WO2016098459A1 - Delayed disintegrating particulate composition - Google Patents

Delayed disintegrating particulate composition Download PDF

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Publication number
WO2016098459A1
WO2016098459A1 PCT/JP2015/080341 JP2015080341W WO2016098459A1 WO 2016098459 A1 WO2016098459 A1 WO 2016098459A1 JP 2015080341 W JP2015080341 W JP 2015080341W WO 2016098459 A1 WO2016098459 A1 WO 2016098459A1
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Prior art keywords
disintegrating
delayed
particle composition
sugar
tablet
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PCT/JP2015/080341
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French (fr)
Japanese (ja)
Inventor
隆弘 平邑
智仁 岡林
森田　哲郎
君子 池田
Original Assignee
株式会社ダイセル
ニチリン化学工業株式会社
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Priority to JP2016564726A priority Critical patent/JPWO2016098459A1/en
Publication of WO2016098459A1 publication Critical patent/WO2016098459A1/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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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

Definitions

  • the present invention relates to a delayed disintegrating particle composition containing a saccharide and various disintegrating tablets containing the composition.
  • Orally disintegrating tablets have been developed as a convenient form that can be safely taken by patients, elderly people, children, etc. who have difficulty swallowing drugs, and can be taken easily without water.
  • Orally disintegrating tablets have sufficient breaking strength (tablet hardness) that does not cause tablet chipping and powdering during tablet production or during transportation or opening, as in the case of ordinary tablets, and quickly in the oral cavity. It is important to have an excellent disintegration property (disintegration time) that disintegrates rapidly.
  • the inventors have developed a method for producing a disintegrating particle composition that imparts higher tablet hardness and disintegration, or higher tablet height without substantially extending disintegration time (patent) Reference 1).
  • a disintegrating particle composition comprising a first disintegrant component composed of acid-type carboxymethylcellulose, a second disintegrant component other than acid-type carboxymethylcellulose, an excipient composed of sugar or sugar alcohol, and four components of crystalline cellulose
  • a first disintegrant component composed of acid-type carboxymethylcellulose
  • a second disintegrant component other than acid-type carboxymethylcellulose an excipient composed of sugar or sugar alcohol
  • four components of crystalline cellulose The thing was developed (patent document 2).
  • the orally disintegrating tablet containing the disintegrating particle composition provided by these conventional techniques is characterized by having a hardness of about 50 to 150 (N) and an extremely short disintegration time in water of 10 to 30 (seconds). Yes.
  • oral preparation such as a solid preparation that gradually disintegrates in the oral cavity and a therapeutic agent for stomatitis
  • oral solid preparations such as a formulation and a troche tablet which start disintegrating after taking an appropriate time in the oral cavity are expected.
  • a preparation containing a crude drug or an X-ray contrast medium as an active ingredient which does not disintegrate in the oral cavity but rapidly disintegrates when reaching the stomach is desired.
  • a preparation containing a crude drug or an X-ray contrast medium as an active ingredient which does not disintegrate in the oral cavity but rapidly disintegrates when reaching the stomach is desired.
  • the existing formulation design for orally disintegrating tablets is used, rapid disintegration in the oral cavity will proceed, so that the disintegration time will not disintegrate until it reaches the stomach. Adjustment means are required.
  • the present invention provides a new particle composition with controlled disintegration time that enables the production of oral solid preparations for pharmaceuticals and various foods whose disintegration start time and disintegration time are in the range of several minutes. That is.
  • the present inventors have intensively studied, and as a result, the conventional disintegrating particles of a fast disintegrating agent having a very short disintegration time (for example, a disintegration time of 60 seconds or less in water).
  • the disintegration time was controlled by adding a large amount of sugar or sugar alcohol, which has been used as an excipient in a composition or the like (hereinafter also referred to as “original compound” for convenience), as a disintegration delay component.
  • original compound for convenience
  • a delayed disintegrating particle composition is obtained, and an oral solid preparation controlled to a desired disintegration time is obtained by tableting a mixture of the particle composition and an active ingredient. It came.
  • the present invention provides the following aspects.
  • a delayed disintegrating particle composition comprising a disintegrant component, a shaping aid, and a sugar or sugar alcohol, wherein the sugar or sugar alcohol content is 80% by weight or more.
  • Aspect 2 The delayed disintegrating particle composition according to aspect 1, wherein the sugar or sugar alcohol content is 90% by weight or more.
  • Aspect 3 The delayed disintegrating particle composition according to embodiments 1 or 2, wherein the sugar alcohol is mannitol and / or maltitol.
  • a food or pharmaceutical disintegrating tablet comprising the delayed disintegrating particle composition according to Aspects 1 to 5.
  • a food or pharmaceutical disintegrating tablet comprising the delayed disintegrating particle composition according to Aspects 1 to 5.
  • Aspect 7 The disintegrating tablet according to Aspect 6, wherein the disintegration time in water is 2 to 5 (min).
  • Aspect 8 The disintegrating tablet according to aspect 7, wherein the disintegration start time in water is 1 to 1.5 minutes.
  • the disintegrating particle composition in which the disintegration time is controlled by a simple means of containing a large amount of saccharide or sugar alcohol as a disintegration delay component in the above-mentioned original formulation.
  • the disintegrating particle composition has a characteristic disintegration profile that begins to disintegrate after a certain period of time after taking, and takes a long time of about 2 to 10 minutes, for example about 2 to 5 minutes. It is possible to provide a disintegrating tablet having low cost.
  • the main features of the delayed disintegrating particle composition of the present invention are a composition comprising a disintegrant component, a shaping aid and a sugar or sugar alcohol, wherein the sugar or sugar alcohol content is preferably 80% by weight or more. Is 90% by weight or more.
  • the delayed disintegrating particle composition of the present invention can be produced, for example, by a simple means in which a large amount of saccharide or sugar alcohol is contained in the above-mentioned original blend.
  • Sugar or sugar alcohol is contained as an excipient in the conventional disintegrating particle composition.
  • a particle composition containing a large amount of these composition sugars or sugar alcohols and having a controlled disintegration time has not been known so far.
  • a composition containing a disintegrant component, an excipienting agent and sugar a composition containing 80% by weight or more of sugar or sugar alcohol and requiring a disintegration time in water of about 1 minute or more. Not known until.
  • the compounding amount of each component other than sugar or sugar alcohol contained in the delayed disintegrating particle composition of the present invention as the disintegrating delay component is the type of each component, the type of disintegrating tablet for which the delayed disintegrating particle composition is used. Further, those skilled in the art can appropriately determine depending on the usage and the like.
  • sugar or sugar alcohol contained in the delayed disintegrating particle composition of the present invention include mannitol, erythritol, xylitol, trehalose, lactose, maltose, maltitol, glucose, sucrose, fructose, mannose, and sorbitol. I can do it.
  • a preferred example is maltitol.
  • One kind of sugar or sugar alcohol may be used, but two or more kinds of compounds appropriately selected from these may be used.
  • any material known to those skilled in the art can be used.
  • acid type carboxymethylcellulose crospovidone, croscarmellose sodium
  • low substituted hydroxypropylcellulose carboxymethylcellulose calcium
  • corn starch potato starch
  • waxy corn starch partially pregelatinized starch
  • pregelatinized starch pregelatinized starch and the like
  • starch One or more components selected from modified starches such as sodium glycolate and hydroxypropyl starch can be contained.
  • Crospovidone is a common name for a cross-linked polymer of 1-vinyl-2-pyrrolidone
  • croscarmellose sodium is a common name for a cross-linked product of sodium carboxymethylcellulose.
  • Acid-type carboxymethylcellulose is a substance called carmellose and is used as a pharmaceutical additive. Similar to acid-type carboxymethylcellulose, for example, calcium salt of carboxymethylcellulose and a crosslinked product of sodium carboxymethylcellulose are both insoluble in water and used as a disintegrant in tablets and the like. On the other hand, sodium salt of carboxymethyl cellulose is water-soluble and is used for the purpose of a binder or the like. In addition, the salt of carboxymethylcellulose may be described as carmellose.
  • Crystalline cellulose and powdered cellulose are white powdery substances that are insoluble in water, obtained by partially depolymerizing ⁇ -cellulose obtained from fibrous plants with acid. It has no taste and is chemically inert, so it does not change even when mixed with drugs, and is used for excipients, especially as excipients, binders or disintegrants when dispensing tablets. Is done. In addition to pharmaceuticals, it is used as an emulsion stabilizer in foods such as cosmetics and dairy products.
