WO2010119851A1 - Orally disintegrating tablet - Google Patents

Orally disintegrating tablet Download PDF

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Publication number
WO2010119851A1
WO2010119851A1 PCT/JP2010/056555 JP2010056555W WO2010119851A1 WO 2010119851 A1 WO2010119851 A1 WO 2010119851A1 JP 2010056555 W JP2010056555 W JP 2010056555W WO 2010119851 A1 WO2010119851 A1 WO 2010119851A1
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WO
WIPO (PCT)
Prior art keywords
mass
particles
coating
orally disintegrating
tablet
Prior art date
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PCT/JP2010/056555
Other languages
French (fr)
Japanese (ja)
Inventor
佑理子 石田
聖治 伊藤
美行 尾林
Original Assignee
ライオン株式会社
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Application filed by ライオン株式会社 filed Critical ライオン株式会社
Priority to JP2011509290A priority Critical patent/JPWO2010119851A1/en
Publication of WO2010119851A1 publication Critical patent/WO2010119851A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention relates to an orally disintegrating tablet containing drug particles having an unpleasant taste, and in particular, an oral disintegration in which the texture is good, the disintegration is good, and the unpleasant taste of the drug is masked It relates to locks.
  • a masking method by adding a flavor, a sweetening agent, or the like, and a masking method by coating a drug particle with a polymer base or the like is known.
  • masking of unpleasant taste by that method alone is difficult, and it can be applied only to limited drugs. Therefore, in order to mask a drug having a low unpleasant taste threshold, it is necessary to suppress the release of the drug in the oral cavity by coating with a polymer base or the like.
  • the normal coating amount may cause fine cracks in the coating film due to tableting pressure during production, In some cases, it is not possible to sufficiently suppress unpleasant taste due to the effect of chewing or peeling due to friction.
  • a method of making the coating layer thicker than usual can be considered, but as a result, sufficient release of the drug in the gastrointestinal tract cannot be ensured, and bioavailability is reduced as compared with a normal preparation. There is a problem.
  • the present invention has been made in view of the above circumstances, and is an orally disintegrating tablet that can be applied to drugs having various unpleasant tastes, has a good texture, good disintegration, and masks the unpleasant taste of drugs.
  • the purpose is to provide.
  • the chewable tablet is a tablet containing the tablet in the oral cavity, which is taken by being disintegrated / dissolved in the oral cavity by chewing or by contact with saliva or shear (friction) between the tongue and upper jaw. is there.
  • An orally disintegrating tablet is a tablet that contains a tablet in the oral cavity and is disintegrated and dissolved mainly by contact with saliva and by shearing between the tongue and upper jaw (mastication is not denied).
  • chewable tablets and orally disintegrating tablets are usually tablets that disintegrate in the oral cavity by chewing, contact with saliva, and sharing between the upper jaw and tongue, and are more effective than tablets taken with water.
  • the present invention has a common problem in that it is easy to feel an unpleasant taste, and is not clearly distinguished.
  • chewable tablets and orally disintegrating tablets are collectively referred to as “orally disintegrating tablets” unless otherwise specified.
  • crospovidone having specific physical properties among crospovidones known as disintegrants that is, an average particle size of 50 ⁇ m or less and a swelling amount of 5 (g )
  • Crospovidone particles having a water / (g) product of 5% by weight and a 5% by weight aqueous suspension with a viscosity of 20 mPa ⁇ s or less not only improve the disintegration (speed) of the tablet but also chew in the oral cavity. Prevents drug particles from being broken or peeled off due to friction and masking, resulting in an unpleasant taste masking of the drug.
  • the tablet disintegrates in the mouth the texture of each particle that makes up the tablet is reduced to reduce the texture. It has been found that it has the effect of significantly improving the above, and has led to the present invention.
  • the present invention provides the following orally disintegrating tablets.
  • A Drug particles in which a drug having an unpleasant taste is coated with a coating agent
  • B an average particle size of 50 ⁇ m or less, a swelling amount of 5 (g) water / (g) product or more, and 5 mass% water suspension
  • An orally disintegrating tablet comprising crospovidone particles having a viscosity (25 ° C.) of a turbid liquid of 20 mPa ⁇ s or less.
  • B The orally disintegrating tablet according to [1], wherein the content of the particles is 1 to 20% by mass.
  • A The orally disintegrating tablet according to [1] or [2], wherein the coating ratio of the coating agent to the drug in the particles is 1 to 60% by mass as a solid content.
  • an orally disintegrating tablet which can be applied to drugs having various unpleasant tastes, has a good texture, has good disintegration, and masks the unpleasant taste of drugs.
  • the orally disintegrating tablet of the present invention comprises (A) drug particles in which a drug having an unpleasant taste is coated with a coating agent, (B) an average particle size of 50 ⁇ m or less, and a swelling amount of 5 (g) water / (g)
  • the product contains crospovidone particles having a product of 5 mass% or more and a viscosity (25 ° C.) of a 5 mass% water suspension of 20 mPa ⁇ s or less.
  • Drug particles are obtained by coating a drug having an unpleasant taste with a coating agent.
  • Drugs with an unpleasant taste include acetaminophen, aspirin, ibuprofen, etenzamide, phenacetin, mefenamic acid, antipyrine, phenylbutazone, sulpyrine, sodium diclofenate, ketoprofen, naproxen, epilysole, thiaramide hydrochloride, indomethacin, pentazocine, chloride Acetylcholine, alimemazine tartrate, cyproheptadine hydrochloride, diphedramine hydrochloride, chlorpheniramine maleate, codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, pentoxyberine citrate, theophylline, aminophylline, ephedrine hydrochloride, epinephrine hydrochloride, sulfuric acid
  • the coating agent in the present invention refers to a component existing on the surface of a drug, and includes a coating base composed of a poorly water-soluble polymer compound and a plasticizer. By using this base, bitterness masking property and dissolution property are improved.
  • the “poorly water-soluble polymer compound” refers to a compound whose amount dissolved in 10,000 mL of water is 1 g or less than 1 mL.
  • Specific examples of the poorly water-soluble polymer compound include ethyl cellulose, aminoacryl methacrylate copolymer, and methacrylic acid copolymer. These can be used individually by 1 type or in combination of 2 or more types. Of these, ethyl cellulose is preferred from the viewpoint of usability and odor.
  • the content of the poorly water-soluble polymer compound is preferably 40 to 90% by mass, more preferably 40 to 80% by mass, based on the total solid content of the coating agent, in consideration of ease of coating, plasticity, elution, and the like. 50 to 70% by mass is particularly preferable.
  • the coating agent in the present invention preferably contains a plasticizer.
  • the plasticizer is presumed to have a function of imparting appropriate spreadability to the solution containing the coating agent and facilitating film formation.
  • the plasticizer include those described in official documents such as standards for pharmaceutical additives such as triacetin and triethyl citrate (Pharmaceutical Daily Inc.). These can be used individually by 1 type or in combination of 2 or more types. Considering film formability, triacetin and triethyl citrate are preferable, and triacetin is more preferable.
  • the content of the plasticizer is preferably 5 to 50% by mass, more preferably 10 to 40% by mass, based on the total solid content of the coating agent.
  • the total solid content (mass ratio) of the plasticizer: poorly water-soluble polymer compound is preferably 0.05: 1 to 0.5: 1, more preferably 0.1: 1 to 0.4: 1.
  • the coating agent may further contain an elution control agent from the viewpoint of improving the masking effect.
  • the elution control agent include sugars such as lactose, trehalose and sucrose, and sugar alcohols such as mannitol, erythritol, xylitol and sorbitol. These can be used alone or in combination of two or more.
  • the elution control agent may not be contained, and the content thereof is preferably 0 to 60% by mass, more preferably 0 to 50% by mass with respect to the total solid content of the coating agent.
  • a sweetener may be added to the coating agent.
  • the sweetener include aspartame, sucralose, erythritol, acesulfame potassium, saccharin sodium, stevia extract, thaumatin, sugar cane extract, heated palatinose, licorice, etc. Can do. Of these, aspartame and sucralose are preferable.
  • the content of the sweetening agent is preferably 0 to 50% by mass with respect to the total solid content of the coating agent.
  • the coating rate is preferably set in the range of 1 to 60% by mass as the solid content with respect to the drug (coating material).
  • a coating rate means the mass% of a coating agent when a drug (coating object) is 100 mass%.
  • the coating rate is 1% by mass or more, a sufficient masking effect is obtained, and when it exceeds 60% by mass, the effect is saturated and the drug release property may be deteriorated.
  • the lower limit of the coating rate is more preferably 3% by mass or more, further preferably 5% by mass or more, and particularly preferably 8% by mass or more. Further, from the viewpoint of drug release, it is preferable to set the coating rate low.
  • the upper limit is preferably 50% by mass or less, 40% by mass or less, 30% by mass or less, 25% by mass or less, It is preferable to set it as 15 mass% or less and 10 mass% or less.
  • coating deterioration due to external force such as impact or friction during manufacture (especially tableting) or taking is suppressed, so a low coating rate
  • a good taste masking effect can be obtained.
  • the average particle size of the particles is preferably 75 to 500 ⁇ m, more preferably 150 to 300 ⁇ m.
  • the average particle size is 1000 ⁇ m, 850 ⁇ m, 500 ⁇ m, 355 ⁇ m, 250 ⁇ m, 150 ⁇ m, and 75 ⁇ m sieves with an inner diameter of 75 mm. Based on the test and measurement, the cumulative particle size is 50%.
  • the content of the drug particles (A) is preferably 80% by mass or less, more preferably 70% by mass or less with respect to the orally disintegrating tablet from the viewpoint of ingestion and tablet physical properties (hardness, friability, disintegration, etc.). 65 mass% or less is particularly preferable.
  • the lower limit is not particularly limited, and can be a set content considering the effectiveness of each drug within the range below the upper limit.
  • Crospovidone particles (crospovidone particles (B)) of the present invention have (1) an average particle size of 50 ⁇ m or less, (2) a swelling amount of 5 (g) water / (g) product or more, and (3) The viscosity of the 5% by mass aqueous suspension is 20 mPa ⁇ s or less.
  • Crospovidone is a cross-linked polyvinyl pyrrolidone, which is a cross-linked polymer having the chemical name 1-ethenyl-2-pyrrolidinone homopolymer.
  • Orally disintegrating tablets disintegrate or bite in the oral cavity (especially between the tongue and upper jaw), causing the drug coating to peel off and unpleasant taste due to the share and impact at that time
  • tablets containing crospovidone particles (B) with the above physical properties collapse into creamy when applied in the oral cavity, and the influence on the coating layer due to friction and impact is suppressed, and the coating does not deteriorate. It can disintegrate and, as a result, has a good texture, good disintegration, and can enhance the masking effect of the unpleasant taste of the drug.
  • the average particle size of the crospovidone particles (B) used in the present invention is 50 ⁇ m or less, preferably 10 to 50 ⁇ m, more preferably 30 ⁇ m or less. If the average particle size exceeds 50 ⁇ m, the friction between the coating particles at the time of tablet disintegration is reduced and the cushioning role for suppressing the roughness is not achieved, and the roughness of the crospovidone particles themselves is also felt, resulting in poor texture. On the other hand, when the thickness is less than 10 ⁇ m, the uniformity of mixing may be deteriorated due to the deterioration of fluidity.
  • the average particle size is measured by a laser scattering diffraction particle size distribution analyzer (LS 13 320, manufactured by Beckman Coulter, Inc.).
  • the swelling amount is 5 (g) water / (g) product or more
  • the swelling amount of the crospovidone particles (B) used in the present invention is 5 (g) water / (g) product or more, and 5 to 20 (G) water / (g) product is preferable, and 5.5 to 8.5 (g) water / (g) product is more preferable.
