WO2019151405A1 - Tablets and method for producing same - Google Patents

Tablets and method for producing same Download PDF

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Publication number
WO2019151405A1
WO2019151405A1 PCT/JP2019/003412 JP2019003412W WO2019151405A1 WO 2019151405 A1 WO2019151405 A1 WO 2019151405A1 JP 2019003412 W JP2019003412 W JP 2019003412W WO 2019151405 A1 WO2019151405 A1 WO 2019151405A1
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WO
WIPO (PCT)
Prior art keywords
tablet
amorphous
drug
lactone
glucono
Prior art date
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PCT/JP2019/003412
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French (fr)
Japanese (ja)
Inventor
慎 井實
林田　知大
洋平 帆足
中野　善夫
勝久 井上
Original Assignee
ニプロ株式会社
全星薬品工業株式会社
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Application filed by ニプロ株式会社, 全星薬品工業株式会社 filed Critical ニプロ株式会社
Priority to JP2019569554A priority Critical patent/JP7336388B2/en
Publication of WO2019151405A1 publication Critical patent/WO2019151405A1/en

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    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • 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 generally to tablets and tablet manufacturing methods, and more specifically to orally disintegrating tablets and manufacturing methods thereof.
  • Orally disintegrating tablets are devised in various ways depending on the purpose, such as rapid disintegration in the oral cavity, smooth mouthfeel and taste. Orally disintegrating tablets dissolve quickly in the oral cavity and can be easily taken without water, so it is expected to become increasingly popular as a dosage form suitable for patients with swallowing problems such as the elderly and children. It is done.
  • the technological transitions related to the production of orally disintegrating tablets can be broadly classified as follows.
  • the so-called first generation is a mold tablet preparation in which a suspension or wet mass of a drug or the like is precisely filled into a mold and solidified by freeze drying, ventilation drying, or the like.
  • R using a PTP pocket as a mold .
  • P. “Zydis” by lyophilization of Scherer (currently Catalent) (UK) has been commercialized.
  • the second generation is an orally disintegrating tablet by a wet molding method in which a mixture of drugs, saccharides and the like wet with an alcohol / aqueous solution is molded at low pressure and then dried.
  • JP-A-5-271054 Patent Document 1 discloses an oral solution in which a mixture containing a medicinal ingredient and a saccharide is tableted with moisture sufficient to wet the particle surface of the saccharide and dried. A method for producing a mold tablet is described.
  • Patent Document 2 a drug and a saccharide are mixed, kneaded with water or a water-containing organic solvent in which polyvinyl alcohol is dissolved, and then wet granules are filled into a mold and passed through a film.
  • a fast disintegrating tablet is described which is compressed into a tablet and dried to produce.
  • the tablet or tablet containing the drug or drug-containing particles, sugar, sugar alcohol, and water-soluble excipients such as a water-soluble binder is pressed at low pressure, then humidified and dried. Orally disintegrating tablet by tableting humidification drying method.
  • Patent Document 3 International Publication WO99 / 47124 (Patent Document 3) and International Publication WO03 / 009831 (Patent Document 4)
  • saccharide B which can be amorphous is coated and / or coated on saccharide A as a binder. It is described that granulated particles are formed at low pressure and then dried by humidification to form tablets.
  • Patent Document 5 JP 2010-155865 A (Patent Document 5) uses a granulated product obtained by granulating sugar or sugar alcohol as a forming component and using a water-insoluble but hydrophilic granulating component.
  • An orally disintegrating tablet consisting of a compression molded product is presented.
  • Patent Document 6 discloses a tablet which foams and rapidly disintegrates in contact with saliva in the oral cavity, and the foaming source is an alkali metal or alkaline earth metal carbonate.
  • an intraoral rapidly disintegrating tablet which is a bicarbonate, and the acid source that reacts with the foaming source is fibrin glycolic acid.
  • the acid source that reacts with the foaming source is fibrin glycolic acid.
  • JP-A-2005-53792 provides a compression-molded preparation that has rapid disintegrability in the mouth and in an aqueous solvent, while maintaining the hardness required for carrying.
  • a compression-molded preparation having gluconolactone added and rapidly disintegrating in the oral cavity has been proposed.
  • JP 2012-162502 Patent Document 10 describes an orally disintegrating tablet containing an active agent, gluconolactone, and sodium stearyl fumarate.
  • the drug content in the tablets is required to enable good swallowing. Efforts are being made to reduce the size of the tablet by increasing it to 55% or more.
  • orally disintegrating tablets include a fast oral disintegration rate, for example, an oral disintegration rate within 1 minute, preferably within 45 seconds, a manufacturing process (including a packaging process), and a distribution process (including medical treatment). ) Is required to be compatible with sufficient hardness that is not broken by external force and conflicting properties. In addition, a high content of the drug and / or drug-containing functional fine particles in the tablet is also required so that the tablet does not increase in size.
  • the preparation produced by the freeze-drying method has a rapid disintegration property, but has a disadvantage that it is weak in strength and cannot measure the hardness.
  • freeze-drying production equipment is required and production takes a long time, it is inferior in terms of industrial productivity and production cost.
  • Patent Documents 1 and 2 have a problem that a special tablet machine of film-mediated compression type is required to prevent this because wrinkle adhesion occurs when compressed into tablets with boil. .
  • the tablets produced by the production methods described in Patent Documents 3 and 4 are packaged together due to low pressure molding and the slightly weak binding power of saccharides that can be amorphous as a binder. There are problems such as difficulty in obtaining tablets having sufficient strength for packaging, and high sugar content.
  • Orally disintegrating tablets by the above-mentioned four generations of formulation methods including those described in Patent Documents 5 to 7 contain drugs and drugs to absorb and disintegrate or dissolve the tablets in the oral cavity. In most cases, it is necessary to form tablets by containing saccharides, sugar alcohols and / or disintegrants in addition to the particles to be formed. In addition, a binder is used in order to make the drug or a mixture containing the drug and a mixture of sugars, sugar alcohols and / or disintegrants into a particulate material with good fluidity and easy to manufacture into a uniform tablet. Often it is necessary to wet granulate.
  • Patent Documents 3 and 8 in order to increase the tablet disintegration time while ensuring sufficient tablet strength, it can be amorphous as a binder that contributes to tablet strength. A large amount of sugar or sugar alcohol and sugar or sugar alcohol as an excipient that contributes to rapid disintegration are simultaneously blended.
  • the orally disintegrating tablets described in Patent Documents 9 and 10 also have rapid disintegration and tablet hardness, but contain a large amount of excipients and disintegrants, and contain a high content of drugs. It is not compatible with this.
  • grains containing the drug include the functional particle which coat
  • the drug and / or drug-containing functional particles are contained in a high content of 50% by weight or more, desirably 65% by weight or more, and more desirably 75% by weight or more, and placed in the oral cavity or water. It is important to develop a method for producing an orally disintegrating tablet that has rapid disintegration and solubility, and has strong strength that does not collapse in the manufacturing process, distribution process, and hospital preparation. Yes.
  • an object of the present invention is to provide a method for producing a tablet capable of containing a drug and / or a drug-containing functional fine particle at a high content while achieving both strength and rapid disintegration, if necessary. It is to provide a tablet containing a high content of a drug and / or drug-containing functional fine particles.
  • gluconic acid gluconic acid hydrate, gluconic acid salt, gluconic acid salt hydrate, glucono- ⁇ -lactone, glucono- ⁇ -lactone hydrate, glucono- ⁇ -lactone salt
  • a hydrate of a salt of glucono- ⁇ -lactone may be simply referred to as “gluconolactone”.
  • a binding agent having a binding power superior to that of sugars or sugar alcohols and having low water viscosity and easily soluble in water can be used, it can bind to drugs and drug-containing functional fine particles.
  • a tablet can be formed by adding a small amount of a lubricant to a granulated or coated product only with the agent. The tablets obtained in this way are likely to have sufficient tablet strength and rapid disintegration.
  • the present inventors have the ability as a binder for producing particles or tablets, and at the time of producing granules for compression molding into tablets under the condition of an additive having low viscosity when placed in water.
  • the present inventors have sought a binder that contributes to the granulation property of the tablet and the moldability when it is made into a tablet and is easily dispersed in the oral cavity when the tablet is included in the oral cavity.
  • gluconolactone is converted to gluconic acid by humidifying and applying water, and conversely, if gluconic acid is dried, the structure changes to crystals of glucono- ⁇ -lactone. Therefore, the present inventors have found a method for utilizing this characteristic.
  • Glucono- ⁇ -lactone has a strong binding force.
  • glucono- ⁇ -lactone becomes gluconic acid, which is an organic carboxylic acid when dissolved in water as described above, and its solution viscosity is low.
  • gluconolactone is rapidly dispersed in water. Therefore, the present inventors presumed that by using a gluconic acid solution or gluconolactone as a binder, a tablet that satisfies both the requirements of both rapid disintegration and strength can be obtained. Further, glucono- ⁇ -lactone has a melting point of 151 to 155 ° C., and it was considered that the same effect could be obtained by the heating / cooling method. As a result of various experiments, as expected, we were able to obtain experimental data to support that assumption.
  • the present inventors have also proposed a method for improving tablet strength by a humidified drying method using tautomerism between glucono- ⁇ -lactone and gluconic acid, and a tablet using this method, particularly an orally disintegrating tablet.
  • the manufacturing method of was found. That is, if gluconolactone is used as a binder and is produced by the low pressure molding humidification drying method, many excipients and disintegrants are blended for its binding power, quick solubility in water, and fast dispersibility. Without being able to produce an orally disintegrating tablet having sufficient tablet strength and, if necessary, rapidly disintegrating in the oral cavity, that is, disintegrating within 1 minute, preferably within 45 seconds. Was newly found.
  • glucuronolactone also has a characteristic that its structure changes to glucuronolactone crystals when it is humidified to give glucuronic acid which is an organic carboxylic acid by applying water, and conversely when glucuronic acid is dried. From the above, it was found that, like gluconolactone, by using it as a binder, it is possible to produce a tablet having sufficient tablet strength and, if necessary, realizing rapid disintegration in the oral cavity.
  • glucuronolactone and glucuronic acid may be simply referred to as “glucuronolactone”.
  • the present invention is configured as follows.
  • the tablet manufacturing method includes a mixing step, a compression molding step, a liquefaction step, and a solidification step.
  • gluconic acid, gluconic acid hydrate, gluconic acid salt, gluconic acid salt hydrate, glucono- ⁇ -lactone, glucono- ⁇ -lactone hydrate, glucono- ⁇ -lactone A step of mixing at least one selected from the group consisting of a salt, a hydrate of glucono- ⁇ -lactone, glucuronolactone, and glucuronic acid with a drug and / or a drug-containing functional fine particle to obtain a mixture It is.
  • the compression molding step is a step of obtaining a molded product by compression molding the mixture obtained in the mixing step.
  • the liquefaction step is a step of liquefying at least the surface or the inside of the molded product compression-molded in the compression molding step.
  • the solidification step is a step including a solidification step of solidifying a molded product whose surface or inside is liquefied at least in the liquefaction step.
  • gluconolactone or glucuronolactone is used as a binder that also serves as a disintegrant.
  • the drug and / or drug-containing functional fine particles can be easily contained in the tablet in an amount of more than 50%, further 65% by weight or more.
  • the liquefaction step is preferably a step of humidifying the molded product compression-molded in the compression molding step.
  • the solidification step is preferably a step of drying a molded product having at least the surface or the interior liquefied in the liquefaction step.
  • the production method according to the present invention is a saccharide that can be made amorphous, sugar alcohols that can be made amorphous, a binder having a high hygroscopic property, a disintegrant, and hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH. It is preferable to further include a step of adding at least one of a non-amorphized saccharide that develops or a non-amorphized saccharide alcohol that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH.
  • non-amorphous saccharides and non-amorphous sugar alcohols By blending such non-amorphous saccharides and non-amorphous sugar alcohols, it is possible to provide a tablet having a hardness that has a positive effect on the stability of unpackaged tablets.
  • the storage condition is 25 ° C. and 75% RH. It is preferable that it is hygroscopic.
  • the strongly hygroscopic binder is preferably povidone, copolyvidone, or polyvinyl alcohol-polyethylene glycol block copolymer.
  • a binder other than the above and a highly hygroscopic additive it can also be used.
  • the disintegrant is preferably a polymer containing a hetero atom other than oxygen or at least one inorganic ion of sodium ion, calcium ion, and magnesium ion.
  • the disintegrant is preferably at least one selected from the group consisting of crospovidone, carmellose calcium, croscarmellose sodium, and sodium starch glycolate.
  • the sugar that can be amorphous or the sugar alcohol that can be amorphous is at least selected from the group consisting of sorbitol, maltose, lactitol, glucose, lactose, and trehalose.
  • sorbitol maltose
  • lactitol glucose
  • lactose lactitol
  • trehalose trehalose
  • a non-amorphous saccharide that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH or a non-amorphous sugar that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH.
  • the sugar alcohol that does not crystallize is preferably at least one selected from the group consisting of mannitol, erythritol, maltitol, and xylitol.
  • the present inventors have increased the water conductivity by adding saccharides and sugar alcohols that can become amorphous having hygroscopicity, binders having high hygroscopicity, or disintegrants, and stronger tablet hardness. It has been found that a rapidly disintegrating orally disintegrating tablet can be produced.
  • the critical relative humidity can be lowered, and the moisture conditions for absorbing moisture It was found that by setting the temperature to about 25 ° C. and 75% RH or less, a strong tablet can be obtained, and effects such as prevention of adhesion between tablets can be realized.
  • blending of non-amorphous (non-amorphous) saccharides and sugar alcohols also has the effect of lowering critical humidity, and the same can be achieved by storing and drying under humidity conditions exceeding 25 ° C. and 75% RH. Of tablets.
  • the tablet according to the present invention comprises a drug and / or drug-containing functional fine particles, gluconic acid, gluconic acid hydrate, gluconic acid salt, gluconic acid salt hydrate, glucono- ⁇ -lactone, glucono - ⁇ -lactone hydrate, glucono- ⁇ -lactone salt, glucono- ⁇ -lactone salt hydrate, glucuronolactone, and at least one selected from the group consisting of glucuronic acid,
  • the content of the drug and / or drug-containing functional fine particles is 50% or more.
  • the tablet according to the present invention is preferably an orally disintegrating tablet.
  • the tablet according to the present invention exhibits hygroscopicity under storage conditions exceeding 75% RH, sugars that can be amorphous, sugar alcohols that can be amorphous, strong hygroscopic binders, disintegrants It is preferable to further include at least one of a non-amorphizing saccharide that does not become amorphous or a non-amorphizing sugar alcohol that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH.
  • the strong hygroscopic binder is preferably hygroscopic under storage conditions of 25 ° C. and 75% RH.
  • the strongly hygroscopic binder is preferably at least one selected from the group consisting of povidone, copolyvidone, or polyvinyl alcohol-polyethylene glycol block copolymer.
  • the disintegrant is preferably a polymer containing a hetero atom other than oxygen or at least one inorganic ion of sodium ion, calcium ion, and magnesium ion.
  • the disintegrant is preferably at least one selected from the group consisting of crospovidone, carmellose calcium, croscarmellose sodium, and sodium starch glycolate.
  • the sugar that can be amorphous or the sugar alcohol that can be amorphous is at least one selected from the group consisting of sorbitol, maltose, lactitol, glucose, lactose, and trehalose. It is preferable that
  • the sugar alcohol not to be refined is at least one selected from the group consisting of mannitol, erythritol, maltitol, xylitol and the like.
  • the tablet manufacturing method includes a mixing step, a compression molding step, a liquefaction step, and a solidification step.
  • gluconic acid, gluconic acid hydrate, gluconic acid salt, gluconic acid salt hydrate, glucono- ⁇ -lactone, glucono- ⁇ -lactone hydrate, glucono- ⁇ -lactone A step of mixing at least one selected from the group consisting of a salt, a hydrate of glucono- ⁇ -lactone, glucuronolactone, and glucuronic acid with a drug and / or a drug-containing functional fine particle to obtain a mixture It is.
  • the mixing process is a manufacturing process for producing a mixed powder for tableting.
  • a small amount of additives may be mixed.
  • the compression molding step is a step of obtaining a molded product by compression molding the mixture obtained in the mixing step.
  • the liquefaction step is a step of liquefying at least the surface or the inside of the molded product compression-molded in the compression molding step.
  • the solidification step is a step including a solidification step of solidifying a molded product whose surface or inside is liquefied at least in the liquefaction step.
  • the drug used in the present invention is not particularly limited as long as it is a therapeutically or prophylactically effective pharmaceutically active ingredient.
  • pharmaceutically active ingredients include hypnotic sedatives, sleep inducers, migraine agents, anti-anxiety agents, antiepileptic agents, antidepressants, anti-parkinsonian agents, neuropsychiatric agents, central nervous system agents, and local anesthetics , Skeletal muscle relaxant, autonomic nerve agent, antipyretic analgesic / anti-inflammatory agent, antispasmodic agent, antipruritic agent, cardiotonic agent, arrhythmic agent, diuretic agent, antihypertensive agent, vasoconstrictor, vasodilator, cardiovascular agent, high fat Antihypertensive agent, Respiratory agent, Antitussive agent, Pesticide, Antitussive agent, Bronchodilator, Antidiarrheal agent, Intestinal agent, Peptic ulcer agent, Gastric digestive agent, Antacid, Laxative, Bile
  • the drug-containing functional fine particles used in the present invention are prepared so that the drug having the above-mentioned pharmaceutical use becomes functional fine particles with controlled drug release, such as bitter taste-masking fine particles, enteric fine particles, and sustained-release fine particles. It has been done.
  • the particle size of the drug-containing functional fine particles is not particularly limited as long as it does not feel a rough feeling in the oral cavity.
  • the average particle size is usually preferably 350 ⁇ m or less, more preferably about 300 ⁇ m or less, and further preferably about 250 ⁇ m or less. If it is larger than 350 ⁇ m, a feeling of strangeness such as a rough feeling in the oral cavity will be strongly recognized, which is not preferable.
  • the functional particles can be used if the longest diameter is 2 mm or less.
  • the average particle diameter may be 2 mm or less, and when the pharmaceutical composition particles have a shape other than a sphere, the average longest diameter is preferably 2 mm or less.
  • Drug-containing functional fine particles can be prepared by a known method.
  • a commercially available microcrystalline cellulose particle (Asahi Kasei Chemicals, trade name: SELPHYA CP102, etc.) is used as a core, and a drug is laminated and coated by a known coating method such as tumbling fluidized coating.
  • An elution control film can be formed by coating a water-insoluble polymer substance such as an agent and a sustained-release film agent, and can be made into drug-containing functional fine particles such as bitterness masking fine particles, enteric fine particles, and sustained-release fine particles.
  • Release control coating agents include ethyl cellulose, ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl copolymer powder, and ethyl cellulose, ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl
  • An aqueous dispersion containing a copolymer and an ethyl acrylate / methyl methacrylate copolymer in the form of latex is used.
  • Enteric coating agents include hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylic acid / methyl methacrylate copolymer, methacrylic acid / ethyl methacrylate copolymer, methacrylic acid / ethyl acrylate There are copolymers. These can be used by dissolving them in an organic solvent such as methanol, ethanol, isopropanol, or dichloromethane, and it is also possible to use an aqueous dispersion containing these water-insoluble polymers in the form of latex.
  • an organic solvent such as methanol, ethanol, isopropanol, or dichloromethane
  • the above-mentioned release control film agent enteric film agent, polyvinyl acetal diethylaminoacetate, methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer, etc. can be used. .
  • waxy substances such as hydrogenated vegetable oil, stearic acid, palmitic acid, cetyl alcohol, stearyl alcohol, and triacetin, triethyl citrate, ethyl acrylate / methyl methacrylate copolymer dispersion It is free to mix and use plasticizers such as.
  • gluconolactone or glucuronolactone is used as a binder that also serves as a disintegrant. If gluconolactone or glucuronolactone is used as a binder and manufactured by the low-pressure molding humidification drying method, excipients and disintegrants are blended for its binding power, quick solubility in water, and fast dispersibility. Therefore, an orally disintegrating tablet having sufficient tablet strength and capable of rapidly disintegrating in the oral cavity, that is, disintegrating within 1 minute, preferably within 45 seconds can be produced.
  • the tablet according to the present invention it is not always necessary to add an additive such as an excipient or a disintegrant that is mixed in a normal orally disintegrating tablet. Therefore, a tablet containing the drug and / or drug-containing functional fine particles in an amount exceeding 50% by weight can be easily produced using a normal tableting machine. Furthermore, if desired, tablets containing a high content of 65% by weight or more can be easily produced.
  • additives such as commonly used excipients, binders, and disintegrants can be freely blended as necessary.
  • This production method preferably contains the drug and / or drug-containing functional fine particles in an amount of more than 50%, more preferably 65% by weight or more, according to a test method according to the 17th revised Japanese Pharmacopoeia. It is also a production method that can be applied in common to the production of miniaturized ordinary tablets whose disintegration time is within 30 minutes.
  • gluconolactone or glucuronolactone may be combined with a hygroscopic component such as a saccharide or sugar alcohol, a highly hygroscopic binder, or a water-swelling disintegrant.
  • a hygroscopic component such as a saccharide or sugar alcohol, a highly hygroscopic binder, or a water-swelling disintegrant.
  • sugars and sugar alcohols for example, sugars and sugar alcohols that can be amorphous such as sorbitol, maltose, lactitol, glucose, lactose, trehalose, and non-amorphous such as mannitol, erythritol, maltitol, xylitol Saccharides and sugar alcohols (which do not become amorphous) are preferred, and trehalose, maltose, and mannitol are more preferred.
  • a hygroscopic binder may be used as an alternative to the sugars or sugar alcohols, or may be formulated together.
  • polyvinylpyrrolidone, copolyvidone, and polyvinyl alcohol-polyethylene glycol block copolymer are preferable.
  • water-swelling disintegrants include crospovidone, carmellose calcium, croscarmellose sodium, sodium starch glycolate, and other heteroatoms other than oxygen such as nitrogen and sulfur, or sodium ions, calcium ions, magnesium ions, etc.
  • a disintegrant made of a polymer containing inorganic ions is preferred.
  • the water conductivity is increased, and the tablets are stronger because they interact with gluconolactone or glucuronolactone. It can be made into a rapidly disintegrating orally disintegrating tablet having hardness.
  • the critical relative humidity can be lowered and absorbed by using gluconolactone or glucuronolactone together with saccharides or sugar alcohols which can be amorphous, or a binder having a strong binding force.
  • saccharides and sugar alcohols that can be amorphous, saccharides and sugar alcohols that do not become amorphous (not amorphous), polyvinylpyrrolidone, copolyvidone, polyvinyl
  • a binder of alcohol-polyethylene glycol block copolymer and a disintegrant of crospovidone carmellose calcium, croscarmellose sodium, sodium starch glycolate, lower humidity conditions, eg 25 ° C. 75% RH-25
  • a stronger tablet can be produced under humidified conditions of 90% RH.
  • saccharides, sugar alcohols, and disintegrating agents can be freely added within a range not impairing tablet strength and necessary disintegration property. Moreover, it is also free to add a binder such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinyl alcohol to contribute to tablet strength.
  • a binder such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinyl alcohol to contribute to tablet strength.
  • the amount of gluconolactone or glucuronolactone used in the present invention is preferably 1 to 50% by weight, more preferably 2 to 30% by weight, based on the weight of the tablet produced in the present invention. Preferably, it is 5 to 20% by weight.
  • the amount is less than 1% by weight, there is a concern that the function as a binder for intraoral quick disintegrating tablets is not sufficiently exhibited.
  • the amount is more than 50% by weight, various problems such as disintegration delay may occur when an intraoral rapidly disintegrating tablet is formed, and good characteristics may not be obtained.
  • additives that are pharmaceutically acceptable and used as additives can be blended.
  • the additive can be blended when the drug-containing functional fine particles are granulated, or can be used by mixing with the granulated drug and / or drug-containing functional fine particles when tableting.
  • additives include excipients, acidulants, foaming agents, artificial sweeteners, flavors, lubricants, colorants, stabilizers, and the like.
  • An additive can be used 1 type or in combination of 2 or more types.
  • the compounding quantity will not be restrict
  • excipients include D-mannitol, lactose, calcium carbonate, calcium hydrogen phosphate, magnesium aluminate metasilicate, and the like.
  • acidulant include citric acid, tartaric acid, malic acid and the like.
  • foaming agent include sodium bicarbonate.
  • artificial sweeteners include saccharin sodium, glycyrrhizin dipotassium, acesulfame potassium, aspartame, stevia, thaumatin and the like.
  • flavor, lemon, lemon lime, orange, menthol, etc. are mentioned, for example.
  • the lubricant examples include magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid, sodium stearyl fumarate and the like.
  • the colorant examples include edible dyes such as edible yellow No. 5, edible red No. 2 and edible blue No. 2; edible lake dyes; and bengara which is an inorganic pigment. Stabilizers are selected after various studies for each drug. These additives can be appropriately added in an appropriate amount by one or a combination of two or more.
  • the drug-containing functional fine particles are produced by a known method.
  • the production method is not particularly limited and can be appropriately selected as long as fine particles having a desired function such as elution control are obtained.
  • a polymer substance such as a controlled release film agent, an enteric film agent, and a bitterness masking film agent is further coated to produce drug-containing functional fine particles.
  • a solution of a polymer substance is added to a drug and microcrystalline cellulose to form a fine particle that approximates a sphere by stirring granulation method or tumbling flow granulation method.
  • a polymer substance such as an agent and a bitter taste masking film is further coated to produce functional fine particles containing a drug.
  • a spray drying fluidized bed granulator is selected for the coating.
  • the solvent used when preparing the drug-containing functional fine particles is, for example, water or an organic solvent.
  • the organic solvent include methanol, ethanol, isopropanol, dichloromethane, and the like. These organic solvents may be used singly or as a mixture of two or more at an appropriate ratio. It may be used.
  • the temperature is set so that the product temperature is about 40 ° C. to about 60 ° C. in the case of coating using water, and the product temperature is about 30 ° C. to about 60 ° C. in the case of using an organic solvent. Furthermore, a spray liquid amount, a spray air amount, and the like are set.
  • Gluconolactone or glucuronolactone is dissolved or dispersed in a solution, granulated with a drug and / or drug-containing functional fine particles, or coated with a drug and / or drug-containing functional fine particles to form a mixture. May be.
  • gluconolactone or glucuronolactone may be mixed with the drug and / or drug-containing functional fine particles in the form of a powder.
  • Granulation or coating method is not particularly limited.
  • a fluidized bed method, a rolling fluidized bed method, a stirring granulation method, a rolling granulation method, or the like can be selected.
  • gluconolactone or glucuronolactone is sprayed onto the drug and / or drug-containing functional microparticles in a solution dissolved and / or suspended in a pharmaceutically acceptable solvent and dried. Is done.
  • a solution obtained by dissolving and / or suspending gluconolactone or glucuronolactone in a pharmaceutically acceptable solvent has low viscosity, and has a drug and / or drug-containing functionality by stirring granulation or fluidized bed granulation.
  • Admixture granulation of fine particles can be performed, but the latter can be performed continuously, which is advantageous in that the operation is simple and requires a short time.
  • the concentration of gluconolactone or glucuronolactone in the solution is usually about 5 to 50% by weight, and more preferably 10 to 40% by weight.
  • gluconolactone or glucuronolactone when mixing gluconolactone or glucuronolactone with a drug and / or drug-containing functional fine particles in powder form, for example, a suitable additive is added to the drug and / or drug-containing functional fine particles as necessary.
  • a suitable additive is added to the drug and / or drug-containing functional fine particles as necessary.
  • a method of mixing a granulated solution using a solution in which a binder such as saccharides, sugar alcohols, and povidone that can become amorphous is dissolved with gluconolactone or glucuronolactone. Also in this case, it is free to mix the above-described additives such as a disintegrant as necessary.
  • the compression molding step is not particularly limited as long as it is carried out by a method of making the tablet shape at a pressure higher than the minimum necessary pressure to maintain the tablet shape.
  • Tableting is performed by a known method. Tableting can be performed using a tableting mixed powder produced in the manufacturing process of a tableting mixed powder and using a normal tableting machine such as a single tableting machine or a rotary tableting machine. Further, the mixed powder for tableting can be made into tablets using an external lubricant tableting machine.
  • the tableting pressure is usually preferably about 0.25 to about 8.0 kN / ⁇ , more preferably about 0.50 to about 6.0 kN / ⁇ , and most preferably about 0.50 to about 5.0 kN / ⁇ . It is not preferable to apply more pressure than necessary because there is concern about the possibility of denaturation of the drug-containing functional fine particles and the possibility of delaying the oral disintegration time.
