into the category as an excipient includes, for example, starch acrylate, L-aspartic acid, aminoethylsulfonic acid, aminoacetic acid, candy (powder), gum arabic, gum arabic powder, alginic acid, sodium alginate , Pregelatinized starch, inositol, ethyl cellulose, ethylene vinyl acetate copolymer, erythritol, sodium chloride, olive oil, kaolin, cocoa butter, casein, fructose, pumice grains, carmellose, carmellose sodium, hydrous silicon dioxide, dry yeast, dry hydroxylation Aluminum gel, dry sodium sulfate, dry magnesium sulfate, agar, agar powder, xylitol, citric acid, sodium citrate, disodium citrate, glycerin, calcium glycerophosphate, sodium gluconate, L- Lutamine, clay, clay grains, croscarmellose sodium, aluminum silicate, synthetic aluminum silicate, hydroxypropyl starch, crystalline cellulose, magnesium silicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, light liquid paraffin , Cinnamon powder, crystalline cellulose, crystalline cellulose / carmellose sodium, microcrystalline crystalline cellulose, pearl millet, synthetic aluminum silicate, synthetic hydrotalcite, sesame oil, wheat flour, wheat starch, wheat germ powder, rice flour (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, dimethylpolysiloxane, tartaric acid, potassium hydrogen tartrate, baked gypsum, sucrose fatty acid ester, magnesium aluminate hydroxide, aluminum hydroxide gel, aluminum hydroxide sodium bicarbonate coprecipitation Product, magnesium hydroxide, squalane, stearyl alcohol, stearic acid, calcium stearate, polyoxyl stearate, magnesium stearate, purified gelatin, purified shellac, purified white sugar, purified white sugar spherical granules, purified montan wax, zein, sorbitan sesquioleate, Cetanol, gypsum, cetostearyl alcohol, shellac, gelatin, sorbitan fatty acid ester, D-sorbitol, tricalcium phosphate, soybean oil, soybean oil unsaponifiable matter, soybean lecithin, defatted powder Talc, ammonium carbonate, calcium carbonate, magnesium carbonate, neutral anhydrous sodium sulfate, low substituted hydroxypropyl cellulose, dextran, dextrin, natural aluminum silicate, corn syrup, corn starch, trehalose, tragacanth, silicon dioxide, calcium lactate, Lactose, hydrotalcite, maltose, white shellac, white petrolatum, sucrose, sucrose, sucrose starch granule, dried green leaf extract powder, dried green leaf green juice, honey, palatinit, palatinose, paraffin, potato starch, semi-digested starch Human serum albumin, hydroxypropyl starch, hydroxypropylcellulose, phytic acid, glucose, glucose hydrate, partially pregelatinized starch, pullulan, Lopylene glycol, powdered reduced maltose water candy, powdered cellulose, pectin, bentonite, sodium polyacrylate, polyethylene glycol, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene, polyoxypropylene, glycol, polystyrene sulfone Sodium acid, polysorbate, polyvinyl acetal diethylaminoacetate, polyvinyl pyrrolidone, maltitol, maltose, D-mannitol, water candy, isopropyl myristate, anhydrous lactose, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granule, aluminum metasilicate Magnesium acid, methylcellulose, cottonseed powder, cottonseed oil, mole, aluminum monostearate, glyceryl monostearate, monostea Sorbitan phosphate, silicic anhydride, medicinal charcoal, peanut oil, aluminum sulfate, calcium sulfate, granular limestone, granular corn starch, liquid paraffin, dl-malic acid, calcium monohydrogen phosphate, calcium hydrogen phosphate, potassium hydrogen phosphate There is sodium hydrogen phosphate,

