WO2007119792A1 - Dry direct compression fast disintegrating tablet - Google Patents

Dry direct compression fast disintegrating tablet Download PDF

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Publication number
WO2007119792A1
WO2007119792A1 PCT/JP2007/058095 JP2007058095W WO2007119792A1 WO 2007119792 A1 WO2007119792 A1 WO 2007119792A1 JP 2007058095 W JP2007058095 W JP 2007058095W WO 2007119792 A1 WO2007119792 A1 WO 2007119792A1
Authority
WO
WIPO (PCT)
Prior art keywords
disintegrating tablet
hydrochloride
active ingredient
dry
crystalline cellulose
Prior art date
Application number
PCT/JP2007/058095
Other languages
French (fr)
Japanese (ja)
Inventor
Taizo Tsubata
Misa Tateda
Satoshi Sakuma
Itsumi Enomoto
Original Assignee
Toa Pharmaceuticals Co., Ltd.
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 Toa Pharmaceuticals Co., Ltd. filed Critical Toa Pharmaceuticals Co., Ltd.
Priority to CN2007800132649A priority Critical patent/CN101420982B/en
Priority to JP2008510987A priority patent/JP5215172B2/en
Priority to KR1020087027556A priority patent/KR101400064B1/en
Publication of WO2007119792A1 publication Critical patent/WO2007119792A1/en

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Classifications

    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a granulated product obtained by mixing an active ingredient and other compounding ingredients, in particular a powder of a specific taste-masking agent and a specific binder, and spraying an aqueous solution of reduced maltose starch.
  • the present invention relates to a dry-type, quick-disintegrating tablet having a practical tablet hardness while maintaining rapid disintegration by devising combinations and a method for producing the same.
  • a wet granulation method and a dry granulation method have been proposed as methods for producing such an intraorally rapidly disintegrating tablet.
  • the wet granulation method for example, the surface of the saccharide particles is moistened with 0.3 to 7% by weight of water to a tablet component containing (1) a medicinal ingredient and a saccharide as an excipient.
  • the disintegration time according to the disintegration test method described in the Japanese Pharmacopoeia No. 12 revision by tableting the mixture containing the medicinal ingredient, saccharide and water and drying is 0.05 to 3.0 min.
  • Patent Document 1 A method for producing an orally disintegrating tablet (Patent Document 1) has been reported.
  • the dry granulation method includes, for example, (2) a tablet that is orally administered without being dispersed in water before administration, and is in the form of fine crystals or fine particles coated so as to mask taste.
  • a rapidly disintegrating multiparticulate tablet obtained by directly compressing a mixed material of an active substance and a mixture containing an excipient has been proposed (Patent Document 2).
  • the mixture containing the excipient is selected from at least one disintegrant and starch, modified starch, or microcrystalline cellulose, and at least one swelling agent that does not produce high viscosity when contacted with water, or It contains at least one solubilizing agent, and tablets do not contain effervescent agents and free organic acids, and rapidly disintegrate in the mouth in the presence of saliva without chewing in less than 60 seconds.
  • Particle tablets It is an agent.
  • the present inventors also previously described (a) active ingredients, (b) acids selected from citrate, tartaric acid, malic acid, lactic acid and ascorbic acid as a solubilizing agent, or alkali metal salts thereof; Metal carbonate; and at least one selected from the group consisting of alkali metal carbonates, and (c) excipients, (d) binders, (e) disintegrants, (f) fluids
  • active ingredients selected from citrate, tartaric acid, malic acid, lactic acid and ascorbic acid as a solubilizing agent, or alkali metal salts thereof; Metal carbonate; and at least one selected from the group consisting of alkali metal carbonates, and (c) excipients, (d) binders, (e) disintegrants, (f) fluids
  • a dry type quick disintegrating tablet characterized by containing a lubricant and (g) a lubricant consisting of a combination of magnesium stearate and sucrose fatty acid ester as a
  • Patent Document 1 Japanese Patent No. 3069458
  • Patent Document 2 Japanese Patent No. 2820319
  • Patent Document 3 Japanese Patent Laid-Open No. 2000-16930
  • Patent Document 4 Japanese Patent Application No. 2006—Specifications of 17401
  • the dry tableting method is a method in which a drug, which is an active ingredient, and other ingredients such as excipients are mixed, and then the mixture is directly tableted (direct compression) to form tablets. In two steps of tableting This is a simple preparation method that can prepare tablets. However, depending on the type of drug or in combination with the mixed components, there is a problem that the target tablet cannot be produced by the direct compression method.
  • the powder mixture of the drug and the component to be added has low fluidity
  • the hopper force of the tableting machine The powder mixture does not flow out, the force that makes tableting impossible, the yield reduction due to cabbing, the tablet It is observed that the weight deviation of is significantly increased.
  • the disintegration of the tablet is improved, there is a problem that the hardness of the tablet cannot be maintained.
  • the present inventors have studied the production of fast disintegrating tablets by direct compression method using zolpidem tartrate or meloxicam as an active ingredient, and in particular, depending on the combination of the mixed components, The tableting efficiency decreases due to the decrease in fluidity of the powder mixture, and the dissolution rate of zolpidem tartrate or meloxicam increases as the particle size of zolpidem tartrate or meloxicam increases. Experience the fact that tableting troubles such as sticking are likely to occur.
  • the present invention provides a fast disintegrating property that is not related to the type of active ingredient to be contained or related to the type of other ingredients to be blended in the production of a fast disintegrating tablet by the direct compression method. It is an object of the present invention to provide a method capable of producing tablets efficiently and a rapidly disintegrating tablet obtained by the production method.
  • the present inventors granulate in advance the components that cause the fluidity of the powder mixture before tableting to be reduced among the components to be added.
  • the flowability of the hopper force of the tableting machine for the powder mixture can be improved and the occurrence of cabbing can be suppressed, and as a result, the weight deviation of the tablet can be reduced. It was thought that a fast disintegrating tablet having a practical tablet hardness could be produced while maintaining the disintegrating property of the tablet.
  • the invention according to claim 1 which is one basic aspect of the present invention, is one or more tastes selected from the group power consisting of erythritol, xylitol, mannitol, lactose, and sucrose.
  • Granules obtained by mixing a powder of one or more binders selected from the group consisting of a crystalline cellulose, crystalline cellulose 'carmellose sodium and carmellose strength rhodium and spraying an aqueous solution of reduced maltose starch. It is a dry-type direct-disintegrating tablet which is characterized by using a product.
  • a more specific aspect of the present invention according to claim 2 is the dry direct-acceleration disintegrating tablet according to claim 1, wherein the granulation is performed by a fluidized bed granulator.
  • Another basic aspect of the present invention is obtained by mixing the granulated product obtained above with an active ingredient, excipient, disintegrant, fluidizer, lubricant and colorant. It is a dry-type direct-disintegrating tablet that is directly compressed from the resulting mixture.
  • the most specific present invention is the above-mentioned dry-type direct-disintegrating tablet that uses zolpidem tartrate or meloxicam as an active ingredient.
  • the invention according to claim 5, which is another aspect of the present invention, comprises at least one flavoring agent selected from the group consisting of erythritol, xylitol, mannitol, lactose, and sucrose, and crystalline cellulose.
  • a flavoring agent selected from the group consisting of erythritol, xylitol, mannitol, lactose, and sucrose
  • crystalline cellulose e.g., Crystalline Cellulose 'Mixing powder of one or more binders selected from the group consisting of carmellose sodium and carmellose potassium, and using a fluidized bed granulator while spraying an aqueous solution of reduced maltose starch.
  • a granulated product obtained by granulation and an active ingredient, an excipient, a disintegrant, a fluidizing agent, a lubricant and a colorant are mixed, and the mixture is directly compressed into tablets.
  • This is a method for producing a quick-disintegrating tablet.
  • the most specific invention according to claim 6 is the above-mentioned method for producing a dry direct-disintegrating tablet that uses zolpidem tartrate or meloxicam as an active ingredient.
  • a rapidly disintegrating tablet that suppresses the occurrence of cabbing with a good spillability of the mixed powdered product with a hopper force of a tableting machine and results in almost no tablet weight deviation, and its A method for producing a rapidly disintegrating tablet by a dry direct compression method is provided.
  • the rapidly disintegrating tablet obtained by the present invention has a desired disintegration rate and practical tablet hardness, and its production method is inexpensive and simple. It is a manufacturing method. Therefore, it has the advantage that the desired rapidly disintegrating tablet can be prepared for various active ingredients.
  • the basis of the present invention is to provide the fluidity by previously granulating the components that cause a decrease in the fluidity of the mixed powder before tableting directly, so that the granulation is performed. It is a direct compression quick disintegrating tablet obtained by mixing an active ingredient and other ingredients using a product and directly compressing the obtained mixed powder.
  • the component that decreases the fluidity of the mixed powder before direct tableting is a component to be blended as a corrigent.
  • Such flavoring agents are erythritol, xylitol, mannitol, lactose and sucrose.
  • the flavoring agent is a component used as an excipient in one aspect, and even when added as an excipient, this and other components, for example, an active ingredient or a binder. It is preferable to granulate etc. in advance.
  • a binder in order to improve the fluidity, is used in order to improve the fluidity. It is better to granulate together.
  • binder examples include crystalline cellulose, crystalline cellulose'carmellose sodium, and carmellose potassium. Of these, crystalline cellulose is particularly preferably used. Examples of the crystalline cellulose include Ceraus PH101, Ceraus PH302 [manufactured by Asahi Kasei Chemicals Corporation].
  • the amount of binder used should be 5 to 20% by weight, preferably about 10% by weight, based on the weight of the final tablet. [0023] In the present invention, it is preferable to granulate both the above-mentioned taste-masking agent and binder, particularly by granulating while spraying an aqueous solution of reduced maltose starch.
  • the reduced maltose starch to be used is powdered reduced maltose starch or reduced maltose starch (also known as maltitol).
  • Starch is added to water and heated to form a paste.
  • a product that has been decomposed and purified is reduced and further purified and concentrated.
  • Smell is a component that has been widely used as an additive in various preparations as a sweetener, base, flavoring agent, and the like.
  • the reduced maltose starch syrup is used as an excipient for a liquid agent used when preparing a granulated product of the above-mentioned corrigent and binder.
  • the ability to granulate while mixing a powder of a flavoring agent and a binder and spraying an aqueous solution of reduced maltose starch as an excipient can be carried out using a fluidized bed granulator, and the granulation itself can be carried out by other known methods.
  • a corrigent that is a causative component that lowers the fluidity of a powder mixture is used, and an aqueous solution of reduced maltose starch that is a specific excipient is used together with a binder.
  • a binder that improves the fluidity, and then mix the powerful granulated product with active ingredients, excipients, disintegrants, fluidizers and lubricants, and mix the resulting mixture directly.
  • the medicinal component used in the dry-type direct hit disintegrating tablet of the present invention is not particularly limited.
  • antibacterial drugs for example, antibacterial
  • Antibiotics include, for example, cephalexin, cefaclor, amoxicillin, bib mecillinam, cefotiam hexetyl, cefadoxyl, cefixime, cefditorn pivoxinole, cefteram pivoxinole, cefpodoximiproxetinole hydrochloride, cefothiplan hydrochloride, , Cefmenoxime hydrochloride, cefthridine sodium, etc., synthetic antibiotics such as ampicillin, cyclacillin, sulbecillin sodium, naliditasic acid, enoxacin, monobatams such as carmonam sodium, penem and carbapenem antibiotics , Paromomycin sulfate, amoxicillin, cefaclonole, cephalexin, acetylsiramycin, minocycline hydrochloride.
  • antituberculosis drug examples include iso-azide, etampitol hydrochloride and the like.
  • antifungal agents examples include miconazole and terbinafine hydrochloride.
  • antiviral agent examples include lamivudine, ribavirin, and acyclovir.
  • anticancer drug examples include 5-fluorouracil, uracil, mitomycin, carmofur, aclarubicin hydrochloride, cyclophosphamide, and tiotepa.
  • vitamin drugs include thiamine hydrochloride, thiamine nitrate, tocophenol acetate, chicotamine, pyridoxal phosphate, cobamide, ascorbic acid, nicotinamide, alpha calcidol, cobamide, vitaroxine, riboflavin butyrate, ascorbic acid and the like. It can be done.
  • corticosteroid preparations examples include prednisolone, triamcinolone, betamethasone and the like.
  • Antiallergic agents include, for example, diphenhydramine hydrochloride, diphenhydramine tannate, triprolidine hydrochloride, promethazine hydrochloride, alimemazine tartrate, mequitazine, diphenyl-tetraoleate, d-chlorfelamine maleate, cyproforme hydrochloride Putazine, clemastine fumarate, ketotifen fumarate, azelastine hydrochloride, oxatomide, chemedastine fumarate, ebastine, cetirizine hydrochloride, fuxofenazine hydrochloride, oral latazine, olopatadine hydrochloride, tralast, amlexanox, tazanolast, pranlukast water Japanese, And ozadarel hydrochloride.
  • Non-steroidal anti-inflammatory drugs include, for example, aspirin, mefenamic acid, tolfenamic acid, indomethacin, indomethacin phanesyl, acemetacin, diclofenac, diclofenac sodium, anfenac sodium, etodolac, mofezolac, sulindac, nabumetone ibuprofen, Examples include ketoprofen, loxoprofen sodium, piroxicam, ampiroxicam, and meloxicam.
  • narcotics examples include morphine hydrochloride, oxycodone hydrochloride, cocaine hydrochloride and the like.
  • migraine drugs include ergotamine tartrate, sumatributane succinate, zolmitriptan, mezirine hydrochloride, dimethothiazine mesylate, and caffeine.
  • Examples of the antidiabetic agent include tolptamide, acetohexamide, chlorpropamide, dalicloviramide, dalibuzole, daribenclamide, glimepiride, buformin hydrochloride, metformin hydrochloride, nateglinide, carbose, voglibose, pioglitazone hydrochloride, epalrestatate, etc. .
  • Examples of the therapeutic agent for hyperlipidemia include pravastatin sodium, simpastatin, lovastatin, flupastatin, atorvastatin and the like.
  • Examples of drugs for treating gout include alopurinol, colchicine, benzbromarone, probenecid and the like.
  • Examples of sedative 'hypnotics include triazolam, mitazolam, protizolam, rilmazaphone hydrochloride, lormadorezem, nimddlezem, flunitrazepam, estazolam, nitrazepam, zolpidem tartrate, and zocpilone tartrate.
  • anti-anxiety drugs examples include flutazolam, clothiazebum, etizolam, alprazolam, lorazepam, bromazepam and the like.
  • antiepileptic drug examples include fetoin, ethotoin, primidone, sodium valproate, carbazepine, clonazepam, ethosuximide, trimethadione, sultiam, acetyl phenetride and the like.
  • Antidepressants include, for example, imibramin hydrochloride, amitriptyline hydrochloride, clomipramine hydrochloride, nortriptyline hydrochloride, phlepramine hydrochloride, doslevine hydrochloride, amoxapine, Examples include protilin, mianserin hydrochloride, trazodone hydrochloride, fluvoxamine maleate, and milnacipran hydrochloride.
  • antipsychotic drug examples include chlorpromazine, thioridazine hydrochloride, propericiadin, fluphenazine, clocapramine hydrochloride, thiaprid hydrochloride, and the like.
  • Examples of psychostimulants include methyl fedate and pemoline.
  • Examples of the cardiotonic agent include amrinone, olprinone hydrochloride, pimopendane and the like.