  • the liquefaction step and the solidification step are preferably performed by a humidification step and a drying step, and may be performed by a heating step and a cooling step, or may be performed by other steps.
  • Gluconolactone or glucuronolactone blended in the tablet is dissolved by humidification or heating and hydrolyzed, and a part thereof is transferred to gluconic acid or glucuronic acid. Next, when this is dried, an intermolecular cyclization reaction (dehydration condensation) occurs and quickly becomes glucono- ⁇ -lactone or glucuronolactone. At this time, glucono- ⁇ -lactone or glucose uniformly dispersed in the tablet is obtained. Chronolactone is firmly bound, and the strength of the tablet is increased.
  • the humidification step and the drying step are not particularly limited as long as the tautomerism between glucono- ⁇ -lactone and gluconic acid or glucuronolactone and glucuronic acid can be used.
  • the humidification condition is determined by the apparent critical relative humidity of the tableting mixed powder containing gluconolactone or glucuronolactone.
  • humidify above the critical relative humidity of the mixed powder.
  • the humidity is preferably about 50 to about 100 RH%, more preferably about 60 to about 90 RH%.
  • the humidification temperature is preferably about 15 to about 50 ° C, more preferably about 20 to about 40 ° C.
  • the humidifying time is preferably 1 to 48 hours, more preferably 8 to 24 hours.
  • the drying process is not particularly limited as long as it is a method for removing moisture absorbed by humidification.
  • the drying conditions are usually preferably about 10 to about 100 ° C., more preferably about 20 to about 70 ° C., and most preferably about 25 to about 60 ° C.
  • the drying time is preferably 30 minutes to 10 hours, and more preferably 1 to 6 hours.
  • the liquefaction step may be a step of heating and melting gluconolactone or glucuronolactone
  • the solidification step may be a step of cooling and solidifying the molten gluconolactone or glucuronolactone.
  • gluconolactone or glucuronolactone blended in the tablet is dissolved by heating, and then cooled in the cooling step to crystallize, whereby the gluconolactone or glucuronolactone is more firmly bound to each other. As a result, the strength of the tablet is improved.
  • the heating is carried out by a known method, and is not particularly limited as long as it is a method capable of dissolving gluconolactone or glucuronolactone blended in the mixed powder for tableting.
  • a heating process can be performed using a ventilation oven, for example.
  • the temperature condition is about 100 to about 175 ° C., preferably about 120 to about 160 ° C., when considering the melting point drop due to the blend or the like.
  • the time condition is appropriately determined depending on the desired tablet strength, disintegration property in the oral cavity, etc., but is usually 1 to 120 minutes, preferably 1 to 60 minutes, and more preferably 2 to 30 minutes.
  • the cooling is performed by a known method and is not particularly limited as long as gluconolactone or glucuronolactone is solidified after being melted.
  • the cooling may be performed, for example, by being left at room temperature or stored in a low temperature environment such as a refrigerator.
  • the tablet manufacturing method includes a mixing step, a compression molding step, a liquefaction step, and a solidification step.
  • gluconic acid, gluconic acid hydrate, gluconic acid salt, gluconic acid salt hydrate, glucono- ⁇ -lactone, glucono- ⁇ -lactone hydrate, glucono- ⁇ -lactone A step of mixing at least one selected from the group consisting of a salt, a hydrate of glucono- ⁇ -lactone, glucuronolactone, and glucuronic acid with a drug and / or a drug-containing functional fine particle to obtain a mixture It is.
  • the compression molding step is a step of obtaining a molded product by compression molding the mixture obtained in the mixing step.
  • the liquefaction step is a step of liquefying at least the surface or the inside of the molded product compression-molded in the compression molding step.
  • the solidification step is a step including a solidification step of solidifying a molded product whose surface or inside is liquefied at least in the liquefaction step.
  • the liquefaction step is preferably a step of humidifying or heating the molded product compression-molded in the compression molding step.
  • the solidification step is preferably a step of drying a molded product having at least the surface or the interior liquefied in the liquefaction step.
  • the production method according to the present invention comprises a sugar that can be amorphous, a sugar alcohol that can be amorphous, a highly hygroscopic binder, a disintegrant, and storage conditions exceeding 25 ° C. and 75% RH.
  • the method further includes a step of adding at least one of a non-amorphous saccharide that exhibits hygroscopicity or a non-amorphous sugar alcohol that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH. .
  • the highly hygroscopic binder is hygroscopic under storage conditions of 25 ° C. and 75% RH.
  • the strongly hygroscopic binder is preferably povidone, copolyvidone, or polyvinyl alcohol-polyethylene glycol block copolymer.
  • the disintegrant is preferably a polymer containing a hetero atom other than oxygen or at least one inorganic ion of sodium ion, calcium ion, and magnesium ion. .
  • the disintegrant is preferably at least one selected from the group consisting of crospovidone, carmellose calcium, croscarmellose sodium, and sodium starch glycolate. .
  • the saccharide that can be amorphous or the sugar alcohol that can be amorphous is selected from the group consisting of sorbitol, maltose, lactitol, glucose, lactose, trehalose, and the like. It is preferable that at least one selected.
  • the sugar alcohol that does not become amorphous is preferably at least one selected from the group consisting of mannitol, erythritol, maltitol, and xylitol.
  • a tablet according to the present invention comprises a drug and / or a drug-containing functional fine particle, gluconic acid, a gluconic acid hydrate, a gluconic acid salt, a gluconic acid salt hydrate, glucono- ⁇ - At least one selected from the group consisting of lactone, glucono- ⁇ -lactone hydrate, glucono- ⁇ -lactone salt, glucono- ⁇ -lactone salt hydrate, glucuronolactone, and glucuronic acid And the content of the drug and / or drug-containing functional fine particles is 50% or more.
  • the tablet according to the present invention is preferably an orally disintegrating tablet.
  • the tablet according to the present invention absorbs moisture under a storage condition exceeding 25 ° C. and 75% RH, sugars that can be amorphous, sugar alcohols that can be amorphous, a highly hygroscopic binder, disintegrant. It is preferable to further include at least one of a non-amorphizing saccharide that exhibits sexiness or a non-amorphizing sugar alcohol that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH.
  • the highly hygroscopic binder is hygroscopic under storage conditions of 25 ° C. and 75% RH.
  • the strongly hygroscopic binder is preferably at least one selected from the group consisting of povidone, copolyvidone, or polyvinyl alcohol-polyethylene glycol block copolymer.
  • the disintegrant is preferably a polymer containing a hetero atom other than oxygen or at least one inorganic ion of sodium ion, calcium ion, and magnesium ion.
  • the disintegrant is preferably at least one selected from the group consisting of crospovidone, carmellose calcium, croscarmellose sodium, and sodium starch glycolate.
  • the sugar that can be amorphous or the sugar alcohol that can be amorphous is selected from the group consisting of sorbitol, maltose, lactitol, glucose, lactose, and trehalose. At least one is preferred.
  • the sugar alcohol that does not become amorphous is preferably at least one selected from the group consisting of mannitol, erythritol, maltitol, and xylitol.
  • the drug substance used in the experiment is as follows. Povidone (trade name: Kollidon 30, BASF), crospovidone (trade name: Kollidon CL-M, BASF), crystalline cellulose (grain) (trade name: SELPHYA CP102, Asahi Kasei Chemical, Hypromellose (trade name: TC-5E, Shin-Etsu) Chemical Industry), Sucralose (trade name: Sucralose P, Saneigen SFI), Ethylcellulose (trade name: Etocel 10, Dow Chemical), Hypromellose (trade name: TC-5R, Shin-Etsu Chemical), Macrogol (trade name: Macrogol 6000, Japanese fats and oils), ethyl cellulose (trade name: Etocel 7, Dow Chemical), glucono- ⁇ -lactone (Wako Pure Chemical Industries), glucono- ⁇ -lactone (Fuso Chemical Industry), calcium stearate (Taihei Chemical Industry) , D-mannitol (trade name: Allitol 50C,
  • crystalline cellulose (Selfia CP102) was taken and sprayed with layering solution 1 using a tumbling fluidized coating granulator (manufactured by POWREC: MP-01), followed by coating by spraying layering solution 2 . After spraying and drying, sieved with 42 mesh and 150 mesh to obtain drug layering fine particles.
  • seal coat fine particles 23.8 g of hypromellose (TC-5E) and 10.2 g of sucralose P were added to 647 g of purified water and dissolved by stirring to prepare a seal coating solution. Particles obtained by spraying a seal coating solution onto 1135 g of drug layering fine particles prepared in step (1) using a tumbling fluid type coating granulator (manufactured by POWREC: MP-01) and coating the surface. Was sieved with 42 mesh and 150 mesh to obtain seal coat fine particles.
  • Controlled release fine particles (i) Production of sustained-release coated fine particles Take 183 g of ethyl cellulose (Etocel 10) and 57.1 g of hypromellose (TC-5R), add 2760 g of 80% ethanol solution, dissolve with stirring, and release controlled coating A solution was prepared. Using 500% of the seal coat fine particles prepared in step (2) and spraying the controlled release coating solution using a tumbling fluid type coating granulator (manufactured by POWREC: MP-01), the resulting particles are dried. After that, it was sieved with 42 mesh and 150 mesh to obtain sustained-release coated fine particles.
  • a tumbling fluid type coating granulator manufactured by POWREC: MP-01
  • the overcoating liquid A is sprayed on 500 g of the sustained-release coated fine particles prepared in the step (3)-(i) using a tumbling flow type coating granulator (manufactured by Paulek: MP-01), and then overcoating Liquid B was sprayed to coat the surface.
  • the particles obtained by drying were sieved with 42 mesh and 150 mesh to obtain overcoating fine particles.
  • the overcoating fine particles correspond to sustained-release ambroxol hydrochloride fine particles.
  • the average particle diameter of the fine particles was about 280 ⁇ m.
  • Example 1 The functional fine particles (sustained release ambroxol hydrochloride fine particles) are coated with glucono- ⁇ -lactone, and only the particles are used to produce tablets mainly composed of the functional fine particles and glucono- ⁇ -lactone.
  • Example 1 Ferric citrate hydrate was granulated with a gluconic acid solution, and only the particles were used to produce tablets mainly composed of only two components of ferric citrate hydrate and gluconic acid (Example 2). ).
  • D-mannitol is regarded as a drug that is easily soluble in water, and only D-mannitol is granulated with a gluconic acid solution, and only the particles are used to produce a tablet mainly composed of two components of D-mannitol and gluconic acid. (Examples 3 and 4). These tablets were evaluated by measuring the hardness and disintegration time in the oral cavity.
  • Example 1 200 g of sustained-release ambroxol hydrochloride fine particles were put into a tumbling fluid type coating granulator (MP-01 type: POWREC Co., Ltd.) and 400 g of a 10% aqueous solution of glucono- ⁇ -lactone was allowed to flow while rolling. The coating was used and dried to obtain lactone-coated sustained-release ambroxol hydrochloride fine particles. Using only these particles, 0.2% of magnesium stearate was blended, and tablets with a weight of 200 mg, a diameter of 8 mm, and a corner plane were produced at a tableting pressure of 3 kN / kg. The tablet had a hardness of 17N. Next, this tablet was stored at 25 ° C.
  • a tablet showing an orally disintegrating property may be simply referred to as a “tablet”.
  • Example 2 300 g of ferric citrate hydrate is taken into a rolling fluidized coating granulator (MP-01 type) and 300 g of 20% aqueous solution prepared by diluting a 50% gluconic acid solution while flowing is used. After spray granulation, the particles were dried to produce particles. Using only these particles, 0.3% of magnesium stearate was added, and tablets with a weight of 250 mg, a diameter of 9 mm, and two-stage R were produced at a tableting pressure of 2.4 kN / kg. Tablet hardness was 15N. The tablets were stored for 16 hours at 25 ° C. and 75% RH in a thermo-hygrostat, and then dried at 40 ° C. for 1 hour and further at 60 ° C. for 3 hours by a draft dryer. The obtained tablet had a hardness of 85 N, a disintegration time in the oral cavity of 90 seconds, and was dried by humidification to obtain a tablet having sufficient strength and a drug content of about 83%.
  • MP-01 type rolling fluidized
  • Example 3 200 g of D-mannitol (Pearlitol 50C) was put into the fluidized bed mode of a rolling fluidized coating granulator (MP-01 type) and diluted to a 20% by weight aqueous solution prepared by diluting a 50% gluconic acid solution. After spray granulation using 100 g, the particles were dried to produce particles. Using only these particles, magnesium stearate as an external lubricant was used to produce tablets having a weight of 185 mg, a diameter of 8.5 mm, and a corner plane at a tableting pressure of 2 kN / kg. The tablet had a hardness of 20N. The tablets were stored for 16 hours at 25 ° C.
  • MP-01 type rolling fluidized coating granulator
  • thermo-hygrostat and 75% RH in a thermo-hygrostat and then dried at 30 ° C. for 3 hours using DRYING OVEN.
  • the obtained tablet had a hardness of 51 N, an oral disintegration time of 20 seconds or less, and was subjected to humidification drying to obtain an orally disintegrating tablet having sufficient strength. This suggested the possibility of obtaining an orally disintegrating tablet with a high content exceeding 80% by weight for a drug that is easily soluble in water.
  • this formulation was a robust formulation that maintained a hardness of 20 N or higher when returned to an environment of 25 ° C. and 75% RH.
  • Example 4 Take 900 g of D-mannitol (Pearitol 50C) and put it into a high-speed agitation granulator (VG-05 type: POWREC Co., Ltd.). Blade rotation speed is 500 rpm, chopper rotation speed is 1500 rpm, and glucono- ⁇ -lactone is 60 g. An aqueous gluconic acid solution dissolved in water was added, granulated for 5 minutes, and dried in a fluidized bed mode of MP-01.
  • the obtained granules were sized, and tableted with a tablet with a tableting pressure of 1.0 to 1.5 kN, a weight of 200 mg, a diameter of 8.0 mm, and a corner plane using magnesium stearate as an external lubricant.
  • the tablet hardness was 16N.
  • This tablet was humidified with a thermo-hygrostat under 25 ° C. and 85% RH for 16 hours and dried at 60 ° C. for 3 hours.
  • the obtained tablet had a hardness of 83 N and a disintegration time of 60 seconds.
  • Example 2 Sustained release ambroxol hydrochloride fine particles coated with D-mannitol and further coated with glucono- ⁇ -lactone on the outer layer, and using only these particles, tablets with calcium stearate as an external lubricant (Example 5). In addition, stirring and granulation were performed in a hydroalcoholic system (Example 6). For comparison, maltose was used instead of glucono- ⁇ -lactone used in Example 5 to produce fine particles coated with maltose. Using only the particles, calcium stearate was made into a tablet as an external lubricant (Comparative Example 1). Next, the tablets were stored at 25 ° C. and 75% RH to 25 ° C. and 90% RH for 16 hours in a thermo-hygrostat, and then dried at 60 ° C. for 3 hours. Measurement and evaluation were performed.
  • Example 5 200 g of sustained-release ambroxol hydrochloride fine particles were put into a tumbling fluid type coating granulator (MP-01 type: POWREC Co., Ltd.), and 10% by weight of D-mannitol (Pairitol 50C) while rolling and flowing. After coating using 100 g of an aqueous solution, coating was performed using 210 g of a 10% by weight aqueous solution of glucono- ⁇ -lactone, followed by drying to obtain lactone-coated sustained-release ambroxol hydrochloride fine particles.
  • MP-01 type POWREC Co., Ltd.
  • D-mannitol 50C D-mannitol
  • tablets having a weight of 231 mg, a diameter of 8.5 mm, and a corner plane were produced using calcium stearate as an external lubricant. Using this tablet, the tablet was humidified and dried as described above and evaluated. The production conditions and test results of the tablets are shown in Table 1.
  • Example 6 750 g of sustained-release ambroxol hydrochloride fine particles were put into a high-speed stirring granulator (VG-05 type: POWREC Co., Ltd.), and water ethanol was added at a weight ratio of 1: Granulation with stirring was carried out for 3 minutes using 380 g of a solution obtained by adding 5 g of PVP to a solution obtained by dissolving glucono- ⁇ -lactone in 50% so as to be 50% by weight. The obtained granulated sustained-release ambroxol hydrochloride fine particles were used, and tablets having a weight of 200 mg, a diameter of 8.0 mm, and a corner plane were produced using magnesium stearate as an external lubricant. Using this tablet, the tablet was humidified and dried as described above and evaluated. The production conditions and test results of the tablets are shown in Table 1.
  • Example 1 A maltose-coated sustained-release ambroxol hydrochloride fine particles were produced in the same manner as in Example 5 using a 10% by weight aqueous solution of maltose instead of the 10% by weight aqueous solution of glucono- ⁇ -lactone. Using this tablet, the tablet was humidified and dried as described above and evaluated. The production conditions and test results of the tablets are shown in Table 1.
  • the test was conducted using maltose, which is supposed to increase tablet hardness by humidified drying using the change from an amorphous state to a crystal, but it is tableted only with particles having an average particle size of about 300 ⁇ m.
  • maltose no increase in tablet hardness was observed up to tablets with sufficient strength.
  • glucono- ⁇ -lactone a clear increase in the hardness of the tablet was confirmed by humidifying at 25 ° C. and 75% RH to 90% RH and drying at 60 ° C.
  • Tablets were prepared using glucono- ⁇ -lactone and maltose or trehalose mixed together and dissolved in water as a binder (Examples 7 to 10). Also, tablets were prepared using a maltose or trehalose plain dissolved in water as a binder (Comparative Examples 2 to 3). Next, after these tablets were stored for 16 hours at 25 ° C. and 75% RH in a thermo-hygrostat, the tablets were dried for 5 hours at 60 ° C., and the tablet hardness and disintegration time in the oral cavity were measured for evaluation. went.
  • Example 7 180 g of D-mannitol (Pearlitol 50C) was added to a rolling fluidized coating granulator (MP-01 type), and while flowing, an aqueous solution of a 1: 1 mixture of glucono- ⁇ -lactone and maltose (20% by weight) ) Spray granulation was performed using 100 g of binder. This granulated product was mixed with 0.5% by weight of magnesium stearate, and a tablet having a weight of 200 mg, a diameter of 8.0 mm, and a corner plane was produced. Table 2 shows the tablet production conditions and test results.
  • Example 8 to 10 180 g of D-mannitol (Pearlitol 50C) was put into a fluidized bed mode of a tumbling fluidized-type coating granulator (MP-01 type), and while flowing, 1: 1, 3: 3 of glucono- ⁇ -lactone and trehalose Spray granulation was carried out using 100 g of an aqueous solution (20% by weight) of a 1 and 9: 1 mixture as a binder. This granulated product was mixed with 0.5% by weight of magnesium stearate, and a tablet having a weight of 200 mg, a diameter of 8.0 mm, and a corner plane was produced.
  • Example 8 was based on a 1: 1 mixture
  • Example 9 was based on a 3: 1 mixture
  • Example 10 was based on a 9: 1 mixture.
  • Table 2 shows the tablet production conditions and test results.
  • Comparative Examples 2 and 3 are tablets manufactured by a method according to Patent Document 3 and Patent Document 8, but only a tablet having a hardness of about 50 N can be obtained even when humidified and dried. On the other hand, it was clearly shown that a tablet prepared by blending maltose or trehalose with glucono- ⁇ -lactone is a tablet having a very strong strength having a strength of 70 N or more.
  • Example 4 200g of sustained-release ambroxol hydrochloride fine particles are put into a tumbling flow type coating granulator (MP-01 type), and 200g of 10% by weight aqueous solution of D-mannitol (Pearlitol 50C) is used while rolling and flowing. Then, after the layering, the dried particles (hereinafter referred to as mannitol-coated ABX fine particles) are mixed with glucono- ⁇ -lactone and with a mixture of glucono- ⁇ -lactone and a water-swellable disintegrant. Tablets were prepared using calcium stearate as an external lubricant (Examples 11 to 15).
  • tablets prepared with mannitol-coated ABX fine particles mixed with maltose or trehalose and those mixed with maltose or trehalose and a water-swelling disintegrant were used as tableting powder, and calcium stearate was used as an external lubricant ( Comparative Examples 4 to 9).
  • these tablets were stored at 35 ° C. 82% RH (potassium chloride saturated solution in a desiccator) or 25 ° C. 90% RH (constant temperature and humidity machine) for 16 hours, and then dried at 60 ° C. for 6 hours. Evaluation was performed by measuring tablet hardness and oral disintegration time.
  • crospovidone polyplastidone XL-10
  • sodium starch glycolate was used in Example 13, Comparative Example 6 and Comparative Example 9.
  • glucono- ⁇ -lactone did not increase the tablet hardness even when it was humidified and dried at 35 ° C and 82% RH, but the product that was stored at 25 ° C and 90% RH had an increased hardness. Admitted.
  • Crospovidone Polyplastidone XL-10, sodium starch glycolate (primogel), carmellose calcium (ECG-505), or croscarmellose sodium (Ac-Di-Sol) added together with glucono- ⁇ -lactone
  • Example 5 A tablet was prepared by mixing glucono- ⁇ -lactone and povidone (Kollidon 30) and dissolving in water as a binder (Example 16). Next, this tablet was humidified and dried, and tablet hardness and oral disintegration time were measured and evaluated.
  • Example 16 270 g of D-mannitol (Pearritol 50C) was put into a fluidized bed mode of a rolling fluidized coating granulator (MP-01 type), and while flowing, a 9: 1 mixture of glucono- ⁇ -lactone and Kollidon 30 was mixed. Spray granulation was performed using 150 g of an aqueous solution (20% by weight) as a binder. This granulated product was mixed with 0.5% by weight of magnesium stearate, and a tablet having a weight of 200 mg, a diameter of 8 mm, and a rounded corner was produced at a tableting pressure of 1.5 kN / kg. Tablet hardness was 17N. The tablets were stored for 15 hours at 25 ° C.
  • the obtained tablet had a hardness of 82 N, an oral disintegration time of 45 seconds, and was dried by humidification, whereby a tablet having sufficient tablet strength was obtained.
  • Example 17 240 g of ferric citrate hydrate was added to a rolling fluidized-type coating granulator (MP-01 type), and while flowing, an aqueous solution of a 1: 1 mixture of glucono- ⁇ -lactone and trehalose (20 wt. %) 120 g of spray granulation was performed as a binder.
  • This granulated product was mixed with 0.5% by weight of magnesium stearate, and tablets with a weight of 200 mg, a diameter of 8 mm, and a rounded corner were produced at a tableting pressure of 2 kN / kg. Tablet hardness was 20N.
  • the tablets were stored for 15 hours at 25 ° C.
  • the obtained tablet had a hardness of 117 N, an oral disintegration time of about 120 seconds, and was wet-dried to obtain a tablet having a strength exceeding 100 N and a drug content of about 90%.
  • This tablet cannot be said to be rapid in the oral disintegration time, but is handled as an extremely miniaturized tablet having excellent properties (for example, a normal tablet) having a drug content having a strength exceeding 100 N of about 90%. be able to.
  • Example 18 Take 850 g of acetaminophen and 50 g of Primogel and put into a high-speed stirring granulator (VG-05 type). Agitation granulation was carried out using a gluconic acid-trehalose aqueous solution as a binder. Magnesium stearate was added to this granulated product with an external lubricant, and tablets with a weight of 200 mg, a diameter of 8.0 mm, and a corner plane were produced at a tableting pressure of 2.5 kN / kg. Tablet hardness was 15N. The tablet was stored at 25 ° C. and 75% RH for 16 hours in a thermo-hygrostat and then dried at 60 ° C. for 3 hours by a vacuum dryer. The obtained tablet had a hardness of 71 N and an oral disintegration time of 25 seconds.
  • Example 19 Take 850 g of metformin and 50 g of Primogel and put them into a high-speed agitation granulator (VG-05 type). Blade rotation speed is 500 rpm, chopper is 1500 rpm, glucono- ⁇ -lactone is 100 g water: ethanol 1: 1 (weight) Agitation granulation was carried out using as a binder a gluconolactone solution dissolved in 200 g of the mixed solution. Magnesium stearate was added to this granulated product with an external lubricant, and tablets with a weight of 200 mg, a diameter of 8.0 mm, and a corner plane were produced at a tableting pressure of 4.0 kN / kg.
  • Tablet hardness was 13N.
  • the tablets were stored for 17 hours at 25 ° C. and 75% RH in a thermo-hygrostat and then dried at 60 ° C. for 3 hours using a vacuum dryer.
  • the tablets obtained had a hardness of 110 N and a disintegration time (JP method) of 38 seconds.
  • Example 20 250 g of abiraterone acetate and 50 g of crospovidone (XL-10) were taken and introduced into a high-speed agitation granulator (HMS-01 type: Fukae Powtech Co., Ltd.), and glucono- ⁇ - at a blade rotation speed of 250 rpm and a chopper of 1800 rpm. Agitation granulation was performed by adding 183.3 g of a solution obtained by dissolving 75 g of lactone and 8.3 g of trehalose in 100 g of water.
  • HMS-01 type Fukae Powtech Co., Ltd.
  • magnesium stearate was used as an external lubricant, and a tablet having a corner plane of 230 mg in weight and 8.5 mm in diameter was produced at a tableting pressure of 0.5 kN / kg. Tablet hardness was 14N.
  • the tablets were stored for 17 hours at 25 ° C. and 92% RH in a constant temperature and humidity machine, and then dried at 60 ° C. for 3 hours using a vacuum dryer. The obtained tablet had a hardness of 65N.
  • Example 21 Add 50 g of nilotinib hydrochloride hydrate and 10 g of crospovidone (XL-10) to a mortar and add 33.4 g of a solution prepared by dissolving 15 g of glucono- ⁇ -lactone and 1.67 g of trehalose in 16.7 g of water. Agitation granulation was performed manually. The granulated product was dried, and then magnesium stearate was used as an external lubricant, and tablets were produced with a corner flat plate with a weight of 230 mg and a diameter of 8.5 mm at a tableting pressure of 0.5 kN / ⁇ . Tablet hardness was 12N. The tablets were stored for 17 hours at 35 ° C. and 85% RH in a constant temperature and humidity machine, and then dried in a vacuum dryer at 60 ° C. for 3 hours. The resulting tablet had a hardness of 38N.
  • Example 22 500 g of D-mannitol (Pearlitol 50C) is put into a high-speed stirring granulator (VG-01 type), and 150 g of an aqueous solution (33% by weight) of a 9: 1 mixture of glucuronolactone and trehalose is combined with stirring. Granulation was performed as an agent. This granulated product was dried in a fluidized bed mode of MP-01 type, passed through a 32 mesh sieve, and then mixed with 0.5% by weight of magnesium stearate, and tableting pressures of 1.5 kN / ⁇ and 3.0 kN / ⁇ were added. Made tablets with a weight of 200 mg, a diameter of 8.0 mm, and a rounded corner.
  • Tablet hardness was 6N and 18N, respectively.
  • the tablets were stored for 15 hours at 25 ° C. and 75% RH in a constant temperature and humidity machine, and then dried at 60 ° C. for 3 hours in a draft dryer.
  • the hardness of the obtained tablets was 43N and 55N, respectively, and the oral disintegration time was 5 seconds and 12 seconds.
  • the tablet having sufficient tablet strength was obtained by humidifying and drying.
  • Test Example 8 As a method for uniformly dispersing glucono- ⁇ -lactone during production without solidifying the mixed mass, a method of spraying glucono- ⁇ -lactone as an aqueous solution (Examples 1, 2, 5, 7 to 10) is adopted. However, in this test example, it was investigated whether or not the pulverized glucono- ⁇ -lactone was mixed with the granulated product and granulated with ethanol to obtain the same effect as the tumbling spray method.
  • Examples 23 to 25 Take 900 g of D-mannitol (Pearitol 50C) and 100 g of glucono- ⁇ -lactone and put into a high-speed stirring granulator (VG-05 type). While mixing and stirring at a blade rotation speed of 500 rpm and a chopper rotation speed of 1500 rpm, add 230 g of ethanol. Added and granulated for 5 minutes. This granulated product was dried, passed through a 32 mesh sieve, and then magnesium stearate was added with an external lubricant to produce tablets having a weight of 200 mg, a diameter of 8.0 mm, and a rounded corner at a tableting pressure of 4.2 kN. .
  • Tablet hardness was 6N and 18N.
  • the tablets were stored for 16 hours at 25 ° C. and 75% RH in a constant temperature and humidity machine, and then dried at 60 ° C. for 3 hours in a draft dryer.