  • crystalline cellulose and / or powdered cellulose examples include Avicel (FMC Corporation), Theolas (Asahi Kasei Chemicals Co., Ltd.), Vivapuer (Lettenberg Meyer), etc.
  • KC Flock Nippon Paper Chemicals
  • ARBOCEL Retttenmeier
  • Solka Flock Solka Flock
  • the delayed disintegrating particle composition of the present invention contains various optional components known to those skilled in the art for the purpose of adjusting various properties such as disintegration strength, binding strength, and tablet feeling.
  • Arbitrary components other than those may be added and mixed as appropriate within a range not impairing the effects of the present invention due to the above components. Examples of such components include disintegrants, excipients, fluidizers, sweeteners, corrigents, fragrances, and coloring agents known to those skilled in the art.
  • disintegrants include inorganic excipients such as light anhydrous silicic acid, hydrous silicon dioxide, anhydrous calcium phosphate, anhydrous calcium hydrogen phosphate, aluminum metasilicate, calcium silicate, magnesium silicate, and magnesium oxide. it can.
  • the delayed disintegrating particle composition of the present invention can contain fine fibrous cellulose.
  • microfibrous cellulose any cellulose known as “microfibrous cellulose” or “microfibrous cellulose” can be used.
  • Microfibrous cellulose is a cellulose that is generally produced from plant fibers and has a fiber diameter (short diameter) or thickness of several nanometers to 1 ⁇ m. This means that the surface area is remarkably increased, the hydrophilicity that is inherent in cellulose is remarkably increased, and a three-dimensional network structure is formed by entanglement of microfibers. To do. Such a dried product of fine fibrous cellulose can be produced by any conventionally known technique. *
  • a preferred example of the microfibrous cellulose contained in the delayed disintegrating particle composition of the present invention is a fiber assembly having an average fiber length of about 0.01 to 2 mm and an average fiber diameter of about 0.001 to 1 ⁇ m.
  • a fine fibrous cellulose having an average fiber diameter of about 0.01 to 0.1 ⁇ m is preferable (Patent Document 2).
  • such a microfibrous cellulose (with a water content of 10 to 35% solids) is a product name “CELISH” series (average fiber diameter of about 0.01 to 0.1 ⁇ m), Daicel Finechem Co., Ltd.
  • Various grades of products are sold.
  • the compounding amount of each component other than sugar or sugar alcohol in the delayed disintegrating particle composition of the present invention depends on the type of each component, the type and use of the disintegrating tablet that is the target of use of the delayed disintegrating particle composition. Those skilled in the art can appropriately determine.
  • the delayed disintegrating particle composition of the present invention can also be produced by various granulation process methods. It does not specifically limit as a granulation means, It can also manufacture by the dry granulation method or the wet granulation process method.
  • the dry granulation method is a process in which various component powders contained in the delayed disintegrating particle composition are mixed as they are or with an appropriate binder, etc. to form a small lump by high pressure, and this is appropriately crushed and granulated.
  • Specific examples of the dry granulation method include a crushing granulation method and a roll compression method.
  • the wet granulation method is a method of forming a composite by dispersing and drying each component in the presence of water.
  • Specific examples of the wet granulation method include spray drying, tumbling granulation, stirring granulation, And spraying methods such as fluidized bed granulation, freeze-drying methods, kneading granulation, and the like, and these can be produced by any method known to those skilled in the art.
  • the raw formulation may be produced by a one-step granulation process in which all of the components contained in the delayed disintegrating particle composition of the present invention are used together, or Each component can be added and mixed as appropriate in a multi-stage wet granulation process.
  • each granulation step various conditions such as spraying speed, air supply temperature, exhaust temperature, air supply amount, etc. can be appropriately determined by those skilled in the art according to the type and amount of each component. .
  • examples of the spray liquid medium include solvents acceptable for pharmaceuticals and foods such as water, ethanol, methanol, and acetone.
  • examples of the spray liquid include an aqueous solution in which less than 10% of the components of the delayed disintegrating particle composition are dissolved, and water or the aqueous solution is particularly preferable.
  • the delayed disintegrating particle composition of the present invention can be easily produced simply by adding and mixing a sugar or a sugar alcohol as a disintegrating delay component to the above-mentioned original composition. Such addition and mixing can be carried out using a method and means for producing any pharmaceutical additive known to those skilled in the art.
  • the delayed disintegrating particle composition of the present invention preferably has the following physical properties. (1) Average particle size: 50 to 200 microns, (2) Water content: 0.5 to 6% by weight.
  • Average particle diameter 2 g of the delayed disintegrating particle composition is measured using a ⁇ 75 mm automatic shaking sieve (M-2 type, Tsutsui Rika Instruments Co., Ltd.).
  • Moisture 5 g of the delayed disintegrating particle composition is measured using a halogen moisture meter (HB43 type, METTLER TOLEDO).
  • the present invention relates to various disintegrating tablets containing such a delayed disintegrating particle composition, in particular, various disintegrating tablets for foods including supplementary foods, nutritional functional foods and health foods, or disintegrating tablets for pharmaceuticals.
  • a delayed disintegrating particle composition in particular, various disintegrating tablets for foods including supplementary foods, nutritional functional foods and health foods, or disintegrating tablets for pharmaceuticals.
  • the content of the delayed disintegrating particle composition in the disintegrating tablet can be appropriately selected by those skilled in the art according to the use and purpose of the disintegrating tablet within a range not impairing the desired effects of the present invention. There are no particular restrictions on the shape and form of the tablet.
  • such a disintegrating tablet contains the delayed disintegrating particle composition of the present invention, it has excellent tablet hardness and desired delayed disintegrating property. That is, as shown in each example of the present specification, for example, when manufactured at a tableting pressure of about 4 to 20 kN, the hardness is 10 to 100 (N), more preferably 12 to 100 (N), and still more preferably. 15 to 100 (N), and the disintegration time in water is 2 to 10 (min), more preferably 2 to 5 (min), and further preferably 3 to 5 (min). Furthermore, it is more preferable that the disintegrating tablet of the present invention has a disintegration start time in water of about 1 to 1.5 minutes, that is, it does not disintegrate for at least about 1 minute after taking.
  • the disintegrating tablet of the present invention may contain an optional component in addition to the delayed disintegrating particle composition.
  • various active ingredients such as various nutritional components such as proteins, sugars, lipids and minerals; various vitamins and their derivatives; various extracts derived from microorganisms, plants or animals
  • health food materials such as sour agents, sweeteners, excipients, surfactants, lubricants, sour agents, sweeteners, flavoring agents, fragrances, colorants, and stabilizers
  • sour agents sweeteners, excipients, surfactants, lubricants, sour agents, sweeteners, flavoring agents, fragrances, colorants, and stabilizers
  • the pharmaceutical disintegrating tablet further includes an excipient, a surfactant, a lubricant, a sour agent, and a sweetener as necessary.
  • other pharmaceutically acceptable ingredients such as flavoring agents, flavoring agents, coloring agents, and stabilizers.
  • these optional components for example, the corresponding components described in the Pharmaceutical Additives Dictionary (Pharmaceutical Daily) and the Japanese Pharmacopoeia can be used.
  • disintegrating tablets can be formulated by any method known to those skilled in the art, such as tableting.
  • Examples of uses / types of medicinal ingredients contained in the disintegrating tablet of the present invention include, for example, central nervous system drugs, peripheral nervous system drugs, sensory organ drugs, vaginal cardiovascular drugs, respiratory organ drugs, digestive organ drugs, Hormonal drugs, urogenital drugs, other drugs for individual organs, vitamins, nourishing tonics, blood and body fluids, other metabolic drugs, cell-use drugs, oncology drugs, radiopharmaceuticals, allergies Drugs, other drugs for tissue cell function, herbal medicines, Kampo medicines, other herbal medicines and medicines based on Kampo medicines, antibiotics, chemotherapeutics, biologicals, drugs for parasites, drugs for other pathogenic organisms, Dispensing drugs, diagnostic drugs, public health drugs, in vitro diagnostic drugs, and the like.
  • Hardness Hardness (N) was measured using a digital Kiya-type hardness meter (Fujiwara Manufacturing Co., Ltd.).
  • Disintegration time in water The disintegration time in water was measured using a disintegration tester (NT-400, Toyama Sangyo Co., Ltd.) according to the method described in the Japanese Pharmacopoeia (but without an auxiliary board). The hardness and disintegration time were each measured 6 times, and the average value thereof was taken as the measurement result.
