WO2020246120A1 - Orally disintegrating tablet and manufacturing method therefor - Google Patents

Orally disintegrating tablet and manufacturing method therefor Download PDF

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Publication number
WO2020246120A1
WO2020246120A1 PCT/JP2020/014429 JP2020014429W WO2020246120A1 WO 2020246120 A1 WO2020246120 A1 WO 2020246120A1 JP 2020014429 W JP2020014429 W JP 2020014429W WO 2020246120 A1 WO2020246120 A1 WO 2020246120A1
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WIPO (PCT)
Prior art keywords
tablet
orally disintegrating
powder
acetaminophen
disintegrating tablet
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PCT/JP2020/014429
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French (fr)
Japanese (ja)
Inventor
祐介 瀧上
実己 山下
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あゆみ製薬株式会社
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Priority to JP2021524680A priority Critical patent/JP7360460B2/en
Publication of WO2020246120A1 publication Critical patent/WO2020246120A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K47/22—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
    • A61K47/36—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
    • 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
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods

Definitions

  • the present invention relates to an orally disintegrating tablet (hereinafter, also referred to as OD tablet) containing a high concentration of acetaminophen. More specifically, the present invention relates to an orally disintegrating tablet which is excellent in tablet hardness and rapid disintegration in the oral cavity while containing acetaminophen in a high concentration. Furthermore, the present invention relates to a method for producing the orally disintegrating tablet.
  • Orally disintegrating tablets are generally tablets that disintegrate and dissolve in a short time with saliva without taking water in the oral cavity.
  • the orally disintegrating tablet is required to have a tablet hardness that can sufficiently withstand the impact that can be received in the manufacturing and distribution processes.
  • it is generally practiced to increase the porosity of tablets in addition to adding disintegrants and excipients to the tablet components.
  • Patent Document 1 relates to a rapidly disintegrating tablet (particularly, an orally disintegrating tablet) having a "porous structure" by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide. ..
  • Patent Document 1 discloses a tablet having a porosity of 30% or more and 50% or less as an example of a tablet having a "porous structure".
  • Patent Document 2 discloses a method for producing an orally disintegrating tablet, which comprises a specific component and has a porosity of 10 to 40%, preferably 20 to 40%.
  • Patent Document 8 discloses an orally disintegrating tablet having a porosity of 20 to 40% by undergoing a humidification and drying step during the manufacturing process.
  • Patent Document 9 describes a mixture containing at least one water-soluble saccharide selected from mannitol, xylitol and erythritol as a formulation component and water to the extent that the particle surface of the saccharide is moistened, at a pressure of 3 to 160 kg / cm 2. Disclosed is a step of obtaining a tablet having a porosity of 20 to 80% by a step of tableting and drying.
  • Acetaminophen is a useful bioactive drug with antipyretic analgesic action that has been used for a long time, and is frequently used by patients of all ages as a pharmaceutical ingredient with few side effects. In general, for adults, 300 to 1000 mg of acetaminophen is orally administered at a time, and the maximum daily dose is 4000 mg / day.
  • the acetaminophen tablets currently on the market include 500 mg tablets, 300 mg tablets and 200 mg tablets having different amounts of active ingredients, and the tablets tend to be large in size due to the high content of acetaminophen. Therefore, miniaturized tablets and orally disintegrating tablets have been developed so that even children and the elderly with weak swallowing ability can easily take them. Examples of small tablets include the tablets disclosed in Patent Documents 3 and 4.
  • Patent Document 3 contains 70 to 85% by mass of acetaminophen, 5 to 15% by mass of crystalline cellulose, and 5 to 10% by mass of hydroxypropyl cellulose, and does not contain Nantenjitsu extract.
  • a circular tablet having a convex surface of 7 to 10 mm in diameter.
  • Patent Document 4 describes a step of blending a dispersant, a lubricant and other additives with unground acetaminophen, and at least once before blending the additives or after blending each additive.
  • the use of unground acetaminophen for the production of tablets which comprises the steps of crushing and sizing to disperse and adhere additives to the surface of acetaminophen particles.
  • Patent Document 5 discloses an oral solid preparation containing acetaminophen containing one or two amino acids selected from the group consisting of (a) glutamic acid and aspartic acid and sucralose.
  • Patent Document 6 describes a bitterness reduction composed of acetaminophen having a crystal particle size of about 100 to about 500 ⁇ m and an essential oil, an essential oil and a high sweetness sweetener, or an essential oil, a high sweetness sweetener and an acidic phospholipid or a lyso form thereof.
  • an orally rapidly disintegrating tablet characterized by containing an ingredient.
  • Patent Document 7 is a method for producing an orally disintegrating tablet containing a disintegrating particle composition and a medicinal ingredient, wherein the first disintegrant component composed of acid-type carboxymethyl cellulose and the second disintegrant component composed of crospovidone.
  • the first wet granulation step and the first wet granulation step which are carried out by spraying water or a spray liquid using water as a solvent, using any two components of the excipient consisting of sugar or sugar alcohol.
  • a second wet granulation step performed by spraying water or a spray liquid using water as a solvent using at least one of the granules obtained in the granulation step and the remaining one component not used in the first wet granulation step.
  • the disintegrating particle composition is produced by a granulation method of at least two steps including, and the mixture containing the disintegrating particle composition and the medicinal ingredient is tableted, and the content of the medicinal ingredient is 40 weight by weight. % Or more, and the distribution coefficient of the medicinal ingredient alone is ⁇ 6.0 to 10.0.
  • Japanese Patent No. 6098634 Japanese Patent No. 5721093 Japanese Patent No. 5499599 JP-A-2018-90638 Japanese Unexamined Patent Publication No. 2014-133728 Japanese Patent No. 3389205 Japanese Patent No. 6302921 Japanese Unexamined Patent Publication No. 2000-95674 JP-A-2008-133294
  • Acetaminophen is commonly used as an antipyretic analgesic for patients of all ages, and there is a need for an orally disintegrating tablet that can be easily taken.
  • acetaminophen has a very low drug price, so the price of the additives to be blended is often higher. Therefore, it is important to contain acetaminophen at a high concentration and reduce the amount of the additive to be added in order to reduce the production cost.
  • the tablets described in Patent Documents 3 and 4 contain a high concentration of acetaminophen, but are not manufactured as orally disintegrating tablets.
  • the oral solid preparation of Patent Document 5 is an orally disintegrating tablet, and the concentration of acetaminophen is 60%.
  • the orally disintegrating tablet described in Patent Document 6 contains about 25% of acetaminophen and about 150 mg in one tablet, and the content of acetaminophen in one tablet is not practically sufficient.
  • the orally disintegrating tablet produced by the method described in Patent Document 7 contains 40 to 50% of acetaminophen and 100 m to 150 mg in one tablet, and the content of acetaminophen in one tablet is practical. Not enough. Further, the method for producing an orally disintegrating tablet described in Patent Document 7 includes at least two wet granulation steps and is complicated.
  • the present invention provides an orally disintegrating tablet having a tablet hardness of 50 N or more and a practical rapid disintegrating property in the oral cavity while containing acetaminophen in a high concentration of 75% by mass or more. It is an issue to be done. Furthermore, the present invention is a problem to be solved to provide an orally disintegrating tablet having a good feeling of administration. An object of the present invention is to provide an orally disintegrating tablet in which the bitterness of acetaminophen is suppressed. In addition, the present invention is a problem to be solved to provide a method for producing the orally disintegrating tablet.
  • the disintegration time measured by dropping an artificial saliva aqueous solution onto an orally disintegrating tablet under the conditions of a liquid feeding rate of 6 mL / min, a dropping height of 80 mm, and a load of 10 g is within 30 seconds.
  • the orally disintegrating tablet according to. [3] The orally disintegrating tablet according to [1] or [2], which has a porosity of less than 20%.
  • An orally disintegrating tablet according to any one of [1] to [6], wherein the crystalline cellulose has a bulk density in the range of 0.10 to 0.15 g / cm 3 .
  • the disintegrant is any one selected from the group consisting of partially pregelatinized starch, crospovidone, croscarmellose sodium, and sodium starch glycolate, according to any one of [1] to [7].
  • the orally disintegrating tablet according to any one of [5] to [8], wherein the sweetening agent is any one selected from the group consisting of aspartame, saccharin, stevia, acesulfame potassium and sucralose.
  • the above-mentioned fragrance is a powder fragrance, which is selected from the group consisting of grapefruit flavor, menthol flavor, menthol powder, peppermint powder, grapefruit extract powder, lemon powder, apple powder, strawberry powder and giant peak powder.
  • the orally disintegrating tablet according to any one of [5] to [9].
  • an orally disintegrating tablet having a tablet hardness of 50 N or more and a practical rapid disintegrating property in the oral cavity while containing acetaminophen in a high concentration. Further, according to the present invention, it is possible to provide an orally disintegrating tablet containing acetaminophen with suppressed bitterness. In addition, according to the present invention, it is possible to provide a method for producing an orally disintegrating tablet which is simple and has a low production cost by adopting a direct tableting method.
  • FIG. 1 shows an electron microscope image of Example 11.
  • the magnification of the upper electron microscope image is 100 times, and the lower one is 300 times.
  • FIG. 2 shows an electron microscope image of Comparative Example 3.
  • the magnification of the upper electron microscope image is 100 times, and the lower one is 300 times.
  • FIG. 3 shows an electron microscope image of Comparative Example 7.
  • the magnification of the upper electron microscope image is 100 times, and the lower one is 300 times.
  • FIG. 4 is a Raman imaging image of the acetaminophen tablet of Example 11.
  • FIG. 5 is a Raman imaging image of the acetaminophen tablet of Comparative Example 3.
  • the numerical range represented by using “-” means a range including the numerical values before and after "-" as the lower limit value and the upper limit value.
  • the present invention is an orally disintegrating tablet containing acetaminophen having a median particle size in the range of 80 to 300 ⁇ m, highly moldable crystalline cellulose, and a disintegrant, and is contained in one tablet of the acetaminophen.
  • the present invention relates to an orally disintegrating tablet having a rate of 75% by mass or more, a content in one tablet of 190 mg or more, and a tablet hardness of 50 N or more.
  • the bioactive drug in the orally disintegrating tablet of the present invention is acetaminophen.
  • Acetaminophen is an antipyretic analgesic and is used as a symptomatic treatment for fever, chills, headache, etc.
  • the orally disintegrating tablet has practically sufficient disintegration or solubility (also referred to as practical orally rapid disintegration in the present specification) by saliva without taking water in the oral cavity. Means a tablet to have.
  • the orally disintegrating tablet is also called an OD tablet. The method for producing the orally disintegrating tablet of the present invention will be described later.
  • the median particle size (D50) of the acetaminophen drug substance (hereinafter, the present acetaminophen drug substance) used in the orally disintegrating tablet of the present invention is in the range of 80 to 300 ⁇ m, preferably in the range of 100 to 250 ⁇ m. , More preferably in the range of 100 to 200 ⁇ m.
  • the particle size distribution of the acetaminophen drug substance is such that D10 is in the range of 5 to 100 ⁇ m, preferably 10 to 100 ⁇ m, more preferably 20 to 100 ⁇ m, and D90 is in the range of 200 to 500 ⁇ m. It is preferably in the range of 250 to 400 ⁇ m, more preferably in the range of 250 to 350 ⁇ m.
  • the volume average particle size (MV) of the present acetaminophen drug substance can be in the range of 80 to 300 ⁇ m, and may be in the range of 100 to 250 ⁇ m.
  • the particle size distribution in the present invention is obtained by volume distribution evaluation using a dry particle size measurement (Laser Micron Sizer LMS-2000e (Seishin Enterprise Co., Ltd.)) by a laser diffraction method, and D10, D50, and D90 are particle size distributions.
  • the particle size is 10%, 50%, and 90% of the cumulative volume from the small diameter side of the particle size. In particular, D50 is called the median particle size.
  • the acetaminophen drug substance can be used that has not been pulverized after crystallization.
  • the acetaminophen drug substance may be one that has not undergone special treatment after crystallization, or may be one that has been sieved after crystallization.
  • the acetaminophen drug substance is sieved after crystallization. This is to obtain a powder containing more particles having a particle size suitable for producing the orally disintegrating tablet of the present invention by sieving.
  • the acetaminophen content in the orally disintegrating tablet of the present invention is 75% by mass or more. This is because if the content of acetaminophen is 75% by mass or more, the tablet does not become excessively large even if 200 to 500 mg of acetaminophen is contained in one tablet.
  • orally disintegrating tablets when the size of the tablet is increased, a large amount of saliva is required at the time of disintegrating in the oral cavity, which causes an adverse effect of reducing the feeling of taking.
  • the content of acetaminophen in one tablet is in the range of 75 to 95% by mass, in the range of 75 to 94% by mass, in the range of 75 to 93% by mass, in the range of 75 to 92% by mass, and in the range of 75 to 91% by mass. , 75 to 90% by mass, 75 to 89% by mass, 80 to 95% by mass, 80 to 94% by mass, 80 to 93% by mass, 80 to 92. It may be in the range of mass%, 80 to 91% by mass, 80 to 90% by mass, or 80 to 89% by mass.
  • containing acetaminophen at a high concentration means that the content of acetaminophen in one tablet is high (for example, the content is 75% by mass or more).
  • the acetaminophen content in the orally disintegrating tablet may be 80% by mass or more, or 85% by mass or more.
  • an orally disintegrating tablet having an acetaminophen content of 500 mg it may be particularly preferable that the content is 85% or more.
  • the orally disintegrating tablet of the present invention has a content of acetaminophen in one tablet of 190 mg or more.
  • a content of acetaminophen in one tablet of 190 mg or more.
  • 300 to 500 mg of acetaminophen is orally administered at a time, so if the content in one tablet is 190 mg or more, one or two tablets may be taken at a time, which is practical. Is.
  • crystalline cellulose there are various types of crystalline cellulose, and in general, they are used properly according to various uses such as disintegrants, excipients, and binders.
  • highly moldable crystalline cellulose can be used as a component added to enhance the moldability of tablets.
  • the highly moldable crystalline cellulose contained in the orally disintegrating tablet of the present invention is a crystalline cellulose having a bulk density in the range of 0.10 to 0.23 g / cm 3 .
  • the bulk density can be measured according to the bulk density measuring method described in "16th Revised Japanese Pharmacopoeia, 3. Powder Physical Property Measuring Method, 3.01 Bulk Density and Tap Densitometry".
  • the highly moldable crystalline cellulose of the present invention may have an average particle size in the range of 20 to 100 ⁇ m.
  • Examples of crystalline cellulose products having such an average particle size and bulk density include, but are not limited to, Theoras (registered trademark) KG-802, OD20-P and KG-1000 (Asahi Kasei Corporation).
  • crystalline cellulose it is preferable to use crystalline cellulose.
  • crystalline cellulose having a high aspect ratio This is because the long and thin shape makes it easy to get entangled and the moldability is good.
  • Examples of the crystalline cellulose product having a more preferable bulk density include, but are not limited to, Theoras (registered trademark) KG-1000 (Asahi Kasei Corporation).
  • the orally disintegrating tablet of the present invention can contain more than 8.5% by mass of highly moldable crystalline cellulose in one tablet.
  • By increasing the content of highly moldable crystalline cellulose in one tablet to more than 8.5% by mass it is possible to produce a tablet having a tablet hardness that can sufficiently withstand the impact that can be received in the production and distribution processes.
  • the present inventors even when acetaminophen is contained in a high concentration (85% by mass), by containing more than 8.5% by mass of highly moldable crystalline cellulose, 50 N or more. It was shown that an orally disintegrating tablet having hardness can be produced.
  • the content of highly moldable crystalline cellulose in one tablet is 8.6% by mass or more, 8.7% by mass or more, 8.8% by mass or more, 8.9% by mass or more, 9.0% by mass or more, It may be 9.5% by mass or more or 10.0% by mass or more.
  • the content of highly moldable crystalline cellulose in one tablet may be 20% by mass or less, 19% by mass or less, 18% by mass or less, 17% by mass or less, 16% by mass or less, 15% by mass. It can be less than or equal to 14.5% by mass or less.
  • the orally disintegrating tablet of the present invention has a tablet hardness of 50 N or more, and may be 51 N or more, 52 N or more, 53 N or more, 54 N or more, 55 N or more, 56 N or more, 57 N or more, 58 N or more, 59 N or more, or 60 N or more.
  • the upper limit of tablet hardness is not particularly limited, but may be 150 N or less, or 100 N or less.
  • the tablet hardness can be measured using a load cell type tablet hardness tester (PC-10, Okada Seiko Co., Ltd.) or the like.
  • Disintegrants include, but are limited to, partially pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, carmellose, sodium carboxymethyl starch, gelatin, starch, corn starch, and potato starch. It is not something that is done.
  • the disintegrant is preferably any one selected from the group consisting of partially pregelatinized starch, crospovidone, croscarmellose sodium, and sodium starch glycolate.
  • the disintegrant can be used in any combination of one or more.
  • the orally disintegrating tablet of the present invention contains a disintegrant in the range of 1.0 to 7.0% by mass, preferably 2.0 to 6.0% by mass in one tablet, and more preferably in one tablet. It can be contained in the range of 2.5 to 5.5% by mass.
  • the orally disintegrating tablet of the present invention can further contain a sweetener.
  • a sweetener include, but are not limited to, aspartame, saccharin, stevia, acesulfame potassium, sucralose, fructose, xylitol, sucrose, glucose, maltitol and the like.
  • the sweetener is preferably any one selected from the group consisting of aspartame, saccharin, stevia, acesulfame potassium and sucralose.
  • the sweetener can be used in any combination of one or more.
  • the orally disintegrating tablet of the present invention contains a sweetener in the range of 0.1 to 6.0% by mass, preferably 0.5 to 5.0% by mass in one tablet, and more preferably in one tablet. It can be contained in the range of 0.7 to 4.0% by mass.
  • the orally disintegrating tablet of the present invention can further contain a fragrance.
  • a powder fragrance can be used.
  • the powdered fragrance include, but are not limited to, grapefruit flavor, menthol flavor, menthol powder, peppermint powder, grapefruit extract powder, lemon powder, apple powder, strawberry powder, and giant peak powder. ..
  • the powder flavor can be used in any combination of one type or two or more types.
  • the orally disintegrating tablet of the present invention contains a powdered flavor in the range of 0.1 to 4.0% by mass, preferably 0.2 to 3.0% by mass in one tablet, and more preferably one tablet. It can be contained in the range of 0.3 to 2.0% by mass.
  • the orally disintegrating tablet of the present invention can further contain additives other than the above-mentioned highly moldable crystalline cellulose, disintegrant, sweetener, flavor and flavoring agent (hereinafter, other additives).
  • additives include excipients such as D-mannitol and lactose, lubricants such as magnesium stearate, light anhydrous silicic acid, anhydrous silicon dioxide, calcium silicate, hydrous silicon dioxide and magnesium aluminometasilicate and the like.
  • examples thereof include a fluidizing agent, a stabilizer such as cyclodextrin, and a colorant, but the present invention is not limited to these, and general additives used in the manufacture of pharmaceutical products can be used.
  • a lubricant and a fluidizing agent When a lubricant and a fluidizing agent are contained, they can be contained in the range of 0.1 to 2.0% by mass or 0.1 to 1.0% by mass in one tablet, respectively.
  • the orally disintegrating tablet is, as described above, a tablet having practically sufficient disintegration or solubility by saliva without taking water in the oral cavity.
  • Practically sufficient disintegration or solubility means that it usually disintegrates or dissolves in the oral cavity in about 1 to 300 seconds, 1 to 150 seconds, 1 to 90 seconds, 1 to 60 seconds, and 1 to 30 seconds. is there. It is a tablet having a disintegration time of 1 to 300 seconds, 1 to 150 seconds, 1 to 90 seconds, 1 to 60 seconds, and 1 to 30 seconds measured by a tricorp tester (registered trademark).
  • the disintegration time measured by Tricorp Tester® has been reported to correlate with the actual disintegration time in the human oral cavity (Yohei Hoashi, on formulation technology using a dry process and development of orally disintegrating tablets). Research, 2013 dissertation, Gifu Pharmaceutical University).
  • the disintegration time measured by Tricorp Tester (registered trademark) is as high as 6 mL / min of artificial saliva aqueous solution at 37 ⁇ 0.5 ° C. on a tablet sandwiched between two wire meshes. It is the time (disintegration time) until the tablet is dropped from 80 mm and the tablet is disintegrated and the two wire meshes are in contact with each other, and the weight (load) of the wire mesh placed on the tablet is 10 g.
  • the components of the artificial saliva aqueous solution are as shown in Table 2 of Examples.
  • the orally disintegrating tablets of the invention have a disintegration time of 30 seconds, 25 seconds, 20 seconds, 15 seconds, or 10 seconds as measured using a Tricorp Tester®. It may be within. In another embodiment, for the orally disintegrating tablets of the present invention, the disintegration time measured using a Tricorp Tester® is 1 to 30 seconds, 1 to 25 seconds, 1 to 20 seconds, 1 to 15 seconds. , Or 1 to 10 seconds.
  • the orally disintegrating tablet of the present invention can have a porosity of less than 25%, and may be 24% or less, 23% or less, 22% or less, 21% or less, 20% or less, 19% or less.
  • the orally disintegrating tablet of the present invention may have a porosity of 1% or more, 2% or more, 3% or more, 4% or more or 5% or more.
  • the orally disintegrating tablet of the present invention has a range of 1% or more and less than 25%, a range of 1% or more and 24% or less, a range of 2% or more and 23% or less, a range of 2% or more and 22% or less, and a range of 3% or more and 22%.
  • It may have a porosity in the following range, 4% or more and 21% or less, or 5% or more and 20% or less.
  • the presence or absence of pores is very important for the physical properties of the tablet, and when the tablet comes into contact with water or saliva, it causes a capillary phenomenon and guides water to the inside of the tablet, which greatly contributes to elution and disintegration.
  • the pore distribution by the mercury intrusion method can be measured using a PoreMaster 60GT (Anton Paar Japan).
  • the orally disintegrating tablet of the present invention can have a porosity of less than 20%, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12 % Or less, 11% or less, 10% or less.
  • the orally disintegrating tablet of the present invention may have a porosity of 1% or more, 2% or more, 3% or more, 4% or more or 5% or more.
  • the orally disintegrating tablet of the present invention has a range of 1% or more and less than 20%, a range of 1% or more and 19% or less, a range of 2% or more and 18% or less, a range of 2% or more and 17% or less, and a range of 3% or more and 16%. It may have a porosity in the following range, 4% or more and 16% or less, or 5% or more and 15% or less.
  • V Volume of disintegrating tablet (cm 3 )
  • W Mass of disintegrating tablet (g)
  • M Density of disintegrating tablet (g / cm 3 )
  • the difference is that the mercury intrusion method measures the pores through which water can flow, while the pycnometer measures all the voids in the entire tablet. Therefore, the porosity based on the mercury intrusion method indicates the proportion of pores distributed in the tablet, and the porosity based on the pycnometer indicates the proportion of voids in the entire tablet.
  • the orally disintegrating tablets disclosed in Patent Documents 1, 2, 8 and 9 all achieve a desired orally disintegrating time by having a porosity of 20% or more.
