WO2019131411A1 - Erythritol granules for orally disintegrating tablets, method for producing same, and orally disintegrating tablets prepared using same - Google Patents

Erythritol granules for orally disintegrating tablets, method for producing same, and orally disintegrating tablets prepared using same Download PDF

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WO2019131411A1
WO2019131411A1 PCT/JP2018/046929 JP2018046929W WO2019131411A1 WO 2019131411 A1 WO2019131411 A1 WO 2019131411A1 JP 2018046929 W JP2018046929 W JP 2018046929W WO 2019131411 A1 WO2019131411 A1 WO 2019131411A1
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erythritol
orally disintegrating
weight
tablet
parts
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PCT/JP2018/046929
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French (fr)
Japanese (ja)
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雄輝 木村
巧 栃尾
真裕子 高橋
浩充 山本
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物産フードサイエンス株式会社
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Priority to JP2019561593A priority Critical patent/JPWO2019131411A1/en
Publication of WO2019131411A1 publication Critical patent/WO2019131411A1/en

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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 erythritol-based granule suitable for producing an orally disintegrating tablet, a method for producing the granule, and an orally disintegrating tablet using the granule.
  • Orally disintegrating tablets generally refer to tablets that disintegrate rapidly in the oral cavity when taken without water or with a small amount of water.
  • An orally disintegrating tablet is a tablet form that has been in high demand in recent years because it can be taken by patients with difficulty in swallowing, elderly people and children, and can be taken easily without water, regardless of the subject. is there.
  • Erythritol is a sugar alcohol with a good sweetness similar to sugar, with no immediate aftertreatment. Erythritol also has zero calories, is non-cariogenic, has a relatively low laxative effect, has no effect on blood sugar levels, and has a flavoring effect that suppresses undesirable tastes such as bitter and bluish. It is expected to be useful as an excipient in the production of tablets such as drugs and supplements, because it has useful properties such as having the
  • Patent Document 1 discloses orally disintegrating tablets containing erythritol, a disintegrant and isomalt
  • Patent Document 2 discloses erythritol, mannitol and hydroxy.
  • An orally disintegrating tablet comprising propylcellulose and acarbose as a medicinal ingredient is disclosed.
  • Patent No. 5902677 gazette Patent No. 5721093 gazette
  • the orally disintegrating tablet containing erythritol and fully utilizing its useful properties has not been provided yet.
  • the present invention has been made to solve such problems, and it is an orally disintegrating tablet utilizing the useful properties of erythritol, a granule suitable for the production thereof, and a method for producing the granule. To aim.
  • the inventors of the present invention have surprisingly found that orally disintegrating tablets having appropriate tablet hardness and short oral disintegration time by combining erythritol and a predetermined disintegrant and then surprisingly, granulating it. It has been found that granules can be obtained which can be produced by the direct striking method.
  • the granules according to the present invention are erythritol granules used for the production of orally disintegrating tablets, and are 5 parts by weight or more and 50 parts by weight or less of crospovidone, and 2 parts by weight with respect to 180 parts by weight of erythritol. More than 15 parts by weight or less of low substituted hydroxypropyl cellulose and / or crystalline cellulose are contained.
  • the granules according to the present invention are prepared by adding 1 part by weight of magnesium stearate to 100 parts by weight of the granules, and then tableting less than 15.0 kN by a dry direct compression method (direct compression method) It is preferable that the tablet has physical properties such that the intraoral disintegration time of the tablet is 30 seconds or less when the tablet is compressed to 8 mm in diameter and formed into a tablet of 200 mg per tablet.
  • the substrate contains 5 to 50 parts by weight of crospovidone with respect to 180 parts by weight of erythritol, and the spray liquid has a low degree of hydroxy substitution.
  • the concentration of propyl cellulose and / or crystalline cellulose is preferably 1.3% by mass or more and 10.0% by mass or less.
  • the orally disintegrating tablet according to the present invention is characterized by containing the erythritol granules for orally disintegrating tablet according to the present invention and a medicinal ingredient or a food material.
  • an orally disintegrating tablet which has appropriate tablet hardness and disintegration time.
  • an orally disintegrating tablet can be produced which makes use of the useful properties of erythritol.
  • the orally disintegrating tablet described above can be produced by a dry direct compression method (direct pressing method), which is a general tablet production method, without requiring a special device or production process. it can.
  • erythritol granules suitable for the production of the above-mentioned orally disintegrating tablet can be obtained.
  • Erythritol granules for orally disintegrating tablets refers to erythritol granules for use in the manufacture of orally disintegrating tablets.
  • Erythritol granule refers to a granule containing erythritol as a main component or an aggregate thereof.
  • the particle diameter of erythritol granules may be larger than the particle diameter of erythritol powder, but from the viewpoint of use for tablet production by the direct compression method, the average particle diameter is preferably 50 ⁇ m or more and less than 250 ⁇ m.
  • the erythritol granules for orally disintegrating tablets according to the present invention are 5 parts by weight or more and 50 parts by weight or less of crospovidone, and 2 parts by weight or more and 15 parts by weight or less of low substituted hydroxypropyl with respect to 180 parts by weight of erythritol.
  • Cellulose and / or crystalline cellulose is contained.
  • Erythritol is a sugar alcohol whose chemical name is 1,2,3,4-Butaneterol and is also called erythritol.
  • powdered erythritol may be a commercially available product, or may be produced and used according to methods known to those skilled in the art.
  • Examples of known methods for producing erythritol include a method in which erythritol-producing bacteria are cultured and produced using glucose or the like as a carbon source, and the product is purified and obtained.
  • erythritol-producing bacteria for example, a microorganism belonging to the genus Trigonopsis or Candida (Japanese Patent Publication No. 47-41549), a microorganism belonging to the genus Toluroposis, the genus Hansenula, the genus Pichia or Debaryomyces (Japanese Patent Publication No.
  • Gazette microorganisms belonging to the genus Moniliella (JP-A 60-110295, JP-A 10-215887), microorganisms belonging to the genus Aureobasidium (JP-B-63-9831), microorganisms belonging to the genus JP-A-10-215887) and the like can be mentioned, and culture conditions can be performed under ordinary conditions suitable for each bacterium.
  • purification of erythritol can be carried out according to a conventional method in the steps of cell separation, separation of erythritol by chromatography, desalting, decolorization, crystallization, crystal decomposition and drying.
  • Crospovidone Crosslinked polyvinyl pyrrolidone
  • polyvinyl polypyrrolidone polyvinyl polypyrrolidone
  • insoluble polyvinyl pyrrolidone polyvinyl pyrrolidone
  • Water-insoluble polymer compound having a crosslinked structure of pyrrolidone moiety of the present invention as the crospovidone, a commercially available product can be used, and the molecular weight, particle size, etc. can be appropriately set according to the desired physical properties, granulation method, etc.
  • crospovidone examples include Kolidon (registered trademark) CL, CL-F, CL-SF, and CL-M (above, BASF), Polyclar 10 (Ashland), and the like.
  • Low substituted Hydroxypropylcellulose is the amount of hydroxypropoxy group introduced in the cellulose derivative (hydroxypropyl cellulose) in which a hydroxypropoxy group (-OCH 2 CHOHCH 3 ) is introduced into the skeleton of cellulose. Is small and is insoluble in water. Since the hydroxypropoxy group is introduced by substituting the hydroxyl group of the cellulose skeleton, the introduction amount is represented by the degree of molar substitution (number of hydroxypropoxyl groups per glucose residue, moles of substitution, MS) Be done.
  • LHPC low-density polyethylene glycol
  • the degree of substitution is, for example, that of MS 0.01 to 2, preferably 0.05 to 1.5, more preferably 0.1 to 1, or 1 to 25 mass of hydroxypropoxyl group in the dry matter %, Preferably 2 to 20% by mass, more preferably 3 to 18% by mass can be used.
  • LHPC commercially available, for example, LH-11, LH-21, LH-22, LH-B1, LH-31, LH-32, NBD-020, NBD-021, NBD-022 (all, Shin-Etsu Chemical Industrial) and the like.
  • Crystalline cellulose (Microcrystalline Cellulose, MCC) is obtained by partially depolymerizing and purifying high purity cellulose such as ⁇ -cellulose obtained as pulp from fibrous plants with an acid.
  • crystalline cellulose can be used without particular limitation on the average degree of polymerization, loss on drying, bulk density, particle diameter, shape and the like.
  • MCCs include, for example, Theorus UF-702, Theorus UF-711, Theorus KG-802, Theorus KG-1000, Theorus PH-101, Theorus PH-101D, Theorus PH-102, Theorus PH-200, Theorus PH -301, Theorus PH-301D, Theorus PH-302, Theorus PH-F20JP (above, Asahi Kasei Chemicals) etc. can be used.
  • the orally disintegrating time of the tablet manufactured by the direct hitting method as it is by mixing the granules or the lubricant alone without mixing the pharmaceutically active ingredient or the food material is the same as the orally disintegrating tablet of the granules. It becomes an index to evaluate use aptitude.