Those classified in the category as the binder 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, agate powder, hydrolyzed gelatin powder, sodium caseinate, fructose, caramel, karaya gum powder, carboxy Vinyl polymer, carboxymethyl ethyl cellulose, carboxymethyl starch sodium, carmellose, carmellose sodium, hydrous silicon dioxide, agar, ume powder, oxa Tan gum, beef tallow hardened oil, guar gum, glycerin, synthetic aluminum silicate, light anhydrous silicic acid, light anhydrous silicic acid-containing hydroxypropylcellulose, crystalline cellulose, hardened oil, copolyvidone, sesame oil, wheat 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 Sorbitan sesquioleate, cetanol, gelatin, shellac, sorbitan fatty acid ester, D-sorbitol, soybean lecithin, calcium carbonate, simple syrup, Xistrin, starch (soluble), corn starch, tragacanth, paraffin, potato starch, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, piperonyl butoxide, Butyl phthalyl butyl 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, polyvinyl alcohol (completely saponified product), polyvinyl alcohol (partially saponified product), polyvinylpyrrolidone, polybutene, sodium polyphosphate, D-mannitol, water candy, light anhydrous silicic acid, magnesium metasilicate aluminate, these Any one of them may be used alone, but two or more kinds can be blended.
Preferably, sugars such as mannitol, xylitol, sorbitol, erythritol, maltitol, lactose, glucose, fructose, maltose, trehalose, palatinit, palatinose, glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, One or more amino acids such as methionine, asparagine, glutamine, proline, phenylalanine, tyrosine, tryptophan, and salts thereof, any of which may be used alone, but two or more may be blended .

  In the collapsible spherical particle composition of the present invention, an active ingredient and other additive ingredients can be blended within a range that does not particularly affect the sphericity and particle strength. The amount of the active ingredient is 0.1 to 75% by weight, preferably 0.1 to 50% by weight, more preferably 0.1 to 30% by weight, based on the entire composition of the present invention. The amount of other additive components is 50% by weight or less, preferably 30% by weight or less, based on the entire composition of the present invention.

When the active ingredient is included in the collapsible particle composition of the present invention, the particle strength is high, so that it can be coated as it is, the lamination process of the active ingredient can be omitted, and production can be performed more easily.
These active ingredients preferably have a smaller particle size in order to increase the sphericity and particle strength of the composition of the present invention. The average particle size is 0.1 to 20 μm, preferably 0.1 to 15 μm, and more preferably 0.1 to 10 μm. As these active ingredients, those obtained by pulverization or air spraying can be used in order to obtain a desired average particle size.

  Examples of other additive components include surfactants. By incorporating a surfactant usually used in the field of pharmaceuticals, the release / elution rate of the active ingredient can be improved. The method of blending can be performed according to information.

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

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

  Antipyretic analgesic and anti-inflammatory agents include actarit, aspirin, acetaminophen, ampiroxicam, ibuprofen, indomethacin, indomethacin farnesyl, etenzamide, etodolac, epilysole, emorphazone, tramadol, buprenorphine hydrochloride, oxaprozin, ketoprofen, sodium salicylate, zaltoprofen sodium, zaltoprofen sodium Sulindac, sulpyrine hydrate, celecoxib, thiaprofenic acid, thiaramide hydrochloride, tenoxicam, naproxen, bucolome, pentazocine, mefenamic acid, meloxicam, mofezolac, loxoprofen sodium hydrate and the like.