  • Oral disintegration time Measured using a tricoop tester (addition rate 6 mL / min, 40 g weight).
  • Example 2 As a comparative example, instead of the delayed disintegrating particle composition of the present invention produced in Example 1, only maltitol (tablet 1) or only crystalline cellulose (tablet 2) was used, and further replaced with maltitol.
  • Each tablet was prepared in the same manner using the composition containing 4% (Tablet 4).
  • the disintegration time in water was still less than 1 minute in the tablet 3 using the disintegrating composition having a sugar or sugar alcohol (trehalose and D-mannitol) content of 74% by weight.
  • the same results were obtained with tablet 4 obtained by changing trehalose to maltitol with the same content.
  • tablet 1 using only maltitol or tablet 2 using only crystalline cellulose the disintegration time in water is extended to about 2 to 7 minutes, but the disintegration starts from about 10 seconds. It has been found that it is not suitable as a drug that is desired to disintegrate rapidly when it reaches the stomach or intestine without disintegrating in the oral cavity or esophagus.
  • the disintegration start time is about 1 to 1.5 minutes and the disintegration time could be delayed to about 3-5 minutes.
  • the present invention greatly contributes to the research and development of various disintegrating tablets having excellent tablet hardness and a disintegration profile that starts to disintegrate after a certain period of time after taking and requires a disintegration time of about 1 minute or more. It is.

Abstract

The purpose of the present invention is to provide a novel particulate composition with a controlled disintegration time, said particulate composition enabling the production of an oral solid preparation usable for medicines and various foods the disintegration starting time and disintegration time of which are accurately controlled in a range of several minutes. Provided are: a delayed disintegrating particulate composition comprising a disintegrating component, an auxiliary filler and a sugar or sugar alcohol, characterized in that the content of the sugar or sugar alcohol is 80% by weight or greater; a method for manufacturing the delayed disintegrating particulate composition; and a disintegrating tablet usable for foods or medicines, said disintegrating tablet comprising the delayed disintegrating particulate composition.

Description

遅延崩壊性粒子組成物Delayed disintegrating particle composition
　本発明は、糖類を含む遅延崩壊性粒子組成物及び該組成物を含む各種の崩壊錠剤等に関する。 The present invention relates to a delayed disintegrating particle composition containing a saccharide and various disintegrating tablets containing the composition.
　これまでに、薬剤の嚥下が困難な患者、高齢者、小児などが安全に服用でき、また水なしで容易に服用できる利便性の高い形態として、口腔内崩壊錠剤が開発されてきた。口腔内崩壊錠剤は、通常の錠剤と同様に錠剤製造時又は輸送中若しくは開封中に錠剤の欠け及び粉化等が生じないような充分な破壊強度（錠剤硬度）を有すると共に、口腔内で速やかに崩壊するような優れた崩壊性（崩壊時間）を有していることが重要である。 So far, orally disintegrating tablets have been developed as a convenient form that can be safely taken by patients, elderly people, children, etc. who have difficulty swallowing drugs, and can be taken easily without water. Orally disintegrating tablets have sufficient breaking strength (tablet hardness) that does not cause tablet chipping and powdering during tablet production or during transportation or opening, as in the case of ordinary tablets, and quickly in the oral cavity. It is important to have an excellent disintegration property (disintegration time) that disintegrates rapidly.
　例えば、本発明者等によって、より優れた錠剤硬度と崩壊性、もしくは実質的に崩壊時間を延長させること無くより高い錠剤高度を賦与する崩壊性粒子組成物の製造方法製造が開発された（特許文献１）。 For example, the inventors have developed a method for producing a disintegrating particle composition that imparts higher tablet hardness and disintegration, or higher tablet height without substantially extending disintegration time (patent) Reference 1).
　更に、酸型カルボキシメチルセルロースからなる第一の崩壊剤成分、酸型カルボキシメチルセルロース以外の第二の崩壊剤成分、糖又は糖アルコールからなる賦形剤、及び結晶セルロースの四成分を含む崩壊性粒子組成物が開発された（特許文献２）。 Furthermore, a disintegrating particle composition comprising a first disintegrant component composed of acid-type carboxymethylcellulose, a second disintegrant component other than acid-type carboxymethylcellulose, an excipient composed of sugar or sugar alcohol, and four components of crystalline cellulose The thing was developed (patent document 2).
　これらの従来技術で提供される崩壊性粒子組成物を含む口腔内崩壊錠剤は、硬度が５０～１５０（Ｎ）程度であり、水中崩壊時間が１０～３０（秒）という極めて短いことを特徴としている。 The orally disintegrating tablet containing the disintegrating particle composition provided by these conventional techniques is characterized by having a hardness of about 50 to 150 (N) and an extremely short disintegration time in water of 10 to 30 (seconds). Yes.
国際公開パンフレットＷＯ２０１３／１４６９１７International publication pamphlet WO2013 / 14617 国際公開パンフレットＷＯ２０１４／０４６０３５International publication pamphlet WO2014 / 046035
　これに対し、これまで皮下注射等で投与していた有効成分（例えばアレルギー治療薬）を口腔内粘膜吸収させる投与方法として、口腔内で徐々に崩壊する固形製剤、並びに口内炎治療薬などのオーラルケア用途として口腔内で適切な時間を要して崩壊が始まる製剤及びトローチ錠などの経口固形剤が期待されている。 On the other hand, as an administration method for absorption of the active ingredient (for example, allergy therapeutic agent) that has been administered by subcutaneous injection until now into the oral mucosa, oral preparation such as a solid preparation that gradually disintegrates in the oral cavity and a therapeutic agent for stomatitis As a use, oral solid preparations such as a formulation and a troche tablet which start disintegrating after taking an appropriate time in the oral cavity are expected.
　更に、例えば有効成分として生薬やX線造影剤等を含む製剤であって、口腔内では崩壊しないで、胃に到達した場合に速やかな崩壊する製剤が望まれている。しかし、既存の口腔内崩壊錠用の製剤設計を利用した場合、口腔内での速やかな崩壊が進行してしまうため、胃に到達するまでは崩壊する事のない適切な崩壊時間とするための調節手段が必要となる。 Furthermore, for example, a preparation containing a crude drug or an X-ray contrast medium as an active ingredient, which does not disintegrate in the oral cavity but rapidly disintegrates when reaching the stomach is desired. However, when the existing formulation design for orally disintegrating tablets is used, rapid disintegration in the oral cavity will proceed, so that the disintegration time will not disintegrate until it reaches the stomach. Adjustment means are required.
　以上のような製剤を製造するに為に、従来技術においては、錠剤等の経口固形剤の崩壊時間を長くする側への調整手段としては、例えば、コーティング剤で製剤全体を被覆する手段が用いられているが、所望の崩壊開始時間および崩壊時間に調整することは困難であった。また、崩壊性が乏しい製剤を基に、崩壊剤の添加量を増量していく等の方法では、錠剤強度や保存安定性との両立が容易ではなかった。 In order to produce the preparation as described above, in the prior art, as a means for adjusting the disintegration time of an oral solid preparation such as a tablet, a means for covering the whole preparation with a coating agent is used, for example. However, it was difficult to adjust to the desired disintegration start time and disintegration time. Moreover, it is not easy to achieve both tablet strength and storage stability by a method such as increasing the amount of disintegrant added based on a preparation with poor disintegration.
　本発明の目的はこのような課題を解決することである。すなわち崩壊開始時間および崩壊時間が数分程度の範囲で緻密に制御された医薬用及び各種食品用の経口固形剤の製造を可能とする、崩壊時間が制御された新たな粒子組成物を提供することである。 The purpose of the present invention is to solve such problems. That is, the present invention provides a new particle composition with controlled disintegration time that enables the production of oral solid preparations for pharmaceuticals and various foods whose disintegration start time and disintegration time are in the range of several minutes. That is.
