Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
  • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
  • A61J3/10—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • 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
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

• the present invention relates to tablets that disintegrate rapidly in the oral cavity.
• Pharmaceuticals o Oral dosage forms include, for example, tablets, capsules, granules, powders, and syrups.
• tablets and capsules are difficult to swallow for the elderly and children who have poor swallowing power.
• Granules and powders may cause discomfort in the mouth after ingestion and may enter the respiratory tract or lungs as a powder, and may not be taken in places without water because they require water when taken .
• Syrups are tedious to weigh when taken, and elderly and children cannot expect accurate weighing.
• a solid molded product that dissolves or disintegrates quickly in the oral cavity can be easily taken by elderly people and children without the need for weighing. The solid molded product can be taken without water.
• Japanese Patent Publication No. Sho 62-504445 describes a solid preparation obtained by freeze-drying an aqueous solution containing gelatin as a main component containing an active ingredient.
• 93/12767 describes a solid preparation obtained by drying a suspension containing agar.
• these formulations have low solids strength, are difficult to push out of PTP (Press Through Pack) packaging, require special formulation technology, require enormous capital investment, etc. There is a problem.
• Japanese Patent Application Laid-Open No. 5-271504 or WO 93/15724 discloses a tablet which is prepared by giving a mixture containing creatures an appropriate amount of water, compressing the mixture under low pressure, and then drying. Preparation methods are described. However, this method also requires special formulation technology, and powder may adhere to the molding die surface when compressed in a wet state, making it difficult to apply it to industrial production.
• the present inventors have studied an orally rapidly disintegrating tablet that can be easily and easily prepared with general equipment without requiring a special preparation technique. As a result, the average particle diameter is 30 m or less.
• a mixture containing a sugar alcohol or sugar such as D-mannitol or lactose as a main component and containing an active ingredient and a disintegrant it was considered difficult to prepare with a conventional compression molding machine 1 minute It was found that a rapidly disintegrating buccal tablet which disintegrated in the oral cavity within a short time and had practically no problem in hardness was obtained.
• the present invention relates to a tablet containing a sugar alcohol or saccharide having an average particle diameter of 30 or less, an active ingredient, and a disintegrant.
• the present invention also relates to a method for producing a tablet, which comprises compression-molding a mixture containing a sugar alcohol or saccharide having an average particle diameter of 30 jum or less, an active ingredient and a disintegrant.
• Sugar alcohols include those commonly used in pharmaceuticals and foods, for example, D-mannitol and sorbitol, and sugars include those commonly used in pharmaceuticals and foods, such as lactose and glucose. In each case, one kind of sugar alcohol or sugar is used.
• Examples of the active ingredient include those described below, but are not particularly limited as long as it is intended for oral administration.
• Antiepileptic drugs sodium balfurate, nitrazebam, phenytoin, etc.
• Analgesic and antipyretic anti-inflammatory drugs aspirin, acetaminophen, ibuprofen, diclofenac sodium, ethenzamide, indomethacin, etc.
• Anti-Parkinson agent Lepodopa, Amandin hydrochloride, Trihexihexyl hydrochloride, Pyroheptin hydrochloride, etc.
• Psychiatry agents Etizolam, amitriptyline hydrochloride, sulpiride, etc.
• Peripheral nervous system drugs >
• Skeletal muscle relaxants chlorphenesin carbamate, chlormezanone, etc.
• Autonomic nervous agents ballet bromide, tofisoham, etc.
• Antispasmodic agent Afroqualol, etc.
• Cardiotonic agent ubide force renone, aminophylline, ethifurin hydrochloride, etc.
• Arrhythmic agent atenolol, vindolol, etc.
• Diuretics spirolactone, trichlormethiazide, furosemide, etc.
• Antihypertensives todolalazine hydrochloride, dicardipine hydrochloride, hydralazine hydrochloride, etc.
• Vasoconstrictors dihydroergotamine mesilate, etc.
• Vasodilators Benidipine hydrochloride, diltiazem hydrochloride, isosorbide dinitrate, etc.
• Agents for hyperlipidemia Clinofibrate, Nicomol, etc.
• drugs for respiratory organs such as f / lenarizine hydrochloride, meclofenoxate hydrochloride, cinnarizine, etc.>
• Stopper and agent hydrochloric acid mouth peramide, dimethicone, etc.
• Peptic acne preparations azulene, L-glutamine, aseglutamido aluminum, setraxax hydrochloride, cimetidine, etc.
• Bile stimulant Anetholt Lichon, Chenodeoxycholic acid, etc.
• Dombellidone tritimbutine maleate, metoclofuramide, cysupride, etc.
• Vitamins alfacalcidol, thiamine hydrochloride, cobamide, vitaloxin, riboflavin citrate, ascorbic acid, phytonadione, etc.