As an anti-parkinsonian agent, amantadine hydrochloride, selegiline hydrochloride, talipexol hydrochloride, proheptin hydrochloride, pramipexol hydrochloride hydrate, masaticol hydrochloride, methixene hydrochloride, entacapone, cabergoline, trihexyphenidyl hydrochloride, droxidopa, biperidene, bromocriptine mesylate, Examples include pergolide mesylate and levodopa.
As neuropsychiatric agents, amitriptyline hydrochloride, amoxan, aripiprazole, imipramine hydrochloride, etizolam, sultopride hydrochloride, sertraline hydrochloride, trazodone hydrochloride, paroxetine hydrochloride hydrate, flolopipamide hydrochloride, perospirone hydrochloride hydrate, mianserin hydrochloride, milnaci hydrochloride Plan, methylphenidate hydrochloride, mosapramine hydrochloride, moperon hydrochloride, lofepramine hydrochloride, oxypertin, olanzapine, carpipramine, clocapramine hydrochloride hydrate, clothiazepam, clomipramine hydrochloride, chlorpromazine, spiperone, sulpiride, zotepine, lithium carbonate, timiperone, haloperidol decanoate , Nemonapride, nortriptyline hydrochloride, haloperidol, hydroxyzine hydrochloride, hydroxyzine pamoate, pimozide, Quetiapine oxalate, fluphenazine, prochlorperazine, propericazine, bromperidol, perphenazine, maprotiline hydrochloride, stipiline maleate, trifloperazine maleate, trimipramine maleate, fluvoxamine maleate, modafinil, risperidone, levomepromazine Etc.
Other drugs for the central nervous system include thioprid hydrochloride, donepezil hydrochloride, tartilelin hydrate, terguride, mazindol, riluzole and the like.

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

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

  Among cardiovascular drugs, examples of the cardiotonic agent include aminophylline hydrate, ethylephrine hydrochloride, isoproterenol hydrochloride, corintheophylline, digitoxin, digoxin, denopamine, pimobendan, proxyphylline, vesnarinone, methyldigoxin, ubidecalenone and the like.

  As an arrhythmia agent, ajmaline, acebutolol hydrochloride, atenolol, alprenolol hydrochloride, arotinolol hydrochloride, aprindine hydrochloride, amiodarone hydrochloride, sotalol hydrochloride, pilcainide hydrochloride, propafenone hydrochloride, bepridil hydrochloride, oxprenolol hydrochloride, Carteolol hydrochloride, quinidine sulfate hydrate, cibenzoline succinate, flecainide acetate, disopyramide, nadolol, pindolol, bufetrol hydrochloride, bisoprolol fumarate, procainamide hydrochloride, propranolol hydrochloride, verapamil hydrochloride, mexiletine hydrochloride, etc. Is mentioned.

Examples of the diuretic include azosemide, chlorthalidone, spironolactone, torasemide, triamterene, trichlormethiazide, hydrochlorothiazide, pyrethanide, bumetanide, furosemide, benzylhydrochlorothiazide, mefluside, mozabaptan hydrochloride and the like.
Antihypertensive agents include azelnidipine, alacepril, alanidipine, indapamide, amosulalol hydrochloride, imidapril hydrochloride, efonidipine hydrochloride, quinapril hydrochloride, seriprolol hydrochloride, tilisolol hydrochloride, temocapril hydrochloride, terazosin hydrochloride, delapril hydrochloride, valnidipine hydrochloride, prazosin hydrochloride, hydrochloric acid Betaxolol, benazepril hydrochloride, bevantolol hydrochloride, manidipine hydrochloride, labetalol hydrochloride, olmesartan medoxomil, cadralazine, captopril, carteolol hydrochloride, carbendilol, candesartan cilexetil, guanabenz acetate, clonidine hydrochloride, cilazapril, cilnidipine hydrochloride, ternidipine hydrochloride, Salt hydrate, trandolapril, tripamide, nicardipine hydrochloride, nipyrazilol, nil Dipine, valsartan, hydralazine hydrochloride, pindolol, felodipine, budralazine, bunazosin hydrochloride, propranolol hydrochloride, perindopril erbumine, benbutrol sulfate, enalapril maleate, bopindolol malonate, doxazosin mesylate, meticrane, methyldopa hydrate, metoprolol Examples thereof include tartrate, lisinopril hydrate, resinamine, reserpine, and losartan potassium.

Examples of the vasoconstrictor include rizatriptan benzoate, midodrine hydrochloride, dihydroergotamine mesylate, eletriptan hydrobromide, sumatriptan, zolmitriptan, and the like.
As vasodilators, isosorbide mononitrate, inositol hexanicotinate, isoxsuprine hydrochloride, dipyridamole, isosorbide nitrate, dilazep hydrochloride hydrate, diltiazem hydrochloride, trapidil, trimetazidine hydrochloride, nicorandil, nisoldipine, nitrendipine, nitroglycerin, nifedipine, Examples include amlodipine besylate, benidipine hydrochloride, hepronicart, verapamil hydrochloride, and the like.