　本発明者らは、上記課題を解決するために、鋭意、研究の結果、崩壊時間が極めて短い（例えば、水中崩壊時間が６０秒以下の崩壊性を有する）速崩壊剤の従来の崩壊性粒子組成物等（以下、便宜上、「原配合物」ともいう）に於いて賦形剤として用いられてきた糖類または糖アルコールを、崩壊遅延成分として多量に添加することにより、崩壊時間が制御された遅延崩壊性粒子組成物が得られ、また該粒子組成物と有効成分の混合物を打錠することで所望の崩壊時間に制御された経口固形剤が得られることを見出し、本発明を完成するに至った。 In order to solve the above problems, the present inventors have intensively studied, and as a result, the conventional disintegrating particles of a fast disintegrating agent having a very short disintegration time (for example, a disintegration time of 60 seconds or less in water). The disintegration time was controlled by adding a large amount of sugar or sugar alcohol, which has been used as an excipient in a composition or the like (hereinafter also referred to as “original compound” for convenience), as a disintegration delay component. In order to complete the present invention, a delayed disintegrating particle composition is obtained, and an oral solid preparation controlled to a desired disintegration time is obtained by tableting a mixture of the particle composition and an active ingredient. It came.
　本発明は、より具体的には以下の態様を提供するものである。 More specifically, the present invention provides the following aspects.
［態様１］
崩壊剤成分、賦形補助剤、及び、糖又は糖アルコールを含む組成物であって、糖又は糖アルコールの含有量が８０重量％以上であることを特徴とする、遅延崩壊性粒子組成物。
［態様２］
糖又は糖アルコールの含有量が９０重量％以上である、態様１記載の遅延崩壊性粒子組成物。
［態様３］
糖アルコールがマンニトール及び／又はマルチトールである、態様１～２記載の遅延崩壊性粒子組成物。
［態様４］
崩壊剤成分として、酸型カルボキシメチルセルロース及び/又はクロスポピドンを含む、態様１ないし３のいずれか一項に記載の遅延崩壊性粒子組成物。
［態様５］
賦形補助剤が結晶性セルロース及び／又は粉末セルロースである、態様１ないし４のいずれか一項に記載の遅延崩壊性粒子組成物。
［態様６］態様１～５に記載の遅延崩壊性粒子組成物を含む食品用または医薬用崩壊錠剤。
［態様７］水中崩壊時間が２～５（分）である、態様６記載の崩壊錠剤。
［態様８］水中崩壊開始時間が１～１．５分である、態様７記載の崩壊錠剤。
［態様９］
水中崩壊時間が６０秒以下の崩壊性粒子組成物に糖又は糖アルコールを添加、混合することを含む、態様１～５のいずれか一項に記載の遅延崩壊性粒子組成物の製造方法。 [Aspect 1]
A delayed disintegrating particle composition comprising a disintegrant component, a shaping aid, and a sugar or sugar alcohol, wherein the sugar or sugar alcohol content is 80% by weight or more.
[Aspect 2]
The delayed disintegrating particle composition according to aspect 1, wherein the sugar or sugar alcohol content is 90% by weight or more.
[Aspect 3]
The delayed disintegrating particle composition according to embodiments 1 or 2, wherein the sugar alcohol is mannitol and / or maltitol.
[Aspect 4]
The delayed disintegrating particle composition according to any one of aspects 1 to 3, comprising acid-type carboxymethylcellulose and / or crospovidone as a disintegrant component.
[Aspect 5]
The delayed disintegrating particle composition according to any one of Embodiments 1 to 4, wherein the shaping aid is crystalline cellulose and / or powdered cellulose.
[Aspect 6] A food or pharmaceutical disintegrating tablet comprising the delayed disintegrating particle composition according to Aspects 1 to 5.
[Aspect 7] The disintegrating tablet according to Aspect 6, wherein the disintegration time in water is 2 to 5 (min).
[Aspect 8] The disintegrating tablet according to aspect 7, wherein the disintegration start time in water is 1 to 1.5 minutes.
[Aspect 9]
The method for producing a delayed disintegrating particle composition according to any one of aspects 1 to 5, comprising adding and mixing a sugar or a sugar alcohol to a disintegrating particle composition having a disintegration time in water of 60 seconds or less.
　本発明によって、上記の原配合物に崩壊遅延成分として糖類又は糖アルコールを多量に含有させる、という簡便な手段によって崩壊時間が制御された遅延崩壊性粒子組成物を製造することができ、該遅延崩壊性粒子組成物を用いることによって、服用してから一定時間経過後に崩壊し始め、崩壊に約２～１０分、例えば、約２～５分という長い時間を要するという、特徴的な崩壊プロファイルを有する崩壊錠剤を低コストで提供することができる。 According to the present invention, it is possible to produce a delayed disintegrating particle composition in which the disintegration time is controlled by a simple means of containing a large amount of saccharide or sugar alcohol as a disintegration delay component in the above-mentioned original formulation. By using the disintegrating particle composition, it has a characteristic disintegration profile that begins to disintegrate after a certain period of time after taking, and takes a long time of about 2 to 10 minutes, for example about 2 to 5 minutes. It is possible to provide a disintegrating tablet having low cost.
　本発明の遅延崩壊性粒子組成物の主な特徴は、崩壊剤成分、賦形補助剤及び糖又は糖アルコールを含む組成物であって、糖又は糖アルコールの含有量が８０重量％以上、好ましくは９０重量％以上である点にある。本発明の遅延崩壊性粒子組成物は、例えば、上記の原配合物に糖類又は糖アルコールを多量に含有させる、という簡便な手段によって製造することが出来る。 The main features of the delayed disintegrating particle composition of the present invention are a composition comprising a disintegrant component, a shaping aid and a sugar or sugar alcohol, wherein the sugar or sugar alcohol content is preferably 80% by weight or more. Is 90% by weight or more. The delayed disintegrating particle composition of the present invention can be produced, for example, by a simple means in which a large amount of saccharide or sugar alcohol is contained in the above-mentioned original blend.
　糖又は糖アルコールは、従来の崩壊性粒子組成物において、賦形剤として含まれている。しかしながら、本発明のように、これら組成物糖又は糖アルコールを多量に含有させ、崩壊時間が制御された粒子組成物はこれまでに知られていない。更に、崩壊剤成分、賦形補助剤及び糖を含む従来の崩壊性組成物において、糖又は糖アルコールを８０重量％以上も含み、水中崩壊時間が約１分以上も要するような組成物はこれまでに知られていない。 Sugar or sugar alcohol is contained as an excipient in the conventional disintegrating particle composition. However, as in the present invention, a particle composition containing a large amount of these composition sugars or sugar alcohols and having a controlled disintegration time has not been known so far. Furthermore, in a conventional disintegrating composition containing a disintegrant component, an excipienting agent and sugar, a composition containing 80% by weight or more of sugar or sugar alcohol and requiring a disintegration time in water of about 1 minute or more. Not known until.
　尚、本発明の遅延崩壊性粒子組成物に崩壊遅延成分として含まれる糖又は糖アルコール以外の各成分の配合量は各成分の種類、遅延崩壊性粒子組成物の使用対象である崩壊錠剤の種類及び用途等に応じて、当業者が適宜決めることが出来る。 In addition, the compounding amount of each component other than sugar or sugar alcohol contained in the delayed disintegrating particle composition of the present invention as the disintegrating delay component is the type of each component, the type of disintegrating tablet for which the delayed disintegrating particle composition is used. Further, those skilled in the art can appropriately determine depending on the usage and the like.
　本発明の遅延崩壊性粒子組成物に含まれる糖又は糖アルコールの代表例として、マンニトール、エリスリトール、キシリトール、トレハロース、ラクトース、マルトース、マルチトール、グルコース、スクロース、フルクトース、マンノース、及びソルビトール等を挙げることが出来る。好適例として、マルチトールを挙げることが出来る。尚、糖又は糖アルコールは１種類でもよいが、これらの中から適当に選択された２種類以上の化合物を用いることも出来る。 Representative examples of the sugar or sugar alcohol contained in the delayed disintegrating particle composition of the present invention include mannitol, erythritol, xylitol, trehalose, lactose, maltose, maltitol, glucose, sucrose, fructose, mannose, and sorbitol. I can do it. A preferred example is maltitol. One kind of sugar or sugar alcohol may be used, but two or more kinds of compounds appropriately selected from these may be used.