  • magnesium stearate (lubricant) is added in a proportion of 1 part by weight to 100 parts by weight of the granules, and then tableted with a direct compression method at a tableting pressure of less than 15.0 kN to obtain a diameter
  • the granules having physical properties such that the oral disintegration time of the tablet is 30 seconds or less when the tablet is formed into a tablet of 200 mg per tablet at 8 mm is a suitable erythritol granule for orally disintegrating tablet.
  • Erythritol granules for orally disintegrating tablets may contain substances other than erythritol, CPVP, LHPC and MCC, as long as the characteristics of the present invention are not impaired.
  • Such substances may include, for example, binders and lubricants for improving processing characteristics, food additives and pharmaceutical additives for improving the taste, palatability and storage properties of tablets, etc. .
  • the addition of binders may be effective for producing tablets with relatively low tableting pressure.
  • binder examples include hydroxypropyl methylcellulose (HPMC), methylcellulose, hydroxyethyl methylcellulose, pullulan, sodium alginate, agar, gelatin, sodium carboxymethylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol and the like.
  • HPMC hydroxypropyl methylcellulose
  • methylcellulose methylcellulose
  • hydroxyethyl methylcellulose pullulan
  • sodium alginate sodium alginate
  • agar gelatin
  • sodium carboxymethylcellulose sodium carboxymethylcellulose
  • polyvinyl pyrrolidone polyvinyl alcohol
  • magnesium stearate glycerine fatty acid ester
  • sorbitan fatty acid ester sucrose fatty acid ester etc.
  • Erythritol granules for orally disintegrating tablets are prepared by flowing low agitation hydroxypropyl cellulose (LHPC) and / or crystalline cellulose (MCC) to a matrix of erythritol powder and crospovidone (CPVP) while flowing or stirring the matrix. It can manufacture by the granulation process of making it dry after spraying the spray liquid to contain. That is, the present invention also provides a method for producing erythritol granules for orally disintegrating tablets having the above granulation step.
  • LHPC low agitation hydroxypropyl cellulose
  • MCC crystalline cellulose
  • CPVP crospovidone
  • the granulation step can be carried out by a fluidized bed granulation method as shown in Test Method (2) of Examples described later, and can also be carried out by a stirring granulation method, a spray drying method or the like.
  • fluidized bed granulation is one method of wet granulation, and hot air is sent from the lower part of the granulation chamber to form a layer in which particles flow by rolling up the raw material powder particles into the air. Then, the liquid (spray liquid) is sprayed to grow the raw material powder particles into granules (granules) by aggregation or coating.
  • Granulation by fluid bed granulation can be performed by a commercially available granulator.
  • the ratio of erythritol to CPVP in the substrate can be appropriately set according to the desired physical properties of the granules, the granulation method, etc.
  • 1 part by weight or more of CPVP is based on 180 parts by weight of erythritol.
  • the amount can be 100 parts by weight or less, 2 parts by weight to 80 parts by weight, 3 parts by weight to 70 parts by weight, 4 parts by weight to 60 parts by weight, 5 parts by weight to 50 parts by weight, and the like.
  • Examples of the dispersion medium of LHPC and / or MCC in the spray liquid include water, alcohols such as ethanol, or mixtures thereof.
  • the spray liquid may be used by adding a food additive such as a binder, a sugar alcohol, a flavor, a coloring agent, a preservative, or a pharmaceutical additive as long as the characteristics of the present invention are not impaired.
  • a food additive such as a binder, a sugar alcohol, a flavor, a coloring agent, a preservative, or a pharmaceutical additive as long as the characteristics of the present invention are not impaired.
  • examples of the binder include hydroxypropyl methylcellulose (HPMC), methylcellulose, hydroxyethyl methylcellulose, pullulan, sodium alginate, agar, gelatin, sodium carboxymethylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol and the like.
  • the spray solution may contain either LHPC or MCC alone, or both LHPC and MCC.
  • concentration of LHPC or MCC when any one of them is contained alone can be appropriately set according to the desired physical properties and granulation method in the erythritol granules for orally disintegrating tablets, but preferably 0.5 to 20% by mass, 0.6 to 19% by mass, 0.7 to 18% by mass, 0.8 to 17% by mass, 0.9 to 16% by mass, 1.0 to 15% by mass, 1.1 to 14% %, 1.2 to 13% by mass, 1.3 to 12% by mass, 1.3 to 11% by mass, 1.3 to 10% by mass, and the like.
  • the concentration of LHPC and MCC in the spray liquid when both are contained is preferably 0.5 to 20% by mass, 0.6 to 19% by mass, and 0.7 to 18 in terms of the total concentration of the two substances.
  • the granulation apparatus in the granulation step is, for example, a batch type fluidized bed granulator such as a normal fluidized bed type granulator, a forced circulation type fluidized bed granulator, a spouted bed type granulator, etc., a box type continuous type fluidized bed
  • a continuous fluid bed granulator such as a granulator or cylindrical continuous fluid bed granulator can be used.
  • the position of the spray nozzle of the spray liquid in the granulating apparatus may be, for example, any of a bottom spray method, a top spray method, and a tangential spray method.
  • the granulation conditions can be appropriately set according to the amount of erythritol and the desired physical properties of erythritol granules, and for example, the hot air inlet temperature is 60 to 100 ° C., and the air volume is 0.4 to 0.8 m 3 / minute.
  • the spray pressure of the spray liquid can be 0.1 to 0.3 MPa.
  • the orally disintegrating tablet according to the present invention is characterized by containing the erythritol granules for orally disintegrating tablet according to the present invention and a medicinal ingredient or a food material.
  • the orally disintegrating tablet can be produced by a tableting process in which a mixture of erythritol granules for orally disintegrating tablet and a medicinal ingredient or a food material is compressed by direct compression method.
  • a tableting process in which a mixture of erythritol granules and a pharmaceutically active ingredient is tableted, pharmaceuticals and quasi-drugs having the form of orally disintegrating tablets can be produced, and a mixture of erythritol granules and a food material If tableted, food and drink such as confectionery (tablet confectionery) and supplement having the form of orally disintegrating tablet can be manufactured.
  • the direct compression method can be carried out according to methods known to those skilled in the art. That is, a mixture of erythritol granules for orally disintegrating tablet and a medicinal ingredient or a food material may be charged into a commercially available tableting machine and compressed into a tablet shape.
  • the tableting pressure and the size of the tablet can be appropriately set in accordance with the use of the product, the components contained therein, and the like.
  • the tableting pressure can be, for example, less than 40.0 kN, less than 35 kN, less than 30 kN, less than 25 kN, less than 20 kN, or less than 15.0 kN with respect to a tablet area of 0.5 cm 2 .
  • the orally disintegrating tablet may contain substances other than erythritol granules for orally disintegrating tablet and medicinal ingredients or food materials as long as the characteristics of the present invention are not impaired.
  • substances may include, for example, binders and lubricants for improving processing characteristics, food additives and pharmaceutical additives for improving the taste, palatability and storage properties of tablets, etc. .
  • the binder include hydroxypropyl methylcellulose (HPMC), methylcellulose, hydroxyethyl methylcellulose, pullulan, sodium alginate, agar, gelatin, sodium carboxymethylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol and the like.
  • magnesium stearate, glycerine fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester etc. can be mentioned, for example.
  • Tableting method Tablets were manufactured by the direct compression method using ERT granules. That is, 1 part by weight of magnesium stearate as a lubricant is added to 100 parts by weight of ERT granules, and then it is charged in a table-type single-shot tableting machine "MINIPRESS MII (RIVA S. A.)", industrially , Squeezable into tablet form with a viable tableting pressure (less than 15 kN). The tablet had a diameter of 8 mm and a weight of 200 mg per tablet. That is, a tablet was manufactured by applying a tableting pressure less than 15.0 kN (300 MPa) to the area of the tablet ( ⁇ ⁇ 0.4 cm ⁇ 0.4 cm ⁇ 0.5 cm 2 ).
  • [4-2] Oral disintegration time The oral disintegration time of the tablet was measured using an orally disintegrating tablet tester (ODT-101, Toyama Sangyo). The measurement conditions were a weight (diameter 15 mm, 15 g), a rotational speed of 25 revolutions / minute (rpm), and a temperature of 37 ⁇ 0.5 ° C.
  • the measured disintegration time is 30 seconds or less, it is "suitable (abbreviation: ⁇ )" as an orally disintegrating tablet, and if it is more than 30 seconds and 60 seconds or less, “suitable (abbreviation: ⁇ )", 60 seconds and 180 seconds or less If it was, it was evaluated as “slightly unsuitable (abbreviation:))", and if it was over 180 seconds, it was evaluated as "improper (abbreviated: x)".