Examples of drugs for hyperlipidemia include atorvastatin calcium hydrate, ezemitib, elastase ES, clinofibrate, clofibrate, colestimide, simvastatin, soysterol, sodium dextran sulfate, nicomol, niceritrol, pivastatin calcium, fenofibrate, Examples include pravastatin sodium, fluvastatin sodium, probucol, bezafibrate, polyenephosphatidylcholine, rosuvastatin calcium and the like.
Other cardiovascular drugs include ifenprodil tartrate, indomethacin, sevelamer hydrochloride, fasudil hydrochloride hydrate, lomerizine hydrochloride, gamma-aminobutyric acid, dihydroergotoxin mesylate, tocopherol nicotinate, nicergoline, bosentan hydrate, Examples include meclofenoxate hydrochloride and amethinium methylsulfate.

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

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

Among the drugs for digestive organs, examples of the antidiarrheal agent / intestinal adjuster include loperamide hydrochloride, dimethicone, resistant lactic acid bacteria preparation, bifidobacteria preparation, berberine chloride hydrate, butyric acid bacteria preparation and the like.
Peptic ulcer agents include sodium azulene sulfonate, aldioxa, bexinate hydrochloride betadex, omeprazole, ornoprostil, gefarnate, cimetidine, sucralfate hydrate, sulpiride, cetraxate hydrochloride, sofalcone, teprenone, troxipide, Nizatidine, pirenzepine hydrochloride hydrate, famotidine, plaunotol, proglumide, polaprezinc, irsogladine maleate, misoprostol, methylmethionine sulfonium chloride, ranitidine hydrochloride, lafutidine, rabeprazole sodium, lansoprazole, clevopride malate, rebamipide hydrochloride Examples include salt.

Examples of the antacid include magnesium oxide, magnesium hydroxide, sodium hydrogen carbonate, precipitated calcium carbonate, magnesium metasilicate aluminate, and the like.
Laxatives include senna extract, sennoside, picosulfate sodium hydrate and the like.
Examples of the astringent include anethole trithione, ursodeoxycholic acid, trepibutone, nicotinic acid / naphthyl acetic acid, and the like.

  Other drugs for digestive organs include acamegasiwa extract, sodium azulenesulfonate, cetylpyridinium chloride, decalinium chloride, azacetron hydrochloride, itopride hydrochloride, indisetron hydrochloride, granisetron hydrochloride, cevimeline hydrochloride hydrate, tropisetron hydrochloride, ramosetron hydrochloride, ondansetron , Kitasamycin acetate, mosapride citrate, domifene bromide, dexamethasone, trimebutine maleate, domperidone, pilocarpine hydrochloride, polycarbophil calcium, mesalazine, metoclopramide and the like.

Examples of salivary gland hormone preparations, thyroid and parathyroid hormone agents include dry thyroid, thiamazole, propylthiouracil, liothyronine sodium, levothyroxine sodium hydrate and the like.
Examples of protein anabolic steroids include mestanolone and methenolone.
Examples of adrenal hormone agents include cortisone acetate, fludrocortisone acetate, dexamethasone, triamcinolone, hydrocortisone, prednisolone, betamazone, methylprednisolone, and the like.

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

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

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

Among the vitamin preparations, examples of vitamin A and D preparations include alphacalcidol, calcitriol, vitamin A, and fare calcitriol.
Examples of the vitamin B1 agent include diceamine hydrochloride, octothiamine, thiamine disulfide, bisbenchamine, fursultiamine, and benfotiamine.
Examples of the vitamin B agent include cobamide, nicotinic acid, pantethine, hydroxocobalamin acetate, pyridoxine hydrochloride, flavin adenine dinucleotide, mecobalamin, folic acid, riboflavin butyrate, pyridoxal phosphate, and the like.
Examples of the vitamin C agent include ascorbic acid, and examples of the vitamin E agent include tocopherol succinate calcium and tocopherol acetate.
Examples of vitamin K agents include phytonadione and menatetrenone.
Examples of other vitamin agents include astaxanthin, fucoxanthin, lutein and the like.