  • Examples of the ⁇ receptor blocker include labetalol hydrochloride, carvedilol, amosuralol hydrochloride, alotinolol hydrochloride, bevantolol hydrochloride, pindolol, carteolol hydrochloride, bufetrol hydrochloride, propranolol hydrochloride, nadolol, dipradilol, hydrochloride Examples include amiodarone and betaxolol hydrochloride.
  • calcium channel antagonists examples include verapamil hydrochloride, diltiazem hydrochloride, difedipine, hydrochloride-cardipine hydrochloride, dirubadipine, iliapine hydrochloride, bepridil hydrochloride, and the like.
  • antiarrhythmic drug examples include sulfated proamide inamide, disopyramide phosphate and the like.
  • diuretics examples include chlorthalidone and trypamide.
  • antihypertensive drug examples include prazosin hydrochloride, bunazosin hydrochloride, terazosin hydrochloride, urapidil, and force dralazine.
  • vasopressor examples include captopril, araspril, lisinopril, imidapril hydrochloride, enalapril maleate, quinapril hydrochloride, cilazapril, delapril hydrochloride, temopower prill hydrochloride, benazepril hydrochloride, and the like.
  • drugs for cerebral circulation / metabolism disorder examples include -sergoline, ifenprodil tartrate, fasudil hydrochloride, ozadarel sodium and the like.
  • antitussive examples include dextromethorphan hydrobromide, cloperastine, and fominoben hydrochloride.
  • Examples of expectorants include bromhexine hydrochloride and ambroxol hydrochloride.
  • bronchodilators include ephedrine hydrochloride, salbutamol sulfate, terbutaline sulfate, proterol hydrochloride, and the like.
  • bronchial asthma drugs examples include beclomethasone propionate, fluticasone propionate, budesodium and the like.
  • Examples of the respiratory accelerator include dimon folamine, doxapram hydrochloride and the like.
  • Examples of gastrointestinal drugs include famotidine, latidine hydrochloride, cimetidine, sucralfate, sulpiride, teprenone, prunotol, 5-aminosalicylic acid, sulfasalazine, omebrazole, lansoprazole, and the like.
  • gastritis drug examples include metocloblamide hydrochloride, domperidone, itopride hydrochloride, mosapride tamate, trimebutine maleate, azasetron hydrochloride, ondansetron hydrochloride, dara-setron hydrochloride, tropisetrin hydrochloride, ramosetron hydrochloride, and the like.
  • Antiemetics include, for example, metocloblamide, ramosetron hydrochloride, dala-setron hydrochloride, ondansetron hydrochloride, azasetron hydrochloride, and the like.
  • Examples of the peptic ulcer drug include omebrazole, rabebrazole sodium, lansoprazole, cimetidine, -zatidine, famotidine, latidine hydrochloride, loxazine hydrochloride, sucralfate, and the like.
  • enteric agents examples include oral peramide hydrochloride, mesalazine, betamethasone and the like.
  • laxative examples include pisacodyl and the like.
  • Examples of the astringent include dehydroconoleic acid and trepeptone.
  • Examples of Parkinson's disease drugs include levodopa, levodopa, amantadine hydrochloride, trihexiphezyl hydrochloride, and pyroheptin hydrochloride.
  • osteoporosis agent examples include ibriflavone.
  • antirheumatic drugs examples include methotrexate, bucillamine, and actactite.
  • Zolpidem tartrate is a white crystalline powder with a bitter taste and water or ethanol. Slightly insoluble in knoll (95%). This drug has the property of being gradually colored (yellow) by light and is clinically used for insomnia (excluding insomnia associated with schizophrenia and manic depression).
  • zorbidem tartrate is administered orally at a dose of 5 to: LOmg once before bedtime.
  • the dose can be started at 5 mg once, and the dose can be adjusted according to age, symptoms and disease. /
  • Meloxicam is a non-steroidal anti-inflammatory / analgesic agent used to treat rheumatoid arthritis, osteoarthritis, low back pain, peri-shoulderitis, and cervical shoulder-arm syndrome. It is a drug that is orally administered in gZ days.
  • excipients used together with drugs such as zolpidem tartrate or meloxicam include lactose, erythritol, D-mannitol, xylitol, maltitol and other sugars, hydroxypropyl starch sodium, crystalline cellulose, Examples thereof include hydroxypropyl starch, anhydrous calcium hydrogen phosphate, synthetic aluminum silicate, and reduced maltose starch.
  • the excipient to be incorporated is 20 to 70% by weight, preferably 30 to 70% by weight, more preferably about 60% by weight, based on the weight of the final tablet! / ,.
  • the disintegrant there may be mentioned one or more kinds selected from crospovidone, carmellose, carmellose calcium, carboxymethyl starch sodium group power.
  • crospovidone and carmellose are used in combination.
  • the content of the disintegrant is 5 to 20% by weight, preferably about 15% by weight, based on the weight of the final tablet.
  • Examples of the fluidizing agent include anhydrous key acids such as light anhydrous key acid (silicon dioxide).
  • anhydrous key acids such as light anhydrous key acid (silicon dioxide).
  • Adsolida 101 [trade name, manufactured by Freund Corporation] can be used.
  • the amount of fluidizing agent is 5 to 3 wt% 0.1 the weight of the final tablet based, it favored properly about 0.5 to 1.5 is of good weight 0/0.
  • magnesium stearate and a sucrose fatty acid ester such as sugar ester B-370F or Surf Hope J-2203F [sucrose behenic acid] B-370 finely pulverized with ester as lubricant; Mitsubishi Chemical Foods Co., Ltd.] is preferably used in combination.
  • the compounding ratio of magnesium stearate and sucrose fatty acid ester is about 1: 1 to 3 and preferably about 1: 1 to 2 by weight.
  • the blending amount of the lubricant is 1.0 to 3% by weight, preferably about 1.0 to 2.0% by weight, based on the weight of the final tablet.
  • a masking agent for masking bitter bitterness can be blended according to a conventional method.
  • a masking agent include sweeteners such as aspartame and tautiman, and flavors such as 1 menthol, dry coat cocoon, brown sugar flavor, dry coat peppermint, and grapefruit coat. Aspartame is preferred.
  • the amount of these masking agents can be appropriately increased or decreased depending on the active ingredient to be contained.
  • Examples of the colorant include yellow iron sesquioxide, iron sesquioxide, black iron oxide (or iron oxides), and an aluminum chelating agent.
  • the dry direct hit disintegrating tablet provided by the present invention can be prepared, for example, by a manufacturing method according to the following steps.
  • This method is generally composed of three steps: a first step of preparing a granulated product composed of a corrigent and a binder, a second step of mixing each component, and then a third step of tableting.
  • a simple and efficient tablet preparation method that can be carried out according to a conventional method. The details are as follows.
  • An aqueous solution of an excipient (eg, powdered reduced maltose starch syrup) is prepared in advance, a taste-masking agent (eg, erythritol) and a binder (eg, crystalline cellulose) are mixed, and a fluidized bed granulator is used. By granulating, a granulated product is obtained.
  • concentration of the above-mentioned excipient aqueous solution varies depending on the type of flavoring agent used, the amount used, etc., and also on the type of binder used, the amount used, etc., and is not particularly limited, but is preferably 10-20%. It is around 15%.
  • the mixing ratio of the excipient and the binder is not particularly limited, but the amount of the binder is preferably in the range of 0.15 to 3.2 per 1 weight of the corrigent.
  • the higher the amount of binder the better the fluidity but the lower the disintegration.
  • the blending ratio of the flavoring agent was increased, the fluidity tended to decrease.
  • an active ingredient for example, zolpidem or meloxicam tartrate
  • an excipient for example, lactose
  • a disintegrant for example, crospovidone, carmellose
  • a fluidizing agent for example, , Light anhydrous anhydride
  • lubricant eg, magnesium stearate, sucrose fatty acid ester
  • flavor eg, 1 menthol
  • colorant eg, yellow iron trioxide, aluminum chelator
  • the mixing in the second step is carried out by using a predetermined amount of each component and active ingredient in accordance with a conventional method, for example, using a mixer [trade name, Bole container mixer; manufactured by Kotopuki Giken Kogyo Co., Ltd.]. This can be done by mixing.
  • the mixing time varies depending on the type of additive used, the amount used, etc., and is not particularly limited, but is preferably 5 to 40 minutes, more preferably 5 to 30 minutes.
  • the lubricant can be added to the mixture later and mixed.
  • the mixing time in this case is not particularly limited depending on the amount of the above mixture used as long as the lubricant can be sufficiently mixed, but usually 2 to: LO minutes, preferably 2 ⁇ 4 minutes.
  • the perfume used in the fast disintegrating tablet provided by the present invention can be added in any of the first step and the second step, preferably in the second step.
  • normally used sweetening agents such as aspartame and solubilizing agents (for example, sodium quenate and sodium hydrogen carbonate) can be further added to the tablet of the present invention as desired. Either of the two steps can be added.
  • the dry direct compression fast disintegrating tablet targeted by the present invention is provided.
  • the obtained tablet has a practical tablet hardness while maintaining desired quick disintegration. It is.
  • a fast disintegrating tablet such as a scored blood cell type circular uncoated tablet having a desired diameter can be easily prepared according to a conventional method without any particular restriction.
  • the obtained tablets were measured for tablet hardness, disintegration time (seconds) according to the disintegration test method of the Japanese Pharmacopoeia, and friability (%) at 200 revolutions.
  • Friction (%) 0.6 0.3 0.5 0.3 0.8 0.5 0.3 0.2
  • Example 6 A typical tablet manufacturing operation example is shown in the formulation of Example 6.
  • Erythritol (flavoring agent, fine powder, manufactured by Nikken Kasei Co., Ltd.] 95.
  • Og crystalline cellulose [Binder, CERATH PH-101, manufactured by Asahi Kasei Chemicals Co., Ltd.] 30.
  • Fluidized bed granulator with mixed powder of Og 15% obtained by previously dissolving powdered reduced maltose starch syrup [former, Amarti, manufactured by Towa Kasei Kogyo Co., Ltd.] in purified water using [trade name MP-01; manufactured by Baurec Co., Ltd.]
  • a granulated product was obtained by granulation using an aqueous solution.
  • tableting was carried out at a set hardness of 5 kp to obtain dry direct compression fast disintegrating tablets (300 mg tablets containing 5 mg of active ingredient).
  • the tablet diameter is usually between about 5 mm and about 20 mm, preferably between about 7 mm and about 15 mm, and a size suitable for taking can be selected.
  • Fluidized bed granulator with mixed powder of erythritol [flavoring agent, fine powder, manufactured by Nikken Kasei Co., Ltd.] 107.5 g, crystalline cellulose [binder, Seras PH-101, manufactured by Asahi Kasei Chemicals Co., Ltd.] 17.5 g 15% obtained by previously dissolving powdered reduced maltose starch syrup [former, Amarti, manufactured by Towa Kasei Kogyo Co., Ltd.] in purified water using [trade name MP-01; manufactured by Baurec Co., Ltd.] For aqueous solution
  • the granulated product obtained above showed the same properties as those obtained in Step 1 of Example 1.
  • the granulated product obtained above showed the same physical properties as those obtained in Step 1 of Example 1.
  • Comparative Example 1 The following components were mixed and directly hit according to a conventional method to prepare a dry type quick-disintegrating tablet.
  • Flavoring agent Erythritol 100.00
  • Test analysis values moisture, specific volume, angle of repose of the mixture of the above ingredients are as follows: angle of repose (°) 39.5 °; specific volume (loose) 2. 03mLZg; specific volume (tap ) 1. 47mLZg; Compression ratio (%) 27.6; Carr index (%) 38.1; Moisture (%) 1.0
  • Test analysis values moisture, specific volume, angle of repose
  • Erythritol (flavoring agent, fine powder, manufactured by Nikken Kasei Co., Ltd.] 95.
  • Og crystalline cellulose [binder, Serus PH-101, manufactured by Asahi Kasei Chemicals Co., Ltd.] 30.
  • Fluidized bed granulator with mixed powder of Og 15% obtained by previously dissolving powdered reduced maltose starch syrup [former, Amarti, manufactured by Towa Kasei Kogyo Co., Ltd.] in purified water using [trade name MP-01; manufactured by Baurec Co., Ltd.]
  • a granulated product was obtained by granulation using an aqueous solution.
  • Granulated product and meloxicam active ingredient, particle size approx. 8 m
  • lactose excipient
  • sucrose fatty acid ester [lubricant, Surf Hop J2203-F, manufactured by Mitsubishi Kasei Foods Co., Ltd.] 5.00 g, aspartame [sweetener, aspartame , Ajinomoto Co., Inc.] 15.00 g, 1 Menthol [fragrance, made by Katsura Kobayashi Co., Ltd.] 0.25 g, Ferric sesquioxide [Coloring agent, produced by Hatake Kasei Co., Ltd.] 0.51 g, added for 30 minutes Mixed.
  • tableting was carried out at a set hardness of 4 kp to obtain a dry direct-breaking rapidly disintegrating tablet (375 mg tablet containing 10 mg of active ingredient).
  • the tablet diameter is usually between about 5 mm and about 20 mm, preferably between about 7 mm and about 15 mm, and a size suitable for administration can be selected.
  • Active ingredient Meloxicam (particle size approx. 8
  • Flavoring agent Erythritol 108.75
  • Test analysis values moisture, specific volume, angle of repose of the mixture of the above ingredients are as follows: angle of repose (°) 39.5 °; specific volume (loose) 1. 83 mLZg; specific volume (tap ) 1. 37mLZg;
  • meloxicam was used which had been surface-modified with light caustic anhydride.
  • Flavoring agent Erythritol 108.75
  • Test analysis values moisture, specific volume, angle of repose of the mixture of each of the above ingredients are as follows: angle of repose (°) 40.0 °; specific volume (loose) 1. 80mL / g; specific volume (Tap) 1. 34mL / g;
  • the direct hit disintegrating tablet of the present invention has a good hardness while being excellent in disintegration in the oral cavity. .
  • a dry-type direct-disintegrating tablet having practical tablet hardness while maintaining rapid disintegration, particularly a direct-disintegrating tablet containing zolpidem tartrate or meloxicam. And its elution behavior is also good. The value is enormous.

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Abstract

It is intended to provide a method capable of producing a desired fast disintegrating tablet with good compression efficiency regardless of the kind of an active ingredient to be contained or the kind of other ingredient to be added and a fast disintegrating tablet obtained by the production method, which is a dry direct compression fast disintegrating tablet obtained by the direct compression of a mixture obtained by mixing a granulated matter obtained by mixing one or more corrigents selected from the group consisting of erythritol, xylitol, mannitol, lactose and sucrose and one or more binder powders selected from the group consisting of crystalline cellulose, crystalline cellulose carmellose sodium and carmellose potassium followed by granulating the mixture using a fluidized bed granulator while spraying an aqueous solution of reduced maltose syrup, an active ingredient, an excipient, a disintegrant, a fluidizer and a lubricant, and particularly, a dry direct compression fast disintegrating tablet containing zolpidem tartrate or meloxicam.

Description

明 細 書  Specification
乾式直打速崩壊性錠剤  Dry type quick-disintegrating tablet
技術分野  Technical field
[0001] 本発明は、有効成分とその他の配合成分、特に特定の矯味剤と特定の結合剤の 粉体を混合し、還元麦芽糖水ァメの水溶液を噴霧しながら得た造粒物との組合せを 工夫することにより、速崩壊性を維持しつつ、実用的な錠剤の硬度を有する、乾式直 打速崩壊性錠剤及びその製造方法に関する。  [0001] The present invention relates to a granulated product obtained by mixing an active ingredient and other compounding ingredients, in particular a powder of a specific taste-masking agent and a specific binder, and spraying an aqueous solution of reduced maltose starch. The present invention relates to a dry-type, quick-disintegrating tablet having a practical tablet hardness while maintaining rapid disintegration by devising combinations and a method for producing the same.
