WO2007018057A1 - Tablet rapidly disintegrating in the oral cavity and method of producing the same - Google Patents

Tablet rapidly disintegrating in the oral cavity and method of producing the same Download PDF

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Publication number
WO2007018057A1
WO2007018057A1 PCT/JP2006/315004 JP2006315004W WO2007018057A1 WO 2007018057 A1 WO2007018057 A1 WO 2007018057A1 JP 2006315004 W JP2006315004 W JP 2006315004W WO 2007018057 A1 WO2007018057 A1 WO 2007018057A1
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WIPO (PCT)
Prior art keywords
cellulose
crystalline cellulose
granulated product
powdered
mann
Prior art date
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PCT/JP2006/315004
Other languages
French (fr)
Japanese (ja)
Inventor
Fujio Sekigawa
Takeshi Honma
Masayuki Arakawa
Original Assignee
Freund Corporation
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Publication of WO2007018057A1 publication Critical patent/WO2007018057A1/en

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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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • 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

Definitions

  • the present invention relates to an orally rapidly disintegrating tablet and a method for producing the same.
  • an orally disintegrating solid preparation obtained by suspending an active ingredient and saccharides, which are also lactose and mantolka, in an agar aqueous solution, filling in a bowl shape, solidifying in a jelly form, and drying.
  • an active ingredient and saccharides which are also lactose and mantolka
  • Zydis (trade name) is an orally disintegrating tablet developed by R. P. Scherer (UK) and marketed mainly in Europe and America. This is said to be obtained by dispersing the active ingredient, gelatin, mantle, sweetener, fragrance, etc. in water and injecting them into a PTP blister bowl, followed by vacuum lyophilization. .
  • the molded products of (1) and (2) are rich in porosity and can be rapidly disintegrated.
  • the hardness is insufficient, and cracking, chipping, etc. are likely to occur during manufacturing, transportation and storage.
  • problems such as complicated manufacturing processes and the need for special formulation technology.
  • Patent Document 2 discloses an intraoral-dissolvable tablet obtained by compressing a mixture containing a medicinal ingredient and a saccharide after adding moisture to the tablet and drying it.
  • the tablet (3) may be improved in terms of hardness.
  • Patent Document 3 compares D-mannitol having an average particle diameter of about 60 m with that obtained by pulverizing it to obtain an average particle diameter of about 20 m. As a result, the former is extremely low in terms of tablet hardness. On the other hand, the latter is described as sufficient. However, D-mann-toll has a problem that the ground ring surface is inferior due to powdering and fluidity deterioration when pulverized.
  • Patent Document 4 discloses an intraoral rapidly disintegrating tablet obtained by compression molding a mixture in the range of 6.5.
  • the tablet of (5) has a relatively high content of crystalline cellulose in the mixture of sugar alcohol and crystalline cellulose of 35 to 50% by mass, so that it feels like a powdery texture derived from crystalline cellulose when taken. There is a problem to be concerned about.
  • Patent Document 5 describes a rapidly disintegrating solid preparation containing an active ingredient, sugar or sugar alcohol having an average particle size of 30 to 300 ⁇ m, a disintegrant and celluloses.
  • Patent Document 2 Japanese Patent Application Laid-Open No. 5-271054
  • Patent Document 3 International Publication No. 97Z47287 Pamphlet
  • Patent Document 4 Japanese Patent Laid-Open No. 11-199517
  • Patent Document 5 Japanese Patent Laid-Open No. 2001-58944
  • an object of the present invention is to provide a crystal cell that has a hardness that can withstand breakage during production, transportation, storage, etc., has a refreshing taste, and is rapidly disintegrated in the oral cavity.
  • the mouth feels like it contains paper or powdered cellulose.
  • Orally fast disintegrating tablets with a unique powdery texture; and such oral disintegrating tablets can be easily used with ordinary equipment and formulation technology without the need for special equipment or formulation technology.
  • Another object is to provide a production method that can be obtained at low cost.
  • the intraoral quick disintegrating tablet of the present invention comprises D-mann-tol granulated product, crystalline cellulose or powdered cellulose, and an active ingredient, and does not contain a disintegrating agent.
  • a disintegrating agent -The mass ratio of Mann-Tall granule to crystalline cellulose or powdered cellulose (D-Mantle granulated product: crystalline cellulose or powdered cellulose) is characterized by 95: 5 to 70:30
  • D-Mantle granulated product crystalline cellulose or powdered cellulose
  • the intraoral quick disintegrating tablet of the present invention contains D-mann-toll granulated product, crystalline cellulose granulated product or powdered cellulose granulated product, and active ingredient, and does not contain a disintegrant.
  • Mass ratio of D-mann-toll granule and crystalline cellulose granule or powder cell granule is 95: 5 to 70:30.
  • the rapidly disintegrating tablet in the oral cavity of the present invention contains D-mannitol, crystalline cellulose and Z or powdered cellulose, and an active ingredient, and does not contain a disintegrant.
  • D-mannitol crystalline cellulose or powdered cellulose
  • the mass ratio of tall to crystalline cellulose or powdered cellulose is 95: 5 to 70:30. Is characterized by being contained as a granulated product containing these components as constituents.
  • the method for producing an orally rapidly disintegrating tablet of the present invention comprises a D-mann-tol granulated product, crystalline cellulose or powdered cellulose, and an active ingredient, and the D-mann-toll granulated product
  • a mixture of 95: 5-70: 30 by weight ratio (D-mann-toll granulated product: crystalline cellulose or powdered cellulose) to crystalline cellulose or powdered cellulose is directly compressed by the powder compression method It is characterized by that.
  • crystalline cellulose or powder cellulose powder is granulated to form a granulated product, and the crystalline cellulose granulated product or powdered cellulose granulated product is mixed into the mixture. May be included.
  • the method for producing an orally rapidly disintegrating tablet of the present invention comprises D-mannthol, crystalline cellulose or powdered cellulose, and an active ingredient, and does not contain a disintegrant,
  • the mass ratio of D-mann-tol to crystalline cellulose or powdered cellulose is 95: 5-70: 30, Cellulose is characterized in that a mixture obtained by adding these components as a granulated product is compression-molded by a direct powder compression method.
  • the rapidly disintegrating tablet in the oral cavity of the present invention has a hardness that can withstand breakage during production, transportation, storage, etc., and has a refreshing taste despite being rapidly disintegrated in the oral cavity. The feeling of touching the powder is suppressed.
  • an intraoral rapidly disintegrating tablet of the present invention has a hardness capable of withstanding breakage during production, transportation, storage, etc., despite being rapidly disintegrated in the oral cavity.
  • Oral quick disintegrating tablets with a refreshing taste and a reduced powdery texture, without special equipment and pharmaceutical technology, can be obtained easily and at low cost using ordinary equipment and pharmaceutical technology This comes out.
  • the intraorally rapidly disintegrating tablet of the present invention contains D-mann-tol granulated product and crystalline cellulose or powdered cellulose in a specific ratio as additive components other than the active component, and does not contain a disintegrant. It is characterized by that.
  • the intraoral quick disintegrating tablet of the present invention contains, as an additive component other than the active ingredient, D-mannitol tall granule and crystalline cellulose granulated product or powdered cellulose granulated product in a specific ratio. It is characterized by not containing disintegrants.
  • the intraoral quick disintegrating tablet of the present invention contains D-mannitol and an additive component other than the active ingredient in a specific ratio, and the above-mentioned D-manntol and crystalline cellulose or powdered cellulose are included as a granulated product containing these components as components, and do not contain disintegrants! It is.
  • Tablet additives usually include excipients, binders, disintegrants, etc., and are defined as follows.
  • Excipients provide a certain size and mass when the amount of the drug (active ingredient) is low and are not suitable for tableting, or to increase the average mass of the tablet to some extent and reduce the mass deviation. It is an additive used for.
  • the binder is an additive used to give a binding force to the mixture of the component powders (tablet powder) and facilitate compression molding.
  • a disintegrant is an additive that imparts disintegration to a tablet in water or gastrointestinal fluid.
  • D-Mann-Tall granules are granulated powdered D-Mann-Tol and are classified as “excipients” described above.
  • powdered D-mann-tol as a granulated product, the fluidity required for tableting is ensured when it is used as an excipient in the direct powder compression method described later, and the “binding agent” described later. Both the hardness and disintegration of the rapidly disintegrating tablet in the oral cavity can be improved without increasing the content of crystalline cellulose, powdered cellulose, or a granulated product thereof.
  • Powdered D-mann-toll (for example, used in Patent Document 4), which is an ungranulated product, is remarkably inferior in fluidity and has a low bonding strength.
  • crystalline cellulose is used to secure the fluidity necessary for tableting in the direct powder compression method described below, and to maintain the hardness and disintegration property of the orally rapidly disintegrating tablet.
  • the content of powdered cellulose or their granulated materials must be increased, resulting in a powdery texture.
  • the volume average particle diameter of the D-mann-toll granulated product is preferably 50 to 300 ⁇ m, more preferably 60 to 200 m. If the volume average particle size is less than 50 m, the fluidity is low, which may make it unsuitable for the direct powder compression method described later. When the volume average particle diameter exceeds 300 m, the disintegration time of the orally rapidly disintegrating tablet tends to be longer. In addition, it may be difficult to ensure the uniformity of the content of the rapidly disintegrating tablet in the oral cavity.
  • the volume average particle size, particle size distribution, etc. of the D-mann-toll granulated product may be controlled by the conditions in granulation and sieving operations.
  • the granulated D-mannthol is obtained by granulating commercially available powdered D-mannthol; granulated D-mannthol marketed directly for tableting, etc. Is mentioned.
  • Examples of commercially available powdered D-mannitol include Toman Kasei Kogyo Co., Ltd., trade names “Mannit! 3 ”, “Mannit S”, ROQUETTE, trade names “PEARITOL25”, “PE ARLITOL35J,” PEARLITOL60 "etc. are mentioned.
  • Examples of commercially available granular D-manntol include trade names “PEARLITOL100SD”, “PEARLITOL200SD”, “PEARLTOL300DC”, etc., manufactured by ROQUETTE. Many commercially available granular D-manntols are produced by spray drying.
  • D-mannitol granule obtained by applying wet granulation method such as fluidized bed granulation method, stirring granulation method, centrifugal rolling granulation method, or centrifugal rolling fluidized bed granulation method O
  • wet granulation method such as fluidized bed granulation method, stirring granulation method, centrifugal rolling granulation method, or centrifugal rolling fluidized bed granulation method O
  • the method for producing the D-mann-toll granulated product is disclosed in JP-A-2001-10979 (Patent No. 3491 887).
  • the D-mann-toll granulated product is produced as follows.
  • D-mannitol In the case of fluidized bed granulation, powdered D-mannitol is charged into a fluidized bed granulation coating device (for example, product name “Flow Coater” manufactured by Freund Sangyo Co., Ltd.) and fluidized air is supplied into the container. Then, D-mann-toll granulated product can be obtained by spraying D-mann-toll aqueous solution to the powdery D-mann-toll while floating.
  • a fluidized bed granulation coating device for example, product name “Flow Coater” manufactured by Freund Sangyo Co., Ltd.
  • a rolling coating apparatus provided with a rotating disk having a ventilation portion
  • a composite granulation coating device for example, Freund Industrial Co., Ltd., trade name "Spilar Flow”
  • a rotating disk having a ventilation part and an automatic A centrifugal tumbling granulation coating device equipped with an ascending / descending dryer for example, Freund Sangyo Co., Ltd., trade name “Darullex”
  • an ascending / descending dryer for example, Freund Sangyo Co., Ltd., trade name “Darullex”
  • D-mannitol granules can be obtained by spraying D-mannitol aqueous solution to the powdery D-mannitol while the powdered D-mannitol is centrifugally tumbling and flowing by the centrifugal force of rotation and supplied dry air.
  • the granulation is followed by drying in the same apparatus.
  • the apparatus used since the apparatus used usually does not have a drying mechanism, the wet granulated product obtained after the granulation operation is transferred to a fluidized bed dryer or a shelf. It is necessary to dry with a dryer or the like.
  • the dried granulated product is adjusted to a target particle size through a sieving step.
  • an alcohol such as ethanol may be added to the D-manntol aqueous solution.
  • D the higher the alcohol concentration in the aqueous mannitol solution, the more likely granulation proceeds.
  • the solubility of D-Manthol in water is about 18g at 20 ° C and about 25g at 30 ° C for low lOOg of water compared to other sugars. Therefore, the concentration of D mannitol in D mannitol aqueous solution is about 15% by mass at 20 ° C. Granulation is possible even with a 15% by mass aqueous solution of 0 mannitol. From the standpoint of efficient granulation, the aqueous solution of D mannitol is preferably as high as possible. In order to increase the solubility of D-mannthol, the aqueous solution may be heated to near the boiling point if necessary. When heated to near the boiling point, the concentration of D-manntol aqueous solution can be increased to about 40% by mass.
  • the amount of the D-mannitol aqueous solution is determined according to the target particle diameter of the D-mannitol tall product.
  • the amount of D-mannitol aqueous solution varies depending on the conditions to be applied, but from the viewpoint of achieving the effects of the present invention, the amount of powdered D-mannitol is 100 parts by mass.
  • the solid content is preferably 5 to 50 parts by mass. If the aqueous solution of D-mannitol (solid content) is less than 5 parts by mass with respect to 100 parts by mass of D-mannitol, the hardness of the rapidly disintegrating tablet in the oral cavity where the moldability of D-mannitol granules is insufficient There is a fear.
  • Crystalline cellulose, powdered cellulose, and granulated products thereof are classified as the above-mentioned “binder”.
  • crystalline cellulose, powdered cellulose, and their granulated products also exhibit a disintegrating function when used in combination with D-mann-toll granulated products.
  • Crystalline cellulose is a white crystalline powder having fluidity, which is obtained by partially depolymerizing and purifying ⁇ -cellulose obtained as fibrous vegetable strength pulp with an acid.
  • Examples of the crystalline cellulose include those manufactured by Asahi Kasei Chemicals Corporation, trade names “Ceras ⁇ 101”, “Ceras ⁇ —102”, “Ceras ⁇ —301”, “Ceras ⁇ —302”, “Ceras ⁇ —F20JP”. Etc.
  • Powdered cellulose is a cellulose obtained as a fibrous vegetable strength pulp, which is treated by partial hydrolysis, etc., if necessary, purified and mechanically pulverized, and is a white powder. is there.
  • powdered cellulose examples include Nippon Paper Chemicals Co., Ltd., trade names "KC Flock W-100", “KC Flock W-200”, “KC Flock W-300”, “KC Flock W-400", etc. Can be mentioned.
  • Crystalline cellulose or powdered cellulose has low fluidity! In the case of the crystalline cellulose or powdered cellulose, the fluidity is insufficient even in the tableting powder (mixture for tableting), and the mass, hardness, disintegration, etc. Variations in properties may be large. In order to improve the fluidity, it is preferable to use crystalline cellulose or powdered cellulose having a low fluidity as a granulated product.
  • crystalline cellulose or powdered cellulose is hardly soluble in water, when it contains a rapidly disintegrating tablet in the oral cavity, it is roughened by force after being disintegrated by the oral disintegrating tablet. There may be a feeling. Therefore, as crystalline cellulose or powdered cellulose, commercially available crystalline cellulose or powdered cellulose, which may be a fine powder type commercial product, is further pulverized to improve fineness. May be used. Note that finely crystalline crystalline cellulose or powdered cellulose has low fluidity, and thus may be granulated and granulated to improve fluidity.
  • the crystalline cellulose granulated product or the powdered cellulose granulated product is obtained by pulverizing the crystalline cellulose or the powdered cellulose as necessary to obtain a fine powder, and then the crystalline cellulose, the powdered cellulose granule, or a product thereof. It is obtained by granulating a fine powder.
  • Examples of the method for pulverizing crystalline cellulose or powdered cellulose include a method using a high-speed rotary mill, a jet mill and the like.
  • a dry granulation method or a wet granulation method can be employed.
  • the crystalline cellulose granulated product or the powdered cellulose granulated product can be easily dispersed in the oral cavity so as not to have a rough feeling after disintegration of the intraoral quick disintegrating tablet.
  • a dry granulation method is preferred.
  • additives such as a lubricant and a fluidizing agent are mixed with the powder to be granulated, and the resulting mixture is mixed with a roll-type high-pressure compression molding machine.
  • a roll-type high-pressure compression molding machine for example, it is roll compression molded by Freund Sangyo Co., Ltd., trade name “Roller Compactor 1”, etc., to form a high-density plate-like molded product (hereinafter sometimes referred to as “flakes”).
  • the flakes are passed through a multi-stage roll crusher and various granulators and, if necessary, screened to obtain a more appropriate particle size distribution. Examples thereof include magnesium, calcium stearate, sucrose fatty acid ester, and hardened oil, and they are usually used in an amount of 5% by mass or less in the granulated powder.
  • granulation may be performed by a fluidized bed granulation method, a stirring granulation method, a spray drying granulation method, a crushing granulation method, or the like.
  • the granulation operation may be carried out by adding a liquid binder such as starch paste or hydroxypropylcellulose.
  • a liquid binder is added to form a soft lump of an appropriate size with a granulator, crushing with a crushing granulator, and then drying with a dryer. Things are obtained.
  • the volume average particle diameter of the crystalline cellulose granulated product or the powdered cellulose granulated product is preferably 30 to 300 ⁇ m, more preferably 50 to 200 ⁇ m.
  • the volume average particle size is less than 30 ⁇ m, the fluidity is low, and there is a possibility that it is not suitable for the direct powder compression method described later. If the volume average particle diameter exceeds 300 m, it may be difficult to ensure the uniformity of the content of the rapidly disintegrating tablet in the oral cavity.