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

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

Among the other metabolic drugs, examples of the liver disease agent include liver hydrolyzate, dichloroacetate diisopyramine, thiopronin, disodium protoporphyrin, malotilate and the like.
Examples of the antidote include disodium calcium edetate, glutathione, sodium hydrogen carbonate, and folinate calcium.
Examples of therapeutic agents for gout include allopurinol, colchicine, probenecid, and benzbromarone.

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

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

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

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

Examples of the synthetic antibacterial agent include moxifloxacin hydrochloride, lomefloxacin hydrochloride, ofloxacin, cipolofloxacin, nalidixic acid, norfloxacin, pipemidic acid hydrate, fleroxacin and the like.
Antiviral agents include acyclovir, adefovir pivoxil, efavirenz, emtricitabine, valacyclovir hydrochloride, entecavir hydrate, zanamivir hydrate, sanylvudine, didanosine, zidovudine, nevirapine, palivizumab, phosamprenavir calcium, saquinavir mesilate, Lamivudine, ritonavir, ribavirin, abacavir sulfate, oseltamivir phosphate, lopinavir ritonavir and the like.
Other chemotherapeutic agents include itraconazole, terbinafine hydrochloride, fluconazole and the like.

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

A method for producing the collapsible spherical particle composition of the present invention will be described below.
The inorganic particles used in the present invention are characterized by the use of fine particles, and any commercially available product can be used as long as the particle size matches. In order to obtain a desired particle size, a large particle size can be pulverized and used.

  As the pulverization method, either wet pulverization or dry pulverization may be used. As the wet pulverization, Nanomizer (product name, manufactured by SGS Engineering Co., Ltd.), Starburst (product name, manufactured by Sugino Machine Co., Ltd.), Ultimateizer (product) Name, Sugino Machine Co., Ltd., Kawasawa Fine Co., Ltd.), Microfluidizer (Product name, High pressure homogenizer such as Mizuho Kogyo Co., Ltd., beads mill, disk mill, homomixer, etc. A ball mill, a hammer mill, a cutter mill, or the like can be used, but a high-pressure homogenizer, a bead mill, a cutter mill, and a hammer mill are preferable, and a high-pressure homogenizer is most preferable because of easy handling of the slurry.

  By this pulverization, the inorganic particles forming the agglomerated particles are better pulverized, and the average particle size in the pulverization is 0.01 to 20 μm, preferably 0.01 to 10 μm, more preferably 0.01. ~ 5 μm. By setting it as this average particle diameter, aggregated particles are dispersed, the aggregation property at the time of drying improves, and it can be set as a disintegrating particle composition with high particle strength and sphericity.

  The disintegrant and the inorganic particles, and if necessary, the water-soluble base can be carried out by any production method as long as the desired physical properties are shown by the component ratio of the composition of the present invention. is there. The wet granulation may be any of freeze drying, rolling bed granulation, stirring granulation, spray drying, fluidized bed granulation, and kneading granulation, but is preferably spray drying with the easiest degree of formation of spherical particles. .

  The solvent for wet granulation may be any pharmaceutically acceptable solvent without affecting the properties of the composition, such as water, ethanol, methanol, acetone, THF, ether, hexane, methylene chloride, chloroform. , Carbon tetrachloride and the like, preferably water, ethanol and methanol which are water-soluble solvents.

As a specific manufacturing method of wet granulation, spray drying will be described in detail.
The disintegrant and inorganic particles, and if necessary, the water-soluble base and / or the active ingredient are suspended in a solvent and spray-dried. The concentration of the suspension may be in a range that allows spray drying, that is, the solid content is 1 to 50% by weight, preferably 10 to 40% by weight. When components such as an active ingredient, a water-soluble base, a surfactant, a binder, a coating agent, an excipient, and a disintegrant are added, they are blended at the time of preparing the suspension and simultaneously spray-dried.