　本発明の遅延崩壊性粒子組成物に含まれる崩壊剤成分としては、当業者に公知の任意の物を使用することができる。例えば、酸型カルボキシメチルセルロース、クロスポビドン、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロースカルシウム、コーンスターチ、バレイショデンプン、ワキシーコーンスターチ、部分α化デンプン、及びα化デンプン等のデンプン、並びに、デンプングリコール酸ナトリウム及びヒドロキシプロピルスターチ等の加工デンプンから選択される任意の一成分以上を含有させることができる。尚、クロスポビドンは１－ビニルー２－ピロリドンの架橋重合物の通称であり、クロスカルメロースナトリウムはカルボキシメチルセルロースナトリウムの架橋物の通称である。 As the disintegrant component contained in the delayed disintegrating particle composition of the present invention, any material known to those skilled in the art can be used. For example, acid type carboxymethylcellulose, crospovidone, croscarmellose sodium, low substituted hydroxypropylcellulose, carboxymethylcellulose calcium, corn starch, potato starch, waxy corn starch, partially pregelatinized starch, pregelatinized starch and the like, and starch One or more components selected from modified starches such as sodium glycolate and hydroxypropyl starch can be contained. Crospovidone is a common name for a cross-linked polymer of 1-vinyl-2-pyrrolidone, and croscarmellose sodium is a common name for a cross-linked product of sodium carboxymethylcellulose.
　酸型カルボキシメチルセルロースは、カルメロースと称される物質であり、医薬品添加剤として使用されている。酸型カルボキシメチルセルロースと同様に、例えばカルボキシメチルセルロースのカルシウム塩及びカルボキシメチルセルロースナトリウムの架橋物はいずれも水に不溶性であり錠剤等に崩壊剤として用いられる。一方、カルボキシメチルセルロースのナトリウム塩は水溶性であり結合剤等の目的で用いられる。尚、カルボキシメチルセルロースの塩がカルメロースと記載される場合もある。 Acid-type carboxymethylcellulose is a substance called carmellose and is used as a pharmaceutical additive. Similar to acid-type carboxymethylcellulose, for example, calcium salt of carboxymethylcellulose and a crosslinked product of sodium carboxymethylcellulose are both insoluble in water and used as a disintegrant in tablets and the like. On the other hand, sodium salt of carboxymethyl cellulose is water-soluble and is used for the purpose of a binder or the like. In addition, the salt of carboxymethylcellulose may be described as carmellose.
　更に、本発明の遅延崩壊性粒子組成物に含まれる賦形補助剤の例として、結晶セルロース及び／又は粉末セルロースを挙げることができる。結晶セルロースおよび粉末セルロースは繊維性植物から得られたα－セルロースを酸で部分的に解重合して精製して得られる、白色の粉末状で水には溶けない物質である。味は無く、化学的に不活性であるために薬物と混合しても変化がなく、医薬品添加物、特に、錠剤を調剤する際の賦形補助剤、結合剤又は崩壊剤等の用途に使用される。更に、医薬品以外には、乳化安定剤等として化粧品及び乳製品等の食品に使用される。 Furthermore, crystalline cellulose and / or powdered cellulose can be mentioned as examples of the shaping aid contained in the delayed disintegrating particle composition of the present invention. Crystalline cellulose and powdered cellulose are white powdery substances that are insoluble in water, obtained by partially depolymerizing α-cellulose obtained from fibrous plants with acid. It has no taste and is chemically inert, so it does not change even when mixed with drugs, and is used for excipients, especially as excipients, binders or disintegrants when dispensing tablets. Is done. In addition to pharmaceuticals, it is used as an emulsion stabilizer in foods such as cosmetics and dairy products.
　当業者に公知の任意の結晶セルロース及び/又は粉末セルロースを使用することが出来るが、その結晶セルロースの代表例として、アビセル（ＦＭＣコーポレーション）、セオラス（旭化成ケミカルズ株式会社）、ビバプアー（レッテンマイヤー）等の市販品を挙げることができ、粉末セルロースの代表例としてはKCフロック（日本製紙ケミカル）、ARBOCEL（レッテンマイヤー）、ソルカフロック（木村産業）を挙げることができる。 Although any crystalline cellulose and / or powdered cellulose known to those skilled in the art can be used, typical examples of the crystalline cellulose include Avicel (FMC Corporation), Theolas (Asahi Kasei Chemicals Co., Ltd.), Vivapuer (Lettenberg Meyer), etc. As typical examples of powdered cellulose, KC Flock (Nippon Paper Chemicals), ARBOCEL (Retttenmeier), and Solka Flock (Kimura Sangyo) can be mentioned.
　更に、本発明の遅延崩壊性粒子組成物には、例えば、崩壊力、結合力及び錠剤の服用感等の諸特性を調整する目的で、当業者に公知の各種の任意成分を、上記の成分以外の任意の成分を、上記の成分による本発明の効果を損なわない範囲で、適宜、添加混合しても良い。このような成分の例として、当業者に公知の、崩壊剤、賦形補助剤、流動化剤、甘味剤、矯味剤、香料及び、着色料等を挙げることが出来る。 Furthermore, the delayed disintegrating particle composition of the present invention contains various optional components known to those skilled in the art for the purpose of adjusting various properties such as disintegration strength, binding strength, and tablet feeling. Arbitrary components other than those may be added and mixed as appropriate within a range not impairing the effects of the present invention due to the above components. Examples of such components include disintegrants, excipients, fluidizers, sweeteners, corrigents, fragrances, and coloring agents known to those skilled in the art.
　例えば、崩壊剤の例として、軽質無水ケイ酸、含水二酸化ケイ素、無水リン酸カルシウム、無水リン酸水素カルシウム、メタケイ酸アルミニウム、ケイ酸カルシウム、ケイ酸マグネシウム、酸化マグネシウムなどの無機賦形剤を挙げることができる。 Examples of disintegrants include inorganic excipients such as light anhydrous silicic acid, hydrous silicon dioxide, anhydrous calcium phosphate, anhydrous calcium hydrogen phosphate, aluminum metasilicate, calcium silicate, magnesium silicate, and magnesium oxide. it can.
　更に、本発明の遅延崩壊性粒子組成物には、微小繊維状セルロースを含むことができる。微小繊維状セルロースとしては、従来公知の「微細繊維状セルロース」又は「微小繊維状セルロース」として知られている任意のセルロースを使用することができる。 Furthermore, the delayed disintegrating particle composition of the present invention can contain fine fibrous cellulose. As the microfibrous cellulose, any cellulose known as “microfibrous cellulose” or “microfibrous cellulose” can be used.
　「微小繊維状セルロース」とは、一般的に、植物繊維から製造され、繊維の径（短径）又は太さが数nm～１μm程度のセルロースであって、原料であるセルロースの基本特性（物理的及び化学的安定性等）を損なわずに、表面積が顕著に増大し、セルロース本来の特徴である親水性が著しく強まるとともに、微小繊維の絡み合いによる三次元網目構造が形成されているものを意味する。このような微小繊維状セルロースの乾燥物は、従来公知の任意の技術によって製造することができる。　 “Microfibrous cellulose” is a cellulose that is generally produced from plant fibers and has a fiber diameter (short diameter) or thickness of several nanometers to 1 μm. This means that the surface area is remarkably increased, the hydrophilicity that is inherent in cellulose is remarkably increased, and a three-dimensional network structure is formed by entanglement of microfibers. To do. Such a dried product of fine fibrous cellulose can be produced by any conventionally known technique. *
　本発明の遅延崩壊性粒子組成物に含まれる微小繊維状セルロースの好適例として、繊維集合体であって、平均繊維長約０．０１～２ｍｍ、及び、平均繊維径約０．００１～１μｍ、好ましくは平均繊維径約０．０１～０．１μｍ、である微小繊維状セルロースを挙げることができる（特許文献２）。例えば、このような微小繊維状セルロース（固形分が１０～３５％の含水状態）は、商品名「セリッシュ（CELISH）」シリーズ（平均繊維径約０．０１～０．１μｍ）としてダイセルファインケム株式会社から各種グレードの製品が販売されている。 A preferred example of the microfibrous cellulose contained in the delayed disintegrating particle composition of the present invention is a fiber assembly having an average fiber length of about 0.01 to 2 mm and an average fiber diameter of about 0.001 to 1 μm. A fine fibrous cellulose having an average fiber diameter of about 0.01 to 0.1 μm is preferable (Patent Document 2). For example, such a microfibrous cellulose (with a water content of 10 to 35% solids) is a product name “CELISH” series (average fiber diameter of about 0.01 to 0.1 μm), Daicel Finechem Co., Ltd. Various grades of products are sold.
　尚、本発明の遅延崩壊性粒子組成物における糖又は糖アルコール以外の各成分の配合量は各成分の種類、遅延崩壊性粒子組成物の使用対象である崩壊錠剤の種類及び用途等に応じて、当業者が適宜決めることが出来る。 The compounding amount of each component other than sugar or sugar alcohol in the delayed disintegrating particle composition of the present invention depends on the type of each component, the type and use of the disintegrating tablet that is the target of use of the delayed disintegrating particle composition. Those skilled in the art can appropriately determine.