  • the porosity of the orally disintegrating tablet of the present invention is less than 10%, which is lower than that of the conventional orally disintegrating tablet. From the component mapping by the Raman imaging image of the tablet surface, it was observed that a part of the disintegrant was exposed on the tablet surface in the orally disintegrating tablet of the present invention, but in the comparative tablet, the disintegrant was on the tablet surface.
  • the present invention provides an acetaminophen-containing orally disintegrating tablet in which bitterness is suppressed.
  • Acetaminophen has a peculiar bitterness.
  • Bitterness is a general term for unpleasant discomfort including bitterness and astringency felt in the oral cavity and pharynx.
  • "suppression of bitterness” means that the bitterness felt when a bitter substance is present in the oral cavity is suppressed, reduced, concealed or masked, and unpleasant discomfort including bitterness and astringency is suppressed or reduced. , May include hiding or masking.
  • “Suppression” means that the "bitterness” felt in the oral cavity is somewhat reduced when used, for example, as compared to the case where sweeteners, flavors, flavoring agents and a specific range of acetaminophen of the present invention are not used. It may include the case where the bitterness is not felt at all, or the case where the bitterness is felt to some extent but is acceptable to humans.
  • the bitterness of the orally disintegrating tablet of the present invention can be evaluated by a sensory evaluation test by a panelist and / or device measurement (taste recognition device, taste sensor).
  • the size of the orally disintegrating tablet of the present invention can be in the range of 6 mm to 18 mm in diameter, in the range of aspect ratios 1 to 3, and in the range of 2 mm to 10 mm in thickness, but is not limited to this range.
  • the shape of the orally disintegrating tablet of the present invention may be a normal tablet or an atypical tablet, and may be, for example, a circular shape, an oval shape, or a caplet shape, but is not limited thereto.
  • Another aspect of the present invention is a step of mixing acetaminophen having a median particle size in the range of 80 to 300 ⁇ m, highly moldable crystalline cellulose, and a disintegrant to obtain a powder mixture, and the powder mixture.
  • the present invention relates to a method for producing an orally disintegrating tablet, which comprises a step of directly tableting to obtain a tablet.
  • the production method of the present invention "a step of mixing acetaminophen having a median particle diameter in the range of 80 to 300 ⁇ m, highly moldable crystalline cellulose, and a disintegrant to obtain a powder mixture" (hereinafter referred to as a mixing step).
  • a mixing step Is a step of mixing the bioactive drug acetaminophen of the orally disintegrating tablet with other components before the orally disintegrating tablet is beaten.
  • Other components are highly moldable crystalline celluloses and disintegrants, as well as sweeteners, flavoring agents and / or other additives.
  • mixing means mixing two or more kinds of powders.
  • the term used in the art is “crushing”, which means crushing particles to obtain smaller particles.
  • mixing in the present specification is an operation that does not have the effect of making the particle size of the powder finer.
  • crushing and sizing used in the technical field means peeling off agglomerated particles. In crushing and sizing and crushing, a strong “shearing force” is applied to the powder, but in mixing, the “shearing force” is weak.
  • the mixing step of this production method can be carried out using, for example, a V-type mixer, a container mixer, or the like.
  • the V-type mixer is a device that rotates a V-shaped mixing container to move the powders and granules in the container as a whole and gives a convection motion to perform quick and uniform mixing.
  • the mixing conditions can be appropriately changed depending on the scale, and can be carried out, for example, at a rotation speed of 5 to 50 rpm for about 1 to 15 minutes.
  • the mixing step of this production method may be carried out by one mixing operation, or may be carried out by dividing into two or more mixing operations.
  • the mixing operation is performed once, all the components contained in the orally disintegrating tablet are put into a V-type mixer or the like and mixed.
  • the mixing operation is divided into two or more times, the components contained in the orally disintegrating tablet can be divided into two or more times according to the type and charged and mixed in a V-type mixer or the like.
  • the lubricant for example, magnesium stearate
  • Mixing after adding the lubricant can be about 1 to 3 minutes.
  • a powder mixture can be obtained by the mixing step of this production method.
  • the powder mixture is a powdery aggregate of the components contained in the orally disintegrating tablet.
  • the powder mixture obtained in the above mixing step is directly tableted and molded. It is a process.
  • direct tableting means tableting by a dry method in which a powder mixture is directly compressed using a mortar to obtain tablets.
  • the locking can be performed using a locking machine (for example, a rotary molding machine).
  • a locking machine for example, a rotary molding machine.
  • the powder filled in the fixed mold is volumetrically weighed and the upper and lower molds are pressed. This can be done by compression molding with a (pestle) and finally discharging from a mold (mortar hole).
  • the tableting pressure can be appropriately set in consideration of the tablet hardness, the pressure resistance tolerance of the tableting punch, etc., but is in the range of 3 to 50 kN, preferably in the range of 5 to 40 kN. Can be.
  • the tableting pressure imparts physical strength such as hardness to the tablet, and if the tableting pressure is low, the tablet hardness may be low.
  • increasing the tableting pressure does not mean that the tablet hardness increases accordingly. For example, depending on the component, the tablet hardness may not increase even if the tableting pressure is increased.
  • the locking pressure is high, damage to the locking punch and locking failure (capping, sticking) are likely to occur. Therefore, when tableting, it is necessary to apply pressure according to the characteristics of the tablet.
  • a wet method such as a fluidized bed granulation method is often used.
  • wet granulation requires a large number of steps and the manufacturing cost is high.
  • Acetaminophen drug substance a) Acetaminophen S (Yamamoto Corporation) (hereinafter referred to as AA drug substance a) b) Dense Powder (SpecGx LLC) (hereinafter referred to as AA API b) c) Acetaminophen SS (Yamamoto Corporation) (hereinafter referred to as AA API c) Crosspovidone (CL-F, BASF) Croscarmellose sodium (Kiccolate (registered trademark) ND-200, Asahi Kasei Corporation) Sodium starch glycolate (Primogel, DEF pharma) Partially pregelatinized starch (PCS PC-10, Asahi Kasei Corporation)
  • Crystalline Cellulose (Theoras (registered trademark) KG-1000, Asahi Kasei Corporation) Crystalline Cellulose (Theoras (registered trademark) KG-802, Asahi Kasei Corporation) Crystalline Cellulose (Theoras (registered trademark) PH-101, Asahi Kasei Corporation) Crystalline Cellulose (Theoras (registered trademark) UF-711, Asahi Kasei Corporation) Magnesium stearate (Taipei Chemical Industry) Magnesium aluminate metasilicate (Neucillin UFL2, Fuji Chemical Industry Co., Ltd.) Aspartame (Ajinomoto kk Aspartame, Ajinomoto Healthy Supply Co., Ltd.) Acesulfame Potassium (Sanet D (registered product), Mitsubishi Corporation Life Sciences) Sucralose (Saneigen) D-mannitol (Granitol (registered trademark) S, Freund Sang
  • a V-type mixer (V-10, Tokuju Seisakusho) is used for mixing tableting powder, and a tableting machine (HT-AP15SS-II, Hata Iron Works) is used for tableting. I used a mortar and pestle.
  • the tableting pressure is set so that the tablet hardness is 50 N or more in consideration of the pressure resistance of the tableting punch.
  • Table 1 shows the measurement results of the particle size of the acetaminophen (AA) drug substance.
  • Hardness measurement of tablets A hardness measurement test was carried out on the tablets produced in Examples and Comparative Examples described later. Hardness measurement was carried out using a hardness tester (PC-10, Okada Seiko).
  • Disintegration test of tablets A disintegration test was carried out on the tablets produced in Examples and Comparative Examples described later.
  • an artificial saliva aqueous solution was dropped onto a tablet sandwiched between two wire meshes using an intraoral (fast) disintegrating tablet measuring device, Tricorp Tester (registered trademark) (Okada Seiko), and the tablet disintegrated. Then, the time (collapse time) until the two wire meshes came into contact with each other was measured.
  • the wire mesh placed on the tablet weighed 10 g.
  • the measurement was carried out by dropping an artificial saliva aqueous solution (see Table 2) at 37 ⁇ 0.5 ° C. from a height of 80 mm at a liquid feeding rate of 6 mL / min. The average value of 5 tablets was measured.
  • Example 1 AA drug substance a 80.0 g, crospovidone 5.0 g, magnesium aluminometasilicate 1.0 g, crystalline cellulose (KG-1000) 13.9 g are mixed and stirred in a V-type mixer (rotation speed 42 rpm, mixing time 10). Minutes) to obtain an intermediate tableting powder. 0.1 g of magnesium stearate was added to the intermediate tableting powder, and further mixing and stirring (rotation speed 42 rpm, mixing time 2 minutes) was performed to obtain a tableting powder.
  • the tableting powder was tableted using a tableting machine and a mortar with a diameter of 9 mm (tablet pressure 15 kN) to obtain tablets having a tablet weight of 379 mg, a tablet thickness of 5.29 mm, and a tablet hardness of 74 N.
  • Example 2 AA drug substance b 80.0 g, crospovidone 4.0 g, magnesium aluminometasilicate 1.0 g, crystalline cellulose (KG-1000) 14.3 g, and anhydrous silicon dioxide 0.5 g are mixed and stirred with a V-type mixer. , Intermediate tableting powder was obtained. 0.2 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a mortar with a diameter of 9 mm (tablet pressure 23 kN) to obtain tablets having a tablet weight of 387 mg, a tablet thickness of 5.51 mm, and a tablet hardness of 60 N.
  • Comparative Example 3 AA drug substance c 80.0 g, crospovidone 4.0 g, magnesium aluminometasilicate 1.0 g, crystalline cellulose (KG-1000) 14.30 g, and anhydrous silicon dioxide 0.5 g are mixed and stirred with a V-type mixer. , Intermediate tableting powder was obtained. 0.2 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a mortar with a diameter of 9.0 mm (tablet pressure 24 KN) to obtain tablets having a tablet weight of 387 mg, a tablet thickness of 5.20 mm and a tablet hardness of 60 N.
  • Comparative Example 4 AA drug substance c 70.0 g, D-mannitol 10.0 g, crospovidone 4.0 g, magnesium aluminometasilicate 1.0 g, crystalline cellulose (KG-1000) 14.30 g, anhydrous silicon dioxide 0.5 g, V type The mixture was mixed and stirred with a mixer to obtain an intermediate tableting powder. 0.2 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder.
  • the tableting powder was tableted using a tableting machine and a mortar with a diameter of 9.0 mm (tablet pressure 8 kN) to obtain tablets having a tablet weight of 390 mg, a tablet thickness of 5.75 mm and a tablet hardness of 51 N. Capping of tablets was observed with the lapse of tableting time, and it was found that they were not suitable for production.
  • Comparative Example 5 AA drug substance c 60.0 g, D-mannitol 20.0 g, crospovidone 4.0 g, magnesium aluminometasilicate 1.0 g, crystalline cellulose (KG-1000) 14.30 g, anhydrous silicon dioxide 0.5 g, V type The mixture was mixed and stirred with a mixer to obtain an intermediate tableting powder. 0.2 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder.
  • the tableting powder was tableted using a tableting machine and a mortar with a diameter of 9.0 mm (tablet pressure 9 KN) to obtain tablets having a tablet weight of 375 mg, a tablet thickness of 5.74 mm and a tablet hardness of 55 N.
  • Comparative Example 6 AA drug substance c 50.0 g, D-mannitol 30.0 g, crospovidone 4.0 g, magnesium aluminometasilicate 1.0 g, crystalline cellulose (KG-1000) 14.30 g, anhydrous silicon dioxide 0.5 g, V type The mixture was mixed and stirred with a mixer to obtain an intermediate tableting powder. 0.2 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder.
  • the tableting powder was tableted using a tableting machine and a mortar with a diameter of 9.0 mm (tablet pressure 10 kN) to obtain tablets having a tablet weight of 387 mg, a tablet thickness of 5.73 mm and a tablet hardness of 63 N.
  • Comparative Example 7 AA drug substance c 40.0 g, D-mannitol 40.0 g, crospovidone 4.0 g, magnesium aluminometasilicate 1.0 g, crystalline cellulose (KG-1000) 14.30 g, anhydrous silicon dioxide 0.5 g, V type The mixture was mixed and stirred with a mixer to obtain an intermediate tableting powder. 0.2 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder.
  • the tableting powder was tableted using a tableting machine and a mortar with a diameter of 9.0 mm (tablet pressure 7 kN) to obtain tablets having a tablet weight of 393 mg, a tablet thickness of 6.01 mm and a tablet hardness of 57 N. There is no problem with the tablet hardness of the tablet, but the content does not satisfy the content desired in practical use.
  • Table 3 summarizes the composition and properties of the above tablets.
  • the tablets of Examples 1 and 2 and Comparative Example 3 contained 80% of acetaminophen, but could be directly tableted. Since the particles of the acetaminophen drug substance are fine, the tablets of Comparative Examples 3 to 7 can be tableted by adding anhydrous silicon dioxide as a fluidizing agent, but they have problems such as sticking. It could occur. Tablets with a tablet hardness of less than 50 N are prone to cracking and chipping during transportation and pharmaceutical packaging machines, and have problems from a practical point of view. However, the tablets of Examples 1 and 2 and Comparative Examples 3 to 7 have a tablet hardness of 50 N. Was able to be tableted to have.
  • the disintegration time of the tablet of Example 1 prepared using the AA drug substance a having a median particle size of 185 ⁇ m was 9 seconds, which was practical as an OD tablet.
  • the disintegration time of the tablet of Example 2 prepared using the AA drug substance b having a median particle size of 115 ⁇ m was 24 seconds, which was practical as an OD tablet.
  • the disintegration time of the tablet of Comparative Example 3 prepared by using the AA drug substance c having a median particle size of 26 ⁇ m was 300 seconds or more, which was not practical as an OD tablet.
  • Disintegration of tablets (Comparative Examples 4 to 6) in which the content of acetaminophen was 70% to 50% and the excipient D-mannitol was added in the production example using the AA drug substance c having a median particle size of 26 ⁇ m. Since the time was 30 seconds or more, it was not practical as an OD tablet. On the other hand, the disintegration time of the tablet containing 40% acetaminophen and 40% D-mannitol (Comparative Example 7) was 19 seconds, but the content of acetaminophen was 157 mg in the tablet, which was practically practical. Did not meet the desired content.
  • Example of Production of OD Tablet with High Acetaminophen Content and Example of Production of OD Tablet with Acetaminophen Content of 60 to 75% by Mass Example 8 AA drug substance a 85.0 g, crospovidone 4.0 g, magnesium aluminometasilicate 1.0 g, and crystalline cellulose (KG-1000) 9.85 g are mixed and stirred in a V-type mixer to prepare an intermediate tableting powder. Obtained. 0.15 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder.
  • the tableting powder was tableted using a tableting machine and a mortar with a diameter of 8.5 mm (tablet pressure 26 kN) to obtain tablets having a tablet weight of 238 mg, a tablet thickness of 3.55 mm, and a tablet hardness of 52 N.
  • Example 9 The tableting powder was prepared by the same composition and method as in Example 8 except that the tableting powder was tableted at a tableting pressure of 18 kN using a 9.0 mm diameter pestle. A tablet having a tablet weight of 353 mg, a tablet thickness of 4.85 mm, and a tablet hardness of 61 N was obtained.
  • Example 10 A tableting powder was prepared by the same composition and method as in Example 8 except that the tablet was tableted at a tableting pressure of 18 kN using a mortar having a major axis of 15.0 and a minor axis of 8.0 mm. An oval tablet having a tablet weight of 595 mg, a tablet thickness of 5.79 mm and a tablet hardness of 73 N was obtained.
  • 15.0 g was mixed and stirred with a V-type mixer to obtain an intermediate tableting powder.
  • 0.2 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder.
  • the tableting powder was tableted using a tableting machine and a 9 mm diameter mortar to obtain tablets.
  • Table 4 summarizes the composition and properties of the above tablets.
  • the tablets of Examples 8 to 10 were prepared using AA API a with a median particle size of 185 ⁇ m.
  • the tablets of Examples 8 to 10 contained 85% acetaminophen, but could be directly tableted. Tablets having a tablet hardness of less than 50 N are prone to cracking and chipping in transportation and pharmaceutical packaging machines, which is problematic from a practical point of view. However, the tablets of Examples 8 to 10 are beaten so as to have a tablet hardness of 50 N or more. It was lockable.
  • the disintegration time of the tablets of Examples 8 to 10 was less than 30 seconds, and they had a practical rapid disintegration property in the oral cavity.
  • the tablets of Comparative Examples A and B and Example C were prepared using AA drug substance a having a median particle size of 185 ⁇ m.
  • the tablets of Comparative Examples A and B and Example C were all directly tabletable.
  • the disintegration time of the tablet of Example C containing 75% of acetaminophen was less than 30 seconds, and it had a practical rapid disintegration property in the oral cavity.
  • the disintegration time of the tablets of Comparative Examples A and B containing 70% and 60% of acetaminophen was 30 seconds or more, which was not suitable as an orally disintegrating tablet.
  • Example 11 Production Example containing a sweetener and powder flavor, Production Example in which the disintegrant is changed
  • Example 11 AA drug substance a 80.0 g, crospovidone 4.0 g, magnesium aluminometasilicate 1.0 g, crystalline cellulose (KG-1000) 13.40 g, aspartame 1.0 g and powder fragrance are mixed in a V-type mixer. The mixture was stirred to obtain an intermediate tableting powder. 0.2 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder.
  • the tableting powder was tableted using a tableting machine and a mortar with a diameter of 9.0 mm (tablet pressure 25 kN) to obtain tablets having a tablet weight of 373 mg, a tablet thickness of 5.20 mm and a tablet hardness of 55 N.
  • Example 12 The crospovidone of Example 11 was changed to croscarmellose sodium, and the mixture was prepared and tableted (tablet pressure 21 kN). Tablets having a tablet weight of 383 mg, a tablet thickness of 5.32 mm, and a tablet hardness of 52 N were obtained.
  • Example 13 The crospovidone of Example 11 was changed to sodium starch glycolate, and the mixture was prepared and tableted (tablet pressure 23 kN). Tablets having a tablet weight of 383 mg, a tablet thickness of 5.25 mm, and a tablet hardness of 51 N were obtained.
  • Example 14 AA drug substance a 80.0 g, crospovidone 3.0 g, magnesium aluminometasilicate 1.0 g, crystalline cellulose (KG-1000) 13.40 g, aspartame 0.8 g, sucralose 0.2 g, powder fragrance 0.4 g , Cyclodextrin (3.4 g) was mixed and stirred with a V-type mixer to obtain an intermediate tableting powder. 0.2 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder.
  • the tableting powder was tableted using a tableting machine and a mortar with a diameter of 9.0 mm (tablet pressure 22 kN) to obtain tablets having a tablet weight of 387 mg, a tablet thickness of 5.31 mm and a tablet hardness of 56 N.
  • Example 15 The AA drug substance a of Example 11 was changed to the AA drug substance b, and the mixture was prepared and tableted (tablet pressure 23 kN). Tablets having a tablet weight of 377 mg, a tablet thickness of 5.51 mm, and a tablet hardness of 50 N were obtained.
  • Table 5 summarizes the composition and properties of the above tablets.
  • the tablets of Examples 11 to 15 were produced by reducing the content of crystalline cellulose (KG-1000) and a disintegrant, and adding a sweetener and a powder flavor, as compared with Example 1. Although the tablets of Examples 11 to 15 contain 80% of acetaminophen, they can be directly tableted and can be tableted so as to have a tablet hardness of 50N.
  • the disintegration time of the tablets of Examples 11 to 15 was within 30 seconds, which was practical as an OD tablet. No significant changes were observed in tablet hardness and disintegration time when croscarmellose sodium or sodium starch glycolate was used instead of crospovidone as the disintegrant.
  • AA drug substance a 85.0 g, crospovidone 5.0 g, magnesium aluminometasilicate 1.0 g, and crystalline cellulose (KG-1000) 8.5 g are mixed and stirred with a V-type mixer to prepare an intermediate tableting powder. Obtained. 0.5 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder.
  • the tableting powder was tableted using a tableting machine and a mortar with a diameter of 8.5 mm (tablet pressure 22 kN) to obtain tablets having a tablet weight of 360 mg, a tablet thickness of 4.91 mm and a tablet hardness of 39 N.
  • Example 17 The content of crystalline cellulose (KG-1000) of Comparative Example 16 was changed to 8.65 g, and the content of magnesium stearate was changed to 0.35 g to obtain a tableting powder.
  • the tableting powder was tableted using a tableting machine and a mortar with a diameter of 9 mm (tablet pressure 21 kN) to obtain tablets having a tablet weight of 353 mg, a tablet thickness of 4.80 mm and a tablet hardness of 52 N.
  • Example 18 The content of crystalline cellulose (KG-1000) of Comparative Example 16 was changed to 8.8 g, and the content of magnesium stearate was changed to 0.2 g to obtain a tableting powder.
  • the tableting powder was tableted using a tableting machine and a mortar with a diameter of 9 mm (tablet pressure 23 kN) to obtain tablets having a tablet weight of 352 mg, a tablet thickness of 4.79 mm, and a tablet hardness of 58 N.
  • Example 19 The content of crystalline cellulose (KG-1000) of Comparative Example 16 was changed to 8.9 g, and the content of magnesium stearate was changed to 0.1 g to obtain a tableting powder.
  • the tableting powder was tableted using a tableting machine and a mortar with a diameter of 9 mm (tablet pressure 15 kN) to obtain tablets having a tablet weight of 359 mg, a tablet thickness of 4.96 mm and a tablet hardness of 71 N.
  • Example 20 The content of crospovidone of Comparative Example 16 was changed to 4 g, the content of crystalline cellulose (KG-1000) was changed to 9.8 g, and the content of magnesium stearate was changed to 0.2 g to obtain a tableting powder.
  • the tableting powder was tableted using a tableting machine and a mortar with a diameter of 9 mm (tablet pressure 24 kN) to obtain tablets having a tablet weight of 354 mg, a tablet thickness of 4.79 mm and a hardness of 64 N.
  • Table 6 summarizes the composition and properties of the above tablets.
  • Example 21 AA drug substance a 80.0 g, partially pregelatinized starch 1.0 g, croscarmellose sodium 3.0 g, crystalline cellulose (KG-1000) 10.0 g, magnesium aluminometasilicate 1.0 g, aspartame 3.0 g, assesulfam Mix and stir 0.3 g of potassium, 0.3 g of grapefruit flavor, 0.3 g of menthol flavor and 0.5 g of hydrous silicon dioxide with a V-type mixer (rotation speed 42 rpm, mixing time 10 minutes) to prepare an intermediate tableting powder. Obtained.
  • 0.2 g of magnesium stearate was added to the intermediate tableting powder, and additional mixing and stirring (rotation speed 42 rpm, mixing time 2 minutes) was performed to obtain a tableting powder.
  • the tableting powder was tableted using a tableting machine and a 9 mm diameter mortar.
  • the bulk density of crystalline cellulose KG-1000 is 0.10 to 0.15 g / cm 3 .
  • Comparative Example 22 Tablets were obtained with the same composition as in Example 21 except that the crystalline cellulose was changed to PH-101.