背景技術  Background art
[0002] 近年、医療用固形製剤において、服用のし易さ等の理由より口腔内速崩壊錠の開 発の要望が高くなつている。口腔内速崩壊錠としての錠剤に求められる要件としては 、 (1)日本薬局方の崩壊試験法により 30秒以内に崩壊すること、 (2)口腔内で 60秒 以内に崩壊することの崩壊性と、（3)摩損度試験 200回転で目立った破損が認めら れな 、ことの硬度等が挙げられる。  [0002] In recent years, in medical solid preparations, there is a growing demand for the development of intraorally rapidly disintegrating tablets for reasons such as ease of taking. The requirements for tablets as fast-disintegrating tablets in the oral cavity are: (1) disintegration within 30 seconds according to the disintegration test method of the Japanese Pharmacopoeia, (2) disintegration of disintegrating within 60 seconds in the oral cavity (3) Abrasion test The hardness and the like of which no noticeable damage was observed at 200 revolutions.
[0003] このような口腔内速崩壊錠の製造方法として、従来から、湿式造粒法と乾式造粒法 が提案されている。湿式造粒法として、例えば、（1)薬効成分と賦形剤としての糖類 とを含む錠剤成分に対して、 0. 3〜7重量％の水分を用いて前記糖類の粒子の表面 を湿らせ、前記薬効成分と糖類と水分とを含む混合物を打錠した後乾燥することによ る、日本薬局方第 12改正に記載されている崩壊試験法による崩壊時間が 0. 05〜3 . 0分である口腔内崩壊型錠剤を製造する方法 (特許文献 1)が報告されている。  [0003] Conventionally, a wet granulation method and a dry granulation method have been proposed as methods for producing such an intraorally rapidly disintegrating tablet. As the wet granulation method, for example, the surface of the saccharide particles is moistened with 0.3 to 7% by weight of water to a tablet component containing (1) a medicinal ingredient and a saccharide as an excipient. The disintegration time according to the disintegration test method described in the Japanese Pharmacopoeia No. 12 revision by tableting the mixture containing the medicinal ingredient, saccharide and water and drying is 0.05 to 3.0 min. A method for producing an orally disintegrating tablet (Patent Document 1) has been reported.
[0004] また、乾式造粒法としては、例えば、（2)投与前に水中に分散させることなく経口投 与する錠剤であって、味覚をマスクするように被覆された微結晶又は微粒子形態の 有効物質と、賦形剤を含む混合物との混合材料を、直接圧縮して得られた急速崩壊 性多粒子錠剤が提案されている (特許文献 2)。この場合、前記賦形剤を含む混合物 としては、少なくとも 1つの崩壊剤、及び澱粉、加工澱粉、あるいは微結晶セルロース から選択され、水と接触して高粘度を生じない少なくとも 1つの膨張剤、又は少なくと も 1つの可溶剤を含むものであり、錠剤は、発泡剤及び遊離の有機酸を含まず、口腔 内で唾液の存在下で咀嚼無しに 60秒より短い時間で崩壊する急速崩壊性多粒子錠 剤である。 [0004] In addition, the dry granulation method includes, for example, (2) a tablet that is orally administered without being dispersed in water before administration, and is in the form of fine crystals or fine particles coated so as to mask taste. A rapidly disintegrating multiparticulate tablet obtained by directly compressing a mixed material of an active substance and a mixture containing an excipient has been proposed (Patent Document 2). In this case, the mixture containing the excipient is selected from at least one disintegrant and starch, modified starch, or microcrystalline cellulose, and at least one swelling agent that does not produce high viscosity when contacted with water, or It contains at least one solubilizing agent, and tablets do not contain effervescent agents and free organic acids, and rapidly disintegrate in the mouth in the presence of saliva without chewing in less than 60 seconds. Particle tablets It is an agent.
[0005] また同様に乾式打錠法として、例えば、（3)水に対する溶解性の高い糖類と膨潤性 の賦形剤とを湿式造粒して調製した顆粒と、結晶セルロースとを打錠して得られる口 腔内速崩錠 (特許文献 3)等が報告されて ヽる。  [0005] Similarly, as a dry tableting method, for example, (3) granules prepared by wet granulation of a saccharide having high solubility in water and a swellable excipient, and crystalline cellulose are tableted. Intraoral quick-disintegrating tablets (Patent Document 3) and the like obtained are reported.
また、本発明者らも先に (a)有効成分、（b)溶解補助剤としてのクェン酸、酒石酸、 リンゴ酸、乳酸及びァスコルビン酸カゝら選択される酸類又はそのアルカリ金属塩;ァ ルカリ金属炭酸水素塩;及びアルカリ金属炭酸塩からなる群から選択される少なくと も 1種を含有し、更に (c)賦形剤、（d)結合剤、（e)崩壊剤、（f)流動化剤及び (g)滑 沢剤としてのステアリン酸マグネシウム及びショ糖脂肪酸エステルの組合せカゝらなる 滑沢剤を含有することを特徴とする乾式直打速崩壊性錠剤及びその製造方法 (特許 文献 4)を出願している。  In addition, the present inventors also previously described (a) active ingredients, (b) acids selected from citrate, tartaric acid, malic acid, lactic acid and ascorbic acid as a solubilizing agent, or alkali metal salts thereof; Metal carbonate; and at least one selected from the group consisting of alkali metal carbonates, and (c) excipients, (d) binders, (e) disintegrants, (f) fluids A dry type quick disintegrating tablet characterized by containing a lubricant and (g) a lubricant consisting of a combination of magnesium stearate and sucrose fatty acid ester as a lubricant (Patent Article 4) has been filed.
[0006] 特許文献 1：特許第 3069458号公報  [0006] Patent Document 1: Japanese Patent No. 3069458
特許文献 2：特許第 2820319号公報  Patent Document 2: Japanese Patent No. 2820319
特許文献 3 :特開 2000— 16930号公報  Patent Document 3: Japanese Patent Laid-Open No. 2000-16930
特許文献 4：特願 2006— 17401号明細書  Patent Document 4: Japanese Patent Application No. 2006—Specifications of 17401
[0007] し力しながら、これらの従来の方法は、例えば、前記（1)の湿式造粒法では、薬効 成分と糖類とを含む錠剤成分に対して、 0. 3〜7重量％の水分を用い、前記糖類の 粒子の表面を湿らせ、乾燥するという煩雑な処理が必要である。また前記（2)の乾式 造粒法は、活性成分 (有効成分)が被覆され微結晶状態にあるときは、微結晶を被覆 するものであり、また有効成分が被覆されない微顆粒状態にある場合には、有効成 分を例えば押出し造粒化、パン内での加工、空気流動層等のような方法により微顆 粒形状にするものであり、煩雑な操作を必要とするものであった。また (3)の乾式打 錠法では、顆粒外に結晶セルロースを配合しないものでは、押し上げレール値が高 ぐ打錠障害が起こる傾向があることが報告されている。また、（4)の乾式直打速崩壊 性錠剤では、メロキシカム原末の粒子形が約 12 m以下になると混合品の流動性が 急激に低下し、打錠効率が低下することが分力つた。  [0007] However, these conventional methods, for example, in the wet granulation method of (1) described above, 0.3 to 7% by weight of moisture with respect to the tablet component containing a medicinal component and a saccharide. This requires a complicated process of moistening and drying the surface of the saccharide particles. In the dry granulation method (2), when the active ingredient (active ingredient) is coated and is in a microcrystalline state, the fine granule is coated, and when the active ingredient is in a fine granule state not coated. In this method, the effective component is formed into a fine condylar shape by a method such as extrusion granulation, processing in a bread, air fluidized bed, and the like, which requires complicated operations. In addition, in the dry tableting method (3), it has been reported that when no crystalline cellulose is blended outside the granules, a tableting failure with a high push-up rail value tends to occur. In addition, in the dry direct compression fast disintegrating tablet of (4), when the particle shape of meloxicam bulk became about 12 m or less, the fluidity of the mixed product suddenly decreased and the tableting efficiency decreased. .
[0008] 乾式打錠法は、有効成分である薬物とその他の賦形剤等の成分を混合した後、当 該混合物を直接打錠 (直打)して錠剤を形成する方法であり、混合、打錠の 2工程で 錠剤を調製することができる簡便な調製方法である。しかしながら、薬物の種類により 、或いは混合成分等との組合せによっては、直打法では目的とする錠剤が製造でき ない問題がある。 [0008] The dry tableting method is a method in which a drug, which is an active ingredient, and other ingredients such as excipients are mixed, and then the mixture is directly tableted (direct compression) to form tablets. In two steps of tableting This is a simple preparation method that can prepare tablets. However, depending on the type of drug or in combination with the mixed components, there is a problem that the target tablet cannot be produced by the direct compression method.
例えば、薬物及び添加する成分の粉体混合物の流動性が低い場合には、打錠機 のホッパー力 粉体混合物が流出せず、打錠不可能となる力、キヤッビングによる収 率の低下、錠剤の重量偏差が著しく大きくなることが観察される。また、錠剤の崩壊 性を改善すると錠剤の硬度が維持できなくなる等の問題があった。  For example, if the powder mixture of the drug and the component to be added has low fluidity, the hopper force of the tableting machine The powder mixture does not flow out, the force that makes tableting impossible, the yield reduction due to cabbing, the tablet It is observed that the weight deviation of is significantly increased. In addition, when the disintegration of the tablet is improved, there is a problem that the hardness of the tablet cannot be maintained.
[0009] 事実、本発明者らは、有効成分として酒石酸ゾルピデム又はメロキシカムを用いて 直接打錠法による速崩壊性錠剤の製造を検討して 、るなかで、混合成分の組合せ によっては、打錠前の粉体混合物の流動性が低下することにより打錠効率が低下す ること、また、酒石酸ゾルピデム又はメロキシカムの粒子径が小さいほど得られる錠剤 力もの酒石酸ゾルピデム又はメロキシカムの溶出速度は早くなるが、杵付着等の打 錠障害が起きやすくなることを経験して 、る。  [0009] In fact, the present inventors have studied the production of fast disintegrating tablets by direct compression method using zolpidem tartrate or meloxicam as an active ingredient, and in particular, depending on the combination of the mixed components, The tableting efficiency decreases due to the decrease in fluidity of the powder mixture, and the dissolution rate of zolpidem tartrate or meloxicam increases as the particle size of zolpidem tartrate or meloxicam increases. Experience the fact that tableting troubles such as sticking are likely to occur.
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0010] したがって本発明は、直接打錠法による速崩壊性錠剤を製造するにあたって、含 有させる有効成分の種類に関係なぐまた配合する他の成分の種類に関係なぐ目 的とする速崩壊性錠剤を打錠効率良く製造し得る方法、並びにその製造方法により 得られる速崩壊性錠剤を提供することを課題とする。 [0010] Therefore, the present invention provides a fast disintegrating property that is not related to the type of active ingredient to be contained or related to the type of other ingredients to be blended in the production of a fast disintegrating tablet by the direct compression method. It is an object of the present invention to provide a method capable of producing tablets efficiently and a rapidly disintegrating tablet obtained by the production method.
[0011] 本発明者等は、上記課題を解決するべく鋭意検討した結果、添加する各成分の中 で、打錠前の粉体混合物の流動性を低下させる原因となる成分を前もって顆粒化す ることにより流動性をもたせれば、粉体混合物の打錠機のホッパー力 の流出性が良 くなり、キヤッビングの発生を抑えると共に、結果として錠剤の重量偏差が小さくするこ とができること、更には、錠剤の崩壊性を維持しつつ、実用的な錠剤の硬度を有する 速崩壊性錠剤が製造できるのではな 、かと考えた。  [0011] As a result of intensive studies to solve the above-mentioned problems, the present inventors granulate in advance the components that cause the fluidity of the powder mixture before tableting to be reduced among the components to be added. The flowability of the hopper force of the tableting machine for the powder mixture can be improved and the occurrence of cabbing can be suppressed, and as a result, the weight deviation of the tablet can be reduced. It was thought that a fast disintegrating tablet having a practical tablet hardness could be produced while maintaining the disintegrating property of the tablet.
[0012] 力かる考え方をもとに検討した結果、特に混合粉体物の流動性を低下させる原因と なる成分は、矯味剤として配合するエリスリトール、キシリトール、マン-トール等に起 因することを確認し、力かる成分を結合剤、例えば結晶セルロースと共に顆粒ィ匕し、 この造粒物と、有効成分並びに他の配合成分を混合した混合粉体物は、その流動 性が良好なものであり、上記した問題点を一気に解決できることを見出し、本発明を 完成させるに至った。 [0012] As a result of examination based on a strong idea, it was found that the components that cause a decrease in the fluidity of the mixed powder are caused by erythritol, xylitol, mannitol and the like blended as a corrigent. Check and granulate the strong ingredients together with a binder, for example crystalline cellulose, The powder mixture obtained by mixing this granulated product with the active ingredient and other compounding ingredients has good fluidity, and it has been found that the above-mentioned problems can be solved at once, and the present invention has been completed. It was.
課題を解決するための手段  Means for solving the problem
[0013] 而して、本発明の一つの基本的態様である請求項 1に記載の発明は、エリスリトー ル、キシリトール、マン-トール、乳糖、ショ糖からなる群力も選ばれる一種以上の矯 味剤と、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、カルメロース力リウ ムからなる群から選ばれる一種以上の結合剤の粉体を混合し、還元麦芽糖水ァメの 水溶液を噴霧して得た造粒物を用いることを特徴とする乾式直打速崩壊性錠剤であ る。  [0013] Thus, the invention according to claim 1, which is one basic aspect of the present invention, is one or more tastes selected from the group power consisting of erythritol, xylitol, mannitol, lactose, and sucrose. Granules obtained by mixing a powder of one or more binders selected from the group consisting of a crystalline cellulose, crystalline cellulose 'carmellose sodium and carmellose strength rhodium and spraying an aqueous solution of reduced maltose starch. It is a dry-type direct-disintegrating tablet which is characterized by using a product.
[0014] より具体的な請求項 2に記載の本発明は、請求項 1に記載の発明において、造粒 を流動層造粒機により行うものである乾式直打速崩壊性錠剤である。  [0014] A more specific aspect of the present invention according to claim 2 is the dry direct-acceleration disintegrating tablet according to claim 1, wherein the granulation is performed by a fluidized bed granulator.
[0015] したがって、本発明の別の基本的態様は、上記で得た造粒物と、有効成分、賦形 剤、崩壊剤、流動化剤、滑沢剤及び着色剤とを混合し、得られた混合物を直接打錠 することを特徴とする乾式直打速崩壊性錠剤である。  Therefore, another basic aspect of the present invention is obtained by mixing the granulated product obtained above with an active ingredient, excipient, disintegrant, fluidizer, lubricant and colorant. It is a dry-type direct-disintegrating tablet that is directly compressed from the resulting mixture.
[0016] 最も具体的な本発明は、有効成分として酒石酸ゾルピデム又はメロキシカムを使用 した上記の乾式直打速崩壊性錠剤である。  [0016] The most specific present invention is the above-mentioned dry-type direct-disintegrating tablet that uses zolpidem tartrate or meloxicam as an active ingredient.