  • Example 1 Examination of additives for disintegrant application in spray liquid (1) Investigation of disintegrant in spray liquid In a granulating apparatus, 180 g of powdered erythritol and 30 g of crospovidone (CPVP) were charged as a substrate, and the spray was carried out. Granulation was performed while spraying 150 mL of the solution. As a spray, No. In the sample No. 1, an aqueous solution (HPMC 1% aqueous solution) in which hydroxypropyl methylcellulose (HPMC) was dissolved to 1.0% was added to No. 1 sample. The sample No.
  • Example 2 Examination of Amount of Additive for Use in Disintegrating Agent in Spray Liquid
  • 180 g of powdered erythritol and 30 g of CPVP were charged as a substrate, and granulation was carried out while spraying 150 mL of the spray liquid.
  • the spray liquid used was an aqueous liquid in which MCC was dispersed in a 1% aqueous solution of HPMC so as to be 1.3%, 3.3%, 6.7% or 10.0%.
  • the tablets were then manufactured and evaluated. The results are shown in Table 4.
  • each of the 10 tablets had an appropriate (o) tablet hardness of 5.0 kgf or more, and the disintegration time was as short as 30 seconds or less, and was suitable as an orally disintegrating tablet (o). From these results, it was revealed that the amount of LHPC and / or MCC in the erythritol granules used for the orally disintegrating tablet is preferably 2 parts by weight or more and 15 parts by weight or less with respect to 180 parts by weight of erythritol. Moreover, in the manufacturing process of the said erythritol granule, it became clear that the density
  • Example 3 Examination of Additives for Binder Application in Spray Liquid
  • 180 g of powdered erythritol and 30 g of CPVP were charged as a substrate, and granulation was carried out while spraying 150 mL of the spray liquid.
  • the spray solution dissolves HPMC in water to 0.0%, 0.5%, 1.0%, 2.5% or 5.0%, and further, 1.3% LHPC and MCC (( 1) An aqueous liquid having an average particle size of 50 ⁇ m and a repose angle of 57 degrees, or (2) an average particle size of 50 ⁇ m and a repose angle of 45 degrees) dispersed to 5.3% was used.
  • the tablets were then manufactured and evaluated. The results are shown in Table 5.
  • No. No. 14-1 has MCC (1).
  • 14-2 used MCC (2), respectively.
  • the amount of HPMC is preferably 7.5 parts by weight or less and more preferably 3.8 parts by weight or less with respect to 180 parts by weight of erythritol. became. Moreover, in the manufacturing process of the said erythritol granule, it became clear that 5.0% or less is preferable and 2.5% or less of the density
  • Example 4 Examination of additive for use as disintegrant in a substrate
  • 180 g of powdered erythritol alone or 180 g of powdered erythritol and 20 g of additive for disintegrant are charged as a substrate, and a spray liquid is prepared. Granulation was performed while spraying 150 mL.
  • CPVP, corn starch (CS), croscarmellose sodium (CMC-Na) or MCC were used as additives for disintegrant use in the substrate as shown in Table 6.
  • the spray liquid used was an aqueous liquid in which 1% of LHPC and 1% of MCC were dispersed in a 1% aqueous solution of HPMC.
  • the tablets were then manufactured and evaluated. The results are shown in Table 6.
  • each of the 20 tablets had a disintegration time of more than 60 seconds and was somewhat unsuitable ( ⁇ ) as an orally disintegrating tablet.
  • no. The 17 tablets had an appropriate (o) tablet hardness of 5.0 kgf or more, a short disintegration time of around 19.2 seconds, and were suitable as orally disintegrating tablets (o). From this result, it was revealed that the inclusion of CPVP makes it possible to produce erythritol granules suitable for orally disintegrating tablets. Moreover, it became clear that it is preferable to make a board
  • substrate contain CPVP in the manufacturing process of the said erythritol granule.
  • Example 5 Examination of Amount of Additive for Use in Disintegrant in Substrate
  • 180 g of powdered erythritol and 0 g, 5 g, 10 g, 20 g, 30 g, 40 g or 50 g of CPVP as a substrate are charged and sprayed. Granulation was performed while spraying 150 mL of the solution.
  • the spray liquid used was an aqueous liquid in which 1% of LHPC and 1% of MCC were dispersed in a 1% aqueous solution of HPMC.
  • the tablets were then manufactured and evaluated. The results are shown in Table 7.
  • each of the 26 tablets has a suitable (o) tablet hardness of 5.0 kgf or more, a short disintegration time of 60 seconds or less, and is suitable as an orally disintegrating tablet (o) or suitable (o) Met. From these results, it has become clear that, in the erythritol granules used for the orally disintegrating tablet, the amount of CPVP is preferably 5 parts by weight or more and 50 parts by weight or less with respect to 180 parts by weight of erythritol.
  • the amount of CPVP in the substrate is preferably 5 parts by weight or more and 50 parts by weight or less with respect to 180 parts by weight of erythritol.
  • Example 6 Production of orally disintegrating tablet (antipyretic and analgesic drug)
  • a granulating apparatus 180 g of powdered erythritol and 30 g of CPVP were charged as a substrate, and granulation was carried out while spraying 150 mL of spray liquid to obtain ERT granules.
  • the spray liquid was an aqueous liquid in which HPMC was dissolved to 0.5% in water, and 1.3% LHPC and 5.3% MCC were dispersed.

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Abstract

[Problem] To provide: orally disintegrating tablets in which the beneficial properties of erythritol are utilized; granules suitable for the production of the orally disintegrating tablets; and a method for producing the granules. [Solution] Erythritol granules for orally disintegrating tablets, each containing 180 parts by weight erythritol, 5 to 50 parts by weight inclusive of crospovidone and 2 to 15 parts by weight inclusive of low-substituted hydroxypropylcellulose and/or crystalline cellulose. According to the present invention, it becomes possible to produce orally disintegrating tablets which have both of proper tablet hardness and proper disintegration time and in which the beneficial properties of erythritol are utilized.

Description

口腔内崩壊錠用エリスリトール顆粒およびその製造方法ならびにそれを用いた口腔内崩壊錠Erythritol granules for orally disintegrating tablets, method for producing the same and orally disintegrating tablets using the same
　本発明は、口腔内崩壊錠の製造に好適なエリスリトールを主成分とする顆粒および当該顆粒の製造方法、ならびに当該顆粒を用いた口腔内崩壊錠に関する。 The present invention relates to an erythritol-based granule suitable for producing an orally disintegrating tablet, a method for producing the granule, and an orally disintegrating tablet using the granule.
　口腔内崩壊錠とは、一般に、水無しで、あるいは少量の水とともに摂取した際に、口腔内で素速く崩壊する形態の錠剤をいう。口腔内崩壊錠は、嚥下が困難な患者や高齢者、小児においても服用可能なこと、係る対象者に限らずとも、水無しで手軽に服用できることから、近年、需要が高まっている錠剤形態である。 Orally disintegrating tablets generally refer to tablets that disintegrate rapidly in the oral cavity when taken without water or with a small amount of water. An orally disintegrating tablet is a tablet form that has been in high demand in recent years because it can be taken by patients with difficulty in swallowing, elderly people and children, and can be taken easily without water, regardless of the subject. is there.
　一方、エリスリトールは、あっさりとして後引きがなく、砂糖に似た好ましい甘味質を持つ糖アルコールである。エリスリトールはまた、カロリーがゼロであること、非う蝕性であること、緩下作用が比較的小さいこと、血糖値に影響しないこと、苦みや青臭みなどの好ましくない味を抑制する矯味矯臭効果を有すること等の有用な性質を有しているため、薬物やサプリメント等の錠剤を製造する際の賦形剤として、利用が期待されている。 Erythritol, on the other hand, is a sugar alcohol with a good sweetness similar to sugar, with no immediate aftertreatment. Erythritol also has zero calories, is non-cariogenic, has a relatively low laxative effect, has no effect on blood sugar levels, and has a flavoring effect that suppresses undesirable tastes such as bitter and bluish. It is expected to be useful as an excipient in the production of tablets such as drugs and supplements, because it has useful properties such as having the
　そこで、エリスリトールを含有する口腔内崩壊錠が研究開発されており、例えば、特許文献１には、エリスリトール、崩壊剤およびイソマルトを含む口腔内崩壊錠が、特許文献２には、エリスリトール、マンニトールおよびヒドロキシプロピルセルロースを含み、薬効成分としてアカルボースを含む口腔内崩壊錠が、それぞれ開示されている。 Therefore, orally disintegrating tablets containing erythritol have been researched and developed. For example, Patent Document 1 discloses orally disintegrating tablets containing erythritol, a disintegrant and isomalt, and Patent Document 2 discloses erythritol, mannitol and hydroxy. An orally disintegrating tablet comprising propylcellulose and acarbose as a medicinal ingredient is disclosed.