  Although the conditions of spray drying are not specifically limited, As a spray dryer, it is preferable to use a disk type or nozzle type spray dryer. And as temperature in the case of spray-drying, inlet temperature is about 120-400 degreeC, and outlet temperature is about 80-300 degreeC.

A granular composition using the disintegrating spherical particle composition of the present invention and a method for producing the granular composition will be described.
The granular composition of the present invention comprises an active ingredient layer centering on the disintegrating spherical particle composition 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 with respect to 100 parts by weight of the collapsible spherical particle composition of the present invention. In addition to the active ingredient, a binder, an excipient, a surfactant, a coating agent, and the like can be blended in the active ingredient layer. The active ingredient may be supported on an excipient and granulated with a binder. The amount of the coating component is 0.01 to 100 parts by weight with respect to 100 parts by weight of the collapsible spherical particle composition of the present invention.

  A binder, a coating agent, an excipient | filler, etc. can be mix | blended with an active ingredient layer and / or a 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. As these, those described above can be used.

  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.

Examples of the surfactant include phospholipid, glycerin fatty acid ester, polyethylene glycol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and the like.
Examples of the fluidizing agent include hydrous silicon dioxide and light anhydrous silicic acid.

  The granular composition of the present invention is a known wet type such as fluidized bed granulation, stirring granulation, rolling bed granulation, spray drying granulation, extrusion granulation using the disintegrating spherical particle composition of the present invention as a nucleating agent. It can be performed by a granulation method, and these conditions can be performed by a conventional method.

While the disintegrating spherical particle composition of the present invention is rolled in a wet granulator, a solution containing a binder is continuously sprayed, and at the same time, a powder comprising an active ingredient and, if necessary, an excipient is supplied. The disintegrating spherical particle composition is coated with the solution / powder and dried to give granules. Alternatively, while the collapsible spherical particle composition is fluidized in a wet granulator, a liquid in which the active ingredient is dissolved or suspended in a binder-containing solution is sprayed to form a powder containing the active ingredient in the collapsible spherical particle composition. The body is coated and dried into granules. Subsequently, a coating solution or a 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 active ingredient is coated, a coating-containing solution or a coating suspension may be sprayed simultaneously. These granulation orders can be appropriately selected according to the type of active ingredient.
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 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 the tablet production method, the granular composition is mixed 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-molded. 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.

  As an additional component that can be blended in the pharmaceutical preparation of the present invention, a binder (for example, carmellose, hydroxypropylcellulose, alginic acid, gelatin, partially pregelatinized starch, popidone, gum arabic, pullulan, dextrin, etc.), excipient (for example, Corn starch, potato starch, rice starch, powdered sugar, lactose, D-mannitol, trehalose, crystalline cellulose, crystalline cellulose / carmellose sodium, magnesium aluminate metasilicate, calcium hydrogen phosphate, hydrotalcite, silicic anhydride, etc.) , Surfactant (for example, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan fatty acid ester, polysorbate, fatty acid glycerin ester, sodium lauryl sulfate, etc.), lubricant (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, Glycyrrhizin dipotassium, 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 pigment, edible lime Iron, etc.), stabilizers (eg sodium edetate, tocopherol, cyclodextrin, etc.), flavoring agents, flavoring agents and the like.

  The disintegrating spherical particle composition of the present invention and the granule composition of the present invention can be used for food, cosmetics and the like in addition to pharmaceutical products. In particular, it is suitable for controlling the absorbability of functional food in the body.

EXAMPLES The present invention will be described below with reference to examples, but these examples do not limit the scope of the present invention.
[Sphericity]
The short diameter and long diameter of each particle were measured from an image taken using an SEM (scanning microscope) (S-3000N, manufactured by Hitachi, Ltd.), and a numerical value was derived from the ratio of the short diameter / long diameter.
[Particle strength]
It measured using the particle hardness measuring apparatus (Grano, Okada Seiko Co., Ltd. product).
[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.).
[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, a 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.

