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WO2007018057A1 - Comprime se desintegrant rapidement dans la cavite buccale et son procede de fabrication - Google Patents

Comprime se desintegrant rapidement dans la cavite buccale et son procede de fabrication 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
Application number
PCT/JP2006/315004
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English (en)
Japanese (ja)
Inventor
Fujio Sekigawa
Takeshi Honma
Masayuki Arakawa
Original Assignee
Freund Corporation
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Filing date
Publication date
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Publication of WO2007018057A1 publication Critical patent/WO2007018057A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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

L'invention concerne un comprimé se désintégrant rapidement dans la cavité buccale pouvant être obtenu facilement à moindre coût et qui est assez résistant pour ne pas se casser lors de la fabrication, le transport et le stockage et similaires, mais qui se désintègre rapidement dans la cavité buccale, qui a un goût rafraîchissant et une texture poudreuse réduite. Elle concerne également le procédé pour le fabriquer. Ce comprimé se désintégrant rapidement dans la cavité buccale contient une substance granulaire à base de D-mannitol, de la cellulose cristalline ou de la cellulose en poudre et un principe actif et ne contient pas de désintégrateur, et le rapport de masse de la substance granulaire à base de D-mannitol sur la cellulose cristalline ou la cellulose en poudre (substance granulaire à base de D-mannitol/cellulose cristalline ou cellulose en poudre) va de 95/5 à 70/30.
PCT/JP2006/315004 2005-08-05 2006-07-28 Comprime se desintegrant rapidement dans la cavite buccale et son procede de fabrication WO2007018057A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009102038A1 (fr) * 2008-02-13 2009-08-20 Dainippon Sumitomo Pharma Co., Ltd. Comprimés se délitant oralement
JP5594285B2 (ja) * 2009-03-16 2014-09-24 ニプロ株式会社 口腔内崩壊錠
JPWO2013125497A1 (ja) * 2012-02-20 2015-07-30 ニプロ株式会社 口腔内崩壊錠の製造方法
JP2015155386A (ja) * 2014-02-20 2015-08-27 フロイント産業株式会社 糖アルコール球形造粒物集合体及びその製造方法、並びに錠剤
JP2015533129A (ja) * 2012-10-16 2015-11-19 ゼンティーバ，カー．エス． チカグレロルを含む固形経口医薬製剤
WO2015198483A1 (fr) * 2014-06-27 2015-12-30 フロイント産業株式会社 Granulés d'excipient, et comprimé
JP6002869B1 (ja) * 2015-10-16 2016-10-05 持田製薬株式会社 ジエノゲスト含有錠剤
CN107823144A (zh) * 2017-11-15 2018-03-23 山东天力药业有限公司 一种高纯度甘露醇直压颗粒的制备方法

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Publication number Priority date Publication date Assignee Title
JPH05306229A (ja) * 1992-03-03 1993-11-19 Lederle Japan Ltd カルシウム含有チユアブル錠
JPH10298061A (ja) * 1997-04-25 1998-11-10 Tanabe Seiyaku Co Ltd 成型製剤及びその製法
JP2000095675A (ja) * 1998-09-22 2000-04-04 Rohto Pharmaceut Co Ltd 口中溶解型又は咀嚼型鼻炎治療用固形内服医薬組成物
JP2002539165A (ja) * 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 舌下またはバッカル投与により送出されるシルデナフィルの制御放出
JP2003034655A (ja) * 2001-05-15 2003-02-07 Takeda Chem Ind Ltd 速崩壊性固形製剤

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05306229A (ja) * 1992-03-03 1993-11-19 Lederle Japan Ltd カルシウム含有チユアブル錠
JPH10298061A (ja) * 1997-04-25 1998-11-10 Tanabe Seiyaku Co Ltd 成型製剤及びその製法
JP2000095675A (ja) * 1998-09-22 2000-04-04 Rohto Pharmaceut Co Ltd 口中溶解型又は咀嚼型鼻炎治療用固形内服医薬組成物
JP2002539165A (ja) * 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 舌下またはバッカル投与により送出されるシルデナフィルの制御放出
JP2003034655A (ja) * 2001-05-15 2003-02-07 Takeda Chem Ind Ltd 速崩壊性固形製剤

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009102038A1 (fr) * 2008-02-13 2009-08-20 Dainippon Sumitomo Pharma Co., Ltd. Comprimés se délitant oralement
JP4989733B2 (ja) * 2008-02-13 2012-08-01 大日本住友製薬株式会社 口腔内崩壊錠
CN102006861B (zh) * 2008-02-13 2012-11-21 大日本住友制药株式会社 口腔崩解片
JP5594285B2 (ja) * 2009-03-16 2014-09-24 ニプロ株式会社 口腔内崩壊錠
JPWO2013125497A1 (ja) * 2012-02-20 2015-07-30 ニプロ株式会社 口腔内崩壊錠の製造方法
JP2015533129A (ja) * 2012-10-16 2015-11-19 ゼンティーバ，カー．エス． チカグレロルを含む固形経口医薬製剤
JP2015155386A (ja) * 2014-02-20 2015-08-27 フロイント産業株式会社 糖アルコール球形造粒物集合体及びその製造方法、並びに錠剤
WO2015198483A1 (fr) * 2014-06-27 2015-12-30 フロイント産業株式会社 Granulés d'excipient, et comprimé
JP6002869B1 (ja) * 2015-10-16 2016-10-05 持田製薬株式会社 ジエノゲスト含有錠剤
WO2017064814A1 (fr) * 2015-10-16 2017-04-20 持田製薬株式会社 Comprimé contenant du diénogest
CN107823144A (zh) * 2017-11-15 2018-03-23 山东天力药业有限公司 一种高纯度甘露醇直压颗粒的制备方法

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