特許第５９０２６７７号公報Patent No. 5902677 gazette 特許第５７２１０９３号公報Patent No. 5721093 gazette
　しかしながら、特許文献１に記載の口腔内崩壊錠が含有するイソマルトも、特許文献２に記載の口腔内崩壊錠が含有するマンニトールも、カロリーがゼロではなく、また、味に影響を与え得る。従って、これらの特許文献に記載の口腔内崩壊錠は、ノンカロリーで矯味矯臭効果を有するエリスリトールを含有する利点を生かし切れていない。このように、従来、エリスリトールを主成分とする口腔内崩壊錠の製造は困難であった。その一因としては、エリスリトールは成形性が低いため、一般に、直打法で打錠するにあたっては、何らかの添加物ないし粒子の改質が必要であったことが考えられる。係る添加物や粒子改質によって形成した錠剤では、口腔内崩壊錠に必要な、短い口腔内崩壊時間を達成することは困難であった。 However, both isomalt contained in the orally disintegrating tablet described in Patent Document 1 and mannitol contained in the orally disintegrating tablet described in Patent Document 2 have non-zero calories and can affect the taste. Therefore, the orally disintegrating tablet described in these patent documents has not yet taken full advantage of containing non-caloric erythritol having a flavoring effect. As described above, conventionally, it has been difficult to produce an orally disintegrating tablet containing erythritol as a main component. One of the reasons is that erythritol has low moldability, and therefore, it is generally considered that some additives or particles need to be modified in direct compression. In tablets formed by such additives or particle modification, it has been difficult to achieve the short intraoral disintegration time required for orally disintegrating tablets.
　すなわち、これらの特許文献を鑑みても、エリスリトールを含有し、かつその有用な性質を十分に生かした口腔内崩壊錠は、未だ提供されている状況ではない。本発明は、このような課題を解決するためになされたものであって、エリスリトールの有用な性質を生かした口腔内崩壊錠、その製造に好適な顆粒および当該顆粒の製造方法を提供することを目的とする。 That is, even in view of these patent documents, the orally disintegrating tablet containing erythritol and fully utilizing its useful properties has not been provided yet. The present invention has been made to solve such problems, and it is an orally disintegrating tablet utilizing the useful properties of erythritol, a granule suitable for the production thereof, and a method for producing the granule. To aim.
　本発明者らは、鋭意研究の結果、驚くべきことに、エリスリトールと所定の崩壊剤とを組み合わせて造粒することにより、適切な錠剤硬度と短い口腔内崩壊時間とを兼ね備えた口腔内崩壊錠を直打法で製造できる顆粒が得られることを見いだした。すなわち、粉末状のエリスリトールに、所定量のクロスポピドンと所定量の低置換度ヒドロキシプロピルセルロースおよび／または結晶セルロースとを添加して造粒し、得られたエリスリトールを主成分とする顆粒（エリスリトール顆粒）により、適切な錠剤硬度と口腔内崩壊時間とを兼ね備えた口腔内崩壊錠を製造できることを見いだした。そこで、この知見に基づいて、下記の各発明を完成した。 The inventors of the present invention have surprisingly found that orally disintegrating tablets having appropriate tablet hardness and short oral disintegration time by combining erythritol and a predetermined disintegrant and then surprisingly, granulating it. It has been found that granules can be obtained which can be produced by the direct striking method. That is, granules obtained by adding a predetermined amount of crospovidone and a predetermined amount of low-substituted hydroxypropyl cellulose and / or crystalline cellulose to powdery erythritol and granulating the obtained erythritol as a main component (erythritol granules (erythritol granules) ) Found that an orally disintegrating tablet having appropriate tablet hardness and oral disintegration time can be produced. Then, based on this knowledge, the following each invention was completed.
（１）本発明に係る顆粒は、口腔内崩壊錠の製造に用いるエリスリトール顆粒であって、１８０重量部のエリスリトールに対して、５重量部以上５０重量部以下のクロスポビドン、ならびに、２重量部以上１５重量部以下の低置換度ヒドロキシプロピルセルロースおよび／または結晶セルロースを含有する。 (1) The granules according to the present invention are erythritol granules used for the production of orally disintegrating tablets, and are 5 parts by weight or more and 50 parts by weight or less of crospovidone, and 2 parts by weight with respect to 180 parts by weight of erythritol. More than 15 parts by weight or less of low substituted hydroxypropyl cellulose and / or crystalline cellulose are contained.
（２）本発明に係る顆粒は、当該顆粒１００重量部に対してステアリン酸マグネシウムを１重量部の割合で添加した後、乾式直接打錠法（直打法）により１５．０ｋＮ未満の打錠圧で打錠して、直径が８ｍｍで１錠当たり２００ｍｇの錠剤に成型した場合に、当該錠剤の口腔内崩壊時間が３０秒以下となる物性を有することが好ましい。 (2) The granules according to the present invention are prepared by adding 1 part by weight of magnesium stearate to 100 parts by weight of the granules, and then tableting less than 15.0 kN by a dry direct compression method (direct compression method) It is preferable that the tablet has physical properties such that the intraoral disintegration time of the tablet is 30 seconds or less when the tablet is compressed to 8 mm in diameter and formed into a tablet of 200 mg per tablet.
（３）本発明に係る顆粒の製造方法は、口腔内崩壊錠の製造に用いるエリスリトール顆粒を製造する方法であって、エリスリトールの粉末およびクロスポビドンからなる基質を流動または攪拌しながら、当該基質に、低置換度ヒドロキシプロピルセルロースおよび／または結晶セルロースを含有する噴霧液を噴霧した後に乾燥させる造粒工程を有する。 (3) The method for producing granules according to the present invention is a method for producing erythritol granules used for producing an orally disintegrating tablet, wherein a substrate comprising erythritol powder and crospovidone is flowed or stirred to the substrate. And a granulating step in which a spray solution containing low substituted hydroxypropyl cellulose and / or crystalline cellulose is sprayed and then dried.
（４）本発明に係る顆粒の製造方法において、前記基質は、エリスリトール１８０重量部に対してクロスポビドンを５重量部以上５０重量部以下含有するものであり、前記噴霧液において、低置換度ヒドロキシプロピルセルロースおよび／または結晶セルロースの濃度は、１．３質量％以上１０．０質量％以下であることが好ましい。 (4) In the method of producing granules according to the present invention, the substrate contains 5 to 50 parts by weight of crospovidone with respect to 180 parts by weight of erythritol, and the spray liquid has a low degree of hydroxy substitution. The concentration of propyl cellulose and / or crystalline cellulose is preferably 1.3% by mass or more and 10.0% by mass or less.
（５）本発明に係る口腔内崩壊錠は、本発明に係る口腔内崩壊錠用エリスリトール顆粒と薬効成分または食品材料とを含むことを特徴とする。 (5) The orally disintegrating tablet according to the present invention is characterized by containing the erythritol granules for orally disintegrating tablet according to the present invention and a medicinal ingredient or a food material.
　本発明によれば、適切な錠剤硬度と崩壊時間とを兼ね備えた口腔内崩壊錠を製造することができる。また、本発明によれば、エリスリトールの有用な性質を生かした口腔内崩壊錠を製造することができる。また、本発明によれば、上述の口腔内崩壊錠を、特別な装置や製造工程を要することなく、一般的な錠剤製造方法である乾式直接打錠法（直打法）により製造することができる。また、本発明によれば、上述の口腔内崩壊錠の製造に好適なエリスリトール顆粒を得ることができる。 According to the present invention, it is possible to produce an orally disintegrating tablet which has appropriate tablet hardness and disintegration time. Further, according to the present invention, an orally disintegrating tablet can be produced which makes use of the useful properties of erythritol. Further, according to the present invention, the orally disintegrating tablet described above can be produced by a dry direct compression method (direct pressing method), which is a general tablet production method, without requiring a special device or production process. it can. Further, according to the present invention, erythritol granules suitable for the production of the above-mentioned orally disintegrating tablet can be obtained.
　以下、本発明に係る口腔内崩壊錠用エリスリトール顆粒、およびその製造方法、ならびにそれを用いた口腔内崩壊錠について詳細に説明する。 Hereinafter, erythritol granules for orally disintegrating tablets according to the present invention, a method for producing the same, and orally disintegrating tablets using the same will be described in detail.
　「口腔内崩壊錠用エリスリトール顆粒」とは、口腔内崩壊錠の製造に用いるためのエリスリトール顆粒をいう。 "Erythritol granules for orally disintegrating tablets" refers to erythritol granules for use in the manufacture of orally disintegrating tablets.
　「エリスリトール顆粒」とは、エリスリトールを主成分とする顆粒またはその集合体をいう。エリスリトール顆粒の粒子径は、エリスリトールの粉末の粒子径よりも大きいものであればよいが、直打法による錠剤製造に使用する観点からは、平均粒子径が５０μｍ以上２５０μｍ未満であることが好ましい。 "Erythritol granule" refers to a granule containing erythritol as a main component or an aggregate thereof. The particle diameter of erythritol granules may be larger than the particle diameter of erythritol powder, but from the viewpoint of use for tablet production by the direct compression method, the average particle diameter is preferably 50 μm or more and less than 250 μm.