[Example 1]
Crospovidone (Collidon CL-SF, manufactured by BASF) 2.22 kg and mannitol (Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd.) 10 kg were suspended in 30 L of water, and further scaly calcium hydrogen phosphate (Fujicalin, Fuji Chemical Industries). Made by a pulverized suspension (solid content concentration 16.2%, average particle size 1.12 μm) 61.73 kg. This turbid liquid was spray-dried using a centrifugal atomizer at a rotation speed of 9000 rpm and a heat input temperature of 165 ° C. and an outlet temperature of 110 ° C. to obtain a collapsible spherical particle composition. FIG. 1 shows an SEM photograph.
Water was added dropwise to the collapsible spherical composition, and optical photographs were taken before dropping and after 3 minutes of dropping the water to confirm the disintegrating property against water. The result is shown in FIG. It can be seen that the composition of the present invention is completely disintegrated.

[Example 2]
2.46 kg of crospovidone and 11.07 kg of mannitol were suspended in 14 L of water, and further a pulverized suspension of magnesium aluminate metasilicate (Neusilin UFL2, manufactured by Fuji Chemical Industry Co., Ltd., solid content concentration 11.3%, average particle size) 98 kg (diameter 1.04 μm) was added to make a uniform suspension. This turbid liquid was spray-dried using a centrifugal atomizer at a rotation speed of 9000 rpm and a heat input temperature of 165 ° C. and an outlet temperature of 110 ° C. to obtain a collapsible spherical particle composition. FIG. 1 shows an SEM photograph.

[Comparative Example 1]
This suspension is made by adding 30 L of water to 61.73 kg of a pulverized suspension of scale-like calcium hydrogen phosphate (Fujicalin, manufactured by Fuji Chemical Industry Co., Ltd., slurry concentration 16.2%, average particle size 1.12 μm). The liquid was spray-dried using a centrifugal atomizer at a rotational speed of 9000 rpm and a heat input temperature of 165 ° C. and an outlet temperature of 110 ° C. to obtain a collapsible spherical particle composition.

[Comparative Example 2]
According to Example 1-4 of JP-A-2005-139168, 650 g of mannitol, 50 g of xylitol, 150 g of crystalline cellulose, 80 g of crospovidone and 70 g of magnesium aluminate metasilicate were uniformly dispersed by adding 1.5 L of water, followed by spray drying. Thus, a white powder having good fluidity was obtained. Although the particle strength was measured, it was below the lower limit of measurement (50 g / mm ² ).

[Table 1] Analysis values

  The collapsible spherical particle composition (Examples 1 and 2) of the present invention has a sphericity of 0.99, which is very close to a sphere, and has sufficient strength, a small static specific volume, and an appropriate water absorption capacity. Yes. Furthermore, it turns out that it has quick disintegration compared with the particle | grains of the comparative example 1. FIG.

[Example 3] Manufacture of granules 140 g of the collapsible spherical particle composition of Example 1 was charged into a fluidized granulator (Freund Sangyo Co., Ltd., Flow Coater Mini FL), and propyloxy was added to 440 g of purified water. A solution obtained by dissolving and suspending 10 g of cellulose and 50 g of pulverized acetaminophen (200 mesh sieve product) was sprayed at a spraying speed of 1 to 4 g / min to obtain active ingredient laminated granules. FIG. 4 shows an SEM photograph.