[0017] さらに本発明の別の態様である請求項 5に記載の発明は、エリスリトール、キシリト ール、マン-トール、乳糖、ショ糖からなる群力 選ばれる一種以上の矯味剤と、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、カルメロースカリウムからなる群 から選ばれる一種以上の結合剤の粉体を混合し、還元麦芽糖水ァメの水溶液を噴 霧しながら流動層造粒機を用いて造粒することにより得られた造粒物と、有効成分、 賦形剤、崩壊剤、流動化剤、滑沢剤及び着色剤を混合し、当該混合物を直接打錠 することを特徴とする乾式直打速崩壊性錠剤の製造方法である。また、最も具体的な 請求項 6に記載の発明は、有効成分として酒石酸ゾルピデム又はメロキシカムを用い た上記の乾式直打速崩壊性錠剤の製造方法である。  [0017] Furthermore, the invention according to claim 5, which is another aspect of the present invention, comprises at least one flavoring agent selected from the group consisting of erythritol, xylitol, mannitol, lactose, and sucrose, and crystalline cellulose. , Crystalline Cellulose 'Mixing powder of one or more binders selected from the group consisting of carmellose sodium and carmellose potassium, and using a fluidized bed granulator while spraying an aqueous solution of reduced maltose starch. A granulated product obtained by granulation and an active ingredient, an excipient, a disintegrant, a fluidizing agent, a lubricant and a colorant are mixed, and the mixture is directly compressed into tablets. This is a method for producing a quick-disintegrating tablet. The most specific invention according to claim 6 is the above-mentioned method for producing a dry direct-disintegrating tablet that uses zolpidem tartrate or meloxicam as an active ingredient.
発明の効果  The invention's effect
[0018] 本発明により、直接打錠前の有効成分を含む粉末状の混合物について、その流動 性が良好なものであり、したがって、打錠機のホッパー力もの混合粉体物の流出性が 良ぐキヤッビングの発生を抑え、結果として錠剤の重量偏差が殆どない速崩壊性錠 剤、及びその乾式直打法による速崩壊性錠剤の製造方法が提供される。 [0018] According to the present invention, for a powdery mixture containing an active ingredient before direct compression, Therefore, a rapidly disintegrating tablet that suppresses the occurrence of cabbing with a good spillability of the mixed powdered product with a hopper force of a tableting machine and results in almost no tablet weight deviation, and its A method for producing a rapidly disintegrating tablet by a dry direct compression method is provided.
[0019] また、本発明により得られた速崩壊性錠剤は、所望の崩壊速度を有すると共に、実 用的な錠剤の硬度を有するものであり、さらにその製造方法は、安価かつ、簡便な製 造方法である。したがって、各種の有効成分について、目的とする速崩壊性錠剤を 調製し得る利点を有して 、る。  [0019] Further, the rapidly disintegrating tablet obtained by the present invention has a desired disintegration rate and practical tablet hardness, and its production method is inexpensive and simple. It is a manufacturing method. Therefore, it has the advantage that the desired rapidly disintegrating tablet can be prepared for various active ingredients.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0020] 本発明の基本は、上記したように、直接打錠前の混合粉体物の流動性を低下させ る原因となる成分を、前もって顆粒ィ匕することにより流動性をもたせ、かかる造粒物を 用いて、有効成分、他の成分を混合し、得られた該混合粉体物を直接打錠して得た 直打速崩壊性錠剤である。  [0020] As described above, the basis of the present invention is to provide the fluidity by previously granulating the components that cause a decrease in the fluidity of the mixed powder before tableting directly, so that the granulation is performed. It is a direct compression quick disintegrating tablet obtained by mixing an active ingredient and other ingredients using a product and directly compressing the obtained mixed powder.
[0021] 本発明者等の検討によれば、直接打錠前の混合粉体の流動性を低下させる成分 は、矯味剤として配合される成分であることが判明した。  [0021] According to the study by the present inventors, it has been found that the component that decreases the fluidity of the mixed powder before direct tableting is a component to be blended as a corrigent.
このような矯味剤としてはエリスリトール、キシリトール、マン-トール、乳糖、ショ糖で ある。  Such flavoring agents are erythritol, xylitol, mannitol, lactose and sucrose.
なお、かかる矯味剤は、ある一面においては賦形剤として使用される成分であり、 賦形剤として添加する場合にあっても、このものと他の成分、たとえは有効成分或い は結合剤等を、予め造粒しておくことは好まし 、ものである。  In addition, the flavoring agent is a component used as an excipient in one aspect, and even when added as an excipient, this and other components, for example, an active ingredient or a binder. It is preferable to granulate etc. in advance.
[0022] 本発明にあっては、カゝかる流動性を低下させる矯味剤を前もって顆粒ィ匕 (造粒)し、 その流動性を向上させるのである力 顆粒ィ匕を行うにあたっては、結合剤と共に顆粒 化するのがよい。 [0022] In the present invention, in order to improve the fluidity, a binder is used in order to improve the fluidity. It is better to granulate together.
そのような結合剤としては、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、カルメロースカリウム等を挙げることができる。そのなかでも特に結晶セルロースが 好ましく使用される。この結晶セルロースとしては、例えば、セォラス PH101、セオラ ス PH302 [旭化成ケミカルズ (株)製]である。  Examples of such a binder include crystalline cellulose, crystalline cellulose'carmellose sodium, and carmellose potassium. Of these, crystalline cellulose is particularly preferably used. Examples of the crystalline cellulose include Ceraus PH101, Ceraus PH302 [manufactured by Asahi Kasei Chemicals Corporation].
用いる結合剤の配合量は、最終錠剤の重量を基準として 5〜20重量％であり、好 ましくは約 10重量％であるのがよい。 [0023] 本発明にお ヽては、上記した矯味剤と結合剤の両者を、特に還元麦芽糖水ァメの 水溶液を噴霧しながら造粒することにより顆粒ィ匕するのがよい。 The amount of binder used should be 5 to 20% by weight, preferably about 10% by weight, based on the weight of the final tablet. [0023] In the present invention, it is preferable to granulate both the above-mentioned taste-masking agent and binder, particularly by granulating while spraying an aqueous solution of reduced maltose starch.
使用する還元麦芽糖水ァメは、粉末還元麦芽糖水ァメ、還元麦芽糖水ァメ (別名マ ルチトール）であり、デンプン類を水に加えて加熱し、のり化し、これにアミラーゼをカロ えて、加水分解し、精製したものを還元し、更に精製濃縮したものである。においは なぐ味は甘ぐこれまでに甘味剤、基剤、矯味剤等として各種製剤の添加物として 広く使用されてきた成分である。  The reduced maltose starch to be used is powdered reduced maltose starch or reduced maltose starch (also known as maltitol). Starch is added to water and heated to form a paste. A product that has been decomposed and purified is reduced and further purified and concentrated. Smell is a component that has been widely used as an additive in various preparations as a sweetener, base, flavoring agent, and the like.
本発明においては、カゝかる還元麦芽糖水ァメは、上記した矯味剤と結合剤の造粒 物の調製する際に用いる、液剤用の賦形剤として使用される。  In the present invention, the reduced maltose starch syrup is used as an excipient for a liquid agent used when preparing a granulated product of the above-mentioned corrigent and binder.
[0024] 本発明にお ヽては、矯味剤と結合剤の粉体を混合し、賦形剤としての還元麦芽糖 水ァメの水溶液を噴霧しながら造粒する力 この造粒は、例えば、流動層造粒機を用 Vヽて行うことができ、その造粒自体は、他の自体公知の方法で行うこともできる。  [0024] In the present invention, the ability to granulate while mixing a powder of a flavoring agent and a binder and spraying an aqueous solution of reduced maltose starch as an excipient. It can be carried out using a fluidized bed granulator, and the granulation itself can be carried out by other known methods.
[0025] 本発明は、その基本的態様としては、粉体混合物の流動性を低下させる原因成分 である矯味剤を、結合剤と共に特定の賦形剤である還元麦芽糖水ァメの水溶液を用 いて造粒し、その流動性を向上させ、その上で、力かる造粒物と、有効成分、賦形剤 、崩壊剤、流動化剤及び滑沢剤を混合し、得られた混合物を直接打錠することを特 徴とする乾式直打速崩壊性錠剤である。  [0025] As a basic aspect of the present invention, a corrigent that is a causative component that lowers the fluidity of a powder mixture is used, and an aqueous solution of reduced maltose starch that is a specific excipient is used together with a binder. To improve the fluidity, and then mix the powerful granulated product with active ingredients, excipients, disintegrants, fluidizers and lubricants, and mix the resulting mixture directly. It is a dry direct-disintegrating tablet that is characterized by tableting.
これにより、所望の速崩壊性と、適度の硬度を有する乾式直打速崩壊性錠剤を得 ることが可能となる。  As a result, it is possible to obtain a dry-type direct-disintegrating tablet having a desired quick disintegrating property and appropriate hardness.
[0026] この場合の本発明の乾式直打速崩壊性錠剤に用いる薬効成分としては、特に制限 されるものではない。例えば、抗菌薬、抗結核薬、抗真菌、抗ウィルス剤、抗ガン剤、 ビタミン剤、副腎皮質ホルモン製剤、抗アレルギー薬、非ステロイド性抗炎症薬、麻 薬、偏頭痛用薬、糖尿病薬、高脂血症治療剤、痛風 ·高尿酸血症用薬、代謝異常症 用薬、鎮静，催眠薬、抗不安薬、抗てんかん薬、抗うつ薬、抗精神病薬、精神刺激薬 、強心薬、 β受容体遮断薬、カルシウムチャンネル拮抗薬、抗不整脈薬、利尿薬、降 圧薬、昇圧薬、脳循環 ·代謝障害用薬、鎮咳薬、去痰薬、気管支拡張薬、気管支喘 息用薬、呼吸促進薬、健胃薬 *消化薬、胃炎用薬、制吐薬、消化性潰瘍薬、止瀉薬 •整腸薬，腸疾患用薬、瀉下剤 (下剤)、利胆剤、パーキンソン病 (症候群)用薬、骨 代謝疾患 ·骨粗鬆症用剤 (骨吸収抑制薬)及びリウマチ ·関節症用薬 (抗リウマチ薬） 等を挙げることができる。 [0026] In this case, the medicinal component used in the dry-type direct hit disintegrating tablet of the present invention is not particularly limited. For example, antibacterial drugs, antituberculosis drugs, antifungals, antiviral drugs, anticancer drugs, vitamins, corticosteroids, antiallergic drugs, nonsteroidal anti-inflammatory drugs, narcotics, migraine drugs, diabetes drugs, Antihyperlipidemic, Gout / Hyperuricemia, Metabolic disorder, Sedation, Hypnotic, Anti-anxiety, Antiepileptic, Antidepressant, Antipsychotic, Psychostimulant, Cardiotonic, β-receptor blocker, calcium channel antagonist, antiarrhythmic drug, diuretic, hypotensive drug, vasopressor, cerebral circulation / metabolic disorder drug, antitussive, expectorant, bronchodilator, bronchial asthma drug, respiratory Accelerator, stomachic medicine * Digestive, gastritis, antiemetic, peptic ulcer, antipruritic agent • Intestinal, intestinal disease, laxative (laxative), antibacterial, Parkinson's disease (syndrome) ,Bone Metabolic diseases · Osteoporosis agent (bone resorption inhibitor) and rheumatism · Arthropathy agent (anti-rheumatic agent).
[0027] 抗生物質としては、例えばセファレキシン、セファクロル、ァモキシシリン、塩酸ビブ メシリナム、塩酸セフォチアムへキセチル、セフアドロキシル、セフィキシム、セフジトレ ンピボキシノレ、セフテラムピボキシノレ、セフポドキシミプロキセチノレ、塩酸セフォチアム 、塩酸セファゾプラン、塩酸セフメノキシム、セフスロジンナトリウムなどのセフエム系、 アンピシリン、シクラシリン、スルベ-シリンナトリウム、ナリジタス酸、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タタム系、ぺネム系及びカルバぺ ネム系抗生物質、硫酸パロモマイシン、ァモキシシリン、セファクロノレ、セファレキシン 、ァセチルスビラマイシン、塩酸ミノサイクリンが挙げられる。  [0027] Antibiotics include, for example, cephalexin, cefaclor, amoxicillin, bib mecillinam, cefotiam hexetyl, cefadoxyl, cefixime, cefditorn pivoxinole, cefteram pivoxinole, cefpodoximiproxetinole hydrochloride, cefothiplan hydrochloride, , Cefmenoxime hydrochloride, cefthridine sodium, etc., synthetic antibiotics such as ampicillin, cyclacillin, sulbecillin sodium, naliditasic acid, enoxacin, monobatams such as carmonam sodium, penem and carbapenem antibiotics , Paromomycin sulfate, amoxicillin, cefaclonole, cephalexin, acetylsiramycin, minocycline hydrochloride.
[0028] 抗結核薬としては、例えばイソ-アジド、塩酸エタンプトール等が挙げられる。  [0028] Examples of the antituberculosis drug include iso-azide, etampitol hydrochloride and the like.
抗真菌薬としては、例えばミコナゾール、塩酸テルビナフイン等が挙げられる。 また、抗ウィルス剤としては、例えばラミブジン、リバビリン、ァシクロビル等が挙げら れる。  Examples of antifungal agents include miconazole and terbinafine hydrochloride. Examples of the antiviral agent include lamivudine, ribavirin, and acyclovir.
抗ガン剤としては、例えば 5—フルォロウラシル、ゥラシル、マイトマイシン、カルモフ ール、塩酸アクラルビシン、シクロホスフアミド、チォテパ等が挙げられる。  Examples of the anticancer drug include 5-fluorouracil, uracil, mitomycin, carmofur, aclarubicin hydrochloride, cyclophosphamide, and tiotepa.
[0029] ビタミン薬としては、例えば塩酸チアミン、硝酸チアミン、酢酸トコフエノール、シコチ ァミン、リン酸ピリドキサール、コバマミド、ァスコルビン酸、ニコチン酸アミド、アルファ カルシドール、コバマイド、ビタロキシン、酪酸リボフラビン、ァスコルビン酸等を挙げ ることがでさる。 [0029] Examples of vitamin drugs include thiamine hydrochloride, thiamine nitrate, tocophenol acetate, chicotamine, pyridoxal phosphate, cobamide, ascorbic acid, nicotinamide, alpha calcidol, cobamide, vitaroxine, riboflavin butyrate, ascorbic acid and the like. It can be done.
副腎皮質ホルモン製剤としては、例えばプレドニゾロン、トリアムシノロン、ベタメタゾ ン等を挙げることができる。  Examples of corticosteroid preparations include prednisolone, triamcinolone, betamethasone and the like.
[0030] 抗アレルギー薬としては、例えば、塩酸ジフェンヒドラミン、タン-ン酸ジフェンヒドラ ミン、塩酸トリプロリジン、塩酸プロメタジン、酒石酸ァリメマジン、メキタジン、テオクル 酸ジフエ-ルビラリン、 d—マレイン酸クロルフエ-ラミン、塩酸シプロへプタジン、フマ ル酸クレマスチン、フマル酸ケトチフェン、塩酸ァゼラスチン、ォキサトミド、フマル酸 ェメダスチン、ェバスチン、塩酸セチリジン、塩酸フエキソフエナジン、口ラタジン、塩 酸ォロパタジン、トラ-ラスト、アンレキサノクス、タザノラスト、プランルカスト水和物、 塩酸ォザダレル等が挙げられる。 [0030] Antiallergic agents include, for example, diphenhydramine hydrochloride, diphenhydramine tannate, triprolidine hydrochloride, promethazine hydrochloride, alimemazine tartrate, mequitazine, diphenyl-tetraoleate, d-chlorfelamine maleate, cyproforme hydrochloride Putazine, clemastine fumarate, ketotifen fumarate, azelastine hydrochloride, oxatomide, chemedastine fumarate, ebastine, cetirizine hydrochloride, fuxofenazine hydrochloride, oral latazine, olopatadine hydrochloride, tralast, amlexanox, tazanolast, pranlukast water Japanese, And ozadarel hydrochloride.