  • the bulk density of crystalline cellulose PH-101 is 0.29 g / cm 3 .
  • Comparative Example 23 Tablets were obtained with the same composition as in Example 21 except that the crystalline cellulose was changed to UF-711.
  • the bulk density of crystalline cellulose UF-711 is 0.22 g / cm 3 .
  • Example 24 Tablets were obtained with the same composition as in Example 21 except that the crystalline cellulose was changed to KG-802.
  • the bulk density of crystalline cellulose KG-802 is 0.21 g / cm 3 .
  • Table 7 summarizes the composition and properties of the above tablets.
  • the tableting pressure was changed to 11 kN, 21 kN, 24 kN, and 27 kN for tableting, and the hardness of the tablet obtained thereby was obtained. Were 32N, 42N, 47N, and 46N, respectively.
  • the tableting pressure was changed to 20 kN, 23 kN, and 25 kN for tableting, and the hardness of the tablet obtained thereby was determined. , 46N, 54N, and 52N, respectively.
  • Example 24 containing KG-802 the tablet hardness did not increase even if the tableting pressure was higher than 23 kN. Therefore, it is considered that a further increase in tablet hardness cannot be expected even if the tableting pressure is further increased to perform tableting.
  • Example 21 containing KG-1000 a practically sufficient tablet hardness was obtained at a tableting pressure of 18 kN.
  • the specific surface area of the orally disintegrating tablet was larger than that of the caronal (registered trademark) tablet 300. It can be said that the larger the specific surface area, the more porous the tablet, and the easier it is for water to be conducted inside the tablet. Since the total pore capacity was small, it was found that there were almost no pores in the submicron region.
  • Table 9 shows the porosities of the tablets of Examples 2 and 11, Comparative Examples 3, 7 and 28 and Caronal® Tablets 300.
  • the porosities of Comparative Example 3 and Comparative Example 28 using the AA drug substance c were 15% and 18%, respectively.
  • the oral disintegration time did not become 30 seconds or less unless the content was lowered to 40% and the content of D-mannitol was increased to increase the porosity to 25% or more (Comparative Example 7). ..
  • the porosities of Example 2 using the AA drug substance b and Example 11 using the AA drug substance a were 19% and 13%, respectively, and tablets produced using the AA drug substance c (Comparative Examples 3 and 28). ) And the porosity were about the same.
  • orally disintegrating tablets are designed to have many pores, which are water passages, in order to achieve rapid disintegration.
  • the orally disintegrating tablets of the present invention (Examples 2 and 11) have a porosity of less than 20% but have physical properties as an orally disintegrating tablets.
  • Tablets produced using AA drug substance a or b have surface pores similar to those of tablets using AA drug substance c, but only when AA drug substance a or b is used in the oral cavity. Since the internal disintegration time of 30 seconds or less can be achieved, it is considered that another factor is involved in the disintegration mechanism of the tablet of the present invention in addition to the porosity.
  • an orally disintegrating tablet containing a high content of the AA drug substance and satisfying the condition that the oral disintegration time was within 30 seconds Conventional orally disintegrating tablets may be manufactured so as to have a porosity of 20% or more to achieve a desired orally disintegrating time (for example, disclosed in Patent Documents 1, 2, 8 and 9). OD tablets).
  • the present invention (Examples 2 and 11). Although the porosity of the orally disintegrating tablet of the present invention is 10% or less, the orally disintegrating time is within 30 seconds, and it is considered that the disintegrating tablet is caused by a mechanism different from that of the conventional orally disintegrating tablet.

Abstract

The present invention addresses the problem of providing an orally disintegrating tablet that includes acetaminophen at a high concentration of 75mass% or more, while having a tablet hardness of 50N or more and having a useful quick oral disintegration property. The present invention provides an orally disintegrating tablet including: acetaminophen with a median grain size in the range 80-300μm; a highly moldable crystalline cellulose; and a disintegrant, wherein the acetaminophen content by percent in one tablet is 75mass% or more, the acetaminophen content by quantity in one tablet is 190mg or more, and the orally disintegrating tablet has a tablet hardness of 50N or more.

Description

口腔内崩壊錠及びその製造方法Orally disintegrating tablets and their manufacturing methods
　本発明は、アセトアミノフェンを高濃度で含有する口腔内崩壊錠（以下、ＯＤ錠とも表記）に関する。より詳細には、アセトアミノフェンを高濃度で含みながら、錠剤硬度及び口腔内速崩壊性に優れた口腔内崩壊錠に関する。さらに、本発明は、前記口腔内崩壊錠の製造方法に関する。 The present invention relates to an orally disintegrating tablet (hereinafter, also referred to as OD tablet) containing a high concentration of acetaminophen. More specifically, the present invention relates to an orally disintegrating tablet which is excellent in tablet hardness and rapid disintegration in the oral cavity while containing acetaminophen in a high concentration. Furthermore, the present invention relates to a method for producing the orally disintegrating tablet.
　近年の医薬品の開発では、有効性や安全性だけではなく、その使用や服用の容易さも重要な要素とされている。医薬品の様々な剤形の中で、錠剤においては服用の容易さから、少量の唾液で速やかに崩壊する口腔内崩壊錠が有用な剤形として研究開発が行われている。 In recent drug development, not only efficacy and safety but also ease of use and administration are important factors. Among various dosage forms of pharmaceuticals, orally disintegrating tablets, which rapidly disintegrate with a small amount of saliva, are being researched and developed as useful dosage forms because of their ease of administration.
　口腔内崩壊錠は一般的に、口腔内で水を服用することなしに、唾液により短時間で崩壊し溶解する錠剤である。また、口腔内崩壊錠は、製造や流通過程で受け得る衝撃に十分に耐えられる錠剤硬度を有することが求められている。このような錠剤物性を満たすためには、錠剤成分に崩壊剤や賦形剤を配合することに加えて、錠剤の空隙率を上げることが一般的に行われている。 Orally disintegrating tablets are generally tablets that disintegrate and dissolve in a short time with saliva without taking water in the oral cavity. In addition, the orally disintegrating tablet is required to have a tablet hardness that can sufficiently withstand the impact that can be received in the manufacturing and distribution processes. In order to satisfy such physical properties of tablets, it is generally practiced to increase the porosity of tablets in addition to adding disintegrants and excipients to the tablet components.
　例えば、特許文献１は、超臨界もしくは亜臨界状態にある二酸化炭素又は液体もしくは気体二酸化炭素にて処理することにより「多孔性構造」を有する、速崩壊性錠剤（特に、口腔内崩壊錠）に関する。特許文献１は、「多孔性構造」を有する錠剤として、空隙率３０％以上５０％以下の錠剤を実施例で開示する。また、特許文献２は、特定成分を含み、空隙率が１０～４０％、好ましくは２０～４０％であることを特徴とする口腔内崩壊錠の製造方法を開示する。特許文献８は製造工程中において加湿と乾燥工程を経ることで２０～４０％の空隙率を有する口腔内崩壊錠を開示する。特許文献９は、処方成分にマンニトール、キシリトール及びエリスリトールから選択された少なくとも１種の水溶性糖類と、前記糖類の粒子表面が湿る程度の水分とを含む混合物を、圧力３～１６０Ｋｇ／ｃｍ2程度で打錠し、乾燥する工程により空隙率２０～８０％の錠剤をえる工程を開示する。　 For example, Patent Document 1 relates to a rapidly disintegrating tablet (particularly, an orally disintegrating tablet) having a "porous structure" by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide. .. Patent Document 1 discloses a tablet having a porosity of 30% or more and 50% or less as an example of a tablet having a "porous structure". Further, Patent Document 2 discloses a method for producing an orally disintegrating tablet, which comprises a specific component and has a porosity of 10 to 40%, preferably 20 to 40%. Patent Document 8 discloses an orally disintegrating tablet having a porosity of 20 to 40% by undergoing a humidification and drying step during the manufacturing process. Patent Document 9 describes a mixture containing at least one water-soluble saccharide selected from mannitol, xylitol and erythritol as a formulation component and water to the extent that the particle surface of the saccharide is moistened, at a pressure of 3 to 160 kg / cm 2. Disclosed is a step of obtaining a tablet having a porosity of 20 to 80% by a step of tableting and drying.
　アセトアミノフェンは古くから用いられている解熱鎮痛作用を持つ有用な生理活性薬物であり、副作用が少ない医薬成分として幅広い年代の患者に繁用されている。通常、成人にはアセトアミノフェンとして、１回３００～１０００ｍｇが経口投与され、１日最大総量は４０００ｍｇ／日である。現在販売されているアセトアミノフェン錠には、有効成分量の異なる、５００ｍｇ錠、３００ｍｇ錠及び２００ｍｇ錠があり、アセトアミノフェン含有量が多いため、錠剤が大型化する傾向がある。そのため、嚥下力が弱い子供や高齢者でも容易に服用できるように、小型化された錠剤や口腔内崩壊錠が開発されている。小型の錠剤の例としては、特許文献３及び４に開示の錠剤がある。 Acetaminophen is a useful bioactive drug with antipyretic analgesic action that has been used for a long time, and is frequently used by patients of all ages as a pharmaceutical ingredient with few side effects. In general, for adults, 300 to 1000 mg of acetaminophen is orally administered at a time, and the maximum daily dose is 4000 mg / day. The acetaminophen tablets currently on the market include 500 mg tablets, 300 mg tablets and 200 mg tablets having different amounts of active ingredients, and the tablets tend to be large in size due to the high content of acetaminophen. Therefore, miniaturized tablets and orally disintegrating tablets have been developed so that even children and the elderly with weak swallowing ability can easily take them. Examples of small tablets include the tablets disclosed in Patent Documents 3 and 4.
　特許文献３は、アセトアミノフェンを７０～８５質量％、結晶セルロースを５～１５質量％、及びヒドロキシプロピルセルロースを５～１０質量％含有し、ナンテンジツエキスを含有しないことを特徴とするＲ型の凸面を有する錠径７～１０ｍｍの円形錠剤を開示する。また、特許文献４は、未粉砕のアセトアミノフェンに分散剤、滑沢剤及びその他の添加剤を配合する工程、並びに、添加剤の配合前又は各添加剤の配合後において少なくとも１回、解砕整粒してアセトアミノフェン粒子の表面に添加剤を分散・付着させる工程を含む、錠剤の製造のための未粉砕のアセトアミノフェンの使用を開示する。 Patent Document 3 contains 70 to 85% by mass of acetaminophen, 5 to 15% by mass of crystalline cellulose, and 5 to 10% by mass of hydroxypropyl cellulose, and does not contain Nantenjitsu extract. Disclosed is a circular tablet having a convex surface of 7 to 10 mm in diameter. Further, Patent Document 4 describes a step of blending a dispersant, a lubricant and other additives with unground acetaminophen, and at least once before blending the additives or after blending each additive. Disclosed is the use of unground acetaminophen for the production of tablets, which comprises the steps of crushing and sizing to disperse and adhere additives to the surface of acetaminophen particles.
　また、アセトアミノフェンを含有する口腔内崩壊錠を開示する文献には、以下の特許文献がある。特許文献５は、アセトアミノフェンに（ａ）グルタミン酸及びアスパラギン酸からなる群より選ばれる１種又は２種のアミノ酸及びスクラロースを含有してなる経口固形製剤を開示する。特許文献６は、結晶粒子径が約１００～約５００μｍのアセトアミノフェンと、精油、精油及び高甘味度甘味剤、又は精油、高甘味度甘味剤及び酸性リン脂質もしくはそのリゾ体からなる苦味低減成分とを含有することを特徴とする口腔内速崩壊錠を開示する。 In addition, the literature that discloses orally disintegrating tablets containing acetaminophen includes the following patent documents. Patent Document 5 discloses an oral solid preparation containing acetaminophen containing one or two amino acids selected from the group consisting of (a) glutamic acid and aspartic acid and sucralose. Patent Document 6 describes a bitterness reduction composed of acetaminophen having a crystal particle size of about 100 to about 500 μm and an essential oil, an essential oil and a high sweetness sweetener, or an essential oil, a high sweetness sweetener and an acidic phospholipid or a lyso form thereof. Disclosed is an orally rapidly disintegrating tablet characterized by containing an ingredient.
　特許文献７は、崩壊性粒子組成物及び薬効成分を含む口腔内崩壊錠剤の製造方法であって、酸型カルボキシメチルセルロースからなる第一の崩壊剤成分、クロスポビドンからなる第二の崩壊剤成分、及び、糖又は糖アルコールから成る賦形剤の三成分の中の任意の二成分を用いて水又は水を溶媒とする噴霧液を噴霧して行う第一湿式造粒工程、及び、第一湿式造粒工程で得られた造粒物と第一湿式造粒工程で用いられなかった残りの一成分を少なくとも用いて水又は水を溶媒とする噴霧液を噴霧して行う第二湿式造粒工程を含む、少なくとも二段階の造粒法で該崩壊性粒子組成物を製造し、該崩壊性粒子組成物及び薬効成分を含む混合物を打錠することを含み、該薬効成分の含有率が４０重量％以上であって、且つ、該薬効成分単独の分配係数が－６．０～１０．０である、前記製造方法を開示する。 Patent Document 7 is a method for producing an orally disintegrating tablet containing a disintegrating particle composition and a medicinal ingredient, wherein the first disintegrant component composed of acid-type carboxymethyl cellulose and the second disintegrant component composed of crospovidone. The first wet granulation step and the first wet granulation step, which are carried out by spraying water or a spray liquid using water as a solvent, using any two components of the excipient consisting of sugar or sugar alcohol. A second wet granulation step performed by spraying water or a spray liquid using water as a solvent using at least one of the granules obtained in the granulation step and the remaining one component not used in the first wet granulation step. The disintegrating particle composition is produced by a granulation method of at least two steps including, and the mixture containing the disintegrating particle composition and the medicinal ingredient is tableted, and the content of the medicinal ingredient is 40 weight by weight. % Or more, and the distribution coefficient of the medicinal ingredient alone is −6.0 to 10.0.
特許第６０９８６３４号公報Japanese Patent No. 6098634 特許第５７２１０９３号公報Japanese Patent No. 5721093 特許第５４９９５９９号公報Japanese Patent No. 5499599 特開２０１８－９０６３８号公報JP-A-2018-90638 特開２０１４－１３３７２８号公報Japanese Unexamined Patent Publication No. 2014-133728 特許第３３８９２０５号公報Japanese Patent No. 3389205 特許第６３０２９２１号公報Japanese Patent No. 6302921 特開２０００－９５６７４号公報Japanese Unexamined Patent Publication No. 2000-95674 特開２００８－１３３２９４号公報JP-A-2008-133294
　アセトアミノフェンは幅広い年代の患者に解熱鎮痛薬として一般的に用いられており、容易に服用できる口腔内崩壊錠が求められている。加えて、アセトアミノフェンは薬価が非常に低いため、配合する添加剤の価格のほうが高いものも多い。そのため、アセトアミノフェンを高濃度で含有させ、添加剤の配合量を減量させることは製造コストを低減させるために重要である。また、服用コンプライアンス及びアドヒアランスの観点から錠剤を小型化するためにアセトアミノフェンを高濃度で含有させることが求められている。 Acetaminophen is commonly used as an antipyretic analgesic for patients of all ages, and there is a need for an orally disintegrating tablet that can be easily taken. In addition, acetaminophen has a very low drug price, so the price of the additives to be blended is often higher. Therefore, it is important to contain acetaminophen at a high concentration and reduce the amount of the additive to be added in order to reduce the production cost. In addition, from the viewpoint of dosage compliance and adherence, it is required to contain acetaminophen in a high concentration in order to miniaturize the tablet.
　しかしながら、従来、高濃度のアセトアミノフェンを含有した口腔内崩壊錠は、提供困難であると考えられていた。製品として求められる錠剤硬度と崩壊時間を満たすため、崩壊剤等の副成分を多量に添加すると、アセトアミノフェン含有率が低下し、必然的に錠剤が大型化し、錠剤が大型化すると口腔内での崩壊時に多量な唾液が必要となるため、服用感の低下につながるという問題があるためである。 However, conventionally, it has been considered difficult to provide an orally disintegrating tablet containing a high concentration of acetaminophen. If a large amount of sub-ingredients such as a disintegrant is added in order to satisfy the tablet hardness and disintegration time required for the product, the acetaminophen content decreases, the tablet inevitably becomes large, and when the tablet becomes large, it is in the oral cavity. This is because a large amount of saliva is required when the tablet collapses, which causes a problem that the feeling of taking the tablet is lowered.
　加えて、製造コストを低減させるために、複雑な工程を有する製造方法よりも、より簡単な製造方法で製造できる口腔内崩壊錠が求められている。例えば、特許文献１、２、７及び８に開示されている空隙率を増加させるための工程を含む方法では製造コストが増大するという問題があった。 In addition, in order to reduce the manufacturing cost, there is a demand for an orally disintegrating tablet that can be manufactured by a simpler manufacturing method than a manufacturing method having a complicated process. For example, there is a problem that the manufacturing cost increases in the method including the step for increasing the porosity disclosed in Patent Documents 1, 2, 7 and 8.
　特許文献３及び４に記載の錠剤はアセトアミノフェンを高濃度で含有するが、口腔内崩壊錠としては製造されていない。特許文献５の経口固形製剤は、口腔内崩壊錠であるが、アセトアミノフェンの濃度は６０％である。特許文献６に記載の口腔内崩壊錠は、アセトアミノフェンを２５％程度、１錠中約１５０ｍｇ含有しており、アセトアミノフェンの１錠中含有量が実用的に十分ではない。特許文献７に記載の方法により製造された口腔内崩壊錠剤はアセトアミノフェンを４０～５０％、１錠中１００ｍ～１５０ｍｇ含有しており、これはアセトアミノフェンの１錠中含有量が実用的に十分ではない。また、特許文献７に記載の口腔内崩壊錠剤の製造方法は、少なくとも２回の湿式造粒工程を含み、複雑である。 The tablets described in Patent Documents 3 and 4 contain a high concentration of acetaminophen, but are not manufactured as orally disintegrating tablets. The oral solid preparation of Patent Document 5 is an orally disintegrating tablet, and the concentration of acetaminophen is 60%. The orally disintegrating tablet described in Patent Document 6 contains about 25% of acetaminophen and about 150 mg in one tablet, and the content of acetaminophen in one tablet is not practically sufficient. The orally disintegrating tablet produced by the method described in Patent Document 7 contains 40 to 50% of acetaminophen and 100 m to 150 mg in one tablet, and the content of acetaminophen in one tablet is practical. Not enough. Further, the method for producing an orally disintegrating tablet described in Patent Document 7 includes at least two wet granulation steps and is complicated.
　上記のように、従来技術において、アセトアミノフェンを７５質量％以上の高濃度で含み、十分な錠剤硬度を備え、且つ実用的な口腔内速崩壊性を有する口腔内崩壊錠は知られていない。よって、本発明は、アセトアミノフェンを７５質量％以上の高濃度で含みながら、錠剤硬度５０Ｎ以上を有し、且つ実用的な口腔内速崩壊性を有する口腔内崩壊錠を提供することを解決すべき課題とする。さらには、本発明は、服用感の良好な口腔内崩壊錠を提供することを解決すべき課題とする。本発明は、アセトアミノフェンの苦味が抑制された口腔内崩壊錠を提供することを解決すべき課題とする。加えて、本発明は、前記口腔内崩壊錠の製造方法を提供することを解決すべき課題とする。 As described above, in the prior art, there is no known orally disintegrating tablet containing acetaminophen in a high concentration of 75% by mass or more, having sufficient tablet hardness, and having practical rapid disintegration in the oral cavity. .. Therefore, it is solved that the present invention provides an orally disintegrating tablet having a tablet hardness of 50 N or more and a practical rapid disintegrating property in the oral cavity while containing acetaminophen in a high concentration of 75% by mass or more. It is an issue to be done. Furthermore, the present invention is a problem to be solved to provide an orally disintegrating tablet having a good feeling of administration. An object of the present invention is to provide an orally disintegrating tablet in which the bitterness of acetaminophen is suppressed. In addition, the present invention is a problem to be solved to provide a method for producing the orally disintegrating tablet.
　上記課題の下、本発明者らは、鋭意検討を行った結果、所定範囲の粒子径を有するアセトアミノフェン原薬と高成形性の結晶セルロースと崩壊剤を混合し、直接打錠して製造することにより、アセトアミノフェンを高濃度で含みながら、錠剤硬度５０Ｎ以上を有し、且つ実用的な口腔内速崩壊性を有する口腔内崩壊錠が得られることを見出した。また、上記のように製造されたアセトアミノフェン含有口腔内崩壊錠の苦味は抑制されており、服用しやすい口腔内崩壊錠が得られることを見出した。本発明は、上記の知見に基づいて完成したものである。 Under the above-mentioned problems, as a result of diligent studies, the present inventors mixed acetaminophen drug substance having a predetermined range of particle size, highly moldable crystalline cellulose, and a disintegrant, and directly tableted the drug. By doing so, it has been found that an orally disintegrating tablet having a tablet hardness of 50 N or more and having a practical rapid disintegrating property in the oral cavity can be obtained while containing acetaminophen in a high concentration. It was also found that the bitterness of the acetaminophen-containing orally disintegrating tablets produced as described above is suppressed, and an orally disintegrating tablets that are easy to take can be obtained. The present invention has been completed based on the above findings.
　即ち、本発明によれば、以下の発明が提供される。
［１］８０～３００μｍの範囲のメジアン粒子径を有するアセトアミノフェンと、高成形性の結晶セルロースと、崩壊剤とを含む口腔内崩壊錠であって、上記アセトアミノフェンの１錠中含有率は７５質量％以上及び１錠中含有量は１９０ｍｇ以上であり、錠剤硬度５０Ｎ以上を有する口腔内崩壊錠。
［２］口腔内崩壊錠に、人工唾液水溶液を、送液速度６ｍＬ／分、滴下高さ８０ｍｍ、及び荷重１０ｇの条件にて、滴下して測定される崩壊時間が３０秒以内である、［１］に記載の口腔内崩壊錠。
［３］空隙率が２０％未満である、［１］又は［２］に記載の口腔内崩壊錠。
［４］錠剤の気孔率が２５％未満である、［１］～［３］の何れか一に記載の口腔内崩壊錠。
［５］甘味剤及び／又は香料をさらに含む、［１］～［４］の何れか一に記載の口腔内崩壊錠。
［６］上記結晶セルロースを１錠中８．５質量％より多く含む、［１］～［５］の何れか一に記載の口腔内崩壊錠。
［７］上記結晶セルロースが、０．１０～０．１５ｇ／ｃｍ３の範囲のかさ密度を有する、［１］～［６］の何れか一に口腔内崩壊錠。
［８］上記崩壊剤が、部分アルファ化デンプン、クロスポビドン、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択される何れかである、［１］～［７］の何れか一に記載の口腔内崩壊錠。
［９］上記甘味剤が、アスパルテーム、サッカリン、ステビア、アセスルファムカリウム及びスクラロースからなる群から選択される何れかである、［５］～［８］の何れか一に記載の口腔内崩壊錠。
［１０］上記香料が粉体香料であり、グレープフルーツフレーバー、メントールフレーバー、メントールパウダー、ペパーミントパウダー、グレープフルーツエキスパウダー、レモンパウダー、アップルパウダー、ストロベリーパウダー及び巨峰パウダーからなる群から選択される何れかである、［５］～［９］の何れか一に記載の口腔内崩壊錠。
［１１］８０～３００μｍの範囲のメジアン粒子径を有するアセトアミノフェンと高成形性の結晶セルロースと崩壊剤とを混合して粉体混合物を得る工程、及び
上記粉体混合物を直接打錠して錠剤を得る工程を含む、
［１］～［１０］の何れか一に記載の口腔内崩壊錠の製造方法。 That is, according to the present invention, the following invention is provided.