  • the swelling amount is less than 5 (g) water / (g) product, the absorption of moisture is small, the function as a disintegrant is not sufficient in the tablet, and the disintegration property is deteriorated.
  • the swelling amount of the present invention can be determined as follows. (I) Add 1 g (M0) sample and 50 mL of distilled water at 20 ° C. to a centrifuge tube, shake and let stand for 15 minutes, then centrifuge (relative centrifugal acceleration 850 [ ⁇ g]; 15 minutes) and remove the supernatant. The mass (M1g) of the swollen sample is measured, and an approximate swelling amount M1 (M1 / M0) is calculated.
  • the viscosity (25 ° C.) of the 5% by mass aqueous suspension is 20 mPa ⁇ s or less
  • the viscosity (25 ° C.) of the 5% by mass aqueous suspension of crospovidone particles (B) used in the present invention is 20 mPa ⁇ s. s or less. Although a minimum is not specifically limited, It is about 10 mPa * s.
  • the viscosity of the aqueous suspension exceeds 20 mPa ⁇ s, it absorbs moisture at the time of tablet disintegration and changes into a gel, which prevents water from entering the tablet and deteriorates disintegration.
  • the viscosity is measured using a B-type viscometer (Toki Sangyo Co., Ltd., RB-80L) under the following conditions (rotor No. H-1, measuring rotation speed 30 rpm, measuring time 1 minute).
  • the content of the crospovidone particles (B) of the present invention is preferably 1 to 20% by mass with respect to the orally disintegrating tablet, the lower limit is more preferably 2% by mass or more, and particularly preferably 5% by mass.
  • the upper limit is more preferably 15% by mass or less, and particularly preferably 10% by mass. If the crospovidone particles (B) are added in an amount exceeding 20% by mass, the hardness and friability may be deteriorated, and if it is less than 1% by mass, the disintegration property may be deteriorated.
  • optional components can be blended within a range that does not impair the effects of the present invention.
  • other active ingredients, excipients, disintegrants other than the crosspolydon particles (B) of the present invention, sweeteners, sour agents, fragrances, lubricants, pigments and the like can be blended. These may be used alone or in appropriate combination of two or more, and an appropriate amount may be blended.
  • antacids such as magnesium aluminate metasilicate and magnesium aluminate silicate can be suitably blended.
  • commercially available products can be used, and Neusilin US2, Neusilin UFL2 (manufactured by Fuji Chemical Industry Co., Ltd.) and the like can be used (content: 5 to 20% by mass with respect to the orally disintegrating tablet).
  • excipients examples include cellulose powders, sugar powders, starches, powders such as silicon dioxide (content: usually 5 to 60% by mass with respect to orally disintegrating tablets).
  • cellulose powders include crystalline cellulose, powdered cellulose, carmellose, hydroxypropylcellulose, hydroxypropylmethylcellulose, low-substituted hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, and ethylcellulose.
  • saccharide powder examples include monosaccharides, disaccharides or higher polysaccharides (sugar (granulated sugar, etc.), lactose, maltose, xylose, isomerized lactose, etc.), sugar alcohols (palatinite, sorbitol, lactitol, erythritol, Xylitol, reduced starch saccharified product, maltitol, mannitol, etc.), starch syrup, isomerized sugar, oligosaccharide, sucrose, trehalose, reduced starch saccharified product (reduced starch decomposed product) and the like are preferable.
  • sugar alcohols palatinite, sorbitol, lactitol, erythritol, Xylitol, reduced starch saccharified product, maltitol, mannitol, etc.
  • starch syrup isomerized sugar, oligosaccharide, sucrose
  • starch powder examples include corn starch (corn starch), potato starch (potato starch), starch such as wheat starch and rice starch, and starch derivatives such as hydroxypropyl starch and partially pregelatinized starch.
  • corn starch corn starch
  • potato starch potato starch
  • starch such as wheat starch and rice starch
  • starch derivatives such as hydroxypropyl starch and partially pregelatinized starch.
  • Starch corn starch (corn starch) is more preferred.
  • the disintegrant for example, croscarmellose or the like can be used.
  • the sweetening agent for example, saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose and the like can be used (content: usually 0.05 to 10% by mass based on orally disintegrating tablet).
  • the sour agent for example, citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid or a salt thereof can be used (content: usually 0.2 to 3 mass based on orally disintegrating tablet) %).
  • flavor, menthol, limonene, vegetable essential oils (mint oil, mint oil, lychee oil, orange oil, lemon oil etc.) etc. can be used, for example.
  • Examples of the lubricant include magnesium stearate and calcium stearate (content: usually 0.5% by mass or less, preferably 0.05 to 0.2% by mass with respect to the orally disintegrating tablet).
  • the particles (A) can be obtained, for example, by coating drug particles having a primary average particle size of 150 to 300 ⁇ m with a coating agent containing a poorly water-soluble polymer compound and a plasticizer. Specifically, it can be obtained by spraying a coating agent dispersion or solution containing a poorly water-soluble polymer compound and a plasticizer onto drug particles.
  • the dispersion medium or solvent include water and ethanol.
  • Coating is performed by a coating apparatus having a fluidized bed, and an apparatus by the Wurster method is particularly preferable.
  • the Wurster method is a method in which the raw material particles and the spray liquid flow in the same direction from the bottom of the fluidized bed toward the top, and includes tangential bottom spray and bottom spray.
  • the coating apparatus using the Wurster method is suitable for suppressing coarse powder because it is easy to suppress aggregation of particles.
  • the conditions for coating are not particularly limited, and commonly used conditions can be used.
  • the exhaust temperature of the coating apparatus is preferably 20 to 70 ° C.
  • the supply air temperature is preferably 60 to 90 ° C.
  • the orally disintegrating tablet of the present invention can be obtained by mixing the above (A) particles, (B) particles and optional components, and tableting. Molding conditions such as tableting pressure vary depending on the tableting machine, the type and content of ingredients, the diameter of the tablet, etc., but are adjusted as appropriate in consideration of tablet physical properties and the like.
  • the size of the orally disintegrating tablet of the present invention is not particularly limited, but is preferably about 6 to 25 mm in diameter, and the tablet hardness is preferably 3 to 20 kgf, more preferably 5 to 15 kgf.
  • the tablet hardness represents the force required for the tablet to break up by standing the tablet vertically on the anvil and applying a static pressure to the tablet with a moving plunger.
  • the tablet hardness meter (Toyama Sangyo Co., Ltd.) )).
  • the oral disintegration rate is preferably less than 60 seconds, and more preferably less than 30 seconds.
  • the oral disintegration rate refers to the time from when the tablet is put into the oral cavity until the tablet is disintegrated by applying shear with the tongue and upper jaw.
  • Preparation Example 1 Acetaminophen coated particles 1 (coating rate 8.8%)] A 30% by weight aqueous dispersion of ethyl cellulose (trade name: Serios Coat: Asahi Kasei Chemicals), sugars and a plasticizer were added to JP purified water, and stirred well to obtain a coating agent solution having the composition described in the table below.
  • ethyl cellulose trade name: Serios Coat: Asahi Kasei Chemicals
  • ⁇ Coating agent solution composition Ethylcellulose 30 mass% aqueous dispersion 178.3 g Mannitol 26.7g Triacetin 13.4g JP purified water 249.6g Total 468.0g Solid content (20%) Ethylcellulose concentration based on solid content: 57.1% Mannitol concentration based on solid content: 28.6% Triacetin concentration based on solid content: 14.3%
  • acetaminophen particles are added, and the air volume is 65 ° C. and the exhaust temperature is 28 to 32 ° C.
  • the coating agent solution prepared in (1) was sprayed at a rate of 10 g / min so that the coating rate with respect to acetaminophen particles was 8.8%. This was cured at an air supply of 80 ° C. for 30 minutes to obtain acetaminophen coated particles 1 (average particle size 300 ⁇ m). The coating rate was 8.8%.
  • Preparation Example 2 Caffeine coated particles 1 (coating rate 30.0%)] A 30% by weight aqueous dispersion of ethyl cellulose (trade name: Serios Coat: Asahi Kasei Chemicals), sugars and a plasticizer were added to JP purified water, and stirred well to obtain a coating agent solution having the composition described in the table below.
  • ethyl cellulose trade name: Serios Coat: Asahi Kasei Chemicals
  • ⁇ Coating agent solution composition Ethylcellulose 30 mass% aqueous dispersion 742.9 g Mannitol 111.4g Triacetin 55.7g JP purified water 1040.0g Total 1950.0g Solid content (20%) Ethylcellulose concentration based on solid content: 57.1% Mannitol concentration based on solid content: 28.6% Triacetin concentration based on solid content: 14.3%
  • HPC-L hydroxypropylcellulose
  • Preparation Example 4 Preparation of granulated mannitol
  • 900 g of D-mannitol (manufactured by Rocket Japan Co., Ltd.) is placed in a fluidized bed granulator multiplex MP-01 (manufactured by POWREC Co., Ltd.), and at an air supply temperature of 80 ° C. and an exhaust temperature of 40-50 ° C., hydroxypropylcellulose 600 g of 12 mass% aqueous solution (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) was sprayed and granulated.
  • HPC-SSL hydroxypropylcellulose 600 g of 12 mass% aqueous solution
  • Preparation Example 5 Preparation of l-menthol / corn starch co-ground product
  • 1000 g of l-menthol and 1000 g of corn starch were put into a polyethylene bag (0.6 m ⁇ 0.4 m) and shaken well by hand.
  • the mixture was put into a pulverizer equipped with a screen of ⁇ 1.0 mm (manufactured by Tokuju Kogakusho Co., Ltd., Fiore F-0 type) and pulverized at a rotation speed of 20 Hz.
  • the pulverized product is sieved with a sieve having an aperture of 850 ⁇ m, and the particles that have not passed through the sieve with an aperture of 850 ⁇ m are again pulverized under the same conditions and combined with the particles that have passed through the sieve with an aperture of 850 ⁇ m.
  • Corn starch co-ground product
  • Examples 1 to 22, Comparative Examples 1 to 7 Using the acetaminophen coated particles 1 and caffeine coated particles 1 obtained in Preparation Examples 1 and 2, each powder was weighed in the amounts shown in Tables 2 to 4, mixed, and then mixed with a rotary tableting machine (manufactured by Kikusui Seisakusho). To obtain tablets with a diameter of 14.7 mm. In tableting, the tableting pressure was adjusted so that the tablet hardness was about 8 kgf (8-9 kgf). The following evaluation was performed about the obtained tablet. The results are also shown in the table.
  • Preparation Example 6 Acetaminophen coated particles 2 (coating rate: 3.0%)] A 30% by weight aqueous dispersion of ethyl cellulose (trade name: Serios Coat: Asahi Kasei Chemicals), sugars and a plasticizer were added to JP purified water, and stirred well to obtain a coating agent solution having the composition described in the table below.
  • ethyl cellulose trade name: Serios Coat: Asahi Kasei Chemicals
  • ⁇ Coating agent solution composition Ethylcellulose 30 mass% aqueous dispersion 178.3 g Mannitol 26.7g Triacetin 13.4g JP purified water 249.6g Total 468.0g Solid content (20%) Ethylcellulose concentration based on solid content: 57.1% Mannitol concentration based on solid content: 28.6% Triacetin concentration based on solid content: 14.3%
  • acetaminophen particles are added, and the air volume is 65 ° C. and the exhaust temperature is 28 to 32 ° C.
  • Coating was performed by spraying the coating agent solution prepared in step 1 at a rate of 10 g / min so that the coating rate with respect to acetaminophen particles was 3.0%. This was cured at an air supply of 80 ° C. for 30 minutes to obtain acetaminophen coated particles 2 (average particle size of 290 ⁇ m). The coating rate was 3.0%.