  • the hardness of the obtained tablet was 38 N, and the oral disintegration time was 17 seconds (Example 23).
  • Example 24 prepared by adding 100 g of glucono- ⁇ -lactone of 80 g and adding 20 g of trehalose (Example 24), a tablet with a tableting pressure of 3.0 kN and a tablet hardness of 14 N was obtained.
  • the tablets treated under the same humidifying and drying conditions as in No. 19 had a hardness of 51 N and a disintegration time of 29 seconds.
  • the tablet obtained with a tableting pressure of 2.2 kN had a hardness of 16 N, and the same humidifying and drying conditions as above.
  • Examples 26 and 27 900 g of D-mannitol (Pearlitol 50C) was put into a high-speed agitation granulator (VG-05 type), mixed and stirred at a blade rotation speed of 500 rpm and a chopper rotation speed of 1500 rpm, and 80 g of glucono ⁇ -lactone and amorphized. Granulation was carried out by adding a solution obtained by dissolving or dispersing 20 g of D-mannitol, which is a non-amorphous (non-amorphous) sugar, in 230 g of ethanol.
  • This granulated product was dried, passed through a 32 mesh sieve, magnesium stearate was added with an external lubricant, and a tablet with a weight of 200 mg, a diameter of 8.0 mm, and a corner plane was produced at a tableting pressure of 4.2 kN. .
  • Tablet hardness was 14N.
  • the tablets were stored for 16 hours at 25 ° C. and 75% RH in a thermo-hygrostat, and then dried for 3 hours at 60 ° C. in a ventilator.
  • the resulting tablets had a hardness of 44 N and disintegrated in the oral cavity. Was 17 seconds. Similarly, after storing for 16 hours at 25 ° C.
  • Example 26 the tablet was dried at 60 ° C. for 3 hours in a draft dryer, and the hardness of the obtained tablet was 97 N (Example 26). .
  • this formulation system 95 g of glucono- ⁇ -lactone and 5 g of D-mannitol are added, a solution dissolved or dispersed in 300 g of ethanol is added, and granules are granulated, and tableted at 4.3 kN.
  • the tablets with a hardness of 14N obtained in the above were treated under the same humidified drying conditions as in Example 26.
  • the hardness was 27N at 25 ° C. and 75% RH for 16 hours, and the disintegration time was 21 seconds.
  • the tablet hardness was 89 N (Example 27).
  • Example 23 was maintained at a sufficient hardness of 21 N even when left for several days at 25 ° C. and 75% RH after humidification drying. Furthermore, the hardness of the preparations obtained by leaving the tablets produced in Example 26 and Example 27 at 25 ° C. and 85% RH for several days at 25 ° C. and 75% RH were 28 N and 30 N in Example 26 and Example 27, respectively. It was.

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Abstract

Provided are: a method for producing tablets which can balance strength and optionally rapid disintegrating property, and which can contain a drug and/or drug-containing functional microparticles at a high content; and tablets. The method for producing tablets includes: a mixing step of mixing at least one component selected from the group consisting of gluconic acid, a hydrate of gluconic acid, a salt of gluconic acid, a hydrate of a salt of gluconic acid, glucono-δ-lactone, a hydrate of glucono-δ-lactone, a salt of glucono-δ-lactone, a hydrate of a salt of glucono-δ-lactone, glucuronolactone and glucuronic acid with a drug and/or drug-containing functional microparticles to produce a mixture; a compression molding step of compression-molding the mixture produced in the mixing step to produce a molded article; a liquefaction step of liquefying at least the surface or inside of the molded article produced by compression molding in the compression molding step; and a solidification step of solidifying the molded article of which at least the surface or inside has been liquefied in the liquefaction step.

Description

錠剤及びその製造方法Tablet and production method thereof
　本発明は、一般的には錠剤と錠剤の製造方法に関し、より特定的には口腔内崩壊錠とその製造方法に関する。 The present invention relates generally to tablets and tablet manufacturing methods, and more specifically to orally disintegrating tablets and manufacturing methods thereof.
　現在、患者が医療の中心に位置づけられるべきであるという考え方が強調されつつある。快適な医療環境を患者に提供するためには、患者の行動やライフスタイルにあった、服用しやすい製剤設計や医療現場で使用しやすい製剤設計をすることが重要となってきている。 Currently, the idea that patients should be positioned at the center of medical care is being emphasized. In order to provide patients with a comfortable medical environment, it has become important to design formulations that are easy to take and that are easy to use in medical settings that match the patient's behavior and lifestyle.
　近年、嚥下困難な重症患者に対して、錠剤や顆粒剤を粉砕して、あるいは散剤をそのまま水に懸濁させて、注射器で経口、経鼻又は直接胃にカテーテルを挿入して、薬物を投入する経管投与法が実施されているが、操作が繁雑で、時にはカテーテルの内径が細いため詰まり易いという問題がある。 In recent years, for severely ill patients who have difficulty swallowing, tablets and granules are crushed or powder is suspended in water as is, and a catheter is inserted into the stomach orally or nasally or directly into the stomach with a syringe. However, there is a problem that the operation is complicated, and sometimes the inner diameter of the catheter is thin, so that it is likely to be clogged.
　これらの状況を背景として、老人や小児もしくは嚥下困難な患者などにも適する剤形として、口中に含んだとき、あるいは水の中に入れたとき、速やかに崩壊分散もしくは溶解する口腔内崩壊錠剤の製剤化研究が精力的に行われている。 Against this backdrop, as a dosage form suitable for the elderly, children, or patients with difficulty swallowing, orally disintegrating tablets that disintegrate or dissolve rapidly when contained in the mouth or when placed in water Formulation research is being conducted energetically.
　口腔内崩壊錠は、口腔内での速崩壊性、滑らかな口あたり、味など、目的に応じていろいろな工夫がなされている。口腔内崩壊錠は、口腔内で速やかに溶解し、水なしでも容易に服薬できるため、高齢者や小児等、嚥下機能に問題のある患者に適した剤形として今後ますます普及するものと考えられる。 Orally disintegrating tablets are devised in various ways depending on the purpose, such as rapid disintegration in the oral cavity, smooth mouthfeel and taste. Orally disintegrating tablets dissolve quickly in the oral cavity and can be easily taken without water, so it is expected to become increasingly popular as a dosage form suitable for patients with swallowing problems such as the elderly and children. It is done.
　口腔内崩壊錠の製造に関わる技術推移は大きくは次のように分類される。いわゆる第一世代としては、薬物等の懸濁液や湿性塊を鋳型に精密充填して、凍結乾燥、通風乾燥等により乾燥固化する鋳型錠製剤であり、例えば、ＰＴＰポケットを鋳型として用いたＲ．Ｐ．Ｓｃｈｅｒｅｒ社（現Ｃａｔａｌｅｎｔ社）（英国）の凍結乾燥による「Ｚｙｄｉｓ」が商品化されている。 The technological transitions related to the production of orally disintegrating tablets can be broadly classified as follows. The so-called first generation is a mold tablet preparation in which a suspension or wet mass of a drug or the like is precisely filled into a mold and solidified by freeze drying, ventilation drying, or the like. For example, R using a PTP pocket as a mold . P. “Zydis” by lyophilization of Scherer (currently Catalent) (UK) has been commercialized.
　第二世代は、薬物、糖類などの混合物を、アルコール・水溶液等で湿潤させたものを低圧で成形させた後乾燥する湿式成形法による口腔内崩壊錠である。例えば、特開平５－２７１０５４号公報（特許文献１）には、薬効成分と糖類とを含む混合物に、糖類の粒子表面が湿る程度の水分を含有させて打錠し、乾燥させる口腔内溶解型錠剤の製造法が記載されている。また、国際公開番号ＷＯ０１／０６４１９０号（特許文献２）には、薬剤、糖類を混合後、ポリビニルアルコールを溶解した水又は含水有機溶媒で練合後、湿性顆粒を鋳型に充填しフィルムを介して圧縮して錠剤の形に成形し、これを乾燥して製する速崩壊性錠剤が記載されている。 The second generation is an orally disintegrating tablet by a wet molding method in which a mixture of drugs, saccharides and the like wet with an alcohol / aqueous solution is molded at low pressure and then dried. For example, JP-A-5-271054 (Patent Document 1) discloses an oral solution in which a mixture containing a medicinal ingredient and a saccharide is tableted with moisture sufficient to wet the particle surface of the saccharide and dried. A method for producing a mold tablet is described. In addition, in International Publication No. WO01 / 064190 (Patent Document 2), a drug and a saccharide are mixed, kneaded with water or a water-containing organic solvent in which polyvinyl alcohol is dissolved, and then wet granules are filled into a mold and passed through a film. A fast disintegrating tablet is described which is compressed into a tablet and dried to produce.
　第三世代では、薬物あるいは薬物を含有する粒子、糖、糖アルコール、水溶性結合剤などの水溶性賦形剤を含む乾燥状態の錠剤材料を低圧力で打錠後、加湿し、乾燥させる低圧打錠加湿乾燥法による口腔内崩壊錠である。国際公開ＷＯ９９／４７１２４号（特許文献３）と国際公開ＷＯ０３／００９８３１号（特許文献４）には、糖類Ａに対し、非晶質になり得る糖類Ｂを結合剤として噴霧して被覆及び／又は造粒した粒子を用い、低圧で成形した後加湿乾燥して錠剤化することが記載されている。 In the third generation, the tablet or tablet containing the drug or drug-containing particles, sugar, sugar alcohol, and water-soluble excipients such as a water-soluble binder is pressed at low pressure, then humidified and dried. Orally disintegrating tablet by tableting humidification drying method. In International Publication WO99 / 47124 (Patent Document 3) and International Publication WO03 / 009831 (Patent Document 4), saccharide B which can be amorphous is coated and / or coated on saccharide A as a binder. It is described that granulated particles are formed at low pressure and then dried by humidification to form tablets.
　第四世代では、一般的な錠剤の製造法を基本として、速やかな崩壊を達成させるために様々な工夫がなされたものである。例えば、特開２０１０－１５５８６５号公報（特許文献５）には、糖又は糖アルコールを賦形成分とし、水不溶性であるが親水性の造粒成分を用いて造粒した造粒物を利用した圧縮成形物よりなる口腔崩壊錠剤が提示されている。また、特開２００８－１２７３１９号公報（特許文献６）には、口腔内において唾液との接触により発泡して速やかに崩壊する錠剤であって、発泡源がアルカリ金属又はアルカリ土類金属の炭酸塩又は重炭酸塩であり、発泡源と反応する酸源が繊維素グリコール酸であることを特徴とする口腔内速崩壊性錠剤が記載されている。さらにまた、特開２００７－１９７４３８号公報（特許文献７）に示されているような直接打錠による口腔内崩壊錠の製法に関する研究にも力が注がれている。 In the fourth generation, various ingenuities have been made to achieve rapid disintegration based on a general tablet manufacturing method. For example, JP 2010-155865 A (Patent Document 5) uses a granulated product obtained by granulating sugar or sugar alcohol as a forming component and using a water-insoluble but hydrophilic granulating component. An orally disintegrating tablet consisting of a compression molded product is presented. Japanese Patent Application Laid-Open No. 2008-127319 (Patent Document 6) discloses a tablet which foams and rapidly disintegrates in contact with saliva in the oral cavity, and the foaming source is an alkali metal or alkaline earth metal carbonate. Alternatively, an intraoral rapidly disintegrating tablet is described, which is a bicarbonate, and the acid source that reacts with the foaming source is fibrin glycolic acid. Furthermore, efforts are also being focused on research on methods for producing orally disintegrating tablets by direct compression as disclosed in Japanese Patent Application Laid-Open No. 2007-197438 (Patent Document 7).
　一方、口腔内崩壊錠の崩壊性の改善だけではなく、口腔内崩壊錠の強度を向上させる方法も提案されている。 On the other hand, not only the improvement of the disintegration property of the orally disintegrating tablet but also a method for improving the strength of the orally disintegrating tablet has been proposed.
　例えば、水膨潤性の崩壊剤を配合しない口腔内崩壊錠あるいは低圧打錠加湿乾燥法による口腔内崩壊錠においては、国際公開ＷＯ９５／２０３８０号（特許文献８）や国際公開ＷＯ９９／４７１２４号（特許文献３）などに示されるように、非晶質になり得る糖又は糖アルコールを結合剤として用い、結合剤が非晶化状態で包含される錠剤に製し、それを加湿溶解させ乾燥させて結晶化する際の結合力の向上が口腔内崩壊錠の強度の向上のために利用されている。 For example, in an orally disintegrating tablet that does not contain a water-swellable disintegrant or an orally disintegrating tablet by a low-pressure tablet humidifying and drying method, International Publication WO95 / 20380 (Patent Document 8) and International Publication WO99 / 47124 (Patent) As shown in the literature 3) and the like, sugar or sugar alcohol that can be amorphous is used as a binder, and the binder is made into a tablet that is included in an amorphous state, and it is wet-dissolved and dried. The improvement of the binding force at the time of crystallization is utilized for the improvement of the strength of the orally disintegrating tablet.
　また、特開２００５－５３７９２号公報（特許文献９）には、口中や水性溶媒中での速やかな崩壊性を有しながら、携帯に必要な硬度が保たれた圧縮成形製剤を提供することを目的として、グルコノラクトンが添加された、口腔内で速崩壊性を有する圧縮成型製剤が提案されている。特開２０１２－１６２５０２号公報（特許文献１０）には、活性薬剤とグルコノラクトンとフマル酸ステアリルナトリウムを含有する口腔内崩壊型錠が記載されている。 JP-A-2005-53792 (Patent Document 9) provides a compression-molded preparation that has rapid disintegrability in the mouth and in an aqueous solvent, while maintaining the hardness required for carrying. As a purpose, a compression-molded preparation having gluconolactone added and rapidly disintegrating in the oral cavity has been proposed. JP 2012-162502 (Patent Document 10) describes an orally disintegrating tablet containing an active agent, gluconolactone, and sodium stearyl fumarate.
　なお、普通錠に関しても、例えば、特表２００８－５３１７４１（特許文献１１）や特開２０１２－３１１６６（特許文献１２）に示されるとおり、良好な嚥下を可能にするために、錠剤中の薬物含量を５５％以上というように高くし、錠剤を小型化する努力がなされている。 As for ordinary tablets, for example, as shown in JP-T-2008-531741 (Patent Document 11) and JP 2012-31166 (Patent Document 12), the drug content in the tablets is required to enable good swallowing. Efforts are being made to reduce the size of the tablet by increasing it to 55% or more.
特開平５－２７１０５４号公報Japanese Patent Laid-Open No. 5-271054 国際公開ＷＯ０１／０６４１９０号International Publication No. WO01 / 064190 国際公開ＷＯ９９／４７１２４号International Publication No. WO99 / 47124 国際公開ＷＯ０３／００９８３１号International Publication WO03 / 009831 特開２０１０－１５５８６５号公報JP 2010-155865 A 特開２００８－１２７３１９号公報JP 2008-127319 A 特開２００７－１９７４３８号公報JP 2007-197438 A 国際公開ＷＯ９５／２０３８０号International Publication No. WO95 / 20380 特開２００５－５３７９２号公報JP 2005-53792 A 特開２０１２－１６２５０２号公報JP 2012-162502 A 特表２００８－５３１７４１号公報Special table 2008-517341 gazette 特開２０１２－３１１６６号公報JP 2012-31166 A
　一般に口腔内崩壊錠には、速い口腔内崩壊速度、例えば１分以内、好ましくは４５秒以内の口腔内崩壊速度と、製造工程（包装工程を含む）及び流通過程（医療現場での取扱いを含む）において外力により壊されない十分な硬度と相反する性質の両立が求められる。また錠剤が大型化しないように、錠剤中の薬物及び／又は薬物含有機能性微粒子の含有量が高いことも求められる。 In general, orally disintegrating tablets include a fast oral disintegration rate, for example, an oral disintegration rate within 1 minute, preferably within 45 seconds, a manufacturing process (including a packaging process), and a distribution process (including medical treatment). ) Is required to be compatible with sufficient hardness that is not broken by external force and conflicting properties. In addition, a high content of the drug and / or drug-containing functional fine particles in the tablet is also required so that the tablet does not increase in size.
　しかしながら、凍結乾燥法によって製造される製剤は、急速な崩壊性を有する反面、強度が弱く、硬度の測定が不可能な程もろいという欠点がある。また、凍結乾燥の製造設備が必要で、製造に長時間を要することから、工業的生産性及び製造コストの点でも劣っている。 However, the preparation produced by the freeze-drying method has a rapid disintegration property, but has a disadvantage that it is weak in strength and cannot measure the hardness. In addition, since freeze-drying production equipment is required and production takes a long time, it is inferior in terms of industrial productivity and production cost.
　特許文献１，２に記載のような湿製顆粒には杵で錠剤に圧縮する際杵付着が生じるため、これを防止するために、フィルム介在圧縮式の特殊な錠剤機が必要という問題がある。 The wet granules as described in Patent Documents 1 and 2 have a problem that a special tablet machine of film-mediated compression type is required to prevent this because wrinkle adhesion occurs when compressed into tablets with boil. .
　特許文献３，４に記載の製造方法で製した錠剤には、低圧成形であることと結合剤として用いる非晶質になり得る糖類の結合力がやや弱いことが相俟って、一包化包装ができる十分な強度を有した錠剤を得がたい、糖類の含有量が高くなる、などの問題がある。 The tablets produced by the production methods described in Patent Documents 3 and 4 are packaged together due to low pressure molding and the slightly weak binding power of saccharides that can be amorphous as a binder. There are problems such as difficulty in obtaining tablets having sufficient strength for packaging, and high sugar content.
　特許文献５～７に記載されているものを含め、上述した４つの世代に亘る製剤化法による口腔内崩壊錠では、口腔内で錠剤を吸水させ崩壊又は溶解させるために、薬物や薬物を含有する粒子に加えて、糖類や糖アルコール類及び／又は崩壊剤を含有させて錠剤化することが必要となっているものが大半である。また、薬物あるいは薬物を含有する粒子と糖類や糖アルコール類及び／又は崩壊剤などの混合物を均質な流動性のよい粒子状物質とし、均質な錠剤に製造しやすくするために、結合剤を用いて湿式で造粒することが必要となることが多い。 Orally disintegrating tablets by the above-mentioned four generations of formulation methods including those described in Patent Documents 5 to 7 contain drugs and drugs to absorb and disintegrate or dissolve the tablets in the oral cavity. In most cases, it is necessary to form tablets by containing saccharides, sugar alcohols and / or disintegrants in addition to the particles to be formed. In addition, a binder is used in order to make the drug or a mixture containing the drug and a mixture of sugars, sugar alcohols and / or disintegrants into a particulate material with good fluidity and easy to manufacture into a uniform tablet. Often it is necessary to wet granulate.
　結合剤を用いて湿式で造粒する場合、結合剤が有する粘性のために、錠剤の速崩壊性や速溶解性に悪影響が及ぶ。この悪影響を低減させるために、従来、同時に配合する糖類や糖アルコール類及び／又は崩壊剤の量を増さざるを得なかった。 When granulating in a wet manner using a binder, the fast disintegration and fast dissolution properties of the tablet are adversely affected due to the viscosity of the binder. In order to reduce this adverse effect, conventionally, it has been necessary to increase the amount of sugars, sugar alcohols and / or disintegrants added at the same time.
　例えば、特許文献３，８に記載されているように、錠剤の強度を十分なものとしながら錠剤の崩壊時間を速くするためには、錠剤強度に寄与する結合剤としての非晶質になり得る糖又は糖アルコール類と、速崩壊性に寄与する賦形剤としての糖又は糖アルコール類を同時に多量に配合している。 For example, as described in Patent Documents 3 and 8, in order to increase the tablet disintegration time while ensuring sufficient tablet strength, it can be amorphous as a binder that contributes to tablet strength. A large amount of sugar or sugar alcohol and sugar or sugar alcohol as an excipient that contributes to rapid disintegration are simultaneously blended.
　特許文献９，１０に記載されている口腔内崩壊錠も、速崩壊性と錠剤硬度を有してはいるが、賦形剤と崩壊剤を大量に含んでおり、薬物を高含有量で含むことと両立することはできていない。 The orally disintegrating tablets described in Patent Documents 9 and 10 also have rapid disintegration and tablet hardness, but contain a large amount of excipients and disintegrants, and contain a high content of drugs. It is not compatible with this.
　このように、従来の口腔内崩壊錠では、良好な崩壊性と錠剤強度を両立させようとすれば、賦形剤や崩壊剤が多量に必要になり、錠剤が必要以上に大きくなり、薬物あるいは薬物を含有する粒子を高含量で含有させることが困難である。なお、ここで言う薬物を含有する粒子には、例えば、苦味マスク皮膜、腸溶性皮膜、徐放性皮膜などを被覆した機能性粒子が包含される。 Thus, in the conventional orally disintegrating tablet, if both good disintegration and tablet strength are to be achieved, a large amount of excipients and disintegrants are required, and the tablet becomes unnecessarily large. It is difficult to contain the drug-containing particles at a high content. In addition, the particle | grains containing the drug said here include the functional particle which coat | covered the bitterness mask film | membrane, the enteric film, the sustained release film | membrane, etc., for example.
　逆に、速崩壊能又は速溶解能を有する成分を配合せず、少量の糖類や結合剤のみを用いて、薬物や機能性粒子の含有量が高い口腔内崩壊錠を製造する方法としては、例えば、湿性塊を鋳型に嵌めたものを乾燥して固形化する方法や、湿性顆粒又は湿性塊をそのまま低圧で成形し乾燥する湿式成形製剤による錠剤化などの方法がある。しかし、このような錠剤化で得られた錠剤は、錠剤強度が十分でない。さらに、特殊な製造機械が必要、製造効率が非常に悪い、製造原価が高いなどのデメリットがあり、汎用性がない。 On the other hand, as a method for producing an orally disintegrating tablet with a high content of drugs and functional particles, using only a small amount of saccharides and a binder without blending a component having a fast disintegrating ability or a fast dissolving ability, For example, there are a method of drying and solidifying a wet mass fitted in a mold, and a method of tableting with a wet-molded preparation in which a wet granule or wet mass is molded as it is at low pressure and dried. However, tablets obtained by such tableting have insufficient tablet strength. Furthermore, there are disadvantages such as the need for special manufacturing machines, very low manufacturing efficiency, and high manufacturing costs, and there is no versatility.
　また、特許文献１１～１２に記載されている普通錠においては、薬物とともに配合する製剤化用添加剤に関して、極力少ない添加量で済むよう薬物に応じて工夫を凝らし、その小型化を実現させているのであって、汎用性のある製造方法ではなく、普通錠においても汎用性のある小型化錠の製造方法は確立されていない。 In addition, in the ordinary tablets described in Patent Documents 11 to 12, the formulation additives to be blended with the drug are devised according to the drug so that the addition amount can be as small as possible, and the miniaturization is realized. Therefore, it is not a general-purpose manufacturing method, and a general-purpose manufacturing method for miniaturized tablets has not been established even for ordinary tablets.
　高齢化社会が到来し、あらゆる領域のいろいろな薬剤において、服用しやすく、取り扱いやすい口腔内崩壊錠が望まれる時代に突入したと考えられ、多くの口腔内崩壊錠の研究成果が報告されている。薬物及び／又は薬物含有機能性粒子を５０重量％以上、望ましくは６５重量％以上、さらに望ましくは７５重量％以上の高含量で含有するものであって、かつ、口腔内あるいは水の中に入れたとき、速やかな崩壊性、溶解性を有するとともに、製造工程、流通過程、病院調剤において、崩れないような強い強度を有する口腔内崩壊錠の製造方法を開発することが重要な課題となっている。この課題を解決することによって、高含量の薬剤を小型化した錠剤とすることができ、患者の行動やライフスタイルにあった、服用しやすく、医療現場で使用しやすい製剤を提供することが可能となる。また、この問題を解決する製造方法が、普通錠の小型化に適用できることは言うまでもない。 With the arrival of an aging society, it is considered that an orally disintegrating tablet that is easy to take and handle for various drugs in all fields is expected, and research results on many orally disintegrating tablets have been reported. . The drug and / or drug-containing functional particles are contained in a high content of 50% by weight or more, desirably 65% by weight or more, and more desirably 75% by weight or more, and placed in the oral cavity or water. It is important to develop a method for producing an orally disintegrating tablet that has rapid disintegration and solubility, and has strong strength that does not collapse in the manufacturing process, distribution process, and hospital preparation. Yes. By resolving this problem, it is possible to make tablets that have a high content in a small size, and it is possible to provide a formulation that is easy to take and easy to use in the medical field that matches the patient's behavior and lifestyle. It becomes. It goes without saying that a manufacturing method that solves this problem can be applied to downsizing of ordinary tablets.
　しかしながら、上述のように、薬物又は薬物を含有する粒子を５０重量％以上の高含量で有し、小型化された服用しやすい口腔内崩壊錠の製剤化については、十分な錠剤強度と十分に速い口腔内崩壊時間を両立させることが困難であるため、効果的な方法は未だ確立されていないのが実状である。 However, as described above, for the formulation of a small-sized orally disintegrating orally disintegrating tablet having a high content of 50% by weight or more of drug-containing particles, sufficient tablet strength and sufficient Since it is difficult to achieve both a fast oral disintegration time, an effective method has not yet been established.
　また、普通錠においても、高含量で薬物又は薬物を含有する粒子を含有する小型化された錠剤を、汎用性のある方法で製造する方法は確立されていない。 In addition, even for ordinary tablets, a method for producing a miniaturized tablet containing a high content of a drug or particles containing a drug by a versatile method has not been established.
　そこで、本発明の目的は、強度と、必要であれば速崩壊性とを両立させながら、さらに、高含量で薬物及び／又は薬物含有機能性微粒子を含むことが可能な錠剤の製造方法と、薬物及び／又は薬物含有機能性微粒子を高含量で含む錠剤を提供することである。 Accordingly, an object of the present invention is to provide a method for producing a tablet capable of containing a drug and / or a drug-containing functional fine particle at a high content while achieving both strength and rapid disintegration, if necessary. It is to provide a tablet containing a high content of a drug and / or drug-containing functional fine particles.
　以下、グルコン酸、グルコン酸の水和物、グルコン酸の塩、グルコン酸の塩の水和物、グルコノ－δ－ラクトン、グルコノ－δ－ラクトンの水和物、グルコノ－δ－ラクトンの塩、及びグルコノ－δ－ラクトンの塩の水和物を、単に「グルコノラクトン」と称する場合もある。 Hereinafter, gluconic acid, gluconic acid hydrate, gluconic acid salt, gluconic acid salt hydrate, glucono-δ-lactone, glucono-δ-lactone hydrate, glucono-δ-lactone salt, In addition, a hydrate of a salt of glucono-δ-lactone may be simply referred to as “gluconolactone”.
　本発明者らは、錠剤の強度を十分なものとしながら錠剤の崩壊時間を速くするために、錠剤強度に寄与する結合剤としての非晶質になり得る糖類又は糖アルコール類と、速崩壊性に寄与する賦形剤としての糖類又は糖アルコール類を同時に多量に配合する必要があるのは、十分な結合力と水への速溶解性を兼ね備えた糖類又は糖アルコール類などがないことにあると考えた。そこで、糖類又は糖アルコール類に優る結合力を有し、かつ水に対する粘性が低く、水に溶けやすい特性を有した結合剤を利用することができれば、薬物や薬物含有機能性微粒子に対し、結合剤のみで造粒あるいはコーティングしたものに、例えば少量の滑沢剤を添加するだけで錠剤化できる。このようにして得られた錠剤は、十分な錠剤強度と速崩壊性を有するものとなる可能性が大きい。 In order to increase the tablet disintegration time while ensuring sufficient tablet strength, the inventors have made sugars or sugar alcohols that can be amorphous as binders that contribute to tablet strength and fast disintegration. The reason why it is necessary to add a large amount of saccharides or sugar alcohols as excipients that contribute to water is that there are no saccharides or sugar alcohols that have sufficient binding power and rapid solubility in water. I thought. Therefore, if a binding agent having a binding power superior to that of sugars or sugar alcohols and having low water viscosity and easily soluble in water can be used, it can bind to drugs and drug-containing functional fine particles. For example, a tablet can be formed by adding a small amount of a lubricant to a granulated or coated product only with the agent. The tablets obtained in this way are likely to have sufficient tablet strength and rapid disintegration.