[1] An orally disintegrating tablet containing acetaminophen having a median particle size in the range of 80 to 300 μm, highly moldable crystalline cellulose, and a disintegrant, and the content of acetaminophen in one tablet. Is an orally disintegrating tablet having 75% by mass or more, a content of 190 mg or more in one tablet, and a tablet hardness of 50 N or more.
[2] The disintegration time measured by dropping an artificial saliva aqueous solution onto an orally disintegrating tablet under the conditions of a liquid feeding rate of 6 mL / min, a dropping height of 80 mm, and a load of 10 g is within 30 seconds. 1] The orally disintegrating tablet according to.
[3] The orally disintegrating tablet according to [1] or [2], which has a porosity of less than 20%.
[4] The orally disintegrating tablet according to any one of [1] to [3], wherein the tablet has a porosity of less than 25%.
[5] The orally disintegrating tablet according to any one of [1] to [4], further comprising a sweetening agent and / or a flavoring agent.
[6] The orally disintegrating tablet according to any one of [1] to [5], which contains the above crystalline cellulose in an amount of more than 8.5% by mass in one tablet.
[7] An orally disintegrating tablet according to any one of [1] to [6], wherein the crystalline cellulose has a bulk density in the range of 0.10 to 0.15 g / cm 3 .
[8] The disintegrant is any one selected from the group consisting of partially pregelatinized starch, crospovidone, croscarmellose sodium, and sodium starch glycolate, according to any one of [1] to [7]. The orally disintegrating tablet described.
[9] The orally disintegrating tablet according to any one of [5] to [8], wherein the sweetening agent is any one selected from the group consisting of aspartame, saccharin, stevia, acesulfame potassium and sucralose.
[10] The above-mentioned fragrance is a powder fragrance, which is selected from the group consisting of grapefruit flavor, menthol flavor, menthol powder, peppermint powder, grapefruit extract powder, lemon powder, apple powder, strawberry powder and giant peak powder. , The orally disintegrating tablet according to any one of [5] to [9].
[11] A step of mixing acetaminophen having a median particle size in the range of 80 to 300 μm, highly moldable crystalline cellulose, and a disintegrant to obtain a powder mixture, and directly tableting the powder mixture. Including the step of obtaining tablets,
The method for producing an orally disintegrating tablet according to any one of [1] to [10].
　本発明によれば、アセトアミノフェンを高濃度で含みながら、錠剤硬度５０Ｎ以上を有し、且つ実用的な口腔内速崩壊性を有する口腔内崩壊錠を提供することができる。また、本発明によれば、苦味が抑制されたアセトアミノフェン含有口腔内崩壊錠を提供することができる。加えて、本発明によれば、直接打錠法を採用し、簡単で製造コストが低い口腔内崩壊錠の製造方法を提供することができる。 According to the present invention, it is possible to provide an orally disintegrating tablet having a tablet hardness of 50 N or more and a practical rapid disintegrating property in the oral cavity while containing acetaminophen in a high concentration. Further, according to the present invention, it is possible to provide an orally disintegrating tablet containing acetaminophen with suppressed bitterness. In addition, according to the present invention, it is possible to provide a method for producing an orally disintegrating tablet which is simple and has a low production cost by adopting a direct tableting method.
図１は、実施例１１の電子顕微鏡像を示す。上の電子顕微鏡像の倍率は１００倍、下は３００倍である。FIG. 1 shows an electron microscope image of Example 11. The magnification of the upper electron microscope image is 100 times, and the lower one is 300 times. 図２は、比較例３の電子顕微鏡像を示す。上の電子顕微鏡像の倍率は１００倍、下は３００倍である。FIG. 2 shows an electron microscope image of Comparative Example 3. The magnification of the upper electron microscope image is 100 times, and the lower one is 300 times. 図３は、比較例７の電子顕微鏡像を示す。上の電子顕微鏡像の倍率は１００倍、下は３００倍である。FIG. 3 shows an electron microscope image of Comparative Example 7. The magnification of the upper electron microscope image is 100 times, and the lower one is 300 times. 図４は、実施例１１のアセトアミノフェン錠剤のラマンイメージング像である。FIG. 4 is a Raman imaging image of the acetaminophen tablet of Example 11. 図５は、比較例３のアセトアミノフェン錠剤のラマンイメージング像である。FIG. 5 is a Raman imaging image of the acetaminophen tablet of Comparative Example 3.
　以下、本発明を実施するための形態を、詳細に説明する。なお、本明細書において「～」を用いて表される数値範囲は「～」の前後に記載される数値を下限値及び上限値として含む範囲を意味する。 Hereinafter, a mode for carrying out the present invention will be described in detail. In this specification, the numerical range represented by using "-" means a range including the numerical values before and after "-" as the lower limit value and the upper limit value.
（口腔内崩壊錠）
　本発明は、８０～３００μｍの範囲のメジアン粒子径を有するアセトアミノフェンと、高成形性の結晶セルロースと、崩壊剤とを含む口腔内崩壊錠であって、前記アセトアミノフェンの１錠中含有率は７５質量％以上及び１錠中含有量は１９０ｍｇ以上であり、錠剤硬度５０Ｎ以上を有する口腔内崩壊錠に関する。 (Orally disintegrating tablet)
The present invention is an orally disintegrating tablet containing acetaminophen having a median particle size in the range of 80 to 300 μm, highly moldable crystalline cellulose, and a disintegrant, and is contained in one tablet of the acetaminophen. The present invention relates to an orally disintegrating tablet having a rate of 75% by mass or more, a content in one tablet of 190 mg or more, and a tablet hardness of 50 N or more.
　本発明の口腔内崩壊錠における生理活性薬物はアセトアミノフェンである。アセトアミノフェンは、解熱鎮痛薬であり、発熱、寒気、頭痛などに対症療法として用いられる。本発明において、口腔内崩壊錠は、口腔内で水を服用することなしに、唾液により実用上十分な崩壊性又は溶解性（本明細書中、実用的な口腔内速崩壊性ともいう）を有する錠剤を意味する。一般に、口腔内崩壊錠は、ＯＤ錠ともいう。本発明の口腔内崩壊錠の製造方法については後述する。 The bioactive drug in the orally disintegrating tablet of the present invention is acetaminophen. Acetaminophen is an antipyretic analgesic and is used as a symptomatic treatment for fever, chills, headache, etc. In the present invention, the orally disintegrating tablet has practically sufficient disintegration or solubility (also referred to as practical orally rapid disintegration in the present specification) by saliva without taking water in the oral cavity. Means a tablet to have. Generally, the orally disintegrating tablet is also called an OD tablet. The method for producing the orally disintegrating tablet of the present invention will be described later.
　本発明の口腔内崩壊錠に用いられるアセトアミノフェン原薬（以下、本アセトアミノフェン原薬）のメジアン粒子径（Ｄ５０）は８０～３００μｍの範囲であり、好ましくは１００～２５０μｍの範囲であり、より好ましくは１００～２００μｍの範囲である。本アセトアミノフェン原薬が有する粒度分布は、Ｄ１０が５～１００μｍの範囲、好ましくは１０～１００μｍの範囲、より好ましくは２０～１００μｍの範囲であり、かつ、Ｄ９０が、２００～５００μｍの範囲、好ましくは２５０～４００μｍの範囲、より好ましくは２５０～３５０μｍの範囲である。製造ロット間により多少の差はあってもよい。また、本アセトアミノフェン原薬の体積平均粒子径（ＭＶ）は、８０～３００μｍの範囲であることができ、１００～２５０μｍの範囲でもよい。なお、本発明における粒度分布はレーザー回折法による乾式粒子径測定（Ｌａｓｅｒ　Ｍｉｃｒｏｎ　Ｓｉｚｅｒ　ＬＭＳ－２０００ｅ（株式会社セイシン企業））を用いた体積分布評価により求められ、Ｄ１０、Ｄ５０、Ｄ９０とは、粒度分布の小径側から各々体積の累積１０％、５０％、９０％の粒子径をいう。特に、Ｄ５０をメジアン粒子径という。 The median particle size (D50) of the acetaminophen drug substance (hereinafter, the present acetaminophen drug substance) used in the orally disintegrating tablet of the present invention is in the range of 80 to 300 μm, preferably in the range of 100 to 250 μm. , More preferably in the range of 100 to 200 μm. The particle size distribution of the acetaminophen drug substance is such that D10 is in the range of 5 to 100 μm, preferably 10 to 100 μm, more preferably 20 to 100 μm, and D90 is in the range of 200 to 500 μm. It is preferably in the range of 250 to 400 μm, more preferably in the range of 250 to 350 μm. There may be some differences depending on the production lot. The volume average particle size (MV) of the present acetaminophen drug substance can be in the range of 80 to 300 μm, and may be in the range of 100 to 250 μm. The particle size distribution in the present invention is obtained by volume distribution evaluation using a dry particle size measurement (Laser Micron Sizer LMS-2000e (Seishin Enterprise Co., Ltd.)) by a laser diffraction method, and D10, D50, and D90 are particle size distributions. The particle size is 10%, 50%, and 90% of the cumulative volume from the small diameter side of the particle size. In particular, D50 is called the median particle size.
　本発明の一実施態様では、本アセトアミノフェン原薬は、晶析後に粉砕処理を受けていないものを用いることができる。本アセトアミノフェン原薬は、晶析後に特別な処理を受けていないものを用いてもよいし、晶析後に篩過処理されたものを用いてもよい。本発明の好ましい実施態様では、本アセトアミノフェン原薬は、晶析後に篩過処理されたものである。篩過処理により、本発明の口腔内崩壊錠の製造に適した粒子径の粒子をより多く含んだ粉体を得るためである。粗大なアセトアミノフェン結晶（例えば、６００μｍ以上）が多く含まれる原薬を使用した場合、アセトアミノフェン高含有の錠剤を打錠成型することは困難であると考えられる。また、アセトアミノフェン微小物（例えば、３０μｍ以下）が多く含まれる原薬を使用して打錠された錠剤は、崩壊性が悪いため口腔内崩壊錠として成り立たないと考えられる。篩過処理により、粗大なアセトアミノフェン結晶やアセトアミノフェン微小物を除去することができる。 In one embodiment of the present invention, the acetaminophen drug substance can be used that has not been pulverized after crystallization. The acetaminophen drug substance may be one that has not undergone special treatment after crystallization, or may be one that has been sieved after crystallization. In a preferred embodiment of the present invention, the acetaminophen drug substance is sieved after crystallization. This is to obtain a powder containing more particles having a particle size suitable for producing the orally disintegrating tablet of the present invention by sieving. When a drug substance containing a large amount of coarse acetaminophen crystals (for example, 600 μm or more) is used, it is considered difficult to tablet-mold a tablet containing a high amount of acetaminophen. Further, it is considered that a tablet tableted using a drug substance containing a large amount of acetaminophen fine substances (for example, 30 μm or less) cannot be used as an orally disintegrating tablet because of its poor disintegration property. By sieving, coarse acetaminophen crystals and acetaminophen fine substances can be removed.
　本発明の口腔内崩壊錠における、アセトアミノフェン含有率は７５質量％以上である。アセトアミノフェンの含有率が７５質量％以上であれば、１錠中にアセトアミノフェンを２００～５００ｍｇ含有させても錠剤が過度に大型化しないためである。口腔内崩壊錠については、錠剤が大型化すると、口腔内での崩壊時に多量な唾液が必要となり、服用感が低下するという弊害が生じる。アセトアミノフェンの１錠中含有率は、７５から９５質量％の範囲、７５から９４質量％の範囲、７５から９３質量％の範囲、７５から９２質量％の範囲、７５から９１質量％の範囲、７５から９０質量％の範囲又は７５から８９質量％の範囲であってもよいし、８０から９５質量％の範囲、８０から９４質量％の範囲、８０から９３質量％の範囲、８０から９２質量％の範囲、８０から９１質量％の範囲、８０から９０質量％の範囲又は８０から８９質量％の範囲であってもよい。なお、本明細書において、アセトアミノフェンを高濃度で含有するとは、１錠中のアセトアミノフェン含有率が高いこと（例えば含有率７５質量％以上）を意味する。 The acetaminophen content in the orally disintegrating tablet of the present invention is 75% by mass or more. This is because if the content of acetaminophen is 75% by mass or more, the tablet does not become excessively large even if 200 to 500 mg of acetaminophen is contained in one tablet. With regard to orally disintegrating tablets, when the size of the tablet is increased, a large amount of saliva is required at the time of disintegrating in the oral cavity, which causes an adverse effect of reducing the feeling of taking. The content of acetaminophen in one tablet is in the range of 75 to 95% by mass, in the range of 75 to 94% by mass, in the range of 75 to 93% by mass, in the range of 75 to 92% by mass, and in the range of 75 to 91% by mass. , 75 to 90% by mass, 75 to 89% by mass, 80 to 95% by mass, 80 to 94% by mass, 80 to 93% by mass, 80 to 92. It may be in the range of mass%, 80 to 91% by mass, 80 to 90% by mass, or 80 to 89% by mass. In addition, in this specification, containing acetaminophen at a high concentration means that the content of acetaminophen in one tablet is high (for example, the content is 75% by mass or more).
　本発明の特定の実施態様では、口腔内崩壊錠における、アセトアミノフェン含有率は８０質量％以上、又は８５質量％以上であってもよい。アセトアミノフェン含有量が５００ｍｇの口腔内崩壊錠を製造する場合には、特に含有率が８５％以上であることが好ましい場合がある。 In a specific embodiment of the present invention, the acetaminophen content in the orally disintegrating tablet may be 80% by mass or more, or 85% by mass or more. When an orally disintegrating tablet having an acetaminophen content of 500 mg is produced, it may be particularly preferable that the content is 85% or more.
　本発明の口腔内崩壊錠は、アセトアミノフェンの１錠中含有量が１９０ｍｇ以上である。成人には通常、アセトアミノフェンとして１回３００～５００ｍｇが経口投与される場合が多いため、１錠中含有量が１９０ｍｇ以上であれば、１回１又は２錠を服用すればよく、実用的である。 The orally disintegrating tablet of the present invention has a content of acetaminophen in one tablet of 190 mg or more. In general, for adults, 300 to 500 mg of acetaminophen is orally administered at a time, so if the content in one tablet is 190 mg or more, one or two tablets may be taken at a time, which is practical. Is.
　結晶セルロースには多様な種類があり、一般に、崩壊剤、賦形剤、結合剤などの様々な用途に応じて使い分けられている。本発明では、錠剤の成形性を高めるために添加される成分として高成形性の結晶セルロースを使用することができる。本発明の口腔内崩壊錠に含有される高成形性の結晶セルロースは、０．１０～０．２３ｇ／ｃｍ３の範囲のかさ密度を有する結晶セルロースである。かさ密度は、「第十六改正日本薬局方、３．粉体物性測定法、３．０１  かさ密度およびタップ密度測定法」に記載のかさ密度の測定方法に準じて測定することができる。本発明の高成形性の結晶セルロースは２０～１００μｍの範囲の平均粒子径を有するものでもよい。このような平均粒子径やかさ密度を有する結晶セルロース製品としては、セオラス（登録商標）ＫＧ－８０２、ＯＤ２０－Ｐ及びＫＧ－１０００（旭化成株式会社）を挙げることができるが、これらに限定されない。 There are various types of crystalline cellulose, and in general, they are used properly according to various uses such as disintegrants, excipients, and binders. In the present invention, highly moldable crystalline cellulose can be used as a component added to enhance the moldability of tablets. The highly moldable crystalline cellulose contained in the orally disintegrating tablet of the present invention is a crystalline cellulose having a bulk density in the range of 0.10 to 0.23 g / cm 3 . The bulk density can be measured according to the bulk density measuring method described in "16th Revised Japanese Pharmacopoeia, 3. Powder Physical Property Measuring Method, 3.01 Bulk Density and Tap Densitometry". The highly moldable crystalline cellulose of the present invention may have an average particle size in the range of 20 to 100 μm. Examples of crystalline cellulose products having such an average particle size and bulk density include, but are not limited to, Theoras (registered trademark) KG-802, OD20-P and KG-1000 (Asahi Kasei Corporation).
　本発明の一実施態様では、０．１０～０．２３ｇ／ｃｍ３の範囲のかさ密度を有する結晶セルロースを用いることが好ましく、０．１０～０．１５ｇ／ｃｍ３の範囲のかさ密度を有する結晶セルロースを用いることがより好ましい。また、高アスペクト比の結晶セルロースを用いることが好ましい。長細い形状のため絡まりやすく、成形性が良いためである。より好ましいかさ密度を有する結晶セルロース製品としては、セオラス（登録商標）ＫＧ－１０００（旭化成株式会社）を挙げることができるが、これに限定されない。 In one embodiment of the present invention, it is preferable to use a crystalline cellulose having a bulk density in the range of 0.10 ~ 0.23g / cm 3, having a bulk density in the range of 0.10 ~ 0.15g / cm 3 It is more preferable to use crystalline cellulose. Further, it is preferable to use crystalline cellulose having a high aspect ratio. This is because the long and thin shape makes it easy to get entangled and the moldability is good. Examples of the crystalline cellulose product having a more preferable bulk density include, but are not limited to, Theoras (registered trademark) KG-1000 (Asahi Kasei Corporation).
　本発明の口腔内崩壊錠は、高成形性の結晶セルロースを１錠中８．５質量％より多く含むことができる。１錠中における高成形性の結晶セルロースの含有率を８．５質量％より高くすることにより、製造や流通過程で受け得る衝撃に十分に耐えられる錠剤硬度を有する錠剤を製造することができる。本発明者らは、後述する実施例において、高濃度でアセトアミノフェンを含む場合（８５質量％）でも、高成形性の結晶セルロースを８．５質量％より多く含有させることにより、５０Ｎ以上の硬度を有する口腔内崩壊錠が製造可能であることを示した。１錠中における高成形性の結晶セルロースの含有率は、８．６質量％以上、８．７質量％以上、８．８質量％以上、８．９質量％以上、９．０質量％以上、９．５質量％以上又は１０．０質量％以上でもよい。また、１錠中における高成形性の結晶セルロースの含有率は、２０質量％以下であってもよく、１９質量％以下、１８質量％以下、１７質量％以下、１６質量％以下、１５質量％以下又は１４．５質量％以下とすることができる。 The orally disintegrating tablet of the present invention can contain more than 8.5% by mass of highly moldable crystalline cellulose in one tablet. By increasing the content of highly moldable crystalline cellulose in one tablet to more than 8.5% by mass, it is possible to produce a tablet having a tablet hardness that can sufficiently withstand the impact that can be received in the production and distribution processes. In the examples described later, the present inventors, even when acetaminophen is contained in a high concentration (85% by mass), by containing more than 8.5% by mass of highly moldable crystalline cellulose, 50 N or more. It was shown that an orally disintegrating tablet having hardness can be produced. The content of highly moldable crystalline cellulose in one tablet is 8.6% by mass or more, 8.7% by mass or more, 8.8% by mass or more, 8.9% by mass or more, 9.0% by mass or more, It may be 9.5% by mass or more or 10.0% by mass or more. The content of highly moldable crystalline cellulose in one tablet may be 20% by mass or less, 19% by mass or less, 18% by mass or less, 17% by mass or less, 16% by mass or less, 15% by mass. It can be less than or equal to 14.5% by mass or less.
　錠剤硬度について、一般的に、５０Ｎ以上の硬度を有する錠剤であれば、例えば錠剤をＰＴＰなどに包装する際の衝撃や、輸送時の衝撃、患者ハンドリング時の力に耐えられると考えられている。本発明の口腔内崩壊錠は、錠剤硬度５０Ｎ以上を有し、５１Ｎ以上、５２Ｎ以上、５３Ｎ以上、５４Ｎ以上、５５Ｎ以上、５６Ｎ以上、５７Ｎ以上、５８Ｎ以上、５９Ｎ以上、又は６０Ｎ以上でもよい。本発明において、錠剤硬度の上限値について、特に制限はないが、１５０Ｎ以下、又は１００Ｎ以下でもよい。錠剤硬度は、ロードセル式錠剤硬度計（ＰＣ－１０、岡田精工株式会社）などを用いて測定することができる。 Regarding tablet hardness, it is generally considered that a tablet having a hardness of 50 N or more can withstand an impact when packaging a tablet in PTP or the like, an impact during transportation, and a force during patient handling. .. The orally disintegrating tablet of the present invention has a tablet hardness of 50 N or more, and may be 51 N or more, 52 N or more, 53 N or more, 54 N or more, 55 N or more, 56 N or more, 57 N or more, 58 N or more, 59 N or more, or 60 N or more. In the present invention, the upper limit of tablet hardness is not particularly limited, but may be 150 N or less, or 100 N or less. The tablet hardness can be measured using a load cell type tablet hardness tester (PC-10, Okada Seiko Co., Ltd.) or the like.
　崩壊剤としては、部分アルファ化デンプン、クロスポビドン、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、カルメロース、カルボキシメチルスターチナトリウム、ゼラチン、デンプン、トウモロコシデンプン、及びバレイショデンプンを挙げることができるが、これらに限定されるものではない。本発明の特定の実施態様において、崩壊剤は、部分アルファ化デンプン、クロスポビドン、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択される何れかであることが好ましい。崩壊剤は、１種類又は２種類以上の任意の組合せにより使用することができる。本発明の口腔内崩壊錠は、崩壊剤を１錠中１．０～７．０質量％の範囲、好ましくは１錠中２．０～６．０質量％の範囲、より好ましくは１錠中２．５～５．５質量％の範囲で含むことができる。 Disintegrants include, but are limited to, partially pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, carmellose, sodium carboxymethyl starch, gelatin, starch, corn starch, and potato starch. It is not something that is done. In certain embodiments of the invention, the disintegrant is preferably any one selected from the group consisting of partially pregelatinized starch, crospovidone, croscarmellose sodium, and sodium starch glycolate. The disintegrant can be used in any combination of one or more. The orally disintegrating tablet of the present invention contains a disintegrant in the range of 1.0 to 7.0% by mass, preferably 2.0 to 6.0% by mass in one tablet, and more preferably in one tablet. It can be contained in the range of 2.5 to 5.5% by mass.