[0031] 非ステロイド性抗炎症薬としては、例えば、アスピリン、メフエナム酸、トルフエナム酸 、インドメタシン、インドメタシンフアルネシル、ァセメタシン、ジクロフエナク、ジクロフエ ナクナトリウム、アンフエナクナトリウム、エトドラク、モフエゾラク、スリンダク、ナブメトン イブプロフェン、ケトプロフェン、ロキソプロフェンナトリウム、ピロキシカム、アンピロキ シカム、メロキシカム等を挙げることができる。  [0031] Non-steroidal anti-inflammatory drugs include, for example, aspirin, mefenamic acid, tolfenamic acid, indomethacin, indomethacin phanesyl, acemetacin, diclofenac, diclofenac sodium, anfenac sodium, etodolac, mofezolac, sulindac, nabumetone ibuprofen, Examples include ketoprofen, loxoprofen sodium, piroxicam, ampiroxicam, and meloxicam.
[0032] 麻薬としては、例えば、塩酸モルヒネ、塩酸ォキシコドン、塩酸コカインなどが挙げら れる。  [0032] Examples of narcotics include morphine hydrochloride, oxycodone hydrochloride, cocaine hydrochloride and the like.
偏頭痛用薬としては、例えば、酒石酸エルゴタミン、コハク酸スマトリブタン、ゾルミト リプタン、塩酸口メジリン、メシル酸ジメトチアジン、カフェイン等が挙げられる。  Examples of migraine drugs include ergotamine tartrate, sumatributane succinate, zolmitriptan, mezirine hydrochloride, dimethothiazine mesylate, and caffeine.
糖尿病用剤としては、例えば、トルプタミド、ァセトへキサミド、クロルプロパミド、ダリ クロビラミド、ダリブゾール、ダリベンクラミド、グリメピリド、塩酸ブホルミン、塩酸メトホル ミン、ナテグリニド、ァカルボース、ボグリボース、塩酸ピオグリタゾン、ェパルレスタツト 等を挙げることができる。  Examples of the antidiabetic agent include tolptamide, acetohexamide, chlorpropamide, dalicloviramide, dalibuzole, daribenclamide, glimepiride, buformin hydrochloride, metformin hydrochloride, nateglinide, carbose, voglibose, pioglitazone hydrochloride, epalrestatate, etc. .
[0033] 高脂血症治療剤としては、例えば、プラバスタチンナトリウム、シンパスタチン、ロバ スタチン、フルパスタチン、アトルバスタチン等を挙げることができる。 [0033] Examples of the therapeutic agent for hyperlipidemia include pravastatin sodium, simpastatin, lovastatin, flupastatin, atorvastatin and the like.
痛風治療薬としては、例えば、ァロプリノール、コルヒチン、ベンズブロマロン、プロ ベネシド等が挙げられる。  Examples of drugs for treating gout include alopurinol, colchicine, benzbromarone, probenecid and the like.
鎮静'催眠薬としては、例えば、トリァゾラム、ミタゾラム、プロチゾラム、塩酸リルマザ ホン、ロルメタパゼム、ニメタパゼム、フルニトラゼパム、エスタゾラム、ニトラゼパム、酒 石酸ゾルピデム、ゾクピロン等が挙げられる。  Examples of sedative 'hypnotics include triazolam, mitazolam, protizolam, rilmazaphone hydrochloride, lormetapazem, nimetapazem, flunitrazepam, estazolam, nitrazepam, zolpidem tartrate, and zocpilone tartrate.
抗不安薬としては、例えば、フルタゾラム、クロチアゼバム、ェチゾラム、アルプラゾ ラム、ロラゼパム、ブロマゼパム等が挙げられる。  Examples of anti-anxiety drugs include flutazolam, clothiazebum, etizolam, alprazolam, lorazepam, bromazepam and the like.
[0034] 抗てんかん薬としては、例えば、フエ-トイン、エトトイン、プリミドン、バルプロ酸ナト リウム、カルマゼピン、クロナゼパム、エトスクシミド、トリメタジオン、スルチアム、ァセ チルフエネトライド等が挙げられる。 [0034] Examples of the antiepileptic drug include fetoin, ethotoin, primidone, sodium valproate, carbazepine, clonazepam, ethosuximide, trimethadione, sultiam, acetyl phenetride and the like.
抗うつ薬としては、例えば、塩酸イミブラミン、塩酸アミトリプチリン、塩酸クロミプラミ ン、塩酸ノルトリプチリン、塩酸口フヱプラミン、塩酸ドスレビン、ァモキサピン、塩酸マ プロチリン、塩酸ミアンセリン、塩酸トラゾドン、マレイン酸フルボキサミン、塩酸ミルナ シプラン等が挙げられる。 Antidepressants include, for example, imibramin hydrochloride, amitriptyline hydrochloride, clomipramine hydrochloride, nortriptyline hydrochloride, phlepramine hydrochloride, doslevine hydrochloride, amoxapine, Examples include protilin, mianserin hydrochloride, trazodone hydrochloride, fluvoxamine maleate, and milnacipran hydrochloride.
抗精神病薬としては、例えば、クロルプロマジン、塩酸チオリダジン、プロペリシアジ ン、フルフエナジン、塩酸クロカプラミン、塩酸チアプリド等が挙げられる。  Examples of the antipsychotic drug include chlorpromazine, thioridazine hydrochloride, propericiadin, fluphenazine, clocapramine hydrochloride, thiaprid hydrochloride, and the like.
精神刺激薬としては、例えば、塩酸メチルフエ-デート、ぺモリン等が挙げられる。 強心剤としては、例えば、アムリノン、塩酸オルプリノン、ピモペンダン等が挙げられ る。  Examples of psychostimulants include methyl fedate and pemoline. Examples of the cardiotonic agent include amrinone, olprinone hydrochloride, pimopendane and the like.
[0035] β受容体遮断薬としては、例えば、塩酸ラベタロール、カルベジロール、塩酸ァモ スラロール、塩酸ァロチノロール、塩酸べバントロール、ピンドロール、塩酸カルテオ ロール、塩酸ブフエトロール、塩酸プロプラノロール、ナドロール、二プラジロール、塩 酸アミオダロン、塩酸べタキソロール等が挙げられる。  [0035] Examples of the β receptor blocker include labetalol hydrochloride, carvedilol, amosuralol hydrochloride, alotinolol hydrochloride, bevantolol hydrochloride, pindolol, carteolol hydrochloride, bufetrol hydrochloride, propranolol hydrochloride, nadolol, dipradilol, hydrochloride Examples include amiodarone and betaxolol hydrochloride.
カルシウムチャンネル拮抗薬としては、例えば、塩酸べラパミル、塩酸ジルチアゼム 、二フエジピン、塩酸-カルジピン、二ルバジピン、塩酸マ-ジピン、塩酸べプリジル 等が挙げられる。  Examples of calcium channel antagonists include verapamil hydrochloride, diltiazem hydrochloride, difedipine, hydrochloride-cardipine hydrochloride, dirubadipine, mardipine hydrochloride, bepridil hydrochloride, and the like.
抗不整脈薬としては、例えば、硫酸プロ力インアミド、リン酸ジソピラミド等が挙げら れる。  Examples of the antiarrhythmic drug include sulfated proamide inamide, disopyramide phosphate and the like.
利尿薬としてはクロルタリドン、トリパミド等が挙げられる。  Examples of diuretics include chlorthalidone and trypamide.
降圧薬としては、例えば、塩酸プラゾシン、塩酸ブナゾシン、塩酸テラゾシン、ゥラピ ジル、力ドララジン等が挙げられる。  Examples of the antihypertensive drug include prazosin hydrochloride, bunazosin hydrochloride, terazosin hydrochloride, urapidil, and force dralazine.
[0036] 昇圧薬としては、例えば、カプトプリル、ァラセプリル、リシノプリル、塩酸イミダプリル 、マレイン酸ェナラプリル、塩酸キナプリル、シラザプリル、塩酸デラプリル、塩酸テモ 力プリル、塩酸べナゼプリル等を挙げることができる。 [0036] Examples of the vasopressor include captopril, araspril, lisinopril, imidapril hydrochloride, enalapril maleate, quinapril hydrochloride, cilazapril, delapril hydrochloride, temopower prill hydrochloride, benazepril hydrochloride, and the like.
脳循環 ·代謝障害用薬としては、例えば、 -セルゴリン、酒石酸ィフェンプロジル、 塩酸ファスジル、ォザダレルナトリウム等が挙げられる。  Examples of drugs for cerebral circulation / metabolism disorder include -sergoline, ifenprodil tartrate, fasudil hydrochloride, ozadarel sodium and the like.
鎮咳薬としては、例えば、臭化水素酸デキストロメトルファン、クロペラスチン、塩酸 ホミノベン等が挙げられる。  Examples of the antitussive include dextromethorphan hydrobromide, cloperastine, and fominoben hydrochloride.
去痰薬としては、例えば塩酸ブロムへキシン、塩酸アンブロキソール等が挙げられ る。 気管支拡張薬としては、例えば、塩酸エフェドリン、硫酸サルブタモール、硫酸テル ブタリン、塩酸プロ力テロール等が挙げられる。 Examples of expectorants include bromhexine hydrochloride and ambroxol hydrochloride. Examples of bronchodilators include ephedrine hydrochloride, salbutamol sulfate, terbutaline sulfate, proterol hydrochloride, and the like.
気管支喘息用薬としては、例えば、プロピオン酸べクロメタゾン、プロピオン酸フル チカゾン、ブデソ-ド等が挙げられる。  Examples of bronchial asthma drugs include beclomethasone propionate, fluticasone propionate, budesodium and the like.
呼吸促進剤としては、例えば、ジモンホラミン、塩酸ドキサプラム等が挙げられる。  Examples of the respiratory accelerator include dimon folamine, doxapram hydrochloride and the like.
[0037] 消化管用薬としては、例えば、ファモチジン、塩酸ラ-チジン、シメチジン、スクラル フアート、スルピリド、テプレノン、プラウノトール、 5—ァミノサリチル酸、スルフアサラジ ン、オメブラゾール、ランソプラゾール等が挙げられる。  [0037] Examples of gastrointestinal drugs include famotidine, latidine hydrochloride, cimetidine, sucralfate, sulpiride, teprenone, prunotol, 5-aminosalicylic acid, sulfasalazine, omebrazole, lansoprazole, and the like.
胃炎用薬としては、例えば、塩酸メトクロブラミド、ドンペリドン、塩酸イトプリド、タエ ン酸モサプリド、マレイン酸トリメブチン、塩酸ァザセトロン、塩酸オンダンセトロン、塩 酸ダラ-セトロン、塩酸トロピセトリン、塩酸ラモセトロン等が挙げられる。  Examples of the gastritis drug include metocloblamide hydrochloride, domperidone, itopride hydrochloride, mosapride tamate, trimebutine maleate, azasetron hydrochloride, ondansetron hydrochloride, dara-setron hydrochloride, tropisetrin hydrochloride, ramosetron hydrochloride, and the like.
制吐剤としては、例えばメトクロブラミド、塩酸ラモセトロン、塩酸ダラ-セトロン、塩 酸オンダンセトロン、塩酸ァザセトロン等が挙げられる。  Antiemetics include, for example, metocloblamide, ramosetron hydrochloride, dala-setron hydrochloride, ondansetron hydrochloride, azasetron hydrochloride, and the like.
[0038] 消化性潰瘍薬としては、例えばオメブラゾール、ラベブラゾールナトリウム、ランソプ ラゾール、シメチジン、 -ザチジン、ファモチジン、塩酸ラ-チジン、塩酸ロキサジンァ セタート、スクラルフアート等が挙げられる。 [0038] Examples of the peptic ulcer drug include omebrazole, rabebrazole sodium, lansoprazole, cimetidine, -zatidine, famotidine, latidine hydrochloride, loxazine hydrochloride, sucralfate, and the like.
止瀉薬 '整腸薬'腸疾患用薬としては、例えば塩酸口ペラミド、メサラジン、ベタメタ ゾン等が挙げられる。  Examples of antidiarrheal agents “enteric agents” for enteric diseases include oral peramide hydrochloride, mesalazine, betamethasone and the like.
瀉下剤（下剤）としては、例えばピサコジル等が挙げられる。  Examples of the laxative (laxative) include pisacodyl and the like.
利胆剤としては、例えばデヒドロコーノレ酸、トレピプトン等が挙げられる。 パーキンソン病薬としては、例えばレボドパ、レポドパ、塩酸アマンタジン、塩酸トリ へキシフエ-ジル、塩酸ピロヘプチン等が挙げられる。  Examples of the astringent include dehydroconoleic acid and trepeptone. Examples of Parkinson's disease drugs include levodopa, levodopa, amantadine hydrochloride, trihexiphezyl hydrochloride, and pyroheptin hydrochloride.
骨粗鬆症用剤としては、例えばイブリフラボン等が挙げられる。  Examples of the osteoporosis agent include ibriflavone.
抗リウマチ薬としては、例えばメトトレキセート、ブシラミン、ァクタリット等が挙げられ る。  Examples of antirheumatic drugs include methotrexate, bucillamine, and actactite.
[0039] 以下に、本発明の乾式直打速崩壊性錠剤の詳細を、有効成分として、例えば、酒 石酸ゾルピデム又はメロキシカムを代表例として説明していく。  [0039] Hereinafter, details of the dry-type direct-disintegrating tablet of the present invention will be described using the active ingredient, for example, zolpidem tartrate or meloxicam as a representative example.
酒石酸ゾルピデムは、白色の結晶性の粉末でにおいはなぐ味は苦ぐ水又はエタ ノール（95%)にやや溶けにくいものである。このものは、光によって徐々に着色（黄 色)する性質を有し、臨床的には、不眠症 (統合失調症及び躁うつ病にともなう不眠 症は除く）に用いられている薬物である。投与量としては、通常、成人には酒石酸ゾ ルビデムとして 1回 5〜： LOmgを就寝直前に経口投与する。なお、高齢者には 1回 5m gから投与を開始し、年齢、症状、疾患により適宜増減することができるが、 1日 lOmg を超えな 、こととされて！/、る。 Zolpidem tartrate is a white crystalline powder with a bitter taste and water or ethanol. Slightly insoluble in knoll (95%). This drug has the property of being gradually colored (yellow) by light and is clinically used for insomnia (excluding insomnia associated with schizophrenia and manic depression). In general, for adults, zorbidem tartrate is administered orally at a dose of 5 to: LOmg once before bedtime. In addition, for elderly patients, the dose can be started at 5 mg once, and the dose can be adjusted according to age, symptoms and disease. /
[0040] 本発明の乾式直打速崩壊性錠剤に用いる酒石酸ゾルピデムの医薬原体の粒子径 は、小さい程その扱いが難しいが溶出は早くなる。したがって、錠剤にした場合の溶 解性が向上することを考慮して、適切な粒径のものを用いることができ、好ましくは、 平均粒子径が 100 m以下のものを使用するのがよい。  [0040] The smaller the particle size of the drug substance of zolpidem tartrate used in the dry direct-disintegrating tablet of the present invention is, the more difficult it is to handle, but the faster the dissolution. Therefore, in view of the improvement in solubility in the case of tablets, those having an appropriate particle size can be used, and those having an average particle size of 100 m or less are preferably used.