　そこで、本発明者らは、粒子あるいは錠剤を製造するための結合剤としての能力を有し、水に入れたときの粘性が低い添加物という条件で、錠剤に圧縮成型するための顆粒製造時の造粒性及び錠剤に製する際の成形性に寄与し、錠剤を口腔内に含んだ際容易に口腔内に分散する結合剤の探求を実施した。 Therefore, the present inventors have the ability as a binder for producing particles or tablets, and at the time of producing granules for compression molding into tablets under the condition of an additive having low viscosity when placed in water. The present inventors have sought a binder that contributes to the granulation property of the tablet and the moldability when it is made into a tablet and is easily dispersed in the oral cavity when the tablet is included in the oral cavity.
　本発明者らは、鋭意検討の結果、グルコノラクトンは加湿して水を付与することによりグルコン酸となり、逆にグルコン酸を乾燥すればグルコノ－δ－ラクトンの結晶へと構造が変化する特性を有していることから、この特性を利用する方法を見出した。 As a result of intensive studies, the inventors of the present invention have found that gluconolactone is converted to gluconic acid by humidifying and applying water, and conversely, if gluconic acid is dried, the structure changes to crystals of glucono-δ-lactone. Therefore, the present inventors have found a method for utilizing this characteristic.
　グルコノ－δ－ラクトンは、結合力が強い。同時に、グルコノ－δ－ラクトンは、上述のように水に溶かすと有機カルボン酸であるグルコン酸となり、その溶液粘度は低い。また、グルコノラクトンの水への分散は速い。そこで本発明者らは、グルコン酸溶液あるいはグルコノラクトンを結合剤として用いることによって、速崩壊性と強度の両特性の要求を満たす錠剤が得られると推測した。また、グルコノ－δ－ラクトンは融点が１５１～１５５℃であり、加熱・冷却法で同様の効果が得られる可能性も考えられた。各種の実験の結果、予想どおり、その推測を裏付ける実験データを得ることができた。 Glucono-δ-lactone has a strong binding force. At the same time, glucono-δ-lactone becomes gluconic acid, which is an organic carboxylic acid when dissolved in water as described above, and its solution viscosity is low. Also, gluconolactone is rapidly dispersed in water. Therefore, the present inventors presumed that by using a gluconic acid solution or gluconolactone as a binder, a tablet that satisfies both the requirements of both rapid disintegration and strength can be obtained. Further, glucono-δ-lactone has a melting point of 151 to 155 ° C., and it was considered that the same effect could be obtained by the heating / cooling method. As a result of various experiments, as expected, we were able to obtain experimental data to support that assumption.
　そして、本発明者らは、グルコノ－δ－ラクトンとグルコン酸の間の互変異性を利用した加湿乾燥法によって錠剤強度を向上させる方法と、この方法を利用した錠剤、特に、口腔内崩壊錠の製造方法を見出した。すなわち、グルコノラクトンを結合剤として用い、低圧成形加湿乾燥法で製すれば、その結合力、水への速溶解性、速分散性のために、多くの賦形剤や崩壊剤を配合することなく、十分な錠剤強度を有し、かつ必要であれば口腔内での速崩壊性、すなわち、１分以内、好ましくは４５秒以内での崩壊を実現させる口腔内崩壊錠を作製しうることを新規に見出した。 The present inventors have also proposed a method for improving tablet strength by a humidified drying method using tautomerism between glucono-δ-lactone and gluconic acid, and a tablet using this method, particularly an orally disintegrating tablet. The manufacturing method of was found. That is, if gluconolactone is used as a binder and is produced by the low pressure molding humidification drying method, many excipients and disintegrants are blended for its binding power, quick solubility in water, and fast dispersibility. Without being able to produce an orally disintegrating tablet having sufficient tablet strength and, if necessary, rapidly disintegrating in the oral cavity, that is, disintegrating within 1 minute, preferably within 45 seconds. Was newly found.
　また、グルクロノラクトンも、加湿して水を付与することにより有機カルボン酸であるグルクロン酸となり、逆にグルクロン酸を乾燥すればグルクロノラクトンの結晶へと構造が変化する特性を有していることから、グルコノラクトンと同様に、結合剤として用いることによって、十分な錠剤強度を有し、かつ必要であれば口腔内での速崩壊性を実現させる錠剤を製造できることを見出した。以下、グルクロノラクトン及びグルクロン酸を単に「グルクロノラクトン」と称する場合もある。 In addition, glucuronolactone also has a characteristic that its structure changes to glucuronolactone crystals when it is humidified to give glucuronic acid which is an organic carboxylic acid by applying water, and conversely when glucuronic acid is dried. From the above, it was found that, like gluconolactone, by using it as a binder, it is possible to produce a tablet having sufficient tablet strength and, if necessary, realizing rapid disintegration in the oral cavity. Hereinafter, glucuronolactone and glucuronic acid may be simply referred to as “glucuronolactone”.
　以上の知見に基づいて、本発明は以下のように構成される。 Based on the above knowledge, the present invention is configured as follows.
　本発明に従った錠剤の製造方法は、混合工程と、圧縮成形工程と、液化工程と、固化工程とを備える。混合工程は、グルコン酸、グルコン酸の水和物、グルコン酸の塩、グルコン酸の塩の水和物、グルコノ－δ－ラクトン、グルコノ－δ－ラクトンの水和物、グルコノ－δ－ラクトンの塩、グルコノ－δ－ラクトンの塩の水和物、グルクロノラクトン、及びグルクロン酸からなる群から選ばれた少なくとも１つと、薬物及び／又は薬物含有機能性微粒子とを混合して混合物を得る工程である。圧縮成形工程は、混合工程において得られた混合物を圧縮成形して成形物を得る工程である。液化工程は、圧縮成形工程において圧縮成形された成形物の少なくとも表面又は内部を液化する工程である。固化工程は、液化工程において少なくとも表面又は内部が液化された成形物を固化する固化工程とを含む工程である。 The tablet manufacturing method according to the present invention includes a mixing step, a compression molding step, a liquefaction step, and a solidification step. In the mixing step, gluconic acid, gluconic acid hydrate, gluconic acid salt, gluconic acid salt hydrate, glucono-δ-lactone, glucono-δ-lactone hydrate, glucono-δ-lactone A step of mixing at least one selected from the group consisting of a salt, a hydrate of glucono-δ-lactone, glucuronolactone, and glucuronic acid with a drug and / or a drug-containing functional fine particle to obtain a mixture It is. The compression molding step is a step of obtaining a molded product by compression molding the mixture obtained in the mixing step. The liquefaction step is a step of liquefying at least the surface or the inside of the molded product compression-molded in the compression molding step. The solidification step is a step including a solidification step of solidifying a molded product whose surface or inside is liquefied at least in the liquefaction step.
　このように、本発明に従った錠剤の製造方法においては、グルコノラクトン又はグルクロノラクトンの少なくとも１つが崩壊剤を兼ねた結合剤として用いられる。その結果、十分な錠剤強度と速崩壊性とを両立させるために、他に賦形剤や崩壊剤等を配合する必要がなくなる。したがって、錠剤に薬物及び／又は薬物含有機能性微粒子を５０％を超える量、さらに６５重量％以上の量、容易に含有させることができる。 Thus, in the tablet production method according to the present invention, at least one of gluconolactone or glucuronolactone is used as a binder that also serves as a disintegrant. As a result, in order to achieve both sufficient tablet strength and quick disintegration, it is not necessary to add other excipients, disintegrants, and the like. Therefore, the drug and / or drug-containing functional fine particles can be easily contained in the tablet in an amount of more than 50%, further 65% by weight or more.
　このようにして、強度と、必要であれば速崩壊性とを両立させながら、高含量で薬物及び／又は薬物含有機能性微粒子を含むことが可能な錠剤の製造方法を提供することができる。 Thus, it is possible to provide a method for producing a tablet capable of containing a drug and / or a drug-containing functional fine particle at a high content while achieving both strength and rapid disintegration, if necessary.
　本発明に従った錠剤の製造方法においては、液化工程は、圧縮成形工程において圧縮成形された成形物を加湿する工程であることが好ましい。 In the tablet manufacturing method according to the present invention, the liquefaction step is preferably a step of humidifying the molded product compression-molded in the compression molding step.
　本発明に従った錠剤の製造方法においては、固化工程は、液化工程において少なくとも表面又は内部が液化された成形物を乾燥する工程であることが好ましい。 In the tablet production method according to the present invention, the solidification step is preferably a step of drying a molded product having at least the surface or the interior liquefied in the liquefaction step.
　本発明に従った製造方法は、非晶質になり得る糖類、非晶質になり得る糖アルコール類、吸湿性の強い結合剤、崩壊剤、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖類、または、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖アルコールの少なくとも１つを添加する工程をさらに含むことが好ましい。 The production method according to the present invention is a saccharide that can be made amorphous, sugar alcohols that can be made amorphous, a binder having a high hygroscopic property, a disintegrant, and hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH. It is preferable to further include a step of adding at least one of a non-amorphized saccharide that develops or a non-amorphized saccharide alcohol that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH.
　このような非晶質化しない糖類、非晶質化しない糖アルコール類を配合することによって、錠剤の無包装品の安定性に好影響を与える硬度を有する錠剤を提供することができる。 By blending such non-amorphous saccharides and non-amorphous sugar alcohols, it is possible to provide a tablet having a hardness that has a positive effect on the stability of unpackaged tablets.
　本発明に従った製造方法においては、非晶質になり得る糖類、非晶質になり得る糖アルコール類、又は吸湿性の強い結合剤を添加する場合は、２５℃７５％ＲＨの保存条件で吸湿性を発現させるものであることが好ましい。 In the production method according to the present invention, when adding a sugar that can be amorphous, a sugar alcohol that can be amorphous, or a binder with strong hygroscopicity, the storage condition is 25 ° C. and 75% RH. It is preferable that it is hygroscopic.
　本発明に従った製造方法においては、吸湿性の強い結合剤は、ポビドン、コポリビドン、あるいはポリビニルアルコール－ポリエチレングリコールブロックコポリマーであることが好ましい。もちろん、上記以外の結合剤で吸湿性の強い添加剤があれば、それも使用できる。 In the production method according to the present invention, the strongly hygroscopic binder is preferably povidone, copolyvidone, or polyvinyl alcohol-polyethylene glycol block copolymer. Of course, if there is a binder other than the above and a highly hygroscopic additive, it can also be used.
　本発明に従った製造方法においては、崩壊剤は、酸素以外のヘテロ原子あるいはナトリウムイオン、カルシウムイオン、マグネシウムイオンの少なくともいずれかの無機イオンを含有する高分子であることが好ましい。 In the production method according to the present invention, the disintegrant is preferably a polymer containing a hetero atom other than oxygen or at least one inorganic ion of sodium ion, calcium ion, and magnesium ion.
　本発明に従った製造方法においては、崩壊剤は、クロスポビドン、カルメロースカルシウム、クロスカルメロースナトリウム、及びデンプングリコール酸ナトリウムからなる群から選ばれる少なくとも１つであることが好ましい。 In the production method according to the present invention, the disintegrant is preferably at least one selected from the group consisting of crospovidone, carmellose calcium, croscarmellose sodium, and sodium starch glycolate.
　本発明に従った製造方法においては、非晶質になり得る糖類又は非晶質になり得る糖アルコール類は、ソルビトール、マルトース、ラクチトール、ブドウ糖、乳糖、及び、トレハロースなどからなる群から選ばれる少なくとも１つであることが好ましい。 In the production method according to the present invention, the sugar that can be amorphous or the sugar alcohol that can be amorphous is at least selected from the group consisting of sorbitol, maltose, lactitol, glucose, lactose, and trehalose. One is preferred.
　本発明に従った製造方法においては、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖類、または、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖アルコールは、マンニトール、エリスリトール、マルチトール、及び、キシリトールからなる群から選ばれる少なくとも１つであることが好ましい。 In the production method according to the present invention, a non-amorphous saccharide that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH, or a non-amorphous sugar that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH. The sugar alcohol that does not crystallize is preferably at least one selected from the group consisting of mannitol, erythritol, maltitol, and xylitol.
　上述のように、本発明に従った錠剤の製造方法においては、十分な錠剤強度と速崩壊性とを両立させるために崩壊剤等の賦形剤を多く添加する必要がない。一方、本発明者らは、吸湿性を有する非晶質になり得る糖類や糖アルコール類、吸湿性の強い結合剤、又は崩壊剤を配合することによって、導水性があがり、より強固な錠剤硬度を有する、速崩壊製の口腔内崩壊錠に製し得ることを見出した。グルコノラクトン又はグルクロノラクトンと共に非晶質になり得る糖類や糖アルコール類、吸湿性の強い結合剤、又は崩壊剤を使用することによって、臨界相対湿度を低下させることができ、吸湿させる湿度条件を２５℃７５％ＲＨ程度以下に設定することで強度の強い錠剤が得られ、錠剤同士の付着防止などの効果を実現させることができることがわかった。また、非晶質化しない（非晶質にならない）糖類や糖アルコール類の配合にも臨界湿度を低下させる作用があり、２５℃７５％ＲＨを超える湿度条件下に保存し乾燥することで同様の錠剤を得られることがわかった。この錠剤は、２５℃７５％ＲＨという開放保存条件下での錠剤硬度の低下が少ないという新たな知見を得ることができた（（社）日本病院薬剤師会「錠剤・カプセル剤の無包装状態での安定性試験法について（答申）」（平成１１年８月２０日）を参照）。要するに、グルコノラクトン又はグルクロノラクトンの臨界相対湿度を低下させる成分の配合が有意義なことを見出した。 As described above, in the tablet manufacturing method according to the present invention, it is not necessary to add a large amount of an excipient such as a disintegrant in order to achieve both sufficient tablet strength and quick disintegration. On the other hand, the present inventors have increased the water conductivity by adding saccharides and sugar alcohols that can become amorphous having hygroscopicity, binders having high hygroscopicity, or disintegrants, and stronger tablet hardness. It has been found that a rapidly disintegrating orally disintegrating tablet can be produced. By using saccharides and sugar alcohols that can become amorphous together with gluconolactone or glucuronolactone, a highly hygroscopic binder, or a disintegrant, the critical relative humidity can be lowered, and the moisture conditions for absorbing moisture It was found that by setting the temperature to about 25 ° C. and 75% RH or less, a strong tablet can be obtained, and effects such as prevention of adhesion between tablets can be realized. In addition, blending of non-amorphous (non-amorphous) saccharides and sugar alcohols also has the effect of lowering critical humidity, and the same can be achieved by storing and drying under humidity conditions exceeding 25 ° C. and 75% RH. Of tablets. This tablet was able to obtain a new finding that there is little decrease in tablet hardness under open storage conditions of 25 ° C. and 75% RH (Japan Hospital Pharmacists Association “Without packaging of tablets and capsules” (Refer to "Study method for stability (report)" (August 20, 1999)). In short, it has been found that the combination of components that lower the critical relative humidity of gluconolactone or glucuronolactone is significant.
　本発明に従った錠剤は、薬物及び／又は薬物含有機能性微粒子と、グルコン酸、グルコン酸の水和物、グルコン酸の塩、グルコン酸の塩の水和物、グルコノ－δ－ラクトン、グルコノ－δ－ラクトンの水和物、グルコノ－δ－ラクトンの塩、グルコノ－δ－ラクトンの塩の水和物、グルクロノラクトン、及びグ　ルクロン酸からなる群から選ばれた少なくとも１つとを含み、薬物及び／又は薬物含有機能性微粒子の含有量が５０％以上である。 The tablet according to the present invention comprises a drug and / or drug-containing functional fine particles, gluconic acid, gluconic acid hydrate, gluconic acid salt, gluconic acid salt hydrate, glucono-δ-lactone, glucono -Δ-lactone hydrate, glucono-δ-lactone salt, glucono-δ-lactone salt hydrate, glucuronolactone, and at least one selected from the group consisting of glucuronic acid, The content of the drug and / or drug-containing functional fine particles is 50% or more.
　本発明に従った錠剤は、口腔内崩壊錠であることが好ましい。 The tablet according to the present invention is preferably an orally disintegrating tablet.
　本発明に従った錠剤は、非晶質になり得る糖類、非晶質になり得る糖アルコール類、吸湿性の強い結合剤、崩壊剤、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖類、または、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖アルコールの少なくとも１つをさらに含むことが好ましい。 The tablet according to the present invention exhibits hygroscopicity under storage conditions exceeding 75% RH, sugars that can be amorphous, sugar alcohols that can be amorphous, strong hygroscopic binders, disintegrants It is preferable to further include at least one of a non-amorphizing saccharide that does not become amorphous or a non-amorphizing sugar alcohol that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH.
　本発明に従った錠剤においては、吸湿性の強い結合剤は、２５℃７５％ＲＨの保存条件で吸湿性を有するものであることが好ましい。 In the tablet according to the present invention, the strong hygroscopic binder is preferably hygroscopic under storage conditions of 25 ° C. and 75% RH.
　本発明に従った錠剤においては、吸湿性の強い結合剤は、ポビドン、コポリビドン、あるいはポリビニルアルコール－ポリエチレングリコールブロックコポリマーからなる群から選ばれる少なくとも１つであることが好ましい。 In the tablet according to the present invention, the strongly hygroscopic binder is preferably at least one selected from the group consisting of povidone, copolyvidone, or polyvinyl alcohol-polyethylene glycol block copolymer.
　本発明に従った錠剤においては、崩壊剤は、酸素以外のヘテロ原子あるいはナトリウムイオン、カルシウムイオン、マグネシウムイオンの少なくともいずれかの無機イオンを含有する高分子であることが好ましい。 In the tablet according to the present invention, the disintegrant is preferably a polymer containing a hetero atom other than oxygen or at least one inorganic ion of sodium ion, calcium ion, and magnesium ion.
　本発明に従った錠剤においては、崩壊剤は、クロスポビドン、カルメロースカルシウム、クロスカルメロースナトリウム、及びデンプングリコール酸ナトリウムからなる群から選ばれる少なくとも１つであることが好ましい。 In the tablet according to the present invention, the disintegrant is preferably at least one selected from the group consisting of crospovidone, carmellose calcium, croscarmellose sodium, and sodium starch glycolate.
　本発明に従った錠剤においては、非晶質になり得る糖類又は非晶質になり得る糖アルコール類は、ソルビトール、マルトース、ラクチトール、ブドウ糖、乳糖、及び、トレハロースからなる群から選ばれる少なくとも１つであることが好ましい。 In the tablet according to the present invention, the sugar that can be amorphous or the sugar alcohol that can be amorphous is at least one selected from the group consisting of sorbitol, maltose, lactitol, glucose, lactose, and trehalose. It is preferable that
　本発明に従った錠剤においては、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖類、または、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖アルコールは、マンニトール、エリスリトール、マルチトール、及び、キシリトールなどからなる群から選ばれる少なくとも１つであることが好ましい。 In the tablet according to the present invention, a non-amorphous saccharide that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH, or an amorphous substance that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH It is preferable that the sugar alcohol not to be refined is at least one selected from the group consisting of mannitol, erythritol, maltitol, xylitol and the like.
　以下に本発明の実施形態について説明する。 Hereinafter, embodiments of the present invention will be described.
　本発明に従った錠剤の製造方法は、混合工程と、圧縮成形工程と、液化工程と、固化工程とを備える。混合工程は、グルコン酸、グルコン酸の水和物、グルコン酸の塩、グルコン酸の塩の水和物、グルコノ－δ－ラクトン、グルコノ－δ－ラクトンの水和物、グルコノ－δ－ラクトンの塩、グルコノ－δ－ラクトンの塩の水和物、グルクロノラクトン、及びグルクロン酸からなる群から選ばれた少なくとも１つと、薬物及び／又は薬物含有機能性微粒子とを混合して混合物を得る工程である。言い換えれば、混合工程は、打錠用混合末を製する製造工程である。混合工程においては、少量の添加剤を混合してもよい。圧縮成形工程は、混合工程において得られた混合物を圧縮成形して成形物を得る工程である。液化工程は、圧縮成形工程において圧縮成形された成形物の少なくとも表面又は内部を液化する工程である。固化工程は、液化工程において少なくとも表面又は内部が液化された成形物を固化する固化工程とを含む工程である。 The tablet manufacturing method according to the present invention includes a mixing step, a compression molding step, a liquefaction step, and a solidification step. In the mixing step, gluconic acid, gluconic acid hydrate, gluconic acid salt, gluconic acid salt hydrate, glucono-δ-lactone, glucono-δ-lactone hydrate, glucono-δ-lactone A step of mixing at least one selected from the group consisting of a salt, a hydrate of glucono-δ-lactone, glucuronolactone, and glucuronic acid with a drug and / or a drug-containing functional fine particle to obtain a mixture It is. In other words, the mixing process is a manufacturing process for producing a mixed powder for tableting. In the mixing step, a small amount of additives may be mixed. The compression molding step is a step of obtaining a molded product by compression molding the mixture obtained in the mixing step. The liquefaction step is a step of liquefying at least the surface or the inside of the molded product compression-molded in the compression molding step. The solidification step is a step including a solidification step of solidifying a molded product whose surface or inside is liquefied at least in the liquefaction step.
　本発明に用いられる薬物としては、治療学的にあるいは予防学的に有効な医薬活性成分であれば特に限定されない。医薬活性成分としては、例えば、催眠鎮静剤、睡眠導入剤、偏頭痛剤、抗不安剤、抗てんかん剤、抗うつ薬、抗パーキンソン剤、精神神経用剤、中枢神経系用薬、局所麻酔剤、骨格筋弛緩剤、自律神経剤、解熱鎮痛消炎剤、鎮けい剤、鎮暈剤、強心剤、不整脈用剤、利尿剤、血圧降下剤、血管収縮剤、血管拡張剤、循環器官用薬、高脂血症剤、呼吸促進剤、鎮咳剤、去たん剤、鎮咳去たん剤、気管支拡張剤、止しゃ剤、整腸剤、消化性潰瘍用剤、健胃消化剤、制酸剤、下剤、利胆剤、消化器官用薬、副腎ホルモン剤、ホルモン剤、泌尿器官用剤、ビタミン剤、止血剤、肝臓疾患用剤、通風治療剤、糖尿病用剤、抗ヒスタミン剤、抗生物質、抗菌剤、抗悪性腫瘍剤、化学療法剤、総合感冒剤、滋養強壮保健薬、骨粗しょう症薬などが挙げられる。薬物の配合量としては、通常治療上有効な量であれば特に制限されないが、製剤全体の６５重量％を超える量での錠剤化も可能であり、１回の薬物投与量が２００ｍｇを超えるような薬物に特に有用と考えられる。 The drug used in the present invention is not particularly limited as long as it is a therapeutically or prophylactically effective pharmaceutically active ingredient. Examples of pharmaceutically active ingredients include hypnotic sedatives, sleep inducers, migraine agents, anti-anxiety agents, antiepileptic agents, antidepressants, anti-parkinsonian agents, neuropsychiatric agents, central nervous system agents, and local anesthetics , Skeletal muscle relaxant, autonomic nerve agent, antipyretic analgesic / anti-inflammatory agent, antispasmodic agent, antipruritic agent, cardiotonic agent, arrhythmic agent, diuretic agent, antihypertensive agent, vasoconstrictor, vasodilator, cardiovascular agent, high fat Antihypertensive agent, Respiratory agent, Antitussive agent, Pesticide, Antitussive agent, Bronchodilator, Antidiarrheal agent, Intestinal agent, Peptic ulcer agent, Gastric digestive agent, Antacid, Laxative, Bile, Digestion Organ drugs, adrenal hormones, hormones, urinary organs, vitamins, hemostats, liver diseases, ventilation treatments, diabetes, antihistamines, antibiotics, antibacterials, anti-neoplastic agents, chemotherapy Medicine, general cold medicine, nourishing tonic health medicine, osteoporosis medicine, etc.The compounding amount of the drug is not particularly limited as long as it is a therapeutically effective amount, but it can be tableted in an amount exceeding 65% by weight of the whole preparation, so that a single drug dose exceeds 200 mg. It is considered to be particularly useful for various drugs.
　本発明に用いられる薬物含有機能性微粒子は、上記のような医薬用途を有する薬物を、苦味隠蔽微粒子、腸溶性微粒子、徐放性微粒子といった、薬物の放出を制御した機能性微粒子となるよう製されたものである。 The drug-containing functional fine particles used in the present invention are prepared so that the drug having the above-mentioned pharmaceutical use becomes functional fine particles with controlled drug release, such as bitter taste-masking fine particles, enteric fine particles, and sustained-release fine particles. It has been done.
　薬物含有機能性微粒子の粒子径は、口腔内でのザラツキ感を感じない範囲であれば特に制限されない。例えば通常平均粒子径として３５０μｍ以下が好ましく、約３００μｍ以下がより好ましく、約２５０μｍ以下がさらに好ましい。３５０μｍより大きいと口腔内のザラツキ感などの違和感が強く認識されることとなり好ましくない。ただし、口腔内でのザラツキ感を問題としない場合は、機能性粒子の粒径は、最長径が２ｍｍ以下であれば使用に供することが可能である。その形状が球に近似できる場合、平均粒子径が２ｍｍ以下であればよく、また医薬組成物粒子が球以外の形状の場合、平均最長径が２ｍｍ以下であることが好ましい。 The particle size of the drug-containing functional fine particles is not particularly limited as long as it does not feel a rough feeling in the oral cavity. For example, the average particle size is usually preferably 350 μm or less, more preferably about 300 μm or less, and further preferably about 250 μm or less. If it is larger than 350 μm, a feeling of strangeness such as a rough feeling in the oral cavity will be strongly recognized, which is not preferable. However, when the roughness in the oral cavity is not a problem, the functional particles can be used if the longest diameter is 2 mm or less. When the shape can approximate a sphere, the average particle diameter may be 2 mm or less, and when the pharmaceutical composition particles have a shape other than a sphere, the average longest diameter is preferably 2 mm or less.
　薬物含有機能性微粒子は、公知の方法により調製することができる。例えば、市販の微結晶セルロース粒（旭化成ケミカルズ、商品名：セルフィアＣＰ１０２など）をコアとして、転動流動コーティングなどの既知のコーティング法により薬物を積層コーティングした後、さらに苦味マスキング皮膜剤、腸溶性皮膜剤、徐放性皮膜剤などの水不溶性高分子物質をコーティングして溶出制御膜を形成させ、苦味隠蔽微粒子、腸溶性微粒子、徐放性微粒子などの薬物含有機能性微粒子とすることができる。 Drug-containing functional fine particles can be prepared by a known method. For example, a commercially available microcrystalline cellulose particle (Asahi Kasei Chemicals, trade name: SELPHYA CP102, etc.) is used as a core, and a drug is laminated and coated by a known coating method such as tumbling fluidized coating. An elution control film can be formed by coating a water-insoluble polymer substance such as an agent and a sustained-release film agent, and can be made into drug-containing functional fine particles such as bitterness masking fine particles, enteric fine particles, and sustained-release fine particles.
　放出制御皮膜剤としては、エチルセルロース、アクリル酸エチル・メタアクリル酸メチル・メタアクリル酸塩化トリメチルアンモニウムエチル共重合体の粉末、並びにエチルセルロース、アクリル酸エチル・メタアクリル酸メチル・メタアクリル酸塩化トリメチルアンモニウムエチル共重合体、及びアクリル酸エチル・メタアクリル酸メチル共重合体をラテックスの形で含有する水分散液などが用いられる。 Release control coating agents include ethyl cellulose, ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl copolymer powder, and ethyl cellulose, ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl An aqueous dispersion containing a copolymer and an ethyl acrylate / methyl methacrylate copolymer in the form of latex is used.
　腸溶性皮膜剤としては、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、メタアクリル酸・メタアクリル酸メチル共重合体、メタアクリル酸・メタアクリル酸エチル共重合体、メタアクリル酸・アクリル酸エチル共重合体などがある。これらをメタノール、エタノール、イソプロパノール、ジクロロメタンなどの有機溶剤を用いて溶解して使用できることは勿論、これら水不溶性高分子をラテックスの形で含有する水分散液を用いることも自由である。 Enteric coating agents include hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylic acid / methyl methacrylate copolymer, methacrylic acid / ethyl methacrylate copolymer, methacrylic acid / ethyl acrylate There are copolymers. These can be used by dissolving them in an organic solvent such as methanol, ethanol, isopropanol, or dichloromethane, and it is also possible to use an aqueous dispersion containing these water-insoluble polymers in the form of latex.
　苦味マスキング皮膜としては、上記の放出制御皮膜剤、腸溶性皮膜剤は勿論、ポリビニルアセタールジエチルアミノアセテート、メタアクリル酸メチル・メタアクリル酸ブチル・メタアクリル酸ジメチルアミノエチル共重合体などを用いることができる。 As the bitter taste masking film, the above-mentioned release control film agent, enteric film agent, polyvinyl acetal diethylaminoacetate, methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer, etc. can be used. .