　本発明の口腔内崩壊錠は、甘味剤をさらに含むことができる。甘味剤としては、アスパルテーム、サッカリン、ステビア、アセスルファムカリウム、スクラロース、果糖、キシリトール、白糖、ブドウ糖又はマルチトール等を挙げることができるが、これらに限定されるものではない。本発明の特定の実施態様において、甘味剤は、アスパルテーム、サッカリン、ステビア、アセスルファムカリウム及びスクラロースからなる群から選択される何れかであることが好ましい。甘味剤は、１種類又は２種類以上の任意の組合せにより使用することができる。本発明の口腔内崩壊錠は、甘味剤を１錠中０．１～６．０質量％の範囲、好ましくは１錠中０．５～５．０質量％の範囲、より好ましくは１錠中０．７～４．０質量％の範囲で含むことができる。 The orally disintegrating tablet of the present invention can further contain a sweetener. Examples of the sweetener include, but are not limited to, aspartame, saccharin, stevia, acesulfame potassium, sucralose, fructose, xylitol, sucrose, glucose, maltitol and the like. In certain embodiments of the invention, the sweetener is preferably any one selected from the group consisting of aspartame, saccharin, stevia, acesulfame potassium and sucralose. The sweetener can be used in any combination of one or more. The orally disintegrating tablet of the present invention contains a sweetener in the range of 0.1 to 6.0% by mass, preferably 0.5 to 5.0% by mass in one tablet, and more preferably in one tablet. It can be contained in the range of 0.7 to 4.0% by mass.
　本発明の口腔内崩壊錠は、香料をさらに含むことができる。香料としては、粉体香料を用いることができる。粉体香料としては、グレープフルーツフレーバー、メントールフレーバー、メントールパウダー、ペパーミントパウダー、グレープフルーツエキスパウダー、レモンパウダー、アップルパウダー、ストロベリーパウダー、又は巨峰パウダー等を挙げることができるが、これらに限定されるものではない。粉体香料は、１種類又は２種類以上の任意の組合せにより使用することができる。本発明の口腔内崩壊錠は、粉体香料を１錠中０．１～４．０質量％の範囲、好ましくは１錠中０．２～３．０質量％の範囲、より好ましくは１錠中０．３～２．０質量％の範囲で含むことができる。 The orally disintegrating tablet of the present invention can further contain a fragrance. As the fragrance, a powder fragrance can be used. Examples of the powdered fragrance include, but are not limited to, grapefruit flavor, menthol flavor, menthol powder, peppermint powder, grapefruit extract powder, lemon powder, apple powder, strawberry powder, and giant peak powder. .. The powder flavor can be used in any combination of one type or two or more types. The orally disintegrating tablet of the present invention contains a powdered flavor in the range of 0.1 to 4.0% by mass, preferably 0.2 to 3.0% by mass in one tablet, and more preferably one tablet. It can be contained in the range of 0.3 to 2.0% by mass.
　本発明の口腔内崩壊錠は、上記高成形性の結晶セルロース、崩壊剤、甘味剤、香料及び矯味剤以外の添加剤（以下、その他の添加剤）をさらに含むことができる。その他の添加剤としては、Ｄ－マンニトール及び乳糖などの賦形剤、ステアリン酸マグネシウム等の滑沢剤、軽質無水ケイ酸、無水二酸化ケイ素、ケイ酸カルシウム、含水二酸化ケイ素及びメタケイ酸アルミン酸マグネシウム等の流動化剤、シクロデキストリン等の安定化剤、着色剤等が挙げられるが、これらに限定されるものではなく、医薬品製造に用いられている一般的な添加剤が使用できる。滑沢剤や流動化剤を含む場合は、それぞれ１錠中０．１～２．０質量％の範囲又は０．１～１．０質量％の範囲で含むことができる。 The orally disintegrating tablet of the present invention can further contain additives other than the above-mentioned highly moldable crystalline cellulose, disintegrant, sweetener, flavor and flavoring agent (hereinafter, other additives). Other additives include excipients such as D-mannitol and lactose, lubricants such as magnesium stearate, light anhydrous silicic acid, anhydrous silicon dioxide, calcium silicate, hydrous silicon dioxide and magnesium aluminometasilicate and the like. Examples thereof include a fluidizing agent, a stabilizer such as cyclodextrin, and a colorant, but the present invention is not limited to these, and general additives used in the manufacture of pharmaceutical products can be used. When a lubricant and a fluidizing agent are contained, they can be contained in the range of 0.1 to 2.0% by mass or 0.1 to 1.0% by mass in one tablet, respectively.
　本発明において、口腔内崩壊錠は、上記のとおり、口腔内で水を服用することなしに、唾液により実用上十分な崩壊性又は溶解性を有する錠剤である。実用上十分な崩壊性又は溶解性とは、通常、口腔内で１から３００秒、１から１５０秒、１から９０秒、１から６０秒程度、１から３０秒程度で崩壊もしくは溶解することである。トリコープテスタ（登録商標）で測定した崩壊時間が１から３００秒、１から１５０秒、１から９０秒、１から６０秒、１から３０秒程度である錠剤である。トリコープテスタ（登録商標）で測定した崩壊時間は、実際のヒト口腔内での崩壊時間を相関すると報告されている（帆足洋平著、乾式プロセスを用いた製剤技術と口腔内崩壊錠の開発に関する研究、平成25年学位論文、岐阜薬科大学）。本発明において、トリコープテスタ（登録商標）で測定した崩壊時間とは、２枚の金網で挟んだ錠剤の上から３７±０．５℃の人工唾液水溶液を送液速度６ｍＬ／分で、高さ８０ｍｍから滴下し、錠剤が崩壊して２枚の金網が接するまでの時間（崩壊時間）であり、錠剤の上に置く金網の重さ（荷重）は１０ｇである。人工唾液水溶液の成分は、実施例の表２に記載のとおりである。 In the present invention, the orally disintegrating tablet is, as described above, a tablet having practically sufficient disintegration or solubility by saliva without taking water in the oral cavity. Practically sufficient disintegration or solubility means that it usually disintegrates or dissolves in the oral cavity in about 1 to 300 seconds, 1 to 150 seconds, 1 to 90 seconds, 1 to 60 seconds, and 1 to 30 seconds. is there. It is a tablet having a disintegration time of 1 to 300 seconds, 1 to 150 seconds, 1 to 90 seconds, 1 to 60 seconds, and 1 to 30 seconds measured by a tricorp tester (registered trademark). The disintegration time measured by Tricorp Tester® has been reported to correlate with the actual disintegration time in the human oral cavity (Yohei Hoashi, on formulation technology using a dry process and development of orally disintegrating tablets). Research, 2013 dissertation, Gifu Pharmaceutical University). In the present invention, the disintegration time measured by Tricorp Tester (registered trademark) is as high as 6 mL / min of artificial saliva aqueous solution at 37 ± 0.5 ° C. on a tablet sandwiched between two wire meshes. It is the time (disintegration time) until the tablet is dropped from 80 mm and the tablet is disintegrated and the two wire meshes are in contact with each other, and the weight (load) of the wire mesh placed on the tablet is 10 g. The components of the artificial saliva aqueous solution are as shown in Table 2 of Examples.
　特定の実施態様では、本発明の口腔内崩壊錠について、トリコープテスタ（登録商標）を用いて測定した崩壊時間が、３０秒以内、２５秒以内、２０秒以内、１５秒以内、又は１０秒以内でもよい。別の実施態様では、本発明の口腔内崩壊錠について、トリコープテスタ（登録商標）を用いて測定した崩壊時間が、１～３０秒、１～２５秒、１～２０秒、１～１５秒、又は１～１０秒でもよい。 In certain embodiments, the orally disintegrating tablets of the invention have a disintegration time of 30 seconds, 25 seconds, 20 seconds, 15 seconds, or 10 seconds as measured using a Tricorp Tester®. It may be within. In another embodiment, for the orally disintegrating tablets of the present invention, the disintegration time measured using a Tricorp Tester® is 1 to 30 seconds, 1 to 25 seconds, 1 to 20 seconds, 1 to 15 seconds. , Or 1 to 10 seconds.
　本発明の口腔内崩壊錠は、錠剤の気孔率が２５％未満であることができ、２４％以下、２３％以下、２２％以下、２１％以下、２０％以下、１９％以下でもよい。本発明の口腔内崩壊錠は、錠剤の気孔率が、１％以上、２％以上、３％以上、４％以上又は５％以上でもよい。本発明の口腔内崩壊錠は、１％以上２５％未満の範囲、１％以上２４％以下の範囲、２％以上２３％以下の範囲、２％以上２２％以下の範囲、３％以上２２％以下の範囲、４％以上２１％以下の範囲、又は５％以上２０％以下の範囲の気孔率を有するものでもよい。細孔の有無は錠剤の物性に非常に重要であり、錠が水や唾液と接触した場合に毛細管現象を発生させ、錠剤内部まで導水し、溶出性や崩壊性に大きく寄与する。 The orally disintegrating tablet of the present invention can have a porosity of less than 25%, and may be 24% or less, 23% or less, 22% or less, 21% or less, 20% or less, 19% or less. The orally disintegrating tablet of the present invention may have a porosity of 1% or more, 2% or more, 3% or more, 4% or more or 5% or more. The orally disintegrating tablet of the present invention has a range of 1% or more and less than 25%, a range of 1% or more and 24% or less, a range of 2% or more and 23% or less, a range of 2% or more and 22% or less, and a range of 3% or more and 22%. It may have a porosity in the following range, 4% or more and 21% or less, or 5% or more and 20% or less. The presence or absence of pores is very important for the physical properties of the tablet, and when the tablet comes into contact with water or saliva, it causes a capillary phenomenon and guides water to the inside of the tablet, which greatly contributes to elution and disintegration.
　錠剤の気孔率（％）は、水銀圧入法による細孔分布測定の結果に基づいて、以下の式により算出することができる。
気孔率（％）＝（全細孔容量 （ＣＣ／ｇ）　／　錠剤の容量　（ＣＣ／ｇ））×１００
　水銀圧入法による細孔分布は、ＰｏｒｅＭａｓｔｅｒ６０ＧＴ（Anton Paar Japan）を用いて測定することができる。 The porosity (%) of the tablet can be calculated by the following formula based on the result of the pore distribution measurement by the mercury intrusion method.
Porosity (%) = (total pore volume (CC / g) / tablet volume (CC / g)) x 100
The pore distribution by the mercury intrusion method can be measured using a PoreMaster 60GT (Anton Paar Japan).
　本発明の口腔内崩壊錠は、空隙率が２０％未満であることができ、１９％以下、１８％以下、１７％以下、１６％以下、１５％以下、１４％以下、１３％以下、１２％以下、１１％以下、１０％以下でもよい。本発明の口腔内崩壊錠は、空隙率が、１％以上、２％以上、３％以上、４％以上又は５％以上でもよい。本発明の口腔内崩壊錠は、１％以上２０％未満の範囲、１％以上１９％以下の範囲、２％以上１８％以下の範囲、２％以上１７％以下の範囲、３％以上１６％以下の範囲、４％以上１６％以下の範囲、又は５％以上１５％以下の範囲の空隙率を有するものでもよい。 The orally disintegrating tablet of the present invention can have a porosity of less than 20%, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12 % Or less, 11% or less, 10% or less. The orally disintegrating tablet of the present invention may have a porosity of 1% or more, 2% or more, 3% or more, 4% or more or 5% or more. The orally disintegrating tablet of the present invention has a range of 1% or more and less than 20%, a range of 1% or more and 19% or less, a range of 2% or more and 18% or less, a range of 2% or more and 17% or less, and a range of 3% or more and 16%. It may have a porosity in the following range, 4% or more and 16% or less, or 5% or more and 15% or less.
　空隙率（％）は、ピクノメーター（UltraPyc 1200e、Anton Paar Japan）から錠の真比重を算出し、それを基に算出することができる。
空隙率（％）＝（Ｖ－Ｗ／Ｍ）／Ｖ×１００
（Ｖ：崩壊錠の体積（ｃｍ３）、Ｗ：崩壊錠の質量（ｇ）、Ｍ：崩壊錠の密度（ｇ／ｃｍ３））
　水銀圧入法は水が流入しうる細孔を測定しているのに対し、ピクノメーターでは錠剤全体の空隙を全て測定しているという違いがある。従って、水銀圧入法に基づく気孔率は、錠剤に分布する細孔の割合を示し、ピクノメーターに基づく空隙率は、錠剤全体の空隙の割合を示す。 The porosity (%) can be calculated based on the true specific gravity of the lock calculated from a pycnometer (UltraPyc 1200e, Anton Paar Japan).
Porosity (%) = (VW / M) / V × 100
(V: Volume of disintegrating tablet (cm 3 ), W: Mass of disintegrating tablet (g), M: Density of disintegrating tablet (g / cm 3 ))
The difference is that the mercury intrusion method measures the pores through which water can flow, while the pycnometer measures all the voids in the entire tablet. Therefore, the porosity based on the mercury intrusion method indicates the proportion of pores distributed in the tablet, and the porosity based on the pycnometer indicates the proportion of voids in the entire tablet.
　口腔内崩壊錠の製造では、口腔内速崩壊性を満たすために錠剤の気孔率や空隙率を上げることが一般的に行われている。例えば、特許文献１、２、８及び９に開示の口腔内崩壊錠はいずれも空隙率２０％以上を有することにより、所望の口腔内崩壊時間を達成している。一方、後述の実施例に示すように本発明の口腔内崩壊錠の空隙率は１０％未満であり、従来の口腔内崩壊錠よりも低い。錠剤表面のラマンイメージング像による成分マッピングから、本発明の口腔内崩壊錠では崩壊剤の一部が錠剤表面に露出している様子が観察されたが、比較例の錠剤では崩壊剤は錠剤表面にはほとんど確認されなかった。本発明は特定の理論に拘束されるものではないが、口腔内崩壊錠の原料に８０～３００μｍの範囲のメジアン粒子径を有するアセトアミノフェン原薬を用いることにより、崩壊剤の錠剤内での局在化が生じ、従来知られていない口腔内崩壊錠の崩壊機序を発現している可能性が示唆された。 In the production of orally disintegrating tablets, it is common practice to increase the porosity and porosity of the tablets in order to satisfy the rapid disintegration property in the oral cavity. For example, the orally disintegrating tablets disclosed in Patent Documents 1, 2, 8 and 9 all achieve a desired orally disintegrating time by having a porosity of 20% or more. On the other hand, as shown in Examples described later, the porosity of the orally disintegrating tablet of the present invention is less than 10%, which is lower than that of the conventional orally disintegrating tablet. From the component mapping by the Raman imaging image of the tablet surface, it was observed that a part of the disintegrant was exposed on the tablet surface in the orally disintegrating tablet of the present invention, but in the comparative tablet, the disintegrant was on the tablet surface. Was rarely confirmed. Although the present invention is not bound by a specific theory, by using an acetaminophen drug substance having a median particle size in the range of 80 to 300 μm as a raw material for an orally disintegrating tablet, a disintegrant can be used in a tablet. It was suggested that localization occurred and that a previously unknown mechanism of disintegration of orally disintegrating tablets may be expressed.
　本発明は別の局面では、苦味が抑制されたアセトアミノフェン含有口腔内崩壊錠を提供する。アセトアミノフェンは、特有の苦味を有する。苦味とは、口腔内や咽頭部で感じる苦味や渋みを含む不快な違和感を総称するものである。本明細書において「苦味の抑制」は、苦味物質が口腔内に存在する場合に感じる苦味が抑制、低減、隠ぺい又はマスキングされることを意味し、苦味とともに渋みを含む不快な違和感が抑制、低減、隠ぺい又はマスキングされることを含んでもよい。「抑制」は、例えば、甘味剤、香料、矯味剤や本発明の特定範囲のアセトアミノフェンを使用しない場合に比較して、使用した場合に口腔内で感じる「苦味」が、いくらか減少することを意味し、苦味を全く感じない場合や、ある程度感じるがヒトにとって許容可能である場合を含んでもよい。本発明の口腔内崩壊錠について、苦味の評価は、パネラーによる官能評価試験及び／又は機器測定（味認識装置、味覚センサー）により実施することができる。後記する実施例において本発明の口腔内崩壊錠の味に関して官能評価試験を行ったところ、「１点：非常に悪い、２点：悪い、３点：どちらでもない、４点：良い、５点：非常によい」の評価で平均３．５点（６人）が得られた。口腔内崩壊錠の原料に８０～３００μｍの範囲のメジアン粒子径を有するアセトアミノフェン原薬を用いることにより、より細粒の原薬を用いた場合よりも、アセトアミノフェン特有の苦味が感じられにくいと考えられる。　 In another aspect, the present invention provides an acetaminophen-containing orally disintegrating tablet in which bitterness is suppressed. Acetaminophen has a peculiar bitterness. Bitterness is a general term for unpleasant discomfort including bitterness and astringency felt in the oral cavity and pharynx. In the present specification, "suppression of bitterness" means that the bitterness felt when a bitter substance is present in the oral cavity is suppressed, reduced, concealed or masked, and unpleasant discomfort including bitterness and astringency is suppressed or reduced. , May include hiding or masking. "Suppression" means that the "bitterness" felt in the oral cavity is somewhat reduced when used, for example, as compared to the case where sweeteners, flavors, flavoring agents and a specific range of acetaminophen of the present invention are not used. It may include the case where the bitterness is not felt at all, or the case where the bitterness is felt to some extent but is acceptable to humans. The bitterness of the orally disintegrating tablet of the present invention can be evaluated by a sensory evaluation test by a panelist and / or device measurement (taste recognition device, taste sensor). When a sensory evaluation test was conducted on the taste of the orally disintegrating tablet of the present invention in the examples described later, "1 point: very bad, 2 points: bad, 3 points: neither, 4 points: good, 5 points". An average of 3.5 points (6 people) was obtained in the evaluation of ": very good". By using an acetaminophen drug substance having a median particle size in the range of 80 to 300 μm as a raw material for an orally disintegrating tablet, a bitter taste peculiar to acetaminophen can be felt as compared with the case of using a finer grain drug substance. It is considered difficult.
　本発明の口腔内崩壊錠の大きさは、径６ｍｍ～１８ｍｍの範囲、アスペクト比１～３の範囲、及び厚さ２ｍｍ～１０ｍｍの範囲とすることができるが、この範囲に限定されない。本発明の口腔内崩壊錠の形状は通常錠でも異型錠でもよく、例えば円形、楕円形、カプレット形状とすることができるが、これらに限定されない。 The size of the orally disintegrating tablet of the present invention can be in the range of 6 mm to 18 mm in diameter, in the range of aspect ratios 1 to 3, and in the range of 2 mm to 10 mm in thickness, but is not limited to this range. The shape of the orally disintegrating tablet of the present invention may be a normal tablet or an atypical tablet, and may be, for example, a circular shape, an oval shape, or a caplet shape, but is not limited thereto.
（口腔内崩壊錠の製造方法）
　本発明の別の局面は、８０～３００μｍの範囲のメジアン粒子径を有するアセトアミノフェンと高成形性の結晶セルロースと崩壊剤とを混合して粉体混合物を得る工程、及び前記粉体混合物を直接打錠して錠剤を得る工程を含む、上記口腔内崩壊錠の製造方法に関する。 (Manufacturing method of orally disintegrating tablets)
Another aspect of the present invention is a step of mixing acetaminophen having a median particle size in the range of 80 to 300 μm, highly moldable crystalline cellulose, and a disintegrant to obtain a powder mixture, and the powder mixture. The present invention relates to a method for producing an orally disintegrating tablet, which comprises a step of directly tableting to obtain a tablet.
　本発明の製造方法の「８０～３００μｍの範囲のメジアン粒子径を有するアセトアミノフェンと高成形性の結晶セルロースと崩壊剤とを混合して粉体混合物を得る工程」（以下、混合工程という）は、口腔内崩壊錠を打錠する前に、口腔内崩壊錠の生理活性薬物のアセトアミノフェンと、その他の成分を混合する工程である。その他の成分とは、高成形性の結晶セルロースと崩壊剤のほか、甘味剤、矯味剤及び／又はその他の添加剤である。 The production method of the present invention "a step of mixing acetaminophen having a median particle diameter in the range of 80 to 300 μm, highly moldable crystalline cellulose, and a disintegrant to obtain a powder mixture" (hereinafter referred to as a mixing step). Is a step of mixing the bioactive drug acetaminophen of the orally disintegrating tablet with other components before the orally disintegrating tablet is beaten. Other components are highly moldable crystalline celluloses and disintegrants, as well as sweeteners, flavoring agents and / or other additives.
　本発明の口腔内崩壊錠の製造方法に用いる８０～３００μｍの範囲のメジアン粒子径を有するアセトアミノフェン、高成形性の結晶セルロース、崩壊剤、甘味剤、香料、矯味剤及びその他の添加剤は、上記（口腔内崩壊錠）に記載のものと同様のものを用いることができる。 The acetaminophen, highly moldable crystalline cellulose, disintegrant, sweetener, flavor, flavoring agent and other additives used in the method for producing an orally disintegrating tablet of the present invention having a median particle size in the range of 80 to 300 μm , The same as those described above (orally disintegrating tablets) can be used.
　本明細書において「混合」は、２種類以上の粉体を混ぜることを意味する。当該分野で用いられる用語に「粉砕」があるが、これは粒子を砕いて小さい粒子を得ることを意味する。一方、本明細書の「混合」は、粉体の粒子径を細かくする作用がない操作である。また、当該技術分野で用いられる「解砕整粒」は、凝集した粒子を引きはがすことを意味する。解砕整粒と粉砕では、粉体に「せん断力」が強くかかるが、混合は「せん断力」が弱い操作である。例えば、微粉領域のアセトアミノフェン粒子が多く凝集している粉体の場合、各粒子を引きはがすための強い「せん断力」が必要となり、この操作が解砕整粒である。さらに強い「せん断力」で粒子を壊す操作は粉砕である。 In the present specification, "mixing" means mixing two or more kinds of powders. The term used in the art is "crushing", which means crushing particles to obtain smaller particles. On the other hand, "mixing" in the present specification is an operation that does not have the effect of making the particle size of the powder finer. In addition, "crushing and sizing" used in the technical field means peeling off agglomerated particles. In crushing and sizing and crushing, a strong "shearing force" is applied to the powder, but in mixing, the "shearing force" is weak. For example, in the case of a powder in which many acetaminophen particles in the fine powder region are agglomerated, a strong "shearing force" is required to peel off each particle, and this operation is crushing and sizing. The operation of breaking particles with a stronger "shear force" is crushing.
　例えば、特許文献４に記載の錠剤の製造は、未粉砕のアセトアミノフェン原薬を原料として使用するが、解砕整粒機を用いてアセトアミノフェンの粒子径が大きな結晶や凝集した塊を選択的に解砕整粒する工程を含むため、錠剤に含まれるアセトアミノフェンの粒子は、未粉砕のアセトアミノフェン原薬よりも細粒化していると考えられる。一方、本発明者らは、本製造方法においては、アセトアミノフェン原薬の粒子径（メジアン粒子径８０～３００μｍ）は、混合工程を経た後でも変化がないことを、粒子径分布測定及び電子顕微鏡像の観察により確認した。 For example, in the production of tablets described in Patent Document 4, uncrushed acetaminophen drug substance is used as a raw material, and crystals or agglomerated lumps having a large particle size of acetaminophen are produced by using a crushing and sizing machine. It is considered that the acetaminophen particles contained in the tablets are finer than the uncrushed acetaminophen drug substance because the step of selectively crushing and sizing is included. On the other hand, the present inventors have determined that in the present production method, the particle size (median particle size 80 to 300 μm) of the acetaminophen drug substance does not change even after the mixing step. It was confirmed by observing the microscopic image.