• Antidiabetic agent daribazole, tributamide, etc.
• Antihistamines homochlorcyclidine hydrochloride, clemastine fumarate, chlorpheniramine maleate, etc.
• Antimetabolites Fluorouracil, decafur, etc.
• Disintegrants are commonly used in pharmaceuticals and foods, for example, croshovidone, cloth Carme-mouth sodium, low-substituted hydroxyx mouth hill cellulose, etc.
• At least one disintegrant is used.
• the tablet of the present invention can be obtained by granulating a mixture containing a sugar alcohol or saccharide having an average particle diameter of 30 m or less, an active ingredient, and a disintegrant using a hammer mill, a jet mill or the like, followed by granulation, followed by compression molding.
• the tablet of the present invention can be prepared by using a hammer mill, a dit mill or the like in the presence of a readily disintegrating disintegration agent to prepare a sugar alcohol or sugar having an average particle size of 30 jum or less, or an active ingredient.
• the mixture can also be obtained by granulating a mixture containing a disintegrant and a disintegrant, followed by compression molding, and then volatilizing the disintegrant.
• the amount of sugar alcohol or saccharide used is preferably 60 to 95%, more preferably 80 to 95% in the tablet.
• the amount of the active ingredient to be used varies depending on the kind of the active ingredient, the dose and the like, but is preferably 0.01 to 30%, more preferably 0.01 to 10% in the tablet.
• the disintegrant is preferably used in an amount of 1 to 3 Omg per dose, and preferably 1 to 10% in the tablet.
• disintegration aid examples include sublimable kampuma, urethane, urea, ammonium bicarbonate, and benzoic acid, with kampuma being particularly preferred.
• the amount of the disintegration aid that easily volatilizes is preferably 1 to 20%, more preferably 1 to 10% in the tablet.
• the granulation method wet granulation using purified water, ethanol, or the like is preferable.
• the granulation is performed using a general fluidized bed granulator, a tumbling stirring granulator, an extrusion granulator, or the like.
• a lubricant is added, mixed and compression molded.
• a binder, an acidulant, a foaming agent, a sweetener, a flavor, a coloring agent, and the like can be added as additives.
• Lubricants include magnesium stearate, stearate, stearyl alcohol, sucrose fatty acid ester, talc, light caffeic anhydride, etc., and binders such as hydroxypropyl pill cellulose, polyvinylpyrrolid Don, hydroxypropyl propyl methylcellulose, partially saponified polyvinyl alcohol, methylcellulose, flurane, etc. Scorbic acid and the like, and foaming agents include sodium hydrogen carbonate, sodium carbonate, calcium carbonate, and the like.
• Sweeteners include asharthame (registered trademark), saccharin, and glycyrrhizin. Flavors include lemon, orange, hine, mint, menthol, etc., and coloring agents include yellow iron trioxide, red iron sesquioxide, tar pigments, etc. .
• the tablet it is preferably 0.01 to 1%, more preferably 0.01 to 0.5%.
• the compression molding method is not particularly limited, but it is preferable to use a rotary tableting machine, an oil pressure breathing machine, or a single-shot tableting machine with excellent productivity.
• a rotary tableting machine When easily disintegrating disintegration aids are used, they are dried by heating or the like after compression molding.
• the lubricant can be applied to the punch and die of the tableting machine in advance without adding the lubricant to the granulated material, and then compression-molded, whereby the effect of the present invention is further enhanced.
• the compression molding pressure is preferably at least 300 kg when a single-tally tableting machine is used.
• the shape of the tablet obtained in the present invention may be a round tablet or various modified tablets having a surface shape such as a normal R surface, a sugar-coated R surface, a sumikaku plane, a sumimaru plane, a two-step R surface, and the like.
• the tablet may be used as a divided tablet with a score line.
• D-mannitol Towa Kasei: average particle size: about 60 urn
• crospovidone Polybrasdon XL-10: GAF
• 100 g were fluidized-bed granulator / dryer (Grat) , WSG-5 type), and sprayed with purified water to obtain granules through granulation and drying processes.
• the mixture After adding 10 g of magnesium stearate to the granulated product and mixing, the mixture was compression-molded using a one-tally type tableting machine (Clean Brescolect Model 12, manufactured by Kikusui Seisakusho).
• the molding conditions were as follows: tablet weight: 200 mg, mold: 8 mm flat, and compression molding pressure: 150, 300, 450, 600, and 800 kg. It was compressed.
• Example 1 Example 1
• D-mannitol (Towa Chemical Co., Ltd .: average particle size of about 60) is ground beforehand using a jet mill (PJM-1_5 type, manufactured by Nippon Pneumatic Co., Ltd.), and the average particle size is about 20 m.
• D-mannitol was obtained, and 189 g of this crushed D-mannitol and 100 g of cross bovidone (Boliplus Don XL-10: GAF) were added to a flow-bed granulator / dryer (Dallas).