　なお、上記水不溶性高分子物質とともに、水素添加植物油、ステアリン酸、パルミチン酸、セチルアルコール、ステアリルアルコールなどのワックス状物質、並びにトリアセチン、クエン酸トリエチル、アクリル酸エチル・メタクリル酸メチル共重合体分散液などの可塑剤を配合して使用することは自由である。 In addition to the above water-insoluble polymer substance, waxy substances such as hydrogenated vegetable oil, stearic acid, palmitic acid, cetyl alcohol, stearyl alcohol, and triacetin, triethyl citrate, ethyl acrylate / methyl methacrylate copolymer dispersion It is free to mix and use plasticizers such as.
　本発明に従った錠剤において、グルコノラクトン又はグルクロノラクトンは、崩壊剤を兼ねた結合剤として用いられる。グルコノラクトン又はグルクロノラクトンを結合剤として用い、低圧成形加湿乾燥法で製すれば、その結合力、水への速溶解性、速分散性のために、賦形剤や崩壊剤を配合することなく、十分な錠剤強度を有し、かつ口腔内での速崩壊性、すなわち、１分以内、好ましくは４５秒以内での崩壊を実現させる口腔内崩壊錠を作製することができる。 In the tablet according to the present invention, gluconolactone or glucuronolactone is used as a binder that also serves as a disintegrant. If gluconolactone or glucuronolactone is used as a binder and manufactured by the low-pressure molding humidification drying method, excipients and disintegrants are blended for its binding power, quick solubility in water, and fast dispersibility. Therefore, an orally disintegrating tablet having sufficient tablet strength and capable of rapidly disintegrating in the oral cavity, that is, disintegrating within 1 minute, preferably within 45 seconds can be produced.
　本発明に従った錠剤においては、通常の口腔内崩壊錠に配合される賦形剤や崩壊剤という添加剤を必ずしも配合する必要がない。そのため、薬物及び／又は薬物含有機能性微粒子を５０重量％を超える量で含有する錠剤を通常の打錠機を用いて容易に製造できる。さらに望めば６５重量％以上の高含量で含有する錠剤をも容易に製造できる。ただし、俗に言う賦形剤、結合剤、崩壊剤などの添加物を必要に応じて自由に配合できることは言うまでもない。なお、この製造方法は、薬物及び／又は薬物含有機能性微粒子を５０％を超える量、さらに６５重量％以上の量で含有するのが好ましく、第十七改正日本薬局方に準じた試験法による崩壊時間が３０分以内の、小型化された普通錠の製造にも共通して応用できる製造方法でもある。 In the tablet according to the present invention, it is not always necessary to add an additive such as an excipient or a disintegrant that is mixed in a normal orally disintegrating tablet. Therefore, a tablet containing the drug and / or drug-containing functional fine particles in an amount exceeding 50% by weight can be easily produced using a normal tableting machine. Furthermore, if desired, tablets containing a high content of 65% by weight or more can be easily produced. However, it goes without saying that additives such as commonly used excipients, binders, and disintegrants can be freely blended as necessary. This production method preferably contains the drug and / or drug-containing functional fine particles in an amount of more than 50%, more preferably 65% by weight or more, according to a test method according to the 17th revised Japanese Pharmacopoeia. It is also a production method that can be applied in common to the production of miniaturized ordinary tablets whose disintegration time is within 30 minutes.
　本発明に従った錠剤においては、グルコノラクトン又はグルクロノラクトンと共に、糖類や糖アルコール類、吸湿性の強い結合剤、あるいは水膨潤性の崩壊剤といった、吸湿性を有する成分を配合してもよい。糖類や糖アルコール類としては、例えばソルビトール、マルトース、ラクチトール、ブドウ糖、乳糖、トレハロースなどの非晶質になり得る糖類や糖アルコール類、及びマンニトール、エリスリトール、マルチトール、キシリトールなどの非晶質化しない（非晶質にならない）糖類や糖アルコール類が好ましく、トレハロース、マルトース、マンニトールがより好ましい。 吸湿性の強い結合剤を上記糖類や糖アルコール類の代替として使用しても、一緒に配合してもよい。その結合剤としては、ポリビニルピロリドン、コポリビドン、ポリビニルアルコール－ポリエチレングリコールブロックコポリマーが好ましい。水膨潤性の崩壊剤としては、例えばクロスポビドン、カルメロースカルシウム、クロスカルメロースナトリウム、デンプングリコール酸ナトリウムなどの、窒素、硫黄等の酸素以外のヘテロ原子あるいはナトリウムイオン、カルシウムイオン、マグネシウムイオン等の無機イオンを含有している高分子からなる崩壊剤が好ましい。 In the tablet according to the present invention, gluconolactone or glucuronolactone may be combined with a hygroscopic component such as a saccharide or sugar alcohol, a highly hygroscopic binder, or a water-swelling disintegrant. Good. As sugars and sugar alcohols, for example, sugars and sugar alcohols that can be amorphous such as sorbitol, maltose, lactitol, glucose, lactose, trehalose, and non-amorphous such as mannitol, erythritol, maltitol, xylitol Saccharides and sugar alcohols (which do not become amorphous) are preferred, and trehalose, maltose, and mannitol are more preferred.結合 A hygroscopic binder may be used as an alternative to the sugars or sugar alcohols, or may be formulated together. As the binder, polyvinylpyrrolidone, copolyvidone, and polyvinyl alcohol-polyethylene glycol block copolymer are preferable. Examples of water-swelling disintegrants include crospovidone, carmellose calcium, croscarmellose sodium, sodium starch glycolate, and other heteroatoms other than oxygen such as nitrogen and sulfur, or sodium ions, calcium ions, magnesium ions, etc. A disintegrant made of a polymer containing inorganic ions is preferred.
　これらの糖類や糖アルコール類、吸湿性の強い結合剤、あるいは崩壊剤をさらに配合することによって、導水性があがる、グルコノラクトン又はグルクロノラクトンと相互作用するなどの理由により、より強固な錠剤硬度を有する、速崩壊性の口腔内崩壊錠に製し得る。なお、この場合、グルコノラクトン又はグルクロノラクトンと共に、非晶質になり得る糖類や糖アルコール類、結合力の強い結合剤を使用することによって、臨界相対湿度を低下させることができ、吸湿させる湿度条件を２５℃７５％ＲＨ程度以下に設定し、錠剤に加湿し乾燥することによって、強度の強い錠剤が得られ、錠剤同士の付着防止などの効果を実現させることができる。 By further blending these sugars, sugar alcohols, highly hygroscopic binders, or disintegrants, the water conductivity is increased, and the tablets are stronger because they interact with gluconolactone or glucuronolactone. It can be made into a rapidly disintegrating orally disintegrating tablet having hardness. In this case, the critical relative humidity can be lowered and absorbed by using gluconolactone or glucuronolactone together with saccharides or sugar alcohols which can be amorphous, or a binder having a strong binding force. By setting the humidity condition to about 25 ° C. and 75% RH or less, and humidifying and drying the tablets, strong tablets can be obtained, and effects such as prevention of adhesion between tablets can be realized.
　ただし、この場合、（社）日本病院薬剤師会「錠剤・カプセル剤の無包装状態での安定性試験法について（答申）」（平成１１年８月２０日）でいう錠剤の開放保存条件下（２５℃７５％ＲＨ環境下保存）において、錠剤強度が低下するという状況が生じる。これに対し、非晶質化しない（非晶質にならない）糖類や糖アルコール類を配合する場合、２５℃７５％ＲＨを超える湿度条件下に保存し乾燥することによって強度の強い錠剤が得られることとなり、錠剤の開放保存条件下における錠剤強度の低下が少ないものを得ることができる。 However, in this case, the open storage condition of the tablet in the Japan Hospital Pharmacists Association “About the Stability Test Method in Unwrapped Tablets and Capsules (Report)” (August 20, 1999) ( Under the conditions of storage at 25 ° C. and 75% RH, a situation occurs in which the tablet strength decreases. On the other hand, when saccharides or sugar alcohols that do not become amorphous (non-amorphous) are blended, a strong tablet can be obtained by storing and drying under humidity conditions exceeding 25 ° C. and 75% RH. That is, it is possible to obtain a tablet with little decrease in tablet strength under the open storage condition of the tablet.
　本発明においては、グルコノラクトン又はグルクロノラクトンとともに、非晶質になり得る糖類や糖アルコール類、非晶質化しない（非晶質にならない）糖類や糖アルコール類、ポリビニルピロリドン、コポリビドン、ポリビニルアルコール－ポリエチレングリコールブロックコポリマーという結合剤、及びクロスポビドン、カルメロースカルシウム、クロスカルメロースナトリウム、デンプングリコール酸ナトリウムという崩壊剤を配合することにより、より低い湿度条件、例えば、２５℃７５％ＲＨ～２５℃９０％ＲＨの加湿条件で、より強固な錠剤を製造できる。錠剤強度や必要な崩壊性を阻害しない範囲において、その他の糖類や糖アルコール類及び崩壊剤を添加することは自由である。また、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルアルコール、などの結合剤を配合して錠剤強度に寄与させることも自由である。 In the present invention, together with gluconolactone or glucuronolactone, saccharides and sugar alcohols that can be amorphous, saccharides and sugar alcohols that do not become amorphous (not amorphous), polyvinylpyrrolidone, copolyvidone, polyvinyl By incorporating a binder of alcohol-polyethylene glycol block copolymer and a disintegrant of crospovidone, carmellose calcium, croscarmellose sodium, sodium starch glycolate, lower humidity conditions, eg 25 ° C. 75% RH-25 A stronger tablet can be produced under humidified conditions of 90% RH. Other saccharides, sugar alcohols, and disintegrating agents can be freely added within a range not impairing tablet strength and necessary disintegration property. Moreover, it is also free to add a binder such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinyl alcohol to contribute to tablet strength.
　本発明に用いられるグルコノラクトン又はグルクロノラクトンの配合量は、本発明で製造される錠剤の重量に対し、１～５０重量％が好ましく、さらに好ましくは２～３０重量％であり、さらにまた好ましくは、５～２０重量％である。１重量％より少ないと、口腔内速崩壊錠用結合剤としての機能を充分に発揮しないことが懸念される。また、５０重量％より多いと、口腔内速崩壊錠とした際に、崩壊遅延などの諸問題を生じ、良好な特性が得られない可能性がある。 The amount of gluconolactone or glucuronolactone used in the present invention is preferably 1 to 50% by weight, more preferably 2 to 30% by weight, based on the weight of the tablet produced in the present invention. Preferably, it is 5 to 20% by weight. When the amount is less than 1% by weight, there is a concern that the function as a binder for intraoral quick disintegrating tablets is not sufficiently exhibited. On the other hand, when the amount is more than 50% by weight, various problems such as disintegration delay may occur when an intraoral rapidly disintegrating tablet is formed, and good characteristics may not be obtained.
　本発明においては、上記の結合剤、糖類や糖アルコール類、吸湿性の強い結合剤、及び崩壊剤以外に、医薬的に許容され、添加物として使用される各種添加剤を配合することができる。添加剤は薬物含有機能性微粒子を造粒する際に配合することもでき、また錠剤化する際に薬物及び／又は薬物含有機能性微粒子を造粒したものと混合して用いることもできる。 In the present invention, in addition to the above-mentioned binders, saccharides and sugar alcohols, strong hygroscopic binders, and disintegrants, various additives that are pharmaceutically acceptable and used as additives can be blended. . The additive can be blended when the drug-containing functional fine particles are granulated, or can be used by mixing with the granulated drug and / or drug-containing functional fine particles when tableting.
　添加剤としては、例えば、賦形剤、酸味料、発泡剤、人工甘味料、香料、滑沢剤、着色剤、安定化剤などが挙げられる。添加剤は１種又は２種以上組合せて使用することができる。また、その配合量は、通常当業者が製薬的に使用し、本発明の効果を損なわない範囲内であれば特に制限されない。 Examples of additives include excipients, acidulants, foaming agents, artificial sweeteners, flavors, lubricants, colorants, stabilizers, and the like. An additive can be used 1 type or in combination of 2 or more types. Moreover, the compounding quantity will not be restrict | limited especially if it is the range which does not impair the effect of this invention normally using a pharmaceutical person skilled in the art.
　賦形剤としては、例えば、Ｄ－マンニトール、乳糖、炭酸カルシウム、リン酸水素カルシウム、メタケイ酸アルミン酸マグネシウムなどが挙げられる。酸味料としては、例えば、クエン酸、酒石酸、リンゴ酸などが挙げられる。発泡剤としては、例えば、重曹などが挙げられる。人口甘味料としては、例えば、サッカリンナトリウム、グリチルリチン二カリウム、アセスルファムカリウム、アスパルテーム、ステビア、ソーマチンなどが挙げられる。香料としては、例えば、レモン、レモンライム、オレンジ、メントールなどが挙げられる。滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、ショ糖脂肪酸エステル、ポリエチレングリコール、タルク、ステアリン酸、フマル酸ステアリルナトリウムなどが挙げられる。着色剤としては、例えば、食用黄色５号、食用赤色２号、食用青色２号などの食用色素；食用レーキ色素；無機顔料であるベンガラなどが挙げられる。安定化剤は、薬物ごとに各種検討がなされた上で選択される。これらの添加剤は、１種又は２種以上組合せて、適宜適量添加することができる。 Examples of excipients include D-mannitol, lactose, calcium carbonate, calcium hydrogen phosphate, magnesium aluminate metasilicate, and the like. Examples of the acidulant include citric acid, tartaric acid, malic acid and the like. Examples of the foaming agent include sodium bicarbonate. Examples of artificial sweeteners include saccharin sodium, glycyrrhizin dipotassium, acesulfame potassium, aspartame, stevia, thaumatin and the like. As a fragrance | flavor, lemon, lemon lime, orange, menthol, etc. are mentioned, for example. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid, sodium stearyl fumarate and the like. Examples of the colorant include edible dyes such as edible yellow No. 5, edible red No. 2 and edible blue No. 2; edible lake dyes; and bengara which is an inorganic pigment. Stabilizers are selected after various studies for each drug. These additives can be appropriately added in an appropriate amount by one or a combination of two or more.
　以下、本発明で用いる薬物含有機能性微粒子の製造と、薬物及び／又は薬物含有機能性微粒子を含有する錠剤の製造の各工程と条件について詳細に説明する。 Hereinafter, the steps and conditions for producing the drug-containing functional fine particles used in the present invention and for producing the tablet containing the drug and / or drug-containing functional fine particles will be described in detail.
　［薬物含有機能性微粒子の製造工程］
　薬物含有機能性微粒子は公知の方法により製造される。溶出制御などの目的とする機能が達成された微粒子が得られるのであれば製造方法は特に制限されず、適宜選択することができる。 [Production process of drug-containing functional fine particles]
The drug-containing functional fine particles are produced by a known method. The production method is not particularly limited and can be appropriately selected as long as fine particles having a desired function such as elution control are obtained.
　例えば、市販の結晶セルロース粒、マンニトールによる粒子、乳糖による粒子、グラニュー糖による粒子、部分アルファー化デンプンによる粒子などに、ヒドロキシプルピルメチルセルロースなどの結合剤を用いて、転動流動コーティングなどの既知のコーティング法により薬物を積層コーティング後、放出制御皮膜剤、腸溶性皮膜剤、苦味マスキング皮膜剤などの高分子物質をさらにコーティングし、薬物含有機能性微粒子に製する。 For example, using commercially available crystalline cellulose granules, particles with mannitol, particles with lactose, particles with granulated sugar, particles with partially pregelatinized starch, etc., using a binder such as hydroxypropylmethylcellulose, etc. After the drug is laminated by the coating method, a polymer substance such as a controlled release film agent, an enteric film agent, and a bitterness masking film agent is further coated to produce drug-containing functional fine particles.
　あるいは、薬物と微結晶セルロースに高分子物質の溶液を加え攪拌造粒法又は転動流動造粒法等により球に近似した微粒子とし、この微粒子に必要に応じて放出制御皮膜剤、腸溶性皮膜剤、苦味マスキング皮膜剤などの高分子物質をさらにコーティングし、薬物含有機能性微粒子に製する。コーティングには、例えば噴霧乾燥式流動層造粒機などが選択される。 Alternatively, a solution of a polymer substance is added to a drug and microcrystalline cellulose to form a fine particle that approximates a sphere by stirring granulation method or tumbling flow granulation method. Further, a polymer substance such as an agent and a bitter taste masking film is further coated to produce functional fine particles containing a drug. For the coating, for example, a spray drying fluidized bed granulator is selected.
　薬物含有機能性微粒子を調製する際に用いられる溶媒は、例えば水、有機溶媒などである。有機溶媒としては、例えばメタノール、エタノール、イソプロパノール、ジクロロメタンなどを挙げることができ、これらの有機溶媒は、１種又は２種類以上適宜の割合で混合して用いてもよく、水との混合液として用いてもよい。水を用いたコーティングの場合には品温が約４０℃～約６０℃、有機溶媒を用いた場合には品温が約３０℃～約６０℃付近の温度となるように、温度が設定され、さらには噴霧液量、噴霧風量などが設定される。 The solvent used when preparing the drug-containing functional fine particles is, for example, water or an organic solvent. Examples of the organic solvent include methanol, ethanol, isopropanol, dichloromethane, and the like. These organic solvents may be used singly or as a mixture of two or more at an appropriate ratio. It may be used. The temperature is set so that the product temperature is about 40 ° C. to about 60 ° C. in the case of coating using water, and the product temperature is about 30 ° C. to about 60 ° C. in the case of using an organic solvent. Furthermore, a spray liquid amount, a spray air amount, and the like are set.
　［混合末製造工程］
　混合末製造工程では、少なくとも薬物及び／又は薬物含有機能性微粒子と、グルコノラクトン又はグルクロノラクトンと、場合によっては崩壊剤等の賦形剤が混合された混合物として、錠剤化用混合末を製造する。 [Mixed powder manufacturing process]
In the mixed powder manufacturing process, at least the drug and / or drug-containing functional fine particles, gluconolactone or glucuronolactone, and, in some cases, an excipient such as a disintegrant, are mixed to form a mixed powder for tableting. To manufacture.
　グルコノラクトン又はグルクロノラクトンは、溶液に溶解又は分散させて、薬物及び／又は薬物含有機能性微粒子と造粒されて、又は、薬物及び／又は薬物含有機能性微粒子にコーティングされて混合物にされてもよい。また、グルコノラクトン又はグルクロノラクトンは、粉末のままで、薬物及び／又は薬物含有機能性微粒子と混合されて混合物にされてもよい。 Gluconolactone or glucuronolactone is dissolved or dispersed in a solution, granulated with a drug and / or drug-containing functional fine particles, or coated with a drug and / or drug-containing functional fine particles to form a mixture. May be. In addition, gluconolactone or glucuronolactone may be mixed with the drug and / or drug-containing functional fine particles in the form of a powder.
　造粒又はコーティングの方法は特に制限されない。造粒又はコーティングの方法として、例えば、流動層法、転動流動層法、撹拌造粒法、転動造粒法などを選択することができる。これらの方法において、グルコノラクトン又はグルクロノラクトンは、製薬的に許容される溶媒に溶解及び／又は懸濁した溶液の状態で、薬物及び／又は薬物含有機能性微粒子に対して噴霧され、乾燥される。 Granulation or coating method is not particularly limited. As the granulation or coating method, for example, a fluidized bed method, a rolling fluidized bed method, a stirring granulation method, a rolling granulation method, or the like can be selected. In these methods, gluconolactone or glucuronolactone is sprayed onto the drug and / or drug-containing functional microparticles in a solution dissolved and / or suspended in a pharmaceutically acceptable solvent and dried. Is done.
　造粒あるいはコーティングにおいては、薬物及び／又は薬物含有機能性微粒子がグルコノラクトン又はグルクロノラクトンと混和された状態、あるいは、グルコノラクトン又はグルクロノラクトンで覆われた状態となることが必要である。グルコノラクトン又はグルクロノラクトンを製薬的に許容される溶媒に溶解及び／又は懸濁した溶液は粘性が低く、撹拌造粒によっても、また流動層造粒によっても薬物及び／又は薬物含有機能性微粒子に対する混和造粒が行えるが、後者は連続で行え、作業が簡便で短時間で済むのがメリットである。溶液中のグルコノラクトン又はグルクロノラクトンの濃度は、通常５～５０重量％程度であり、１０～４０重量％であることがより好ましい。 In granulation or coating, it is necessary that the drug and / or drug-containing functional fine particles be mixed with gluconolactone or glucuronolactone, or covered with gluconolactone or glucuronolactone. is there. A solution obtained by dissolving and / or suspending gluconolactone or glucuronolactone in a pharmaceutically acceptable solvent has low viscosity, and has a drug and / or drug-containing functionality by stirring granulation or fluidized bed granulation. Admixture granulation of fine particles can be performed, but the latter can be performed continuously, which is advantageous in that the operation is simple and requires a short time. The concentration of gluconolactone or glucuronolactone in the solution is usually about 5 to 50% by weight, and more preferably 10 to 40% by weight.
　薬物及び／又は薬物含有機能性微粒子とグルコノラクトン又はグルクロノラクトンとの造粒又はコーティングにおいて、又は、造粒又はコーティングされた後、必要に応じて前述した添加剤が混合され、錠剤化用混合末が調製される。 For granulation or coating of drug and / or drug-containing functional fine particles and gluconolactone or glucuronolactone, or after granulation or coating, the above-mentioned additives are mixed as necessary for tableting A mixed powder is prepared.
　一方、グルコノラクトン又はグルクロノラクトンを粉末のまま薬物及び／又は薬物含有機能性微粒子と混合する場合は、例えば、薬物及び／又は薬物含有機能性微粒子に必要に応じて適切な添加剤を配合し、非晶質になり得る糖類や糖アルコール類、ポビドンなどの結合剤を溶解した溶液を用いて造粒したものと、グルコノラクトン又はグルクロノラクトンとを混合する方法などがある。この場合にも、必要に応じて崩壊剤などの前述した添加剤を混合することは自由である。 On the other hand, when mixing gluconolactone or glucuronolactone with a drug and / or drug-containing functional fine particles in powder form, for example, a suitable additive is added to the drug and / or drug-containing functional fine particles as necessary. In addition, there is a method of mixing a granulated solution using a solution in which a binder such as saccharides, sugar alcohols, and povidone that can become amorphous is dissolved with gluconolactone or glucuronolactone. Also in this case, it is free to mix the above-described additives such as a disintegrant as necessary.
　［圧縮成形工程］
　圧縮成形工程は、錠剤の形状を維持させるため必要最小限の圧力以上で錠剤の形状とする方法で実施されれば特に制限されない。 [Compression molding process]
The compression molding step is not particularly limited as long as it is carried out by a method of making the tablet shape at a pressure higher than the minimum necessary pressure to maintain the tablet shape.
　圧縮成形工程の一例は打錠である。打錠は公知の方法で行われる。打錠は、錠剤化用混合末の製造工程で製した錠剤化用混合末を用い、例えば単発打錠機又はロータリー打錠機など通常の打錠機を用いて行うことができる。また、錠剤化用混合末を外部滑沢打錠機を用いて錠剤とすることもできる。打錠圧は、通常約０．２５～約８．０ｋＮ／杵が好ましく、約０．５０～約６．０ｋＮ／杵がより好ましく、約０．５０～約５．０ｋＮ／杵が最も好ましい。必要以上に圧力をかけることは、薬物含有機能性微粒子の変性が生じる可能性や口腔内崩壊時間が遅くなる可能性などが心配され好ましくない。 An example of the compression molding process is tableting. Tableting is performed by a known method. Tableting can be performed using a tableting mixed powder produced in the manufacturing process of a tableting mixed powder and using a normal tableting machine such as a single tableting machine or a rotary tableting machine. Further, the mixed powder for tableting can be made into tablets using an external lubricant tableting machine. The tableting pressure is usually preferably about 0.25 to about 8.0 kN / 杵, more preferably about 0.50 to about 6.0 kN / 杵, and most preferably about 0.50 to about 5.0 kN / 杵. It is not preferable to apply more pressure than necessary because there is concern about the possibility of denaturation of the drug-containing functional fine particles and the possibility of delaying the oral disintegration time.
　［液化工程及び固化工程］
　液化工程と固化工程は、加湿工程と乾燥工程によって実施されることが好ましく、加熱工程と冷却工程によって実施されてもよく、他の工程によって実施されてもよい。 [Liquefaction process and solidification process]
The liquefaction step and the solidification step are preferably performed by a humidification step and a drying step, and may be performed by a heating step and a cooling step, or may be performed by other steps.
　［加湿工程と乾燥工程］
　錠剤中に配合されたグルコノラクトン又はグルクロノラクトンは、加湿あるいは加熱により溶解し加水分解されて一部がグルコン酸又はグルクロン酸へと転移する。次いでこれを乾燥することにより分子間環化反応（脱水縮合）が起こり速やかにグルコノ－δ－ラクトン又はグルクロノラクトンとなるが、その際錠剤中に均一に分散されたグルコノ－δ－ラクトン又はグルクロノラクトンが強固に結合されることとなり、錠剤の強度が高められる。 [Humidification process and drying process]
Gluconolactone or glucuronolactone blended in the tablet is dissolved by humidification or heating and hydrolyzed, and a part thereof is transferred to gluconic acid or glucuronic acid. Next, when this is dried, an intermolecular cyclization reaction (dehydration condensation) occurs and quickly becomes glucono-δ-lactone or glucuronolactone. At this time, glucono-δ-lactone or glucose uniformly dispersed in the tablet is obtained. Chronolactone is firmly bound, and the strength of the tablet is increased.
　一方、圧縮成形工程において、錠剤を成形する際の圧力が低いことと、グルコノラクトン又はグルクロノラクトンの水溶性が高くかつ粘性が低いという性質によって、錠剤の強度が高められても、水への分散性は速く、水中での錠剤の崩壊が遅くなることはない。 On the other hand, in the compression molding process, even when the strength of the tablet is increased due to the low pressure when molding the tablet and the high water solubility and low viscosity of gluconolactone or glucuronolactone, The dispersibility is fast and the disintegration of the tablet in water does not slow down.
　加湿工程と乾燥工程は、グルコノ－δ－ラクトンとグルコン酸あるいはグルクロノラクトンとグルクロン酸の間の互変異性が利用できる方法であれば特に制限されない。 The humidification step and the drying step are not particularly limited as long as the tautomerism between glucono-δ-lactone and gluconic acid or glucuronolactone and glucuronic acid can be used.
　加湿工程において、加湿の条件は、グルコノラクトン又はグルクロノラクトンが配合された錠剤化用混合末の見かけの臨界相対湿度により決定される。通常、混合末の臨界相対湿度以上に加湿する。例えば、湿度として約５０～約１００ＲＨ％が好ましく、約６０～約９０ＲＨ％がさらに好ましい。加湿の温度は約１５～約５０℃とすることが好ましく、約２０～約４０℃とすることがさらに好ましい。加湿時間は、１～４８時間とすることが好ましく、８～２４時間がさらに好ましい。 In the humidification step, the humidification condition is determined by the apparent critical relative humidity of the tableting mixed powder containing gluconolactone or glucuronolactone. Usually, humidify above the critical relative humidity of the mixed powder. For example, the humidity is preferably about 50 to about 100 RH%, more preferably about 60 to about 90 RH%. The humidification temperature is preferably about 15 to about 50 ° C, more preferably about 20 to about 40 ° C. The humidifying time is preferably 1 to 48 hours, more preferably 8 to 24 hours.
　乾燥工程は、加湿により吸収した水分を除去する方法であれば特に制限されない。乾燥条件としては、通常約１０～約１００℃とするのが好ましく、約２０～約７０℃がさらに好ましく、約２５～約６０℃が最も好ましい。乾燥時間は、３０分～１０時間が好ましく、１～６時間がより好ましい。 The drying process is not particularly limited as long as it is a method for removing moisture absorbed by humidification. The drying conditions are usually preferably about 10 to about 100 ° C., more preferably about 20 to about 70 ° C., and most preferably about 25 to about 60 ° C. The drying time is preferably 30 minutes to 10 hours, and more preferably 1 to 6 hours.
　［加熱工程と冷却工程］
　液化工程は、グルコノラクトン又はグルクロノラクトンを加熱して溶融する工程であってもよく、固化工程は、溶融されたグルコノラクトン又はグルクロノラクトンを冷却して固化させる工程であってもよい。 [Heating process and cooling process]
The liquefaction step may be a step of heating and melting gluconolactone or glucuronolactone, and the solidification step may be a step of cooling and solidifying the molten gluconolactone or glucuronolactone. .