　本製造方法の混合工程は、例えば、Ｖ型混合機やコンテナミキサー等を用いて実施することができる。Ｖ型混合機は、Ｖ形状の混合容器を回転させることで、容器内の粉粒体を全体に移動し、対流運動を与えることで、速やかで均一な混合を行う装置である。Ｖ型混合機を用いることで、通常、粉粒体に無理な力をかけない緩和な混合が可能である。混合条件は、スケールによって適宜変更することができるが、例えば回転速度５～５０ｒｐｍで１～１５分間程度実施することができる。 The mixing step of this production method can be carried out using, for example, a V-type mixer, a container mixer, or the like. The V-type mixer is a device that rotates a V-shaped mixing container to move the powders and granules in the container as a whole and gives a convection motion to perform quick and uniform mixing. By using a V-type mixer, it is usually possible to perform mild mixing without applying an excessive force to the powder or granular material. The mixing conditions can be appropriately changed depending on the scale, and can be carried out, for example, at a rotation speed of 5 to 50 rpm for about 1 to 15 minutes.
　本製造方法の混合工程は、１回の混合操作で実施してもよいし、あるいは２回以上の混合操作に分けて実施することができる。１回の混合操作で行う場合には、口腔内崩壊錠に含まれる全ての成分がＶ型混合機等に投入され、混合される。２回以上の混合操作に分けて行う場合には、口腔内崩壊錠に含まれる成分を種類の別に２回以上に分けてＶ型混合機等に投入・混合することができる。例えば１回目の混合の際には、滑沢剤（例えば、ステアリン酸マグネシウム）以外の成分をＶ型混合機等に投入し混合し、滑沢剤は、１回目の混合後に添加し、再度、混合することができる。これにより、滑沢剤の展延を防ぐことができる。滑沢剤を加えた後の混合は、１～３分間程度とすることができる。本製造方法の混合工程により、粉体混合物を得ることができる。粉体混合物は、口腔内崩壊錠に含まれる成分の粉状の集合体である。 The mixing step of this production method may be carried out by one mixing operation, or may be carried out by dividing into two or more mixing operations. When the mixing operation is performed once, all the components contained in the orally disintegrating tablet are put into a V-type mixer or the like and mixed. When the mixing operation is divided into two or more times, the components contained in the orally disintegrating tablet can be divided into two or more times according to the type and charged and mixed in a V-type mixer or the like. For example, at the time of the first mixing, components other than the lubricant (for example, magnesium stearate) are put into a V-type mixer or the like and mixed, and the lubricant is added after the first mixing and again. Can be mixed. This can prevent the spread of the lubricant. Mixing after adding the lubricant can be about 1 to 3 minutes. A powder mixture can be obtained by the mixing step of this production method. The powder mixture is a powdery aggregate of the components contained in the orally disintegrating tablet.
　本発明の製造方法の「前記粉体混合物を直接打錠して錠剤を得る工程」（以下、打錠工程という）は、上記混合工程で得られた粉体混合物を直接打錠し、成型する工程である。本明細書において、直接打錠とは、杵臼を用いて、粉体混合物を直接圧縮して錠剤を得る、乾式法による打錠を意味する。 In the "step of directly tableting the powder mixture to obtain a tablet" (hereinafter referred to as a tableting step) of the production method of the present invention, the powder mixture obtained in the above mixing step is directly tableted and molded. It is a process. As used herein, direct tableting means tableting by a dry method in which a powder mixture is directly compressed using a mortar to obtain tablets.
　打錠は、具体的には、打錠機（例えば、回転式成型機）を用いて行うことができ、例えば、固定金型（臼穴）に充填された粉末を容積秤量し、上下金型（杵）によって圧縮成型し最終的に金型（臼穴）から放出することにより行うことができる。 Specifically, the locking can be performed using a locking machine (for example, a rotary molding machine). For example, the powder filled in the fixed mold (mortar hole) is volumetrically weighed and the upper and lower molds are pressed. This can be done by compression molding with a (pestle) and finally discharging from a mold (mortar hole).
　本発明の製造方法においては、打錠圧は、錠剤硬度や打錠用杵の耐圧許容度等を考慮して適宜設定することができるが、３～５０ｋＮの範囲、好ましくは５～４０ｋＮの範囲とすることができる。打錠圧は、錠剤に硬度等の物理的な強度を付与するものであり、打錠圧が低いと、錠剤硬度が低くなる可能性がある。しかし、打錠圧を高くすれば、それに伴って錠剤硬度が高くなるというものではなく、例えば成分により、打錠圧を高くしても錠剤硬度が高くならない場合もある。また、打錠圧が高いと、打錠用杵の損傷や打錠障害（キャッピング、スティッキング）が生じやすい。従って、打錠の際には、錠剤の特性に応じた圧力をかける必要がある。 In the production method of the present invention, the tableting pressure can be appropriately set in consideration of the tablet hardness, the pressure resistance tolerance of the tableting punch, etc., but is in the range of 3 to 50 kN, preferably in the range of 5 to 40 kN. Can be. The tableting pressure imparts physical strength such as hardness to the tablet, and if the tableting pressure is low, the tablet hardness may be low. However, increasing the tableting pressure does not mean that the tablet hardness increases accordingly. For example, depending on the component, the tablet hardness may not increase even if the tableting pressure is increased. Further, when the locking pressure is high, damage to the locking punch and locking failure (capping, sticking) are likely to occur. Therefore, when tableting, it is necessary to apply pressure according to the characteristics of the tablet.
　錠剤の製造方法では、流動層造粒法など湿式の方法がよく用いられている。しかし、湿式造粒は、工程数が多く、製造原価も割高となる。本発明によれば、乾式の粉体を直接打錠する方法により、簡単で製造コストが低い口腔内崩壊錠の製造方法を提供することができる。 In the tablet manufacturing method, a wet method such as a fluidized bed granulation method is often used. However, wet granulation requires a large number of steps and the manufacturing cost is high. According to the present invention, it is possible to provide a method for producing an orally disintegrating tablet which is simple and has a low production cost by a method of directly tableting a dry powder.
　以下の例に基づいて本発明をより具体的に説明するが、本発明はこれらの例に限定されるものではない。なお、本明細書において、特に記載しない限り、「％」は質量基準であり、数値範囲はその端点を含むものとして記載される。 The present invention will be described in more detail based on the following examples, but the present invention is not limited to these examples. In the present specification, unless otherwise specified, "%" is based on mass, and the numerical range is described as including its end points.
（１）錠剤の製造法
　以下の実施例及び比較例において、以下の試薬を使用して、アセトアミノフェンを含む錠剤を製造した。
アセトアミノフェン原薬
　ａ）　アセトアミノフェンＳ（山本化学工業株式会社）（以下、ＡＡ原薬ａと記載する）
　ｂ）　Dense Powder（SpecGx LLC)（以下、ＡＡ原薬ｂと記載する）
　ｃ)　アセトアミノフェンＳＳ（山本化学工業株式会社）（以下、ＡＡ原薬ｃと記載する）
クロスポビドン（ＣＬ－Ｆ、ＢＡＳＦ）
クロスカルメロースナトリウム（キッコレート（登録商標）ＮＤ－２００、旭化成株式会社）
デンプングリコール酸ナトリウム（Ｐｒｉｍｏｊｅｌ、ＤＥＦ　ｐｈａｒｍａ）
部分アルファ化デンプン（ＰＣＳ　ＰＣ-１０、旭化成株式会社） (1) Method for producing tablets In the following Examples and Comparative Examples, tablets containing acetaminophen were produced using the following reagents.
Acetaminophen drug substance a) Acetaminophen S (Yamamoto Corporation) (hereinafter referred to as AA drug substance a)
b) Dense Powder (SpecGx LLC) (hereinafter referred to as AA API b)
c) Acetaminophen SS (Yamamoto Corporation) (hereinafter referred to as AA API c)
Crosspovidone (CL-F, BASF)
Croscarmellose sodium (Kiccolate (registered trademark) ND-200, Asahi Kasei Corporation)
Sodium starch glycolate (Primogel, DEF pharma)
Partially pregelatinized starch (PCS PC-10, Asahi Kasei Corporation)
結晶セルロース（セオラス（登録商標）　ＫＧ－１０００、旭化成株式会社）
結晶セルロース（セオラス（登録商標）　ＫＧ－８０２、旭化成株式会社）
結晶セルロース（セオラス（登録商標）　ＰＨ－１０１、旭化成株式会社）
結晶セルロース（セオラス（登録商標）　ＵＦ－７１１、旭化成株式会社）
ステアリン酸マグネシウム（太平化学産業）
メタケイ酸アルミン酸マグネシウム（ノイシリン　ＵＦＬ２、富士化学工業株式会社）
アスパルテーム（味の素ｋｋアスパルテーム、味の素ヘルシーサプライ株式会社）
アセスルファムカリウム（サネットD（登録商品）、三菱商事ライフサイエンス）
スクラロース（三栄源）
Ｄ－マンニトール（グラニュトール（登録商標）Ｓ、フロイント産業株式会社）
無水二酸化ケイ素（Ａｅｒｏｓｉｌ　２００、日本アエロジル株式会社）
シクロデキストリン（樋口商会）
含水二酸化ケイ素　（カープレックス♯80（登録商品）、エボニック ジャパン株式会社）粉体香料：グレープフルーツフレーバー（高田香料）
粉体香料：メントールフレーバー（高田香料）
粉体香料：アップル香料（高田香料） Crystalline Cellulose (Theoras (registered trademark) KG-1000, Asahi Kasei Corporation)
Crystalline Cellulose (Theoras (registered trademark) KG-802, Asahi Kasei Corporation)
Crystalline Cellulose (Theoras (registered trademark) PH-101, Asahi Kasei Corporation)
Crystalline Cellulose (Theoras (registered trademark) UF-711, Asahi Kasei Corporation)
Magnesium stearate (Taipei Chemical Industry)
Magnesium aluminate metasilicate (Neucillin UFL2, Fuji Chemical Industry Co., Ltd.)
Aspartame (Ajinomoto kk Aspartame, Ajinomoto Healthy Supply Co., Ltd.)
Acesulfame Potassium (Sanet D (registered product), Mitsubishi Corporation Life Sciences)
Sucralose (Saneigen)
D-mannitol (Granitol (registered trademark) S, Freund Sangyo Co., Ltd.)
Anhydrous Silicon Dioxide (Aerosil 200, Nippon Aerosil Co., Ltd.)
Cyclodextrin (Higuchi Shokai)
Hydrous Silicon Dioxide (Carplex # 80 (Registered Product), Ebony Japan Co., Ltd.) Powder Fragrance: Grapefruit Flavor (Takata Fragrance)
Powder fragrance: Menthol flavor (Takata fragrance)
Powder fragrance: Apple fragrance (Takata fragrance)
　錠剤の製造工程において、打錠粉体の混合にはＶ型混合機（Ｖ－１０、徳寿製作所）、打錠には打錠機（ＨＴ－ＡＰ１５ＳＳ－II、畑鐵工所）及び平面スミ角の杵臼を使用した。打錠は、打錠成型が可能である場合は、打錠用杵の耐圧許容度等を考慮し、錠剤硬度が５０Ｎ以上となるように、打錠圧を設定して実施した。 In the tablet manufacturing process, a V-type mixer (V-10, Tokuju Seisakusho) is used for mixing tableting powder, and a tableting machine (HT-AP15SS-II, Hata Iron Works) is used for tableting. I used a mortar and pestle. When tableting can be performed, the tableting pressure is set so that the tablet hardness is 50 N or more in consideration of the pressure resistance of the tableting punch.
（２）アセトアミノフェン原薬の粒子径測定
　上記３種類のアセトアミノフェン原薬についてレーザー回折法による乾式粒子径測定を実施した。粒度分布の測定には、Ｌａｓｅｒ　Ｍｉｃｒｏｎ　Ｓｉｚｅｒ　ＬＭＳ－２０００ｅ（株式会社セイシン企業）を用いた。測定時の分散圧縮空気圧は０．５ｂａｒで実施した。 (2) Measurement of particle size of acetaminophen drug substance The dry particle size measurement of the above three types of acetaminophen drug substance was carried out by laser diffraction method. A Laser Micron Sizer LMS-2000e (Seishin Enterprise Co., Ltd.) was used for measuring the particle size distribution. The dispersed compressed air pressure at the time of measurement was 0.5 bar.
　アセトアミノフェン(ＡＡ)原薬の粒子径の測定結果を表１に示す。
Figure JPOXMLDOC01-appb-T000001
 Table 1 shows the measurement results of the particle size of the acetaminophen (AA) drug substance.
Figure JPOXMLDOC01-appb-T000001
（３）錠剤の硬度測定
　後述する実施例及び比較例で製造した錠剤について、硬度測定試験を実施した。硬度測定は硬度計（ＰＣ－１０、岡田精工）を用いて実施した。 (3) Hardness measurement of tablets A hardness measurement test was carried out on the tablets produced in Examples and Comparative Examples described later. Hardness measurement was carried out using a hardness tester (PC-10, Okada Seiko).
（４）錠剤の崩壊性試験
　後述する実施例及び比較例で製造した錠剤について、崩壊性試験を実施した。崩壊性試験は、口腔内（速）崩壊錠測定装置　トリコープテスタ（登録商標）（岡田精工）を用いて、２枚の金網で挟んだ錠剤の上から人工唾液水溶液を滴下し、錠剤が崩壊して２枚の金網が接するまでの時間（崩壊時間）を測定した。錠剤の上に置く金網の重さは１０ｇであった。測定は、３７±０．５℃の人工唾液水溶液（表２を参照）を高さ８０ｍｍから、６ｍＬ／分の送液速度で滴下して実施した。５錠の平均値を測定した。
Figure JPOXMLDOC01-appb-T000002
 (4) Disintegration test of tablets A disintegration test was carried out on the tablets produced in Examples and Comparative Examples described later. In the disintegration test, an artificial saliva aqueous solution was dropped onto a tablet sandwiched between two wire meshes using an intraoral (fast) disintegrating tablet measuring device, Tricorp Tester (registered trademark) (Okada Seiko), and the tablet disintegrated. Then, the time (collapse time) until the two wire meshes came into contact with each other was measured. The wire mesh placed on the tablet weighed 10 g. The measurement was carried out by dropping an artificial saliva aqueous solution (see Table 2) at 37 ± 0.5 ° C. from a height of 80 mm at a liquid feeding rate of 6 mL / min. The average value of 5 tablets was measured.
Figure JPOXMLDOC01-appb-T000002
（５）粒子径が異なるＡＡ原薬ａ～ｃを用いたＯＤ錠剤の製造例
実施例１
　ＡＡ原薬ａ　８０．０ｇ、クロスポビドン５．０ｇ、メタケイ酸アルミン酸マグネシウム１．０ｇ、結晶セルロース（ＫＧ－１０００）１３．９ｇをＶ型混合機にて混合撹拌（回転速度４２ｒｐｍ、混合時間１０分）し、中間打錠粉体を得た。中間打錠粉体に、ステアリン酸マグネシウム０．１ｇを添加し、さらに追加の混合撹拌（回転速度４２ｒｐｍ、混合時間２分）をして打錠粉体を得た。打錠粉体を打錠機と直径９ｍｍ杵臼を使用して打錠し（打錠圧１５ｋＮ）、錠剤重量３７９ｍｇ、錠厚５．２９ｍｍ、錠剤硬度７４Ｎの錠剤を得た。 (5) Example of Production of OD Tablets Using AA Drug Substances a to C with Different Particle Diameters Example 1
AA drug substance a 80.0 g, crospovidone 5.0 g, magnesium aluminometasilicate 1.0 g, crystalline cellulose (KG-1000) 13.9 g are mixed and stirred in a V-type mixer (rotation speed 42 rpm, mixing time 10). Minutes) to obtain an intermediate tableting powder. 0.1 g of magnesium stearate was added to the intermediate tableting powder, and further mixing and stirring (rotation speed 42 rpm, mixing time 2 minutes) was performed to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a mortar with a diameter of 9 mm (tablet pressure 15 kN) to obtain tablets having a tablet weight of 379 mg, a tablet thickness of 5.29 mm, and a tablet hardness of 74 N.
実施例２
　ＡＡ原薬ｂ　８０．０ｇ、クロスポビドン４．０ｇ、メタケイ酸アルミン酸マグネシウム１．０ｇ、結晶セルロース（ＫＧ－１０００）１４．３ｇ、無水二酸化ケイ素０．５ｇをＶ型混合機にて混合撹拌し、中間打錠粉体を得た。中間打錠粉体に、ステアリン酸マグネシウム０．２ｇを添加し、さらに追加の撹拌混合をして打錠粉体を得た。打錠粉体を打錠機と直径９ｍｍ杵臼を使用して打錠し（打錠圧２３ｋＮ）、錠剤重量３８７ｍｇ、錠厚５．５１ｍｍ、錠剤硬度６０Ｎの錠剤を得た。 Example 2
AA drug substance b 80.0 g, crospovidone 4.0 g, magnesium aluminometasilicate 1.0 g, crystalline cellulose (KG-1000) 14.3 g, and anhydrous silicon dioxide 0.5 g are mixed and stirred with a V-type mixer. , Intermediate tableting powder was obtained. 0.2 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a mortar with a diameter of 9 mm (tablet pressure 23 kN) to obtain tablets having a tablet weight of 387 mg, a tablet thickness of 5.51 mm, and a tablet hardness of 60 N.
比較例３
　ＡＡ原薬ｃ　８０．０ｇ、クロスポビドン４．０ｇ、メタケイ酸アルミン酸マグネシウム１．０ｇ、結晶セルロース（ＫＧ－１０００）１４．３０ｇ、無水二酸化ケイ素０．５ｇをＶ型混合機にて混合撹拌し、中間打錠粉体を得た。中間打錠粉体へステアリン酸マグネシウム０．２ｇを添加し、さらに追加の撹拌混合をして打錠粉体を得た。打錠粉体を打錠機と直径９．０ｍｍ杵臼を使用して打錠し（打錠圧２４ＫＮ）、錠剤重量３８７ｍｇ、錠厚５．２０ｍｍ、錠剤硬度６０Ｎの錠剤を得た。 Comparative Example 3
AA drug substance c 80.0 g, crospovidone 4.0 g, magnesium aluminometasilicate 1.0 g, crystalline cellulose (KG-1000) 14.30 g, and anhydrous silicon dioxide 0.5 g are mixed and stirred with a V-type mixer. , Intermediate tableting powder was obtained. 0.2 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a mortar with a diameter of 9.0 mm (tablet pressure 24 KN) to obtain tablets having a tablet weight of 387 mg, a tablet thickness of 5.20 mm and a tablet hardness of 60 N.
比較例４
　ＡＡ原薬ｃ　７０．０ｇ、Ｄ－マンニトール１０．０ｇ、クロスポビドン４．０ｇ、メタケイ酸アルミン酸マグネシウム１．０ｇ、結晶セルロース（ＫＧ－１０００）１４．３０ｇ、無水二酸化ケイ素０．５ｇをＶ型混合機にて混合撹拌し、中間打錠粉体を得た。中間打錠粉体へステアリン酸マグネシウム０．２ｇを添加し、さらに追加の撹拌混合をして打錠粉体を得た。打錠粉体を打錠機と直径９．０ｍｍ杵臼を使用して打錠し（打錠圧８ｋＮ）、錠剤重量３９０ｍｇ、錠厚５．７５ｍｍ、錠剤硬度５１Ｎの錠剤を得た。打錠時間経過とともに錠剤のキャッピングが観察され、製造に適さないことがわかった。 Comparative Example 4
AA drug substance c 70.0 g, D-mannitol 10.0 g, crospovidone 4.0 g, magnesium aluminometasilicate 1.0 g, crystalline cellulose (KG-1000) 14.30 g, anhydrous silicon dioxide 0.5 g, V type The mixture was mixed and stirred with a mixer to obtain an intermediate tableting powder. 0.2 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a mortar with a diameter of 9.0 mm (tablet pressure 8 kN) to obtain tablets having a tablet weight of 390 mg, a tablet thickness of 5.75 mm and a tablet hardness of 51 N. Capping of tablets was observed with the lapse of tableting time, and it was found that they were not suitable for production.
比較例５
　ＡＡ原薬ｃ　６０．０ｇ、Ｄ－マンニトール２０．０ｇ、クロスポビドン４．０ｇ、メタケイ酸アルミン酸マグネシウム１．０ｇ、結晶セルロース（ＫＧ－１０００）１４．３０ｇ、無水二酸化ケイ素０．５ｇをＶ型混合機にて混合撹拌し、中間打錠粉体を得た。中間打錠粉体へステアリン酸マグネシウム０．２ｇを添加し、さらに追加の撹拌混合をして打錠粉体を得た。打錠粉体を打錠機と直径９．０ｍｍ杵臼を使用して打錠し（打錠圧９ＫＮ）、錠剤重量３７５ｍｇ、錠厚５．７４ｍｍ、錠剤硬度５５Ｎの錠剤を得た。 Comparative Example 5
AA drug substance c 60.0 g, D-mannitol 20.0 g, crospovidone 4.0 g, magnesium aluminometasilicate 1.0 g, crystalline cellulose (KG-1000) 14.30 g, anhydrous silicon dioxide 0.5 g, V type The mixture was mixed and stirred with a mixer to obtain an intermediate tableting powder. 0.2 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a mortar with a diameter of 9.0 mm (tablet pressure 9 KN) to obtain tablets having a tablet weight of 375 mg, a tablet thickness of 5.74 mm and a tablet hardness of 55 N.
比較例６
　ＡＡ原薬ｃ　５０．０ｇ、Ｄ－マンニトール３０．０ｇ、クロスポビドン４．０ｇ、メタケイ酸アルミン酸マグネシウム１．０ｇ、結晶セルロース（ＫＧ－１０００）１４．３０ｇ、無水二酸化ケイ素０．５ｇをＶ型混合機にて混合撹拌し、中間打錠粉体を得た。中間打錠粉体へステアリン酸マグネシウム０．２ｇを添加し、さらに追加の撹拌混合をして打錠粉体を得た。打錠粉体を打錠機と直径９．０ｍｍ杵臼を使用して打錠し（打錠圧１０ｋＮ）、錠剤重量３８７ｍｇ、錠厚５．７３ｍｍ、錠剤硬度６３Ｎの錠剤を得た。 Comparative Example 6
AA drug substance c 50.0 g, D-mannitol 30.0 g, crospovidone 4.0 g, magnesium aluminometasilicate 1.0 g, crystalline cellulose (KG-1000) 14.30 g, anhydrous silicon dioxide 0.5 g, V type The mixture was mixed and stirred with a mixer to obtain an intermediate tableting powder. 0.2 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a mortar with a diameter of 9.0 mm (tablet pressure 10 kN) to obtain tablets having a tablet weight of 387 mg, a tablet thickness of 5.73 mm and a tablet hardness of 63 N.