  • Preparation Example 7 Caffeine coating particle 2 (coating rate 50.0%)] A 30% by weight aqueous dispersion of ethyl cellulose (trade name: Serios Coat: Asahi Kasei Chemicals), sugars and a plasticizer were added to JP purified water, and stirred well to obtain a coating agent solution having the composition described in the table below.
  • ethyl cellulose trade name: Serios Coat: Asahi Kasei Chemicals
  • ⁇ Coating agent solution composition Ethylcellulose 30% by weight aqueous dispersion 1142.0 g Mannitol 171.6g Triacetin 85.8g JP0.6 Purified Water 1600.6g Total 3000.0g Solid content (20%) Ethylcellulose concentration based on solid content: 57.1% Mannitol concentration based on solid content: 28.6% Triacetin concentration based on solid content: 14.3%
  • Examples 23 to 31 Using the acetaminophen coated particles 1 and 2 and caffeine coated particles 2 obtained in Preparation Examples 1, 6 and 7, each powder was weighed in the amounts shown in Table 5 and mixed, and then a rotary tableting machine (Kikusui Seisakusho) was used. Manufactured) to obtain a tablet having a diameter of 14.7 mm. In tableting, the tableting pressure was adjusted so that the tablet hardness was about 8 kgf (8-9 kgf). The following evaluation was performed about the obtained tablet. The results are also shown in the table.

Abstract

Disclosed is an orally disintegrating tablet which is applicable to various medicinal agents having unpleasant tastes, has good feeling upon ingestion, and has good disintegrating properties, and in which the unpleasant taste of a medicinal agent contained therein is masked. The orally disintegrating tablet comprises: (A) particles of a medicinal agent having an unpleasant taste, which have been coated with a coating agent; and (B) crospovidone particles which has an average particle diameter of 50 μm or less and a swelling degree of 5 (g) water/ (g) product or more, and of which a 5% by mass-aqueous suspension has a viscosity (25˚C) of 20 mPa·s or less.

Description

口腔内崩壊錠Orally disintegrating tablets
　本発明は、不快な味を有する薬物粒子を含有する口腔内崩壊錠に関するものであり、詳細には、食感が良好で、崩壊性がよく、薬物の不快な味がマスキングされた口腔内崩壊錠に関するものである。 The present invention relates to an orally disintegrating tablet containing drug particles having an unpleasant taste, and in particular, an oral disintegration in which the texture is good, the disintegration is good, and the unpleasant taste of the drug is masked It relates to locks.
　近年、種々薬物のチュアブル錠または口腔内崩壊錠といった水無しで服用させる錠剤への適用が図られている。しかし、苦味等不快な味を有する薬物に関しては、チュアブル錠または口腔内崩壊錠への配合が比較的閾値の高いもの、すなわち不快な味の弱いものに限定されているのが実情である。従って、様々な強さの不快な味を有する薬物に汎用され、チュアブル錠または口腔内崩壊錠の特性を損なうことがなく、かつバイオアベイラビリティを低下させることのない、実用レベルのマスキング技術が望まれている。 In recent years, application to tablets that can be taken without water such as chewable tablets or orally disintegrating tablets of various drugs has been attempted. However, regarding drugs having an unpleasant taste such as a bitter taste, the fact is that the incorporation into chewable tablets or orally disintegrating tablets is limited to those having a relatively high threshold, that is, those having an unpleasant taste. Therefore, there is a demand for a masking technique at a practical level that is widely used for drugs having an unpleasant taste with various strengths, does not impair the characteristics of chewable tablets or orally disintegrating tablets, and does not reduce bioavailability. ing.
　不快な味を有する薬物は数多く存在するが、薬物の不快な味の強さによってマスキング方法が異なる。具体的にはフレーバー、甘味剤等を添加する等嬌味によってマスキングする方法や、薬物粒子に高分子基剤等を用いたコーティングを施すことによるマスキング方法等が知られている。嬌味によるマスキングの方法においては、その方法のみでの不快な味のマスキングは困難であり、ごく限られた薬物にしか適用できない。従って不快な味の閾値が低い薬物をマスキングするには、高分子基剤等によるコーティングによって、口腔内における薬物の放出を抑制する必要がある。 There are many drugs with an unpleasant taste, but the masking method varies depending on the intensity of the unpleasant taste of the drug. Specifically, a masking method by adding a flavor, a sweetening agent, or the like, and a masking method by coating a drug particle with a polymer base or the like is known. In the method of masking by taste, masking of unpleasant taste by that method alone is difficult, and it can be applied only to limited drugs. Therefore, in order to mask a drug having a low unpleasant taste threshold, it is necessary to suppress the release of the drug in the oral cavity by coating with a polymer base or the like.
　不快な味の閾値が低い薬物にコーティングを施しチュアブル錠または口腔内崩壊錠とする場合、通常のコーティング量では、製造時における打錠圧によるコーティング膜の微細な割れや、服用時における口腔内での咀嚼や摩擦による剥れ等の影響で、十分に不快な味の抑制ができない場合がある。これを解決するためには、通常よりも厚いコーティング層とする方法が考えられるが、その結果、消化管内における薬物の十分な放出を確保できず、通常製剤と比較するとバイオアベイラビリティが低下してしまうという問題がある。 When a drug with a low unpleasant taste threshold is coated to make a chewable tablet or orally disintegrating tablet, the normal coating amount may cause fine cracks in the coating film due to tableting pressure during production, In some cases, it is not possible to sufficiently suppress unpleasant taste due to the effect of chewing or peeling due to friction. In order to solve this, a method of making the coating layer thicker than usual can be considered, but as a result, sufficient release of the drug in the gastrointestinal tract cannot be ensured, and bioavailability is reduced as compared with a normal preparation. There is a problem.
特開２０００－９５７０７号公報JP 2000-95707 A 特開２００４－２６６７５号公報JP 2004-26675 A
　本発明は上記事情に鑑みなされたもので、種々の不快な味を有する薬物に適用ができ、食感が良好で、崩壊性がよく、薬物の不快な味がマスキングされた口腔内崩壊錠を提供することを目的とする。
　なお、本発明において、チュアブル錠は、錠剤を口腔内に含み、咀嚼により、あるいは唾液との接触や舌と上顎間のシェア（摩擦）によって、錠剤を口腔内で崩壊・溶解させ服用する錠剤である。口腔内崩壊錠は、錠剤を口腔内に含み、主に唾液との接触や舌と上顎間のシアーによって崩壊・溶解させる錠剤である（咀嚼を否定するものではない）。このように、通常、チュアブル錠と口腔内崩壊錠は、何れも咀嚼や唾液との接触、上顎と舌間のシェアで錠剤を口腔内で崩壊させる錠剤であり、水で服用する錠剤よりも薬物の不快な味を感じやすい点で本発明の共通する課題を有するものであって、明確には区別されない。
　以下、本発明において、チュアブル錠及び口腔内崩壊錠を、特に断りがない限り、統合して「口腔内崩壊錠」と記す。 The present invention has been made in view of the above circumstances, and is an orally disintegrating tablet that can be applied to drugs having various unpleasant tastes, has a good texture, good disintegration, and masks the unpleasant taste of drugs. The purpose is to provide.
In the present invention, the chewable tablet is a tablet containing the tablet in the oral cavity, which is taken by being disintegrated / dissolved in the oral cavity by chewing or by contact with saliva or shear (friction) between the tongue and upper jaw. is there. An orally disintegrating tablet is a tablet that contains a tablet in the oral cavity and is disintegrated and dissolved mainly by contact with saliva and by shearing between the tongue and upper jaw (mastication is not denied). Thus, chewable tablets and orally disintegrating tablets are usually tablets that disintegrate in the oral cavity by chewing, contact with saliva, and sharing between the upper jaw and tongue, and are more effective than tablets taken with water. The present invention has a common problem in that it is easy to feel an unpleasant taste, and is not clearly distinguished.
Hereinafter, in the present invention, chewable tablets and orally disintegrating tablets are collectively referred to as “orally disintegrating tablets” unless otherwise specified.
　本発明者らは、上記目的を達成するため鋭意検討した結果、崩壊剤として知られるクロスポビドンの中で、特定の物性を有するクロスポビドン、つまり、平均粒径５０μｍ以下、膨潤量が５（ｇ）ｗａｔｅｒ／（ｇ）ｐｒｏｄｕｃｔ以上、及び５質量％水懸濁液の粘度が２０ｍＰａ・ｓ以下であるクロスポビドン粒子が、錠剤の崩壊性（速度）を向上させるだけでなく、口腔内での咀嚼や摩擦による薬物粒子の被覆の壊れや剥れを抑制して薬物の不快な味マスキングに優れ、さらに口腔内で錠剤が崩壊する際、錠剤を構成する各粒子によるざらつき感を低減して食感を著しく向上させる作用を有することを知見し、本発明をなすに至ったものである。 As a result of intensive studies to achieve the above object, the present inventors have found that crospovidone having specific physical properties among crospovidones known as disintegrants, that is, an average particle size of 50 μm or less and a swelling amount of 5 (g ) Crospovidone particles having a water / (g) product of 5% by weight and a 5% by weight aqueous suspension with a viscosity of 20 mPa · s or less not only improve the disintegration (speed) of the tablet but also chew in the oral cavity. Prevents drug particles from being broken or peeled off due to friction and masking, resulting in an unpleasant taste masking of the drug. Further, when the tablet disintegrates in the mouth, the texture of each particle that makes up the tablet is reduced to reduce the texture. It has been found that it has the effect of significantly improving the above, and has led to the present invention.
　従って、本発明は下記口腔内崩壊錠を提供する。
［１］．（Ａ）不快な味を有する薬物がコーティング剤で被覆された薬物粒子と、（Ｂ）平均粒径５０μｍ以下、膨潤量が５（ｇ）ｗａｔｅｒ／（ｇ）ｐｒｏｄｕｃｔ以上、及び５質量％水懸濁液の粘度（２５℃）が２０ｍＰａ・ｓ以下であるクロスポビドン粒子とを含有する口腔内崩壊錠。
［２］．（Ｂ）粒子の含有量が１～２０質量％である［１］記載の口腔内崩壊錠。
［３］．（Ａ）粒子中の、薬物に対するコーティング剤のコーティング率が、固形分として１～６０質量％である［１］又は［２］記載の口腔内崩壊錠。 Accordingly, the present invention provides the following orally disintegrating tablets.
[1]. (A) Drug particles in which a drug having an unpleasant taste is coated with a coating agent, (B) an average particle size of 50 μm or less, a swelling amount of 5 (g) water / (g) product or more, and 5 mass% water suspension An orally disintegrating tablet comprising crospovidone particles having a viscosity (25 ° C.) of a turbid liquid of 20 mPa · s or less.
[2]. (B) The orally disintegrating tablet according to [1], wherein the content of the particles is 1 to 20% by mass.
[3]. (A) The orally disintegrating tablet according to [1] or [2], wherein the coating ratio of the coating agent to the drug in the particles is 1 to 60% by mass as a solid content.
　本発明によれば、種々の不快な味を有する薬物に適用ができ、食感が良好で、崩壊性がよく、薬物の不快な味がマスキングされた口腔内崩壊錠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 which can be applied to drugs having various unpleasant tastes, has a good texture, has good disintegration, and masks the unpleasant taste of drugs.
