WO2020246120A1 - 口腔内崩壊錠及びその製造方法 - Google Patents

口腔内崩壊錠及びその製造方法 Download PDF

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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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tablet
orally disintegrating
powder
acetaminophen
disintegrating tablet
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PCT/JP2020/014429
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English (en)
French (fr)
Japanese (ja)
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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/ja
Publication of WO2020246120A1 publication Critical patent/WO2020246120A1/ja

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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.

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