比較例７
　ＡＡ原薬ｃ　４０．０ｇ、Ｄ－マンニトール４０．０ｇ、クロスポビドン４．０ｇ、メタケイ酸アルミン酸マグネシウム１．０ｇ、結晶セルロース（ＫＧ－１０００）１４．３０ｇ、無水二酸化ケイ素０．５ｇをＶ型混合機にて混合撹拌し、中間打錠粉体を得た。中間打錠粉体へステアリン酸マグネシウム０．２ｇを添加し、さらに追加の撹拌混合をして打錠粉体を得た。打錠粉体を打錠機と直径９．０ｍｍ杵臼を使用して打錠し（打錠圧７ｋＮ）、錠剤重量３９３ｍｇ、錠厚６．０１ｍｍ、錠剤硬度５７Ｎの錠剤を得た。錠剤の錠剤硬度としては問題ないが、実用上で望まれる含有量を満たしていない。 Comparative Example 7
AA drug substance c 40.0 g, D-mannitol 40.0 g, crospovidone 4.0 g, magnesium aluminometasilicate 1.0 g, crystalline cellulose (KG-1000) 14.30 g, anhydrous silicon dioxide 0.5 g, V type The mixture was mixed and stirred with a mixer to obtain an intermediate tableting powder. 0.2 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a mortar with a diameter of 9.0 mm (tablet pressure 7 kN) to obtain tablets having a tablet weight of 393 mg, a tablet thickness of 6.01 mm and a tablet hardness of 57 N. There is no problem with the tablet hardness of the tablet, but the content does not satisfy the content desired in practical use.
　表３に、上記の錠剤の組成及び性状をまとめて示す。
Figure JPOXMLDOC01-appb-T000003
 Table 3 summarizes the composition and properties of the above tablets.
Figure JPOXMLDOC01-appb-T000003
　実施例１～２及び比較例３の錠剤は、アセトアミノフェンを８０％含有するが、直接打錠可能であった。なお、比較例３～７の錠剤は、アセトアミノフェン原薬の粒子が細かいために、流動化剤の無水二酸化ケイ素を添加することにより打錠可能となったが、スティッキングなどの打錠障害が生じる場合があった。錠剤硬度５０Ｎ未満の錠剤は、輸送や医薬品の分包機などで割れ欠けが生じやすくなり実用的な観点から問題があるが、実施例１～２及び比較例３～７の錠剤は、錠剤硬度５０Ｎを有するように打錠することができた。 The tablets of Examples 1 and 2 and Comparative Example 3 contained 80% of acetaminophen, but could be directly tableted. Since the particles of the acetaminophen drug substance are fine, the tablets of Comparative Examples 3 to 7 can be tableted by adding anhydrous silicon dioxide as a fluidizing agent, but they have problems such as sticking. It could occur. Tablets with a tablet hardness of less than 50 N are prone to cracking and chipping during transportation and pharmaceutical packaging machines, and have problems from a practical point of view. However, the tablets of Examples 1 and 2 and Comparative Examples 3 to 7 have a tablet hardness of 50 N. Was able to be tableted to have.
　メジアン粒子径１８５μｍを有するＡＡ原薬ａを使用して作成した実施例１の錠剤の崩壊時間は９秒であり、ＯＤ錠として実用的であった。メジアン粒子径１１５μｍを有するＡＡ原薬ｂを使用して作成した実施例２の錠剤の崩壊時間２４秒であり、ＯＤ錠として実用的であった。一方、メジアン粒子径２６μｍを有するＡＡ原薬ｃを使用して作成した比較例３の錠剤の崩壊時間３００秒以上であり、ＯＤ錠としては実用的ではなかった。 The disintegration time of the tablet of Example 1 prepared using the AA drug substance a having a median particle size of 185 μm was 9 seconds, which was practical as an OD tablet. The disintegration time of the tablet of Example 2 prepared using the AA drug substance b having a median particle size of 115 μm was 24 seconds, which was practical as an OD tablet. On the other hand, the disintegration time of the tablet of Comparative Example 3 prepared by using the AA drug substance c having a median particle size of 26 μm was 300 seconds or more, which was not practical as an OD tablet.
　メジアン粒子径２６μｍを有するＡＡ原薬ｃを使用した製造例において、アセトアミノフェンの含量を７０％～５０％とし、賦形剤のＤ－マンニトールを添加した錠剤（比較例４～６）の崩壊時間は３０秒以上であったため、ＯＤ錠としては実用的ではなかった。一方、アセトアミノフェンを４０％及びＤ－マンニトールを４０％含有する錠剤（比較例７）の崩壊時間は、１９秒となったが、アセトアミノフェンの含有量が錠剤中１５７ｍｇとなり、実用上で望まれる含有量を満たさなかった。 Disintegration of tablets (Comparative Examples 4 to 6) in which the content of acetaminophen was 70% to 50% and the excipient D-mannitol was added in the production example using the AA drug substance c having a median particle size of 26 μm. Since the time was 30 seconds or more, it was not practical as an OD tablet. On the other hand, the disintegration time of the tablet containing 40% acetaminophen and 40% D-mannitol (Comparative Example 7) was 19 seconds, but the content of acetaminophen was 157 mg in the tablet, which was practically practical. Did not meet the desired content.
（６）アセトアミノフェン高含有ＯＤ錠剤の製造例及びアセトアミノフェン含有率６０～７５質量％のＯＤ錠剤の製造例
実施例８
　ＡＡ原薬ａ　８５．０ｇ、クロスポビドン４．０ｇ、メタケイ酸アルミン酸マグネシウム１．０ｇ、結晶セルロース（ＫＧ－１０００）９．８５ｇをＶ型混合機にて混合撹拌し、中間打錠粉体を得た。中間打錠粉体に、ステアリン酸マグネシウム０．１５ｇを添加し、さらに追加の撹拌混合をして打錠粉体を得た。打錠粉体を打錠機と直径８．５ｍｍ杵臼を使用して打錠し（打錠圧２６ｋＮ）、錠剤重量２３８ｍｇ、錠厚３．５５ｍｍ、錠剤硬度５２Ｎの錠剤を得た。 (6) Example of Production of OD Tablet with High Acetaminophen Content and Example of Production of OD Tablet with Acetaminophen Content of 60 to 75% by Mass Example 8
AA drug substance a 85.0 g, crospovidone 4.0 g, magnesium aluminometasilicate 1.0 g, and crystalline cellulose (KG-1000) 9.85 g are mixed and stirred in a V-type mixer to prepare an intermediate tableting powder. Obtained. 0.15 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a mortar with a diameter of 8.5 mm (tablet pressure 26 kN) to obtain tablets having a tablet weight of 238 mg, a tablet thickness of 3.55 mm, and a tablet hardness of 52 N.
実施例９
　打錠粉体を、直径９．０ｍｍ杵臼を使用して、打錠圧１８ｋＮで打錠したほかは、実施例８と同様の組成及び方法で打錠粉体を調製した。錠剤重量３５３ｍｇ、錠厚４．８５ｍｍ、錠剤硬度６１Ｎの錠剤を得た。 Example 9
The tableting powder was prepared by the same composition and method as in Example 8 except that the tableting powder was tableted at a tableting pressure of 18 kN using a 9.0 mm diameter pestle. A tablet having a tablet weight of 353 mg, a tablet thickness of 4.85 mm, and a tablet hardness of 61 N was obtained.
実施例１０
　長径１５．０×短径８．０ｍｍの杵臼を使用して、打錠圧１８ｋＮで打錠したほかは、実施例８と同様の組成及び方法で打錠粉体を調製した。錠剤重量５９５ｍｇ、錠厚５．７９ｍｍ、錠剤硬度７３Ｎの楕円形の錠剤を得た。 Example 10
A tableting powder was prepared by the same composition and method as in Example 8 except that the tablet was tableted at a tableting pressure of 18 kN using a mortar having a major axis of 15.0 and a minor axis of 8.0 mm. An oval tablet having a tablet weight of 595 mg, a tablet thickness of 5.79 mm and a tablet hardness of 73 N was obtained.
比較例Ａ―Ｂ、実施例Ｃ
　ＡＡ原薬ａ６０．０ｇ、７０．０ｇ又は７５．０ｇ、クロスカルメロースナトリウム３．０ｇ、含水二酸化ケイ素０．５ｇ、甘味料、フレーバー、及び結晶セルロース（ＫＧ－１０００）３０．０、２０．０又は１５．０ｇをＶ型混合機にて混合撹拌し、中間打錠粉体を得た。中間打錠粉体に、ステアリン酸マグネシウム０．２ｇを添加し、さらに追加の撹拌混合をして打錠粉体を得た。打錠粉体を打錠機と直径９ｍｍ杵臼を使用して打錠し錠剤を得た。 Comparative Examples AB, C
AA API a60.0g, 70.0g or 75.0g, croscarmellose sodium 3.0g, hydrous silicon dioxide 0.5g, sweeteners, flavors, and crystalline cellulose (KG-1000) 30.0, 20.0 Alternatively, 15.0 g was mixed and stirred with a V-type mixer to obtain an intermediate tableting powder. 0.2 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a 9 mm diameter mortar to obtain tablets.
　表４に、上記の錠剤の組成及び性状をまとめて示す。
Figure JPOXMLDOC01-appb-T000004
 Table 4 summarizes the composition and properties of the above tablets.
Figure JPOXMLDOC01-appb-T000004
　実施例８～１０の錠剤は、メジアン粒子径１８５μｍを有するＡＡ原薬ａを使用して作成した。実施例８～１０の錠剤は、アセトアミノフェンを８５％含有するが、直接打錠可能であった。錠剤硬度５０Ｎ未満の錠剤は、輸送や医薬品の分包機などで割れ欠けが生じやすくなり実用的な観点から問題があるが、実施例８～１０の錠剤は、錠剤硬度５０Ｎ以上を有するように打錠可能であった。実施例８～１０の錠剤の崩壊時間は３０秒未満であり、実用的な口腔内速崩壊性を有していた。
　比較例Ａ及びＢ並びに実施例Ｃの錠剤は、メジアン粒子径１８５μｍを有するＡＡ原薬ａを使用して作成した。比較例Ａ及びＢ並びに実施例Ｃの錠剤はいずれも、直接打錠可能であった。アセトアミノフェンを７５％含有する実施例Ｃの錠剤の崩壊時間は３０秒未満であり、実用的な口腔内速崩壊性を有していた。一方、アセトアミノフェンを７０％及び６０％含有するそれぞれ比較例Ａ及びＢの錠剤の崩壊時間は３０秒以上となり口腔内崩壊錠としては適当ではなかった。 The tablets of Examples 8 to 10 were prepared using AA API a with a median particle size of 185 μm. The tablets of Examples 8 to 10 contained 85% acetaminophen, but could be directly tableted. Tablets having a tablet hardness of less than 50 N are prone to cracking and chipping in transportation and pharmaceutical packaging machines, which is problematic from a practical point of view. However, the tablets of Examples 8 to 10 are beaten so as to have a tablet hardness of 50 N or more. It was lockable. The disintegration time of the tablets of Examples 8 to 10 was less than 30 seconds, and they had a practical rapid disintegration property in the oral cavity.
The tablets of Comparative Examples A and B and Example C were prepared using AA drug substance a having a median particle size of 185 μm. The tablets of Comparative Examples A and B and Example C were all directly tabletable. The disintegration time of the tablet of Example C containing 75% of acetaminophen was less than 30 seconds, and it had a practical rapid disintegration property in the oral cavity. On the other hand, the disintegration time of the tablets of Comparative Examples A and B containing 70% and 60% of acetaminophen was 30 seconds or more, which was not suitable as an orally disintegrating tablet.
（７）甘味剤及び粉体香料を含有した製造例、崩壊剤を変更した製造例
実施例１１
　ＡＡ原薬ａ　８０．０ｇ、クロスポビドン４．０ｇ、メタケイ酸アルミン酸マグネシウム１．０ｇ、結晶セルロース（ＫＧ－１０００）１３．４０ｇ、アスパルテーム１．０ｇ及び粉体香料をＶ型混合機にて混合撹拌し、中間打錠粉体を得た。中間打錠粉体へステアリン酸マグネシウム０．２ｇを添加し、さらに追加の撹拌混合をして打錠粉体を得た。打錠粉体を打錠機と直径９．０ｍｍ杵臼を使用して打錠し（打錠圧２５ｋＮ）、錠剤重量３７３ｍｇ、錠厚５．２０ｍｍ、錠剤硬度５５Ｎの錠剤を得た。 (7) Production Example containing a sweetener and powder flavor, Production Example in which the disintegrant is changed Example 11
AA drug substance a 80.0 g, crospovidone 4.0 g, magnesium aluminometasilicate 1.0 g, crystalline cellulose (KG-1000) 13.40 g, aspartame 1.0 g and powder fragrance are mixed in a V-type mixer. The mixture was stirred to obtain an intermediate tableting powder. 0.2 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a mortar with a diameter of 9.0 mm (tablet pressure 25 kN) to obtain tablets having a tablet weight of 373 mg, a tablet thickness of 5.20 mm and a tablet hardness of 55 N.
実施例１２
　実施例１１のクロスポビドンをクロスカルメロースナトリウムに変更し、調製・打錠（打錠圧２１ｋＮ）した。錠剤重量３８３ｍｇ、錠厚５．３２ｍｍ、錠剤硬度５２Ｎの錠剤を得た。 Example 12
The crospovidone of Example 11 was changed to croscarmellose sodium, and the mixture was prepared and tableted (tablet pressure 21 kN). Tablets having a tablet weight of 383 mg, a tablet thickness of 5.32 mm, and a tablet hardness of 52 N were obtained.
実施例１３
　実施例１１のクロスポビドンをデンプングリコール酸ナトリウムに変更し、調製・打錠（打錠圧２３ｋＮ）した。錠剤重量３８３ｍｇ、錠厚５．２５ｍｍ、錠剤硬度５１Ｎの錠剤を得た。 Example 13
The crospovidone of Example 11 was changed to sodium starch glycolate, and the mixture was prepared and tableted (tablet pressure 23 kN). Tablets having a tablet weight of 383 mg, a tablet thickness of 5.25 mm, and a tablet hardness of 51 N were obtained.
実施例１４
　ＡＡ原薬ａ　８０．０ｇ、クロスポビドン３．０ｇ、メタケイ酸アルミン酸マグネシウム１．０ｇ、結晶セルロース（ＫＧ－１０００）１３．４０ｇ、アスパルテーム０．８ｇ、スクラロース０．２ｇ、粉体香料０．４ｇ、シクロデキストリン３．４ｇをＶ型混合機にて混合撹拌し、中間打錠粉体を得た。中間打錠粉体に、ステアリン酸マグネシウム０．２ｇを添加し、さらに追加の撹拌混合をして打錠粉体を得た。打錠粉体を打錠機と直径９．０ｍｍ杵臼を使用して打錠し（打錠圧２２ｋＮ）、錠剤重量３８７ｍｇ、錠厚５．３１ｍｍ、錠剤硬度５６Ｎの錠剤を得た。 Example 14
AA drug substance a 80.0 g, crospovidone 3.0 g, magnesium aluminometasilicate 1.0 g, crystalline cellulose (KG-1000) 13.40 g, aspartame 0.8 g, sucralose 0.2 g, powder fragrance 0.4 g , Cyclodextrin (3.4 g) was mixed and stirred with a V-type mixer to obtain an intermediate tableting powder. 0.2 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a mortar with a diameter of 9.0 mm (tablet pressure 22 kN) to obtain tablets having a tablet weight of 387 mg, a tablet thickness of 5.31 mm and a tablet hardness of 56 N.
実施例１５
　実施例１１のＡＡ原薬ａをＡＡ原薬ｂに変更し、調製・打錠（打錠圧２３ｋＮ）した。錠剤重量３７７ｍｇ、錠厚５．５１ｍｍ、錠剤硬度５０Ｎの錠剤を得た。 Example 15
The AA drug substance a of Example 11 was changed to the AA drug substance b, and the mixture was prepared and tableted (tablet pressure 23 kN). Tablets having a tablet weight of 377 mg, a tablet thickness of 5.51 mm, and a tablet hardness of 50 N were obtained.
　表５に、上記の錠剤の組成及び性状をまとめて示す。
Figure JPOXMLDOC01-appb-T000005
 Table 5 summarizes the composition and properties of the above tablets.
Figure JPOXMLDOC01-appb-T000005
　実施例１１～１５の錠剤は、実施例１と比較して、結晶セルロース（ＫＧ－１０００）及び崩壊剤の含有量を減らし、甘味剤及び粉体香料を添加して製造された。実施例１１～１５の錠剤は、アセトアミノフェンを８０％含有するが、直接打錠可能であり、錠剤硬度５０Ｎを有するように打錠することができた。 The tablets of Examples 11 to 15 were produced by reducing the content of crystalline cellulose (KG-1000) and a disintegrant, and adding a sweetener and a powder flavor, as compared with Example 1. Although the tablets of Examples 11 to 15 contain 80% of acetaminophen, they can be directly tableted and can be tableted so as to have a tablet hardness of 50N.
　実施例１１～１５の錠剤の崩壊時間は、いずれも３０秒以内であり、ＯＤ錠として実用的であった。崩壊剤をクロスポビドンに替えて、クロスカルメロースナトリウムやデンプングリコール酸ナトリウムを用いても、錠剤硬度と崩壊時間に大きな変化は観察されなかった。 The disintegration time of the tablets of Examples 11 to 15 was within 30 seconds, which was practical as an OD tablet. No significant changes were observed in tablet hardness and disintegration time when croscarmellose sodium or sodium starch glycolate was used instead of crospovidone as the disintegrant.
（８）結晶セルロース含量が異なる製造例
比較例１６
　ＡＡ原薬ａ　８５．０ｇ、クロスポビドン５．０ｇ、メタケイ酸アルミン酸マグネシウム１．０ｇ、結晶セルロース（ＫＧ－１０００）８．５ｇをＶ型混合機にて混合撹拌し、中間打錠粉体を得た。中間打錠粉体へステアリン酸マグネシウム０．５ｇを添加し、さらに追加の撹拌混合をして打錠粉体を得た。打錠粉体を打錠機と直径８．５ｍｍ杵臼を使用して打錠し（打錠圧２２ｋＮ）、錠剤重量３６０ｍｇ、錠厚４．９１ｍｍ、錠剤硬度３９Ｎの錠剤を得た。 (8) Production Example with Different Crystal Cellulose Content Comparative Example 16
AA drug substance a 85.0 g, crospovidone 5.0 g, magnesium aluminometasilicate 1.0 g, and crystalline cellulose (KG-1000) 8.5 g are mixed and stirred with a V-type mixer to prepare an intermediate tableting powder. Obtained. 0.5 g of magnesium stearate was added to the intermediate tableting powder, and the mixture was further stirred and mixed to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a mortar with a diameter of 8.5 mm (tablet pressure 22 kN) to obtain tablets having a tablet weight of 360 mg, a tablet thickness of 4.91 mm and a tablet hardness of 39 N.
実施例１７
　比較例１６の結晶セルロース（ＫＧ－１０００）の含量を８．６５ｇに、ステアリン酸マグネシウムの含量を０．３５ｇに変更して、打錠粉体を得た。打錠粉体を打錠機と直径９ｍｍ杵臼を使用して打錠し（打錠圧２１ｋＮ）、錠剤重量３５３ｍｇ、錠厚４．８０ｍｍ、錠剤硬度５２Ｎの錠剤を得た。 Example 17
The content of crystalline cellulose (KG-1000) of Comparative Example 16 was changed to 8.65 g, and the content of magnesium stearate was changed to 0.35 g to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a mortar with a diameter of 9 mm (tablet pressure 21 kN) to obtain tablets having a tablet weight of 353 mg, a tablet thickness of 4.80 mm and a tablet hardness of 52 N.
実施例１８
　比較例１６の結晶セルロース（ＫＧ－１０００）の含量を８．８ｇに、ステアリン酸マグネシウムの含量を０．２ｇに変更して、打錠粉体を得た。打錠粉体を打錠機と直径９ｍｍ杵臼を使用して打錠し（打錠圧２３ｋＮ）、錠剤重量３５２ｍｇ、錠厚４．７９ｍｍ、錠剤硬度５８Ｎの錠剤を得た。 Example 18
The content of crystalline cellulose (KG-1000) of Comparative Example 16 was changed to 8.8 g, and the content of magnesium stearate was changed to 0.2 g to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a mortar with a diameter of 9 mm (tablet pressure 23 kN) to obtain tablets having a tablet weight of 352 mg, a tablet thickness of 4.79 mm, and a tablet hardness of 58 N.
実施例１９
　比較例１６の結晶セルロース（ＫＧ－１０００）の含量を８．９ｇに、ステアリン酸マグネシウムの含量を０．１ｇに変更して、打錠粉体を得た。打錠粉体を打錠機と直径９ｍｍ杵臼を使用して打錠し（打錠圧１５ｋＮ）、錠剤重量３５９ｍｇ、錠厚４．９６ｍｍ、錠剤硬度７１Ｎの錠剤を得た。 Example 19
The content of crystalline cellulose (KG-1000) of Comparative Example 16 was changed to 8.9 g, and the content of magnesium stearate was changed to 0.1 g to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a mortar with a diameter of 9 mm (tablet pressure 15 kN) to obtain tablets having a tablet weight of 359 mg, a tablet thickness of 4.96 mm and a tablet hardness of 71 N.
実施例２０
　比較例１６のクロスポビドンを４ｇに、結晶セルロース（ＫＧ－１０００）の含量を９．８ｇに、ステアリン酸マグネシウムの含量を０．２ｇに変更して、打錠粉体を得た。打錠粉体を打錠機と直径９ｍｍ杵臼を使用して打錠し（打錠圧２４ｋＮ）、錠剤重量３５４ｍｇ、錠厚４．７９ｍｍ、硬度６４Ｎの錠剤を得た。 Example 20
The content of crospovidone of Comparative Example 16 was changed to 4 g, the content of crystalline cellulose (KG-1000) was changed to 9.8 g, and the content of magnesium stearate was changed to 0.2 g to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a mortar with a diameter of 9 mm (tablet pressure 24 kN) to obtain tablets having a tablet weight of 354 mg, a tablet thickness of 4.79 mm and a hardness of 64 N.
　表６に、上記の錠剤の組成及び性状をまとめて示す。
Figure JPOXMLDOC01-appb-T000006
 Table 6 summarizes the composition and properties of the above tablets.
Figure JPOXMLDOC01-appb-T000006
　比較例１６と実施例１７～２０に基づいて、結晶セルロースの含量が、錠剤硬度に影響を与えることが明らかになった。 Based on Comparative Example 16 and Examples 17 to 20, it was clarified that the content of crystalline cellulose affects the tablet hardness.
（９）結晶セルロースの種類が異なる製造例
　以下の製造例では、４種類の結晶セルロースを使用した。
　実施例２１
　ＡＡ原薬ａ　８０．０ｇ、部分アルファ化デンプン１．０ｇ、クロスカルメロースナトリウム３．０ｇ、結晶セルロース（ＫＧ－１０００）１０．０ｇ、メタケイ酸アルミン酸マグネシウム１．０ｇ、アスパルテーム３．０ｇ、アセスルファムカリウム０．３ｇ、グレープフルーツフレーバー０．３ｇ、メントールフレーバー０．３ｇ及び含水二酸化ケイ素０．５ｇをＶ型混合機にて混合撹拌（回転速度４２ｒｐｍ、混合時間１０分）し、中間打錠粉体を得た。中間打錠粉体に、ステアリン酸マグネシウム０．２ｇを添加し、さらに追加の混合撹拌（回転速度４２ｒｐｍ、混合時間２分）をして打錠粉体を得た。打錠粉体を打錠機と直径９ｍｍ杵臼を使用して打錠を得た。結晶セルロースＫＧ－１０００のかさ密度は、０．１０～０．１５ｇ／ｃｍ３である。 (9) Production Examples with Different Types of Crystalline Cellulose In the following production examples, four types of crystalline cellulose were used.