  • D Mannitol crystalline cellulose or powdered cellulose granulated product is granulated using the powdered materials of each of these ingredients as raw materials. It has a function as a combined excipient.
  • the powdered materials of these components are used as raw materials.
  • Apply wet granulation methods such as fluidized bed granulation method, stirring granulation method, centrifugal tumbling granulation method, or centrifugal tumbling fluidized bed granulation method with the operation of adding D-mannitol aqueous solution.
  • the granulated product obtained by is preferred.
  • the operation method is basically the same as that for obtaining the D-mann-toggle granule described above, but any granulation method is applied from the viewpoint of shortening the disintegration time of the rapidly disintegrating tablet in the oral cavity.
  • the D-mannthol powder is first charged and the D-mannitol solution is added. It is desirable to continue the granulation with additional charging. This is due to the fact that in D-mannitol crystalline cellulose or powdered cellulose granulate, D-mannitol is present as a granulated product consisting of its components (D-mannitol) in a uniform mixture. It is considered effective to shorten the time.
  • the amount of D-mantitol aqueous solution is powdery D—Adds 5 to 50% by mass of solid to 100 parts by mass It is preferable to be at the point of time.
  • D-mannitol granule and crystalline cellulose or powdered cellulose can be used as components other than the active ingredient.
  • the mass ratio of D-mannitol component to crystalline cellulose or powdered cellulose component is 95: 5 to 70:30, 85 : 15-70: 30 is preferable.
  • the specific force of the crystalline cellulose or the powdered cellulose component is less than 5% by mass, the hardness of the orally rapidly disintegrating tablet becomes insufficient.
  • the ratio of the crystalline cellulose or powder cell mouth ingredient exceeds 30% by mass, a powdery touch feeling due to the crystalline cellulose or powdered cellulose occurs at the time of taking.
  • disintegrants generally include starch, carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like.
  • crystalline cellulose or powdered cellulose is used as a granulated product in a powdered state or by granulation, or in combination with D-manntol granulated product, or the crystalline cellulose or powdered cellulose is used as D-mantitol.
  • crystalline cellulose or powdered cellulose is used as a granulated product in a powdered state or by granulation, or in combination with D-manntol granulated product, or the crystalline cellulose or powdered cellulose is used as D-mantitol.
  • the active ingredient may be any active ingredient that can be administered orally.
  • active ingredient for example, hypnotic sedatives, antipyretic analgesics, antipsychotic agents, autonomic agents, antiparkinson agents, antihistamines, cardiotonics, diuretics , Antihypertensive agent, vasoconstrictor, arteriosclerotic agent, antitussive expectorant, vitamin Drugs, nourishing tonics, antibiotics, gastrointestinal drugs and the like.
  • lactose lactose, starch, or a mixture of lactose and starch as the excipient, and use it as a trituration by mixing evenly into the excipients. May be.
  • additives necessary for the purpose of concealing an unpleasant taste such as bitterness derived from the active ingredient, entericizing, sustained release, etc. are added, and a known method is applied. Then, the mixture may be granulated and then coated by a known method.
  • the intraoral quick disintegrating tablet of the present invention may contain a fluidizing agent, a lubricant, a flavoring agent, a sweetening agent, a corrigent, a coloring agent, etc., which are used for ordinary tablets, if necessary.
  • the fluidizing agent light anhydrous caustic acid or the like is used for the purpose of ensuring good fluidity in the tableting mixture or improving the hardness of the intraoral quick disintegrating tablet.
  • the amount of the fluidizing agent is preferably 0.1 to 0.5% by mass in the tableting mixture (100% by mass).
  • the lubricant examples include magnesium stearate, calcium stearate, sucrose fatty acid ester, and hardened oil.
  • the amount of the lubricant is preferably 5% by mass or less in the intraoral rapidly disintegrating tablet (100% by mass).
  • the method for producing an orally rapidly disintegrating tablet is roughly classified into a direct powder compression method and a granule compression method.
  • the direct powder compression method is a method in which a pharmaceutical product (active ingredient) and an additive are mixed and directly compressed into tablets with a tableting machine.
  • the granule compression method is a method in which a pharmaceutical product (active ingredient) is mixed as it is or with the required additives added and mixed evenly into granules by an appropriate method, followed by compression with a lubricant and the like. is there.
  • the granule compression method is usually applied.
  • the rapidly disintegrating tablet in the buccal cavity of the present invention is a force in which D-mannitol and crystalline cellulose or powdered cellulose are used as essential components other than the active component. And including as crystalline cellulose or powdered cellulose, 2) D-mann-toll granule and crystalline cellulose granulated product or powdered cellulose granulated product, and 3) D-mantitol, granulated cellulose or powdered cellulose
  • the active ingredient may be mixed as a mixture with components other than the active ingredient using a tableting machine such as a rotary tableting machine or a single tableting machine by a known direct powder compression method. It is manufactured by doing.
  • Tableting compression load is usually 4 to 15 kN per punch
  • Appropriate pressure is the mass per orally disintegrating tablet, type of active ingredient, addition Depending on the amount, etc., if the pressure is less than 4 kN, the hardness of the orally rapidly disintegrating tablet may decrease, which may hinder handling. If the pressure exceeds 15 kN, the disintegration time of the orally rapidly disintegrating tablet will be reduced. Tends to be longer.
  • the intraoral rapidly disintegrating tablet of the present invention may be further coated by a known method.
  • the intraoral quick disintegrating tablet of the present invention can be taken without an uncomfortable feeling such as softening and disintegrating rapidly in the oral cavity, and feeling of touching the tongue even when it is taken without using water. is there.
  • the disintegration time of the orally rapidly disintegrating tablet of the present invention is preferably 30 seconds or less when operated without using an auxiliary board in the disintegration test method of the Japanese Pharmacopoeia and the operation method for tablets. 20 seconds The following is more preferable.
  • the tablet hardness of the rapidly disintegrating tablet in the oral cavity of the present invention depends on the size of the tablet and cannot be defined unconditionally, but it is preferably about 30 to 150 N as measured by a tablet hardness meter.
  • the intraoral rapidly disintegrating tablet of the present invention contains D-mannitol and crystalline cellulose or powdered cellulose as essential components, and the D-mannitol is used as a granulated product. Or it is used in the form of a constituent of the granulate, but it disintegrates rapidly in the oral cavity even though it does not contain a disintegrant. This is considered to be due to the fact that the disintegrating function is exhibited when used in combination with crystalline cellulose or powdered cellulose strength D-mann-toll granule. Crystalline cellulose or powdered cellulose is used as a binder, and is usually used in the hope of functioning as a disintegrant. I can't.
  • p. 146 of the same book explains the crystalline cellulose and includes the following. “On the other hand, this substance has high water absorption and quick introduction of water into the tablet. Also, the substance is weak in action as a disintegrant with little swelling by water. Mix this with a drug in water. Once granulated and dried, the granulate is no longer dispersed in water and its amount must be limited for use in wet granulation. "
  • the reason why crystalline cellulose or powdered cellulose contributes to fast disintegration is not clear.
  • crystalline cellulose or powdered cellulose enters the rapidly disintegrating tablet in oral cavity with high water absorption. Because of the rapid introduction of water, it can be considered that it acts as a disintegration aid in connection with some properties of D-mantle granules.
  • the rapidly disintegrating tablet in the oral cavity according to the present invention it is considered that the fact that the normal disintegrant does not show the effect of promoting disintegration is also related to some property of the D-mann-tol granulate. .
  • crystalline cellulose or powdered cellulose exhibits binding properties and contributes to increasing the hardness of the intraoral rapidly disintegrating tablet.
  • the hardness of an orally rapidly disintegrating tablet is further increased.
  • D-mann-toll granule when used alone as an additive, an intraoral rapidly disintegrating tablet having sufficient hardness and disintegration cannot be obtained, but crystalline cellulose or Can be used in a specific mass ratio with powdered cellulose to obtain an orally rapidly disintegrating tablet satisfying these properties.
  • the intraorally rapidly disintegrating tablet of the present invention includes a D-mann-tol granulated product obtained by granulating powdered D-manntol which is not powdery D-manntol. Therefore, even if the content of crystalline cellulose or powdered cellulose is suppressed, the hardness and disintegration satisfying the practicality of an orally rapidly disintegrating tablet are ensured. Therefore, it is possible to increase the content of D-mann-toll with a refreshing and powerful taste, and to suppress the content of crystal cell mouth or powdered cellulose that gives a powdery texture. Therefore, it becomes a quick disintegrating tablet in the oral cavity with a refreshing taste and a reduced powdery texture.
  • differences in the production method of intraoral rapidly disintegrating tablets may affect the difference in the content of crystalline cellulose or powdered cellulose. That is, while the production method of the present invention is a direct powder compression method, in Patent Document 4, the granule compression method is mainly used, and it is considered that crystalline cellulose is changed by wet granulation.
  • Powdered D-manthol (ROQUETTE, trade name “PEARLITOL35”) 1. 5 kg was dissolved in 4.5 kg of 50 ° C. warm water to prepare D-manthol aqueous solution.
  • Powdered D-Manthol (ROQUETTE, trade name “PEARLITOL35”) 5 kg was charged into a centrifugal tumbling granulation coating device (Freund Sangyo Co., Ltd., trade name “Darullex GX-40”). D Mannitol aqueous solution was sprayed and granulated by centrifugal tumbling fluidized bed granulation method to obtain D Manntor granulated product. The granulated material was sieved using a 150 m sieve. As a result of measuring the volume average particle diameter using a laser diffraction particle size distribution analyzer (trade name “Microtrac particle size analyzer” manufactured by Nikkiso Co., Ltd.), the result is 95 ⁇ m.
  • a laser diffraction particle size distribution analyzer trade name “Microtrac particle size analyzer” manufactured by Nikkiso Co., Ltd.
  • Tableting machine Rotary tableting machine, HT-P15A-III type (Hatatake Works).
  • Dosage form Round tablet with 8mm diameter, Mass: 200mgZl tablet.
  • Tablet hardness was measured by a tablet hardness meter (Freund Industrial Co., Ltd. under the trade name "S C hleuniger hardness tester 6D").
  • Comparative Example 1 has a high content of crystalline cellulose, it was almost satisfactory in terms of tablet hardness and disintegration, but a clear powdery feeling was felt in the dosing test.
  • Comparative Example 2 since the disintegrant was added, the disintegration time was long, which was unsatisfactory as an orally fast disintegrating tablet.
  • the active ingredient was changed to thiamine hydrochloride (vitamin), a tableting mixture was prepared according to the formulation in Table 2, and tableting was performed in the same manner as in Example 1 except that the mass per tablet was 180 mg. An intraoral rapidly disintegrating tablet was obtained.
  • thiamine hydrochloride vitamin
  • the obtained intraoral quick disintegrating tablet was evaluated in the same manner as in Example 1.
  • Table 2 shows the evaluation results.
  • the intraorally rapidly disintegrating tablets of Examples 3 and 4 exhibited desirable properties as intraoral rapidly disintegrating tablets.
  • the fast-disintegrating tablet in the oral cavity of Comparative Example 3 using carmellose calcium which is known as a disintegrant, has a very low tablet hardness and a long disintegration time. It was unsatisfactory as an intraoral quick disintegrating tablet.
  • Powdered D-mannitol (manufactured by Towa Kasei Kogyo Co., Ltd., trade name “Mannit P”) 5 kg is charged into a fluidized bed granulation coating device (Freund Sangyo Co., Ltd., trade name “Flow Coater FLO-5”). Then, granulation was carried out by spraying the whole amount of an aqueous solution of D-Manetol to obtain a D-Mannitol granulated product. The granulated material was sieved using a 125 ⁇ m sieve. The volume average particle diameter was 85 ⁇ m.
  • Example 2 An intraoral rapidly disintegrating tablet was obtained in the same manner as in Example 1 except that this D-mann-tol granulate was used.
  • the tablet hardness was 65 N, the disintegration time was 13 seconds, and in the dose test almost no discomfort was observed.
  • Powdered D—Mann-Tall (manufactured by Towa Kasei Kogyo Co., Ltd., trade name “Mannit P”) 3 kg is stirred into a granulator (Fukae Kogyo Co., Ltd., trade name “High Speed Mixer FS-25”). Then, 3 kg of 20 mass 0 / oD-mantitol aqueous solution heated to 50 ° C was added thereto, stirring granulation was performed while rotating the agitator and chopper, and after completion, the granulated product was taken out.
  • a granulator Frukae Kogyo Co., Ltd., trade name “High Speed Mixer FS-25”.
  • the obtained wet granulated product was dried with the fluidized bed granulation coating apparatus of Example 5, and after drying, it was sieved using a 355 m sieve to obtain a D-mann-toll granulated product having a volume average particle size of 195 ⁇ m. Obtained.
  • D—Man-tall granulated product manufactured by ROQUETTE, which is said to be spray-dried, trade name “PEARLITOL 200SD” (average particle size 163 ⁇ m) 77.2 parts by mass, crystalline cellulose, 19.3 parts by mass ( D-Mann-Tall granulate and crystalline cellulose mass ratio 80:20), chlorophenol-lamin maleate 3.0 parts by weight, magnesium stearate 0.5 parts by weight were prepared to prepare a mixture for tableting Then, tableting was performed under the same conditions as in Example 1 to obtain an intraorally rapidly disintegrating tablet. Tablet hardness is 81N and disintegration time is 23 seconds. There was hardly any sense of incongruity.
  • the crystalline cellulose of Example 1 (volume average particle size: 57 m) was pulverized using a jet mill (trade name “TJ60 turbo counter jet mill” manufactured by Freund Industrial Co., Ltd.), and the volume average particle size of 13 A fine powder of ⁇ m was obtained.
  • the angle of repose of the raw material crystalline cellulose was 46 degrees, whereas the angle of repose of fine powder was 60 degrees or more (difficult to measure accurately), and the fluidity decreased.
  • 0.5 g of magnesium stearate was added to lOOg of fine powder and shaken and mixed in a polyethylene bag to obtain a raw material powder.
  • the raw powder is compression-molded at a pressure of lOMPa, and the resulting flakes are screened. And then sieved using a 355 m sieve to obtain a crystalline cellulose granulated product having a volume average particle diameter of 105 m.
  • the repose angle of the crystalline cellulose granule was 42 degrees, and the fluidity was remarkably improved.
  • Example 2 in Table 1 a tableting mixture was prepared in the same manner as in Example 2 except that a crystalline cellulose granulated material was used instead of the crystalline cellulose, and a direct powder compression method was used. Tableting was performed under the following conditions to obtain an orally rapidly disintegrating tablet.
  • Tablet press Single-type tablet press, FY—SS-7 (Fuji Pharmaceutical Machinery Co., Ltd.).
  • Dosage form Flat tablet with a diameter of 10mm, Mass: 300mgZl tablet.
  • Example 9 The obtained intraorally rapidly disintegrating tablets were evaluated.
  • the tablet hardness was 92N, the disintegration time was 15 seconds, and it was almost uncomfortable in the dose test.
  • a feeling of roughness on the tongue was evaluated separately from the evaluation of powderiness. As a result, the feeling of roughness was strong at a level where both became a minor problem.
  • the properties of the orally rapidly disintegrating tablet were further improved in Example 9 by using a crystalline cellulose granulated product that was less rough than in Example 2.
  • Fine grade powdered cellulose manufactured by Nippon Paper Chemicals Co., Ltd., trade name “KC Flock” W-400GJ, volume average particle size: 26 ⁇ m
  • light anhydrous caustic anhydride Fraund Sangyo Co., Ltd., trade name “Ad Solitor 101”
  • 10 Tokuju Seisakusho Co., Ltd. was mixed at 40 rpm for 2 minutes, then 5 g of magnesium stearate was added and mixed for 5 minutes to obtain a raw material powder.
  • the raw powder is compacted at a pressure of 8 MPa by roll compression using the brand name “Roller Compactor TF-mini” manufactured by Freund Sangyo Co., Ltd., and the resulting flakes are coarsely pulverized with a granulator equipped with a screen.
  • the product size was adjusted with Freund Sangyo Co., Ltd., “Rolldara-Yureta”, and sieved using a 355 ⁇ m sieve to obtain a powdered cellulose granulated product with a volume average particle size of 95 m .
  • the angle of repose of the raw material powdered cellulose was 60 degrees or more, while the angle of repose of the powdered cellulose granule was 42 degrees, and the fluidity was remarkably improved.
  • Powdered D-manthol (ROQUETTE, trade name “PEARLITOL50C”) 2.5 kg was dissolved in 7.5 kg of 50 ° C. warm water to prepare a D-mannthol aqueous solution.
  • Powdered D-Mann-Tall (ROQUETTE, trade name “PEARLITOL50C”) 3.1 kg was charged into the centrifugal tumbling granulation coating apparatus of Example 1, and D-Mann-Tol aqueous solution 5. Okg was sprayed on it.
  • the remaining D-manntol aqueous solution (5 kg) was sprayed with a granulation operation to obtain a D-manntol crystal cellulose granulated product having a volume average particle diameter of 84 ⁇ m.
  • the tablet hardness was 65N and the disintegration time was 19 seconds.
  • the rapidly disintegrating tablet in the oral cavity of the present invention disintegrates rapidly in the oral cavity and has a refreshing taste as a main additive component, and therefore has a property that it is easy to take, and many active ingredients It is useful as a preparation for oral administration.
  • the number of manufacturing processes and the management of raw materials can be reduced, and no special equipment is required. It is possible to manufacture with

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Abstract

A tablet rapidly disintegrating in the oral cavity which can be obtained easily at a low cost and has a hardness enough to withstand breaks during production, transportation, storage and the like while disintegrating rapidly in the oral cavity, and has a refreshing taste and a reduced powdery texture and a method of producing the same are provided. This tablet disintegrating in the oral cavity contains a D-mannitol granulated substance, crystalline cellulose or powdered cellulose and an active ingredient and does not contain a disintegrator and the mass ratio of the D-mannitol granulated substance to the crystalline cellulose or powdered cellulose (D-mannitol granulated substance : crystalline cellulose or powdered cellulose) is 95:5 to 70:30.