　加熱工程で、錠剤中に配合されたグルコノラクトン又はグルクロノラクトンなどを加熱により溶かし、次いで冷却工程で冷却して結晶化させる際、グルコノラクトン又はグルクロノラクトン同士がより強固に結合されることとなり、錠剤の強度が向上される。 In the heating step, gluconolactone or glucuronolactone blended in the tablet is dissolved by heating, and then cooled in the cooling step to crystallize, whereby the gluconolactone or glucuronolactone is more firmly bound to each other. As a result, the strength of the tablet is improved.
　加熱工程において、加熱は、公知の方法で行われ、打錠用混合末に配合されたグルコノラクトン又はグルクロノラクトンなどを溶かすことができる方法であれば特に制限されない。加熱工程は、例えば、通風オーブンを用いて行うことができる。温度条件は、配合物などによる融点降下を考慮するとき、約１００～約１７５℃であり、好ましくは約１２０～約１６０℃である。時間条件は、所望する錠剤強度、口腔内崩壊性などによって適宜決定されるが、通常１～１２０分であり、好ましくは１～６０分であり、さらに好ましくは２～３０分である。 In the heating step, the heating is carried out by a known method, and is not particularly limited as long as it is a method capable of dissolving gluconolactone or glucuronolactone blended in the mixed powder for tableting. A heating process can be performed using a ventilation oven, for example. The temperature condition is about 100 to about 175 ° C., preferably about 120 to about 160 ° C., when considering the melting point drop due to the blend or the like. The time condition is appropriately determined depending on the desired tablet strength, disintegration property in the oral cavity, etc., but is usually 1 to 120 minutes, preferably 1 to 60 minutes, and more preferably 2 to 30 minutes.
　冷却工程において、冷却は、公知の方法により行われ、グルコノラクトン又はグルクロノラクトンなどが溶融した後、固化する方法であれば特に制限されない。冷却は、例えば室温下での放置や、冷蔵庫などの低温環境下での保存によって行われてもよい。 In the cooling step, the cooling is performed by a known method and is not particularly limited as long as gluconolactone or glucuronolactone is solidified after being melted. The cooling may be performed, for example, by being left at room temperature or stored in a low temperature environment such as a refrigerator.
　本発明を要約すると、以下の通りである。 The summary of the present invention is as follows.
　（１）本発明に従った錠剤の製造方法は、混合工程と、圧縮成形工程と、液化工程と、固化工程とを備える。混合工程は、グルコン酸、グルコン酸の水和物、グルコン酸の塩、グルコン酸の塩の水和物、グルコノ－δ－ラクトン、グルコノ－δ－ラクトンの水和物、グルコノ－δ－ラクトンの塩、グルコノ－δ－ラクトンの塩の水和物、グルクロノラクトン、及びグルクロン酸からなる群から選ばれた少なくとも１つと、薬物及び／又は薬物含有機能性微粒子とを混合して混合物を得る工程である。圧縮成形工程は、混合工程において得られた混合物を圧縮成形して成形物を得る工程である。液化工程は、圧縮成形工程において圧縮成形された成形物の少なくとも表面又は内部を液化する工程である。固化工程は、液化工程において少なくとも表面又は内部が液化された成形物を固化する固化工程とを含む工程である。 (1) The tablet manufacturing method according to the present invention includes a mixing step, a compression molding step, a liquefaction step, and a solidification step. In the mixing step, gluconic acid, gluconic acid hydrate, gluconic acid salt, gluconic acid salt hydrate, glucono-δ-lactone, glucono-δ-lactone hydrate, glucono-δ-lactone A step of mixing at least one selected from the group consisting of a salt, a hydrate of glucono-δ-lactone, glucuronolactone, and glucuronic acid with a drug and / or a drug-containing functional fine particle to obtain a mixture It is. The compression molding step is a step of obtaining a molded product by compression molding the mixture obtained in the mixing step. The liquefaction step is a step of liquefying at least the surface or the inside of the molded product compression-molded in the compression molding step. The solidification step is a step including a solidification step of solidifying a molded product whose surface or inside is liquefied at least in the liquefaction step.
　このようにすることにより、速崩壊性と強度を両立させながら、高含有量の薬物及び／又は薬物含有機能性微粒子を含むことが可能な錠剤の製造方法を提供することができる。 By doing so, it is possible to provide a method for producing a tablet capable of containing a high content of drug and / or drug-containing functional fine particles while achieving both rapid disintegration and strength.
　（２）本発明に従った錠剤の製造方法においては、液化工程は、圧縮成形工程において圧縮成形された成形物を加湿又は加熱する工程であることが好ましい。 (2) In the tablet production method according to the present invention, the liquefaction step is preferably a step of humidifying or heating the molded product compression-molded in the compression molding step.
　（３）本発明に従った錠剤の製造方法においては、固化工程は、液化工程において少なくとも表面又は内部が液化された成形物を乾燥する工程であることが好ましい。 (3) In the method for producing a tablet according to the present invention, the solidification step is preferably a step of drying a molded product having at least the surface or the interior liquefied in the liquefaction step.
　（４）本発明に従った製造方法は、非晶質になり得る糖類、非晶質になり得る糖アルコール類、吸湿性の強い結合剤、崩壊剤、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖類、または、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖アルコールの少なくとも１つを添加する工程をさらに含むことが好ましい。 (4) The production method according to the present invention comprises a sugar that can be amorphous, a sugar alcohol that can be amorphous, a highly hygroscopic binder, a disintegrant, and storage conditions exceeding 25 ° C. and 75% RH. Preferably, the method further includes a step of adding at least one of a non-amorphous saccharide that exhibits hygroscopicity or a non-amorphous sugar alcohol that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH. .
　（５）本発明に従った錠剤の製造方法においては、吸湿性の強い結合剤は、２５℃７５％ＲＨの保存条件で吸湿性を有するようなものであることが好ましい。 (5) In the tablet manufacturing method according to the present invention, it is preferable that the highly hygroscopic binder is hygroscopic under storage conditions of 25 ° C. and 75% RH.
　（６）本発明に従った製造方法においては、吸湿性の強い結合剤は、ポビドン、コポリビドン、あるいはポリビニルアルコール－ポリエチレングリコールブロックコポリマーであることが好ましい。 (6) In the production method according to the present invention, the strongly hygroscopic binder is preferably povidone, copolyvidone, or polyvinyl alcohol-polyethylene glycol block copolymer.
　（７）本発明に従った錠剤の製造方法においては、崩壊剤は、酸素以外のヘテロ原子あるいはナトリウムイオン、カルシウムイオン、マグネシウムイオンの少なくともいずれかの無機イオンを含有する高分子であることが好ましい。 (7) In the method for producing a tablet according to the present invention, the disintegrant is preferably a polymer containing a hetero atom other than oxygen or at least one inorganic ion of sodium ion, calcium ion, and magnesium ion. .
　（８）本発明に従った錠剤の製造方法においては、崩壊剤は、クロスポビドン、カルメロースカルシウム、クロスカルメロースナトリウム、及びデンプングリコール酸ナトリウムからなる群から選ばれる少なくとも１つであることが好ましい。 (8) In the tablet production method according to the present invention, the disintegrant is preferably at least one selected from the group consisting of crospovidone, carmellose calcium, croscarmellose sodium, and sodium starch glycolate. .
　（９）本発明に従った製造方法においては、非晶質になり得る糖類又は非晶質になり得る糖アルコール類は、ソルビトール、マルトース、ラクチトール、ブドウ糖、乳糖、及び、トレハロースなどからなる群から選ばれる少なくとも１つであることが好ましい。 (9) In the production method according to the present invention, the saccharide that can be amorphous or the sugar alcohol that can be amorphous is selected from the group consisting of sorbitol, maltose, lactitol, glucose, lactose, trehalose, and the like. It is preferable that at least one selected.
　（１０）本発明に従った製造方法においては、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖類、または、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖アルコールは、マンニトール、エリスリトール、マルチトール、及び、キシリトールからなる群から選ばれる少なくとも１つであることが好ましい。 (10) In the production method according to the present invention, a non-amorphous saccharide that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH, or hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH. The sugar alcohol that does not become amorphous is preferably at least one selected from the group consisting of mannitol, erythritol, maltitol, and xylitol.
　（１１）本発明に従った錠剤は、薬物及び／又は薬物含有機能性微粒子と、グルコン酸、グルコン酸の水和物、グルコン酸の塩、グルコン酸の塩の水和物、グルコノ－δ－ラクトン、グルコノ－δ－ラクトンの水和物、グルコノ－δ－ラクトンの塩、グルコノ－δ－ラクトンの塩の水和物、グルクロノラクトン、及びグルクロン酸からなる群から選ばれた少なくとも１つとを含み、薬物及び／又は薬物含有機能性微粒子の含有量が５０％以上である。 (11) A tablet according to the present invention comprises a drug and / or a drug-containing functional fine particle, gluconic acid, a gluconic acid hydrate, a gluconic acid salt, a gluconic acid salt hydrate, glucono-δ- At least one selected from the group consisting of lactone, glucono-δ-lactone hydrate, glucono-δ-lactone salt, glucono-δ-lactone salt hydrate, glucuronolactone, and glucuronic acid And the content of the drug and / or drug-containing functional fine particles is 50% or more.
　（１２）本発明に従った錠剤は、口腔内崩壊錠であることが好ましい。 (12) The tablet according to the present invention is preferably an orally disintegrating tablet.
　（１３）本発明に従った錠剤は、非晶質になり得る糖類、非晶質になり得る糖アルコール類、吸湿性の強い結合剤、崩壊剤、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖類、または、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖アルコールの少なくとも１つをさらに含むことが好ましい。 (13) The tablet according to the present invention absorbs moisture under a storage condition exceeding 25 ° C. and 75% RH, sugars that can be amorphous, sugar alcohols that can be amorphous, a highly hygroscopic binder, disintegrant. It is preferable to further include at least one of a non-amorphizing saccharide that exhibits sexiness or a non-amorphizing sugar alcohol that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH.
　（１４）本発明に従った錠剤においては、吸湿性の強い結合剤は、２５℃７５％ＲＨの保存条件で吸湿性を有するようなものであることが好ましい。 (14) In the tablet according to the present invention, it is preferable that the highly hygroscopic binder is hygroscopic under storage conditions of 25 ° C. and 75% RH.
　（１５）本発明に従った錠剤においては、吸湿性の強い結合剤は、ポビドン、コポリビドン、あるいはポリビニルアルコール－ポリエチレングリコールブロックコポリマーからなる群から選ばれる少なくとも１つであることが好ましい。 (15) In the tablet according to the present invention, the strongly hygroscopic binder is preferably at least one selected from the group consisting of povidone, copolyvidone, or polyvinyl alcohol-polyethylene glycol block copolymer.
　（１６）本発明に従った錠剤においては、崩壊剤は、酸素以外のヘテロ原子あるいはナトリウムイオン、カルシウムイオン、マグネシウムイオンの少なくともいずれかの無機イオンを含有する高分子であることが好ましい。 (16) In the tablet according to the present invention, the disintegrant is preferably a polymer containing a hetero atom other than oxygen or at least one inorganic ion of sodium ion, calcium ion, and magnesium ion.
　（１７）本発明に従った錠剤においては、崩壊剤は、クロスポビドン、カルメロースカルシウム、クロスカルメロースナトリウム、及びデンプングリコール酸ナトリウムからなる群から選ばれる少なくとも１つであることが好ましい。 (17) In the tablet according to the present invention, the disintegrant is preferably at least one selected from the group consisting of crospovidone, carmellose calcium, croscarmellose sodium, and sodium starch glycolate.
　（１８）本発明に従った錠剤においては、非晶質になり得る糖類又は非晶質になり得る糖アルコール類は、ソルビトール、マルトース、ラクチトール、ブドウ糖、乳糖、及び、トレハロースからなる群から選ばれる少なくとも１つであることが好ましい。 (18) In the tablet according to the present invention, the sugar that can be amorphous or the sugar alcohol that can be amorphous is selected from the group consisting of sorbitol, maltose, lactitol, glucose, lactose, and trehalose. At least one is preferred.
　（１９）本発明に従った錠剤においては、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖類、または、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖アルコールは、マンニトール、エリスリトール、マルチトール、及び、キシリトールからなる群から選ばれる少なくとも１つであることが好ましい。 (19) In the tablet according to the present invention, a non-amorphous saccharide that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH, or hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH The sugar alcohol that does not become amorphous is preferably at least one selected from the group consisting of mannitol, erythritol, maltitol, and xylitol.
　以下、実施例により本発明をより具体的に説明するが、本発明はこれらの実施例により限定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.
　実験に用いた製剤原料は次のとおりである。ポビドン（商品名：コリドン３０、ＢＡＳＦ）、クロスポビドン（商品名：コリドンＣＬ－Ｍ、ＢＡＳＦ）、結晶セルロース（粒）（商品名：セルフィアＣＰ１０２、旭化成ケミカル、ヒプロメロース（商品名：ＴＣ－５Ｅ、信越化学工業）、スクラロース（商品名：スクラロースＰ、三栄源エスエフアイ）、エチルセルロース（商品名：エトセル１０、Ｄｏｗ  Ｃｈｅｍｉｃａｌ）、ヒプロメロース（商品名：ＴＣ－５Ｒ、信越化学工業）、マクロゴール（商品名：マクロゴール６０００、日本油脂）、エチルセルロース（商品名：エトセル７、Ｄｏｗ  Ｃｈｅｍｉｃａｌ）、グルコノ－δ－ラクトン（和光純薬工業）、グルコノ－δ－ラクトン（扶桑化学工業）、ステアリン酸カルシウム（太平化学産業）、Ｄ－マンニトール（商品名：ペアリトール５０Ｃ、ロケットジャパン）、ステアリン酸マグネシウム（太平化学産業）、グルコン酸（５０％グルコン酸溶液、和光純薬工業）、マルトース（商品名：サンマルトミドリ、林原商事）、トレハロース（旭化成ケミカルズ）、クロスポビドン（商品名：ポリプラスドンＸＬ－１０、Ａｓｈｌａｎｄ）、デンプングリコール酸ナトリウム（商品名：プリモジェル、ＤＦＥ　Ｐｈａｒｍａ）、カルメロースカルシウム（商品名：ＥＣＧ－５０５、五徳薬品）、クロスカルメロースナトリウム（商品名：Ａｃ－Ｄｉ－Ｓｏｌ、ウイルバー・エリス）。クエン酸第二鉄水和物（関東化学）。 The drug substance used in the experiment is as follows. Povidone (trade name: Kollidon 30, BASF), crospovidone (trade name: Kollidon CL-M, BASF), crystalline cellulose (grain) (trade name: SELPHYA CP102, Asahi Kasei Chemical, Hypromellose (trade name: TC-5E, Shin-Etsu) Chemical Industry), Sucralose (trade name: Sucralose P, Saneigen SFI), Ethylcellulose (trade name: Etocel 10, Dow Chemical), Hypromellose (trade name: TC-5R, Shin-Etsu Chemical), Macrogol (trade name: Macrogol 6000, Japanese fats and oils), ethyl cellulose (trade name: Etocel 7, Dow Chemical), glucono-δ-lactone (Wako Pure Chemical Industries), glucono-δ-lactone (Fuso Chemical Industry), calcium stearate (Taihei Chemical Industry) , D-mannitol (trade name: Allitol 50C, Rocket Japan), magnesium stearate (Taihei Chemical Industry), gluconic acid (50% gluconic acid solution, Wako Pure Chemical Industries), maltose (trade name: San Marto Midori, Hayashibara Corporation), trehalose (Asahi Kasei Chemicals), Crospovidone (trade name: Polyplastidone XL-10, Ashland), sodium starch glycolate (trade name: Primogel, DFE Pharma), carmellose calcium (trade name: ECG-505, Gotoku Pharmaceutical), croscarmellose sodium (Product name: Ac-Di-Sol, Wilber Ellis) Ferric citrate hydrate (Kanto Chemical).
（徐放性アンブロキソール塩酸塩微粒子の製造）
（１）薬物レイヤリング微粒子の製造
　アンブロキソール塩酸塩を２３２ｇ、ポビドン（コリドン３０）を５６．８ｇ、クロスポビドン（コリドンＣＬ－Ｍ）を５６．８ｇとり精製水１９６３ｇに加えて撹拌し、分散又は溶解させてレイヤリング液１を調製した。アンブロキソール塩酸塩を２３２ｇ、ポビドン（コリドン３０）を５６．８ｇとり精製水１９６３ｇに加えて撹拌し、分散又は溶解させてレイヤリング液２を調製した。結晶セルロース（セルフィアＣＰ１０２）を５００ｇとり転動流動型コーティング造粒機（パウレック社製：ＭＰ－０１）を用いてレイヤリング液１を噴霧した後、引続きレイヤリング液２を噴霧しコーティングを行った。噴霧後乾燥した後、４２メッシュと１５０メッシュで篩過し、薬物レイヤリング微粒子を得た。 (Production of sustained-release ambroxol hydrochloride fine particles)
(1) Production of drug layering microparticles 232 g of ambroxol hydrochloride, 56.8 g of povidone (Collidon 30) and 56.8 g of crospovidone (Collidon CL-M) were added to 1963 g of purified water and stirred to disperse. Alternatively, the layering solution 1 was prepared by dissolution. 232 g of ambroxol hydrochloride and 56.8 g of povidone (Kollidon 30) were added to 1963 g of purified water, stirred and dispersed or dissolved to prepare layering solution 2. 500 g of crystalline cellulose (Selfia CP102) was taken and sprayed with layering solution 1 using a tumbling fluidized coating granulator (manufactured by POWREC: MP-01), followed by coating by spraying layering solution 2 . After spraying and drying, sieved with 42 mesh and 150 mesh to obtain drug layering fine particles.
（２）シールコート微粒子の製造
　ヒプロメロース（ＴＣ－５Ｅ）を２３．８ｇ、スクラロースＰを１０．２ｇとり、精製水６４７ｇに加え撹拌溶解させシールコーティング液を調製した。工程（１）で調製した薬物レイヤリング微粒子１１３５ｇに転動流動型コーティング造粒機（パウレック社製：ＭＰ－０１）を用いて、シールコーティング液を噴霧し、表面にコーティングして得られた粒子を４２メッシュと１５０メッシュで篩過し、シールコート微粒子を得た。 (2) Manufacture of seal coat fine particles 23.8 g of hypromellose (TC-5E) and 10.2 g of sucralose P were added to 647 g of purified water and dissolved by stirring to prepare a seal coating solution. Particles obtained by spraying a seal coating solution onto 1135 g of drug layering fine particles prepared in step (1) using a tumbling fluid type coating granulator (manufactured by POWREC: MP-01) and coating the surface. Was sieved with 42 mesh and 150 mesh to obtain seal coat fine particles.
（３）制御放出微粒子
（ｉ）徐放性コーティング微粒子の製造
　エチルセルロース（エトセル１０）を１８３ｇ、ヒプロメロース（ＴＣ－５Ｒ）を５７．１ｇとり、８０％エタノール液２７６０ｇを加え、撹拌溶解させ放出制御皮膜溶液を調製した。工程（２）で調製したシールコート微粒子５００ｇに、転動流動型コーティング造粒機（パウレック社製：ＭＰ－０１）を用いて、放出制御皮膜溶液を噴霧しコーティングして得られた粒子を乾燥した後、４２メッシュと１５０メッシュで篩過し、徐放性コーティング微粒子を得た。 (3) Controlled release fine particles (i) Production of sustained-release coated fine particles Take 183 g of ethyl cellulose (Etocel 10) and 57.1 g of hypromellose (TC-5R), add 2760 g of 80% ethanol solution, dissolve with stirring, and release controlled coating A solution was prepared. Using 500% of the seal coat fine particles prepared in step (2) and spraying the controlled release coating solution using a tumbling fluid type coating granulator (manufactured by POWREC: MP-01), the resulting particles are dried. After that, it was sieved with 42 mesh and 150 mesh to obtain sustained-release coated fine particles.
（ｉｉ）オーバーコーティング微粒子の製造
　ヒプロメロース（ＴＣ－５Ｒ）を１５．２ｇ、マクロゴール６０００を６０．８ｇとり、精製水６００．４ｇに加えて溶解し、オーバーコーティング液Ａを調製した。また、エチルセルロース（エトセル７）を４０．８ｇ、ヒプロメロース（ＴＣ－５Ｒ）を１７．５ｇとり、８０％エタノール液に加え攪拌溶解させオーバーコーティング液Ｂを調製した。工程（３）－（ｉ）で調製した徐放性コーティング微粒子５００ｇに転動流動型コーティング造粒機（パウレック社製：ＭＰ－０１）を用いて、オーバーコーティング液Ａを噴霧した後、オーバーコーティング液Ｂを噴霧し、表面をコーティングした。乾燥して得られた粒子を、４２メッシュと１５０メッシュで篩過し、オーバーコーティング微粒子を得た。該オーバーコーティング微粒子が徐放性アンブロキソール塩酸塩微粒子に相当する。この微粒子の平均粒子径は約２８０μｍであった。 (Ii) Production of Overcoating Fine Particles 15.2 g of hypromellose (TC-5R) and 60.8 g of macrogol 6000 were taken and dissolved in 600.4 g of purified water to prepare an overcoating solution A. Further, 40.8 g of ethyl cellulose (Ethocel 7) and 17.5 g of hypromellose (TC-5R) were added to an 80% ethanol solution and dissolved by stirring to prepare an overcoating solution B. The overcoating liquid A is sprayed on 500 g of the sustained-release coated fine particles prepared in the step (3)-(i) using a tumbling flow type coating granulator (manufactured by Paulek: MP-01), and then overcoating Liquid B was sprayed to coat the surface. The particles obtained by drying were sieved with 42 mesh and 150 mesh to obtain overcoating fine particles. The overcoating fine particles correspond to sustained-release ambroxol hydrochloride fine particles. The average particle diameter of the fine particles was about 280 μm.
［試験例１］
　機能性微粒子（徐放性アンブロキソール塩酸塩微粒子）にグルコノ－δ－ラクトンをコーティングし、その粒子のみを用い、機能性微粒子とグルコノ－δ－ラクトンの２成分のみを主体とした錠剤を製した（実施例１）。クエン酸第二鉄水和物をグルコン酸溶液で造粒し、その粒子のみを用い、クエン酸第二鉄水和物とグルコン酸の２成分のみを主体とした錠剤に製した（実施例２）。また、Ｄ－マンニトールを水に溶けやすい薬物に見立て、Ｄ－マンニトールのみをグルコン酸溶液で造粒し、その粒子のみを用い、Ｄ－マンニトールとグルコン酸の２成分を主体とした錠剤を製造方法を変えて製した（実施例３、４）。これらの錠剤の硬度と口腔内崩壊時間を測定して評価を行った。 [Test Example 1]
The functional fine particles (sustained release ambroxol hydrochloride fine particles) are coated with glucono-δ-lactone, and only the particles are used to produce tablets mainly composed of the functional fine particles and glucono-δ-lactone. (Example 1). Ferric citrate hydrate was granulated with a gluconic acid solution, and only the particles were used to produce tablets mainly composed of only two components of ferric citrate hydrate and gluconic acid (Example 2). ). Also, D-mannitol is regarded as a drug that is easily soluble in water, and only D-mannitol is granulated with a gluconic acid solution, and only the particles are used to produce a tablet mainly composed of two components of D-mannitol and gluconic acid. (Examples 3 and 4). These tablets were evaluated by measuring the hardness and disintegration time in the oral cavity.
［実施例１］
　徐放性アンブロキソール塩酸塩微粒子２００ｇを転動流動型コーティング造粒機（ＭＰ－０１型：株式会社パウレック）に投入し、転動流動させながら、グルコノ－δ－ラクトンの１０％水溶液を４００ｇ使用してコーティングを行い乾燥してラクトン被覆徐放性アンブロキソール塩酸塩微粒子を得た。この粒子のみを用いて、ステアリン酸マグネシウムを０．２％配合して、打錠圧３ｋＮ／杵にて重量２００ｍｇ、直径８ｍｍ、隅角平面の錠剤を製した。錠剤は硬度１７Ｎであった。つぎに、この錠剤を恒温恒湿機にて２５℃９０％ＲＨ下に１６時間保存した後、通風乾燥機で４０℃で１時間後６０℃で３時間乾燥して、錠剤硬度と口腔内崩壊時間を測定した。得られた錠剤の強度は６０Ｎ、口腔内崩壊時間は３０秒で、加湿乾燥することによって、十分な強度を有する機能性微粒子を約８３％含有する錠剤（詳しくは口腔内崩壊錠）が得られた。尚、実施例において、口腔内崩壊性を示す錠剤（口腔内崩壊錠）を単に「錠剤」と称する場合もある。 [Example 1]
200 g of sustained-release ambroxol hydrochloride fine particles were put into a tumbling fluid type coating granulator (MP-01 type: POWREC Co., Ltd.) and 400 g of a 10% aqueous solution of glucono-δ-lactone was allowed to flow while rolling. The coating was used and dried to obtain lactone-coated sustained-release ambroxol hydrochloride fine particles. Using only these particles, 0.2% of magnesium stearate was blended, and tablets with a weight of 200 mg, a diameter of 8 mm, and a corner plane were produced at a tableting pressure of 3 kN / kg. The tablet had a hardness of 17N. Next, this tablet was stored at 25 ° C. and 90% RH for 16 hours in a thermo-hygrostat, then dried at 40 ° C. for 1 hour and then at 60 ° C. for 3 hours in a ventilator to obtain tablet hardness and disintegration in the oral cavity. Time was measured. The obtained tablet has a strength of 60 N, an orally disintegrating time of 30 seconds, and is dried by humidification to obtain a tablet containing about 83% functional fine particles having sufficient strength (specifically an orally disintegrating tablet). It was. In the examples, a tablet showing an orally disintegrating property (orally disintegrating tablet) may be simply referred to as a “tablet”.
［実施例２］
　クエン酸第二鉄水和物を３００ｇとり転動流動型コーティング造粒機（ＭＰ－０１型）に投入し、流動させながら、５０％グルコン酸溶液を薄めて製した２０重量％水溶液を３００ｇ使用して噴霧造粒を行った後乾燥して粒子を製した。この粒子のみを用い、ステアリン酸マグネシウムを０．３％添加して、打錠圧２．４ｋＮ／杵にて重量２５０ｍｇ、直径９ｍｍ、２段Ｒの錠剤を製した。錠剤硬度は１５Ｎであった。この錠剤を恒温恒湿機にて２５℃７５％ＲＨ下に１６時間保存した後、通風乾燥機により４０℃で１時間後さらに６０℃で３時間乾燥した。得られた錠剤の硬度は８５Ｎ、口腔内崩壊時間は９０秒で、加湿乾燥することによって、十分な強度を有する薬物含量が約８３％の錠剤が得られた。 [Example 2]
300 g of ferric citrate hydrate is taken into a rolling fluidized coating granulator (MP-01 type) and 300 g of 20% aqueous solution prepared by diluting a 50% gluconic acid solution while flowing is used. After spray granulation, the particles were dried to produce particles. Using only these particles, 0.3% of magnesium stearate was added, and tablets with a weight of 250 mg, a diameter of 9 mm, and two-stage R were produced at a tableting pressure of 2.4 kN / kg. Tablet hardness was 15N. The tablets were stored for 16 hours at 25 ° C. and 75% RH in a thermo-hygrostat, and then dried at 40 ° C. for 1 hour and further at 60 ° C. for 3 hours by a draft dryer. The obtained tablet had a hardness of 85 N, a disintegration time in the oral cavity of 90 seconds, and was dried by humidification to obtain a tablet having sufficient strength and a drug content of about 83%.