　本発明に係る口腔内崩壊錠用エリスリトール顆粒は、１８０重量部のエリスリトールに対して、５重量部以上５０重量部以下のクロスポビドン、ならびに、２重量部以上１５重量部以下の低置換度ヒドロキシプロピルセルロースおよび／または結晶セルロースを含有する。 The erythritol granules for orally disintegrating tablets according to the present invention are 5 parts by weight or more and 50 parts by weight or less of crospovidone, and 2 parts by weight or more and 15 parts by weight or less of low substituted hydroxypropyl with respect to 180 parts by weight of erythritol. Cellulose and / or crystalline cellulose is contained.
　エリスリトールは、化学名が１，２，３，４－Ｂｕｔａｎｅｔｅｒｏｌである糖アルコールであり、エリトリトールとも呼ばれる。本発明において、粉末状のエリスリトールは市販品を用いてもよく、当業者に公知の方法に従って製造して用いてもよい。 Erythritol is a sugar alcohol whose chemical name is 1,2,3,4-Butaneterol and is also called erythritol. In the present invention, powdered erythritol may be a commercially available product, or may be produced and used according to methods known to those skilled in the art.
　エリスリトールの公知の製造方法としては、グルコースなどを炭素源としてエリスリトール生産菌を培養して生産させ、これを精製して得る方法を挙げることができる。ここで、エリスリトール生産菌としては、例えば、トリゴノプシス属またはカンジダ属に属する微生物（特公昭４７－４１５４９号公報）、トルロプシス属、ハンゼヌラ属、ピヒア属またはデバリオミセス属に属する微生物（特公昭５１－２１０７２号公報）、モニリエラ属に属する微生物（特開昭６０－１１０２９５号公報、特開平１０－２１５８８７）、オーレオバシデュウム属に属する微生物（特公昭６３－９８３１号公報）、イエロビア属に属する微生物（特開平１０－２１５８８７号公報）などを挙げることができ、培養条件は、各菌に適した通常の条件で行うことができる。また、エリスリトールの精製は、菌体分離、クロマトグラフィーによるエリスリトールの分取、脱塩、脱色、晶析、結晶分解および乾燥の工程を常法に従って行うことができる。 Examples of known methods for producing erythritol include a method in which erythritol-producing bacteria are cultured and produced using glucose or the like as a carbon source, and the product is purified and obtained. Here, as erythritol-producing bacteria, for example, a microorganism belonging to the genus Trigonopsis or Candida (Japanese Patent Publication No. 47-41549), a microorganism belonging to the genus Toluroposis, the genus Hansenula, the genus Pichia or Debaryomyces (Japanese Patent Publication No. 51-21072) Gazette), microorganisms belonging to the genus Moniliella (JP-A 60-110295, JP-A 10-215887), microorganisms belonging to the genus Aureobasidium (JP-B-63-9831), microorganisms belonging to the genus JP-A-10-215887) and the like can be mentioned, and culture conditions can be performed under ordinary conditions suitable for each bacterium. In addition, purification of erythritol can be carried out according to a conventional method in the steps of cell separation, separation of erythritol by chromatography, desalting, decolorization, crystallization, crystal decomposition and drying.
　クロスポビドン（Cross-linked polyvinylpyrolidone、ＣＰＶＰ）は、「架橋ポリビニルピロリドン」、「ポリビニルポリピロリドン」、「不溶性ポリビニルピロリドン」とも呼ばれ、Ｎ－ビニル－２－ピロリドンが重合してなるポリビニルピロリドン（ＰＶＰ）のピロリドン部分が架橋された構造を有する、水に不溶な高分子化合物である。本発明において、クロスポビドンは市販品を用いることができ、その分子量や粒子径などは、口腔内崩壊錠用エリスリトール顆粒における所望の物性や造粒方法などに応じて適宜設定することができる。市販のクロスポビドンとしては、例えば、Ｋｏｌｉｄｏｎ（登録商標）ＣＬ、ＣＬ－Ｆ、ＣＬ－ＳＦおよびＣＬ－Ｍ（以上、ＢＡＳＦ）、Ｐｏｌｙｃｌａｒ １０（Ａｓｈｌａｎｄ）などを挙げることができる。 Crospovidone (Cross-linked polyvinyl pyrrolidone) (CPVP) is also called “crosslinked polyvinyl pyrrolidone”, “polyvinyl polypyrrolidone”, or “insoluble polyvinyl pyrrolidone”, and is polyvinyl pyrrolidone (PVP) formed by polymerization of N-vinyl-2-pyrrolidone. Water-insoluble polymer compound having a crosslinked structure of pyrrolidone moiety of In the present invention, as the crospovidone, a commercially available product can be used, and the molecular weight, particle size, etc. can be appropriately set according to the desired physical properties, granulation method, etc. of the erythritol granules for orally disintegrating tablets. Examples of commercially available crospovidone include Kolidon (registered trademark) CL, CL-F, CL-SF, and CL-M (above, BASF), Polyclar 10 (Ashland), and the like.
　低置換度ヒドロキシプロピルセルロース（Low Substituted Hydroxypropylcellulose、ＬＨＰＣ）は、セルロースの骨格にヒドロキシプロポキシ基（－ＯＣＨ２ＣＨＯＨＣＨ３）が導入されてなるセルロース誘導体（ヒドロキシプロピルセルロース）のうち、ヒドロキシプロポキシ基の導入量が小さく、水に不溶性を示すものをいう。ヒドロキシプロポキシ基は、セルロース骨格の水酸基を置換することにより導入されることから、その導入量は、モル置換度（１グルコース残基あたりのヒドロキシプロポキシル基の数、moles of substitution、ＭＳ）で表される。 Low substituted Hydroxypropylcellulose (Low substituted Hydroxypropylcellulose, LHPC) is the amount of hydroxypropoxy group introduced in the cellulose derivative (hydroxypropyl cellulose) in which a hydroxypropoxy group (-OCH 2 CHOHCH 3 ) is introduced into the skeleton of cellulose. Is small and is insoluble in water. Since the hydroxypropoxy group is introduced by substituting the hydroxyl group of the cellulose skeleton, the introduction amount is represented by the degree of molar substitution (number of hydroxypropoxyl groups per glucose residue, moles of substitution, MS) Be done.
　本発明において、ＬＨＰＣは市販品を用いることができ、その置換度や分子量、粒子径などは、口腔内崩壊錠用エリスリトール顆粒における所望の物性や造粒方法などに応じて適宜設定することができる。置換度は、例えば、ＭＳが０．０１～２、好ましくは０．０５～１．５、より好ましくは０．１～１のもの、あるいは、乾燥物中にヒドロキシプロポキシル基を１～２５質量％、好ましくは２～２０質量％、より好ましくは３～１８質量％含有するものを用いることができる。また、市販のＬＨＰＣとしては、例えば、ＬＨ－１１、ＬＨ－２１、ＬＨ－２２、ＬＨ－Ｂ１、ＬＨ－３１、ＬＨ－３２、ＮＢＤ－０２０、ＮＢＤ－０２１、ＮＢＤ－０２２（以上、信越化学工業）などを挙げることができる。 In the present invention, commercially available LHPC can be used, and the degree of substitution, molecular weight, particle size, etc. can be appropriately set according to the desired physical properties, granulation method, etc. in erythritol granules for orally disintegrating tablets. . The degree of substitution is, for example, that of MS 0.01 to 2, preferably 0.05 to 1.5, more preferably 0.1 to 1, or 1 to 25 mass of hydroxypropoxyl group in the dry matter %, Preferably 2 to 20% by mass, more preferably 3 to 18% by mass can be used. Moreover, as LHPC commercially available, for example, LH-11, LH-21, LH-22, LH-B1, LH-31, LH-32, NBD-020, NBD-021, NBD-022 (all, Shin-Etsu Chemical Industrial) and the like.
　結晶セルロース（Microcrystalline Cellulose、ＭＣＣ）は、繊維性植物からパルプとして得られるα－セルロース等の高純度のセルロースを、酸で部分的に解重合し精製したものである。本発明において、結晶セルロースは、その平均重合度や乾燥減量値、かさ密度、粒子径、形状等に特に制限無く用いることができる。市販のＭＣＣとしては、例えば、セオラス　ＵＦ－７０２、セオラス　ＵＦ－７１１、セオラス　ＫＧ－８０２、セオラス　ＫＧ－１０００、セオラス　ＰＨ－１０１、セオラス　ＰＨ－１０１Ｄ、セオラス　ＰＨ－１０２、セオラス　ＰＨ－２００、セオラス　ＰＨ－３０１、セオラス　ＰＨ－３０１Ｄ、セオラス　ＰＨ－３０２、セオラス　ＰＨ－Ｆ２０ＪＰ（以上、旭化成ケミカルズ）などを用いることができる。 Crystalline cellulose (Microcrystalline Cellulose, MCC) is obtained by partially depolymerizing and purifying high purity cellulose such as α-cellulose obtained as pulp from fibrous plants with an acid. In the present invention, crystalline cellulose can be used without particular limitation on the average degree of polymerization, loss on drying, bulk density, particle diameter, shape and the like. Commercially available MCCs include, for example, Theorus UF-702, Theorus UF-711, Theorus KG-802, Theorus KG-1000, Theorus PH-101, Theorus PH-101D, Theorus PH-102, Theorus PH-200, Theorus PH -301, Theorus PH-301D, Theorus PH-302, Theorus PH-F20JP (above, Asahi Kasei Chemicals) etc. can be used.