[Example 4] Manufacture of granules 500 g of the collapsible spherical particle composition of Example 2 was charged into a fluidized granulator / dryer [manufactured by Pauleck Co., Ltd., multiplex MP-01], 10 g of hydroxypropylcellulose and ground acetamino A solution in which 50 g of phen (200 mesh sieve product) was dissolved and suspended in 440 g of purified water was sprayed at a spray rate of ˜5 g / min to form active ingredient laminated particles. 30.43 g of hydroxypropyl methylcellulose (Metroses SM-04, manufactured by Shin-Etsu Chemical Co., Ltd.) is dissolved in water in the active component laminated particles, and then 150.82 g of talc, methacrylic acid / ethyl acrylate copolymer (eudragit) NE30D (manufactured by Degussa) and a solution in which 500 g was dissolved and suspended were sprayed at a spraying speed of 3 to 5 g / min to obtain coating particles. The particles were placed orally to confirm the taste. I did not feel bitter for the first minute.

[Example 5] Manufacture of tablets 30 parts by weight of coated particles of Example 4, 69.5 parts by weight of excipient F-MELT TypeC (manufactured by Fuji Chemical Industry Co., Ltd.) for intraoral rapidly disintegrating tablets, magnesium stearate 0 The mixture was mixed at a ratio of 5 parts by weight, and tableted with a tableting tester (manufactured by Sankyo Piotech Co., Ltd.) at a set pressure of 300 kgf to obtain an orally rapidly disintegrating tablet. The disintegration time in the oral cavity was 18 seconds, and after that, no bitterness was felt until it was sublingual.

Claims (12)

10% to 90% by weight of inorganic particles and 1% to 50% by weight of a disintegrant with respect to the entire disintegrating spherical particle composition, a sphericity of 0.8 to 1, a particle strength of 100 to 2000 g / mm ² , The average particle size is 10 to 500 μm, the static specific volume is 1.5 to 5.0 mL / g, the specific surface area is 0.15 to 500 m ² / g, and the disintegration time when in contact with water is 10 minutes or less. A disintegrating spherical particle composition characterized by the above. Sphericality is 0.85-1, particle strength is 200-1000 g / mm ² , average particle size is 20-300 μm, static specific volume is 1.5-4.0 mL / g, specific surface area is 0.20. The collapsible spherical particle composition according to claim 1, which is 400 m ² / g. The disintegrating spherical particle composition according to any one of claims 1 to 2, wherein an apparent average particle diameter of the inorganic particles is 0.01 to 20 µm. Inorganic particles are magnesium aluminate metasilicate, magnesium aluminate silicate, calcium silicate, aluminum silicate, zeolite, anhydrous silicic acid, hydrous silicic acid, calcium hydrogen phosphate, calcium phosphate, hydrapatite, talc, dry hydroxylation The collapsible spherical particle composition according to any one of claims 1 to 3, which is aluminum gel, synthetic hydrotalcite, magnesium carbonate, or calcium carbonate. The disintegrant is crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, hydroxypropylcellulose, crystalline cellulose, carmellose, carmellose sodium, carmellose calcium, and starch. The disintegrating spherical particle composition described in 1. The collapsible spherical particle composition according to any one of claims 1 to 5, wherein the inorganic particles are 20 to 80 wt% and the disintegrant is 2 to 40 wt% with respect to the entire disintegrating spherical particle composition. The disintegrating spherical particle composition according to any one of claims 1 to 6, wherein the water-soluble base is blended in an amount of 5 to 85% by weight based on the entire disintegrating spherical particles. The water-soluble base is mannitol, xylitol, erythritol, sorbitol, maltitol, lactose, sucrose, glucose, fructose, maltose, trehalose, palatinit, palatinose, glycine, alanine, or glutamic acid. The disintegrating spherical particle composition according to item. The disintegrating spherical particle composition according to any one of claims 1 to 8, wherein the active ingredient is blended in an amount of 0.1 to 75% by weight based on the entire disintegrating spherical particles. A disintegrating spherical particle composition comprising an active ingredient layer and optionally a coating layer around the disintegrating spherical particle composition according to any one of claims 1 to 9. The compression molding formed by containing the disintegrating spherical particle composition of any one of Claims 1-10. The disintegrating sphere according to any one of claims 1 to 11, comprising a step of suspending the disintegrant and the inorganic particles, if necessary, the water-soluble base and / or the active ingredient in water, followed by spray drying. A method for producing a particle composition.

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