Description

明 細 書  Specification
口腔内速崩壊錠およびその製造法  Intraoral rapidly disintegrating tablet and method for producing the same
技術分野  Technical field
[0001] 本発明は、口腔内速崩壊錠およびその製造法に関する。  [0001] The present invention relates to an orally rapidly disintegrating tablet and a method for producing the same.
本願は、 2005年 8月 5日に、日本に出願された特願 2005— 227634号に基づき 優先権を主張し、その内容をここに援用する。  This application claims priority based on Japanese Patent Application No. 2005-227634 filed in Japan on August 5, 2005, the contents of which are incorporated herein by reference.
背景技術  Background art
[0002] ヒトは加齢と共に燕下力が低下し、通常の錠剤では服用に困難を来すことが少なく ない。このため近年、服用が容易な、口腔内で速やかに崩壊する口腔内速崩壊錠の 研究が盛んに行われ、実際に多くの製品が市販されている。  [0002] As humans age, their armpit power decreases, and regular tablets often make it difficult to take. For this reason, in recent years, researches have been actively conducted on rapidly disintegrating tablets in the oral cavity that are easy to take and rapidly disintegrate in the oral cavity, and many products are actually on the market.
例えば、（1)活性成分と乳糖およびマン-トールカもなる糖類とを、寒天水溶液に 懸濁し、铸型に充填し、ゼリー状に固化した後、乾燥させて得られる口腔内崩壊性の 固形製剤が、特許文献 1に記載されている。  For example, (1) an orally disintegrating solid preparation obtained by suspending an active ingredient and saccharides, which are also lactose and mantolka, in an agar aqueous solution, filling in a bowl shape, solidifying in a jelly form, and drying. Is described in Patent Document 1.
[0003] また、（2)R. P. Scherer社 (イギリス）により開発され、欧米を中心に市販されてい る口腔内崩壊錠に「Zydis (商品名）」がある。これは、主薬と、ゼラチンと、マン-トー ルと、甘味剤、香料等とを水に分散させ、 PTPブリスターの铸型に注入した後、真空 凍結乾燥して得られるものであると 、われる。 [0003] Further, (2) “Zydis (trade name)” is an orally disintegrating tablet developed by R. P. Scherer (UK) and marketed mainly in Europe and America. This is said to be obtained by dispersing the active ingredient, gelatin, mantle, sweetener, fragrance, etc. in water and injecting them into a PTP blister bowl, followed by vacuum lyophilization. .
(1)、（2)の成型物は、多孔性に富み、急速な崩壊性が得られる。しかし、硬度が不 足し、製造時、輸送時、保存時等に割れ、カケ等が発生しやすい。また、製造工程が 煩雑であり、特殊な製剤技術を要する等の問題がある。  The molded products of (1) and (2) are rich in porosity and can be rapidly disintegrated. However, the hardness is insufficient, and cracking, chipping, etc. are likely to occur during manufacturing, transportation and storage. In addition, there are problems such as complicated manufacturing processes and the need for special formulation technology.
[0004] (3)薬効成分と糖類とを含む混合物を、水分を含ませて打錠した後、乾燥して得ら れる口腔内溶解型錠剤が、特許文献 2に記載されている。 [0004] (3) Patent Document 2 discloses an intraoral-dissolvable tablet obtained by compressing a mixture containing a medicinal ingredient and a saccharide after adding moisture to the tablet and drying it.
(3)の錠剤は、硬度の点で改善される可能性がある。しかし、糖類を含む混合物に 水分を均一に含ませる、障害を伴うことなく打錠を行う等の点で特殊な製剤技術を必 要とする問題がある。  The tablet (3) may be improved in terms of hardness. However, there are problems that require special formulation technology in terms of uniformly containing water in a mixture containing saccharides and performing tableting without any obstacles.
[0005] (4)平均粒子径 30 μ m以下の糖アルコールまたは糖類、活性成分および崩壊剤 を組み合わせ、この混合物を造粒した後、圧縮成形して得られる口腔内速崩壊錠が 、特許文献 3に記載されている。 [0005] (4) An intraoral rapidly disintegrating tablet obtained by combining a sugar alcohol or saccharide having an average particle size of 30 μm or less, an active ingredient and a disintegrant, granulating the mixture, and then compression-molding the mixture. Patent Document 3 describes.
特許文献 3には、平均粒子径約 60 mの D—マンニトールと、これを粉砕して平均 粒子径を約 20 mとしたものとを比較した結果、錠剤硬度の点では、前者は著しく低 いのに対して、後者は充分であることが記載されている。し力し、 D—マン-トールは 、微粉砕することにより、粉立ち、流動性低下といったノヽンドリング面が劣る問題があ る。  Patent Document 3 compares D-mannitol having an average particle diameter of about 60 m with that obtained by pulverizing it to obtain an average particle diameter of about 20 m. As a result, the former is extremely low in terms of tablet hardness. On the other hand, the latter is described as sufficient. However, D-mann-toll has a problem that the ground ring surface is inferior due to powdering and fluidity deterioration when pulverized.
[0006] (5)薬物と、結晶セルロースと、糖アルコールとを含有し、崩壊剤を含まな!/、もので あって、結晶セルロースと糖アルコールとの質量比を 5 : 5〜3. 5 : 6. 5の範囲で混合 したものを圧縮成形して得られた口腔内速崩壊性錠剤が、特許文献 4に記載されて いる。  [0006] (5) Contains a drug, crystalline cellulose, and sugar alcohol, and does not include a disintegrant! /, And the mass ratio of crystalline cellulose to sugar alcohol is 5: 5 to 3.5. : Patent Document 4 discloses an intraoral rapidly disintegrating tablet obtained by compression molding a mixture in the range of 6.5.
(5)の錠剤は、糖アルコールと結晶セルロースとの混合物中の結晶セルロースの含 有量が 35〜50質量％と比較的多いことから、服用時の結晶セルロースに由来する 粉っぽい舌触り感が気になる問題がある。  The tablet of (5) has a relatively high content of crystalline cellulose in the mixture of sugar alcohol and crystalline cellulose of 35 to 50% by mass, so that it feels like a powdery texture derived from crystalline cellulose when taken. There is a problem to be worried about.
[0007] (6)活性成分、平均粒子径が 30〜300 μ mの糖または糖アルコール、崩壊剤およ びセルロース類を含有する速崩壊性固形製剤が、特許文献 5に記載されている。  [0007] (6) Patent Document 5 describes a rapidly disintegrating solid preparation containing an active ingredient, sugar or sugar alcohol having an average particle size of 30 to 300 μm, a disintegrant and celluloses.
(6)の固形製剤は、（5)の錠剤に比べ、崩壊剤の成分をさらに加える必要があるこ とから、製造における各成分の管理、ハンドリング等の点で煩雑さが増す問題がある 特許文献 1：特許第 2807346号公報  Compared with the tablet of (5), the solid preparation of (6) requires the addition of a disintegrant component, which has the problem of increasing complexity in terms of management and handling of each component in the manufacturing process. 1: Japanese Patent No. 2807346
特許文献 2：特開平 5 - 271054号公報  Patent Document 2: Japanese Patent Application Laid-Open No. 5-271054
特許文献 3：国際公開第 97Z47287号パンフレット  Patent Document 3: International Publication No. 97Z47287 Pamphlet
特許文献 4:特開平 11— 199517号公報  Patent Document 4: Japanese Patent Laid-Open No. 11-199517
特許文献 5：特開 2001— 58944号公報  Patent Document 5: Japanese Patent Laid-Open No. 2001-58944
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
[0008] よって、本発明の目的は、口腔内で速やかに崩壊するにも関わらず、製造時、輸送 時、保存時等において破損に耐え得る硬度を有し、味質がさわやかで、結晶セル口 ースまたは粉末セルロースを直接口に含んだときに感じられる、紙を口に含んだよう な特異な粉っぽい舌触り感が抑えられた口腔内速崩壊錠;およびこのような口腔内 速崩壊錠を、特殊な設備、製剤技術を必要とせず、通常の設備、製剤技術によって 容易に、かつ低コストで得ることができる製造法を提供することにある。 Accordingly, an object of the present invention is to provide a crystal cell that has a hardness that can withstand breakage during production, transportation, storage, etc., has a refreshing taste, and is rapidly disintegrated in the oral cavity. The mouth feels like it contains paper or powdered cellulose. Orally fast disintegrating tablets with a unique powdery texture; and such oral disintegrating tablets can be easily used with ordinary equipment and formulation technology without the need for special equipment or formulation technology. Another object is to provide a production method that can be obtained at low cost.
課題を解決するための手段  Means for solving the problem
[0009] 本発明の口腔内速崩壊錠は、 D—マン-トール造粒物と、結晶セルロースまたは粉 末セルロースと、活性成分とを含有し、崩壊剤を含まないものであって、前記 D—マ ン-トール造粒物と結晶セルロースまたは粉末セルロースとの質量比（D—マン-ト 一ル造粒物：結晶セルロースまたは粉末セルロース）が 95： 5〜70： 30であることを特 徴とする。  [0009] The intraoral quick disintegrating tablet of the present invention comprises D-mann-tol granulated product, crystalline cellulose or powdered cellulose, and an active ingredient, and does not contain a disintegrating agent. -The mass ratio of Mann-Tall granule to crystalline cellulose or powdered cellulose (D-Mantle granulated product: crystalline cellulose or powdered cellulose) is characterized by 95: 5 to 70:30 And
本発明の口腔内速崩壊錠は、 D—マン-トール造粒物と、結晶セルロース造粒物 または粉末セルロース造粒物と、活性成分とを含有し、崩壊剤を含まないものであつ て、前記 D—マン-トール造粒物と結晶セルロース造粒物または粉末セル口ース造 粒物との質量比（D—マン-トール造粒物：結晶セルロース造粒物または粉末セル口 一ス造粒物）が 95： 5〜70： 30であることを特徴とする。  The intraoral quick disintegrating tablet of the present invention contains D-mann-toll granulated product, crystalline cellulose granulated product or powdered cellulose granulated product, and active ingredient, and does not contain a disintegrant. Mass ratio of D-mann-toll granule and crystalline cellulose granule or powder cell granule (D-man-tol granule: crystalline cellulose granule or powder cell granule (Granule) is 95: 5 to 70:30.
[0010] 本発明の口腔内速崩壊錠は、 D—マン-トールと、結晶セルロースおよび Zまたは 粉末セルロースと、活性成分とを含有し、崩壊剤を含まないものであって、前記 D— マン-トールと結晶セルロースまたは粉末セルロースとの質量比（D—マン-トール： 結晶セルロースまたは粉末セルロース）が 95： 5〜70： 30であり、前記 D—マン-トー ルと、結晶セルロースまたは粉末セルロースは、これら成分を構成成分とする造粒物 として含まれることを特徴とする。  [0010] The rapidly disintegrating tablet in the oral cavity of the present invention contains D-mannitol, crystalline cellulose and Z or powdered cellulose, and an active ingredient, and does not contain a disintegrant. -The mass ratio of tall to crystalline cellulose or powdered cellulose (D-mann-toll: crystalline cellulose or powdered cellulose) is 95: 5 to 70:30. Is characterized by being contained as a granulated product containing these components as constituents.
[0011] 本発明の口腔内速崩壊錠の製造法は、 D—マン-トール造粒物と、結晶セルロー スまたは粉末セルロースと、活性成分とを含有し、前記 D—マン-トール造粒物と結 晶セルロースまたは粉末セルロースとの質量比（D—マン-トール造粒物：結晶セル ロースまたは粉末セルロース）が 95： 5〜70： 30である混合物を、直接粉末圧縮法に より圧縮成形することを特徴とする。  [0011] The method for producing an orally rapidly disintegrating tablet of the present invention comprises a D-mann-tol granulated product, crystalline cellulose or powdered cellulose, and an active ingredient, and the D-mann-toll granulated product A mixture of 95: 5-70: 30 by weight ratio (D-mann-toll granulated product: crystalline cellulose or powdered cellulose) to crystalline cellulose or powdered cellulose is directly compressed by the powder compression method It is characterized by that.
本発明の口腔内速崩壊錠の製造法においては、結晶セルロースまたは粉末セル口 ースをあら力じめ造粒して造粒物とし、結晶セルロース造粒物または粉末セルロース 造粒物を混合物に含ませてもよ ヽ。 [0012] 本発明の口腔内速崩壊錠の製造法は、 D—マン-トールと、結晶セルロースまたは 粉末セルロースと、活性成分とを含有し、崩壊剤を含まないものであって、前記 D— マン-トールと結晶セルロースまたは粉末セルロースとの質量比（D—マン-トール： 結晶セルロースまたは粉末セルロース）が 95： 5〜70： 30であり、前記 D—マン-トー ルと、結晶セルロースまたは粉末セルロースは、これら成分を構成成分とする造粒物 として加えて得られる混合物を、直接粉末圧縮法により圧縮成形することを特徴とす る。 In the method for producing an orally rapidly disintegrating tablet according to the present invention, crystalline cellulose or powder cellulose powder is granulated to form a granulated product, and the crystalline cellulose granulated product or powdered cellulose granulated product is mixed into the mixture. May be included. [0012] The method for producing an orally rapidly disintegrating tablet of the present invention comprises D-mannthol, crystalline cellulose or powdered cellulose, and an active ingredient, and does not contain a disintegrant, The mass ratio of D-mann-tol to crystalline cellulose or powdered cellulose (D-mann-tol: crystalline cellulose or powdered cellulose) is 95: 5-70: 30, Cellulose is characterized in that a mixture obtained by adding these components as a granulated product is compression-molded by a direct powder compression method.
発明の効果  The invention's effect
[0013] 本発明の口腔内速崩壊錠は、口腔内で速やかに崩壊するにも関わらず、製造時、 輸送時、保存時等において破損に耐え得る硬度を有し、かつ味質がさわやかで、粉 つぽ 、舌触り感が抑えられて 、る。  [0013] The rapidly disintegrating tablet in the oral cavity of the present invention has a hardness that can withstand breakage during production, transportation, storage, etc., and has a refreshing taste despite being rapidly disintegrated in the oral cavity. The feeling of touching the powder is suppressed.
[0014] また、本発明の口腔内速崩壊錠の製造法によれば、口腔内で速やかに崩壊するに も関わらず、製造時、輸送時、保存時等において破損に耐え得る硬度を有し、味質 がさわやかで、粉っぽい舌触り感が抑えられた口腔内速崩壊錠を、特殊な設備、製 剤技術を必要とせず、通常の設備、製剤技術によって容易に、かつ低コストで得るこ とがでさる。  [0014] In addition, according to the method for producing an intraoral rapidly disintegrating tablet of the present invention, it has a hardness capable of withstanding breakage during production, transportation, storage, etc., despite being rapidly disintegrated in the oral cavity. Oral quick disintegrating tablets with a refreshing taste and a reduced powdery texture, without special equipment and pharmaceutical technology, can be obtained easily and at low cost using ordinary equipment and pharmaceutical technology This comes out.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0015] <口腔内速崩壊錠 >  [0015] <Intraoral rapidly disintegrating tablet>
本発明の口腔内速崩壊錠は、活性成分以外の添加剤成分として、 D—マン-トー ル造粒物と、結晶セルロースまたは粉末セルロースとを特定の割合で含有すること、 崩壊剤を含まな ヽことを特徴とするものである。  The intraorally rapidly disintegrating tablet of the present invention contains D-mann-tol granulated product and crystalline cellulose or powdered cellulose in a specific ratio as additive components other than the active component, and does not contain a disintegrant. It is characterized by that.
また、本発明の口腔内速崩壊錠は、活性成分以外の添加剤成分として、 D—マン 二トール造粒物と、結晶セルロース造粒物または粉末セルロース造粒物とを特定の 割合で含有すること、崩壊剤を含まな ヽことを特徴とするものである。  Moreover, the intraoral quick disintegrating tablet of the present invention contains, as an additive component other than the active ingredient, D-mannitol tall granule and crystalline cellulose granulated product or powdered cellulose granulated product in a specific ratio. It is characterized by not containing disintegrants.
[0016] また、本発明の口腔内速崩壊錠は、活性成分以外の添加剤成分として、 D—マン 二トールと、結晶セルロースまたは粉末セルロースとを特定の割合で含有するもので あって、前記 D—マン-トールと、結晶セルロースまたは粉末セルロースは、これら成 分を構成成分とする造粒物として含まれること、崩壊剤を含まな!/ヽことを特徴とするも のである。 [0016] Further, the intraoral quick disintegrating tablet of the present invention contains D-mannitol and an additive component other than the active ingredient in a specific ratio, and the above-mentioned D-manntol and crystalline cellulose or powdered cellulose are included as a granulated product containing these components as components, and do not contain disintegrants! It is.
[0017] 錠剤の添加剤には、通常、賦形剤、結合剤、崩壊剤等があり、次のように定義され る。  [0017] Tablet additives usually include excipients, binders, disintegrants, etc., and are defined as follows.
賦形剤は、薬品 (活性成分)の量が少なくて打錠に適していない場合、一定の大き さおよび質量を与えるため、または、錠剤の平均質量をある程度大きくし、質量偏差 を小さくするために用いられる添加剤である。  Excipients provide a certain size and mass when the amount of the drug (active ingredient) is low and are not suitable for tableting, or to increase the average mass of the tablet to some extent and reduce the mass deviation. It is an additive used for.
結合剤は、成分粉末の混合物 (打錠末）に結合力を与え、圧縮成形を容易にする ために用いられる添加剤である。  The binder is an additive used to give a binding force to the mixture of the component powders (tablet powder) and facilitate compression molding.
崩壊剤は、水中または消化管液中で錠剤に崩壊性を与える添加剤である。  A disintegrant is an additive that imparts disintegration to a tablet in water or gastrointestinal fluid.
[0018] (D—マン-トール造粒物） [0018] (D—Mann-Tall granulate)