　以下、本発明について詳細に説明する。
　本発明の口腔内崩壊錠は、（Ａ）不快な味を有する薬物がコーティング剤で被覆された薬物粒子と、（Ｂ）平均粒径５０μｍ以下、膨潤量が５（ｇ）ｗａｔｅｒ／（ｇ）ｐｒｏｄｕｃｔ以上、及び５質量％水懸濁液の粘度（２５℃）が２０ｍＰａ・ｓ以下であるクロスポビドン粒子とを含有するものである。 Hereinafter, the present invention will be described in detail.
The orally disintegrating tablet of the present invention comprises (A) drug particles in which a drug having an unpleasant taste is coated with a coating agent, (B) an average particle size of 50 μm or less, and a swelling amount of 5 (g) water / (g) The product contains crospovidone particles having a product of 5 mass% or more and a viscosity (25 ° C.) of a 5 mass% water suspension of 20 mPa · s or less.
（Ａ）薬物粒子
　薬物粒子（薬物粒子（Ａ））は、不快な味を有する薬物がコーティング剤で被覆されたものである。
　不快な味を有する薬物としては、アセトアミノフェン、アスピリン、イブプロフェン、エテンザミド、フェナセチン、メフェナム酸、アンチピリン、フェニルブタゾン、スルピリン、ジクロフェナトリウム、ケトプロフェン、ナプロキセン、エピリゾール、塩酸チアラミド、インドメタシン、ペンタゾシン、塩化アセチルコリン、酒石酸アリメマジン、塩酸シプロヘプタジン、塩酸ジフェドラミン、マレイン酸クロルフェニラミン、リン酸コデイン、リン酸ジヒドロコデイン、臭化水素酸デキストロメトルファン、クエン酸ペントキシベリン、テオフィリン、アミノフィリン、塩酸エフェドリン、塩酸エピネフリン、硫酸サルブタモール、塩酸トリメトキノール、塩酸プロカテロール、塩酸メチルエフェドリン、塩酸フェニルプロパノールアミン、グアイフェネシン、トラネキサム酸、無水カフェイン、カフェイン、サリチル酸コリン、サリチル酸ナトリウム等が挙げられ、１種単独で又は２種以上を併用してもよい。中でも、アセトアミノフェン及びカフェインが好ましい。 (A) Drug particles Drug particles (drug particles (A)) are obtained by coating a drug having an unpleasant taste with a coating agent.
Drugs with an unpleasant taste include acetaminophen, aspirin, ibuprofen, etenzamide, phenacetin, mefenamic acid, antipyrine, phenylbutazone, sulpyrine, sodium diclofenate, ketoprofen, naproxen, epilysole, thiaramide hydrochloride, indomethacin, pentazocine, chloride Acetylcholine, alimemazine tartrate, cyproheptadine hydrochloride, diphedramine hydrochloride, chlorpheniramine maleate, codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, pentoxyberine citrate, theophylline, aminophylline, ephedrine hydrochloride, epinephrine hydrochloride, sulfuric acid Salbutamol, Trimethquinol hydrochloride, Procaterol hydrochloride, Methylephedrine hydrochloride, Phenylpropanol hydrochloride Emissions, guaifenesin, tranexamic acid, caffeine anhydrous, caffeine, choline salicylate, sodium salicylate, and the like, may be used in combination alone or in admixture. Of these, acetaminophen and caffeine are preferable.
　本発明におけるコーティング剤とは、薬物の表面に存在している成分をいい、水難溶性高分子化合物及び可塑剤からなるコーティング基剤を含むものである。この基剤を用いることにより、苦味マスキング性及び溶出性が向上する。なお、「水難溶性高分子化合物」とは、水１００００ｍＬに溶解する量が１ｇ又は１ｍＬ未満である化合物をいう。水難溶性高分子化合物としては、具体的には、エチルセルロース、アミノアクリルメタクリレートコポリマー、メタクリル酸コポリマー等が挙げられる。これらは１種単独で又は２種以上を適宜組み合わせて用いることができる。中でも、使用性、臭いの点から、エチルセルロースが好ましい。水難溶性高分子化合物の含有量は、コーティングしやすさ、可塑性、溶出性等を考慮すると、コーティング剤の総固形分に対して４０～９０質量％が好ましく、４０～８０質量％がより好ましく、５０～７０質量％が特に好ましい。 The coating agent in the present invention refers to a component existing on the surface of a drug, and includes a coating base composed of a poorly water-soluble polymer compound and a plasticizer. By using this base, bitterness masking property and dissolution property are improved. The “poorly water-soluble polymer compound” refers to a compound whose amount dissolved in 10,000 mL of water is 1 g or less than 1 mL. Specific examples of the poorly water-soluble polymer compound include ethyl cellulose, aminoacryl methacrylate copolymer, and methacrylic acid copolymer. These can be used individually by 1 type or in combination of 2 or more types. Of these, ethyl cellulose is preferred from the viewpoint of usability and odor. The content of the poorly water-soluble polymer compound is preferably 40 to 90% by mass, more preferably 40 to 80% by mass, based on the total solid content of the coating agent, in consideration of ease of coating, plasticity, elution, and the like. 50 to 70% by mass is particularly preferable.
　本発明におけるコーティング剤には可塑剤が含まれることが好ましい。可塑剤はコーティング剤を含む溶液に適度な展延性を与え、成膜しやすくする機能を有すると推測される。可塑剤としては、トリアセチン、クエン酸トリエチル等の医薬品添加物規格（（株）薬事日報社）等の公定書に記載されているものが挙げられる。これらは、１種単独で又は２種以上を適宜組み合わせて用いることができる。成膜性を考慮するとトリアセチン、クエン酸トリエチルが好ましく、トリアセチンがさらに好ましい。可塑剤の含有量はコーティング剤の総固形分に対して５～５０質量％が好ましく、１０～４０質量％がより好ましい。また、可塑剤：水難溶性高分子化合物の総固形分（質量比）＝０．０５：１～０．５：１が好ましく、０．１：１～０．４：１がより好ましい。 The coating agent in the present invention preferably contains a plasticizer. The plasticizer is presumed to have a function of imparting appropriate spreadability to the solution containing the coating agent and facilitating film formation. Examples of the plasticizer include those described in official documents such as standards for pharmaceutical additives such as triacetin and triethyl citrate (Pharmaceutical Daily Inc.). These can be used individually by 1 type or in combination of 2 or more types. Considering film formability, triacetin and triethyl citrate are preferable, and triacetin is more preferable. The content of the plasticizer is preferably 5 to 50% by mass, more preferably 10 to 40% by mass, based on the total solid content of the coating agent. The total solid content (mass ratio) of the plasticizer: poorly water-soluble polymer compound is preferably 0.05: 1 to 0.5: 1, more preferably 0.1: 1 to 0.4: 1.
　コーティング剤には、マスキング効果向上の点から、さらに溶出制御剤を配合してもよい。溶出制御剤としては、乳糖、トレハロース、白糖等の糖、マンニトール、エリスリトール、キシリトール、ソルビトール等の糖アルコール等が挙げられ、これらは１種単独で又は２種以上を適宜組み合わせて用いることができる。溶出制御剤は含まれなくてもよく、その含有量はコーティング剤の総固形分に対して０～６０質量％が好ましく、０～５０質量％がより好ましい。 The coating agent may further contain an elution control agent from the viewpoint of improving the masking effect. Examples of the elution control agent include sugars such as lactose, trehalose and sucrose, and sugar alcohols such as mannitol, erythritol, xylitol and sorbitol. These can be used alone or in combination of two or more. The elution control agent may not be contained, and the content thereof is preferably 0 to 60% by mass, more preferably 0 to 50% by mass with respect to the total solid content of the coating agent.
　コーティング剤には甘味剤を配合してもよい。甘味剤としては、アスパルテーム、スクラロース、エリスリトール、アセスルファムカリウム、サッカリンナトリウム、ステビア抽出物、ソーマチン、サトウキビ抽出物、パラチノース加熱物、カンゾウ等が挙げられ、１種単独で又は２種以上を適宜組み合わせて用いることができる。中でも、アスパルテーム、スクラロースが好ましい。甘味剤の含有量はコーティング剤の総固形分に対して０～５０質量％が好ましい。 A sweetener may be added to the coating agent. Examples of the sweetener include aspartame, sucralose, erythritol, acesulfame potassium, saccharin sodium, stevia extract, thaumatin, sugar cane extract, heated palatinose, licorice, etc. Can do. Of these, aspartame and sucralose are preferable. The content of the sweetening agent is preferably 0 to 50% by mass with respect to the total solid content of the coating agent.
　コーティング率は、薬物（被被覆物）に対して、固形分として１～６０質量％の範囲で設定するとよい。なお、コーティング率とは、薬物（被被覆物）１００質量％とした場合のコーティング剤の質量％をいう。コーティング率は、１質量％以上で十分なマスキング効果が得られ、６０質量％を超えると効果が飽和している上、薬物放出性が悪くなるおそれがある。安定なマスキング効果を得る点から、コーティング率の下限は３質量％以上がより好ましく、５質量％以上、特に８質量％以上がさらに好ましい。また、薬物放出性の点から、コーティング率は低く設定することが好ましく、具体的には、例えば、上限は５０質量％以下が好ましく、４０質量％以下、３０質量％以下、２５質量％以下、１５質量％以下、１０質量％以下とすることが好ましい。本発明では、特定のクロスポビドンを用いることにより、製造（特に打錠）時や服用時の衝撃や摩擦などの外力によるコーティングの劣化（割れ、剥れなど）が抑制されるので、低いコーティング率でも良好な味マスキング効果を得ることができる。 The coating rate is preferably set in the range of 1 to 60% by mass as the solid content with respect to the drug (coating material). In addition, a coating rate means the mass% of a coating agent when a drug (coating object) is 100 mass%. When the coating rate is 1% by mass or more, a sufficient masking effect is obtained, and when it exceeds 60% by mass, the effect is saturated and the drug release property may be deteriorated. From the viewpoint of obtaining a stable masking effect, the lower limit of the coating rate is more preferably 3% by mass or more, further preferably 5% by mass or more, and particularly preferably 8% by mass or more. Further, from the viewpoint of drug release, it is preferable to set the coating rate low. Specifically, for example, the upper limit is preferably 50% by mass or less, 40% by mass or less, 30% by mass or less, 25% by mass or less, It is preferable to set it as 15 mass% or less and 10 mass% or less. In the present invention, by using a specific crospovidone, coating deterioration (cracking, peeling, etc.) due to external force such as impact or friction during manufacture (especially tableting) or taking is suppressed, so a low coating rate However, a good taste masking effect can be obtained.
　（Ａ）粒子の平均粒径は７５～５００μｍが好ましく、１５０～３００μｍがより好ましい。なお、本発明において、平均粒径は、１０００μｍ、８５０μｍ、５００μｍ、３５５μｍ、２５０μｍ、１５０μｍ、７５μｍの内径７５ｍｍのふるいを用い、サンプル量１０ｇで、日局「粉体粒度測定法」第２法に基づき試験を行い測定した際の累積の５０％粒子径とする。 (A) The average particle size of the particles is preferably 75 to 500 μm, more preferably 150 to 300 μm. In the present invention, the average particle size is 1000 μm, 850 μm, 500 μm, 355 μm, 250 μm, 150 μm, and 75 μm sieves with an inner diameter of 75 mm. Based on the test and measurement, the cumulative particle size is 50%.
　薬物粒子（Ａ）の含有量は、服用性及び錠剤物性（硬度、摩損度、崩壊性等）の点から、口腔内崩壊錠に対して８０質量％以下が好ましく、７０質量％以下がより好ましく、６５質量％以下が特に好ましい。下限は特に限定されず、前記上限以下の範囲で各薬物の有効性を考慮した設定含有量とすることができる。 The content of the drug particles (A) is preferably 80% by mass or less, more preferably 70% by mass or less with respect to the orally disintegrating tablet from the viewpoint of ingestion and tablet physical properties (hardness, friability, disintegration, etc.). 65 mass% or less is particularly preferable. The lower limit is not particularly limited, and can be a set content considering the effectiveness of each drug within the range below the upper limit.