[0041] また、メロキシカムは、関節リウマチ、変形性関節症、腰痛症、肩関節周囲炎、頸肩 腕症候群の治療に使用される非ステロイド性消炎 ·鎮痛薬であり、臨床的に 1回 1 Om gZ日の量で経口的に投与される薬物である。  [0041] Meloxicam is a non-steroidal anti-inflammatory / analgesic agent used to treat rheumatoid arthritis, osteoarthritis, low back pain, peri-shoulderitis, and cervical shoulder-arm syndrome. It is a drug that is orally administered in gZ days.
[0042] 本発明の乾式直打速崩壊性錠剤に用いるメロキシカムの医薬原体の粒子径は、小 さい程その扱いが難しいが溶出は早くなる。したがって、錠剤にした場合の溶解性が 向上することを考慮して、適切な粒径のものを用いることができ、好ましくは、平均粒 子径 11 μ m以下であり、より好ましくは平均粒子径が 1〜11 μ m、特に好ましくは平 均粒子径が 6〜11 μ mのものを使用するのがよい。  [0042] The smaller the particle size of the drug substance of meloxicam used in the dry direct hit disintegrating tablet of the present invention, the more difficult it is to handle, but the faster the dissolution. Therefore, in view of the improvement in solubility in the case of tablets, those having an appropriate particle size can be used, preferably an average particle size of 11 μm or less, more preferably an average particle size. Is preferably 1 to 11 μm, particularly preferably an average particle diameter of 6 to 11 μm.
[0043] この酒石酸ゾルピデム又はメロキシカムを代表例とする薬物と共に使用される賦形 剤としては、乳糖、エリスリトール、 D—マン-トール、キシリトール、マルチトール等の 糖類、ヒドロキシプロピルスターチナトリウム、結晶セルロース、ヒドロキシプロピルスタ ーチ、無水リン酸水素カルシウム、合成ケィ酸アルミニウム、還元麦芽糖水ァメ等を 挙げることができる。  [0043] Examples of excipients used together with drugs such as zolpidem tartrate or meloxicam include lactose, erythritol, D-mannitol, xylitol, maltitol and other sugars, hydroxypropyl starch sodium, crystalline cellulose, Examples thereof include hydroxypropyl starch, anhydrous calcium hydrogen phosphate, synthetic aluminum silicate, and reduced maltose starch.
配合する賦形剤は、最終錠剤の重量を基準として 20〜70重量％、好ましくは 30〜 70重量％であり、より好ましくは約 60重量％であるのがよ!/、。  The excipient to be incorporated is 20 to 70% by weight, preferably 30 to 70% by weight, more preferably about 60% by weight, based on the weight of the final tablet! / ,.
[0044] 崩壊剤としては、クロスポビドン、カルメロース、カルメロースカルシウム、カルボキシ メチルスターチナトリウム力もなる群力も選ばれる一種以上を挙げることができる。好ま しくは、クロスポビドン、カルメロースの併用である。 崩壊剤の配合量は、最終錠剤の重量を基準として 5〜20重量％であり、好ましくは 約 15重量％であるのがよい。 [0044] As the disintegrant, there may be mentioned one or more kinds selected from crospovidone, carmellose, carmellose calcium, carboxymethyl starch sodium group power. Preferably, crospovidone and carmellose are used in combination. The content of the disintegrant is 5 to 20% by weight, preferably about 15% by weight, based on the weight of the final tablet.
[0045] 流動化剤としては、軽質無水ケィ酸 (二酸化ケイ素)等の無水ケィ酸類が挙げられ る。好ましくは、アドソリダ一 101 [商品名、フロイント産業 (株)製]を挙げることができ る。流動化剤の配合量は、最終錠剤の重量を基準として 0. 5〜3重量％であり、好ま しくは約 0. 5〜1. 5重量0 /0であるのがよい。 [0045] Examples of the fluidizing agent include anhydrous key acids such as light anhydrous key acid (silicon dioxide). Preferably, Adsolida 101 [trade name, manufactured by Freund Corporation] can be used. The amount of fluidizing agent is 5 to 3 wt% 0.1 the weight of the final tablet based, it favored properly about 0.5 to 1.5 is of good weight 0/0.
[0046] 本発明が提供する速崩壊性錠剤において、滑沢剤としてはステアリン酸マグネシゥ ム及びショ糖脂肪酸エステル、例えば、シュガーエステル B— 370F、或いはサーフ ホープ J - 2203F [ショ糖べへニン酸エステルを滑沢剤用として B - 370を微粉砕し たもの；三菱化学フーズ (株)製]の両者を併用して使用するのが好ま 、。 [0046] In the rapidly disintegrating tablet provided by the present invention, as a lubricant, magnesium stearate and a sucrose fatty acid ester such as sugar ester B-370F or Surf Hope J-2203F [sucrose behenic acid] B-370 finely pulverized with ester as lubricant; Mitsubishi Chemical Foods Co., Ltd.] is preferably used in combination.
ステアリン酸マグネシウム及びショ糖脂肪酸エステルの配合比は、重量比で 1： 1〜 3程度、好ましくは 1 : 1〜2程度であるのがよい。  The compounding ratio of magnesium stearate and sucrose fatty acid ester is about 1: 1 to 3 and preferably about 1: 1 to 2 by weight.
また、滑沢剤の配合量は、最終錠剤の重量を基準として 1. 0〜3重量％、好ましく は約 1. 0〜2. 0重量％である。  The blending amount of the lubricant is 1.0 to 3% by weight, preferably about 1.0 to 2.0% by weight, based on the weight of the final tablet.
[0047] なお、有効成分が苦みを有する場合には、常法に従って、力かる苦みをマスキング するマスキング剤を配合することができる。そのようなマスキング剤としては、ァスパル テーム、タウチマン等の甘味剤、或いは 1 メントール、ドライコートヮユラ、黒糖フレー バー、ドライコートペパーミント、グレープフルーツコート等の香料を挙げることができ る。好ましくはアスパルテームである。 [0047] When the active ingredient has bitterness, a masking agent for masking bitter bitterness can be blended according to a conventional method. Examples of such a masking agent include sweeteners such as aspartame and tautiman, and flavors such as 1 menthol, dry coat cocoon, brown sugar flavor, dry coat peppermint, and grapefruit coat. Aspartame is preferred.
これらのマスキング剤の配合量は、含有させる有効成分により、その使用量を適宜 増減することができる。  The amount of these masking agents can be appropriately increased or decreased depending on the active ingredient to be contained.
[0048] 着色剤としては、黄色三二酸化鉄、三二酸化鉄、黒酸化鉄 (もしくは酸化鉄類)、ァ ルミ-ゥムキレート剤を挙げることができる。  [0048] Examples of the colorant include yellow iron sesquioxide, iron sesquioxide, black iron oxide (or iron oxides), and an aluminum chelating agent.
[0049] 本発明が提供する乾式直打速崩壊性錠剤は、例えば、以下の工程による製造方 法で調製することができる。  [0049] The dry direct hit disintegrating tablet provided by the present invention can be prepared, for example, by a manufacturing method according to the following steps.
かかる方法は、概略、先ず矯味剤と結合剤からなる造粒物を調製する第一工程、 各成分を混合する第二工程、次いで打錠する第三工程の 3工程からなり、各工程自 体は常法に従って行うことができる簡便、かつ効率的な錠剤の調製方法である。 その詳細を示せば、以下のようになる。 This method is generally composed of three steps: a first step of preparing a granulated product composed of a corrigent and a binder, a second step of mixing each component, and then a third step of tableting. Is a simple and efficient tablet preparation method that can be carried out according to a conventional method. The details are as follows.
[0050] [第一工程]  [0050] [First step]
予め、賦形剤 (例えば、粉末還元麦芽糖水ァメ)の水溶液を調製し、矯味剤 (例え ば、エリスリトール）と結合剤（例えば、結晶セルロース）を混合し、流動層造粒機を用 いて造粒することにより、造粒物を得る。上記の賦形剤の水溶液の濃度は、用いる矯 味剤の種類、使用量等により、また用いる結合剤の種類、使用量等により異なり、特 に制限されないが好ましくは 10〜20%、よりこのましくは 15%付近である。  An aqueous solution of an excipient (eg, powdered reduced maltose starch syrup) is prepared in advance, a taste-masking agent (eg, erythritol) and a binder (eg, crystalline cellulose) are mixed, and a fluidized bed granulator is used. By granulating, a granulated product is obtained. The concentration of the above-mentioned excipient aqueous solution varies depending on the type of flavoring agent used, the amount used, etc., and also on the type of binder used, the amount used, etc., and is not particularly limited, but is preferably 10-20%. It is around 15%.
賦形剤と結合剤の配合比は特に限定されないが、好ましくは矯味剤の 1重量当たり 、結合剤の量が 0. 15〜3. 2の範囲である。結合剤の量が多くなるほど、流動性は改 善されるが、崩壊性が低下する。また、矯味剤の配合比が多くなると流動性が低下す る傾向が見られた。  The mixing ratio of the excipient and the binder is not particularly limited, but the amount of the binder is preferably in the range of 0.15 to 3.2 per 1 weight of the corrigent. The higher the amount of binder, the better the fluidity but the lower the disintegration. In addition, when the blending ratio of the flavoring agent was increased, the fluidity tended to decrease.
[0051] [第二工程]  [0051] [Second step]
上記第一工程で得られた造粒物と、有効成分 (例えば、酒石酸ゾルピデム又はメロ キシカム）、賦形剤（例えば、乳糖)、崩壊剤（例えば、クロスポビドン、カルメロース）、 流動化剤（例えば、軽質無水ケィ酸）、滑沢剤（例えば、ステアリン酸マグネシウム、シ ョ糖脂肪酸エステル）、香料 (例えば、 1 メントール）、着色剤（例えば、黄色三二酸 化鉄、アルミニウムキレート剤)を混合し、粉体混合物を得る。  The granulated product obtained in the first step, an active ingredient (for example, zolpidem or meloxicam tartrate), an excipient (for example, lactose), a disintegrant (for example, crospovidone, carmellose), a fluidizing agent (for example, , Light anhydrous anhydride), lubricant (eg, magnesium stearate, sucrose fatty acid ester), flavor (eg, 1 menthol), colorant (eg, yellow iron trioxide, aluminum chelator) To obtain a powder mixture.
[0052] この第二工程の混合は、所定量の各成分、有効成分を、常法にしたがって、例え ば、混合機 [商品名、ボーレコンテナーミキサー;コトプキ技研工業 (株)製]を用いて 混合することにより行うことができる。この混合時間は、用いる添加剤の種類、使用量 等により異なり特に限定されるものではないが、好ましくは 5〜40分間、より好ましくは 5〜30分間混合する。 [0052] The mixing in the second step is carried out by using a predetermined amount of each component and active ingredient in accordance with a conventional method, for example, using a mixer [trade name, Bole container mixer; manufactured by Kotopuki Giken Kogyo Co., Ltd.]. This can be done by mixing. The mixing time varies depending on the type of additive used, the amount used, etc., and is not particularly limited, but is preferably 5 to 40 minutes, more preferably 5 to 30 minutes.
[0053] なお、滑沢剤については、上記混合物に後で添加し、混合することもできる。この場 合の混合時間は、滑沢剤が十分に混合し得る時間であればよぐ上記混合物の使用 量等により特に限定されるものではないが、通常、 2〜： LO分間、好ましくは 2〜4分間 である。  [0053] The lubricant can be added to the mixture later and mixed. The mixing time in this case is not particularly limited depending on the amount of the above mixture used as long as the lubricant can be sufficiently mixed, but usually 2 to: LO minutes, preferably 2 ~ 4 minutes.
[0054] [第三工程]  [0054] [Third step]
カゝくして製造された上記の第二工程で得られた粉体混合物を用いて、直接打錠す ることにより、目的とする本発明の速崩壊性錠剤を得ることができる。 Direct compression using the powder mixture obtained in the second step above Thus, the intended quick disintegrating tablet of the present invention can be obtained.
[0055] 本発明が提供する速崩壊性錠剤に用いる香料は、前記第一工程カゝら第二工程ま でのいずれでも添加することができる力 好ましくは第二工程で添加するのがよい。 また、本発明の錠剤に、所望によりさらに、アスパルテーム、等の通常用いられる甘 味剤、溶解補助剤 (例えばクェン酸ナトリウム、炭酸水素ナトリウム)を添加することが できるが、前記第一工程力も第二工程のいずれでも添加することができる。 [0055] The perfume used in the fast disintegrating tablet provided by the present invention can be added in any of the first step and the second step, preferably in the second step. In addition, normally used sweetening agents such as aspartame and solubilizing agents (for example, sodium quenate and sodium hydrogen carbonate) can be further added to the tablet of the present invention as desired. Either of the two steps can be added.
[0056] 以上により、本発明が目的とする乾式直打速崩壊性錠剤が提供されるが、得られた 錠剤は、所望の速崩壊性を維持しつつ、実用的な錠剤の硬度を有するものである。 [0056] As described above, the dry direct compression fast disintegrating tablet targeted by the present invention is provided. The obtained tablet has a practical tablet hardness while maintaining desired quick disintegration. It is.
[0057] なお、錠剤の形態としては、特に制限はなぐ常法に従って、例えば、所望の直径 を有する割線入り血球型円形素錠等の速崩壊性錠剤を簡便に調製することができる 実施例 [0057] It should be noted that, as a tablet form, a fast disintegrating tablet such as a scored blood cell type circular uncoated tablet having a desired diameter can be easily prepared according to a conventional method without any particular restriction.
[0058] 以下に、実施例をあげて本発明を詳しく説明するが、これらは本発明を限定するも のではない。  [0058] Hereinafter, the present invention will be described in detail by way of examples, but these examples do not limit the present invention.
[0059] 実施例 1〜8： [0059] Examples 1-8:
下記表 1に記載の配合 (配合量: g)により、上記した各工程に準じて造粒、混合し、 目的とする錠剤の硬度を設定し、粉体混合物を打錠することにより、酒石酸ゾルビデ ム含有の速崩壊性錠剤を得た。  By blending (mixing amount: g) described in Table 1 below, granulation and mixing according to the above-described steps, setting the hardness of the target tablet, and tableting the powder mixture, sorbide tartrate A rapidly disintegrating tablet containing a sucrose was obtained.
[0060] 得られた錠剤につ!ヽて、錠剤の硬度、 日本薬局方の崩壊試験法による崩壊時間（ 秒)、摩損度試験 200回転での摩損度 (％)を測定した。 [0060] The obtained tablets were measured for tablet hardness, disintegration time (seconds) according to the disintegration test method of the Japanese Pharmacopoeia, and friability (%) at 200 revolutions.
また、口腔内の崩壊時間 (秒)を測定した。  In addition, the disintegration time (second) in the oral cavity was measured.
その結果を、併せて表 1中に示した。  The results are also shown in Table 1.