D—マン-トール造粒物は、粉末状 D—マン-トールを造粒したものであり、上述の 「賦形剤」に分類される。粉末状 D—マン-トールを造粒物とすることにより、後述の 直接粉末圧縮法における賦形剤として用いる場合に打錠末に必要な流動性が確保 され、かつ「結合剤」である後述の結晶セルロース、粉末セルロース、またはそれらの 造粒物の含有量を増やすことなぐ口腔内速崩壊錠の硬度および崩壊性のいずれも 向上する。未造粒物である粉末状 D—マン-トール (例えば、特許文献 4で用いられ たもの）は、流動性に著しく劣り、結合力も小さい。また粉末状 D—マン-トールを用 いた場合、後述の直接粉末圧縮法における打錠末に必要な流動性の確保、および 口腔内速崩壊錠の硬度および崩壊性の維持のために、結晶セルロース、粉末セル ロース、またはそれらの造粒物の含有量を増やさなければならず、粉っぽい舌触り感 が生じてしまう。  D-Mann-Tall granules are granulated powdered D-Mann-Tol and are classified as “excipients” described above. By using powdered D-mann-tol as a granulated product, the fluidity required for tableting is ensured when it is used as an excipient in the direct powder compression method described later, and the “binding agent” described later. Both the hardness and disintegration of the rapidly disintegrating tablet in the oral cavity can be improved without increasing the content of crystalline cellulose, powdered cellulose, or a granulated product thereof. Powdered D-mann-toll (for example, used in Patent Document 4), which is an ungranulated product, is remarkably inferior in fluidity and has a low bonding strength. In addition, when powdered D-manntol is used, crystalline cellulose is used to secure the fluidity necessary for tableting in the direct powder compression method described below, and to maintain the hardness and disintegration property of the orally rapidly disintegrating tablet. In addition, the content of powdered cellulose or their granulated materials must be increased, resulting in a powdery texture.
[0019] D—マン-トール造粒物の体積平均粒子径は、 50〜300 μ mが好ましぐ 60〜20 0 mがより好ましい。体積平均粒子径が 50 m未満では、流動性が低くなり、後述 の直接粉末圧縮法に適さなくなるおそれがある。体積平均粒子径が 300 mを超え ると、口腔内速崩壊錠の崩壊時間が長くなる傾向がある。また、口腔内速崩壊錠の 含量均一性の確保が困難になるおそれがある。 D—マン-トール造粒物の体積平均 粒子径、粒度分布等は、造粒およびふるい操作における条件によりコントロールすれ ばよい。 [0020] D—マン-トール造粒物としては、市販されている粉末状 D—マン-トールを造粒し たもの；直接打錠用に市販されている顆粒状の D—マン-トール等が挙げられる。 市販の粉末状 D—マンニトールとしては、例えば、東和化成工業 (株)製、商品名「 マンニット！3」、 「マンニット S」、ROQUETTE社製、商品名「PEARITOL25」、「PE ARLITOL35J、「PEARLITOL60」等が挙げられる。 [0019] The volume average particle diameter of the D-mann-toll granulated product is preferably 50 to 300 µm, more preferably 60 to 200 m. If the volume average particle size is less than 50 m, the fluidity is low, which may make it unsuitable for the direct powder compression method described later. When the volume average particle diameter exceeds 300 m, the disintegration time of the orally rapidly disintegrating tablet tends to be longer. In addition, it may be difficult to ensure the uniformity of the content of the rapidly disintegrating tablet in the oral cavity. The volume average particle size, particle size distribution, etc. of the D-mann-toll granulated product may be controlled by the conditions in granulation and sieving operations. [0020] The granulated D-mannthol is obtained by granulating commercially available powdered D-mannthol; granulated D-mannthol marketed directly for tableting, etc. Is mentioned. Examples of commercially available powdered D-mannitol include Toman Kasei Kogyo Co., Ltd., trade names “Mannit! 3 ”, “Mannit S”, ROQUETTE, trade names “PEARITOL25”, “PE ARLITOL35J,” PEARLITOL60 "etc. are mentioned.
市販の顆粒状の D—マン-トールとしては、例えば、 ROQUETTE社製、商品名「 PEARLITOL100SD」、「PEARLITOL200SD」、「PEARLTOL300DC」等が 挙げられる。市販の顆粒状の D—マン-トールは、スプレードライ法等により製造され ているものが多い。  Examples of commercially available granular D-manntol include trade names “PEARLITOL100SD”, “PEARLITOL200SD”, “PEARLTOL300DC”, etc., manufactured by ROQUETTE. Many commercially available granular D-manntols are produced by spray drying.
[0021] D—マン-トール造粒物としては、口腔内速崩壊錠がより速やかに崩壊するという 観点からは、粉末状 D—マン-トールに、 D—マン-トール水溶液をカ卩える操作を伴 う、流動層造粒法、撹拌造粒法、遠心転動造粒法、または遠心転動流動層造粒法な どの湿式造粒法を適用することによって得られる D—マンニトール造粒物が好ましい o前記 D—マン-トール造粒物の製造法は、特開 2001— 10979号公報（特許 3491 887号公報）に開示されている。  [0021] From the viewpoint that the intraoral rapidly disintegrating tablet disintegrates more rapidly as the D-mann-tol granulated product, an operation of covering the powdered D-mann-tol with an aqueous D-mann-toll solution. D-mannitol granule obtained by applying wet granulation method such as fluidized bed granulation method, stirring granulation method, centrifugal rolling granulation method, or centrifugal rolling fluidized bed granulation method O The method for producing the D-mann-toll granulated product is disclosed in JP-A-2001-10979 (Patent No. 3491 887).
[0022] D—マン-トール造粒物は、具体的には次のようにして製造される。  [0022] Specifically, the D-mann-toll granulated product is produced as follows.
流動層造粒法の場合、流動層造粒コーティング装置 (例えば、フロイント産業 (株） 製、商品名「フローコーター」）に粉末状 D—マン-トールを仕込み、容器内に流動空 気を供給し、粉末状 D—マン-トールを浮遊流動させながら、これに D—マン-トー ル水溶液をスプレーすることによって D—マン-トール造粒物が得られる。  In the case of fluidized bed granulation, powdered D-mannitol is charged into a fluidized bed granulation coating device (for example, product name “Flow Coater” manufactured by Freund Sangyo Co., Ltd.) and fluidized air is supplied into the container. Then, D-mann-toll granulated product can be obtained by spraying D-mann-toll aqueous solution to the powdery D-mann-toll while floating.
[0023] 撹拌造粒法の場合、撹拌造粒機 (例えば、深江工業 (株)製、商品名「ハイスピード ミキサー」）に粉末状 D—マン-トールを仕込み、容器内で撹拌しながら、これに D— マン-トール水溶液を滴下またはスプレーすることによって D—マン-トール造粒物 が得られる。  [0023] In the case of the stirring granulation method, powdered D-manntol is charged into an agitation granulator (for example, “High Speed Mixer” manufactured by Fukae Kogyo Co., Ltd.) and stirred in a container. A D-mannthol granule can be obtained by dripping or spraying an aqueous solution of D-mannthol.
[0024] 遠心転動造粒法の場合、通気部を有する回転円板を備えた転動コーティング装置  [0024] In the case of centrifugal rolling granulation, a rolling coating apparatus provided with a rotating disk having a ventilation portion
(例えば、フロイント産業 (株)製、商品名「CFダラ二ユレ一ター」）に粉末状 D—マンニ トールを仕込み、容器内で円板の回転による遠心力およびスリットエアーによって粉 末状 D—マン-トールを遠心転動させながら、これに D—マン-トール水溶液をスプ レーすることによって D—マン-トール造粒物が得られる。 (For example, Freund Sangyo Co., Ltd., trade name “CF Dara Niyureta”) D-mannitol is charged with powder, and powdery D- While rotating mannitol, sprinkle D-manntol aqueous solution on it. D-Mann-Tall granules are obtained by laying.
[0025] 遠心転動流動層造粒法の場合、複合型造粒コーティング装置 (例えば、フロイント産 業 (株)製、商品名「スパイラーフロー」）、または、通気部を有する回転円板と自動昇 降式乾燥装置とを備えた遠心転動造粒コーティング装置 (例えばフロイント産業 (株） 製、商品名「ダラ-ュレックス」）に粉末状 D—マン-トールを仕込み、容器内で円板 の回転による遠心力および供給される乾燥空気によって粉末状 D マン-トールを 遠心転動流動させながら、これに D—マン-トール水溶液をスプレーすることによつ て D マンニトール造粒物が得られる。  [0025] In the case of a centrifugal rolling fluidized bed granulation method, a composite granulation coating device (for example, Freund Industrial Co., Ltd., trade name "Spilar Flow"), or a rotating disk having a ventilation part and an automatic A centrifugal tumbling granulation coating device equipped with an ascending / descending dryer (for example, Freund Sangyo Co., Ltd., trade name “Darullex”) is charged with powdered D-mann-toll, and the disc is placed inside the container. D-mannitol granules can be obtained by spraying D-mannitol aqueous solution to the powdery D-mannitol while the powdered D-mannitol is centrifugally tumbling and flowing by the centrifugal force of rotation and supplied dry air.
[0026] 流動層造粒法および遠心転動流動層造粒法の場合には、造粒に引き続いて同一 装置内で乾燥も行われる。一方、撹拌造粒法および遠心転動造粒法の場合には、 用いられる装置が通常、乾燥機構を持たないため、造粒操作の後に得られる湿潤造 粒物を流動層乾燥機、棚段乾燥機等によって乾燥することが必要である。  [0026] In the fluidized bed granulation method and the centrifugal rolling fluidized bed granulation method, the granulation is followed by drying in the same apparatus. On the other hand, in the case of the agitation granulation method and the centrifugal rolling granulation method, since the apparatus used usually does not have a drying mechanism, the wet granulated product obtained after the granulation operation is transferred to a fluidized bed dryer or a shelf. It is necessary to dry with a dryer or the like.
いずれの造粒法を適用した場合でも、乾燥された造粒物は、ふるい工程を経て目 標とする粒度に調整される。  Regardless of which granulation method is applied, the dried granulated product is adjusted to a target particle size through a sieving step.
[0027] D—マン-トール水溶液には、所望によりエタノール等のアルコールを添カ卩してもよ い。 D マン-トール水溶液中のアルコール濃度が高濃度であるほど、造粒が進み やすい傾向がある。  [0027] If desired, an alcohol such as ethanol may be added to the D-manntol aqueous solution. D The higher the alcohol concentration in the aqueous mannitol solution, the more likely granulation proceeds.
D マン-トールの水に対する溶解度は、他の糖類に比べて低ぐ水 lOOgに対し て 20°Cで約 18g、 30°Cで約 25gである。したがって、 D マン-トール水溶液中の D マン-トール濃度は、 20°Cで最高約 15質量％である。 15質量％の0 マン-トー ル水溶液であっても造粒は可能である力 造粒を効率的に行う点で、 D マン-トー ル水溶液はできるだけ高濃度が好ましい。 D—マン-トールの溶解度を高くするため 、水溶液を加熱してもよぐ必要ならば水溶液を沸点近くまで加熱してもよい。沸点近 くまで加熱した場合、 D—マン-トール水溶液の濃度を約 40質量％に上げることがで きる。  The solubility of D-Manthol in water is about 18g at 20 ° C and about 25g at 30 ° C for low lOOg of water compared to other sugars. Therefore, the concentration of D mannitol in D mannitol aqueous solution is about 15% by mass at 20 ° C. Granulation is possible even with a 15% by mass aqueous solution of 0 mannitol. From the standpoint of efficient granulation, the aqueous solution of D mannitol is preferably as high as possible. In order to increase the solubility of D-mannthol, the aqueous solution may be heated to near the boiling point if necessary. When heated to near the boiling point, the concentration of D-manntol aqueous solution can be increased to about 40% by mass.
[0028] D マン-トール水溶液の量は、 D マン-トール造粒物の目標とする粒子径に応 じて決定される。 D マン-トール水溶液の量は、適用する条件等により変動するが 、本発明の効果を達成する観点からは、粉末状 D マン-トール 100質量部に対し て、固形分で 5〜50質量部が好ましい。 D マンニトール水溶液（固形分)が粉末状 D マン-トール 100質量部に対して 5質量部未満では、 D マン-トール造粒物の 成形性が充分でなぐ口腔内速崩壊錠の硬度が低下するおそれがある。 D マンニ トール水溶液（固形分）が、粉末状 D—マン-トール 100質量部に対して 50質量部を 超えると、 D マン-トール造粒物の製造に著しく時間を要するようになりコスト的に 不利になる。 [0028] The amount of the D-mannitol aqueous solution is determined according to the target particle diameter of the D-mannitol tall product. The amount of D-mannitol aqueous solution varies depending on the conditions to be applied, but from the viewpoint of achieving the effects of the present invention, the amount of powdered D-mannitol is 100 parts by mass. In addition, the solid content is preferably 5 to 50 parts by mass. If the aqueous solution of D-mannitol (solid content) is less than 5 parts by mass with respect to 100 parts by mass of D-mannitol, the hardness of the rapidly disintegrating tablet in the oral cavity where the moldability of D-mannitol granules is insufficient There is a fear. If the amount of D-mannitol aqueous solution (solid content) exceeds 50 parts by mass with respect to 100 parts by mass of powdered D-manntol, it will take much time to produce D-mannitol granulated material, and cost will be increased. It will be disadvantageous.
[0029] (結晶セルロース、粉末セルロース、それらの造粒物）  [0029] (crystalline cellulose, powdered cellulose, granulated product thereof)
結晶セルロース、粉末セルロース、それらの造粒物は、前述の「結合剤」に分類され る。また、結晶セルロース、粉末セルロース、それらの造粒物は、 D—マン-トール造 粒物と併用することによって、崩壊機能も発揮する。  Crystalline cellulose, powdered cellulose, and granulated products thereof are classified as the above-mentioned “binder”. In addition, crystalline cellulose, powdered cellulose, and their granulated products also exhibit a disintegrating function when used in combination with D-mann-toll granulated products.
[0030] 結晶セルロースとは、繊維性植物力 パルプとして得た α セルロースを酸で部分 的に解重合し、精製したものであり、流動性がある白色の結晶性の粉末である。 結晶セルロースとしては、例えば、旭化成ケミカルズ (株)製、商品名「セォラス ΡΗ 101」、 「セォラス ΡΗ— 102」、 「セォラス ΡΗ— 301」、 「セォラス ΡΗ— 302」、 「セォ ラス ΡΗ— F20JP」等が挙げられる。 [0030] Crystalline cellulose is a white crystalline powder having fluidity, which is obtained by partially depolymerizing and purifying α-cellulose obtained as fibrous vegetable strength pulp with an acid. Examples of the crystalline cellulose include those manufactured by Asahi Kasei Chemicals Corporation, trade names “Ceras セ 101”, “Ceras セ —102”, “Ceras ΡΗ—301”, “Ceras ΡΗ—302”, “Ceras ΡΗ—F20JP”. Etc.
[0031] 粉末セルロースとは、繊維性植物力 パルプとして得た a セルロースを、必要に 応じて部分的加水分解等で処理した後、精製し、機械的に粉砕したものであり、白色 の粉末である。 [0031] Powdered cellulose is a cellulose obtained as a fibrous vegetable strength pulp, which is treated by partial hydrolysis, etc., if necessary, purified and mechanically pulverized, and is a white powder. is there.
粉末セルロースとしては、例えば、日本製紙ケミカル (株)製、商品名「KCフロック W — 100」、 「KCフロック W— 200」、 「KCフロック W— 300」、 「KCフロック W— 400」等 が挙げられる。  Examples of powdered cellulose include Nippon Paper Chemicals Co., Ltd., trade names "KC Flock W-100", "KC Flock W-200", "KC Flock W-300", "KC Flock W-400", etc. Can be mentioned.
[0032] 結晶セルロースまたは粉末セルロースは、流動性が低!、ものの場合、打錠末 (打錠 用混合物）においても流動性が不足し、口腔内速崩壊錠の質量、硬度、崩壊性等の 性質のばらつきが大きくなることがある。流動性が低 、結晶セルロースまたは粉末セ ルロースは、流動性を改善するために、あら力じめ造粒し、造粒物として用いることが 好ましい。  [0032] Crystalline cellulose or powdered cellulose has low fluidity! In the case of the crystalline cellulose or powdered cellulose, the fluidity is insufficient even in the tableting powder (mixture for tableting), and the mass, hardness, disintegration, etc. Variations in properties may be large. In order to improve the fluidity, it is preferable to use crystalline cellulose or powdered cellulose having a low fluidity as a granulated product.
[0033] 結晶セルロースまたは粉末セルロースは、水にほとんど溶けないため、口腔内速崩 壊錠を含んだ場合、口腔内速崩壊錠の崩壊後に人によってはわず力ながらざらつき 感を感じることがある。よって、結晶セルロースまたは粉末セルロースとしては、ざらつ き感を改善するために、微粉末タイプの市販品を用いてもよぐ市販の結晶セルロー スまたは粉末セルロースをさらに粉砕して微粉末としたものを用いてもよい。なお、微 粉末の結晶セルロースまたは粉末セルロースは、流動性が低いため、流動性を改善 するために、造粒し、造粒物としてもよい。 [0033] Since crystalline cellulose or powdered cellulose is hardly soluble in water, when it contains a rapidly disintegrating tablet in the oral cavity, it is roughened by force after being disintegrated by the oral disintegrating tablet. There may be a feeling. Therefore, as crystalline cellulose or powdered cellulose, commercially available crystalline cellulose or powdered cellulose, which may be a fine powder type commercial product, is further pulverized to improve fineness. May be used. Note that finely crystalline crystalline cellulose or powdered cellulose has low fluidity, and thus may be granulated and granulated to improve fluidity.
[0034] 結晶セルロース造粒物または粉末セルロース造粒物は、必要に応じて結晶セル口 ースまたは粉末セルロースを粉砕して微粉末とした後、結晶セルロース、粉末セル口 ース、またはそれらの微粉末を造粒することによって得られる。  [0034] The crystalline cellulose granulated product or the powdered cellulose granulated product is obtained by pulverizing the crystalline cellulose or the powdered cellulose as necessary to obtain a fine powder, and then the crystalline cellulose, the powdered cellulose granule, or a product thereof. It is obtained by granulating a fine powder.
結晶セルロースまたは粉末セルロースの粉砕方法としては、高速回転式ミル、ジェ ットミル等を用いる方法が挙げられる。  Examples of the method for pulverizing crystalline cellulose or powdered cellulose include a method using a high-speed rotary mill, a jet mill and the like.
[0035] 造粒方法としては、乾式造粒法または、湿式造粒法が採用できる。これらのうち、口 腔内速崩壊錠の崩壊後のざらつき感が伴うことがな 、ように、結晶セルロース造粒物 または粉末セルロース造粒物を口腔内で容易に単位粒子に分散させる点から、乾式 造粒法が好ましい。 [0035] As the granulation method, a dry granulation method or a wet granulation method can be employed. Among these, the crystalline cellulose granulated product or the powdered cellulose granulated product can be easily dispersed in the oral cavity so as not to have a rough feeling after disintegration of the intraoral quick disintegrating tablet. A dry granulation method is preferred.