（Ｂ）クロスポビドン粒子
　本発明のクロスポビドン粒子（クロスポビドン粒子（Ｂ））は、（１）平均粒径５０μｍ以下、（２）膨潤量が５（ｇ）ｗａｔｅｒ／（ｇ）ｐｒｏｄｕｃｔ以上、及び（３）５質量％水懸濁液の粘度が２０ｍＰａ・ｓ以下である。クロスポビドンとは、架橋ポリビニルピロリドンであり、１－エテニル－２－ピロリジノンホモポリマーという化学名を有し架橋されている重合物である。 (B) Crospovidone particles The crospovidone particles (crospovidone particles (B)) of the present invention have (1) an average particle size of 50 μm or less, (2) a swelling amount of 5 (g) water / (g) product or more, and (3) The viscosity of the 5% by mass aqueous suspension is 20 mPa · s or less. Crospovidone is a cross-linked polyvinyl pyrrolidone, which is a cross-linked polymer having the chemical name 1-ethenyl-2-pyrrolidinone homopolymer.
　口腔内崩壊錠は口腔内で（特に舌と上あごの間で）シェアをかけて崩壊させたり噛みくだいたりするため、その際のシェアや衝撃で薬物のコーティングが剥れ不快な味が出てしまうが、上記物性のクロスポビドン粒子（Ｂ）を配合した錠剤は、口腔内でシェアをかけた際にクリーミーに崩れ、摩擦や衝撃によるコーティング層への影響が抑制され、コーティングが劣化せずに崩壊でき、結果、食感が良好で、崩壊性がよく、薬物の不快な味のマスキング効果を高めることができる。 Orally disintegrating tablets disintegrate or bite in the oral cavity (especially between the tongue and upper jaw), causing the drug coating to peel off and unpleasant taste due to the share and impact at that time However, tablets containing crospovidone particles (B) with the above physical properties collapse into creamy when applied in the oral cavity, and the influence on the coating layer due to friction and impact is suppressed, and the coating does not deteriorate. It can disintegrate and, as a result, has a good texture, good disintegration, and can enhance the masking effect of the unpleasant taste of the drug.
　以下に、本発明で使用されるクロスポビドン粒子（Ｂ）の特性について説明する。
（１）平均粒径５０μｍ以下
　本発明で使用されるクロスポビドン粒子（Ｂ）の平均粒径は５０μｍ以下であり、１０～５０μｍが好ましく、３０μｍ以下がより好ましい。平均粒径が５０μｍを超えると、錠剤崩壊時におけるコーティング粒子間での摩擦を和らげザラツキを抑えるクッション的役割を果たせず、またクロスポビドン粒子自体のザラつきも感じ、食感が悪くなる。また、１０μｍ未満だと、流動性の悪化により混合均一性が悪くなるおそれがある。尚、平均粒子径はレーザー散乱回折法粒度分布測定装置（ベックマン・コールター（株）製、ＬＳ　１３　３２０）により測定する。 Below, the characteristic of the crospovidone particle | grains (B) used by this invention is demonstrated.
(1) Average particle size of 50 μm or less The average particle size of the crospovidone particles (B) used in the present invention is 50 μm or less, preferably 10 to 50 μm, more preferably 30 μm or less. If the average particle size exceeds 50 μm, the friction between the coating particles at the time of tablet disintegration is reduced and the cushioning role for suppressing the roughness is not achieved, and the roughness of the crospovidone particles themselves is also felt, resulting in poor texture. On the other hand, when the thickness is less than 10 μm, the uniformity of mixing may be deteriorated due to the deterioration of fluidity. The average particle size is measured by a laser scattering diffraction particle size distribution analyzer (LS 13 320, manufactured by Beckman Coulter, Inc.).
（２）膨潤量が５（ｇ）ｗａｔｅｒ／（ｇ）ｐｒｏｄｕｃｔ以上
　本発明で使用されるクロスポビドン粒子（Ｂ）の膨潤量は５（ｇ）ｗａｔｅｒ／（ｇ）ｐｒｏｄｕｃｔ以上であり、５～２０（ｇ）ｗａｔｅｒ／（ｇ）ｐｒｏｄｕｃｔが好ましく、５．５～８．５（ｇ）ｗａｔｅｒ／（ｇ）ｐｒｏｄｕｃｔがより好ましい。膨潤量が５（ｇ）ｗａｔｅｒ／（ｇ）ｐｒｏｄｕｃｔ未満の場合、水分の吸収が少なく、錠剤中で崩壊剤としての機能が十分でなく崩壊性が悪化する。また、２０（ｇ）ｗａｔｅｒ／（ｇ）ｐｒｏｄｕｃｔを超えると、崩壊剤が水分を吸収しすぎ、口中の水分がなくなることにより食感が悪化するおそれがある。なお、本発明の膨潤量は、以下のようにして求めることができる。
（ｉ）１ｇ（Ｍ０）のサンプルと２０℃の蒸留水５０ｍＬを遠心管に加え、振とうさせ１５分間静止後、遠心分離（相対遠心加速度８５０［×ｇ］；１５分）にかけ、上澄みを取り除き、膨潤したサンプルの質量（Ｍ１ｇ）を測定し、概算の膨潤量Ｍ１（Ｍ１／Ｍ０）を算出する。
（ｉｉ）次に、蒸留水量を２Ｍ１ｍＬに変えて（１）の操作を行い、膨潤したサンプルの質量（Ｍ２ｇ）を測定し、正確な膨潤量Ｍ２（Ｍ２／Ｍ０）を算出する。この正確な膨潤量Ｍ２（Ｍ２／Ｍ０）が本発明の膨潤量である。 (2) The swelling amount is 5 (g) water / (g) product or more The swelling amount of the crospovidone particles (B) used in the present invention is 5 (g) water / (g) product or more, and 5 to 20 (G) water / (g) product is preferable, and 5.5 to 8.5 (g) water / (g) product is more preferable. When the swelling amount is less than 5 (g) water / (g) product, the absorption of moisture is small, the function as a disintegrant is not sufficient in the tablet, and the disintegration property is deteriorated. Moreover, when it exceeds 20 (g) water / (g) product, there exists a possibility that a disintegrating agent may absorb a water | moisture content too much and food texture may deteriorate because the water | moisture content in a mouth is lose | eliminated. The swelling amount of the present invention can be determined as follows.
(I) Add 1 g (M0) sample and 50 mL of distilled water at 20 ° C. to a centrifuge tube, shake and let stand for 15 minutes, then centrifuge (relative centrifugal acceleration 850 [× g]; 15 minutes) and remove the supernatant. The mass (M1g) of the swollen sample is measured, and an approximate swelling amount M1 (M1 / M0) is calculated.
(Ii) Next, the amount of distilled water is changed to 2M1 mL, the operation of (1) is performed, the mass (M2g) of the swollen sample is measured, and an accurate swelling amount M2 (M2 / M0) is calculated. This exact swelling amount M2 (M2 / M0) is the swelling amount of the present invention.
（３）５質量％水懸濁液の粘度（２５℃）が２０ｍＰａ・ｓ以下
　本発明で使用されるクロスポビドン粒子（Ｂ）の５質量％水懸濁液の粘度（２５℃）は２０ｍＰａ・ｓ以下である。下限は特に限定されないが、１０ｍＰａ・ｓ程度である。水懸濁液の粘度が２０ｍＰａ・ｓを超えると、錠剤崩壊時に水分を吸収することによりゲル状に変化し、錠剤内部への水の浸入を防いでしまい、崩壊性が悪化する。粘度は、Ｂ型粘度計（東機産業（株）、ＲＢ－８０Ｌ）を用いて、以下の条件（ローターＮｏ．Ｈ－１、測定回転数３０ｒｐｍ、測定時間１分）で測定する。 (3) The viscosity (25 ° C.) of the 5% by mass aqueous suspension is 20 mPa · s or less The viscosity (25 ° C.) of the 5% by mass aqueous suspension of crospovidone particles (B) used in the present invention is 20 mPa · s. s or less. Although a minimum is not specifically limited, It is about 10 mPa * s. When the viscosity of the aqueous suspension exceeds 20 mPa · s, it absorbs moisture at the time of tablet disintegration and changes into a gel, which prevents water from entering the tablet and deteriorates disintegration. The viscosity is measured using a B-type viscometer (Toki Sangyo Co., Ltd., RB-80L) under the following conditions (rotor No. H-1, measuring rotation speed 30 rpm, measuring time 1 minute).
　上述の（１）平均粒径５０μｍ以下、（２）膨潤量が５（ｇ）ｗａｔｅｒ／（ｇ）ｐｒｏｄｕｃｔ以上、及び（３）５質量％水懸濁液の粘度（２５℃）が２０ｍＰａ・ｓ以下の条件を全て満たすクロスポビドンとしては、例えば、ＢＡＳＦジャパン（株）製コリドンＣＬ－ＳＦ（平均粒子径１５～３５μｍ、膨潤量７．５～９．０（ｇ）ｗａｔｅｒ／（ｇ）ｐｒｏｄｕｃｔ、５質量％水懸濁液の粘度（２５℃）が１５～２０ｍＰａ・ｓ）や、ＢＡＳＦジャパン（株）製コリドンＣＬ－Ｆ（平均粒子径２５～４５μｍ、膨潤量５．０～６．５（ｇ）ｗａｔｅｒ／（ｇ）ｐｒｏｄｕｃｔ、５質量％水懸濁液の粘度（２５℃）が１１０～１６ｍＰａ・ｓ）等が挙げられる。 (1) Average particle size of 50 μm or less, (2) Swelling amount is 5 (g) water / (g) product or more, and (3) Viscosity (25 ° C.) of 5 mass% water suspension is 20 mPa · s. As crospovidone satisfying all the following conditions, for example, Kollidon CL-SF (average particle size 15 to 35 μm, swelling amount 7.5 to 9.0 (g) water / (g) product, manufactured by BASF Japan Ltd., The viscosity (25 ° C.) of a 5% by mass aqueous suspension is 15 to 20 mPa · s), and Coridon CL-F (average particle size 25 to 45 μm, swelling amount 5.0 to 6.5 (manufactured by BASF Japan Ltd.) g) water / (g) product, viscosity of a 5 mass% aqueous suspension (25 ° C.) is 110 to 16 mPa · s) and the like.
　本発明のクロスポビドン粒子（Ｂ）の含有量は、口腔内崩壊錠に対して１～２０質量％が好ましく、下限は２質量％以上がより好ましく、５質量％が特に好ましい。上限は１５質量％以下がより好ましく、１０質量％が特に好ましい。クロスポビドン粒子（Ｂ）を、２０質量％を超えて配合すると、硬度及び摩損度が悪化するおそれがあり、１質量％未満であると崩壊性が悪化するおそれがある。 The content of the crospovidone particles (B) of the present invention is preferably 1 to 20% by mass with respect to the orally disintegrating tablet, the lower limit is more preferably 2% by mass or more, and particularly preferably 5% by mass. The upper limit is more preferably 15% by mass or less, and particularly preferably 10% by mass. If the crospovidone particles (B) are added in an amount exceeding 20% by mass, the hardness and friability may be deteriorated, and if it is less than 1% by mass, the disintegration property may be deteriorated.