　薬効成分や食品材料などを混合せず、顆粒のみ、あるいはこれに滑沢剤を添加したのみで、そのまま直打法により製造した錠剤の口腔内崩壊時間は、当該顆粒の口腔内崩壊錠への使用適性を評価する指標となる。本発明においては、顆粒１００重量部に対してステアリン酸マグネシウム（滑沢剤）を１重量部の割合で添加した後、直打法により１５．０ｋＮ未満の打錠圧で打錠して、直径が８ｍｍで１錠当たり２００ｍｇの錠剤に成型した場合に、当該錠剤の口腔内崩壊時間が３０秒以下となる物性を有する顆粒を、好適な口腔内崩壊錠用エリスリトール顆粒としている。 The orally disintegrating time of the tablet manufactured by the direct hitting method as it is by mixing the granules or the lubricant alone without mixing the pharmaceutically active ingredient or the food material is the same as the orally disintegrating tablet of the granules. It becomes an index to evaluate use aptitude. In the present invention, magnesium stearate (lubricant) is added in a proportion of 1 part by weight to 100 parts by weight of the granules, and then tableted with a direct compression method at a tableting pressure of less than 15.0 kN to obtain a diameter The granules having physical properties such that the oral disintegration time of the tablet is 30 seconds or less when the tablet is formed into a tablet of 200 mg per tablet at 8 mm is a suitable erythritol granule for orally disintegrating tablet.
　口腔内崩壊錠用エリスリトール顆粒は、本発明の特徴を損なわない限りにおいて、エリスリトール、ＣＰＶＰ、ＬＨＰＣおよびＭＣＣ以外の物質を含んでいてもよい。そのような物質としては、例えば、加工特性を改良するための結合剤や滑沢剤、錠剤の風味や嗜好性、保存性などを改良するための食品添加物や医薬品添加物を挙げることができる。例えば、結合剤の添加は、比較的低い打錠圧によって錠剤を製造するために有効な場合がある。結合剤としては、例えば、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）やメチルセルロース、ヒドロキシエチルメチルセルロース、プルラン、アルギン酸ナトリウム、寒天、ゼラチン、カルボキシメチルセルロースナトリウム、ポリビニルピロリドン、ポリビニルアルコールなどを挙げることができる。また、滑沢剤としては、例えば、ステアリン酸マグネシウム、グリセリン脂肪酸エステル、ソルビタン酸脂肪酸エステル、ショ糖脂肪酸エステルなどを挙げることができる。 Erythritol granules for orally disintegrating tablets may contain substances other than erythritol, CPVP, LHPC and MCC, as long as the characteristics of the present invention are not impaired. Such substances may include, for example, binders and lubricants for improving processing characteristics, food additives and pharmaceutical additives for improving the taste, palatability and storage properties of tablets, etc. . For example, the addition of binders may be effective for producing tablets with relatively low tableting pressure. Examples of the binder include hydroxypropyl methylcellulose (HPMC), methylcellulose, hydroxyethyl methylcellulose, pullulan, sodium alginate, agar, gelatin, sodium carboxymethylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol and the like. Moreover, as a lubricant, magnesium stearate, glycerine fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester etc. can be mentioned, for example.
　口腔内崩壊錠用エリスリトール顆粒は、エリスリトールの粉末およびクロスポビドン（ＣＰＶＰ）からなる基質を流動または攪拌しながら、当該基質に、低置換度ヒドロキシプロピルセルロース（ＬＨＰＣ）および／または結晶セルロース（ＭＣＣ）を含有する噴霧液を噴霧した後乾燥させる造粒工程により製造することができる。すなわち、本発明は、上記造粒工程を有する口腔内崩壊錠用エリスリトール顆粒の製造方法をも提供する。 Erythritol granules for orally disintegrating tablets are prepared by flowing low agitation hydroxypropyl cellulose (LHPC) and / or crystalline cellulose (MCC) to a matrix of erythritol powder and crospovidone (CPVP) while flowing or stirring the matrix. It can manufacture by the granulation process of making it dry after spraying the spray liquid to contain. That is, the present invention also provides a method for producing erythritol granules for orally disintegrating tablets having the above granulation step.
　上記造粒工程は、後述する実施例の試験方法（２）に示すように、流動層造粒法により行うことができるほか、攪拌造粒法、噴霧乾燥法などにより行うこともできる。ここで、流動層造粒法とは、湿式造粒の一方法であり、造粒室の下部から熱風を送り込み、原料粉粒体を空中に巻き上げることにより粒子が流動する状態になる層を形成してから、液体（噴霧液）を噴霧して、凝集や被覆により原料粉粒体を粒状物（顆粒）に成長させる方法である。流動層造粒法による造粒は、市販の造粒装置により行うことができる。 The granulation step can be carried out by a fluidized bed granulation method as shown in Test Method (2) of Examples described later, and can also be carried out by a stirring granulation method, a spray drying method or the like. Here, fluidized bed granulation is one method of wet granulation, and hot air is sent from the lower part of the granulation chamber to form a layer in which particles flow by rolling up the raw material powder particles into the air. Then, the liquid (spray liquid) is sprayed to grow the raw material powder particles into granules (granules) by aggregation or coating. Granulation by fluid bed granulation can be performed by a commercially available granulator.
　すなわち、上記造粒工程を流動層造粒法により行う場合は、エリスリトールの粉末およびＣＰＶＰからなる基質を熱風で流動しながら、当該基質にＬＨＰＣおよび／またはＭＣＣを含有する噴霧液を噴霧した後、当該熱風により乾燥させることにより、口腔内崩壊錠用エリスリトール顆粒を製造することができる。 That is, when the above granulation step is carried out by a fluidized bed granulation method, after spraying a spray solution containing LHPC and / or MCC onto the substrate while flowing the substrate consisting of erythritol powder and CPVP with hot air, By drying with the hot air, erythritol granules for orally disintegrating tablets can be produced.
　基質におけるエリスリトールとＣＰＶＰとの量比は、顆粒における所望の物性や造粒方法などに応じて適宜設定することができるが、好適には、エリスリトール１８０重量部に対して、ＣＰＶＰが１重量部以上１００重量部以下、２重量部以上８０重量部以下、３重量部以上７０重量部以下、４重量部以上６０重量部以下、５重量部以上５０重量部以下などとすることができる。 The ratio of erythritol to CPVP in the substrate can be appropriately set according to the desired physical properties of the granules, the granulation method, etc. Preferably, 1 part by weight or more of CPVP is based on 180 parts by weight of erythritol. The amount can be 100 parts by weight or less, 2 parts by weight to 80 parts by weight, 3 parts by weight to 70 parts by weight, 4 parts by weight to 60 parts by weight, 5 parts by weight to 50 parts by weight, and the like.
　噴霧液におけるＬＨＰＣおよび／またはＭＣＣの分散媒は、例えば、水やエタノールなどのアルコール、あるいはこれらの混合物などを挙げることができる。噴霧液には、本発明の特徴を損なわない限りにおいて、結合剤や糖アルコール、香料や着色料、保存料などの食品添加物や医薬品添加物を添加して用いてもよい。結合剤としては、例えば、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）、メチルセルロース、ヒドロキシエチルメチルセルロース、プルラン、アルギン酸ナトリウム、寒天、ゼラチン、カルボキシメチルセルロースナトリウム、ポリビニルピロリドン、ポリビニルアルコールなどを挙げることができる。 Examples of the dispersion medium of LHPC and / or MCC in the spray liquid include water, alcohols such as ethanol, or mixtures thereof. The spray liquid may be used by adding a food additive such as a binder, a sugar alcohol, a flavor, a coloring agent, a preservative, or a pharmaceutical additive as long as the characteristics of the present invention are not impaired. Examples of the binder include hydroxypropyl methylcellulose (HPMC), methylcellulose, hydroxyethyl methylcellulose, pullulan, sodium alginate, agar, gelatin, sodium carboxymethylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol and the like.