　本発明の遅延崩壊性粒子組成物は、又、各種の造粒工程法で製造することもできる。造粒手段としては特に限定されず、乾式造粒法、もしくは湿式造粒工程法などにより製造することもできる。 The delayed disintegrating particle composition of the present invention can also be produced by various granulation process methods. It does not specifically limit as a granulation means, It can also manufacture by the dry granulation method or the wet granulation process method.
　乾式造粒法は、該遅延崩壊性粒子組成物に含まれる各種の成分粉末をそのまま、または適当な結合剤などと混合し、強圧により小塊とし、これを適当に破砕して造粒する工程を含む。乾式造粒法の具体的な例としては破砕造粒法やロール圧縮法等を挙げることができる。 The dry granulation method is a process in which various component powders contained in the delayed disintegrating particle composition are mixed as they are or with an appropriate binder, etc. to form a small lump by high pressure, and this is appropriately crushed and granulated. including. Specific examples of the dry granulation method include a crushing granulation method and a roll compression method.
　湿式造粒法は水の存在下で各成分を分散させ乾燥することによって複合体を形成する方法であり、湿式造粒法の具体例としては、噴霧乾燥、転動造粒、撹拌造粒、及び流動層造粒などの噴霧法、凍結乾燥法、並びに、混練造粒等を挙げることができ、これらの当業者に公知の任意の方法で製造することができる。 The wet granulation method is a method of forming a composite by dispersing and drying each component in the presence of water. Specific examples of the wet granulation method include spray drying, tumbling granulation, stirring granulation, And spraying methods such as fluidized bed granulation, freeze-drying methods, kneading granulation, and the like, and these can be produced by any method known to those skilled in the art.
　湿式造粒工程法で製造する場合に、本発明の遅延崩壊性粒子組成物に含まれる成分の全てを一緒に用いる一段階の造粒工程で原配合物を製造しても良いし、又は、複数段階の湿式造粒工程において各成分を適宜添加混合することもできる。
  When producing by a wet granulation process method, the raw formulation may be produced by a one-step granulation process in which all of the components contained in the delayed disintegrating particle composition of the present invention are used together, or Each component can be added and mixed as appropriate in a multi-stage wet granulation process.
　尚、上記の製造方法の複数の湿式造粒工程において、遅延崩壊性粒子組成物に含まれる各成分の中のいずれの一もしくは二種類の成分を用いるかは、それらの種類・量等に応じて当業者が適宜決めることが出来る。 In addition, in the plurality of wet granulation steps of the above production method, which one or two of the components contained in the delayed disintegrating particle composition is used depends on the type and amount thereof. Thus, those skilled in the art can appropriately determine.
　更に、各造粒工程において、噴霧(スプレー)速度やエアー給気温度、排気温度、エアー給気量などの諸条件は、各成分の種類・量等に応じて当業者が適宜決めることが出来る。 Further, in each granulation step, various conditions such as spraying speed, air supply temperature, exhaust temperature, air supply amount, etc. can be appropriately determined by those skilled in the art according to the type and amount of each component. .
　各造粒工程のいずれにおいても、噴霧液の媒体としては、例えば水、エタノール、メタノール、及びアセトン等の医薬品や食品に許容される溶媒を挙げることができる。或いは噴霧液として、１０％未満の該遅延崩壊性粒子組成物の成分を溶解させた水溶液などが挙げられるが、特に水または該水溶液が好ましい。 In any of the granulation steps, examples of the spray liquid medium include solvents acceptable for pharmaceuticals and foods such as water, ethanol, methanol, and acetone. Alternatively, examples of the spray liquid include an aqueous solution in which less than 10% of the components of the delayed disintegrating particle composition are dissolved, and water or the aqueous solution is particularly preferable.
　或いは、本発明の遅延崩壊性粒子組成物は、上記の原配合物に崩壊遅延成分として更に糖又は糖アルコールを、添加混合するだけで容易に製造することができる。尚、かかる添加混合は、当業者に公知の任意の医薬添加剤を製造する方法・手段を使用して実施することが出来る。 Alternatively, the delayed disintegrating particle composition of the present invention can be easily produced simply by adding and mixing a sugar or a sugar alcohol as a disintegrating delay component to the above-mentioned original composition. Such addition and mixing can be carried out using a method and means for producing any pharmaceutical additive known to those skilled in the art.
　本発明の遅延崩壊性粒子組成物は以下のような物性を有していることが好ましい。
（１）平均粒子径：５０～２００ミクロン、（２）水分：０．５～６重量％。 The delayed disintegrating particle composition of the present invention preferably has the following physical properties.
(1) Average particle size: 50 to 200 microns, (2) Water content: 0.5 to 6% by weight.
　これら物性値は以下の条件・方法で測定される。
　平均粒子径：遅延崩壊性粒子組成物２ｇを、φ７５ｍｍ自動振とう篩器（M－２型、筒井理化学器械株式会社）を用いて測定する。
　水分：遅延崩壊性粒子組成物５ｇをハロゲン水分測定器（ＨＢ４３型、メトラートレド株式会社）を用いて測定する。 These physical property values are measured under the following conditions and methods.
Average particle diameter: 2 g of the delayed disintegrating particle composition is measured using a φ75 mm automatic shaking sieve (M-2 type, Tsutsui Rika Instruments Co., Ltd.).
Moisture: 5 g of the delayed disintegrating particle composition is measured using a halogen moisture meter (HB43 type, METTLER TOLEDO).
　更に、本発明は、このような遅延崩壊性粒子組成物を含む各種の崩壊錠剤、特に、補助食品、栄養機能食品及び健康食品等を含む各種食品用崩壊錠剤または医薬用の崩壊錠剤にも係る。崩壊錠剤中の遅延崩壊性粒子組成物の含有量は、本発明の所望の効果を損なわない範囲で、崩壊錠剤の用途・目的などに応じて、当業者が適宜、選択することができる。又、錠剤の形状・形態等には特に制約はない。 Furthermore, the present invention relates to various disintegrating tablets containing such a delayed disintegrating particle composition, in particular, various disintegrating tablets for foods including supplementary foods, nutritional functional foods and health foods, or disintegrating tablets for pharmaceuticals. . The content of the delayed disintegrating particle composition in the disintegrating tablet can be appropriately selected by those skilled in the art according to the use and purpose of the disintegrating tablet within a range not impairing the desired effects of the present invention. There are no particular restrictions on the shape and form of the tablet.
　このような崩壊錠剤は、本発明の遅延崩壊性粒子組成物が含まれているために、優れた錠剤硬度と所望の遅延された崩壊性を有する。即ち、本明細書の各実施例が示すように、例えば、打錠圧約４～２０ｋＮで製造した場合に、硬度が１０～１００（Ｎ）、より好ましくは１２～１００（Ｎ）、更に好ましくは１５～１００（Ｎ）、及び、水中崩壊時間が２～１０（分）、より好ましくは２～５（分）、更に好ましくは３～５（分）であることを特徴とする。更に、本発明の崩壊錠剤は、水中崩壊開始時間が約１～１．５分であること、即ち、服用後の少なくとも約１分程度は崩壊しないことがより好ましい。 Since such a disintegrating tablet contains the delayed disintegrating particle composition of the present invention, it has excellent tablet hardness and desired delayed disintegrating property. That is, as shown in each example of the present specification, for example, when manufactured at a tableting pressure of about 4 to 20 kN, the hardness is 10 to 100 (N), more preferably 12 to 100 (N), and still more preferably. 15 to 100 (N), and the disintegration time in water is 2 to 10 (min), more preferably 2 to 5 (min), and further preferably 3 to 5 (min). Furthermore, it is more preferable that the disintegrating tablet of the present invention has a disintegration start time in water of about 1 to 1.5 minutes, that is, it does not disintegrate for at least about 1 minute after taking.
　崩壊錠剤の用途・目的などに応じて、本発明の崩壊錠剤には、遅延崩壊性粒子組成物以外に、任意の成分を含むことができる。 Depending on the application and purpose of the disintegrating tablet, the disintegrating tablet of the present invention may contain an optional component in addition to the delayed disintegrating particle composition.