• the mixture was charged into a granulated product (WS G-5 type, manufactured by Utosha Co., Ltd.), sprayed with purified water, and subjected to granulation and drying processes to obtain a granulated product.
• Compression molding was carried out using a one-piece tablet press (Kikusui Seisakusho, Clean Press Cocto 12 type), under the same molding conditions as in Comparative Example 1.
• the mixture was charged into a granulation dryer (Daratt, WSG-5), sprayed with purified water, and subjected to granulation and drying processes to obtain granules. After adding and mixing 10 g of magnesium stearate to the granulated product, the mixture was compression-molded using a rotary tableting machine (Kikusui Seisakusho, Clean 7 Resect 12 type). The molding conditions were the same as in Comparative Example 1.
• Lactose (DMV: average particle size: about 80 m) is ground beforehand using a jet mill (Pneumatic PJ M-1: Nippon Type 5) to reduce the average particle size to about
• Example 2 Using the granules obtained in Example 1, extremely small amounts of magnesium stearate were added to a mold (8 mm diameter flat mold) and a die of a hydraulic press machine (manufactured by Riken Seiki Co., Ltd., P-1B type). Small amount application Then, a tablet was obtained with a tablet weight of 20 Omg and a compression molding pressure of 50 kg / cm.
• Example 2 140 g of ground D-mannitol used in Example 1, 140 g of Dombellidone i, 0 g of crospovidone (Polyplasdone XL-10: GAF) and 40 g of camphor-40 g in a plastic bag After mixing, the tablet weight is set to 20 Omg and the mold to a diameter of 9 mm. Tablets were obtained at 1500 kg / cm 2 . The tablets were dried in a vacuum dryer at 80 ° C. under vacuum for 10 minutes. Next, the tablet hardness and disintegration time of the tablet of the present invention will be described with reference to test examples. Test example
• Tablet hardness and disintegration time of the tablets obtained in Examples 1 and 2 and Comparative Examples 1 and 2 were measured.
• the tablet hardness was measured using a tablet breaking strength measuring device (manufactured by Toyama Sangyo: TH-203 CP type).
• the tablet disintegration time was measured by placing the tablet on a No. 10 wire mesh, dropping water at a rate of 4 m1Z from the top, and measuring the time until the tablet passed through the wire mesh. Was taken as the disintegration time.
• Table 1 shows the evaluation results.
• Example 3 For each of the tablets obtained in Examples 3 and 4, tablet hardness and disintegration time were measured in the same manner as described above. As a result, the tablet obtained in Example 3 had a disintegration time of about 10 seconds while retaining sufficient hardness of about 6.5 kgf. In addition, the tablet obtained in Example 4 had a hardness of about 4 kgf and a very fast disintegration time in the oral cavity of about 2 seconds.
• a tablet that disintegrates rapidly in the oral cavity is provided.

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Cited By (37)

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• 1997
  • 1997-06-12 DK DK97927372T patent/DK0914818T3/da active
  • 1997-06-12 WO PCT/JP1997/002032 patent/WO1997047287A1/ja not_active Ceased
  • 1997-06-12 PT PT97927372T patent/PT914818E/pt unknown
  • 1997-06-12 US US09/147,374 patent/US20010014340A1/en not_active Abandoned
  • 1997-06-12 AT AT97927372T patent/ATE297191T1/de active
  • 1997-06-12 EA EA199900028A patent/EA001898B1/ru not_active IP Right Cessation
  • 1997-06-12 AU AU31895/97A patent/AU733032C/en not_active Expired
  • 1997-06-12 CA CA002258159A patent/CA2258159C/en not_active Expired - Lifetime
  • 1997-06-12 EP EP97927372A patent/EP0914818B1/en not_active Revoked
  • 1997-06-12 DE DE69739967T patent/DE69739967D1/de not_active Expired - Lifetime
  • 1997-06-12 JP JP50144898A patent/JP3797387B2/ja not_active Expired - Lifetime
  • 1997-06-12 CN CNB971955204A patent/CN1154479C/zh not_active Expired - Lifetime
  • 1997-06-12 EP EP05012137A patent/EP1598061B1/en not_active Expired - Lifetime
  • 1997-06-12 ES ES97927372T patent/ES2243998T3/es not_active Expired - Lifetime
  • 1997-06-12 DE DE69733476T patent/DE69733476T2/de not_active Expired - Lifetime
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• 2005
  • 2005-09-16 JP JP2005269822A patent/JP2006077018A/ja active Pending
• 2009
  • 2009-07-31 JP JP2009179843A patent/JP2009256372A/ja active Pending
• 2012
  • 2012-04-23 JP JP2012097573A patent/JP5484514B2/ja not_active Expired - Lifetime

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