乾式造粒法を適用する場合には、まず、造粒対象の粉体に必要に応じて滑沢剤、 流動化剤等の添加剤を混合し、得られた混合物をロール式高圧圧縮成形機 (例えば フロイント産業 (株)製、商品名「ローラーコンパクタ一」などによりロール圧縮成形し、 高密度の板状成型物（以下、「フレーク」ということもある）とする。次いで、目的の粒度 となるように、このフレークを多段式ロール解砕機や各種の製粒機を通し、必要があ ればさらに適当な粒度分布になるように篩い分けを行う。滑沢剤としては、例えばス テアリン酸マグネシウム、ステアリン酸カルシウム、ショ糖脂肪酸エステル、硬化油など が挙げられ、通常、造粒粉体中 5質量％以下の量で使用される。  When applying the dry granulation method, first, if necessary, additives such as a lubricant and a fluidizing agent are mixed with the powder to be granulated, and the resulting mixture is mixed with a roll-type high-pressure compression molding machine. (For example, it is roll compression molded by Freund Sangyo Co., Ltd., trade name “Roller Compactor 1”, etc., to form a high-density plate-like molded product (hereinafter sometimes referred to as “flakes”). The flakes are passed through a multi-stage roll crusher and various granulators and, if necessary, screened to obtain a more appropriate particle size distribution. Examples thereof include magnesium, calcium stearate, sucrose fatty acid ester, and hardened oil, and they are usually used in an amount of 5% by mass or less in the granulated powder.
湿式造粒法を適用する場合には、流動層造粒法、撹拌造粒法、噴霧乾燥造粒法、 破砕型造粒法などによって造粒を行えばよい。これらの湿式造粒法では、デンプン のり液、ヒドロキシプロピルセルロース液などの液状の結合剤をカ卩えて造粒操作を行 えばよい。破砕型造粒法の場合、液状の結合剤を添加して造粒機で適当な大きさの 軟塊を作り、破砕造粒機を用いて破砕し、ついで乾燥機で乾燥することで造粒物が 得られる。 [0036] 結晶セルロース造粒物または粉末セルロース造粒物の体積平均粒子径は、 30〜3 00 μ mが好ましぐ 50-200 μ mがより好ましい。体積平均粒子径が 30 μ m未満で は、流動性が低くなり、後述の直接粉末圧縮法に適さなくなるおそれがある。体積平 均粒子径が 300 mを超えると、口腔内速崩壊錠の含量均一性の確保が困難にな るおそれがある。 When the wet granulation method is applied, granulation may be performed by a fluidized bed granulation method, a stirring granulation method, a spray drying granulation method, a crushing granulation method, or the like. In these wet granulation methods, the granulation operation may be carried out by adding a liquid binder such as starch paste or hydroxypropylcellulose. In the case of the crushing granulation method, a liquid binder is added to form a soft lump of an appropriate size with a granulator, crushing with a crushing granulator, and then drying with a dryer. Things are obtained. [0036] The volume average particle diameter of the crystalline cellulose granulated product or the powdered cellulose granulated product is preferably 30 to 300 µm, more preferably 50 to 200 µm. When the volume average particle size is less than 30 μm, the fluidity is low, and there is a possibility that it is not suitable for the direct powder compression method described later. If the volume average particle diameter exceeds 300 m, it may be difficult to ensure the uniformity of the content of the rapidly disintegrating tablet in the oral cavity.
[0037] (D マン-トール ·結晶セルロースまたは粉末セルロース造粒物）  [0037] (D Mann-Tall · crystalline cellulose or powdered cellulose granulate)
D マン-トール ·結晶セルロースまたは粉末セルロース造粒物は、これら各成分の 粉末状のものを原料に用いて造粒したものであり、後述の直接粉末圧縮法において 、結合性と崩壊性とを兼ね備えた賦形剤としての機能を持つものである。  D Mannitol crystalline cellulose or powdered cellulose granulated product is granulated using the powdered materials of each of these ingredients as raw materials. It has a function as a combined excipient.
[0038] D—マン-トール '結晶セルロースまたは粉末セルロース造粒物としては、口腔内 速崩壊錠がより速やかに崩壊するという観点からは、これら各成分の粉末状のものを 原料に用いて、 D—マン-トール水溶液を加える操作を伴う、流動層造粒法、撹拌造 粒法、遠心転動造粒法、または遠心転動流動層造粒法などの湿式造粒法を適用す ることによって得られる造粒物が好ましい。操作方法としては、前記の D—マン-トー ル造粒物を得る操作法と基本的に同様であるが、口腔内速崩壊錠の崩壊時間を短く する観点からは、どの造粒法を適用する場合でも、はじめに D—マン-トール粉末の みを仕込み、 D マン-トール溶液を加える操作を行って造粒を行い、造粒が特定 の段階まで進んだ時点で、結晶セルロースまたは粉末セルロースを追加的に仕込ん で、造粒を継続することが望ましい。これは D マン-トール '結晶セルロースまたは 粉末セルロース造粒物中、 D マン-トールは均一な混合物としてでななぐその成 分 (D マン-トール)からなる造粒物として存在することが、崩壊時間を短くすること に効果的と考えられる。結晶セルロースまたは粉末セルロースを追加的に仕込む適 切なタイミングは一概に規定できないが、 D マン-トール水溶液の量力 粉末状 D —マン-トール 100質量部に対して、固形分で 5〜50質量％加えられた時点である ことが好ましい。  [0038] From the viewpoint that the rapidly disintegrating tablet in the oral cavity is more rapidly disintegrated as the D-mann-thor 'crystalline cellulose or the powdered cellulose granule, the powdered materials of these components are used as raw materials. Apply wet granulation methods such as fluidized bed granulation method, stirring granulation method, centrifugal tumbling granulation method, or centrifugal tumbling fluidized bed granulation method with the operation of adding D-mannitol aqueous solution. The granulated product obtained by is preferred. The operation method is basically the same as that for obtaining the D-mann-toggle granule described above, but any granulation method is applied from the viewpoint of shortening the disintegration time of the rapidly disintegrating tablet in the oral cavity. However, when the granulation is carried out to the specified stage, the D-mannthol powder is first charged and the D-mannitol solution is added. It is desirable to continue the granulation with additional charging. This is due to the fact that in D-mannitol crystalline cellulose or powdered cellulose granulate, D-mannitol is present as a granulated product consisting of its components (D-mannitol) in a uniform mixture. It is considered effective to shorten the time. Although it is not possible to unconditionally specify the appropriate timing for additionally adding crystalline cellulose or powdered cellulose, the amount of D-mantitol aqueous solution is powdery D—Adds 5 to 50% by mass of solid to 100 parts by mass It is preferable to be at the point of time.
[0039] 本発明の口腔内速崩壊錠において、活性成分以外の成分としては、 1) D—マン- トール造粒物と、結晶セルロースまたは粉末セルロースと力もなる場合、 2) D—マン 二トール造粒物と、結晶セルロース造粒物または粉末セルロース造粒物からなる場 合、 3) D—マン-トールと、結晶セルロースまたは粉末セルロースを構成成分とする 造粒物からなる 3通りがある。これらいずれの場合においても、 D—マン-トール成分 と結晶セルロースまたは粉末セルロース成分との質量比（D—マンニトール成分：結 晶セルロースまたは粉末セルロース成分）は 95： 5〜70： 30であり、 85： 15〜70： 30 が好ましい。また、結晶セルロースまたは粉末セルロース成分の割合力 5質量％未 満では、口腔内速崩壊錠の硬度が不十分になる。結晶セルロースまたは粉末セル口 ース成分の割合が、 30質量％を超えると、服用時に、結晶セルロースまたは粉末セ ルロースによる粉っぽい舌触り感が生ずる。 [0039] In the intraoral quick disintegrating tablet of the present invention, as components other than the active ingredient, 1) D-mannitol granule and crystalline cellulose or powdered cellulose can be used. 2) D-mannitol A place consisting of a granulated product and a crystalline cellulose granulated product or a powdered cellulose granulated product 3) There are three types of granulated products that contain D-mannthol and crystalline cellulose or powdered cellulose as constituents. In any of these cases, the mass ratio of D-mannitol component to crystalline cellulose or powdered cellulose component (D-mannitol component: crystalline cellulose or powdered cellulose component) is 95: 5 to 70:30, 85 : 15-70: 30 is preferable. In addition, when the specific force of the crystalline cellulose or the powdered cellulose component is less than 5% by mass, the hardness of the orally rapidly disintegrating tablet becomes insufficient. When the ratio of the crystalline cellulose or powder cell mouth ingredient exceeds 30% by mass, a powdery touch feeling due to the crystalline cellulose or powdered cellulose occurs at the time of taking.
[0040] (崩壊剤） [0040] (Disintegrant)
崩壊剤としては、通常、でんぷん、カルメロースカルシウム、クロスカルメロースナトリ ゥム、カルボキシメチルスターチナトリウム等が挙げられる。  Examples of disintegrants generally include starch, carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like.
本発明において、結晶セルロースまたは粉末セルロースは、粉末状態または造粒 により造粒物として、 D—マン-トール造粒物との併用により、あるいは当該結晶セル ロースまたは粉末セルロースは、 D—マン-トールの粉末と共に造粒により造粒物と して使用することにより、崩壊機能も発揮する。よって、本発明においては、これら崩 壊剤は必要とされない。  In the present invention, crystalline cellulose or powdered cellulose is used as a granulated product in a powdered state or by granulation, or in combination with D-manntol granulated product, or the crystalline cellulose or powdered cellulose is used as D-mantitol. When used as a granulated product by granulation with this powder, it also exhibits a disintegrating function. Therefore, these disintegrants are not required in the present invention.
[0041] なお、崩壊剤を (i)結晶セルロースまたは粉末セルロースと置き換えて用いたり、 (ii )結晶セルロースまたは粉末セルロースに追加して用いても、本発明の目的とする効 果は得られない。すなわち、（i)の場合には、口腔内速崩壊錠の硬度が低くなり、製 造時、輸送時等の摩損、割れ、欠け等を起こしやすぐまた、崩壊時間に関しても望 ましいレベルのものは得られない。（その場合には、口腔内速崩壊錠の硬度が低下 する傾向にあり、崩壊時間もむしろ遅くなる傾向がある。このように本発明においては 、結晶セルロースまたは粉末セルロースに加え、通常の崩壊剤を用いた場合には、 結合剤としての機能はもとより、崩壊剤としての機能も充分に発揮されない。  [0041] Even if the disintegrant is used in place of (i) crystalline cellulose or powdered cellulose, or (ii) used in addition to crystalline cellulose or powdered cellulose, the intended effect of the present invention cannot be obtained. . In other words, in the case of (i), the hardness of the rapidly disintegrating tablet in the oral cavity becomes low, causing wear, cracking, chipping, etc. during production, transportation, etc. You can't get anything. (In that case, the hardness of the orally rapidly disintegrating tablet tends to decrease, and the disintegration time tends to be rather slow. Thus, in the present invention, in addition to crystalline cellulose or powdered cellulose, a normal disintegrant is used. When is used, not only the function as a binder but also the function as a disintegrant is not sufficiently exhibited.
[0042] (活性成分）  [0042] (Active ingredient)
活性成分としては、経口投与可能な活性成分であればよぐ例えば、催眠'鎮静剤 、解熱鎮痛消炎剤、精神神経用剤、自律神経用剤、抗パーキンソン剤、抗ヒスタミン 剤、強心剤、利尿剤、血圧降下剤、血管収縮剤、動脈硬化用剤、鎮咳去痰剤、ビタミ ン剤、滋養強壮薬、抗生物質、胃腸薬等が挙げられる。活性成分は、含量均一性を 確保する目的で、あら力じめ乳糖、でんぷん、または乳糖とでんぷんとの混合物を賦 形剤に用い、前記賦形剤に均等に混和することによる倍散として用いてもよい。 活性成分には、活性成分に由来する苦み等の不快な味を隠蔽する、腸溶化する、 徐放化する等の目的で、あら力じめ必要な添加剤を加え、公知の方法を適用して造 粒することにより微粒状にした後、公知の方法によりコーティングを施してもよい。 The active ingredient may be any active ingredient that can be administered orally.For example, hypnotic sedatives, antipyretic analgesics, antipsychotic agents, autonomic agents, antiparkinson agents, antihistamines, cardiotonics, diuretics , Antihypertensive agent, vasoconstrictor, arteriosclerotic agent, antitussive expectorant, vitamin Drugs, nourishing tonics, antibiotics, gastrointestinal drugs and the like. For the purpose of ensuring the uniformity of the content of the active ingredient, use lactose lactose, starch, or a mixture of lactose and starch as the excipient, and use it as a trituration by mixing evenly into the excipients. May be. To the active ingredient, additives necessary for the purpose of concealing an unpleasant taste such as bitterness derived from the active ingredient, entericizing, sustained release, etc. are added, and a known method is applied. Then, the mixture may be granulated and then coated by a known method.
[0043] (他の成分）  [0043] (Other ingredients)
本発明の口腔内速崩壊錠は、必要に応じて、通常の錠剤に用いられる、流動化剤 、滑沢剤、香料、甘味剤、矯味剤、着色剤等を含有してもよい。  The intraoral quick disintegrating tablet of the present invention may contain a fluidizing agent, a lubricant, a flavoring agent, a sweetening agent, a corrigent, a coloring agent, etc., which are used for ordinary tablets, if necessary.
流動化剤としては、打錠用混合物における良好な流動性を確保する、または口腔 内速崩壊錠の硬度を改善する目的で、軽質無水ケィ酸等が用いられる。流動化剤の 量は、打錠用混合物（100質量％)中、 0. 1〜0. 5質量％が好ましい。  As the fluidizing agent, light anhydrous caustic acid or the like is used for the purpose of ensuring good fluidity in the tableting mixture or improving the hardness of the intraoral quick disintegrating tablet. The amount of the fluidizing agent is preferably 0.1 to 0.5% by mass in the tableting mixture (100% by mass).
滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、ショ糖 脂肪酸エステル、硬化油等が挙げられる。滑沢剤の量は、口腔内速崩壊錠（100質 量％)中、 5質量％以下が好ましい。  Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, and hardened oil. The amount of the lubricant is preferably 5% by mass or less in the intraoral rapidly disintegrating tablet (100% by mass).
[0044] <口腔内速崩壊錠の製造法 > [0044] <Method for producing intraorally rapidly disintegrating tablet>
口腔内速崩壊錠の製造法は、直接粉末圧縮法と顆粒圧縮法とに大別される。直接 粉末圧縮法は、医薬品 (活性成分)と添加剤とを混合し、直接、打錠機で錠剤に圧縮 成形する方法である。顆粒圧縮法は、医薬品 (活性成分)をそのまま、または必要な 添加剤を加えて均等に混和したものを、適当な方法で顆粒状とした後、滑沢剤等を 加えて圧縮成形する方法である。従来のように粉末状 D—マン-トールを賦形剤とし て用いて錠剤を製造する場合は、通常、顆粒圧縮法が適用される。一方、本発明の ように D—マン-トール造粒物を賦形剤として用いて錠剤を製造する場合には、直接 粉末圧縮法が適用される。 D—マン-トール造粒物は、粉末状 D—マン-トールに比 ベ、圧縮成形性に優れている。  The method for producing an orally rapidly disintegrating tablet is roughly classified into a direct powder compression method and a granule compression method. The direct powder compression method is a method in which a pharmaceutical product (active ingredient) and an additive are mixed and directly compressed into tablets with a tableting machine. The granule compression method is a method in which a pharmaceutical product (active ingredient) is mixed as it is or with the required additives added and mixed evenly into granules by an appropriate method, followed by compression with a lubricant and the like. is there. When tablets are produced using powdered D-manntol as an excipient as in the past, the granule compression method is usually applied. On the other hand, when a tablet is produced using D-mann-tol granulate as an excipient as in the present invention, the direct powder compression method is applied. D-Mann-Tall granules are superior to powdered D-Mann-Toll in terms of compression moldability.
[0045] 本発明の口腔内速崩壊錠剤は、活性成分以外の必須成分として、 D—マンニトー ル、および結晶セルロースまたは粉末セルロースが用いられる力 それら成分は、 1) D—マン-トール造粒物と、結晶セルロースまたは粉末セルロースとして含む場合と、 2) D—マン-トール造粒物と、結晶セルロース造粒物または粉末セルロース造粒物 として含む場合と、 3) D—マン-トールと、結晶セルロースまたは粉末セルロースを構 成成分とする造粒物として含む場合があり、当該活性成分は、活性成分以外の成分 との混合物として、公知の直接粉末圧縮法により、ロータリー型打錠機、単発打錠機 等の打錠機を用いて打錠することにより製造される。 [0045] The rapidly disintegrating tablet in the buccal cavity of the present invention is a force in which D-mannitol and crystalline cellulose or powdered cellulose are used as essential components other than the active component. And including as crystalline cellulose or powdered cellulose, 2) D-mann-toll granule and crystalline cellulose granulated product or powdered cellulose granulated product, and 3) D-mantitol, granulated cellulose or powdered cellulose The active ingredient may be mixed as a mixture with components other than the active ingredient using a tableting machine such as a rotary tableting machine or a single tableting machine by a known direct powder compression method. It is manufactured by doing.
打錠の条件としては、通常の錠剤を製造する場合の条件が適用される。打錠 (圧縮 成开 の際の圧力 (compression load)は、通常、杵当たり (per punch)4kN〜15kNで ある。適切な圧力は、口腔内速崩壊錠当たりの質量、活性成分の種類、添加量等に より異なるが、圧力が 4kN未満では、口腔内速崩壊錠の硬度が低下するおそれがあ り、取扱いに支障を来す。圧力が 15kNを超えると、口腔内速崩壊錠の崩壊時間が 長くなる傾向がある。  As conditions for tableting, conditions for producing ordinary tablets are applied. Tableting (compression load is usually 4 to 15 kN per punch) Appropriate pressure is the mass per orally disintegrating tablet, type of active ingredient, addition Depending on the amount, etc., if the pressure is less than 4 kN, the hardness of the orally rapidly disintegrating tablet may decrease, which may hinder handling.If the pressure exceeds 15 kN, the disintegration time of the orally rapidly disintegrating tablet will be reduced. Tends to be longer.
本発明の口腔内速崩壊錠剤には、さらに公知の方法によりコーティングを施しても よい。  The intraoral rapidly disintegrating tablet of the present invention may be further coated by a known method.