　噴霧液は、ＬＨＰＣまたはＭＣＣをいずれか単独で含むものでもよく、ＬＨＰＣおよびＭＣＣをいずれも含むものでもよい。いずれかを単独で含む場合のＬＨＰＣまたはＭＣＣの濃度は、口腔内崩壊錠用エリスリトール顆粒における所望の物性や造粒方法などに応じて適宜設定することができるが、好適には、０．５～２０質量％、０．６～１９質量％、０．７～１８質量％、０．８～１７質量％、０．９～１６質量％、１．０～１５質量％、１．１～１４質量％、１．２～１３質量％、１．３～１２質量％、１．３～１１質量％、１．３～１０質量％などとすることができる。 The spray solution may contain either LHPC or MCC alone, or both LHPC and MCC. The concentration of LHPC or MCC when any one of them is contained alone can be appropriately set according to the desired physical properties and granulation method in the erythritol granules for orally disintegrating tablets, but preferably 0.5 to 20% by mass, 0.6 to 19% by mass, 0.7 to 18% by mass, 0.8 to 17% by mass, 0.9 to 16% by mass, 1.0 to 15% by mass, 1.1 to 14% %, 1.2 to 13% by mass, 1.3 to 12% by mass, 1.3 to 11% by mass, 1.3 to 10% by mass, and the like.
　また、いずれも含む場合の噴霧液におけるＬＨＰＣおよびＭＣＣの濃度は、両物質の合計の濃度で、好適には、０．５～２０質量％、０．６～１９質量％、０．７～１８質量％、０．８～１７質量％、０．９～１６質量％、１．０～１５質量％、１．１～１４質量％、１．２～１３質量％、１．３～１２質量％、１．３～１１質量％、１．３～１０質量％などとすることができる。 In addition, the concentration of LHPC and MCC in the spray liquid when both are contained is preferably 0.5 to 20% by mass, 0.6 to 19% by mass, and 0.7 to 18 in terms of the total concentration of the two substances. Mass, 0.8 to 17 mass%, 0.9 to 16 mass%, 1.0 to 15 mass%, 1.1 to 14 mass%, 1.2 to 13 mass%, 1.3 to 12 mass% , 1.3 to 11% by mass, 1.3 to 10% by mass, and the like.
　造粒工程における造粒装置は、例えば、通常流動層型造粒機や強制循環型流動層造粒機、噴流層型造粒機などのバッチ式流動層造粒機、箱型連続式流動層造粒機や円筒型連続式流動層造粒機などの連続式流動層造粒機を用いることができる。造粒装置における噴霧液のスプレーノズルの位置は、例えば、底部スプレー方式、トップスプレー方式、接線スプレー方式のいずれであってもよい。造粒条件はエリスリトールの仕込み量やエリスリトール顆粒における所望の物性などに応じて適宜設定することができるが、例えば、熱風入口温度を６０～１００℃、風量を０．４～０．８ｍ３／分、噴霧液の噴霧圧力を０．１～０．３ＭＰａとすることができる。 The granulation apparatus in the granulation step is, for example, a batch type fluidized bed granulator such as a normal fluidized bed type granulator, a forced circulation type fluidized bed granulator, a spouted bed type granulator, etc., a box type continuous type fluidized bed A continuous fluid bed granulator such as a granulator or cylindrical continuous fluid bed granulator can be used. The position of the spray nozzle of the spray liquid in the granulating apparatus may be, for example, any of a bottom spray method, a top spray method, and a tangential spray method. The granulation conditions can be appropriately set according to the amount of erythritol and the desired physical properties of erythritol granules, and for example, the hot air inlet temperature is 60 to 100 ° C., and the air volume is 0.4 to 0.8 m 3 / minute. The spray pressure of the spray liquid can be 0.1 to 0.3 MPa.
　最後に、本発明に係る口腔内崩壊錠は、本発明に係る口腔内崩壊錠用エリスリトール顆粒と薬効成分または食品材料とを含むことを特徴とする。 Finally, the orally disintegrating tablet according to the present invention is characterized by containing the erythritol granules for orally disintegrating tablet according to the present invention and a medicinal ingredient or a food material.
　口腔内崩壊錠は、口腔内崩壊錠用エリスリトール顆粒と薬効成分または食品材料との混合物を直打法により打錠する打錠工程により製造することができる。当該打錠工程において、エリスリトール顆粒と薬効成分との混合物を打錠すれば、口腔内崩壊錠の形態を有する医薬品や医薬部外品を製造することができ、エリスリトール顆粒と食品材料との混合物を打錠すれば、口腔内崩壊錠の形態を有する菓子（錠菓）やサプリメントなどの飲食品を製造することができる。 The orally disintegrating tablet can be produced by a tableting process in which a mixture of erythritol granules for orally disintegrating tablet and a medicinal ingredient or a food material is compressed by direct compression method. In the tableting process, if a mixture of erythritol granules and a pharmaceutically active ingredient is tableted, pharmaceuticals and quasi-drugs having the form of orally disintegrating tablets can be produced, and a mixture of erythritol granules and a food material If tableted, food and drink such as confectionery (tablet confectionery) and supplement having the form of orally disintegrating tablet can be manufactured.
　上記打錠工程において、直打法は、当業者に公知の方法に従って行うことができる。すなわち、口腔内崩壊錠用エリスリトール顆粒と薬効成分または食品材料との混合物を市販の打錠機に仕込み、錠剤の形状に圧縮成型すればよい。打錠圧や錠剤のサイズは、製品の用途や含有成分等に応じて適宜設定することができる。打錠圧としては、例えば、錠剤の面積０．５ｃｍ２に対して、４０．０ｋＮ未満、３５ｋＮ未満、３０ｋＮ未満、２５ｋＮ未満、２０ｋＮ未満、あるいは１５．０ｋＮ未満などとすることができる。 In the above-mentioned tableting step, the direct compression method can be carried out according to methods known to those skilled in the art. That is, a mixture of erythritol granules for orally disintegrating tablet and a medicinal ingredient or a food material may be charged into a commercially available tableting machine and compressed into a tablet shape. The tableting pressure and the size of the tablet can be appropriately set in accordance with the use of the product, the components contained therein, and the like. The tableting pressure can be, for example, less than 40.0 kN, less than 35 kN, less than 30 kN, less than 25 kN, less than 20 kN, or less than 15.0 kN with respect to a tablet area of 0.5 cm 2 .
　なお、口腔内崩壊錠には、本発明の特徴を損なわない限りにおいて、口腔内崩壊錠用エリスリトール顆粒および薬効成分または食品材料以外の物質を含んでいてもよい。そのような物質としては、例えば、加工特性を改良するための結合剤や滑沢剤、錠剤の風味や嗜好性、保存性などを改良するための食品添加物や医薬品添加物を挙げることができる。結合剤としては、例えば、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）やメチルセルロース、ヒドロキシエチルメチルセルロース、プルラン、アルギン酸ナトリウム、寒天、ゼラチン、カルボキシメチルセルロースナトリウム、ポリビニルピロリドン、ポリビニルアルコールなどを挙げることができる。また、滑沢剤としては、例えば、ステアリン酸マグネシウム、グリセリン脂肪酸エステル、ソルビタン酸脂肪酸エステル、ショ糖脂肪酸エステルなどを挙げることができる。 The orally disintegrating tablet may contain substances other than erythritol granules for orally disintegrating tablet and medicinal ingredients or food materials as long as the characteristics of the present invention are not impaired. Such substances may include, for example, binders and lubricants for improving processing characteristics, food additives and pharmaceutical additives for improving the taste, palatability and storage properties of tablets, etc. . Examples of the binder include hydroxypropyl methylcellulose (HPMC), methylcellulose, hydroxyethyl methylcellulose, pullulan, sodium alginate, agar, gelatin, sodium carboxymethylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol and the like. Moreover, as a lubricant, magnesium stearate, glycerine fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester etc. can be mentioned, for example.
　以下、本発明について、各実施例に基づいて説明する。なお、本発明の技術的範囲は、これらの実施例によって示される特徴に限定されない。 Hereinafter, the present invention will be described based on each example. The technical scope of the present invention is not limited to the features shown by these embodiments.
＜試験方法＞
　本実施例は、別段に記載のない限り下記（１）～（４）の方法で行った。また、本実施例においては、別段に記載のない限り「％」は「質量％」を意味する。また、エリスリトールは「ＥＲＴ」と表記する場合がある。 <Test method>
This example was carried out by the following methods (1) to (4) unless otherwise stated. Moreover, in the present Example, unless otherwise indicated, "%" means "mass%." In addition, erythritol may be described as "ERT".
（１）材料
　エリスリトールは「エリスリトール　１００Ｍ（白色粉末、医薬品添加物規格）（物産フードサイエンス社）」を用いた。また、造粒時の添加物は、特段の記載の無い限り表１に示す市販品を用いた。
Figure JPOXMLDOC01-appb-T000001
 (1) Material erythritol used "Erythritol 100M (white powder, pharmaceutical additive specification) (Products Food Science Co., Ltd.)". Moreover, the additive at the time of granulation used the commercial item shown in Table 1 unless otherwise indicated.