［実施例３］
　Ｄ－マンニトール（ペアリトール５０Ｃ）を２００ｇとり転動流動型コーティング造粒機（ＭＰ－０１型）の流動層モードに投入し、流動させながら、５０％グルコン酸溶液を薄めて製した２０重量％水溶液を１００ｇ使用して噴霧造粒を行った後乾燥して粒子を製した。この粒子のみを用い、ステアリン酸マグネシウムを外部滑沢剤として、打錠圧２ｋＮ／杵にて重量１８５ｍｇ、直径８．５ｍｍ、隅角平面の錠剤を製した。錠剤は硬度２０Ｎであった。この錠剤を恒温恒湿機にて２５℃７５％ＲＨ下に１６時間保存した後、ＤＲＹＩＮＧ　ＯＶＥＮにより３０℃で３時間乾燥した。得られた錠剤の硬度は５１Ｎ、口腔内崩壊時間は２０秒以内で、加湿乾燥することによって、十分な強度を有する口腔内崩壊錠が得られた。このことから、水に溶けやすい薬物に関しては、薬物含量が８０重量％を超える高含量の口腔内崩壊錠が得られる可能性が示唆された。また、この製剤については、２５℃７５％ＲＨの環境に戻す時、硬度は２０Ｎ以上を保つ頑健な製剤であった。 [Example 3]
200 g of D-mannitol (Pearlitol 50C) was put into the fluidized bed mode of a rolling fluidized coating granulator (MP-01 type) and diluted to a 20% by weight aqueous solution prepared by diluting a 50% gluconic acid solution. After spray granulation using 100 g, the particles were dried to produce particles. Using only these particles, magnesium stearate as an external lubricant was used to produce tablets having a weight of 185 mg, a diameter of 8.5 mm, and a corner plane at a tableting pressure of 2 kN / kg. The tablet had a hardness of 20N. The tablets were stored for 16 hours at 25 ° C. and 75% RH in a thermo-hygrostat and then dried at 30 ° C. for 3 hours using DRYING OVEN. The obtained tablet had a hardness of 51 N, an oral disintegration time of 20 seconds or less, and was subjected to humidification drying to obtain an orally disintegrating tablet having sufficient strength. This suggested the possibility of obtaining an orally disintegrating tablet with a high content exceeding 80% by weight for a drug that is easily soluble in water. In addition, this formulation was a robust formulation that maintained a hardness of 20 N or higher when returned to an environment of 25 ° C. and 75% RH.
［実施例４］
　Ｄ－マンニトール（ペアリトール５０Ｃ）を９００ｇをとり高速撹拌造粒機（ＶＧ－０５型：株式会社パウレック）に投入し、ブレード回転数５００ｒｐｍ、チョッパー回転数１５００ｒｐｍで、グルコノ－δ－ラクトン６０ｇを２４０ｇの水に溶解したグルコン酸水溶液を添加して５分間造粒し、ＭＰ－０１の流動層モードで乾燥した。得られた顆粒を整粒後、ステアリン酸マグネシウムを外部滑沢剤として、打錠圧１．０～１．５ｋNで、重量２００ｍｇ、直径８．０ｍｍ、隅角平面の杵で打錠した。錠剤の硬度は１６Ｎであった。この錠剤を恒温恒湿機にて２５℃８５％ＲＨ下１６時間加湿し、６０℃で３時間乾燥した。得られた錠剤は硬度は８３Ｎで、崩壊時間は６０秒であった。 [Example 4]
Take 900 g of D-mannitol (Pearitol 50C) and put it into a high-speed agitation granulator (VG-05 type: POWREC Co., Ltd.). Blade rotation speed is 500 rpm, chopper rotation speed is 1500 rpm, and glucono-δ-lactone is 60 g. An aqueous gluconic acid solution dissolved in water was added, granulated for 5 minutes, and dried in a fluidized bed mode of MP-01. The obtained granules were sized, and tableted with a tablet with a tableting pressure of 1.0 to 1.5 kN, a weight of 200 mg, a diameter of 8.0 mm, and a corner plane using magnesium stearate as an external lubricant. The tablet hardness was 16N. This tablet was humidified with a thermo-hygrostat under 25 ° C. and 85% RH for 16 hours and dried at 60 ° C. for 3 hours. The obtained tablet had a hardness of 83 N and a disintegration time of 60 seconds.
［試験例２］
　徐放性アンブロキソール塩酸塩微粒子に対し、Ｄ－マンニトールを被覆し更にその外層にグルコノ－δ－ラクトンを被覆した微粒子を製し、この粒子のみを用い、ステアリン酸カルシウムを外部滑沢剤として錠剤に製した（実施例５）。加えて、水アルコール系で撹拌造粒を行った（実施例６）また比較として、実施例５で使用したグルコノ－δ－ラクトンに替えてマルトースを用い、マルトースを被覆した微粒子を製し、この粒子のみを用い、ステアリン酸カルシウムを外部滑沢剤として錠剤に製した（比較例１）。つぎに、この錠剤を恒温恒湿機にて２５℃７５％ＲＨ～２５℃９０％ＲＨ下に１６時間保存した後、６０℃で３時間乾燥した錠剤を用い、錠剤硬度と口腔内崩壊時間を測定して評価を行った。 [Test Example 2]
Sustained release ambroxol hydrochloride fine particles coated with D-mannitol and further coated with glucono-δ-lactone on the outer layer, and using only these particles, tablets with calcium stearate as an external lubricant (Example 5). In addition, stirring and granulation were performed in a hydroalcoholic system (Example 6). For comparison, maltose was used instead of glucono-δ-lactone used in Example 5 to produce fine particles coated with maltose. Using only the particles, calcium stearate was made into a tablet as an external lubricant (Comparative Example 1). Next, the tablets were stored at 25 ° C. and 75% RH to 25 ° C. and 90% RH for 16 hours in a thermo-hygrostat, and then dried at 60 ° C. for 3 hours. Measurement and evaluation were performed.
［実施例５］
　徐放性アンブロキソール塩酸塩微粒子２００ｇを転動流動型コーティング造粒機（ＭＰ－０１型：株式会社パウレック）に投入し、転動流動させながら、Ｄ－マンニトール（ペアリトール５０Ｃ）の１０重量％水溶液を１００ｇ使用してコーティングした後、引き続いてグルコノ－δ－ラクトンの１０重量％水溶液を２１０ｇ使用してコーティングを行い乾燥してラクトン被覆徐放性アンブロキソール塩酸塩微粒子を得た。この粒子のみを用い、ステアリン酸カルシウムを外部滑沢剤として、重量２３１ｍｇ、直径８．５ｍｍ、隅角平面の錠剤を製した。この錠剤を用いて上記のとおりに錠剤の加湿乾燥を行い、評価を実施した。錠剤の製造条件と試験結果を表１に示した。 [Example 5]
200 g of sustained-release ambroxol hydrochloride fine particles were put into a tumbling fluid type coating granulator (MP-01 type: POWREC Co., Ltd.), and 10% by weight of D-mannitol (Pairitol 50C) while rolling and flowing. After coating using 100 g of an aqueous solution, coating was performed using 210 g of a 10% by weight aqueous solution of glucono-δ-lactone, followed by drying to obtain lactone-coated sustained-release ambroxol hydrochloride fine particles. Using only these particles, tablets having a weight of 231 mg, a diameter of 8.5 mm, and a corner plane were produced using calcium stearate as an external lubricant. Using this tablet, the tablet was humidified and dried as described above and evaluated. The production conditions and test results of the tablets are shown in Table 1.
［実施例６］
　徐放性アンブロキソール塩酸塩微粒子７５０ｇを高速撹拌造粒機（ＶＧ－０５型：株式会社パウレック）に投入し、ブレード５００ｒｐｍ、チョッパー１０００ｒｐｍで転動流動させながら、水エタノールを重量比で１：１の液にグルコノ－δ－ラクトンを５０重量％になるように溶解した液にＰＶＰを５ｇ加えた液を３８０ｇ使用して３分間撹拌造粒を行った。得られた造粒徐放性アンブロキソール塩酸塩微粒子を用い、ステアリン酸マグネシウムを外部滑沢剤として、重量２００ｍｇ、直径８．０ｍｍ、隅角平面の錠剤を製した。この錠剤を用いて上記のとおりに錠剤の加湿乾燥を行い、評価を実施した。錠剤の製造条件と試験結果を表１に示した。 [Example 6]
750 g of sustained-release ambroxol hydrochloride fine particles were put into a high-speed stirring granulator (VG-05 type: POWREC Co., Ltd.), and water ethanol was added at a weight ratio of 1: Granulation with stirring was carried out for 3 minutes using 380 g of a solution obtained by adding 5 g of PVP to a solution obtained by dissolving glucono-δ-lactone in 50% so as to be 50% by weight. The obtained granulated sustained-release ambroxol hydrochloride fine particles were used, and tablets having a weight of 200 mg, a diameter of 8.0 mm, and a corner plane were produced using magnesium stearate as an external lubricant. Using this tablet, the tablet was humidified and dried as described above and evaluated. The production conditions and test results of the tablets are shown in Table 1.
［比較例１］
　グルコノ－δ－ラクトンの１０重量％水溶液に替えてマルトースの１０重量％水溶液を用い、実施例５と同じ方法でコーティング操作を行いマルトース被覆徐放性アンブロキソール塩酸塩微粒子を製した。この錠剤を用いて上記のとおりに錠剤の加湿乾燥を行い、評価を実施した。錠剤の製造条件と試験結果を表１に示した。 [Comparative Example 1]
A maltose-coated sustained-release ambroxol hydrochloride fine particles were produced in the same manner as in Example 5 using a 10% by weight aqueous solution of maltose instead of the 10% by weight aqueous solution of glucono-δ-lactone. Using this tablet, the tablet was humidified and dried as described above and evaluated. The production conditions and test results of the tablets are shown in Table 1.
　非晶質状態から結晶への変化を利用して、加湿乾燥することによって錠剤硬度が上昇するとされているマルトースを対照として試験を実施したが、平均粒子径が３００μｍ程度の粒子のみで錠剤化するとき、マルトースでは十分な強度を有した錠剤までの錠剤硬度の上昇は観察されなかった。対して、グルコノ－δ－ラクトンを使用したものは、２５℃７５％ＲＨ～９０％ＲＨ条件下で加湿し、６０℃で乾燥することによって、明らかな錠剤の硬度上昇が確認された。 The test was conducted using maltose, which is supposed to increase tablet hardness by humidified drying using the change from an amorphous state to a crystal, but it is tableted only with particles having an average particle size of about 300 μm. When maltose, no increase in tablet hardness was observed up to tablets with sufficient strength. On the other hand, in the case of using glucono-δ-lactone, a clear increase in the hardness of the tablet was confirmed by humidifying at 25 ° C. and 75% RH to 90% RH and drying at 60 ° C.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
［試験例３］
　グルコノ－δ－ラクトンとマルトースあるいはトレハロースを混合し、水に溶解したものを結合剤として用い錠剤を製した（実施例７～１０）。また、マルトースあるいはトレハロース単味を水に溶解したものを結合剤として用いて錠剤を製した（比較例２～３）。つぎに、これらの錠剤を恒温恒湿機にて２５℃７５％ＲＨ下に１６時間保存した後、６０℃で５時間乾燥した錠剤を用い、錠剤硬度と口腔内崩壊時間を測定して評価を行った。 [Test Example 3]
Tablets were prepared using glucono-δ-lactone and maltose or trehalose mixed together and dissolved in water as a binder (Examples 7 to 10). Also, tablets were prepared using a maltose or trehalose plain dissolved in water as a binder (Comparative Examples 2 to 3). Next, after these tablets were stored for 16 hours at 25 ° C. and 75% RH in a thermo-hygrostat, the tablets were dried for 5 hours at 60 ° C., and the tablet hardness and disintegration time in the oral cavity were measured for evaluation. went.
［実施例７］
　Ｄ－マンニトール（ペアリトール５０Ｃ）を１８０ｇとり転動流動型コーティング造粒機（ＭＰ－０１型）に投入し、流動させながら、グルコノ－δ－ラクトンとマルトースの１：１混合物の水溶液（２０重量％）１００ｇを結合剤として噴霧造粒を行った。この造粒物にステアリン酸マグネシウムを０．５重量％配合し、重量２００ｍｇ、直径８．０ｍｍ、隅角平面の錠剤を製した。錠剤の製造条件と試験結果を表２に示した。 [Example 7]
180 g of D-mannitol (Pearlitol 50C) was added to a rolling fluidized coating granulator (MP-01 type), and while flowing, an aqueous solution of a 1: 1 mixture of glucono-δ-lactone and maltose (20% by weight) ) Spray granulation was performed using 100 g of binder. This granulated product was mixed with 0.5% by weight of magnesium stearate, and a tablet having a weight of 200 mg, a diameter of 8.0 mm, and a corner plane was produced. Table 2 shows the tablet production conditions and test results.
［実施例８～１０］
　Ｄ－マンニトール（ペアリトール５０Ｃ）を１８０ｇとり転動流動型コーティング造粒機（ＭＰ－０１型）の流動層モードに投入し、流動させながら、グルコノ－δ－ラクトンとトレハロースの１：１、３：１及び９：１混合物の水溶液（２０重量％）１００ｇを結合剤として噴霧造粒を行った。この造粒物にステアリン酸マグネシウムを０．５重量％配合し、重量２００ｍｇ、直径８．０ｍｍ、隅角平面の錠剤を製した。１：１の混合物によるものを実施例８、３：１の混合物によるものを実施例９、９：１の混合物によるものを実施例１０とした。錠剤の製造条件と試験結果を表２に示した。 [Examples 8 to 10]
180 g of D-mannitol (Pearlitol 50C) was put into a fluidized bed mode of a tumbling fluidized-type coating granulator (MP-01 type), and while flowing, 1: 1, 3: 3 of glucono-δ-lactone and trehalose Spray granulation was carried out using 100 g of an aqueous solution (20% by weight) of a 1 and 9: 1 mixture as a binder. This granulated product was mixed with 0.5% by weight of magnesium stearate, and a tablet having a weight of 200 mg, a diameter of 8.0 mm, and a corner plane was produced. Example 8 was based on a 1: 1 mixture, Example 9 was based on a 3: 1 mixture, and Example 10 was based on a 9: 1 mixture. Table 2 shows the tablet production conditions and test results.
［比較例２～３］
　Ｄ－マンニトール（ペアリトール５０Ｃ）を１８０ｇとり転動流動型コーティング造粒機（ＭＰ－０１型）の流動層モードに投入し、流動させながら、マルトースあるいはトレハロースの水溶液（２０重量％）１００ｇを結合剤として噴霧造粒を行った。この造粒物にステアリン酸マグネシウムを０．５重量％配合し、重量２００ｍｇ、直径８．０ｍｍ、隅角平面の錠剤を製した。マルトースで製した錠剤を比較例２、トレハロースで製した錠剤を比較例３とした。錠剤の製造条件と試験結果を表２に示した。 [Comparative Examples 2 to 3]
Take 180g of D-mannitol (Pearitol 50C) and put it into the fluidized bed mode of a tumbling fluidized coating granulator (MP-01 type) and let 100g of maltose or trehalose aqueous solution (20wt%) bind as it is flowing. Spray granulation was carried out. This granulated product was mixed with 0.5% by weight of magnesium stearate, and a tablet having a weight of 200 mg, a diameter of 8.0 mm, and a corner plane was produced. A tablet made of maltose was used as Comparative Example 2, and a tablet made of trehalose was used as Comparative Example 3. Table 2 shows the tablet production conditions and test results.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　比較例２及び３は、特許文献３及び特許文献８に準ずる方法で製した錠剤であるが、加湿乾燥しても５０Ｎ程度の硬度を有した錠剤が得られるに過ぎない。対して、グルコノ－δ－ラクトンにマルトースあるいはトレハロースを配合して製した錠剤は、７０Ｎ以上の強度を有した非常に強い強度を有した錠剤となることが明確に示された。 Comparative Examples 2 and 3 are tablets manufactured by a method according to Patent Document 3 and Patent Document 8, but only a tablet having a hardness of about 50 N can be obtained even when humidified and dried. On the other hand, it was clearly shown that a tablet prepared by blending maltose or trehalose with glucono-δ-lactone is a tablet having a very strong strength having a strength of 70 N or more.
［試験例４］
　徐放性アンブロキソール塩酸塩微粒子２００ｇを転動流動型コーティング造粒機（ＭＰ－０１型）に投入し、転動流動させながら、Ｄ－マンニトール（ペアリトール５０Ｃ）の１０重量％水溶液を２００ｇ使用しレイヤリングを行った後乾燥した粒子（以下マンニトール被覆ＡＢＸ微粒子と呼称する）に、グルコノ－δ－ラクトンを混合したもの及びグルコノ－δ－ラクトンと水膨潤性の崩壊剤を混合したものを打錠末とし、ステアリン酸カルシウムを外部滑沢剤として錠剤を製した（実施例１１～１５）。また、マンニトール被覆ＡＢＸ微粒子に、マルトースあるいはトレハロースを混合したもの及びマルトースあるいはトレハロースと水膨潤性の崩壊剤を混合したものを打錠末とし、ステアリン酸カルシウムを外部滑沢剤として、錠剤を製した（比較例４～９）。つぎに、これらの錠剤を３５℃８２％ＲＨ（デシケータ中での塩化カリウム飽和液）あるいは２５℃９０％ＲＨ（恒温恒湿機）下に１６時間保存した後、６０℃で６時間乾燥し、錠剤硬度と口腔内崩壊時間を測定して評価を行った。 [Test Example 4]
200g of sustained-release ambroxol hydrochloride fine particles are put into a tumbling flow type coating granulator (MP-01 type), and 200g of 10% by weight aqueous solution of D-mannitol (Pearlitol 50C) is used while rolling and flowing. Then, after the layering, the dried particles (hereinafter referred to as mannitol-coated ABX fine particles) are mixed with glucono-δ-lactone and with a mixture of glucono-δ-lactone and a water-swellable disintegrant. Tablets were prepared using calcium stearate as an external lubricant (Examples 11 to 15). Also, tablets prepared with mannitol-coated ABX fine particles mixed with maltose or trehalose and those mixed with maltose or trehalose and a water-swelling disintegrant were used as tableting powder, and calcium stearate was used as an external lubricant ( Comparative Examples 4 to 9). Next, these tablets were stored at 35 ° C. 82% RH (potassium chloride saturated solution in a desiccator) or 25 ° C. 90% RH (constant temperature and humidity machine) for 16 hours, and then dried at 60 ° C. for 6 hours. Evaluation was performed by measuring tablet hardness and oral disintegration time.
［実施例１１～１５］
　マンニトール被覆ＡＢＸ微粒子、グルコノ－δ－ラクトン粉末及び水膨潤性の崩壊剤を表３に示す配合で混合し、重量２００ｍｇ、直径８．０ｍｍ、隅角平面の錠剤に製した。錠剤の製造条件と試験結果を表４に示した。 [Examples 11 to 15]
Mannitol-coated ABX fine particles, glucono-δ-lactone powder and a water-swellable disintegrant were mixed in the formulation shown in Table 3 to prepare tablets having a weight of 200 mg, a diameter of 8.0 mm, and a corner plane. Table 4 shows the tablet production conditions and test results.
［比較例４～９］
　マンニトール被覆ＡＢＸ微粒子、マルトースあるいはトレハロース及び水膨潤性の崩壊剤を表３に示す配合で混合し、重量２００ｍｇ、直径８ｍｍ、隅角平面の錠剤に製した。錠剤の製造条件と試験結果を表４に示した。 [Comparative Examples 4 to 9]
Mannitol-coated ABX fine particles, maltose or trehalose and a water-swellable disintegrant were mixed in the formulation shown in Table 3 to prepare tablets having a weight of 200 mg, a diameter of 8 mm and a corner plane. Table 4 shows the tablet production conditions and test results.
Figure JPOXMLDOC01-appb-T000003
 ａ）水膨潤性崩壊剤としては、実施例１２、比較例５及び比較例８にクロスポビドン（ポリプラスドンＸＬ－１０）を、実施例１３，比較例６及び比較例９にデンプングリコール酸ナトリウム（プリモジェル）を、実施例１４にカルメロースカルシウム（ＥＣＧ－５０５）を、また実施例１５にクロスカルメロースナトリウム（Ａｃ－Ｄｉ－Ｓｏｌ）を使用した。
Figure JPOXMLDOC01-appb-T000003
 a) As the water-swellable disintegrant, crospovidone (polyplastidone XL-10) was used in Example 12, Comparative Example 5 and Comparative Example 8, and sodium starch glycolate was used in Example 13, Comparative Example 6 and Comparative Example 9. (Primogel), carmellose calcium (ECG-505) in Example 14, and croscarmellose sodium (Ac-Di-Sol) in Example 15.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　グルコノ－δ－ラクトンを単純混合したものは、３５℃８２％ＲＨ下保存で加湿し乾燥しても錠剤硬度はアップしなかったが、２５℃９０％ＲＨ下に保存したものには硬度アップが認められた。グルコノ－δ－ラクトンとともにクロスポビドン（ポリプラスドンＸＬ－１０、デンプングリコール酸ナトリウム（プリモジェル）、カルメロースカルシウム（ＥＣＧ－５０５）、又はクロスカルメロースナトリウム（Ａｃ－Ｄｉ－Ｓｏｌ）を添加したものに関しては、３５℃８２％ＲＨ下保存においても、顕著な硬度アップが観察され、これら水膨潤性崩壊剤の添加効果が実証された。また、非晶質状態から結晶への変化を利用して、加湿乾燥することによって錠剤硬度が上昇するとされているマルトース及びトレハロースを対照として同様の試験を実施したが、３５℃８２％ＲＨ下保存、２５℃９０％ＲＨ下保存のいずれにおいても錠剤硬度の上昇は観察されなかった。 A simple mixture of glucono-δ-lactone did not increase the tablet hardness even when it was humidified and dried at 35 ° C and 82% RH, but the product that was stored at 25 ° C and 90% RH had an increased hardness. Admitted. Crospovidone (Polyplastidone XL-10, sodium starch glycolate (primogel), carmellose calcium (ECG-505), or croscarmellose sodium (Ac-Di-Sol) added together with glucono-δ-lactone) With regard to the water, a significant increase in hardness was observed even when stored at 35 ° C. and 82% RH, and the effect of adding these water-swellable disintegrants was demonstrated. The same test was carried out using maltose and trehalose, which are supposed to increase tablet hardness by humid drying, as a control, but the tablet hardness of both 35 ° C 82% RH storage and 25 ° C 90% RH storage An increase was not observed.
［試験例５］
　グルコノ－δ－ラクトンとポビドン（コリドン３０）を混合し、水に溶解したものを結合剤として用い錠剤を製した（実施例１６）。つぎに、この錠剤を用い、加湿乾燥させて錠剤硬度と口腔内崩壊時間を測定し評価を行った。 [Test Example 5]
A tablet was prepared by mixing glucono-δ-lactone and povidone (Kollidon 30) and dissolving in water as a binder (Example 16). Next, this tablet was humidified and dried, and tablet hardness and oral disintegration time were measured and evaluated.
［実施例１６］
Ｄ－マンニトール（ペアリトール５０Ｃ）を２７０ｇとり転動流動型コーティング造粒機（ＭＰ－０１型）の流動層モードに投入し、流動させながら、グルコノ－δ－ラクトンとコリドン３０の９：１混合物の水溶液（２０重量％）１５０ｇを結合剤として噴霧造粒を行った。この造粒物にステアリン酸マグネシウムを０．５重量％配合し、打錠圧１．５ｋＮ／杵にて重量２００ｍｇ、直径８ｍｍ、隅丸平面の錠剤を製した。錠剤硬度は１７Ｎであった。この錠剤を恒温恒湿機にて２５℃７５％ＲＨ下に１５時間保存した後、通風乾燥機にて６０℃で３時間乾燥した。得られた錠剤の硬度は８２Ｎ、口腔内崩壊時間は４５秒で、加湿乾燥することによって、十分な錠剤強度を有する錠剤が得られた。 [Example 16]
270 g of D-mannitol (Pearritol 50C) was put into a fluidized bed mode of a rolling fluidized coating granulator (MP-01 type), and while flowing, a 9: 1 mixture of glucono-δ-lactone and Kollidon 30 was mixed. Spray granulation was performed using 150 g of an aqueous solution (20% by weight) as a binder. This granulated product was mixed with 0.5% by weight of magnesium stearate, and a tablet having a weight of 200 mg, a diameter of 8 mm, and a rounded corner was produced at a tableting pressure of 1.5 kN / kg. Tablet hardness was 17N. The tablets were stored for 15 hours at 25 ° C. and 75% RH in a constant temperature and humidity machine, and then dried at 60 ° C. for 3 hours in a draft dryer. The obtained tablet had a hardness of 82 N, an oral disintegration time of 45 seconds, and was dried by humidification, whereby a tablet having sufficient tablet strength was obtained.
［試験例６］
　様々な薬物を用い、グルコノ－δ－ラクトンと非晶質になり得る糖類や糖アルコール類の混合物を結合剤として用いる実験を実施した（実施例１７～２１）。 [Test Example 6]
Experiments were carried out using various drugs and using a mixture of glucono-δ-lactone and sugars or sugar alcohols that can be amorphous as binders (Examples 17 to 21).
［実施例１７］
　クエン酸第二鉄水和物を２４０ｇとり転動流動型コーティング造粒機（ＭＰ－０１型）に投入し、流動させながら、グルコノ－δ－ラクトンとトレハロースの１：１混合物の水溶液（２０重量％）１２０ｇを結合剤として噴霧造粒を行った。この造粒物にステアリン酸マグネシウムを０．５重量％配合し、打錠圧２ｋＮ／杵にて重量２００ｍｇ、直径８ｍｍ、隅丸平面の錠剤を製した。錠剤硬度は２０Ｎであった。この錠剤を恒温恒湿機にて２５℃７５％ＲＨ下に１５時間保存した後、真空乾燥機により６０℃で１時間乾燥した。得られた錠剤の硬度は１１７Ｎ、口腔内崩壊時間は約１２０秒で、加湿乾燥することによって、１００Ｎを超える強度を有する薬物含量が約９０％の錠剤が得られた。この錠剤は、口腔内崩壊時間が迅速とはいえないが、１００Ｎを超える強度を有する薬物含量が約９０％の、極度に小型化された、優れた特性を有する錠剤（例えば普通錠）として取り扱うことができる。 [Example 17]
240 g of ferric citrate hydrate was added to a rolling fluidized-type coating granulator (MP-01 type), and while flowing, an aqueous solution of a 1: 1 mixture of glucono-δ-lactone and trehalose (20 wt. %) 120 g of spray granulation was performed as a binder. This granulated product was mixed with 0.5% by weight of magnesium stearate, and tablets with a weight of 200 mg, a diameter of 8 mm, and a rounded corner were produced at a tableting pressure of 2 kN / kg. Tablet hardness was 20N. The tablets were stored for 15 hours at 25 ° C. and 75% RH in a constant temperature and humidity machine, and then dried at 60 ° C. for 1 hour using a vacuum dryer. The obtained tablet had a hardness of 117 N, an oral disintegration time of about 120 seconds, and was wet-dried to obtain a tablet having a strength exceeding 100 N and a drug content of about 90%. This tablet cannot be said to be rapid in the oral disintegration time, but is handled as an extremely miniaturized tablet having excellent properties (for example, a normal tablet) having a drug content having a strength exceeding 100 N of about 90%. be able to.
　［実施例１８］
　アセトアミノフェンを８５０ｇおよびプリモジェル５０ｇをとり高速撹拌造粒機（ＶＧ－０５型）に投入し、ブレード回転数５００ｒｐｍ、チョッパー１５００ｒｐｍで、グルコノ－δ－ラクトン６５ｇおよびトレハロース３５ｇを２５０ｇの水に溶かしたグルコン酸―トレハロース水溶液を結合剤として撹拌造粒を行った。この造粒物にステアリン酸マグネシウムを外部滑沢で添加し、打錠圧２．５ｋＮ／杵にて重量２００ｍｇ、直径８．０ｍｍ、隅角平面の錠剤を製した。錠剤硬度は１５Ｎであった。この錠剤を恒温恒湿機にて２５℃７５％ＲＨ下に１６時間保存した後、真空乾燥機により６０℃で３時間乾燥した。得られた錠剤の硬度は７１Ｎ、口腔内崩壊時間は２５秒であった。 [Example 18]
Take 850 g of acetaminophen and 50 g of Primogel and put into a high-speed stirring granulator (VG-05 type). Agitation granulation was carried out using a gluconic acid-trehalose aqueous solution as a binder. Magnesium stearate was added to this granulated product with an external lubricant, and tablets with a weight of 200 mg, a diameter of 8.0 mm, and a corner plane were produced at a tableting pressure of 2.5 kN / kg. Tablet hardness was 15N. The tablet was stored at 25 ° C. and 75% RH for 16 hours in a thermo-hygrostat and then dried at 60 ° C. for 3 hours by a vacuum dryer. The obtained tablet had a hardness of 71 N and an oral disintegration time of 25 seconds.