[0046] 本発明の口腔内速崩壊錠は、水を用いずに服用した場合でも、口腔内で速やかに 軟化、崩壊し、舌触り感が気になる等の違和感を伴うことなく服用が可能である。本 発明の口腔内速崩壊錠の崩壊時間は、日本薬局方の崩壊試験法、錠剤に対する操 作法において、補助盤を用いずに操作した場合に、 30秒以下であることが好ましぐ 20秒以下であることがより好ましい。本発明の口腔内速崩壊錠の錠剤硬度は、錠剤 の大きさにも依存するために一概に規定できないが、錠剤硬度計による測定値で 30 〜150N程度が好ましい。  [0046] The intraoral quick disintegrating tablet of the present invention can be taken without an uncomfortable feeling such as softening and disintegrating rapidly in the oral cavity, and feeling of touching the tongue even when it is taken without using water. is there. The disintegration time of the orally rapidly disintegrating tablet of the present invention is preferably 30 seconds or less when operated without using an auxiliary board in the disintegration test method of the Japanese Pharmacopoeia and the operation method for tablets. 20 seconds The following is more preferable. The tablet hardness of the rapidly disintegrating tablet in the oral cavity of the present invention depends on the size of the tablet and cannot be defined unconditionally, but it is preferably about 30 to 150 N as measured by a tablet hardness meter.
[0047] (作用）  [0047] (Action)
以上説明したように、本発明の口腔内速崩壊錠にあっては、 D—マン-トールと、 結晶セルロースまたは粉末セルロースとを必須成分として含み、当該 D—マン-トー ルは造粒物として、あるいは造粒物の構成成分中の形で使用されるが、崩壊剤を含 んでいないにもかかわらず、口腔内で速やかに崩壊する。これは、結晶セルロースま たは粉末セルロース力 D—マン-トール造粒物と併用されることによって、崩壊機能 も発揮するからであると考えられる。結晶セルロースまたは粉末セルロースは、結合 剤として用いられるものであって、通常、崩壊剤としての機能を期待する用い方はさ れない。 As described above, the intraoral rapidly disintegrating tablet of the present invention contains D-mannitol and crystalline cellulose or powdered cellulose as essential components, and the D-mannitol is used as a granulated product. Or it is used in the form of a constituent of the granulate, but it disintegrates rapidly in the oral cavity even though it does not contain a disintegrant. This is considered to be due to the fact that the disintegrating function is exhibited when used in combination with crystalline cellulose or powdered cellulose strength D-mann-toll granule. Crystalline cellulose or powdered cellulose is used as a binder, and is usually used in the hope of functioning as a disintegrant. I can't.
[0048] 例えば、「第十四改正日本薬局方解説書」，廣川書店， 2001年には、次のような記 載がある。「粉末として用いられる結合剤としては結晶セルロースが汎用される。」（p. A— 64)、「崩壊剤は水中または消化管液中で錠剤に崩壊性を与える添加剤である 。でんぷん (薬剤の 5%、必要に応じ 10〜20%程度カ卩える）が最も広く用いられる。 最近は崩壊能のすぐれたカルメロースカルシウム、クロスカルメロースナトリウム、カル ボキシメチルスターチナトリウムなども使用されている。」（p. A— 64〜A— 65)  [0048] For example, “The 14th revised Japanese Pharmacopoeia Manual”, Yodogawa Shoten, 2001, has the following statement. “Crystalline cellulose is widely used as a binder used as a powder.” (P. A-64), “A disintegrant is an additive that imparts disintegration to tablets in water or gastrointestinal fluid. The most widely used are carmellose calcium, croscarmellose sodium, and carboxymethyl starch sodium, which have excellent disintegration ability. ”(P. A—64 to A—65)
[0049] また、津田恭介、野上寿編， 「薬剤製造法 (上） 医薬品開発基礎講座 XI」，地人書 館， 1971年， p. 135には、直接粉末圧縮法における結合剤の解説があり、結合剤と して用いられる物質について多数の例示がある力 結晶セルロースおよび粉末セル ロース（ここでは α—セルロースとして記載されているが粉末セルロースと同義である )も含まれている。  [0049] Also, Tsusuke Keisuke, Nogami Kotobuki, “Pharmaceutical Manufacturing Method (Part 1) Pharmaceutical Development Fundamentals XI”, Jinjinkan, 1971, p. 135, describes the binders in the direct powder compression method. Also included are forceful crystalline cellulose and powdered cellulose (denoted here as α-cellulose but synonymous with powdered cellulose) that have numerous examples of substances used as binders.
また、同書 p. 146には、結晶セルロースについて解説があり、次のような記載があ る。「 方この物質は、吸水性が大きく錠剤内部への水の導入が速ぐ · · ·また水 による膨潤が少なぐ崩壊剤としての作用は弱い。これと薬剤との混合物を、水で練 合して造粒し、乾燥すると、この造粒物はもはや水中では分散せず、湿式造粒法に おける使用ではその量を制限する必要がある。」  Also, p. 146 of the same book explains the crystalline cellulose and includes the following. “On the other hand, this substance has high water absorption and quick introduction of water into the tablet. Also, the substance is weak in action as a disintegrant with little swelling by water. Mix this with a drug in water. Once granulated and dried, the granulate is no longer dispersed in water and its amount must be limited for use in wet granulation. "
[0050] 本発明の口腔内速崩壊錠において、結晶セルロースまたは粉末セルロースが速い 崩壊性に寄与する理由は明らかでないが、結晶セルロースまたは粉末セルロースは 、吸水性が大きぐ口腔内速崩壊錠内部への水の導入が速いために、 D—マン-ト 一ル造粒物の何らかの性質と結びつ 、て、 、わば崩壊助剤的な働きをして 、ること が考えられる。一方、本発明の口腔内速崩壊錠において、通常の崩壊剤が崩壊性 の促進に効果を示さないのは、同様に D—マン-トール造粒物の何らかの性質と関 わっていると考えられる。  [0050] In the rapidly disintegrating tablet in the oral cavity of the present invention, the reason why crystalline cellulose or powdered cellulose contributes to fast disintegration is not clear. However, crystalline cellulose or powdered cellulose enters the rapidly disintegrating tablet in oral cavity with high water absorption. Because of the rapid introduction of water, it can be considered that it acts as a disintegration aid in connection with some properties of D-mantle granules. On the other hand, in the rapidly disintegrating tablet in the oral cavity according to the present invention, it is considered that the fact that the normal disintegrant does not show the effect of promoting disintegration is also related to some property of the D-mann-tol granulate. .
[0051] また、本発明の口腔内速崩壊錠にあっては、結晶セルロースまたは粉末セルロース が結合性を発揮し、口腔内速崩壊錠の硬度を高くすることに寄与している。また、硬 度を低下させる崩壊剤を含んでいないため、口腔内速崩壊錠の硬度はさらに高くな る。 以上のように、 D—マン-トール造粒物を添加剤として単独で用いた場合には、充 分な硬度と崩壊性とを併せ持つ口腔内速崩壊錠は得られないが、結晶セルロースま たは粉末セルロースと特定の質量比で用いることでそれらの性質が満足される口腔 内速崩壊錠を得ることができる。 [0051] In the intraoral rapidly disintegrating tablet of the present invention, crystalline cellulose or powdered cellulose exhibits binding properties and contributes to increasing the hardness of the intraoral rapidly disintegrating tablet. In addition, since it does not contain a disintegrant that lowers the hardness, the hardness of an orally rapidly disintegrating tablet is further increased. As described above, when D-mann-toll granule is used alone as an additive, an intraoral rapidly disintegrating tablet having sufficient hardness and disintegration cannot be obtained, but crystalline cellulose or Can be used in a specific mass ratio with powdered cellulose to obtain an orally rapidly disintegrating tablet satisfying these properties.
[0052] また、本発明の口腔内速崩壊錠にあっては、粉末状 D—マン-トールではなぐ粉 末状 D—マン-トールを造粒した D—マン-トール造粒物を含んで!/、るため、結晶セ ルロースまたは粉末セルロースの含有量を抑えても、口腔内速崩壊錠における実用 性を満足する硬度および崩壊性が確保される。よって、さわや力ゝな味質を持つ D—マ ン-トールの含有量を増やすことができ、かつ粉っぽい舌触り感を与える結晶セル口 ースまたは粉末セルロースの含有量を抑えることができるため、味質がさわやかで、 粉っぽい舌触り感が抑えられた口腔内速崩壊錠となる。 [0052] The intraorally rapidly disintegrating tablet of the present invention includes a D-mann-tol granulated product obtained by granulating powdered D-manntol which is not powdery D-manntol. Therefore, even if the content of crystalline cellulose or powdered cellulose is suppressed, the hardness and disintegration satisfying the practicality of an orally rapidly disintegrating tablet are ensured. Therefore, it is possible to increase the content of D-mann-toll with a refreshing and powerful taste, and to suppress the content of crystal cell mouth or powdered cellulose that gives a powdery texture. Therefore, it becomes a quick disintegrating tablet in the oral cavity with a refreshing taste and a reduced powdery texture.
[0053] すなわち、造粒操作をカ卩えた D—マン-トールを用いることによって、結晶セルロー スまたは粉末セルロースの結合性および崩壊性に対する効果を促進していると考え られる。一方、未造粒である、粉末状 D—マン-トールをそのまま用いた場合、例え ば、特許文献 4に示されるように、結晶セルロースと糖アルコールとの質量比を 5 : 5〜 3. 5 : 6. 5の範囲にする必要がある。このように結晶セルロースの含有量を多くしなけ れば目的の効果が得られないのは、 D—マン-トールの形状の違いにあると考えら れる。 [0053] That is, it is considered that the effect on the binding and disintegration properties of crystalline cellulose or powdered cellulose is promoted by using D-manntol with a granulation operation. On the other hand, when powdered D-manntol which is not granulated is used as it is, for example, as shown in Patent Document 4, the mass ratio of crystalline cellulose to sugar alcohol is 5: 5 to 3.5. : 6.5 Must be in range. The reason why the desired effect cannot be obtained unless the content of crystalline cellulose is increased is considered to be due to the difference in the shape of D-manntol.
また、口腔内速崩壊錠の製造方法の違いが、結晶セルロースまたは粉末セルロー スの含有量の違いに影響している可能性もある。すなわち、本発明の製造法は、直 接粉末圧縮法であるのに対し、特許文献 4では顆粒圧縮法が主体であり、結晶セル ロースが湿式造粒により変化を生じていることが考えられる。  In addition, differences in the production method of intraoral rapidly disintegrating tablets may affect the difference in the content of crystalline cellulose or powdered cellulose. That is, while the production method of the present invention is a direct powder compression method, in Patent Document 4, the granule compression method is mainly used, and it is considered that crystalline cellulose is changed by wet granulation.
[0054] また、本発明の口腔内速崩壊錠の製造法にあっては、崩壊剤を用いないため、必 須とされる添加剤成分の種類が少なくなり、製造における工程数および原材料の管 理に要する労力が少なくて済む。また、 D—マン-トール造粒物を用い、直接粉末圧 縮法により製造しているため、特別な設備を必要としない。よって、本発明の口腔内 速崩壊錠の製造法によれば、特殊な製剤でありながら、特殊な設備、製剤技術を必 要とせず、通常の設備、製剤技術によって容易に、かつ低コストで得ることができる。 [0055] 〔実施例 1〜2、比較例 1〜2〕 [0054] Further, in the method for producing an orally rapidly disintegrating tablet of the present invention, since a disintegrant is not used, the types of essential additive components are reduced, and the number of steps in production and the tube of raw materials are reduced. Less labor is required for reasoning. In addition, no special equipment is required because it is manufactured directly by the powder compression method using D-mann-tall granules. Therefore, according to the method for producing an orally rapidly disintegrating tablet of the present invention, although it is a special preparation, it does not require special equipment and preparation technology, and it is easy and low-cost with ordinary equipment and preparation technology. Obtainable. [Examples 1-2 and Comparative Examples 1-2]
粉末状 D マン-トール（ROQUETTE社製、商品名「PEARLITOL35」） 1. 5k gを 4. 5kgの 50°C温水に溶かし、 D マン-トール水溶液を調製した。  Powdered D-manthol (ROQUETTE, trade name “PEARLITOL35”) 1. 5 kg was dissolved in 4.5 kg of 50 ° C. warm water to prepare D-manthol aqueous solution.
粉末状 D マン-トール (ROQUETTE社製、商品名「PEARLITOL35」） 5kgを 遠心転動造粒コーティング装置 (フロイント産業 (株)製、商品名「ダラ-ュレックス G X— 40」）に仕込み、これに D マン-トール水溶液をスプレーして、遠心転動流動 層造粒法により造粒し、 D マン-トール造粒物を得た。造粒物は 150 mのふるい を用いてふるい分けた。レーザー回折式粒度分布測定装置（日機装 (株)製、商品名 「マイクロトラック粒度分析計」）を用いて体積平均粒子径を測定した結果、 95 μ mで めつに。  Powdered D-Manthol (ROQUETTE, trade name “PEARLITOL35”) 5 kg was charged into a centrifugal tumbling granulation coating device (Freund Sangyo Co., Ltd., trade name “Darullex GX-40”). D Mannitol aqueous solution was sprayed and granulated by centrifugal tumbling fluidized bed granulation method to obtain D Manntor granulated product. The granulated material was sieved using a 150 m sieve. As a result of measuring the volume average particle diameter using a laser diffraction particle size distribution analyzer (trade name “Microtrac particle size analyzer” manufactured by Nikkiso Co., Ltd.), the result is 95 μm.
[0056] 活性成分としてマレイン酸クロルフエ-ラミン (抗ヒスタミン剤）、賦形剤として上記 D マンニトール造粒物、結合剤として結晶セルロース (旭化成ケミカル (株)製、商品 名「セォラス PH— 101」）、崩壊剤としてカルメロースカルシウム (-チリンィ匕学工業（ 株)製、商品名「ECG— 505」、滑沢剤としてステアリン酸マグネシウムを用い、表 1の 処方にて前記打錠末を調製し、直接粉末圧縮法により、下記条件にて打錠を行い、 口腔内速崩壊錠を得た。  [0056] Chlorfelamamine maleate (antihistamine) as an active ingredient, D mannitol granulated product as an excipient, crystalline cellulose (trade name "Seol PH-101" manufactured by Asahi Kasei Chemical Co., Ltd.) as a binder, disintegration Carmellose calcium as a preparation (trade name “ECG-505”, manufactured by Chiryin Chemical Co., Ltd.), magnesium stearate as a lubricant, and the tableting powder prepared according to the formulation shown in Table 1 and directly powdered Tableting was performed by the compression method under the following conditions to obtain an orally rapidly disintegrating tablet.
(打錠条件）  (Tabletting conditions)
打錠機：ロータリー打錠機、 HT-P15A— III型 (畑鉄工所)。  Tableting machine: Rotary tableting machine, HT-P15A-III type (Hatatake Works).
打錠圧： 5kN。  Tableting pressure: 5kN.
剤型:径 8mmの円形錠、質量： 200mgZl錠。  Dosage form: Round tablet with 8mm diameter, Mass: 200mgZl tablet.
[0057] 得られた口腔内速崩壊錠について、下記の評価を行った。評価結果を表 1に示す [0057] The following evaluation was performed on the obtained intraorally rapidly disintegrating tablets. The evaluation results are shown in Table 1.
(錠剤硬度） (Tablet hardness)
錠剤硬度は、錠剤硬度計 (フロイント産業 (株)製、商品名「SChleuniger硬度計 6D 」）によって測定した。 Tablet hardness was measured by a tablet hardness meter (Freund Industrial Co., Ltd. under the trade name "S C hleuniger hardness tester 6D").
(崩壊時間）  (Collapse time)
崩壊試験は、日本薬局方の崩壊試験法、錠剤に対する操作法を適用し、補助盤を 用いずに操作した。 [0058] [表 1] For the disintegration test, the disintegration test method of the Japanese Pharmacopoeia and the operation method for tablets were applied and operated without using an auxiliary board. [0058] [Table 1]
Figure imgf000018_0001
Figure imgf000018_0001
[0059] 実施例 2の口腔内速崩壊錠は、錠剤硬度、崩壊時間ともに充分に満足できるレ ベルであり、また服用試験においては、ほとんど違和感が認められな力 た。  [0059] The rapidly disintegrating tablet in the oral cavity of Example 2 was sufficiently satisfactory in both tablet hardness and disintegration time.
一方、比較例 1は、結晶セルロースの含有量が多いため、錠剤硬度および崩壊性 の点ではほぼ満足されるものの、服用試験において明らかな粉っぽさが感じられた。 比較例 2は、崩壊剤を加えたため、崩壊時間が長くなり、口腔内速崩壊錠としては不 満足なものであった。  On the other hand, since Comparative Example 1 has a high content of crystalline cellulose, it was almost satisfactory in terms of tablet hardness and disintegration, but a clear powdery feeling was felt in the dosing test. In Comparative Example 2, since the disintegrant was added, the disintegration time was long, which was unsatisfactory as an orally fast disintegrating tablet.
[0060] 〔実施例 3〜4、比較例 3〕  [Examples 3 to 4, Comparative Example 3]
活性成分を塩酸チアミン (ビタミン剤）に変更し、表 2の処方にて打錠用混合物を調 製し、 1錠当たり質量を 180mgとした以外は実施例 1と同様にして打錠を行い、口腔 内速崩壊錠を得た。  The active ingredient was changed to thiamine hydrochloride (vitamin), a tableting mixture was prepared according to the formulation in Table 2, and tableting was performed in the same manner as in Example 1 except that the mass per tablet was 180 mg. An intraoral rapidly disintegrating tablet was obtained.
粉末セルロースとしては、日本製紙ケミカル (株)製、商品名「KCフロック W— 300」 を用いた。  As the powdered cellulose, trade name “KC Flock W-300” manufactured by Nippon Paper Chemical Co., Ltd. was used.
得られた口腔内速崩壊錠について、実施例 1と同様の評価を行った。評価結果を 表 2に示す。  The obtained intraoral quick disintegrating tablet was evaluated in the same manner as in Example 1. Table 2 shows the evaluation results.
[0061] [表 2] 処方（質量部） 実施例 3 実施例 4 比較例 3 [0061] [Table 2] Formulation (parts by mass) Example 3 Example 4 Comparative Example 3
塩酸チアミン 2. Q 2. 3 2, 8  Thiamine hydrochloride 2. Q 2. 3 2, 8
D-マンニトール造粒物 フ 2. 5 72. 5 72. 5  D-mannitol granulate 2. 5 72. 5 72.5
餹晶セルロース 24. 2 ―  Quartz cellulose 24.2-
粉末セルロース - 24. 2 一  Powdered cellulose-24. 2
カルメロ一スカルシウム ―  Carmeloose calcium
ステアリン酸マグネシウム 0. 5 0, 5 0, 5  Magnesium stearate 0. 5 0, 5 0, 5
D-マンニトール造粒物と  D-mannitol granules
結晶セルロースまたは 75 : 25 75 : 25 - 粉末セルロースとの質量比  Crystalline cellulose or 75:25 75:25-Mass ratio with powdered cellulose
錠剤硬度（N) 78 73 23  Tablet hardness (N) 78 73 23
崩壊時間（水）（補助盤なし〉 1秒 1 3秒 1分ヰ 0秒  Collapse time (Wed) (without auxiliary panel) 1 second 1 3 seconds 1 minute ヰ 0 seconds
ほとんど ほとんど  Almost almost
服用試験結果 粉つぼい感じ  Taking test results Feeling powdery
違和感なし 違和惑なし  No sense of incongruity No sense of incongruity
[0062] 実施例 3、 4の口腔内速崩壊錠は、口腔内速崩壊錠として望ましい性質を示した。 [0062] The intraorally rapidly disintegrating tablets of Examples 3 and 4 exhibited desirable properties as intraoral rapidly disintegrating tablets.