[0061] [表 1] 実 施 例 [0061] [Table 1] Example
1 2 3 4 5 6 7 8  1 2 3 4 5 6 7 8
酒石酸ゾル ピデ 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0  Tartrate sol Pide 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0
ム  Mu
トー 95.0 95.0 95.0 95.0 95.0 95.0 95.0 95.0  Toe 95.0 95.0 95.0 95.0 95.0 95.0 95.0 95.0
結晶セ 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0  Crystalline 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0
還元麦芽糖  Reduced maltose
5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0  5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0
水ァメ  Water
1 ーメ ン トー 0.15 0.15 0.15 0.15 0.15 0.15  1 -Mentor 0.15 0.15 0.15 0.15 0.15 0.15
テ 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0  Te 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0
黄色三二酸化鉄 0.15 0.15 0.15 0.15  Yellow ferric oxide 0.15 0.15 0.15 0.15
乳糖 105.6 105.6 105.45 105.45 105.3 105.3 105.3 105.3  Lactose 105.6 105.6 105.45 105.45 105.3 105.3 105.3 105.3
クロスポピ ドン 45.0 45.0 45.0 45.0 33.0 33.0 33.0 33.0  Cross poppy don 45.0 45.0 45.0 45.0 33.0 33.0 33.0 33.0
ロ 12.0 12.0 12.0 12.0  B 12.0 12.0 12.0 12.0
軽質無水ケィ酸 3.9 3.9 3.9 3.9 3.9 3.9 3.9 3.9  Light anhydrous anhydrous 3.9 3.9 3.9 3.9 3.9 3.9 3.9 3.9
ショ糖脂肪酸  Sucrose fatty acid
3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0  3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0
テア リ ン酸  Tearic acid
1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5  1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5
マグネシゥム  Magnesium
錠剤の物性値  Tablet physical properties
設定硬度 （Kp) 5 7 5 7 3 5 7 9  Set hardness (Kp) 5 7 5 7 3 5 7 9
平均硬度 （Kp) 4.5 7.0 4.9 7.0 2.9 4.9 6.9 9.5  Average hardness (Kp) 4.5 7.0 4.9 7.0 2.9 4.9 6.9 9.5
摩損度 （％) 0.6 0.3 0.5 0.3 0.8 0.5 0.3 0.2  Friction (%) 0.6 0.3 0.5 0.3 0.8 0.5 0.3 0.2
崩壊試験 （秒） 14-17 19-24 14-19 17-23 13-18 15-20 15-24 19-28  Collapse test (seconds) 14-17 19-24 14-19 17-23 13-18 15-20 15-24 19-28
口腔内の崩壊  Disintegration in the oral cavity
30-40 45-50 30-40 40-50 25-35 35-40 40-45 55-60  30-40 45-50 30-40 40-50 25-35 35-40 40-45 55-60
(秒）  (Seconds)
[0062] 代表的な錠剤の製造操作例を、実施例 6の配合処方で示す。 [0062] A typical tablet manufacturing operation example is shown in the formulation of Example 6.
[工程 1]  [Process 1]
エリスリトール [矯味剤、微粉、 日研化成 (株)製] 95. Og、結晶セルロース [結合剤 、セォラス PH— 101、旭化成ケミカルズ (株)製] 30. Ogの混合粉体を流動層造粒機 [商品名 MP— 01 ; (株)バウレック製]を使用し、予め粉末還元麦芽糖水ァメ [賦形 剤、アマルティ、東和化成工業 (株)製]を精製水に溶解させて得た 15%水溶液を用 い、造粒することにより造粒物を得た。  Erythritol [flavoring agent, fine powder, manufactured by Nikken Kasei Co., Ltd.] 95. Og, crystalline cellulose [Binder, CERATH PH-101, manufactured by Asahi Kasei Chemicals Co., Ltd.] 30. Fluidized bed granulator with mixed powder of Og 15% obtained by previously dissolving powdered reduced maltose starch syrup [former, Amarti, manufactured by Towa Kasei Kogyo Co., Ltd.] in purified water using [trade name MP-01; manufactured by Baurec Co., Ltd.] A granulated product was obtained by granulation using an aqueous solution.
[0063] 上記製法で得られた造粒物の分析値以下のとおりであった。  [0063] The analysis value of the granulated product obtained by the above production method was as follows.
安息角（° ) 51. 5 ;比容積 (ルーズ) 2. 45mLZg ;比容積 (タップ） 2. 27mLZg ;水 分（％) 0. 6 ;平均粒子径 m) 88. 75  Angle of repose (°) 51.5; Specific volume (loose) 2. 45 mLZg; Specific volume (tap) 2. 27 mLZg; Moisture content (%) 0.6; Average particle size m) 88. 75
[0064] [工程 2]  [0064] [Step 2]
上記造粒物と酒石酸ゾルピデム (有効成分） 5. 0g、乳糖 (賦形剤） 105. 3g、クロス ポビドン (崩壊剤、クロスポビドン XL、 ISP製） 33. 0g、カルメロース [崩壊剤、 NS- 3 00、五徳薬品 (株)製] 12. 0g、軽質無水ケィ酸 [流動化剤、フロイント産業 (株)製] 3 . 90g、ステアリン酸マグネシウム（滑沢剤） 1. 50g、ショ糖脂肪酸エステル [滑沢剤、 シュガーエステル B—370F、三菱化成フーズ (株）製] 3. 0g、アスパルテーム [甘味 剤、アスパルテーム、味の素 (株）] 6. 00g、 1 メントール [香料、小林桂 (株)製] 0. 1The above granulated product and zolpidem tartrate (active ingredient) 5.0 g, lactose (excipient) 105. 3 g, crospovidone (disintegrant, crospovidone XL, manufactured by ISP) 33.0 g, carmellose [disintegrant, NS-3 00, manufactured by Gotoku Pharmaceutical Co., Ltd.] 12.0 g, light anhydrous key acid [fluidizing agent, manufactured by Freund Sangyo Co., Ltd.] 3.90 g, magnesium stearate (lubricant) 1.50 g, sucrose fatty acid ester [ Lubricant, Sugar Ester B-370F, manufactured by Mitsubishi Kasei Foods Co., Ltd.] 3.0g, Aspartame [Sweetness Agent, aspartame, Ajinomoto Co., Inc.] 6.00 g, 1 menthol [fragrance, manufactured by Katsura Kobayashi Co., Ltd.] 0.1
5g、黄色三二酸化鉄 [着色剤、葵巳化成 (株)製] 0. 15gを添加し、 3分間混合した。 5 g of yellow iron sesquioxide [Coloring agent, manufactured by Hatake Kasei Co., Ltd.] 0.15 g was added and mixed for 3 minutes.
[0065] 上記混合法で得られた粉体混合物の分析値は以下のとおりであった。 [0065] Analytical values of the powder mixture obtained by the above mixing method were as follows.
安息角（° ) 39. 0 ;比容積 (ルーズ) 2. 45mLZg ;比容積 (タップ） 1. 86mLZg ;圧 縮比（％) 24. 1 ;水分 (％) 0. 8  Angle of repose (°) 39.0; Specific volume (loose) 2. 45mLZg; Specific volume (tap) 1. 86mLZg; Compression ratio (%) 24.1; Moisture (%) 0.8
[0066] [工程 3] [0066] [Step 3]
上記工程 2で得られた粉体混合物を用い、設定硬度 5kpで打錠することにより乾式 直打速崩壊性錠剤を得た (有効成分を 5mg含有する 300mg錠)。  Using the powder mixture obtained in the above step 2, tableting was carried out at a set hardness of 5 kp to obtain dry direct compression fast disintegrating tablets (300 mg tablets containing 5 mg of active ingredient).
[0067] 前記各実施例において、香料として 1—メントールを添加して錠剤を調製したものは 、不快な苦みが緩和された。 [0067] In each of the above Examples, unpleasant bitterness was alleviated in the case where a tablet was prepared by adding 1-menthol as a fragrance.
錠剤の直径は、通常約 5mm〜約 20mm、好ましくは約 7mm〜約 15mmの間で、 服用に適した大きさを選択することができる。  The tablet diameter is usually between about 5 mm and about 20 mm, preferably between about 7 mm and about 15 mm, and a size suitable for taking can be selected.
[0068] 実飾 19 : [0068] Decoration 19:
エリスリトール [矯味剤、微粉、 日研化成 (株)製] 107. 5g、結晶セルロース [結合剤 、セォラス PH— 101、旭化成ケミカルズ (株)製] 17. 5gの混合粉体を流動層造粒機 [商品名 MP— 01 ; (株)バウレック製]を使用し、予め粉末還元麦芽糖水ァメ [賦形 剤、アマルティ、東和化成工業 (株)製]を精製水に溶解させて得た 15%水溶液を用 Fluidized bed granulator with mixed powder of erythritol [flavoring agent, fine powder, manufactured by Nikken Kasei Co., Ltd.] 107.5 g, crystalline cellulose [binder, Seras PH-101, manufactured by Asahi Kasei Chemicals Co., Ltd.] 17.5 g 15% obtained by previously dissolving powdered reduced maltose starch syrup [former, Amarti, manufactured by Towa Kasei Kogyo Co., Ltd.] in purified water using [trade name MP-01; manufactured by Baurec Co., Ltd.] For aqueous solution
V、造粒することにより造粒物を得た。 V. A granulated product was obtained by granulation.
上記で得られた造粒物は、実施例 1の工程 1で得られたものと同等の性質を示した  The granulated product obtained above showed the same properties as those obtained in Step 1 of Example 1.
[0069] 実施例 10 : [0069] Example 10:
エリスリトール [矯味剤、微粉、 日研化成 (株)製] 30. Og、結晶セルロース [結合剤 、セォラス PH— 101、旭化成ケミカルズ (株)製] 95. Ogの混合粉体を流動層造粒機 [商品名 MP— 01 ; (株)バウレック製]を使用し、予め粉末還元麦芽糖水ァメ [賦形 剤、アマルティ、東和化成工業 (株)製]を精製水に溶解させて得た 15%水溶液を用 Erythritol [flavoring agent, fine powder, manufactured by Nikken Kasei Co., Ltd.] 30. Og, crystalline cellulose [binder, Seras PH-101, manufactured by Asahi Kasei Chemicals Co., Ltd.] 95. Fluidized bed granulator with mixed powder of Og 15% obtained by previously dissolving powdered reduced maltose starch syrup [former, Amarti, manufactured by Towa Kasei Kogyo Co., Ltd.] in purified water using [trade name MP-01; manufactured by Baurec Co., Ltd.] For aqueous solution
V、造粒することにより造粒物を得た。 V. A granulated product was obtained by granulation.
上記で得られた造粒物は、実施例 1の工程 1で得たものと同等の物性値を示した。  The granulated product obtained above showed the same physical properties as those obtained in Step 1 of Example 1.
[0070] 比較例 1 : 下記の各成分を、常法に従って、混合し、直打することにより乾式直打速崩壊性錠 剤の調製を試みた。 [0070] Comparative Example 1: The following components were mixed and directly hit according to a conventional method to prepare a dry type quick-disintegrating tablet.
配合目的 成分名 重量 (g)  Purpose of formulation Ingredient name Weight (g)
有効成分 酒石酸ゾルピデム 5.00  Active ingredient Zolpidem tartrate 5.00
賦形剤 乳糖 105.60  Excipient Lactose 105.60
結合剤 結晶セルロース 30.00  Binder Crystalline cellulose 30.00
矯味剤 エリスリトール 100.00  Flavoring agent Erythritol 100.00
崩壊剤 クロスポビドン 45.00  Disintegrant crospovidone 45.00
流動化剤 軽質無水ケィ酸 3.90  Superplasticizer Light Caustic Anhydride 3.90
矯味剤 アスパルテーム 6.00  Flavoring agent Aspartame 6.00
滑沢剤 ショ糖脂肪酸エステル 3.00  Lubricant Sucrose fatty acid ester 3.00
滑沢剤 ステアリン酸マグネシ 'ム 1.50  Lubricant Magnesium stearate 1.50
素 錠 (合計） 300.00  Uncoated tablets (total) 300.00
[0071] 上記の各配合成分の混合物の試験分析値 (水分、比容積、安息角）を以下に示す 安息角（° ) 39. 5° ；比容積 (ルーズ) 2. 03mLZg ;比容積 (タップ） 1. 47mLZg ; 圧縮比（％) 27. 6 ;Carrの指数（％) 38. 1 ;水分（％) 1. 0  [0071] Test analysis values (moisture, specific volume, angle of repose) of the mixture of the above ingredients are as follows: angle of repose (°) 39.5 °; specific volume (loose) 2. 03mLZg; specific volume (tap ) 1. 47mLZg; Compression ratio (%) 27.6; Carr index (%) 38.1; Moisture (%) 1.0
[0072] 結果として、得られた混合物の流動性が不良であって、打錠効率が低下した。 [0072] As a result, the fluidity of the obtained mixture was poor, and the tableting efficiency was reduced.
[0073] 比較例 2 : [0073] Comparative Example 2:
前記比較例 1の調製法において、滑沢剤（ショ糖脂肪酸エステルとステアリン酸マグ ネシゥム)をタルク (滑沢剤 ·流動化剤）に代え、混合物を調製し、打錠を試みた。  In the preparation method of Comparative Example 1, the lubricant (sucrose fatty acid ester and magnesium stearate) was replaced with talc (lubricant / fluidizer) to prepare a mixture, and tableting was attempted.
配合目的 成分名 重量 (g)  Purpose of formulation Ingredient name Weight (g)
有効成分 酒石酸ゾルピデム 5.00  Active ingredient Zolpidem tartrate 5.00
賦形剤 乳糖 100.10  Excipient Lactose 100.10
結合剤 結晶セルロース 30.00  Binder Crystalline cellulose 30.00
矯味剤 エリスリトール 95.00  Flavoring agent Erythritol 95.00
崩壊剤 クロスポビドン 45.00  Disintegrant crospovidone 45.00
流動化剤 軽質無水ケィ酸 3.90 矯味剤 アスパルテーム 6.00 Superplasticizer Light Caustic anhydride 3.90 Flavoring agent Aspartame 6.00
流動化，滑沢剤 タルク 15M  Fluidization, Lubricant Talc 15M
素 錠 (合計） 300.00  Uncoated tablets (total) 300.00
[0074] 上記各配合成分の混合物の試験分析値 (水分、比容積、安息角）を以下に示す。 [0074] Test analysis values (moisture, specific volume, angle of repose) of the mixture of each of the above-described blending components are shown below.
安息角（° )45. 5° ；比容積 (ルーズ） 1. 94mLZg;比容積 (タップ） 1. 36mLZg; 圧縮比（％) 29. 9 ;Carrの指数（％)42. 6 ;水分（％) 0. 8  Angle of repose (°) 45.5 °; Specific volume (loose) 1. 94mLZg; Specific volume (tap) 1. 36mLZg; Compression ratio (%) 29.9; Carr index (%) 42.6; Moisture (%) ) 0.8
[0075] 結果として、得られた混合物の流動性は不良であって、打錠効率が低下した。 As a result, the fluidity of the obtained mixture was poor and the tableting efficiency was lowered.
[0076] 実施例 11〜19： [0076] Examples 11-19:
下記表 2に記載の配合 (配合量: g)により、上記した各工程に準じて造粒、混合し、 目的とする錠剤の硬度を設定し、粉体混合物を打錠することにより、メロキシカム含有 の速崩壊性錠剤を得た。  Containing meloxicam by granulating and mixing according to the above-mentioned steps according to the formulation shown in Table 2 below (blending amount: g), setting the hardness of the target tablet, and compressing the powder mixture A fast disintegrating tablet was obtained.
[0077] 得られた錠剤につ!ヽて、錠剤の硬度、 日本薬局方の崩壊試験法による崩壊時間（ 秒)、摩損度試験 200回転での摩損度を測定した。 [0077] The tablets obtained were measured for tablet hardness, disintegration time (seconds) according to the disintegration test method of the Japanese Pharmacopoeia, and friability at 200 revolutions.