　例えば、食品用崩壊錠剤の場合は、各種の有効成分、例えば、タンパク質、糖質、脂質及びミネラル等の各種の栄養成分；各種ビタミン類及びそれらの誘導体；微生物、植物又は動物由来の各種抽出物等の健康食品素材；並びに、酸味料、甘味料、賦形剤、界面活性剤、滑沢剤、酸味料、甘味料、矯味剤、香料、着色剤、及び安定化剤などの、食品衛生法第10条に基づく各種の指定添加物または既存添加物、一般飲食物添加物リストに収載されている、食品成分（食品添加物）として許容されるその他の任意の成分を含むことが出来る For example, in the case of food disintegrating tablets, various active ingredients such as various nutritional components such as proteins, sugars, lipids and minerals; various vitamins and their derivatives; various extracts derived from microorganisms, plants or animals And health food materials such as sour agents, sweeteners, excipients, surfactants, lubricants, sour agents, sweeteners, flavoring agents, fragrances, colorants, and stabilizers It can contain any other ingredients that are acceptable as food ingredients (food additives) listed in the list of various specified or existing additives and general food and beverage additives under Article 10.
　又、医薬用の崩壊錠剤は、遅延崩壊性粒子組成物及び薬効成分（有効成分）に加えて、更に、必要に応じて、賦形剤、界面活性剤、滑沢剤、酸味料、甘味料、矯味剤、香料、着色剤、安定化剤など医薬上許容されるその他の任意の成分を含むことが出来る。これら任意成分として、例えば、医薬品添加物辞典（薬事日報社）、日本薬局方に記載の該当成分を用いることができる。尚、含まれる薬効成分及び助剤の用途・種類に特に制限はない。又、本発明の所望の効果が奏される限り、遅延崩壊性粒子組成物、薬効成分、及び、任意成分の配合割合に特に制限はなく、当業者が適宜決めることが出来る。このような崩壊錠剤は、打錠等の当業者に公知の任意の方法によって製剤化することが出来る。本発明の崩壊錠剤に含まれる薬効成分の用途・種類としては、例えば、中枢神経系用薬、末梢神経系用薬、感覚器官用薬、 循環器用薬、呼吸器官用薬、消化器官用薬、ホルモン剤、泌尿生殖器官薬、その他の個々の器官系用医薬品、ビタミン剤、滋養強壮薬、血液・体液用薬、その他の代謝性医薬品、細胞賦活用薬、腫瘍用薬、放射性医薬品、アレルギー用薬、その他の組織細胞機能用医薬品、 生薬、漢方製剤、その他の生薬及び漢方処方に基づく医薬品、抗生物質製剤、化学療法剤、生物学的製剤、寄生動物に対する薬、その他の病原生物に対する医薬品、 調剤用薬、診断用薬、公衆衛生用薬、体外診断用医薬品等を挙げることができる。 In addition to the delayed disintegrating particle composition and the medicinal component (active ingredient), the pharmaceutical disintegrating tablet further includes an excipient, a surfactant, a lubricant, a sour agent, and a sweetener as necessary. , And other pharmaceutically acceptable ingredients such as flavoring agents, flavoring agents, coloring agents, and stabilizers. As these optional components, for example, the corresponding components described in the Pharmaceutical Additives Dictionary (Pharmaceutical Daily) and the Japanese Pharmacopoeia can be used. In addition, there is no restriction | limiting in particular in the use and kind of medicinal component and adjuvant which are contained. Moreover, as long as the desired effect of this invention is show | played, there will be no restriction | limiting in particular in the mixture ratio of a delayed disintegrating particle composition, a medicinal component, and arbitrary components, and those skilled in the art can determine suitably. Such disintegrating tablets can be formulated by any method known to those skilled in the art, such as tableting. Examples of uses / types of medicinal ingredients contained in the disintegrating tablet of the present invention include, for example, central nervous system drugs, peripheral nervous system drugs, sensory organ drugs, vaginal cardiovascular drugs, respiratory organ drugs, digestive organ drugs, Hormonal drugs, urogenital drugs, other drugs for individual organs, vitamins, nourishing tonics, blood and body fluids, other metabolic drugs, cell-use drugs, oncology drugs, radiopharmaceuticals, allergies Drugs, other drugs for tissue cell function, herbal medicines, Kampo medicines, other herbal medicines and medicines based on Kampo medicines, antibiotics, chemotherapeutics, biologicals, drugs for parasites, drugs for other pathogenic organisms, Dispensing drugs, diagnostic drugs, public health drugs, in vitro diagnostic drugs, and the like.
　尚、本明細書において引用された全ての先行技術文献の記載内容は、参照として本明細書に組み入れられる。 In addition, the description content of all prior art documents cited in this specification is incorporated in this specification as a reference.
　以下、本発明を実施例によりさらに具体的に説明するが本発明はこれら実施例に制限されるものではない。 Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.
［硬度および崩壊性の評価］
　実施例および比較例で得た各錠剤について、以下の方法によって硬度及び水中崩壊時間を測定した。硬度及び水中崩壊時間の測定結果を表１に示す。 [Evaluation of hardness and disintegration]
About each tablet obtained by the Example and the comparative example, hardness and disintegration time in water were measured with the following method. Table 1 shows the results of measurement of hardness and disintegration time in water.
　尚、これら物性値は以下の条件・方法で測定した。
　硬度：デジタル木屋式硬度計（ 株式会社藤原製作所）を用いて、硬度（N）を測定した。
　水中崩壊時間：日本薬局方記載の方法（ただし、補助盤なし）に従い、崩壊試験器（ＮＴ－４００、富山産業株式会社）を用いて、水中崩壊時間を測定した。
硬度および崩壊時間はそれぞれ６回の測定を行い、それらの平均値を測定結果とした。
　口腔内崩壊時間：トリコープテスタ（添加速度６ｍL/min、４０ｇの錘）を使用して測定した。 These physical property values were measured under the following conditions and methods.
Hardness: Hardness (N) was measured using a digital Kiya-type hardness meter (Fujiwara Manufacturing Co., Ltd.).
Disintegration time in water: The disintegration time in water was measured using a disintegration tester (NT-400, Toyama Sangyo Co., Ltd.) according to the method described in the Japanese Pharmacopoeia (but without an auxiliary board).
The hardness and disintegration time were each measured 6 times, and the average value thereof was taken as the measurement result.
Oral disintegration time: Measured using a tricoop tester (addition rate 6 mL / min, 40 g weight).
［参考例］
　まず、従来の崩壊性粒子組成物に相当する「原配合物A」（D-マンニトール３３．３重量％、酸型カルボキシメチルセルロース９．５重量％、クロスポビドン４．８重量％、結晶セルロース１１．９重量％）５９．５重量％とステアリン酸マグネシウム（太平化学産業株式会社）０．５重量％、有効成分の例示として硫酸バリウム４０．０重量％を含む崩壊錠剤を、本明細書に記載の流動層造粒による湿式造粒法により製造し、次いで、簡易錠剤成形機（ＨＡＮＤＴＡＢ－１００、市橋精機株式会社）を用い、所定の打錠圧縮力において打錠し、直径８．０ｍｍ、隅角平錠、重量２５０ｍｇの錠剤を得た。 [Reference example]
First, “raw compound A” (D-mannitol 33.3% by weight, acid-type carboxymethylcellulose 9.5% by weight, crospovidone 4.8% by weight, crystalline cellulose 11.3% corresponding to the conventional disintegrating particle composition. A disintegrating tablet containing 99.5% by weight, 59.5% by weight, 0.5% by weight of magnesium stearate (Taihei Chemical Industrial Co., Ltd.), and 40.0% by weight of barium sulfate as an example of an active ingredient is described herein. Manufactured by a wet granulation method using fluidized bed granulation, and then tableted using a simple tableting machine (HANDTAB-100, Ichihashi Seiki Co., Ltd.) with a predetermined tableting compression force, diameter 8.0 mm, corner angle A flat tablet having a weight of 250 mg was obtained.
［硬度および崩壊性試験の評価］
　次に、それらの錠剤硬度及び水中崩壊時間を測定した。その結果を以下の表１に示す。 [Evaluation of hardness and disintegration test]
Next, their tablet hardness and underwater disintegration time were measured. The results are shown in Table 1 below.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　表１の結果から、原配合物Aに単に硫酸バリウムを含有させた場合には、成形性は大幅に低下し、打錠圧縮力を14kN（8mmφ杵の限界近く）まで上げても、好ましい硬度は得られなかった。更に、各種錠剤において水中崩壊時間は１５～２０秒であって、従来の崩壊錠剤と同程度の水中崩壊時間であった。 From the results in Table 1, when barium sulfate is simply contained in the raw compound A, the moldability is greatly reduced, and even when the tableting compression force is increased to 14 kN (near the limit of 8 mmφ 杵), the preferred hardness Was not obtained. Furthermore, the disintegration time in water of each tablet was 15 to 20 seconds, which was the same disintegration time in water as that of the conventional disintegration tablet.