　本発明の口腔内崩壊錠には、本発明の効果を損なわない範囲で、任意成分を配合することができる。任意成分としては、他の有効成分、賦形剤、本発明のクロスポリドン粒子（Ｂ）以外の崩壊剤、甘味剤、酸味剤、香料、滑沢剤、色素等を配合することができる。これらは１種単独で又は２種以上を適宜組み合わせ、適量を配合することができる。 In the orally disintegrating tablet of the present invention, optional components can be blended within a range that does not impair the effects of the present invention. As optional components, other active ingredients, excipients, disintegrants other than the crosspolydon particles (B) of the present invention, sweeteners, sour agents, fragrances, lubricants, pigments and the like can be blended. These may be used alone or in appropriate combination of two or more, and an appropriate amount may be blended.
　他の有効成分としては、例えば、メタケイ酸アルミン酸マグネシウム、ケイ酸アルミン酸マグネシウム等の制酸剤が好適に配合し得る。これらは市販のものを用いることができ、ノイシリンＵＳ２、ノイシリンＵＦＬ２（富士化学工業（株）製）等を用いることができる（含有量：口腔内崩壊錠に対して５～２０質量％）。 As other active ingredients, for example, antacids such as magnesium aluminate metasilicate and magnesium aluminate silicate can be suitably blended. As these, commercially available products can be used, and Neusilin US2, Neusilin UFL2 (manufactured by Fuji Chemical Industry Co., Ltd.) and the like can be used (content: 5 to 20% by mass with respect to the orally disintegrating tablet).
　賦形剤としては、セルロース類の粉体、糖類の粉体、デンプン類、二酸化ケイ素等の粉体等が挙げられる（含有量：口腔内崩壊錠に対して通常５～６０質量％）。セルロース類の粉体として具体的には、結晶セルロース、粉末セルロース、カルメロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、低置換度ヒドロキシプロピルセルロース、ヒドロキシメチルセルロース、メチルセルロース、エチルセルロース等が挙げられる。 Examples of excipients include cellulose powders, sugar powders, starches, powders such as silicon dioxide (content: usually 5 to 60% by mass with respect to orally disintegrating tablets). Specific examples of the cellulose powder include crystalline cellulose, powdered cellulose, carmellose, hydroxypropylcellulose, hydroxypropylmethylcellulose, low-substituted hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, and ethylcellulose.
　糖類の粉体として具体的には、単糖類、二糖類以上の多糖類（砂糖（グラニュー糖等）、乳糖、麦芽糖、キシロース、異性化乳糖等）、糖アルコール（パラチニット、ソルビトール、ラクチトール、エリスリトール、キシリトール、還元澱粉糖化物、マルチトール、マンニトール等）、水飴、異性化糖類、オリゴ糖、スクロース、トレハロース、還元澱粉糖化物（還元澱粉分解物）等が好ましい。 Specific examples of the saccharide powder include monosaccharides, disaccharides or higher polysaccharides (sugar (granulated sugar, etc.), lactose, maltose, xylose, isomerized lactose, etc.), sugar alcohols (palatinite, sorbitol, lactitol, erythritol, Xylitol, reduced starch saccharified product, maltitol, mannitol, etc.), starch syrup, isomerized sugar, oligosaccharide, sucrose, trehalose, reduced starch saccharified product (reduced starch decomposed product) and the like are preferable.
　デンプン類の粉体として具体的には、トウモロコシデンプン（コーンスターチ）、バレイショデンプン（ポテトスターチ）、コムギデンプン、コメデンプン等のデンプン、ヒドロキシプロピルスターチ、部分α化デンプン等のデンプン誘導体等が好ましく、トウモロコシデンプン（コーンスターチ）がより好ましい。 Specific examples of the starch powder include corn starch (corn starch), potato starch (potato starch), starch such as wheat starch and rice starch, and starch derivatives such as hydroxypropyl starch and partially pregelatinized starch. Starch (corn starch) is more preferred.
　崩壊剤としては、例えば、クロスカルメロース等を用いることができる。甘味剤としては、例えば、サッカリンナトリウム、アスパルテーム、ステビア、グリチルリチン酸ジカリウム、アセスルファムカリウム、ソーマチン、スクラロース等を用いることができる（含有量：口腔内崩壊錠に対して通常０．０５～１０質量％）。酸味剤としては、例えば、クエン酸、酒石酸、リンゴ酸、コハク酸、フマル酸、乳酸又はそれらの塩等を用いることができる（含有量：口腔内崩壊錠に対して通常０．２～３質量％）。香料としては、例えば、メントール、リモネン、植物精油（ハッカ油、ミント油、ライチ油、オレンジ油、レモン油等）等を用いることができる。 As the disintegrant, for example, croscarmellose or the like can be used. As the sweetening agent, for example, saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose and the like can be used (content: usually 0.05 to 10% by mass based on orally disintegrating tablet). As the sour agent, for example, citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid or a salt thereof can be used (content: usually 0.2 to 3 mass based on orally disintegrating tablet) %). As a fragrance | flavor, menthol, limonene, vegetable essential oils (mint oil, mint oil, lychee oil, orange oil, lemon oil etc.) etc. can be used, for example.
　滑沢剤としては、ステアリン酸マグネシウム、ステアリン酸カルシウム等を挙げることができる（含有量：口腔内崩壊錠に対して通常０．５質量％以下、好ましくは０．０５～０．２質量％）。 Examples of the lubricant include magnesium stearate and calcium stearate (content: usually 0.5% by mass or less, preferably 0.05 to 0.2% by mass with respect to the orally disintegrating tablet).
　本発明の口腔内崩壊錠の製造方法について下記に示す。
　（Ａ）粒子は、例えば、一次平均粒径１５０～３００μｍの薬物粒子に、水難溶性高分子化合物及び可塑剤を含むコーティング剤をコーティングすることにより、得ることができる。具体的には、水難溶性高分子化合物及び可塑剤を含むコーティング剤分散液又は溶液を、薬物粒子に噴霧することにより得ることができる。分散媒又は溶媒としては、水、エタノール等が挙げられる。 It shows below about the manufacturing method of the orally disintegrating tablet of this invention.
The particles (A) can be obtained, for example, by coating drug particles having a primary average particle size of 150 to 300 μm with a coating agent containing a poorly water-soluble polymer compound and a plasticizer. Specifically, it can be obtained by spraying a coating agent dispersion or solution containing a poorly water-soluble polymer compound and a plasticizer onto drug particles. Examples of the dispersion medium or solvent include water and ethanol.
　コーティングは流動層を有するコーティング装置により行われ、特に、ワースター法による装置が好ましい。ワースター法とは、流動層底部から上部に向かって原料粒子と噴霧液が同方向に流動する方法であり、タンジェンシャルボトムスプレー、ボトムスプレー等がある。ワースター法によるコーティング装置においては、粒子の凝集を抑制しやすいことから粗粉の抑制に適している。 Coating is performed by a coating apparatus having a fluidized bed, and an apparatus by the Wurster method is particularly preferable. The Wurster method is a method in which the raw material particles and the spray liquid flow in the same direction from the bottom of the fluidized bed toward the top, and includes tangential bottom spray and bottom spray. The coating apparatus using the Wurster method is suitable for suppressing coarse powder because it is easy to suppress aggregation of particles.
　コーティングを行う際の条件としては、特に限定されず、通常用いられている条件が使用できる。例えば、コーティング装置の排気温度は、２０～７０℃が好ましく、給気温度は６０～９０℃が好ましい。 The conditions for coating are not particularly limited, and commonly used conditions can be used. For example, the exhaust temperature of the coating apparatus is preferably 20 to 70 ° C., and the supply air temperature is preferably 60 to 90 ° C.
　本発明の口腔内崩壊錠は、上記（Ａ）粒子、（Ｂ）粒子及び任意成分を混合し、打錠することにより、得ることができる。打錠圧等の成型条件は、打錠機、成分の種類や含有量、錠剤の径等により異なるが、錠剤物性等を考慮して、適宜調整する。 The orally disintegrating tablet of the present invention can be obtained by mixing the above (A) particles, (B) particles and optional components, and tableting. Molding conditions such as tableting pressure vary depending on the tableting machine, the type and content of ingredients, the diameter of the tablet, etc., but are adjusted as appropriate in consideration of tablet physical properties and the like.
　本発明の口腔内崩壊錠の大きさは特に限定されないが、直径６～２５ｍｍ程度が好ましく、その錠剤硬度は、３～２０ｋｇｆが好ましく、５～１５ｋｇｆがより好ましい。なお、錠剤硬度は、錠剤を金床の上に垂直に立て、移動プランジャーで錠剤に静的圧力を加え、錠剤が破壊されるまでに要する力を表し、錠剤硬度測定器（富山産業（株））を用いて測定することができる。また、口腔内崩壊速度は６０秒未満が好ましく、３０秒未満がより好ましい。なお、口腔内崩壊速度とは、錠剤を口腔内に入れ、舌と上顎でシアーをかけて錠剤が崩壊し終わるまでの時間をいう。 The size of the orally disintegrating tablet of the present invention is not particularly limited, but is preferably about 6 to 25 mm in diameter, and the tablet hardness is preferably 3 to 20 kgf, more preferably 5 to 15 kgf. The tablet hardness represents the force required for the tablet to break up by standing the tablet vertically on the anvil and applying a static pressure to the tablet with a moving plunger. The tablet hardness meter (Toyama Sangyo Co., Ltd.) )). The oral disintegration rate is preferably less than 60 seconds, and more preferably less than 30 seconds. The oral disintegration rate refers to the time from when the tablet is put into the oral cavity until the tablet is disintegrated by applying shear with the tongue and upper jaw.
　以下、実施例及び比較例を示し、本発明を具体的に説明するが、本発明は下記の実施例に制限されるものではない。なお、下記の例において特に明記のない場合は、組成の「％」は質量％を示す。 Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In the following examples, unless otherwise specified, “%” in the composition represents mass%.
　　［調製例１：アセトアミノフェンコーティング粒子１（コーティング率８．８％）］
　日局精製水にエチルセルロース３０質量％水分散液（商品名セリオスコート：旭化成ケミカルズ）、糖類及び可塑剤を入れ、よく攪拌して、下表に記載する組成のコーティング剤溶液を得た。
＜コーティング剤溶液組成＞
エチルセルロース３０質量％水分散液　　１７８．３ｇ
マンニトール　　　　　　　　　　　　　　２６．７ｇ
トリアセチン　　　　　　　　　　　　　　１３．４ｇ
日局精製水　　　　　　　　　　　　　　２４９．６ｇ　　　
　　合計　　　　　　　　　　　　　　　４６８．０ｇ
固形分濃度　　　　　　　　　　　　　　（２０％）
固形分に対するエチルセルロース濃度：５７．１％
固形分に対するマンニトール濃度：２８．６％
固形分に対するトリアセチン濃度：１４．３％ [Preparation Example 1: Acetaminophen coated particles 1 (coating rate 8.8%)]
A 30% by weight aqueous dispersion of ethyl cellulose (trade name: Serios Coat: Asahi Kasei Chemicals), sugars and a plasticizer were added to JP purified water, and stirred well to obtain a coating agent solution having the composition described in the table below.