また、口腔内の崩壊時間 (秒)を測定した。  In addition, the disintegration time (second) in the oral cavity was measured.
その結果を、併せて表 2中に示した。  The results are also shown in Table 2.
[0078] [表 2] [0078] [Table 2]
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000020_0001
Figure imgf000020_0002
[工程 1] [Process 1]
エリスリトール [矯味剤、微粉、 日研化成 (株)製] 95. Og、結晶セルロース [結合剤 、セォラス PH— 101、旭化成ケミカルズ (株)製] 30. Ogの混合粉体を流動層造粒機 [商品名 MP— 01 ; (株)バウレック製]を使用し、予め粉末還元麦芽糖水ァメ [賦形 剤、アマルティ、東和化成工業 (株)製]を精製水に溶解させて得た 15%水溶液を用 い、造粒することにより造粒物を得た。  Erythritol [flavoring agent, fine powder, manufactured by Nikken Kasei Co., Ltd.] 95. Og, crystalline cellulose [binder, Serus PH-101, manufactured by Asahi Kasei Chemicals Co., Ltd.] 30. Fluidized bed granulator with mixed powder of Og 15% obtained by previously dissolving powdered reduced maltose starch syrup [former, Amarti, manufactured by Towa Kasei Kogyo Co., Ltd.] in purified water using [trade name MP-01; manufactured by Baurec Co., Ltd.] A granulated product was obtained by granulation using an aqueous solution.
[0080] 上記製法で得られた造粒物の分析値以下のとおりであった。  [0080] The analysis value of the granulated product obtained by the above production method was as follows.
安息角（° ) 51. 5 ;比容積 (ルーズ) 2. 45mLZg ;比容積 (タップ） 2. 27mLZg ;水 分（％) 0. 6 ;平均粒子径 m) 88. 75  Angle of repose (°) 51.5; Specific volume (loose) 2. 45mLZg; Specific volume (tap) 2. 27mLZg; Water content (%) 0.6; Average particle size m) 88. 75
[0081] [工程 2]  [0081] [Step 2]
上記造粒物とメロキシカム (有効成分、粒子径約 8 m) 13. 33g、乳糖 (賦形剤） 1 61. 64g、クロスポビドン（崩壊剤、クロスポビドン XL、 ISP製） 75. 00g、クェン酸ナト リウム [溶解補助剤、小松屋化学 (株)製]、炭酸水素ナトリウム [溶解補助剤、旭化成 ケミカルズ (株)製]、軽質無水ケィ酸 [流動化剤、フロイント産業 (株)製] 6. 51g、ス テアリン酸マグネシウム（滑沢剤） 3. 51g、ショ糖脂肪酸エステル [滑沢剤、サーフホ ープ J2203— F、三菱化成フーズ (株)製] 5. 00g、アスパルテーム [甘味剤、ァスパ ルテーム、味の素 (株）] 15. 00g、 1 メントール [香料、小林桂 (株)製] 0. 25g、三 二酸化鉄 [着色剤、葵巳化成 (株)製] 0. 51gを添加し、 30分間混合した。  Granulated product and meloxicam (active ingredient, particle size approx. 8 m) 13. 33 g, lactose (excipient) 1 61. 64 g, crospovidone (disintegrant, crospovidone XL, ISP) 75.00 g, kenic acid Sodium [dissolution aid, manufactured by Komatsuya Chemical Co., Ltd.], sodium hydrogen carbonate [dissolution aid, manufactured by Asahi Kasei Chemicals Corporation], light anhydrous caustic acid [fluidizing agent, manufactured by Freund Sangyo Co., Ltd.] 6. 51 g, magnesium stearate (lubricant) 3. 51 g, sucrose fatty acid ester [lubricant, Surf Hop J2203-F, manufactured by Mitsubishi Kasei Foods Co., Ltd.] 5.00 g, aspartame [sweetener, aspartame , Ajinomoto Co., Inc.] 15.00 g, 1 Menthol [fragrance, made by Katsura Kobayashi Co., Ltd.] 0.25 g, Ferric sesquioxide [Coloring agent, produced by Hatake Kasei Co., Ltd.] 0.51 g, added for 30 minutes Mixed.
[0082] 上記混合法で得られた粉体混合物の分析値は以下のとおりであった。  [0082] Analytical values of the powder mixture obtained by the above mixing method were as follows.
安息角（° ) 37. 5 ;比容積 (ルーズ) 2. OlmLZg ;比容積 (タップ） 1. 61mLZg ;圧 縮比（％) 24. 96 ;水分（％) 0. 8  Angle of repose (°) 37.5; Specific volume (loose) 2. OlmLZg; Specific volume (tap) 1. 61 mLZg; Compression ratio (%) 24. 96; Moisture (%) 0.8
[0083] [工程 3]  [0083] [Step 3]
上記工程 2で得られた粉体混合物を用い、設定硬度 4kpで打錠することにより乾式 直打速崩壊性錠剤を得た (有効成分を 10mg含有する 375mg錠)。  Using the powder mixture obtained in the above step 2, tableting was carried out at a set hardness of 4 kp to obtain a dry direct-breaking rapidly disintegrating tablet (375 mg tablet containing 10 mg of active ingredient).
[0084] 前記各実施例において、香料として 1—メントールを添加して錠剤を調製したものは 、不快な苦みが緩和された。 [0084] In each of the above Examples, unpleasant bitterness was alleviated in the case where a tablet was prepared by adding 1-menthol as a fragrance.
錠剤の直径は、通常約 5mm〜約 20mm、好ましくは約 7mm〜約 15mmの間で、 服用に適した大きさを選択することができる。 [0085] 比較例 3 : The tablet diameter is usually between about 5 mm and about 20 mm, preferably between about 7 mm and about 15 mm, and a size suitable for administration can be selected. [0085] Comparative Example 3:
下記の各成分を、常法に従って、混合し、直打することにより乾式直打速崩壊性錠 剤の調製を試みた。  The following components were mixed and directly hit according to a conventional method to prepare a dry type quick-disintegrating tablet.
配合目的 成分名 重量 (g)  Composition purpose Ingredient name Weight (g)
有効成分 メロキシカム (粒子径約 8  Active ingredient Meloxicam (particle size approx. 8
賦形剤 乳糖 116.25  Excipient Lactose 116.25
結合剤 結晶セルロース 37.50  Binder Crystalline cellulose 37.50
矯味剤 エリスリトール 108.75  Flavoring agent Erythritol 108.75
崩壊剤 クロスポビドン 56.25  Disintegrant crospovidone 56.25
溶解補助剤 クェン酸ナトリウム 15.00  Solubilizer Sodium Quenate 15.00
溶解補助剤 炭酸水素ナトリウム 3.75  Solubilizer Sodium bicarbonate 3.75
流動化剤 軽質無水ケィ酸 4.88  Superplasticizer Light key anhydrous 4.88
矯味剤 アスパルテーム 11.25 o  Flavoring agent Aspartame 11.25 o
滑沢剤 ショ糖脂肪酸エステル 3.75  Lubricant Sucrose fatty acid ester 3.75
滑沢剤 ステアリン酸マグネシウム 2.63  Lubricant Magnesium stearate 2.63
香料 1 メントール 0.19  Fragrance 1 Menthol 0.19
羞色料 青色 1号アルミニウムレー:キ 0.19  Amber color Blue No. 1 aluminum lay: Ki 0.19
375.39  375.39
[0086] 上記の各配合成分の混合物の試験分析値 (水分、比容積、安息角）を以下に示す 安息角（° ) 39. 5° ；比容積 (ルーズ） 1. 83mLZg ;比容積 (タップ） 1. 37mLZg ; [0086] Test analysis values (moisture, specific volume, angle of repose) of the mixture of the above ingredients are as follows: angle of repose (°) 39.5 °; specific volume (loose) 1. 83 mLZg; specific volume (tap ) 1. 37mLZg;
Carrの指数（％) 33. 85 ;水分（％) 0. 8 Carr's index (%) 33. 85; moisture (%) 0.8
[0087] 結果として、得られた混合物の流動性が不良であって、打錠効率が低下した。 [0087] As a result, the fluidity of the obtained mixture was poor, and the tableting efficiency was reduced.
[0088] 比較例 4 : [0088] Comparative Example 4:
下記の各成分を、常法に従って混合し、直打することにより乾式直打速崩壊性錠剤 の調製を試みた。ただしメロキシカムは軽質無水ケィ酸で予め表面改質したものを使 用した。  The following components were mixed according to a conventional method, and a direct compression quick disintegrating tablet was prepared by direct compression. However, meloxicam was used which had been surface-modified with light caustic anhydride.
配合目的 成分名 重量 (g) 有効成分 メロキシカム (粒子径約 8 Purpose of formulation Ingredient name Weight (g) Active ingredient Meloxicam (particle size approx. 8
賦形剤 乳糖 116.25  Excipient Lactose 116.25
結合剤 結晶セルロース 37.50  Binder Crystalline cellulose 37.50
矯味剤 エリスリトール 108.75  Flavoring agent Erythritol 108.75
崩壊剤 クロスポビドン 56.25  Disintegrant crospovidone 56.25
溶解補助剤 クェン酸ナトリウム 15.00  Solubilizer Sodium Quenate 15.00
溶解補助剤 炭酸水素ナトリウム 3.75  Solubilizer Sodium bicarbonate 3.75
流動化剤 軽質無水ケィ酸 4.88  Superplasticizer Light key anhydrous 4.88
矯味剤 アスパルテーム 11.25  Flavoring agent Aspartame 11.25
滑沢剤 ショ糖脂肪酸エステル 3.75  Lubricant Sucrose fatty acid ester 3.75
滑沢剤 ステアリン酸マグネシウム 2.63  Lubricant Magnesium stearate 2.63
香料 1 メントール 0.19  Fragrance 1 Menthol 0.19
羞色料 青色 1号アルミニウムレー:キ 0.19 o  Amber color Blue No. 1 aluminum lay: Ki 0.19 o
375.39  375.39
[0089] 上記の各配合成分の混合物の試験分析値 (水分、比容積、安息角）を以下に示す 安息角（° ) 40. 0° ；比容積 (ルーズ） 1. 80mL/g；比容積 (タップ） 1. 34mL/g； [0089] Test analysis values (moisture, specific volume, angle of repose) of the mixture of each of the above ingredients are as follows: angle of repose (°) 40.0 °; specific volume (loose) 1. 80mL / g; specific volume (Tap) 1. 34mL / g;
Carrの指数（％) 34. 61 ;水分（％) 0. 8 Carr's index (%) 34. 61; moisture (%) 0.8
[0090] 結果として、得られた混合物の流動性が不良であって、打錠効率が低下した。 [0090] As a result, the flowability of the obtained mixture was poor, and the tableting efficiency was lowered.
[0091] 以上の各表に示した結果からも判明するように、本発明の直打速崩壊性錠剤は、 良好な硬度を持つ一方、 口腔内での崩壊性に優れていることが理解させる。 [0091] As can be seen from the results shown in the above tables, it is understood that the direct hit disintegrating tablet of the present invention has a good hardness while being excellent in disintegration in the oral cavity. .
なお、上記実施例は有効成分として酒石酸ゾルピデム又はメロキシカムを使用した 具体例を示したが、他の有効成分であっても、同様に直打速崩壊性錠剤が製造でき ることはいうまでもない。  In addition, although the said Example showed the specific example which used zolpidem tartrate or meloxicam as an active ingredient, even if it is another active ingredient, it cannot be overemphasized that a direct hit disintegrating tablet can be manufactured similarly. .
産業上の利用可能性  Industrial applicability
[0092] 以上記載のように、本発明により、速崩壊性を維持しつつ、実用的な錠剤の硬度を 有する乾式直打速崩壊性錠剤、特に酒石酸ゾルピデム又はメロキシカム含有の直打 速崩壊性錠剤が提供され、その溶出挙動も良好なものであることから、医療上の価 値は多大なものである。 [0092] As described above, according to the present invention, a dry-type direct-disintegrating tablet having practical tablet hardness while maintaining rapid disintegration, particularly a direct-disintegrating tablet containing zolpidem tartrate or meloxicam. And its elution behavior is also good. The value is enormous.

Claims

請求の範囲 The scope of the claims
[1] エリスリトール、キシリトール、マン-トール、乳糖、ショ糖からなる群力も選ばれる一 種以上の矯味剤と、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、カルメ ロースカリウム力 なる群力 選ばれる一種以上の結合剤の粉体を混合し、還元麦芽 糖水ァメの水溶液を噴霧して得た造粒物を用いることを特徴とする乾式直打速崩壊 性錠剤。  [1] One or more flavoring agents selected from the group strength consisting of erythritol, xylitol, mannitol, lactose, and sucrose, and one or more flavoring agents selected from crystalline cellulose, crystalline cellulose 'carmellose sodium, and carmellose potassium strength A dry-type quick-disintegrating tablet characterized by using a granulated product obtained by mixing powder of a binder and spraying an aqueous solution of a reduced maltose sugar solution.
[2] 造粒を流動層造粒機により行うものである請求項 1に記載の乾式直打速崩壊性錠 剤。  [2] The dry direct hit fast disintegrating tablet according to claim 1, wherein the granulation is performed by a fluidized bed granulator.
[3] 請求項 1又は 2に記載の造粒物と、有効成分、賦形剤、崩壊剤、流動化剤及び滑 沢剤を混合し、得られた混合物を直接打錠することを特徴とする乾式直打速崩壊性 錠剤。  [3] The granulated product according to claim 1 or 2 is mixed with an active ingredient, an excipient, a disintegrant, a fluidizing agent, and a lubricant, and the obtained mixture is directly compressed into tablets. Dry direct hit speed disintegrating tablets.
[4] 有効成分が酒石酸ゾルピデム又はメロキシカムである請求項 1、 2又は 3に記載の 乾式直打速崩壊性錠剤。  [4] The dry direct-disintegrating tablet according to claim 1, 2 or 3, wherein the active ingredient is zolpidem tartrate or meloxicam.
[5] エリスリトール、キシリトール、マン-トール、乳糖、ショ糖からなる群力も選ばれる一 種以上の矯味剤と、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、カルメ ロースカリウム力 なる群力 選ばれる一種以上の結合剤の粉体を混合し、還元麦芽 糖水ァメの水溶液を噴霧しながら流動層造粒機を用いて造粒することにより得られる 造粒物と、有効成分、賦形剤、崩壊剤、流動化剤及び滑沢剤を混合し、得られた混 合物を直接打錠することを特徴とする乾式直打速崩壊性錠剤の製造方法。  [5] One or more taste-masking agents selected from the group strength consisting of erythritol, xylitol, mannitol, lactose, and sucrose, and one or more types selected from the group strength consisting of crystalline cellulose, crystalline cellulose 'carmellose sodium, and carmellose potassium A granulated product obtained by mixing a powder of a binder and granulating with a fluidized bed granulator while spraying an aqueous solution of reduced malt sugar solution, active ingredient, excipient, disintegrant A method for producing a dry-type direct-disintegrating tablet, which comprises mixing a fluidizing agent and a lubricant and directly compressing the resulting mixture.
[6] 有効成分が酒石酸ゾルピデム又はメロキシカムである請求項 5に記載の乾式直打 速崩壊性錠剤の製造方法。  [6] The method for producing a dry direct-disintegrating tablet according to claim 5, wherein the active ingredient is zolpidem tartrate or meloxicam.
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