［遅延崩壊性粒子組成物の製造］
　上記参考例に記載の方法によって、原配合物Aにマルチトールを加えて混合し、マルチトール８０重量％含む本発明の遅延崩壊性粒子組成物を製造した。
尚、該遅延崩壊性粒子組成物における、尚、糖（D-マンニトール及びマルチトール）の合計量は、９１重量％であった。 [Production of Delayed Disintegrating Particle Composition]
By the method described in the above Reference Example, maltitol was added to the original formulation A and mixed to produce a delayed disintegrating particle composition of the present invention containing 80% by weight of maltitol.
The total amount of sugars (D-mannitol and maltitol) in the delayed disintegrating particle composition was 91% by weight.
［崩壊錠剤の製造］
　これらの遅延崩壊性粒子組成物（５９．５重量％）と、滑沢剤であるステアリン酸マグネシウム（太平化学産業株式会社）０．５重量％及び有効成分の例として、硫酸バリウム（４０重量％）を含む崩壊錠剤を、簡易錠剤成形機（ＨＡＮＤＴＡＢ－１００、市橋精機株式会社）を用い、所定の打錠圧縮力において打錠し、直径８．０ｍｍ、隅角平錠、重量２５０ｍｇの錠剤５を得た。 [Manufacture of disintegrating tablets]
These delayed disintegrating particle compositions (59.5% by weight), 0.5% by weight of magnesium stearate (Taihei Chemical Industrial Co., Ltd.) as a lubricant, and barium sulfate (40% by weight) as an example of active ingredients ) In a predetermined tableting compression force using a simple tableting machine (HANDTAB-100, Ichihashi Seiki Co., Ltd.). Got.
　なお、比較例として、実施例１で製造した本発明の遅延崩壊性粒子組成物に代えて、マルチトールのみ（錠剤１）又は結晶セルロースのみ（錠剤２）を使用し、更に、マルチトールに代えてトレハロースを原配合物Aに加えて混合して得られたトレハロース４０重量％を含む組成物（錠剤３）、及び原配合物Aにマルチトールを加えて混合して得られたマルチトール40重量％を含む組成物（錠剤４）を使用して、同様の方法で各錠剤を製造した。 As a comparative example, instead of the delayed disintegrating particle composition of the present invention produced in Example 1, only maltitol (tablet 1) or only crystalline cellulose (tablet 2) was used, and further replaced with maltitol. A composition (tablet 3) containing 40% by weight of trehalose obtained by adding trehalose to raw formulation A and mixing, and maltitol obtained by adding maltitol to raw formulation A and mixing 40% Each tablet was prepared in the same manner using the composition containing 4% (Tablet 4).
［硬度および崩壊性試験の評価］
　以上の実施例および比較例で得た各錠剤について、以下の方法によって硬度、水中崩壊時間、及び、口腔内崩壊時間を測定した。これらの測定結果を表２に示す。 [Evaluation of hardness and disintegration test]
About each tablet obtained by the above Example and Comparative Example, hardness, disintegration time in water, and disintegration time in the oral cavity were measured by the following methods. These measurement results are shown in Table 2.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　その結果、糖又は糖アルコール（トレハロース及び）D-マンニトール）の含量が７４重量％である崩壊性組成物を用いた錠剤３では、水中崩壊時間は未だ１分未満であった。又、トレハロースを同含量のマルチトールに変えて得られた錠剤４も同様な結果であった。さらにマルチトールのみを用いた錠剤１又は結晶セルロースのみを用いた錠剤２では水中崩壊時間は約２～７分と延長されたものの、崩壊が約10秒から開始するために、例えば、嚥下造影剤等の、口腔内又は食道では崩壊せずに、胃や腸に到達した場合に速やかに崩壊することが望まれる薬剤として適していないことが判明した。 As a result, the disintegration time in water was still less than 1 minute in the tablet 3 using the disintegrating composition having a sugar or sugar alcohol (trehalose and D-mannitol) content of 74% by weight. The same results were obtained with tablet 4 obtained by changing trehalose to maltitol with the same content. Furthermore, in tablet 1 using only maltitol or tablet 2 using only crystalline cellulose, the disintegration time in water is extended to about 2 to 7 minutes, but the disintegration starts from about 10 seconds. It has been found that it is not suitable as a drug that is desired to disintegrate rapidly when it reaches the stomach or intestine without disintegrating in the oral cavity or esophagus.
　これらに対して、マルチトールを８０重量％含む本発明の遅延崩壊性粒子組成物（糖又は糖アルコール含量が９１重量％）から製造された錠剤５の場合には、崩壊開始時間は約１～１．５分であり、且つ、崩壊時間を約３～５分まで遅延させることができた。 On the other hand, in the case of the tablet 5 produced from the delayed disintegrating particle composition of the present invention (sugar or sugar alcohol content is 91 wt%) containing 80 wt% maltitol, the disintegration start time is about 1 to 1.5 minutes and the disintegration time could be delayed to about 3-5 minutes.
　本発明は、優れた錠剤硬度と、服用してから一定時間経過後に崩壊し始め、約１分以上の崩壊時間を要するような崩壊プロファイルを有する各種の崩壊錠剤等の研究・開発に大いに資するものである。 The present invention greatly contributes to the research and development of various disintegrating tablets having excellent tablet hardness and a disintegration profile that starts to disintegrate after a certain period of time after taking and requires a disintegration time of about 1 minute or more. It is.

Claims (9)

  1. 崩壊剤成分、賦形補助剤、及び、糖又は糖アルコールを含む組成物であって、糖又は糖アルコールの含有量が８０重量％以上であることを特徴とする、遅延崩壊性粒子組成物。 A delayed disintegrating particle composition comprising a disintegrant component, a shaping aid, and a sugar or sugar alcohol, wherein the sugar or sugar alcohol content is 80% by weight or more.
  2. 糖又は糖アルコールの含有量が９０重量％以上である、請求項１記載の遅延崩壊性粒子組成物。 The delayed disintegrating particle composition according to claim 1, wherein the content of sugar or sugar alcohol is 90% by weight or more.
  3. 糖アルコールがマンニトール及び／又はマルチトールである、請求項１～２記載の遅延崩壊性粒子組成物。 The delayed disintegrating particle composition according to claim 1 or 2, wherein the sugar alcohol is mannitol and / or maltitol.
  4. 崩壊剤成分として、酸型カルボキシメチルセルロース及び/又はクロスポピドンを含む、請求項１ないし３のいずれか一項に記載の遅延崩壊性粒子組成物。 The delayed disintegrating particle composition according to any one of claims 1 to 3, comprising acid carboxymethylcellulose and / or crospovidone as a disintegrant component.
  5. 賦形補助剤が結晶性セルロース及び／又は粉末セルロースである、請求項１ないし４のいずれか一項に記載の遅延崩壊性粒子組成物。 The delayed disintegrating particle composition according to any one of claims 1 to 4, wherein the shaping aid is crystalline cellulose and / or powdered cellulose.
  6. 請求項１～５に記載の遅延崩壊性粒子組成物を含む食品用または医薬用崩壊錠剤。 A food or pharmaceutical disintegrating tablet comprising the delayed disintegrating particle composition according to any one of claims 1 to 5.
  7. 水中崩壊時間が２～５（分）である、請求項６記載の崩壊錠剤。 The disintegrating tablet according to claim 6, wherein the disintegration time in water is 2 to 5 (min).
  8. 水中崩壊開始時間が１～１．５分である、請求項７記載の崩壊錠剤。 The disintegrating tablet according to claim 7, wherein the disintegration start time in water is 1 to 1.5 minutes.
  9. 水中崩壊時間が６０秒以下の崩壊性粒子組成物に糖又は糖アルコールを添加、混合することを含む、請求項１～５のいずれか一項に記載の遅延崩壊性粒子組成物の製造方法。 The method for producing a delayed disintegrating particle composition according to any one of claims 1 to 5, comprising adding and mixing a sugar or a sugar alcohol to a disintegrating particle composition having a disintegration time in water of 60 seconds or less.
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