<Coating agent solution composition>
Ethylcellulose 30 mass% aqueous dispersion 178.3 g
Mannitol 26.7g
Triacetin 13.4g
JP purified water 249.6g
Total 468.0g
Solid content (20%)
Ethylcellulose concentration based on solid content: 57.1%
Mannitol concentration based on solid content: 28.6%
Triacetin concentration based on solid content: 14.3%
　次いで、流動層造粒機マルチプレックスＭＰ－０１ワースター仕様（パウレック社製）を用い、アセトアミノフェン粒子８００ｇを入れ、これに給気温度６５℃、排気温度２８～３２℃になる風量で、上記で調製したコーティング剤溶液を、１０ｇ／ｍｉｎの速度で、アセトアミノフェン粒子に対するコーティング率８．８％になるように噴霧してコーティングを行った。これを給気８０℃で３０分間キュアリングし、アセトアミノフェンコーティング粒子１（平均粒径３００μｍ）を得た。コーティング率８．８％であった。 Next, using a fluidized bed granulator multiplex MP-01 Wurster specification (manufactured by POWREC), 800 g of acetaminophen particles are added, and the air volume is 65 ° C. and the exhaust temperature is 28 to 32 ° C. The coating agent solution prepared in (1) was sprayed at a rate of 10 g / min so that the coating rate with respect to acetaminophen particles was 8.8%. This was cured at an air supply of 80 ° C. for 30 minutes to obtain acetaminophen coated particles 1 (average particle size 300 μm). The coating rate was 8.8%.
　　［調製例２：カフェインコーティング粒子１（コーティング率３０．０％）］
　日局精製水にエチルセルロース３０質量％水分散液（商品名セリオスコート：旭化成ケミカルズ）、糖類及び可塑剤を入れ、よく攪拌して、下表に記載する組成のコーティング剤溶液を得た。
＜コーティング剤溶液組成＞
エチルセルロース３０質量％水分散液　　７４２．９ｇ
マンニトール　　　　　　　　　　　　　１１１．４ｇ
トリアセチン　　　　　　　　　　　　　　５５．７ｇ
日局精製水　　　　　　　　　　　　　１０４０．０ｇ　　　
　　合計　　　　　　　　　　　　　　１９５０．０ｇ　　　
固形分濃度　　　　　　　　　　　　　　（２０％）
固形分に対するエチルセルロース濃度：５７．１％
固形分に対するマンニトール濃度：２８．６％
固形分に対するトリアセチン濃度：１４．３％ [Preparation Example 2: Caffeine coated particles 1 (coating rate 30.0%)]
A 30% by weight aqueous dispersion of ethyl cellulose (trade name: Serios Coat: Asahi Kasei Chemicals), sugars and a plasticizer were added to JP purified water, and stirred well to obtain a coating agent solution having the composition described in the table below.
<Coating agent solution composition>
Ethylcellulose 30 mass% aqueous dispersion 742.9 g
Mannitol 111.4g
Triacetin 55.7g
JP purified water 1040.0g
Total 1950.0g
Solid content (20%)
Ethylcellulose concentration based on solid content: 57.1%
Mannitol concentration based on solid content: 28.6%
Triacetin concentration based on solid content: 14.3%
　次いで、流動層造粒機マルチプレックスＭＰ－０１ワースター仕様（パウレック社製）を用い、カフェイン粒子１０００ｇを入れ、これに給気温度８０℃、排気温度３５～４５℃になる風量で、上記で調製したコーティング剤溶液を、２０ｇ／ｍｉｎの速度で、カフェイン粒子に対するコーティング率３０．０％になるように噴霧してコーティングを行った。これを給気８０℃で３０分間キュアリングし、カフェインコーティング粒子１（平均粒径３７０μｍ）を得た。コーティング率３０．０％であった。 Next, using a fluidized bed granulator multiplex MP-01 Wurster specification (manufactured by POWREC), 1000 g of caffeine particles are added, and the air volume is 80 ° C. and the exhaust temperature is 35 to 45 ° C. Coating was performed by spraying the prepared coating agent solution at a rate of 20 g / min so that the coating rate with respect to caffeine particles was 30.0%. This was cured at an air supply of 80 ° C. for 30 minutes to obtain caffeine coating particles 1 (average particle size of 370 μm). The coating rate was 30.0%.
　　［調製例３：エリスリトール造粒品の調製］
　エリスリトール（エリスリトール、三栄源エフ・エフ・アイ（株）製）３２００ｇとトウモロコシデンプン（精製乾燥滅菌コーンスターチ、松谷化学工業（株）製）６００ｇを混ぜ、スパイラーフローＳＦＣ－５型（フロイント産業（株）製）に入れ、給気温度９０℃、排気温度３５～４５℃で、ヒドロキシプロピルセルロース６質量％水溶液（ＨＰＣ－Ｌ、日本曹達（株）製）を２４００ｇ噴霧し造粒した。 [Preparation Example 3: Preparation of erythritol granulated product]
Erythritol (erythritol, Saneigen FFI Co., Ltd.) 3200g and corn starch (refined dry sterilized corn starch, Matsutani Chemical Industry Co., Ltd.) 600g are mixed, and Spirer Flow SFC-5 type (Freund Sangyo Co., Ltd.) 2400 g of a 6% by weight aqueous solution of hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) was sprayed and granulated at an air supply temperature of 90 ° C. and an exhaust temperature of 35 to 45 ° C.
　　［調製例４：マンニトール造粒品の調製］
　Ｄ－マンニトール（ロケットジャパン（株）製）９００ｇを流動層造粒機マルチプレックスＭＰ－０１（（株）パウレック製）に入れ、給気温度８０℃、排気温度４０～５０℃で、ヒドロキシプロピルセルロース１２質量％水溶液（ＨＰＣ－ＳＳＬ、日本曹達（株）製）を６００ｇ噴霧し造粒した。 [Preparation Example 4: Preparation of granulated mannitol]
900 g of D-mannitol (manufactured by Rocket Japan Co., Ltd.) is placed in a fluidized bed granulator multiplex MP-01 (manufactured by POWREC Co., Ltd.), and at an air supply temperature of 80 ° C. and an exhaust temperature of 40-50 ° C., hydroxypropylcellulose 600 g of 12 mass% aqueous solution (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) was sprayed and granulated.
　　［調製例５：ｌ－メントール／トウモロコシデンプン共粉砕品の調製］
　ｌ－メントール１０００ｇ及びトウモロコシデンプン（精製乾燥滅菌コーンスターチ、松谷化学工業（株）製）１０００ｇをポリエチレン製の袋（０．６ｍ×０．４ｍ）に投入し、手で良く振り混ぜた。その混合物をφ１．０ｍｍのスクリーンを装着した粉砕機（（株）徳寿工作所製、フィオーレＦ－０型）に投入し２０Ｈｚの回転数で粉砕した。その後、粉砕物を目開き８５０μｍの篩で篩過し、目開き８５０μｍの篩を通過しなかった粒子を再度、同条件で粉砕し、目開き８５０μｍの篩を通過した粒子と合わせてｌ－メントール／トウモロコシデンプン共粉砕品とした。 [Preparation Example 5: Preparation of l-menthol / corn starch co-ground product]
1000 g of l-menthol and 1000 g of corn starch (refined and sterilized corn starch, manufactured by Matsutani Chemical Industry Co., Ltd.) were put into a polyethylene bag (0.6 m × 0.4 m) and shaken well by hand. The mixture was put into a pulverizer equipped with a screen of φ1.0 mm (manufactured by Tokuju Kogakusho Co., Ltd., Fiore F-0 type) and pulverized at a rotation speed of 20 Hz. Thereafter, the pulverized product is sieved with a sieve having an aperture of 850 μm, and the particles that have not passed through the sieve with an aperture of 850 μm are again pulverized under the same conditions and combined with the particles that have passed through the sieve with an aperture of 850 μm. / Corn starch co-ground product.
　　［実施例１～２２、比較例１～７］
　調製例１及び２で得られたアセトアミノフェンコーティング粒子１及びカフェインコーティング粒子１を使用し、表２～４に示す量で各粉末を量り、混合後、ロータリー打錠機（菊水製作所製）で打錠し、直径１４．７ｍｍの錠剤を得た。打錠にあたっては錠剤硬度が約８ｋｇｆ（８～９ｋｇｆ）となるように打錠圧を調整した。得られた錠剤について、下記評価を行った。結果を表中に併記する。 [Examples 1 to 22, Comparative Examples 1 to 7]
Using the acetaminophen coated particles 1 and caffeine coated particles 1 obtained in Preparation Examples 1 and 2, each powder was weighed in the amounts shown in Tables 2 to 4, mixed, and then mixed with a rotary tableting machine (manufactured by Kikusui Seisakusho). To obtain tablets with a diameter of 14.7 mm. In tableting, the tableting pressure was adjusted so that the tablet hardness was about 8 kgf (8-9 kgf). The following evaluation was performed about the obtained tablet. The results are also shown in the table.
＜苦味のマスキング性＞
　（Ａ）パネラー７人が錠剤１錠を口に含み、舌と上顎でシアーをかけて溶解した際に感じた苦味の強さを下記５段階で評価し平均値を算出した。評価点が３以下であれば許容できる。
　（Ｂ）パネラー７人が錠剤１錠を口に含み奥歯で３回咀嚼した後、舌と上顎でシアーをかけて溶解した際に感じた苦味の強さを下記５段階で評価し平均値を算出した。評価点が３以下であれば許容できる。
［評価点］
１：苦味を感じない
２：苦味をやや感じる
３：苦味を少し感じる
４：苦味をかなり感じる
５：苦味を非常に感じる <Masking of bitterness>
(A) Seven panelists included one tablet in their mouths, and evaluated the bitterness intensity felt when they were dissolved by applying shear with the tongue and upper jaw, and the average value was calculated. If the evaluation score is 3 or less, it is acceptable.
(B) After 7 panelists put one tablet in their mouth and chewed with their back teeth three times, the bitterness intensity felt when they were melted by applying sheer on the tongue and upper jaw was evaluated in the following five levels, and the average value was calculated. Calculated. If the evaluation score is 3 or less, it is acceptable.
[Evaluation points]
1: Feel no bitterness 2: Feel bitterness slightly 3: Feel bitterness slightly 4: Feel bitterness considerably 5: Feel bitterness very much
＜崩壊性＞
　パネラー７人が錠剤１錠を口に含み、舌と上顎でシアーをかけて錠剤が崩壊し終わるまでの時間を測定した。結果を下記評価基準で示す。崩壊時間が６０秒以上だと、コーティング顆粒のコーティングが溶け、苦味マスキング性が劣る。
［評価基準］
○：崩壊時間が平均３０秒未満
△：崩壊時間が平均３０秒以上６０秒未満
×：崩壊時間が平均６０秒以上 <Disintegration>
Seven panelists included one tablet in their mouth, sheered the tongue and upper jaw, and measured the time until the tablet had disintegrated. A result is shown by the following evaluation criteria. When the disintegration time is 60 seconds or more, the coating of the coated granule dissolves and the bitterness masking property is inferior.
[Evaluation criteria]
○: Collapse time average less than 30 seconds Δ: Collapse time average 30 seconds or more and less than 60 seconds ×: Collapse time average 60 seconds or more
＜食感＞
　パネラー７人が錠剤１錠を口に含み、舌と上顎でシアーをかけて溶解した際に感じたザラツキの強さを下記５段階で評価し平均値を算出した。評価点が２以下であれば許容できる。ザラツキを強く感じるほど、舌と上顎で強くシアーをかけるので、コーティング顆粒同士の摩擦によりコーティングがはがれマスキング性が低下し、錠剤としての服用性が悪化する。
［評価点］
１：ザラツキを感じない
２：ザラツキをやや感じる
３：ザラツキを少し感じる
４：ザラツキをかなり感じる <Food texture>
Seven panelists included one tablet in their mouths, and evaluated the strength of the roughness when they were dissolved by applying shear with the tongue and upper jaw, and the average value was calculated. An evaluation score of 2 or less is acceptable. The stronger the feeling of roughness, the more sheer is applied to the tongue and upper jaw, so that the coating peels off due to the friction between the coated granules and the masking property is lowered, and the dosage as a tablet deteriorates.