　［実施例１９］
　メトホルミンを８５０ｇおよびプリモジェル５０ｇをとり高速撹拌造粒機（ＶＧ－０５型）に投入し、ブレード回転数５００ｒｐｍ、チョッパー１５００ｒｐｍで、グルコノ－δ－ラクトン１００ｇを水：エタノールを１：１（重量）に混合した液２００ｇに溶かしたグルコノラクトン溶液を結合剤として撹拌造粒を行った。この造粒物にステアリン酸マグネシウムを外部滑沢で添加し、打錠圧４．０ｋＮ／杵にて重量２００ｍｇ、直径８．０ｍｍ、隅角平面の錠剤を製した。錠剤硬度は１３Ｎであった。この錠剤を恒温恒湿機にて２５℃７５％ＲＨ下に１７時間保存した後、真空乾燥機により６０℃で３時間乾燥した。得られた錠剤の硬度は１１０Ｎ、崩壊時間（ＪＰ法）は３８秒であった。 [Example 19]
Take 850 g of metformin and 50 g of Primogel and put them into a high-speed agitation granulator (VG-05 type). Blade rotation speed is 500 rpm, chopper is 1500 rpm, glucono-δ-lactone is 100 g water: ethanol 1: 1 (weight) Agitation granulation was carried out using as a binder a gluconolactone solution dissolved in 200 g of the mixed solution. Magnesium stearate was added to this granulated product with an external lubricant, and tablets with a weight of 200 mg, a diameter of 8.0 mm, and a corner plane were produced at a tableting pressure of 4.0 kN / kg. Tablet hardness was 13N. The tablets were stored for 17 hours at 25 ° C. and 75% RH in a thermo-hygrostat and then dried at 60 ° C. for 3 hours using a vacuum dryer. The tablets obtained had a hardness of 110 N and a disintegration time (JP method) of 38 seconds.
　［実施例２０］
　アビラテロン酢酸エステルを２５０ｇおよびクロスポビドン（ＸＬ－１０）５０ｇをとり高速撹拌造粒機（ＨＭＳ－０１型：深江パウテック(株)）に投入し、ブレード回転数２５０ｒｐｍ、チョッパー１８００ｒｐｍで、グルコノ－δ－ラクトン７５ｇおよびトレハロース８．３ｇを水１００ｇに溶解した液１８３．３ｇを添加して撹拌造粒を行った。この造粒物を乾燥後、ステアリン酸マグネシウムを外部滑沢とし、打錠圧０．５ｋＮ／杵にて重量２３０ｍｇ、直径８．５ｍｍの隅角平面の錠剤を製した。錠剤硬度は１４Ｎであった。この錠剤を恒温恒湿機にて２５℃９２％ＲＨ下に１７時間保存した後、真空乾燥機により６０℃で３時間乾燥した。得られた錠剤の硬度は６５Ｎであった。 [Example 20]
250 g of abiraterone acetate and 50 g of crospovidone (XL-10) were taken and introduced into a high-speed agitation granulator (HMS-01 type: Fukae Powtech Co., Ltd.), and glucono-δ- at a blade rotation speed of 250 rpm and a chopper of 1800 rpm. Agitation granulation was performed by adding 183.3 g of a solution obtained by dissolving 75 g of lactone and 8.3 g of trehalose in 100 g of water. After the granulated product was dried, magnesium stearate was used as an external lubricant, and a tablet having a corner plane of 230 mg in weight and 8.5 mm in diameter was produced at a tableting pressure of 0.5 kN / kg. Tablet hardness was 14N. The tablets were stored for 17 hours at 25 ° C. and 92% RH in a constant temperature and humidity machine, and then dried at 60 ° C. for 3 hours using a vacuum dryer. The obtained tablet had a hardness of 65N.
　［実施例２１］
　ニロチニブ塩酸塩水和物を５０ｇおよびクロスポビドン（ＸＬ－１０）１０ｇをとり乳鉢に投入し、グルコノ－δ－ラクトン１５ｇおよびトレハロース１．６７ｇを水１６．７ｇに溶解した液３３．４ｇを添加してマニュアルで撹拌造粒を行った。この造粒物を乾燥後、ステアリン酸マグネシウムを外部滑沢とし、打錠圧０．５ｋＮ／杵にて重量２３０ｍｇ、直径８．５ｍｍの隅角平面の杵で錠剤を製した。錠剤硬度は１２Ｎであった。この錠剤を恒温恒湿機にて３５℃８５％ＲＨ下に１７時間保存した後、真空乾燥機により６０℃で３時間乾燥した。得られた錠剤の硬度は３８Ｎであった。 [Example 21]
Add 50 g of nilotinib hydrochloride hydrate and 10 g of crospovidone (XL-10) to a mortar and add 33.4 g of a solution prepared by dissolving 15 g of glucono-δ-lactone and 1.67 g of trehalose in 16.7 g of water. Agitation granulation was performed manually. The granulated product was dried, and then magnesium stearate was used as an external lubricant, and tablets were produced with a corner flat plate with a weight of 230 mg and a diameter of 8.5 mm at a tableting pressure of 0.5 kN / 杵. Tablet hardness was 12N. The tablets were stored for 17 hours at 35 ° C. and 85% RH in a constant temperature and humidity machine, and then dried in a vacuum dryer at 60 ° C. for 3 hours. The resulting tablet had a hardness of 38N.
［試験例７］
　上記実施例では主にグルコノラクトン－グルコン酸系の例を示したが、グルクロノラクトン－グルクロン酸系の試験を行った。グルクロノラクトンとトレハロースを混合し、水に溶解したものを結合剤として用い錠剤を製した（実施例２２）。つぎに、この錠剤を用い、加湿乾燥させて錠剤硬度と口腔内崩壊時間を測定し評価を行った。 [Test Example 7]
In the above examples, an example of a gluconolactone-gluconic acid system was mainly shown, but a glucuronolactone-glucuronic acid system was tested. Glucuronolactone and trehalose were mixed and dissolved in water to produce a tablet using a binder (Example 22). Next, this tablet was humidified and dried, and tablet hardness and oral disintegration time were measured and evaluated.
［実施例２２］
　Ｄ－マンニトール（ペアリトール５０Ｃ）を５００ｇとり高速撹拌造粒機（ＶＧ－０１型）に投入し、混合撹拌させながら、グルクロノラクトンとトレハロースの９：１混合物の水溶液（３３重量％）１５０ｇを結合剤として造粒を行った。この造粒物をＭＰ－０１型の流動層モードで乾燥し、３２メッシュの篩で篩過後ステアリン酸マグネシウムを０．５重量％配合し、打錠圧１．５ｋＮ／杵及び３．０ｋＮ／杵にて重量２００ｍｇ、直径８．０ｍｍ、隅丸平面の錠剤を製した。錠剤硬度はそれぞれ６Ｎ及び１８Ｎであった。この錠剤を恒温恒湿機にて２５℃７５％ＲＨ下に１５時間保存した後、通風乾燥機にて６０℃で３時間乾燥した。得られた錠剤の硬度はそれぞれ４３Ｎ及び５５Ｎであり、口腔内崩壊時間は５秒及び１２秒であった。グルクロノラクトンの場合もグルコノ－δ－ラクトン同様に、加湿乾燥することによって、十分な錠剤強度を有する錠剤が得られた。 [Example 22]
500 g of D-mannitol (Pearlitol 50C) is put into a high-speed stirring granulator (VG-01 type), and 150 g of an aqueous solution (33% by weight) of a 9: 1 mixture of glucuronolactone and trehalose is combined with stirring. Granulation was performed as an agent. This granulated product was dried in a fluidized bed mode of MP-01 type, passed through a 32 mesh sieve, and then mixed with 0.5% by weight of magnesium stearate, and tableting pressures of 1.5 kN / 杵 and 3.0 kN / 杵 were added. Made tablets with a weight of 200 mg, a diameter of 8.0 mm, and a rounded corner. Tablet hardness was 6N and 18N, respectively. The tablets were stored for 15 hours at 25 ° C. and 75% RH in a constant temperature and humidity machine, and then dried at 60 ° C. for 3 hours in a draft dryer. The hardness of the obtained tablets was 43N and 55N, respectively, and the oral disintegration time was 5 seconds and 12 seconds. In the case of glucuronolactone as well as glucono-δ-lactone, the tablet having sufficient tablet strength was obtained by humidifying and drying.
　以上実施例を通して説明してきたグルコノ－δ－ラクトン（一部グルクロノラクトン）を配合した処方系では、主に水溶媒での検討を行ってきたが、グルコノ－δ－ラクトンを水溶液としたグルコン酸との平衡液を使う方法では、湿塊を製造する場合に固化する傾向がある場合もあることがわかった。そこで、グルコノ－δ－ラクトンの固化現象を押さえる製造方法として、エタノールを用いる方法の検討を行った。 In the formulation system containing glucono-δ-lactone (partially glucuronolactone) described above through the examples, investigations have mainly been carried out with aqueous solvents, but gluconic acid with glucono-δ-lactone as an aqueous solution has been studied. It has been found that the method using the equilibrium liquid may tend to solidify when the wet mass is produced. Therefore, as a production method for suppressing the solidification phenomenon of glucono-δ-lactone, a method using ethanol was examined.
［試験例８］
グルコノ－δ－ラクトンを製造中に均一に、混合マスを固まらせることなく分散させる方法として、グルコノ－δ－ラクトンを水溶液として噴霧する方法（実施例１，２，５，７～１０）が採用されているが、この試験例では、粉砕したグルコノ－δ－ラクトンを造粒品に混ぜ込み、エタノールで造粒することで、転動噴霧法と同じ効果があるかどうかを調べた。またこの系にいくつかの賦形剤（トレハロース、コリドン３０等）を加えた系をエタノールで練合造粒した製法での加湿乾燥の効果を調べた（実施例２３～２５）。さらに、非晶質化しない糖の効果を調べた（実施例２６、２７）。 [Test Example 8]
As a method for uniformly dispersing glucono-δ-lactone during production without solidifying the mixed mass, a method of spraying glucono-δ-lactone as an aqueous solution (Examples 1, 2, 5, 7 to 10) is adopted. However, in this test example, it was investigated whether or not the pulverized glucono-δ-lactone was mixed with the granulated product and granulated with ethanol to obtain the same effect as the tumbling spray method. In addition, the effect of humidification drying in a method in which a system in which some excipients (trehalose, Kollidon 30, etc.) were added to this system and kneaded and granulated with ethanol was examined (Examples 23 to 25). Furthermore, the effect of sugar that does not become amorphous was examined (Examples 26 and 27).
［実施例２３～２５］
　Ｄ－マンニトール（ペアリトール５０Ｃ）９００ｇおよびグルコノ－δ－ラクトン１００ｇをとり高速撹拌造粒機（ＶＧ－０５型）に投入し、ブレード回転数５００ｒｐｍ、チョッパー回転数１５００ｒｐｍで混合撹拌させながら、エタノール２３０ｇを添加して５分間造粒を行った。この造粒物を乾燥し、３２メッシュの篩で篩過後ステアリン酸マグネシウムを外部滑沢で添加し、打錠圧４．２ｋＮにて重量２００ｍｇ、直径８．０ｍｍ、隅丸平面の錠剤を製した。錠剤硬度は６Ｎ及び１８Ｎであった。この錠剤を恒温恒湿機にて２５℃７５％ＲＨ下に１６時間保存した後、通風乾燥機にて６０℃で３時間乾燥した。得られた錠剤の硬度は３８Ｎであり、口腔内崩壊時間は１７秒であった（実施例２３）。この処方系のグルコノ－δ－ラクトン１００ｇを８０ｇとし、トレハロース２０ｇを加えて製した系（実施例２４）では、３．０ｋＮの打錠圧で、錠剤硬度は１４Ｎの錠剤が得られ、実施例１９と同じ加湿乾燥条件で処遇した錠剤は、硬度５１Ｎ、崩壊時間は２９秒であった。さらにグルコノ－δ－ラクトン１００ｇを９０ｇとし、コリドン３０を１０ｇ加えた系（実施例２５）では、２．２ｋＮの打錠圧で得られた錠剤の硬度は１６Ｎで、上記と同じ加湿乾燥条件下で処遇した錠剤は、硬度６６Ｎおよび崩壊時間は３５秒であった。 [Examples 23 to 25]
Take 900 g of D-mannitol (Pearitol 50C) and 100 g of glucono-δ-lactone and put into a high-speed stirring granulator (VG-05 type). While mixing and stirring at a blade rotation speed of 500 rpm and a chopper rotation speed of 1500 rpm, add 230 g of ethanol. Added and granulated for 5 minutes. This granulated product was dried, passed through a 32 mesh sieve, and then magnesium stearate was added with an external lubricant to produce tablets having a weight of 200 mg, a diameter of 8.0 mm, and a rounded corner at a tableting pressure of 4.2 kN. . Tablet hardness was 6N and 18N. The tablets were stored for 16 hours at 25 ° C. and 75% RH in a constant temperature and humidity machine, and then dried at 60 ° C. for 3 hours in a draft dryer. The hardness of the obtained tablet was 38 N, and the oral disintegration time was 17 seconds (Example 23). In this system (Example 24) prepared by adding 100 g of glucono-δ-lactone of 80 g and adding 20 g of trehalose (Example 24), a tablet with a tableting pressure of 3.0 kN and a tablet hardness of 14 N was obtained. The tablets treated under the same humidifying and drying conditions as in No. 19 had a hardness of 51 N and a disintegration time of 29 seconds. Further, in the system (Example 25) in which 100 g of glucono-δ-lactone and 90 g of Kollidon 30 were added (Example 25), the tablet obtained with a tableting pressure of 2.2 kN had a hardness of 16 N, and the same humidifying and drying conditions as above. The tablets treated with a hardness of 66 N and a disintegration time of 35 seconds.
［実施例２６、２７］
　Ｄ－マンニトール（ペアリトール５０Ｃ）を９００ｇとり高速撹拌造粒機（ＶＧ－０５型）に投入し、ブレード回転数５００ｒｐｍ、チョッパー回転数１５００ｒｐｍで混合撹拌させながら、グルコノδ－ラクトン８０ｇおよび非晶質化しない（非晶質にならない）糖であるＤ－マンニトールの２０ｇをエタノール２３０ｇに溶解乃至分散させた液を添加して造粒を行った。この造粒物を乾燥し、３２メッシュの篩で篩過後ステアリン酸マグネシウムを外部滑沢で添加し、打錠圧４．２ｋＮにて重量２００ｍｇ、直径８．０ｍｍ、隅角平面の錠剤を製した。錠剤硬度は１４Ｎであった。この錠剤を恒温恒湿機にて２５℃７５％ＲＨ下に１６時間保存した後、通風乾燥機にて６０℃で３時間乾燥し、得られた錠剤の硬度は４４Ｎであり、口腔内崩壊時間は１７秒であった。同様に恒温恒湿機にて２５℃８５％ＲＨ下に１６時間保存した後、通風乾燥機にて６０℃で３時間乾燥し、得られた錠剤の硬度は９７Ｎであった（実施例２６）。この処方系で、グルコノ－δ－ラクトンを９５ｇ、Ｄ－マンニトール５ｇとし、エタノール３００ｇに溶解乃至分散させた液を添加し造粒製せられた顆粒を用いて、４．３ｋＮで打錠することで得られた硬度１４Ｎの錠剤は、実施例２６と同じ加湿乾燥条件で処遇したところ、２５℃７５％ＲＨ１６時間で硬度２７Ｎ、崩壊時間は２１秒であった。２５℃８５％ＲＨ１６時間では錠剤硬度は８９Ｎになった（実施例２７）。 [Examples 26 and 27]
900 g of D-mannitol (Pearlitol 50C) was put into a high-speed agitation granulator (VG-05 type), mixed and stirred at a blade rotation speed of 500 rpm and a chopper rotation speed of 1500 rpm, and 80 g of glucono δ-lactone and amorphized. Granulation was carried out by adding a solution obtained by dissolving or dispersing 20 g of D-mannitol, which is a non-amorphous (non-amorphous) sugar, in 230 g of ethanol. This granulated product was dried, passed through a 32 mesh sieve, magnesium stearate was added with an external lubricant, and a tablet with a weight of 200 mg, a diameter of 8.0 mm, and a corner plane was produced at a tableting pressure of 4.2 kN. . Tablet hardness was 14N. The tablets were stored for 16 hours at 25 ° C. and 75% RH in a thermo-hygrostat, and then dried for 3 hours at 60 ° C. in a ventilator. The resulting tablets had a hardness of 44 N and disintegrated in the oral cavity. Was 17 seconds. Similarly, after storing for 16 hours at 25 ° C. and 85% RH in a constant temperature and humidity machine, the tablet was dried at 60 ° C. for 3 hours in a draft dryer, and the hardness of the obtained tablet was 97 N (Example 26). . In this formulation system, 95 g of glucono-δ-lactone and 5 g of D-mannitol are added, a solution dissolved or dispersed in 300 g of ethanol is added, and granules are granulated, and tableted at 4.3 kN. The tablets with a hardness of 14N obtained in the above were treated under the same humidified drying conditions as in Example 26. The hardness was 27N at 25 ° C. and 75% RH for 16 hours, and the disintegration time was 21 seconds. At 25 ° C. and 85% RH for 16 hours, the tablet hardness was 89 N (Example 27).
この粉砕グルコノ－δ－ラクトンを加えて、エタノールで撹拌造粒した実施例では、いずれも加湿乾燥を施すことで、錠剤硬度が高くなることが示された。また、実施例２３の錠剤では、加湿乾燥後に２５℃７５％ＲＨに数日放置することでも、２１Ｎと十分な硬度が維持されていた。さらに、実施例２６および実施例２７の２５℃８５％ＲＨで製した錠剤を、２５℃７５％ＲＨに数日放置した製剤の硬度は、実施例２６および実施例２７でそれぞれ２８Ｎおよび３０Ｎであった。このことから、グルコノ－δ－ラクトンに非晶質化しない糖を配合すれば、７５％ＲＨよりも８５％ＲＨで明らかに硬度が高くなり、さらに７５％ＲＨでの戻りが大きくないため、無包装保存状態での硬度を維持し、市場での使用に十分耐えうる錠剤が得られることがわかった。 In the examples in which this pulverized glucono-δ-lactone was added and stirred and granulated with ethanol, it was shown that the tablet hardness was increased by humidification drying. In addition, the tablet of Example 23 was maintained at a sufficient hardness of 21 N even when left for several days at 25 ° C. and 75% RH after humidification drying. Furthermore, the hardness of the preparations obtained by leaving the tablets produced in Example 26 and Example 27 at 25 ° C. and 85% RH for several days at 25 ° C. and 75% RH were 28 N and 30 N in Example 26 and Example 27, respectively. It was. From this, if sugar that does not become amorphous is added to glucono-δ-lactone, the hardness is clearly higher at 85% RH than 75% RH, and the return at 75% RH is not large. It has been found that tablets that can maintain the hardness in the package storage state and can sufficiently withstand use in the market can be obtained.
　以上に開示された実施の形態と実施例はすべての点で例示であって制限的なものではないと考慮されるべきである。本発明の範囲は、以上の説明ではなく、請求の範囲によって示され、請求の範囲と均等の意味及び範囲内でのすべての変形を含むものである。 It should be considered that the embodiments and examples disclosed above are illustrative and non-restrictive in every respect. The scope of the present invention is defined by the terms of the claims, rather than the description above, and includes all modifications within the scope and meaning equivalent to the terms of the claims.

Claims (19)

  1. 　グルコン酸、グルコン酸の水和物、グルコン酸の塩、グルコン酸の塩の水和物、グルコノ－δ－ラクトン、グルコノ－δ－ラクトンの水和物、グルコノ－δ－ラクトンの塩、グルコノ－δ－ラクトンの塩の水和物、グルクロノラクトン、及びグルクロン酸からなる群から選ばれた少なくとも１つと、薬物及び／又は薬物含有機能性微粒子とを混合して混合物を得る混合工程と、
    　前記混合工程において得られた混合物を圧縮成形して成形物を得る圧縮成形工程と、
    　前記圧縮成形工程において圧縮成形された成形物の少なくとも表面又は内部を液化する液化工程と、
    　前記液化工程において少なくとも表面又は内部が液化された成形物を固化する固化工程とを含む、錠剤の製造方法。     Gluconic acid, gluconic acid hydrate, gluconic acid salt, gluconic acid salt hydrate, glucono-δ-lactone, glucono-δ-lactone hydrate, glucono-δ-lactone salt, glucono- a mixing step of mixing at least one selected from the group consisting of a salt hydrate of δ-lactone, glucuronolactone, and glucuronic acid with a drug and / or drug-containing functional fine particles to obtain a mixture;
    A compression molding step to obtain a molded product by compression molding the mixture obtained in the mixing step;
    A liquefaction step of liquefying at least the surface or the inside of the molded product compression-molded in the compression molding step;
    The tablet manufacturing method including the solidification process which solidifies the molding by which the surface or the inside was liquefied in the said liquefaction process.
  2. 　前記液化工程は、前記圧縮成形工程において圧縮成形された成形物を加湿する工程である、請求項１に記載の製造方法。 The manufacturing method according to claim 1, wherein the liquefaction step is a step of humidifying the molded product compression-molded in the compression molding step.
  3. 　前記固化工程は、前記液化工程において少なくとも表面又は内部が液化された成形物を乾燥する工程である、請求項１又は請求項２に記載の製造方法。 The manufacturing method according to claim 1 or 2, wherein the solidification step is a step of drying a molded product whose surface or inside is liquefied at least in the liquefaction step.
  4. 　非晶質になり得る糖類、非晶質になり得る糖アルコール類、吸湿性の強い結合剤、崩壊剤、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖類、または、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖アルコールの少なくとも１つを添加する工程をさらに含む、請求項１から請求項３までのいずれか１項に記載の製造方法。 Saccharides that can be amorphous, sugar alcohols that can be amorphous, strong hygroscopic binders, disintegrants, non-amorphous saccharides that exhibit hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH, Alternatively, the method further comprises the step of adding at least one non-amorphous sugar alcohol that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH. The manufacturing method as described.
  5. 　前記吸湿性の強い結合剤は、２５℃７５％ＲＨの保存条件で吸湿性を有するものである、請求項４に記載の製造方法。 The manufacturing method according to claim 4, wherein the highly hygroscopic binder is hygroscopic under storage conditions of 25 ° C and 75% RH.
  6. 　前記吸湿性の強い結合剤は、ポビドン、コポリビドン、あるいはポリビニルアルコール－ポリエチレングリコールブロックコポリマーからなる群から選ばれる少なくとも１つである、請求項４又は請求項５に記載の製造方法。 The production method according to claim 4 or 5, wherein the highly hygroscopic binder is at least one selected from the group consisting of povidone, copolyvidone, or polyvinyl alcohol-polyethylene glycol block copolymer.
  7. 　前記崩壊剤は、酸素以外のヘテロ原子あるいはナトリウムイオン、カルシウムイオン、マグネシウムイオンの少なくともいずれかの無機イオンを含有する高分子である、請求項４に記載の製造方法。 The production method according to claim 4, wherein the disintegrant is a polymer containing a hetero atom other than oxygen or at least one inorganic ion of sodium ion, calcium ion, and magnesium ion.
  8. 　前記崩壊剤は、クロスポビドン、カルメロースカルシウム、クロスカルメロースナトリウム、及び、デンプングリコール酸ナトリウムからなる群から選ばれる少なくとも１つである、請求項４又は請求項７に記載の製造方法。 The production method according to claim 4 or 7, wherein the disintegrant is at least one selected from the group consisting of crospovidone, carmellose calcium, croscarmellose sodium, and sodium starch glycolate.
  9. 　前記非晶質になり得る糖類又は前記非晶質になり得る糖アルコール類は、ソルビトール、マルトース、ラクチトール、ブドウ糖、乳糖、及び、トレハロースからなる群から選ばれる少なくとも１つである、請求項４に記載の製造方法。 The sugar that can be amorphous or the sugar alcohol that can be amorphous is at least one selected from the group consisting of sorbitol, maltose, lactitol, glucose, lactose, and trehalose. The manufacturing method as described.
  10. 　前記２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖類、または、前記２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖アルコールは、マンニトール、エリスリトール、マルチトール、及び、キシリトールからなる群から選ばれる少なくとも１つである、請求項４に記載の製造方法。 The non-amorphous saccharide that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH, or the non-amorphous sugar alcohol that exhibits hygroscopicity under storage conditions above 25 ° C. and 75% RH, The production method according to claim 4, which is at least one selected from the group consisting of mannitol, erythritol, maltitol, and xylitol.
  11. 　薬物及び／又は薬物含有機能性微粒子と、
    　グルコン酸、グルコン酸の水和物、グルコン酸の塩、グルコン酸の塩の水和物、グルコノ－δ－ラクトン、グルコノ－δ－ラクトンの水和物、グルコノ－δ－ラクトンの塩、グルコノ－δ－ラクトンの塩の水和物、グルクロノラクトン、及び、グルクロン酸からなる群から選ばれた少なくとも１つとを含み、
    　前記薬物及び／又は前記薬物含有機能性微粒子の含有量が５０％以上である、錠剤。     A drug and / or a drug-containing functional fine particle;
    Gluconic acid, gluconic acid hydrate, gluconic acid salt, gluconic acid salt hydrate, glucono-δ-lactone, glucono-δ-lactone hydrate, glucono-δ-lactone salt, glucono- hydrate of a salt of δ-lactone, glucuronolactone, and at least one selected from the group consisting of glucuronic acid,
    A tablet in which the content of the drug and / or the drug-containing functional fine particles is 50% or more.
  12. 　口腔内崩壊錠である、請求項１１に記載の錠剤。 The tablet according to claim 11, which is an orally disintegrating tablet.
  13. 　非晶質になり得る糖類、非晶質になり得る糖アルコール類、吸湿性の強い結合剤、崩壊剤、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖類、または、２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖アルコールの少なくとも１つを含む、請求項１１又は請求項１２に記載の錠剤。 Saccharides that can be amorphous, sugar alcohols that can be amorphous, strong hygroscopic binders, disintegrants, non-amorphous saccharides that exhibit hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH, Alternatively, the tablet according to claim 11 or 12, comprising at least one sugar alcohol that does not become amorphous and exhibits hygroscopicity under storage conditions exceeding 25 ° C and 75% RH.
  14. 　前記吸湿性の強い結合剤は、２５℃７５％ＲＨの保存条件で吸湿性を有するものである、請求項１３に記載の錠剤。 The tablet according to claim 13, wherein the highly hygroscopic binder has hygroscopicity under storage conditions of 25 ° C and 75% RH.
  15. 　前記吸湿性の強い結合剤は、ポビドン、コポリビドン、あるいはポリビニルアルコール－ポリエチレングリコールブロックコポリマーからなる群から選ばれる少なくとも１つである、請求項１３又は請求項１４に記載の錠剤。 The tablet according to claim 13 or 14, wherein the highly hygroscopic binder is at least one selected from the group consisting of povidone, copolyvidone, or polyvinyl alcohol-polyethylene glycol block copolymer.
  16. 　前記崩壊剤は、酸素以外のヘテロ原子あるいはナトリウムイオン、カルシウムイオン、マグネシウムイオンの少なくともいずれかの無機イオンを含有する高分子である、請求項１３に記載の錠剤。 The tablet according to claim 13, wherein the disintegrant is a polymer containing a hetero atom other than oxygen or at least one inorganic ion of sodium ion, calcium ion, and magnesium ion.
  17. 　前記崩壊剤は、クロスポビドン、カルメロースカルシウム、クロスカルメロースナトリウム、及び、デンプングリコール酸ナトリウムからなる群から選ばれる少なくとも１つである、請求項１３又は請求項１６に記載の錠剤。 The tablet according to claim 13 or 16, wherein the disintegrant is at least one selected from the group consisting of crospovidone, carmellose calcium, croscarmellose sodium, and sodium starch glycolate.
  18. 　前記非晶質になり得る糖類又は前記非晶質になり得る糖アルコール類は、ソルビトール、マルトース、ラクチトール、ブドウ糖、乳糖、及び、トレハロースからなる群から選ばれる少なくとも１つである、請求項１３に記載の錠剤。 The sugar that can be amorphous or the sugar alcohol that can be amorphous is at least one selected from the group consisting of sorbitol, maltose, lactitol, glucose, lactose, and trehalose. The tablet described.
  19. 　前記２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖類、または、前記２５℃７５％ＲＨを超える保存条件で吸湿性を発現する非晶質化しない糖アルコールは、マンニトール、エリスリトール、マルチトール、及び、キシリトールからなる群から選ばれる少なくとも１つである、請求項１３に記載の錠剤。 The non-amorphous saccharide that exhibits hygroscopicity under storage conditions exceeding 25 ° C. and 75% RH, or the non-amorphous sugar alcohol that exhibits hygroscopicity under storage conditions above 25 ° C. and 75% RH, The tablet according to claim 13, which is at least one selected from the group consisting of mannitol, erythritol, maltitol, and xylitol.
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