Example 21
AA drug substance a 80.0 g, partially pregelatinized starch 1.0 g, croscarmellose sodium 3.0 g, crystalline cellulose (KG-1000) 10.0 g, magnesium aluminometasilicate 1.0 g, aspartame 3.0 g, assesulfam Mix and stir 0.3 g of potassium, 0.3 g of grapefruit flavor, 0.3 g of menthol flavor and 0.5 g of hydrous silicon dioxide with a V-type mixer (rotation speed 42 rpm, mixing time 10 minutes) to prepare an intermediate tableting powder. Obtained. 0.2 g of magnesium stearate was added to the intermediate tableting powder, and additional mixing and stirring (rotation speed 42 rpm, mixing time 2 minutes) was performed to obtain a tableting powder. The tableting powder was tableted using a tableting machine and a 9 mm diameter mortar. The bulk density of crystalline cellulose KG-1000 is 0.10 to 0.15 g / cm 3 .
　比較例２２
　結晶セルロースをＰＨ－１０１に変更した以外は実施例２１と同様の組成にて、錠剤を得た。結晶セルロースＰＨ－１０１のかさ密度は、０．２９ｇ／ｃｍ３である。 Comparative Example 22
Tablets were obtained with the same composition as in Example 21 except that the crystalline cellulose was changed to PH-101. The bulk density of crystalline cellulose PH-101 is 0.29 g / cm 3 .
　比較例２３
　結晶セルロースをＵＦ－７１１に変更した以外は実施例２１と同様の組成にて、錠剤を得た。結晶セルロースＵＦ－７１１のかさ密度は、０．２２ｇ／ｃｍ３である。 Comparative Example 23
Tablets were obtained with the same composition as in Example 21 except that the crystalline cellulose was changed to UF-711. The bulk density of crystalline cellulose UF-711 is 0.22 g / cm 3 .
　実施例２４
　結晶セルロースをＫＧ－８０２に変更した以外は実施例２１と同様の組成にて、錠剤を得た。結晶セルロースＫＧ－８０２のかさ密度は、０．２１ｇ／ｃｍ３である。 Example 24
Tablets were obtained with the same composition as in Example 21 except that the crystalline cellulose was changed to KG-802. The bulk density of crystalline cellulose KG-802 is 0.21 g / cm 3 .
　表７に、上記の錠剤の組成及び性状をまとめて示す。
Figure JPOXMLDOC01-appb-T000007
 Table 7 summarizes the composition and properties of the above tablets.
Figure JPOXMLDOC01-appb-T000007
　また、比較例２３の錠剤（結晶セルロースＵＦ－７１１を含む）を製造する際に、打錠圧を１１ｋＮ、２１ｋＮ、２４ｋＮ、及び２７ｋＮに変化させて打錠を行い、それにより得られ錠剤の硬度は、順に３２Ｎ、４２Ｎ、４７Ｎ、及び４６Ｎであった。
　同様に、実施例２４の錠剤（結晶セルロースＫＧ－８０２を含む）を製造する際に、打錠圧を２０ｋＮ、２３ｋＮ、及び２５ｋＮに変化させて打錠を行い、それにより得られ錠剤の硬度は、順に４６Ｎ、５４Ｎ、及び５２Ｎであった。 Further, when the tablet of Comparative Example 23 (including crystalline cellulose UF-711) was produced, the tableting pressure was changed to 11 kN, 21 kN, 24 kN, and 27 kN for tableting, and the hardness of the tablet obtained thereby was obtained. Were 32N, 42N, 47N, and 46N, respectively.
Similarly, when producing the tablet of Example 24 (including crystalline cellulose KG-802), the tableting pressure was changed to 20 kN, 23 kN, and 25 kN for tableting, and the hardness of the tablet obtained thereby was determined. , 46N, 54N, and 52N, respectively.
　上記結果から、結晶セルロースＫＧ－１０００及びＫＧ－８０２を各々使用した実施例２１及び２４では、５０Ｎ以上の錠剤硬度を達成することができた。但し、ＫＧ－８０２を含む実施例２４については、打錠圧を２３ｋＮよりも高くしても、錠剤硬度は上昇しなかった。そのため、打錠圧をより上げて打錠を行ったとしても更なる錠剤硬度の上昇は見込めないと考えられる。一方、ＫＧ－１０００を含む実施例２１では、打錠圧１８ｋＮで、実用的に十分な錠剤硬度が得られた。 From the above results, in Examples 21 and 24 using the crystalline celluloses KG-1000 and KG-802, respectively, a tablet hardness of 50 N or more could be achieved. However, in Example 24 containing KG-802, the tablet hardness did not increase even if the tableting pressure was higher than 23 kN. Therefore, it is considered that a further increase in tablet hardness cannot be expected even if the tableting pressure is further increased to perform tableting. On the other hand, in Example 21 containing KG-1000, a practically sufficient tablet hardness was obtained at a tableting pressure of 18 kN.
（１０）錠剤の表面観察
　打錠された錠剤の表面状態を観察するため、電子顕微鏡にて表面状態を観察した。画像倍率は１００倍及び３００倍にて観察した。図１から３に電子顕微鏡像を示す。
　電子顕微鏡にて表面状態を観察した結果、実施例１１の錠剤表面は滑らかで細孔がないことが確認され、比較例３及び比較例７においては、細孔や錠剤表面の凹凸が確認された。 (10) Observation of the surface of the tablet In order to observe the surface condition of the tableted tablet, the surface condition was observed with an electron microscope. The image magnification was observed at 100 times and 300 times. The electron microscope images are shown in FIGS. 1 to 3.
As a result of observing the surface state with an electron microscope, it was confirmed that the tablet surface of Example 11 was smooth and had no pores, and in Comparative Example 3 and Comparative Example 7, the pores and the unevenness of the tablet surface were confirmed. ..
（１１）錠剤の比表面積測定
　打錠された錠剤の表面状態を定量的に観察するため、窒素吸着法による比表面積の測定を実施した。実験にはＡｕｔｏｓｏｒｂ－ｉＱ２ＸＲ（Anton Paar Japan）を用いた。測定時に錠剤は破砕せずに錠剤の形状のまま測定した。測定時の吸着ガスは窒素ガスを用い、吸着温度は７７ケルビンで実施した。一般的な（非ＯＤ錠、素錠）アセトアミノフェン含有錠剤（カロナール（登録商標）錠300、あゆみ製薬株式会社）の比表面積についても、同様に測定した。測定結果を表８に示す。 (11) Measurement of specific surface area of tablets In order to quantitatively observe the surface condition of tablets that have been tableted, the specific surface area was measured by the nitrogen adsorption method. Autosorb-iQ2XR (Anton Paar Japan) was used in the experiment. At the time of measurement, the tablets were measured in the shape of tablets without being crushed. Nitrogen gas was used as the adsorption gas at the time of measurement, and the adsorption temperature was 77 Kelvin. The specific surface area of general (non-OD tablets, uncoated tablets) acetaminophen-containing tablets (Caronal (registered trademark) tablet 300, AYUMI Pharmaceutical Corporation) was also measured in the same manner. The measurement results are shown in Table 8.
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
　カロナール（登録商標）錠３００の比表面積と比較して、口腔内崩壊錠の比表面積がより広いことがわかった。比表面積が広いほど、より多孔性であるということができ、錠剤内部に導水されやすい。全細孔容量はいずれも小さいことから、サブミクロン領域における細孔はほぼ存在していないことがわかった。 It was found that the specific surface area of the orally disintegrating tablet was larger than that of the caronal (registered trademark) tablet 300. It can be said that the larger the specific surface area, the more porous the tablet, and the easier it is for water to be conducted inside the tablet. Since the total pore capacity was small, it was found that there were almost no pores in the submicron region.
（１２）錠剤の細孔分布測定
　実施例２及び１１、比較例３、７及び２８の錠剤について、水銀圧入法による細孔分布の測定を実施した。測定にはＰｏｒｅＭａｓｔｅｒ６０ＧＴ（Anton Paar Japan）を使用した。測定時には錠剤は粉砕せずに錠剤の形状のまま測定した。サンプルのセルには０．５ccのスモール標準セルを用いて実施した。カロナール（登録商標）錠300（あゆみ製薬株式会社）の細孔分布についても、同様に測定した。 (12) Measurement of pore size distribution of tablets The pore size distribution of the tablets of Examples 2 and 11 and Comparative Examples 3, 7 and 28 was measured by the mercury intrusion method. A PoleMaster 60GT (Anton Paar Japan) was used for the measurement. At the time of measurement, the tablets were measured in the shape of tablets without being crushed. A 0.5 cc small standard cell was used as the sample cell. The pore distribution of Caronal (registered trademark) Tablets 300 (AYUMI Pharmaceutical Corporation) was also measured in the same manner.
　実施例２及び１１、比較例３、７及び２８の錠剤並びにカロナール（登録商標）錠300の気孔率を表９に示す。
Figure JPOXMLDOC01-appb-T000009
 Table 9 shows the porosities of the tablets of Examples 2 and 11, Comparative Examples 3, 7 and 28 and Caronal® Tablets 300.
Figure JPOXMLDOC01-appb-T000009
　錠剤が有する空孔を水銀圧入法において測定した結果、ＡＡ原薬ｃを用いた比較例３及び比較例２８の気孔率はそれぞれ１５％及び１８％であった。ＡＡ原薬ｃを用いると含有量を４０％まで下げＤ－マンニトールの含有量を増加させて気孔率を２５％以上にしなければ口腔内崩壊時間が３０秒以下とならなかった（比較例７）。
　ＡＡ原薬ｂを用いた実施例２及びＡＡ原薬ａを用いた実施例１１の気孔率はそれぞれ１９％及び１３％であり、ＡＡ原薬ｃを用いて製造した錠剤（比較例３及び２８）と気孔率は同等程度であった。 As a result of measuring the pores of the tablets by the mercury injection method, the porosities of Comparative Example 3 and Comparative Example 28 using the AA drug substance c were 15% and 18%, respectively. When the AA drug substance c was used, the oral disintegration time did not become 30 seconds or less unless the content was lowered to 40% and the content of D-mannitol was increased to increase the porosity to 25% or more (Comparative Example 7). ..
The porosities of Example 2 using the AA drug substance b and Example 11 using the AA drug substance a were 19% and 13%, respectively, and tablets produced using the AA drug substance c (Comparative Examples 3 and 28). ) And the porosity were about the same.
　一般的に口腔内崩壊錠は速やかな崩壊を実現するため、水の通り道である細孔が多くなるようにデザインする。本発明の口腔内崩壊錠（実施例２及び１１）は、気孔率が２０％未満であるが口腔内崩壊錠としての物性を有している。
　ＡＡ原薬ａ又はｂを用いて製造した錠剤は、ＡＡ原薬ｃを用いた場合の錠剤と同程度の表面細孔を有しているが、ＡＡ原薬ａ又はｂを用いた場合のみ口腔内崩壊時間３０秒以下を達成できていることから、本発明の錠剤の崩壊メカニズムには気孔率のほかに、別の要因が関与していると考えられる。 In general, orally disintegrating tablets are designed to have many pores, which are water passages, in order to achieve rapid disintegration. The orally disintegrating tablets of the present invention (Examples 2 and 11) have a porosity of less than 20% but have physical properties as an orally disintegrating tablets.
Tablets produced using AA drug substance a or b have surface pores similar to those of tablets using AA drug substance c, but only when AA drug substance a or b is used in the oral cavity. Since the internal disintegration time of 30 seconds or less can be achieved, it is considered that another factor is involved in the disintegration mechanism of the tablet of the present invention in addition to the porosity.
（１３）錠剤の空隙率
　実施例２及び１１、比較例３、７及び２８の錠剤並びにカロナール（登録商標）錠300（あゆみ製薬株式会社）について空隙率（％）を算出した。
　錠剤の空隙率（％）は、ピクノメーター（UltraPyc 1200e、Anton Paar Japan）から錠の真比重を算出し、それを基に算出した。
空隙率（％）＝（Ｖ－Ｗ／Ｍ）／Ｖ×１００
（Ｖ：崩壊錠の体積（ｃｍ３）、Ｗ：崩壊錠の質量（ｇ）、Ｍ：崩壊錠の密度（ｇ／ｃｍ３））
Figure JPOXMLDOC01-appb-T000010
 (13) Porosity of Tablets The porosity (%) was calculated for the tablets of Examples 2 and 11, Comparative Examples 3, 7 and 28, and Caronal (registered trademark) tablet 300 (AYUMI Pharmaceutical Corporation).
The porosity (%) of the tablet was calculated based on the true specific gravity of the tablet calculated from a pycnometer (UltraPyc 1200e, Anton Paar Japan).
Porosity (%) = (VW / M) / V × 100
(V: Volume of disintegrating tablet (cm 3 ), W: Mass of disintegrating tablet (g), M: Density of disintegrating tablet (g / cm 3 ))
Figure JPOXMLDOC01-appb-T000010
　ＡＡ原薬ａ及びＡＡ原薬ｂをそれぞれ用いた実施例２及び１１の口腔内崩壊錠の空隙率は１０％以下であり、ＡＡ原薬ｃを用いた比較例３及び２８並びにカロナール錠３００（非ＯＤ錠）の空隙率と同程度であった。
　ＡＡ原薬ｃを用いた比較例３及び２８は、口腔内崩壊時間３０秒以内を達成していない。ＡＡ原薬ｃを用いて口腔内崩壊時間３０秒以下を達成する錠剤を製造しようとすると、ＡＡ原薬ｃ含有率を４０％にして空隙率を確保しなければならなかった（比較例７）。一方、ＡＡ原薬ａ又はｂを用いると、ＡＡ原薬を高含有で含み、且つ口腔内崩壊時間３０秒以内の条件を満たす口腔内崩壊錠を製造することが可能であった。
　従来の口腔内崩壊錠では、空隙率２０％以上となるように製造し、所望の口腔内崩壊時間を達成している場合がある（例えば、特許文献１、２、８及び９に開示されているＯＤ錠）。本発明（実施例２及び１１）。本発明の口腔内崩壊錠の空隙率は１０％以下であるが口腔内崩壊時間３０秒以内を達成しており、従来の口腔内崩壊錠とは異なるメカニズムにより崩壊を生じていると考えられる。 The porosity of the orally disintegrating tablets of Examples 2 and 11 using AA drug substance a and AA drug substance b, respectively, was 10% or less, and Comparative Examples 3 and 28 using AA drug substance c and Caronal Tablets 300 ( It was about the same as the porosity of non-OD tablets).
Comparative Examples 3 and 28 using the AA drug substance c did not achieve the oral disintegration time of 30 seconds or less. In order to produce a tablet that achieves an oral disintegration time of 30 seconds or less using the AA drug substance c, the porosity must be secured by setting the AA drug substance c content to 40% (Comparative Example 7). .. On the other hand, when the AA drug substance a or b was used, it was possible to produce an orally disintegrating tablet containing a high content of the AA drug substance and satisfying the condition that the oral disintegration time was within 30 seconds.
Conventional orally disintegrating tablets may be manufactured so as to have a porosity of 20% or more to achieve a desired orally disintegrating time (for example, disclosed in Patent Documents 1, 2, 8 and 9). OD tablets). The present invention (Examples 2 and 11). Although the porosity of the orally disintegrating tablet of the present invention is 10% or less, the orally disintegrating time is within 30 seconds, and it is considered that the disintegrating tablet is caused by a mechanism different from that of the conventional orally disintegrating tablet.
（１４）錠剤表面の成分マッピング
　崩壊のメカニズムを明らかとするため、実施例１１と比較例３の錠剤表面の成分マッピングを行った。装置はラマン顕微鏡（ａｌｐｈａ３００ＲＳＡ、励起波長：５３２ｎｍ、測定波数範囲：約１２５～３８００ｃｍ－１）を使用した。その結果、を図４（実施例１１）、図５（比較例３）に示す。
　図４においては崩壊剤の一部が錠剤表面に露出している様子が確認され、図５においては錠剤表面にはほとんど確認されなかった。アセトアミノフェン粒子（ＡＡ原薬ａ）を用いることで崩壊剤がアセトアミノフェンの粒子間に局在化し、結果として錠剤の崩壊を促進していると推察される。 (14) Component mapping of tablet surface In order to clarify the mechanism of disintegration, component mapping of the tablet surface of Example 11 and Comparative Example 3 was performed. The apparatus used was a Raman microscope (alpha300RSA, excitation wavelength: 532 nm, measurement wavenumber range: about 125 to 3800 cm -1 ). The results are shown in FIGS. 4 (11) and 5 (comparative example 3).
In FIG. 4, it was confirmed that a part of the disintegrant was exposed on the tablet surface, and in FIG. 5, it was hardly confirmed on the tablet surface. It is presumed that the disintegrant is localized between the acetaminophen particles by using the acetaminophen particles (AA drug substance a), and as a result, the disintegration of the tablet is promoted.
（１５）官能評価試験
　下記処方のアセトアミノフェン高含有口腔内崩壊錠に関して、官能評価試験を行った。
Figure JPOXMLDOC01-appb-T000011
 (15) Sensory evaluation test A sensory evaluation test was conducted on an orally disintegrating tablet containing a high amount of acetaminophen having the following formulation.
Figure JPOXMLDOC01-appb-T000011
　味及び口腔内崩壊速度に関して、以下の５段階で評価した。
１点：非常に悪い、２点：悪い、３点：どちらでもない、４点：良い、５点：非常によい
　なお、評価は６名のパネラーで実施し、その平均点を以下の表にまとめた。味及び口腔内崩壊速度に関して、優れていた。
Figure JPOXMLDOC01-appb-T000012
   The taste and the rate of disintegration in the oral cavity were evaluated on the following five stages.
1 point: very bad, 2 points: bad, 3 points: neither, 4 points: good, 5 points: very good In addition, the evaluation was carried out by 6 panelists, and the average score is shown in the table below. Summarized. It was excellent in terms of taste and rate of disintegration in the oral cavity.
Figure JPOXMLDOC01-appb-T000012

Claims (11)

  1. 　８０～３００μｍの範囲のメジアン粒子径を有するアセトアミノフェンと、高成形性の結晶セルロースと、崩壊剤とを含む口腔内崩壊錠であって、前記アセトアミノフェンの１錠中含有率は７５質量％以上及び１錠中含有量は１９０ｍｇ以上であり、錠剤硬度５０Ｎ以上を有する口腔内崩壊錠。 An orally disintegrating tablet containing acetaminophen having a median particle size in the range of 80 to 300 μm, highly moldable crystalline cellulose, and a disintegrant, and the content of the acetaminophen in one tablet is 75 mass by mass. % Or more and the content in one tablet is 190 mg or more, and the orally disintegrating tablet having a tablet hardness of 50 N or more.
  2. 　口腔内崩壊錠に、人工唾液水溶液を、送液速度６ｍＬ／分、滴下高さ８０ｍｍ、及び荷重１０ｇの条件にて、滴下して測定される崩壊時間が３０秒以内である、請求項１に記載の口腔内崩壊錠。 The disintegration time measured by dropping an artificial saliva aqueous solution onto an orally disintegrating tablet under the conditions of a liquid feeding rate of 6 mL / min, a dropping height of 80 mm, and a load of 10 g is 30 seconds or less, according to claim 1. The orally disintegrating tablet described.
  3. 　空隙率が２０％未満である、請求項１又は２に記載の口腔内崩壊錠。 The orally disintegrating tablet according to claim 1 or 2, wherein the porosity is less than 20%.
  4. 　錠剤の気孔率が２５％未満である、請求項１～３の何れか一項に記載の口腔内崩壊錠。 The orally disintegrating tablet according to any one of claims 1 to 3, wherein the tablet has a porosity of less than 25%.
  5. 　甘味剤及び／又は香料をさらに含む、請求項１～４の何れか一項に記載の口腔内崩壊錠。 The orally disintegrating tablet according to any one of claims 1 to 4, further comprising a sweetening agent and / or a flavoring agent.
  6. 　前記結晶セルロースを１錠中８．５質量％より多く含む、請求項１～５の何れか一項に記載の口腔内崩壊錠。 The orally disintegrating tablet according to any one of claims 1 to 5, which contains more than 8.5% by mass of the crystalline cellulose in one tablet.
  7. 　前記結晶セルロースが、０．１０～０．１５ｇ／ｃｍ３の範囲のかさ密度を有する、請求項１～６の何れか一項に口腔内崩壊錠。 The orally disintegrating tablet according to any one of claims 1 to 6, wherein the crystalline cellulose has a bulk density in the range of 0.10 to 0.15 g / cm 3 .
  8. 　前記崩壊剤が、部分アルファ化デンプン、クロスポビドン、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択される何れかである、請求項１～７の何れか一項に記載の口腔内崩壊錠。 The oral cavity according to any one of claims 1 to 7, wherein the disintegrant is selected from the group consisting of partially pregelatinized starch, crospovidone, croscarmellose sodium, and sodium starch glycolate. Disintegrating tablet.
  9. 　前記甘味剤が、アスパルテーム、サッカリン、ステビア、アセスルファムカリウム及びスクラロースからなる群から選択される何れかである、請求項５～８の何れか一項に記載の口腔内崩壊錠。 The orally disintegrating tablet according to any one of claims 5 to 8, wherein the sweetening agent is any one selected from the group consisting of aspartame, saccharin, stevia, acesulfame potassium and sucralose.
  10. 　前記香料が粉体香料であり、グレープフルーツフレーバー、メントールフレーバー、メントールパウダー、ペパーミントパウダー、グレープフルーツエキスパウダー、レモンパウダー、アップルパウダー、ストロベリーパウダー及び巨峰パウダーからなる群から選択される何れかである、請求項５～９の何れか一項に記載の口腔内崩壊錠。 Claim that the perfume is a powder perfume and is selected from the group consisting of grapefruit flavor, menthol flavor, menthol powder, peppermint powder, grapefruit extract powder, lemon powder, apple powder, strawberry powder and giant peak powder. The orally disintegrating tablet according to any one of 5 to 9.
  11. 　８０～３００μｍの範囲のメジアン粒子径を有するアセトアミノフェンと高成形性の結晶セルロースと崩壊剤とを混合して粉体混合物を得る工程、及び
    前記粉体混合物を直接打錠して錠剤を得る工程を含む、
    請求項１～１０の何れか一項に記載の口腔内崩壊錠の製造方法。
          A step of mixing acetaminophen having a median particle size in the range of 80 to 300 μm, highly moldable crystalline cellulose, and a disintegrant to obtain a powder mixture, and directly tableting the powder mixture to obtain tablets. Including the process,
    The method for producing an orally disintegrating tablet according to any one of claims 1 to 10.
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JP2018150242A (en) * 2017-03-09 2018-09-27 旭化成株式会社 Cellulose composite

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