[Evaluation points]
1: Does not feel rough 2: Feels slightly rough 3: Feels rough slightly 4: Feels rough
　実施例及び比較例で使用した市販崩壊剤について、下記に示す。
Figure JPOXMLDOC01-appb-T000001
 It shows below about the commercial disintegrating agent used by the Example and the comparative example.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　　［調製例６：アセトアミノフェンコーティング粒子２（コーティング率３．０％）］
　日局精製水にエチルセルロース３０質量％水分散液（商品名セリオスコート：旭化成ケミカルズ）、糖類及び可塑剤を入れ、よく攪拌して、下表に記載する組成のコーティング剤溶液を得た。
＜コーティング剤溶液組成＞
エチルセルロース３０質量％水分散液　　１７８．３ｇ
マンニトール　　　　　　　　　　　　　　２６．７ｇ
トリアセチン　　　　　　　　　　　　　　１３．４ｇ
日局精製水　　　　　　　　　　　　　　２４９．６ｇ　　　
　　合計　　　　　　　　　　　　　　　４６８．０ｇ
固形分濃度　　　　　　　　　　　　　　（２０％）
固形分に対するエチルセルロース濃度：５７．１％
固形分に対するマンニトール濃度：２８．６％
固形分に対するトリアセチン濃度：１４．３％ [Preparation Example 6: Acetaminophen coated particles 2 (coating rate: 3.0%)]
A 30% by weight aqueous dispersion of ethyl cellulose (trade name: Serios Coat: Asahi Kasei Chemicals), sugars and a plasticizer were added to JP purified water, and stirred well to obtain a coating agent solution having the composition described in the table below.
<Coating agent solution composition>
Ethylcellulose 30 mass% aqueous dispersion 178.3 g
Mannitol 26.7g
Triacetin 13.4g
JP purified water 249.6g
Total 468.0g
Solid content (20%)
Ethylcellulose concentration based on solid content: 57.1%
Mannitol concentration based on solid content: 28.6%
Triacetin concentration based on solid content: 14.3%
　次いで、流動層造粒機マルチプレックスＭＰ－０１ワースター仕様（パウレック社製）を用い、アセトアミノフェン粒子８００ｇを入れ、これに給気温度６５℃、排気温度２８～３２℃になる風量で、上記で調製したコーティング剤溶液を、１０ｇ／ｍｉｎの速度で、アセトアミノフェン粒子に対するコーティング率３．０％になるように噴霧してコーティングを行った。これを給気８０℃で３０分間キュアリングし、アセトアミノフェンコーティング粒子２（平均粒径２９０μｍ）を得た。コーティング率３．０％であった。 Next, using a fluidized bed granulator multiplex MP-01 Wurster specification (manufactured by POWREC), 800 g of acetaminophen particles are added, and the air volume is 65 ° C. and the exhaust temperature is 28 to 32 ° C. Coating was performed by spraying the coating agent solution prepared in step 1 at a rate of 10 g / min so that the coating rate with respect to acetaminophen particles was 3.0%. This was cured at an air supply of 80 ° C. for 30 minutes to obtain acetaminophen coated particles 2 (average particle size of 290 μm). The coating rate was 3.0%.
　　［調製例７：カフェインコーティング粒子２（コーティング率５０．０％）］
　日局精製水にエチルセルロース３０質量％水分散液（商品名セリオスコート：旭化成ケミカルズ）、糖類及び可塑剤を入れ、よく攪拌して、下表に記載する組成のコーティング剤溶液を得た。
＜コーティング剤溶液組成＞
エチルセルロース３０質量％水分散液　１１４２．０ｇ
マンニトール　　　　　　　　　　　　　１７１．６ｇ
トリアセチン　　　　　　　　　　　　　　８５．８ｇ
日局精製水　　　　　　　　　　　　　１６００．６ｇ　　　
　　合計　　　　　　　　　　　　　　３０００．０ｇ　　　
固形分濃度　　　　　　　　　　　　　　（２０％）
固形分に対するエチルセルロース濃度：５７．１％
固形分に対するマンニトール濃度：２８．６％
固形分に対するトリアセチン濃度：１４．３％ [Preparation Example 7: Caffeine coating particle 2 (coating rate 50.0%)]
A 30% by weight aqueous dispersion of ethyl cellulose (trade name: Serios Coat: Asahi Kasei Chemicals), sugars and a plasticizer were added to JP purified water, and stirred well to obtain a coating agent solution having the composition described in the table below.
<Coating agent solution composition>
Ethylcellulose 30% by weight aqueous dispersion 1142.0 g
Mannitol 171.6g
Triacetin 85.8g
JP0.6 Purified Water 1600.6g
Total 3000.0g
Solid content (20%)
Ethylcellulose concentration based on solid content: 57.1%
Mannitol concentration based on solid content: 28.6%
Triacetin concentration based on solid content: 14.3%
　次いで、流動層造粒機マルチプレックスＭＰ－０１ワースター仕様（パウレック社製）を用い、カフェイン粒子１０００ｇを入れ、これに給気温度８０℃、排気温度３５～４５℃になる風量で、上記で調製したコーティング剤溶液を、２０ｇ／ｍｉｎの速度で、カフェイン粒子に対するコーティング率５０．０％になるように噴霧してコーティングを行った。これを給気８０℃で３０分間キュアリングし、カフェインコーティング粒子２（平均粒径３７０μｍ）を得た。コーティング率５０．０％であった。 Next, using a fluidized bed granulator multiplex MP-01 Wurster specification (manufactured by POWREC), 1000 g of caffeine particles are added, and the air volume is 80 ° C. and the exhaust temperature is 35 to 45 ° C. Coating was performed by spraying the prepared coating agent solution at a rate of 20 g / min so that the coating rate with respect to caffeine particles was 50.0%. This was cured at a supply air of 80 ° C. for 30 minutes to obtain caffeine coating particles 2 (average particle size of 370 μm). The coating rate was 50.0%.
　　［実施例２３～３１］
　調製例１、６及び７で得られたアセトアミノフェンコーティング粒子１、２及びカフェインコーティング粒子２を使用し、表５に示す量で各粉末を量り、混合後、ロータリー打錠機（菊水製作所製）で打錠し、直径１４．７ｍｍ錠剤を得た。打錠にあたっては錠剤硬度が約８ｋｇｆ（８～９ｋｇｆ）となるように打錠圧を調整した。得られた錠剤について、下記評価を行った。結果を表中に併記する。 [Examples 23 to 31]
Using the acetaminophen coated particles 1 and 2 and caffeine coated particles 2 obtained in Preparation Examples 1, 6 and 7, each powder was weighed in the amounts shown in Table 5 and mixed, and then a rotary tableting machine (Kikusui Seisakusho) was used. Manufactured) to obtain a tablet having a diameter of 14.7 mm. In tableting, the tableting pressure was adjusted so that the tablet hardness was about 8 kgf (8-9 kgf). The following evaluation was performed about the obtained tablet. The results are also shown in the table.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
＜使用原料＞
アセトアミノフェン（タイコヘルスケアジャパン（株）、ＳＰＥＣＩＡＬ　ＧＲＡＮＵＬＡＲ）
カフェイン（（株）静岡カフェイン工業所、無水カフェイン）
エチルセルロース水分散液（旭化成（株）、セリオスコートＥＣ－３０Ａ）
トリアセチン（大八化学工業（株）、トリアセチン）
マンニトール（ロケットジャパン（株）、ＰＥＡＲＬＩＴＯＬ　５０Ｃ）
エリスリトール（三栄源エフ・エフ・アイ（株））
トウモロコシデンプン（松谷化学工業（株）、精製乾燥滅菌コーンスターチ）
ｌ－メントール（東洋薄荷工業（株））
メタケイ酸アルミン酸マグネシウム（富士化学工業（株）ノイシリンＵＳ２）
アスパルテーム（味の素（株）、ＫＫアスパルテーム）
スクラロース（三栄源エフ・エフ・アイ（株）、食品添加物スクラロース）
ステアリン酸マグネシウム（太平化学産業（株）、ステアリン酸マグネシウム　植物性）
香料（高砂香料工業（株）ペパーミントミクロンＺＤ－７７４１） <Raw materials>
Acetaminophen (Tyco Healthcare Japan Co., Ltd., SPECIAL GRANULAR)
Caffeine (Shizuoka Caffeine Industrial Co., Ltd., anhydrous caffeine)
Ethylcellulose aqueous dispersion (Asahi Kasei Corporation, Cerios Coat EC-30A)
Triacetin (Daihachi Chemical Industry Co., Ltd., Triacetin)
Mannitol (Rocket Japan, PEARLITOL 50C)
Erythritol (Saneigen FFI Co., Ltd.)
Corn starch (Matsutani Chemical Co., Ltd., refined and dried sterilized corn starch)
l-Menthol (Toyo Hikaru Industry Co., Ltd.)
Magnesium aluminate metasilicate (Fuji Chemical Co., Ltd. Neusilin US2)
Aspartame (Ajinomoto Co., Inc., KK Aspartame)
Sucralose (Sanyogen FFI Co., Ltd., food additive sucralose)
Magnesium stearate (Taihei Chemical Industry Co., Ltd., magnesium stearate vegetable)
Fragrance (Takasago Fragrance Industry Co., Ltd. Peppermint Micron ZD-7741)
　クロスポビドンに関してコリドンＣＬ－ＳＦ及びコリドンＣＬ－Ｆを他の複数ロットを用いて実施例１～２８の実験を繰り返し行ったところ、同様の結果が得られた。その際のコリドンＣＬ－ＳＦ及びコリドンＣＬ－Ｆの物性は表６の通りであった。 Regarding the crospovidone, when the experiments of Examples 1 to 28 were repeated using other lots of Kollidon CL-SF and Kollidon CL-F, similar results were obtained. Table 6 shows the physical properties of Kollidon CL-SF and Kollidon CL-F.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006

Claims (3)

  1. 　（Ａ）不快な味を有する薬物がコーティング剤で被覆された薬物粒子と、（Ｂ）平均粒径５０μｍ以下、膨潤量が５（ｇ）ｗａｔｅｒ／（ｇ）ｐｒｏｄｕｃｔ以上、及び５質量％水懸濁液の粘度（２５℃）が２０ｍＰａ・ｓ以下であるクロスポビドン粒子とを含有する口腔内崩壊錠。 (A) Drug particles in which a drug having an unpleasant taste is coated with a coating agent, (B) an average particle size of 50 μm or less, a swelling amount of 5 (g) water / (g) product or more, and 5 mass% water suspension An orally disintegrating tablet comprising crospovidone particles having a viscosity (25 ° C.) of a turbid liquid of 20 mPa · s or less.
  2. 　（Ｂ）粒子の含有量が１～２０質量％である請求項１記載の口腔内崩壊錠。 The orally disintegrating tablet according to claim 1, wherein the content of (B) particles is 1 to 20% by mass.
  3. 　（Ａ）粒子中の、薬物に対するコーティング剤のコーティング率が、固形分として１～６０質量％である請求項１又は２記載の口腔内崩壊錠。 (A) The orally disintegrating tablet according to claim 1 or 2, wherein the coating ratio of the coating agent to the drug in the particles is 1 to 60% by mass as a solid content.
PCT/JP2010/056555 2009-04-14 2010-04-13 Orally disintegrating tablet WO2010119851A1 (en)

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JPWO2018021265A1 (en) * 2016-07-27 2019-01-17 沢井製薬株式会社 Composition for adding orally disintegrating tablets
JP2019182818A (en) * 2018-04-17 2019-10-24 ライオン株式会社 Intraoral disintegrable tablet for removing tongue coating and method for removing tongue coating
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JPWO2018021265A1 (en) * 2016-07-27 2019-01-17 沢井製薬株式会社 Composition for adding orally disintegrating tablets
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