WO2007119792A1 - Comprimé à délitement rapide obtenu par compression directe à sec - Google Patents

Comprimé à délitement rapide obtenu par compression directe à sec 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
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WIPO (PCT)
Prior art keywords
disintegrating tablet
hydrochloride
active ingredient
dry
crystalline cellulose
Prior art date
Application number
PCT/JP2007/058095
Other languages
English (en)
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/zh
Priority to KR1020087027556A priority patent/KR101400064B1/ko
Priority to JP2008510987A priority patent/JP5215172B2/ja
Publication of WO2007119792A1 publication Critical patent/WO2007119792A1/fr

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    • 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

L'invention a pour objet un procédé permettant de produire un comprimé à délitement rapide souhaité avec un bon rendement de compression indépendamment de la nature de l'ingrédient actif qu'il doit contenir ou de la nature d'autres ingrédients à ajouter, et un comprimé à délitement rapide obtenu par le procédé de production, lequel est un comprimé à délitement rapide obtenu par compression directe à sec obtenu par la compression directe d'un mélange obtenu en mélangeant : une matière granulée obtenue en mélangeant un ou plusieurs adjuvants sélectionnés dans le groupe constitué de l'érythritol, du xylitol, du mannitol, du lactose et du sucrose et une ou plusieurs poudres de liant sélectionnées dans le groupe constitué de la cellulose cristalline, et de la carmellose sodique et de la carmellose potassique de la cellulose cristalline puis en granulant le mélange en utilisant un granulateur à lit fluidisé tout en pulvérisant une solution aqueuse de sirop de maltose réduit ; un ingrédient actif ; un excipient ; un délitant ; un fluidifiant ; et un lubrifiant, et en particulier un comprimé à délitement rapide obtenu par compression directe à sec contenant du tartrate de zolpidem ou du méloxicam.
PCT/JP2007/058095 2006-04-13 2007-04-12 Comprimé à délitement rapide obtenu par compression directe à sec WO2007119792A1 (fr)

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JP2009256349A (ja) * 2008-03-28 2009-11-05 Kowa Co 錠剤
WO2010061846A1 (fr) * 2008-11-25 2010-06-03 田辺三菱製薬株式会社 Comprimé à délitement oral rapide, et procédé pour produire celui-ci
JP2010143836A (ja) * 2008-12-16 2010-07-01 Nichi-Iko Pharmaceutical Co Ltd 口腔内崩壊錠用組成物
KR20150003740A (ko) * 2012-04-24 2015-01-09 다이이찌 산쿄 가부시키가이샤 구강내 붕괴정 및 그 제조 방법
JP2015515984A (ja) * 2012-04-30 2015-06-04 ヴェロサイエンス，リミテッド・ライアビリティー・カンパニー ブロモクリプチン製剤

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CN101618026B (zh) * 2009-07-06 2011-03-16 江苏飞马药业有限公司 美洛昔康片及其生产工艺和用途
CN101869236A (zh) * 2010-06-09 2010-10-27 山东福田药业有限公司 可直接压片的木糖醇颗粒及其制备方法
KR101226271B1 (ko) 2011-01-14 2013-01-25 에스케이하이닉스 주식회사 안티퓨즈를 이용한 프로그래밍회로
CN103202817B (zh) * 2013-04-28 2014-10-08 山东天力药业有限公司 一种可直压性甘露醇颗粒的制备方法
CN103494821B (zh) * 2013-10-01 2018-09-25 迪沙药业集团有限公司 一种头孢克肟组合物

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JP2000016930A (ja) * 1998-04-27 2000-01-18 Taisho Pharmaceut Co Ltd 口腔内速崩錠及びその製造方法
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JP2009256349A (ja) * 2008-03-28 2009-11-05 Kowa Co 錠剤
WO2010061846A1 (fr) * 2008-11-25 2010-06-03 田辺三菱製薬株式会社 Comprimé à délitement oral rapide, et procédé pour produire celui-ci
JP2010143836A (ja) * 2008-12-16 2010-07-01 Nichi-Iko Pharmaceutical Co Ltd 口腔内崩壊錠用組成物
JP2017008112A (ja) * 2012-04-24 2017-01-12 第一三共株式会社 口腔内崩壊錠及びその製造方法
KR20150003740A (ko) * 2012-04-24 2015-01-09 다이이찌 산쿄 가부시키가이샤 구강내 붕괴정 및 그 제조 방법
JP2018058910A (ja) * 2012-04-24 2018-04-12 第一三共株式会社 口腔内崩壊錠及びその製造方法
KR101943686B1 (ko) 2012-04-24 2019-01-29 다이이찌 산쿄 가부시키가이샤 구강내 붕괴정 및 그 제조 방법
JP2015515984A (ja) * 2012-04-30 2015-06-04 ヴェロサイエンス，リミテッド・ライアビリティー・カンパニー ブロモクリプチン製剤
US9522117B2 (en) 2012-04-30 2016-12-20 Veroscience Llc Bromocriptine formulations
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US11000522B2 (en) 2012-04-30 2021-05-11 Veroscience Llc Bromocriptine formulations
US11666567B2 (en) 2012-04-30 2023-06-06 Veroscience Llc Bromocriptine formulations

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CN101420982A (zh) 2009-04-29
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