一方、崩壊剤として知られたカルメロースカルシウムを用いた比較例 3の口腔内速 崩壊錠は、錠剤硬度が著しく低ぐ崩壊時間は長ぐ服用試験においては粉っぽい 感じの不快感が感じられ、口腔内速崩壊錠としては不満足なものであった。  On the other hand, the fast-disintegrating tablet in the oral cavity of Comparative Example 3 using carmellose calcium, which is known as a disintegrant, has a very low tablet hardness and a long disintegration time. It was unsatisfactory as an intraoral quick disintegrating tablet.
[0063] 〔実施例 5〕  [Example 5]
寸  Size
粉末状 D—マンニトール (東和化成工業 (株)製、商品名「マンニット P」） 2kgを 50 °Cの温水 6kgに溶かし、 8kgの 25質量％D—マン-トール水溶液を調製した。  2 kg of powdered D-mannitol (manufactured by Towa Kasei Kogyo Co., Ltd., trade name “Mannit P”) was dissolved in 6 kg of hot water at 50 ° C. to prepare 8 kg of 25 mass% D-mannitol aqueous solution.
粉末状 D—マンニトール (東和化成工業 (株)製、商品名「マンニット P」） 5kgを流動 層造粒コーティング装置 (フロイント産業 (株)製、商品名「フローコーター FLO— 5」） に仕込み、これに D—マンェトール水溶液を全量スプレーすることにより造粒を行 、、 D—マン-トール造粒物を得た。造粒物は 125 μ mのふるいを用いてふるい分けた。 体積平均粒子径は 85 μ mであった。  Powdered D-mannitol (manufactured by Towa Kasei Kogyo Co., Ltd., trade name “Mannit P”) 5 kg is charged into a fluidized bed granulation coating device (Freund Sangyo Co., Ltd., trade name “Flow Coater FLO-5”). Then, granulation was carried out by spraying the whole amount of an aqueous solution of D-Manetol to obtain a D-Mannitol granulated product. The granulated material was sieved using a 125 μm sieve. The volume average particle diameter was 85 μm.
この D—マン-トール造粒物を用いた以外は、実施例 1と同様にして口腔内速崩壊 錠を得た。錠剤硬度は 65Nであり、崩壊時間は 13秒であり、服用試験においてはほ とんど違和感は認められな力 た。  An intraoral rapidly disintegrating tablet was obtained in the same manner as in Example 1 except that this D-mann-tol granulate was used. The tablet hardness was 65 N, the disintegration time was 13 seconds, and in the dose test almost no discomfort was observed.
[0064] 〔実施例 6〕 [Example 6]
粉末状 D—マン-トール (東和化成工業 (株)製、商品名「マンニット P」） 2kgを遠心 転動造粒コーティング装置 (フロイント産業 (株)製、商品名「CF— 360」）に仕込み、 これに 50°Cに加温した 20質量0 /oD—マン-トール水溶液 2kgをスプレーした。得ら れた湿潤造粒物を実施例 5の流動層造粒コーティング装置で乾燥し、乾燥後 250 μ mのふるレ、を用いてふるレ、分け、体積平均粒子径 140 μ mの D—マン-トール造粒 物を得た。 Powdered D—Mann-Tall (Towa Kasei Kogyo Co., Ltd., trade name “Mannit P”) 2 kg is applied to a centrifugal tumbling granulation coating device (Freund Sangyo Co., Ltd., trade name “CF-360”). This was sprayed and sprayed with 2 kg of 20 mass 0 / oD-mannitol aqueous solution heated to 50 ° C. The obtained wet granulated product is dried in the fluidized bed granulation coating apparatus of Example 5, and after drying, sieved using a 250 μm sieve, divided into D—with a volume average particle diameter of 140 μm. Mann-Tall granulation I got a thing.
[0065] この D—マン-トール造粒物 55. 3質量部、結晶セルロース 23. 7質量部（D—マン 二トール造粒物と結晶セルロースとの質量比 = 70 : 30)、活性成分としてァスコルビ ン酸 (ビタミン剤） 20質量部、滑沢剤として硬化油 1. 0質量部を混合して打錠用混合 物を調製し、打錠圧を 8kNとした以外は実施例 1と同じ条件で打錠を行い、口腔内 速崩壊錠を得た。錠剤硬度は 83Nであり、崩壊時間は 16秒であり、服用試験におい てはほとんど違和感は認められな力つた。  [0065] 55 parts by mass of this D-mann-toll granulated product, 23.7 parts by mass of crystalline cellulose (mass ratio of D-mannitol tall granulated product to crystalline cellulose = 70:30), as an active ingredient Ascorbic acid (vitamin) 20 parts by weight, hardened oil as lubricant, 1.0 part by weight was mixed to prepare a tableting mixture, and the same conditions as in Example 1 except that the tableting pressure was 8 kN. Tableting was carried out with a to obtain an orally rapidly disintegrating tablet. The tablet hardness was 83N and the disintegration time was 16 seconds, which was almost uncomfortable in the dose test.
[0066] 〔実施例 7〕  [Example 7]
粉末状 D—マン-トール (東和化成工業 (株)製、商品名「マンニット P」） 3kgを撹拌 造粒機 (深江工業 (株)製、商品名「ハイスピードミキサー FS— 25」）に仕込み、これ に 50°Cに加温した 20質量0 /oD—マン-トール水溶液 3kgを加え、アジテーターおよ びチョッパーを回転しながら撹拌造粒を行い、終了後、造粒物を取り出した。得られ た湿潤造粒物を実施例 5の流動層造粒コーティング装置で乾燥し、乾燥後 355 m のふるいを用いてふるい分け、体積平均粒子径 195 μ mの D—マン-トール造粒物 を得た。 Powdered D—Mann-Tall (manufactured by Towa Kasei Kogyo Co., Ltd., trade name “Mannit P”) 3 kg is stirred into a granulator (Fukae Kogyo Co., Ltd., trade name “High Speed Mixer FS-25”). Then, 3 kg of 20 mass 0 / oD-mantitol aqueous solution heated to 50 ° C was added thereto, stirring granulation was performed while rotating the agitator and chopper, and after completion, the granulated product was taken out. The obtained wet granulated product was dried with the fluidized bed granulation coating apparatus of Example 5, and after drying, it was sieved using a 355 m sieve to obtain a D-mann-toll granulated product having a volume average particle size of 195 μm. Obtained.
[0067] この D—マン-トール造粒物 72. 4質量部、結晶セルロース 24. 1質量部（D—マン 二トール造粒物と結晶セルロースとの質量比 = 75： 25)、活性成分としてリボフラビン (ビタミン剤） 3質量部、滑沢剤としてステアリン酸マグネシウム 0. 5質量部を混合して 打錠用混合物を調製し、打錠圧を 7kNとした以外は実施例 1と同じ条件で打錠を行 い、口腔内速崩壊錠を得た。錠剤硬度は 83Nであり、崩壊時間は 16秒であり、服用 試験においてはほとんど違和感は認められな力つた。  [0067] 74.4 parts by mass of this D-mann-toll granulated product, 24.1 parts by mass of crystalline cellulose (mass ratio of D-mannitol tall granulated product to crystalline cellulose = 75:25), as an active ingredient Riboflavin (vitamin) 3 parts by weight and 0.5 parts by weight of magnesium stearate as a lubricant were mixed to prepare a tableting mixture, and the tableting pressure was 7 kN. The tablet was taken to obtain an orally rapidly disintegrating tablet. The tablet hardness was 83N and the disintegration time was 16 seconds.
[0068] 〔実施例 8〕  [Example 8]
D—マン-トール造粒物として、スプレードライ法によるといわれる ROQUETTE社 製、商品名「PEARLITOL 200SD」（平均粒子径 163 μ m) 77. 2質量部、結晶セ ルロース、 19. 3質量部（D—マン-トール造粒物と結晶セルロースとの質量比 =80 : 20)、マレイン酸クロルフエ-ラミン 3. 0質量部、ステアリン酸マグネシウム 0. 5質量 部を混合して打錠用混合物を調製し、実施例 1と同じ条件で打錠を行い、口腔内速 崩壊錠を得た。錠剤硬度は 81Nであり、崩壊時間は 23秒であり、服用試験において はほとんど違和感は認められなかつた。 D—Man-tall granulated product manufactured by ROQUETTE, which is said to be spray-dried, trade name “PEARLITOL 200SD” (average particle size 163 μm) 77.2 parts by mass, crystalline cellulose, 19.3 parts by mass ( D-Mann-Tall granulate and crystalline cellulose mass ratio = 80:20), chlorophenol-lamin maleate 3.0 parts by weight, magnesium stearate 0.5 parts by weight were prepared to prepare a mixture for tableting Then, tableting was performed under the same conditions as in Example 1 to obtain an intraorally rapidly disintegrating tablet. Tablet hardness is 81N and disintegration time is 23 seconds. There was hardly any sense of incongruity.
[0069] 〔実施例 9〕  [Example 9]
実施例 1の結晶セルロース（体積平均粒子径： 57 m)をジェットミル（フロイント産 業 (株)製、商品名「TJ60型ターボカウンタージェットミル」）を用いて粉砕し、体積平 均粒子径 13 μ mの微粉末を得た。原料の結晶セルロースの安息角が 46度であった のに対し、微粉末の安息角は 60度以上 (正確な測定困難)であり、流動性が低下し ていた。微粉末 lOOgにステアリン酸マグネシウム 0. 5gを加え、ポリエチレンバッグ中 で振り混ぜて混合し、原料粉末を得た。ロール式高圧圧縮成形機 (フロイント産業（ 株)製、商品名「ローラーコンパクタ一 TF— rabo」）を用い、 lOMPaの圧力で原料粉 末を圧縮成形し、得られたフレークをスクリーン付き整粒機で整粒し、 355 mのふる いを用いてふるい分け、体積平均粒子径 105 mの結晶セルロース造粒物を得た。 結晶セルロース造粒物の安息角は 42度であり、流動性は著しく改善されて 、た。  The crystalline cellulose of Example 1 (volume average particle size: 57 m) was pulverized using a jet mill (trade name “TJ60 turbo counter jet mill” manufactured by Freund Industrial Co., Ltd.), and the volume average particle size of 13 A fine powder of μm was obtained. The angle of repose of the raw material crystalline cellulose was 46 degrees, whereas the angle of repose of fine powder was 60 degrees or more (difficult to measure accurately), and the fluidity decreased. 0.5 g of magnesium stearate was added to lOOg of fine powder and shaken and mixed in a polyethylene bag to obtain a raw material powder. Using a roll-type high-pressure compression molding machine (Freund Sangyo Co., Ltd., trade name “Roller Compactor TF-RABO”), the raw powder is compression-molded at a pressure of lOMPa, and the resulting flakes are screened. And then sieved using a 355 m sieve to obtain a crystalline cellulose granulated product having a volume average particle diameter of 105 m. The repose angle of the crystalline cellulose granule was 42 degrees, and the fluidity was remarkably improved.
[0070] 表 1の実施例 2の処方において、結晶セルロースの代わりに結晶セルロース造粒物 を用いた以外は、実施例 2と同様にして打錠用混合物を調製し、直接粉末圧縮法に より、下記条件にて打錠を行い、口腔内速崩壊錠を得た。 [0070] In the formulation of Example 2 in Table 1, a tableting mixture was prepared in the same manner as in Example 2 except that a crystalline cellulose granulated material was used instead of the crystalline cellulose, and a direct powder compression method was used. Tableting was performed under the following conditions to obtain an orally rapidly disintegrating tablet.
(打錠条件）  (Tabletting conditions)
打錠機:単式打錠機、 FY— SS— 7 (富士薬品機械 (株)）。  Tablet press: Single-type tablet press, FY—SS-7 (Fuji Pharmaceutical Machinery Co., Ltd.).
打錠圧： 10kN。  Tableting pressure: 10kN.
剤型:径 10mmの平形錠、質量： 300mgZl錠。  Dosage form: Flat tablet with a diameter of 10mm, Mass: 300mgZl tablet.
[0071] 得られた口腔内速崩壊錠について、評価を行った。錠剤硬度は 92Nであり、崩壊 時間は 15秒であり、服用試験においてはほとんど違和感は認められな力つた。さらに 、実施例 9および実施例 2で得られた口腔内速崩壊錠について、粉っぽさの評価と は別に、舌に対するざらつき感を評価した。この結果、ざらつき感は両者とも少なぐ 問題になるレベルではな力つた。なお、実施例 9の方が、実施例 2よりもざらつき感が 少なぐ結晶セルロース造粒物を用いることによって、口腔内速崩壊錠の性質がさら に改善されることがわかった。  [0071] The obtained intraorally rapidly disintegrating tablets were evaluated. The tablet hardness was 92N, the disintegration time was 15 seconds, and it was almost uncomfortable in the dose test. Further, with respect to the intraorally rapidly disintegrating tablets obtained in Example 9 and Example 2, a feeling of roughness on the tongue was evaluated separately from the evaluation of powderiness. As a result, the feeling of roughness was strong at a level where both became a minor problem. In addition, it was found that the properties of the orally rapidly disintegrating tablet were further improved in Example 9 by using a crystalline cellulose granulated product that was less rough than in Example 2.
[0072] 〔実施例 10〕  [Example 10]
微粒子グレードの粉末セルロース（日本製紙ケミカル (株)製、商品名「KCフロック W-400GJ、体積平均粒子径： 26 μ m) 1kgと、流動化剤として軽質無水ケィ酸 (フ ロイント産業 (株)製、商品名「アドソリター 101」）3gとを、 V型混合機 V— 10 ( (株)徳 寿製作所）により毎分 40回転で 2分間混合し、ついで、ステアリン酸マグネシウム 5g を加えて 5分間混合し、原料粉末を得た。フロイント産業 (株)製、商品名「ローラーコ ンパクター TF— mini」を用いたロール圧縮法により、 8MPaの圧力で原料粉末を圧 縮成形し、得られたフレークをスクリーン付き整粒機で粗粉砕し、さらにフロイント産業 (株）製、商品名「ロールダラ-ユレ一ター」で整粒し、 355 μ mのふるいを用いてふる い分け、体積平均粒子径 95 mの粉末セルロース造粒物を得た。原料の粉末セル ロースの安息角が 60度以上であつたのに対し、粉末セルロース造粒物の安息角は 4 2度であり、流動性は著しく改善されていた。 Fine grade powdered cellulose (manufactured by Nippon Paper Chemicals Co., Ltd., trade name “KC Flock” W-400GJ, volume average particle size: 26 μm) 1kg and light anhydrous caustic anhydride (Freund Sangyo Co., Ltd., trade name “Ad Solitor 101”) 3g as a fluidizing agent. 10 (Tokuju Seisakusho Co., Ltd.) was mixed at 40 rpm for 2 minutes, then 5 g of magnesium stearate was added and mixed for 5 minutes to obtain a raw material powder. The raw powder is compacted at a pressure of 8 MPa by roll compression using the brand name “Roller Compactor TF-mini” manufactured by Freund Sangyo Co., Ltd., and the resulting flakes are coarsely pulverized with a granulator equipped with a screen. In addition, the product size was adjusted with Freund Sangyo Co., Ltd., “Rolldara-Yureta”, and sieved using a 355 μm sieve to obtain a powdered cellulose granulated product with a volume average particle size of 95 m . The angle of repose of the raw material powdered cellulose was 60 degrees or more, while the angle of repose of the powdered cellulose granule was 42 degrees, and the fluidity was remarkably improved.
[0073] 粉末セルロース造粒物 23. 85質量部、実施例 1の D—マン-トール造粒物 55. 65 質量部（D—マン-トール造粒物と粉末セルロース造粒物との質量比 = 70 : 30)、活 性成分としてァスコルビン酸 (ビタミン剤） 20質量部、滑沢剤としてステアリン酸マグネ シゥム 0. 5質量部を混合して打錠用混合物を調製し、打錠圧を 8kNとした以外は実 施例 1と同じ条件で打錠を行い、口腔内速崩壊錠を得た。錠剤硬度は 72Nであり、 崩壊時間は 18秒であり、服用試験にぉ ヽてはほとんど違和感は認められなかった。 また、ざらつき感の評価を行ったところ、ざらつき感はほとんど感じられな力つた。  [0073] 23.85 parts by mass of powdered cellulose granulated product, D-mann-toll granulated product of Example 1 55.65 parts by mass (mass ratio of D-mann-toll granulated product to powdered cellulose granulated product = 70:30), 20 parts by weight of ascorbic acid (vitamin) as the active ingredient, and 0.5 parts by weight of magnesium stearate as the lubricant were mixed to prepare a tableting mixture, and the tableting pressure was 8 kN. Except that, tableting was performed under the same conditions as in Example 1 to obtain an orally rapidly disintegrating tablet. The tablet hardness was 72N, the disintegration time was 18 seconds, and almost no sense of incongruity was observed in the administration test. Moreover, when the rough feeling was evaluated, the rough feeling was almost unnoticeable.
[0074] [実施例 11]  [0074] [Example 11]
粉末状 D—マン-トール（ROQUETTE社製、商品名「PEARLITOL50C」） 2. 5 kgを 7. 5kgの 50°C温水に溶かし、 D—マン-トール水溶液を調製した。粉末状 D— マン-トール (ROQUETTE社製、商品名「PEARLITOL50C」）3. 1kgを実施例 1 の遠心転動造粒コーティング装置に仕込み、これに D—マン-トール水溶液 5. Okg をスプレーした時点（固形分で 1. 25kg,仕込んだ粉末状 D—マン-トール 100質量 %に対して 40. 3質量％)で実施例 1の結晶セルロース 1. 4kgを追カ卩的に仕込み、さ らに残りの D—マン-トール水溶液 5. Okgをスプレーして造粒操作を行い、体積平 均粒子径が 84 μ mの D—マン-トール '結晶セルロース造粒物を得た。  Powdered D-manthol (ROQUETTE, trade name “PEARLITOL50C”) 2.5 kg was dissolved in 7.5 kg of 50 ° C. warm water to prepare a D-mannthol aqueous solution. Powdered D-Mann-Tall (ROQUETTE, trade name “PEARLITOL50C”) 3.1 kg was charged into the centrifugal tumbling granulation coating apparatus of Example 1, and D-Mann-Tol aqueous solution 5. Okg was sprayed on it. At the time (1.25 kg in solids, 40.3% by mass with respect to 100% by mass of powdered D-mannthol charged) 1.4 kg of crystalline cellulose of Example 1 was additionally charged. The remaining D-manntol aqueous solution (5 kg) was sprayed with a granulation operation to obtain a D-manntol crystal cellulose granulated product having a volume average particle diameter of 84 μm.
この D—マン-トール ·結晶セルロース造粒物（D—マン-トールと結晶セルロース との質量比 =80 : 20) 96. 3質量部、活性成分である塩酸チアミン 3質量部、ステアリ ン酸マグネシウム 0. 7質量部を混合して打錠用混合物を調製し、実施例 1と同じ条 件で打錠を行い、口腔内速崩壊錠を得た。錠剤硬度は 65Nであり、崩壊時間は 19 秒であり、服用試験においてほとんど違和感は認められな力つた。 This D-mann-tol crystalline cellulose granulate (mass ratio of D-mann-tol to crystalline cellulose = 80:20) 96. 3 parts by mass, 3 parts by mass of thiamine hydrochloride as an active ingredient, steari A mixture for tableting was prepared by mixing 0.7 part by mass of magnesium acid, and tableting was performed under the same conditions as in Example 1 to obtain an orally rapidly disintegrating tablet. The tablet hardness was 65N and the disintegration time was 19 seconds.
産業上の利用可能性 Industrial applicability
本発明の口腔内速崩壊錠は、口腔内で速やかに崩壊し、さわやかな味質を持つマ ン-トールを主要な添加剤成分とすることから、服用しやすい性質があり、多くの活性 成分に対する経口投与製剤として有用である。また、必須とされる添加剤成分が少な いことから、製造における工程数および原材料の管理に要する労力が少なくてすみ 、かつ特別な設備を要しないことから、特殊な製剤でありながら、低いコストでの製造 が可能である。  The rapidly disintegrating tablet in the oral cavity of the present invention disintegrates rapidly in the oral cavity and has a refreshing taste as a main additive component, and therefore has a property that it is easy to take, and many active ingredients It is useful as a preparation for oral administration. In addition, since there are few essential additive components, the number of manufacturing processes and the management of raw materials can be reduced, and no special equipment is required. It is possible to manufacture with

Claims

請求の範囲 The scope of the claims
[1] D—マン-トール造粒物と、  [1] D—Mann-Tall granulate,
結晶セルロースまたは粉末セルロースと、  Crystalline cellulose or powdered cellulose;
活性成分とを含有し、  Containing active ingredients,
崩壊剤を含まな!/、ものであって、  Does not contain disintegrant! /
前記 D—マン-トール造粒物と結晶セルロースまたは粉末セルロースとの質量比（D マン-トール造粒物：結晶セルロースまたは粉末セルロース）力 95： 5〜70： 30で あることを特徴とする口腔内速崩壊錠。  The oral cavity characterized by having a mass ratio of D-Mann-Tall granulated product to crystalline cellulose or powdered cellulose (D Mann-Tall granulated product: crystalline cellulose or powdered cellulose) 95: 5 to 70:30 Inner speed disintegrating tablet.
[2] D—マン-トール造粒物と、 [2] D—Mann-Tall granulate,
結晶セルロース造粒物または粉末セルロース造粒物と、  Crystalline cellulose granules or powdered cellulose granules,
活性成分とを含有し、  Containing active ingredients,
崩壊剤を含まな!/、ものであって、  Does not contain disintegrant! /
前記 D—マン-トール造粒物と結晶セルロース造粒物または粉末セルロース造粒物 との質量比（D—マン-トール造粒物：結晶セルロース造粒物または粉末セルロース 造粒物）力 95： 5〜70： 30であることを特徴とする口腔内速崩壊錠。  Mass ratio of D-mann-toll granule to crystalline cellulose granulated product or powdered cellulose granulated product (D-mann-toll granulated product: crystalline cellulose granulated product or powdered cellulose granulated product) Force 95: An orally rapidly disintegrating tablet characterized by being 5 to 70:30.
[3] D—マンニトーノレと、 [3] D—mannito
結晶セルロースまたは粉末セルロースと、  Crystalline cellulose or powdered cellulose;
活性成分とを含有し、  Containing active ingredients,
崩壊剤を含まな!/、ものであって、  Does not contain disintegrant! /
前記 D—マン-トールと結晶セルロースまたは粉末セルロースとの質量比（D マン 二トール：結晶セルロースまたは粉末セルロース）が 95： 5〜70： 30であり、 前記 D マン-トールと、結晶セルロースまたは粉末セルロースは、これら成分を構 成成分とする造粒物として含まれることを特徴とする口腔内速崩壊錠。  The mass ratio of D-mannitol and crystalline cellulose or powdered cellulose (Dmannitol: crystalline cellulose or powdered cellulose) is 95: 5 to 70:30, and the D-mannitol and crystalline cellulose or powdered Cellulose is contained as a granulated product containing these components as constituents, and is an orally rapidly disintegrating tablet.
[4] D—マン-トール造粒物と、結晶セルロースまたは粉末セルロースと、活性成分とを 含有し、崩壊剤を含まず、前記 D—マン-トール造粒物と結晶セルロースまたは粉末 セルロースとの質量比（D—マン-トール造粒物：結晶セルロースまたは粉末セル口 ース）が 95 : 5〜70： 30である混合物を、直接粉末圧縮法により圧縮成形することを 特徴とする口腔内速崩壊錠の製造法。 [4] A D-mann-tol granulated product, comprising crystalline cellulose or powdered cellulose and an active ingredient, and containing no disintegrant, Intraoral speed characterized by compression molding a mixture with a mass ratio (D-mann-toll granulated product: crystalline cellulose or powder cell mouth) of 95: 5 to 70:30 by direct powder compression method Production method of disintegrating tablets.
[5] 結晶セルロースまたは粉末セルロースをあら力じめ造粒して造粒物とし、結晶セル口 一ス造粒物または粉末セルロース造粒物を混合物に含ませることを特徴とする請求 項 4記載の口腔内速崩壊錠の製造法。 [5] The crystalline cellulose or powdered cellulose is granulated to make a granulated product, and the crystal cell mouth granulated product or the powdered cellulose granulated product is included in the mixture. Of the method for producing rapidly disintegrating tablets in the oral cavity.
[6] D—マンニトーノレと、 [6] D—mannito
結晶セルロースまたは粉末セルロースと、  Crystalline cellulose or powdered cellulose;
活性成分とを含有し、  Containing active ingredients,
崩壊剤を含まな!/、ものであって、  Does not contain disintegrant! /
前記 D—マン-トールと結晶セルロースまたは粉末セルロースとの質量比（D—マン 二トール：結晶セルロースまたは粉末セルロース）が 95： 5〜70： 30であり、 前記 D—マン-トールと、結晶セルロースまたは粉末セルロースは、これら成分を構 成成分とする造粒物として加えて得られる混合物を、直接粉末圧縮法により圧縮成 形することを特徴とする口腔内速崩壊錠の製造法。  The mass ratio of D-mann-tol and crystalline cellulose or powdered cellulose (D-mannitol: crystalline cellulose or powdered cellulose) is 95: 5-70: 30, and the D-mann-toll and crystalline cellulose Alternatively, powdered cellulose is a method for producing an orally rapidly disintegrating tablet, characterized in that a mixture obtained by adding these ingredients as a granulated product is directly compressed by a powder compression method.
PCT/JP2006/315004 2005-08-05 2006-07-28 Tablet rapidly disintegrating in the oral cavity and method of producing the same WO2007018057A1 (en)

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Cited By (8)

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Publication number Priority date Publication date Assignee Title
WO2009102038A1 (en) * 2008-02-13 2009-08-20 Dainippon Sumitomo Pharma Co., Ltd. Orally disintegrating tablets
JP5594285B2 (en) * 2009-03-16 2014-09-24 ニプロ株式会社 Orally disintegrating tablets
JPWO2013125497A1 (en) * 2012-02-20 2015-07-30 ニプロ株式会社 Method for producing orally disintegrating tablets
JP2015155386A (en) * 2014-02-20 2015-08-27 フロイント産業株式会社 Spherical granulated material aggregate of sugar alcohol, production method thereof, and tablet
JP2015533129A (en) * 2012-10-16 2015-11-19 ゼンティーバ，カー．エス． Solid oral pharmaceutical formulation containing ticagrelor
WO2015198483A1 (en) * 2014-06-27 2015-12-30 フロイント産業株式会社 Excipient granules, and tablet
JP6002869B1 (en) * 2015-10-16 2016-10-05 持田製薬株式会社 Dienogest-containing tablets
CN107823144A (en) * 2017-11-15 2018-03-23 山东天力药业有限公司 A kind of preparation method of high-purity mannitol vertical compression particle

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JPH05306229A (en) * 1992-03-03 1993-11-19 Lederle Japan Ltd Chewable tablet containing calcium
JPH10298061A (en) * 1997-04-25 1998-11-10 Tanabe Seiyaku Co Ltd Shaped preparation and its production
JP2000095675A (en) * 1998-09-22 2000-04-04 Rohto Pharmaceut Co Ltd Oral solid pharmaceutical composition for treating rhinitis of intraoral soluble type or mastication type
JP2002539165A (en) * 1999-03-16 2002-11-19 ペンテツク・フアーマシユーテイカルズ・インコーポレイテツド Controlled release of sildenafil delivered by sublingual or buccal administration
JP2003034655A (en) * 2001-05-15 2003-02-07 Takeda Chem Ind Ltd Fast degradable solid tablet

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JPH05306229A (en) * 1992-03-03 1993-11-19 Lederle Japan Ltd Chewable tablet containing calcium
JPH10298061A (en) * 1997-04-25 1998-11-10 Tanabe Seiyaku Co Ltd Shaped preparation and its production
JP2000095675A (en) * 1998-09-22 2000-04-04 Rohto Pharmaceut Co Ltd Oral solid pharmaceutical composition for treating rhinitis of intraoral soluble type or mastication type
JP2002539165A (en) * 1999-03-16 2002-11-19 ペンテツク・フアーマシユーテイカルズ・インコーポレイテツド Controlled release of sildenafil delivered by sublingual or buccal administration
JP2003034655A (en) * 2001-05-15 2003-02-07 Takeda Chem Ind Ltd Fast degradable solid tablet

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009102038A1 (en) * 2008-02-13 2009-08-20 Dainippon Sumitomo Pharma Co., Ltd. Orally disintegrating tablets
JP4989733B2 (en) * 2008-02-13 2012-08-01 大日本住友製薬株式会社 Orally disintegrating tablets
CN102006861B (en) * 2008-02-13 2012-11-21 大日本住友制药株式会社 Orally disintegrating tablets
JP5594285B2 (en) * 2009-03-16 2014-09-24 ニプロ株式会社 Orally disintegrating tablets
JPWO2013125497A1 (en) * 2012-02-20 2015-07-30 ニプロ株式会社 Method for producing orally disintegrating tablets
JP2015533129A (en) * 2012-10-16 2015-11-19 ゼンティーバ，カー．エス． Solid oral pharmaceutical formulation containing ticagrelor
JP2015155386A (en) * 2014-02-20 2015-08-27 フロイント産業株式会社 Spherical granulated material aggregate of sugar alcohol, production method thereof, and tablet
WO2015198483A1 (en) * 2014-06-27 2015-12-30 フロイント産業株式会社 Excipient granules, and tablet
JP6002869B1 (en) * 2015-10-16 2016-10-05 持田製薬株式会社 Dienogest-containing tablets
WO2017064814A1 (en) * 2015-10-16 2017-04-20 持田製薬株式会社 Dienogest-containing tablet
CN107823144A (en) * 2017-11-15 2018-03-23 山东天力药业有限公司 A kind of preparation method of high-purity mannitol vertical compression particle

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