Figure JPOXMLDOC01-appb-T000001
（２）造粒方法
　粉末状のエリスリトールから顆粒の形状のエリスリトール（ＥＲＴ顆粒）の製造は、流動層造粒法により行った。すなわち、造粒装置「マルチプレックス　ＦＤ－ＭＰ－０１ＮＤ（パウレック社）」に、基質として粉末状のエリスリトール、またはエリスリトールと添加物とを仕込み、熱風入口温度が８０℃、風量が０．６ｍ３／分、噴霧圧力が０．２ＭＰａにて、噴霧液を噴霧しながら造粒を行った。噴霧液には、水、または水に添加物を溶解もしくは分散してなる水性液体を用いた。 (2) Granulation method The manufacture of erythritol in the form of granules from powdery erythritol (ERT granules) was carried out by a fluidized bed granulation method. That is, powdered erythritol as a substrate or erythritol and an additive are charged into a granulating apparatus “Multiplex FD-MP-01ND (Powrex Inc.)”, the hot air inlet temperature is 80 ° C., the air volume is 0.6 m 3 / Granulation was performed while spraying the spray liquid at a spray pressure of 0.2 MPa for a minute. As the spray liquid, water or an aqueous liquid obtained by dissolving or dispersing the additive in water was used.
（３）打錠方法
　ＥＲＴ顆粒を用いて、直打法により錠剤を製造した。すなわち、ＥＲＴ顆粒１００重量部に対して、滑沢剤としてステアリン酸マグネシウム１重量部を添加した後、卓上型単発式打錠機「ＭＩＮＩＰＲＥＳＳ　ＭＩＩ（ＲＩＶＡ　Ｓ．Ａ．社）」に仕込み、産業上、実施可能な打錠圧（１５ｋＮ未満）で、錠剤の形状に圧縮成型した。錠剤のサイズは、直径が８ｍｍ、１錠当たりの重量は２００ｍｇとした。すなわち、錠剤の面積（π×０．４ｃｍ×０．４ｃｍ≒０．５ｃｍ２）に対して１５．０ｋＮ（３００ＭＰａ）未満の打錠圧をかけることにより錠剤を製造した。 (3) Tableting method Tablets were manufactured by the direct compression method using ERT granules. That is, 1 part by weight of magnesium stearate as a lubricant is added to 100 parts by weight of ERT granules, and then it is charged in a table-type single-shot tableting machine "MINIPRESS MII (RIVA S. A.)", industrially , Squeezable into tablet form with a viable tableting pressure (less than 15 kN). The tablet had a diameter of 8 mm and a weight of 200 mg per tablet. That is, a tablet was manufactured by applying a tableting pressure less than 15.0 kN (300 MPa) to the area of the tablet (π × 0.4 cm × 0.4 cm ≒ 0.5 cm 2 ).
（４）評価項目および評価方法
［４－１］錠剤硬度
　錠剤の硬度は、ロードセル式錠剤硬度計（ＰＣ－３０、岡田精工）を用いて測定した。測定した錠剤硬度が５．０キログラム重（ｋｇｆ）以上であれば、製品の硬度として「適する（○）」、５．０ｋｇｆ未満であれば、「不適（×）」と評価した。 (4) Evaluation Items and Evaluation Method [4-1] Tablet Hardness The hardness of the tablet was measured using a load cell tablet hardness tester (PC-30, Okada Seiko Co., Ltd.). When the measured tablet hardness was 5.0 kilograms weight (kgf) or more, the product was evaluated as "Suitable (○)" as the hardness of the product, and as "not suitable (x)" when it was less than 5.0 kgf.
［４－２］口腔内崩壊時間
　錠剤の口腔内崩壊時間は、口腔内崩壊錠試験器（ＯＤＴ－１０１、富山産業）を用いて測定した。測定条件は、錘（直径１５ｍｍ、１５ｇ）、回転数２５回転／分（ｒｐｍ）、温度３７±０．５℃とした。測定した崩壊時間が３０秒以下であれば、口腔内崩壊錠として「好適（略記：◎）」、３０秒超６０秒以下であれば「適する（略記：○）」、６０秒超１８０秒以下であれば「やや不適（略記：△）」、１８０秒超であれば「不適（略記：×）」と評価した。 [4-2] Oral disintegration time The oral disintegration time of the tablet was measured using an orally disintegrating tablet tester (ODT-101, Toyama Sangyo). The measurement conditions were a weight (diameter 15 mm, 15 g), a rotational speed of 25 revolutions / minute (rpm), and a temperature of 37 ± 0.5 ° C. If the measured disintegration time is 30 seconds or less, it is "suitable (abbreviation: ◎)" as an orally disintegrating tablet, and if it is more than 30 seconds and 60 seconds or less, "suitable (abbreviation: ○)", 60 seconds and 180 seconds or less If it was, it was evaluated as "slightly unsuitable (abbreviation:))", and if it was over 180 seconds, it was evaluated as "improper (abbreviated: x)".
＜実施例１＞噴霧液における崩壊剤用途の添加物の検討
（１）噴霧液における崩壊剤の検討
　造粒装置に、基質として粉末状のエリスリトール１８０ｇとクロスポビドン（ＣＰＶＰ）３０ｇとを仕込み、噴霧液１５０ｍＬを噴霧しながら造粒を行った。噴霧液として、Ｎｏ．１の試料には、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）を１．０％となるよう溶解した水溶液（ＨＰＭＣ１％水溶液）を、Ｎｏ．２の試料には、ＨＰＭＣ１％水溶液に低置換度ヒドロキシプロピルセルロース（ＬＨＰＣ）を６．７％となるよう分散した水性液体を、Ｎｏ．３の試料には、ＨＰＭＣ１％水溶液に結晶セルロース（ＭＣＣ）を６．７％となるよう分散した水性液体を、それぞれ用いた。その後、錠剤を製造して評価した。その結果を表２に示す。
Figure JPOXMLDOC01-appb-T000002
 <Example 1> Examination of additives for disintegrant application in spray liquid (1) Investigation of disintegrant in spray liquid In a granulating apparatus, 180 g of powdered erythritol and 30 g of crospovidone (CPVP) were charged as a substrate, and the spray was carried out. Granulation was performed while spraying 150 mL of the solution. As a spray, No. In the sample No. 1, an aqueous solution (HPMC 1% aqueous solution) in which hydroxypropyl methylcellulose (HPMC) was dissolved to 1.0% was added to No. 1 sample. The sample No. 2 was an aqueous liquid in which low-substituted hydroxypropyl cellulose (LHPC) was dispersed in a 1% aqueous solution of HPMC so as to be 6.7%. The aqueous liquid which disperse | distributed crystalline cellulose (MCC) so that it might become 6.7% in HPMC1% aqueous solution was used for the sample of 3, respectively. The tablets were then manufactured and evaluated. The results are shown in Table 2.
Figure JPOXMLDOC01-appb-T000002
　表２に示すように、Ｎｏ．１の錠剤の崩壊時間は、口腔内崩壊錠として適する（○）ものの、４３．５秒前後とやや長かった。これに対して、Ｎｏ．２およびＮｏ．３の錠剤の崩壊時間は、いずれも３０秒以下で短く、口腔内崩壊錠として好適（◎）であった。この結果から、ＬＨＰＣまたはＭＣＣを含有させることにより、口腔内崩壊錠に好適なエリスリトール顆粒を製造できることが明らかになった。また、当該エリスリトール顆粒の製造工程では、噴霧液にＬＨＰＣおよび／またはＭＣＣを含有させることが好ましいことが明らかになった。 As shown in Table 2, no. Although the disintegration time of the tablet 1 was suitable as an orally disintegrating tablet (o), it was a little long, around 43.5 seconds. On the other hand, no. 2 and No. The disintegration time of each of the tablets of 3 was short in 30 seconds or less, and it was suitable as an orally disintegrating tablet (錠). From these results, it was revealed that the inclusion of LHPC or MCC makes it possible to produce erythritol granules suitable for orally disintegrating tablets. Moreover, it became clear that it is preferable to make LSPC and / or MCC contain in a spray liquid in the manufacturing process of the said erythritol granule.
（２）ＬＨＰＣおよびＭＣＣを併用した場合の検討
　造粒装置に、基質として粉末状のエリスリトール１８０ｇとＣＰＶＰ３０ｇとを仕込み、噴霧液１５０ｍＬを噴霧しながら造粒を行った。噴霧液は、ＨＰＭＣ１％水溶液にＬＨＰＣおよびＭＣＣを表３に示す濃度となるよう分散した水性液体を用いた。その後、錠剤を製造して評価した。その結果を表３に示す。
Figure JPOXMLDOC01-appb-T000003
 (2) Examination in the case of using LHPC and MCC in combination In a granulating apparatus, 180 g of powdered erythritol and 30 g of CPVP as substrates were charged, and granulation was carried out while spraying 150 mL of a spray liquid. As the spray liquid, an aqueous liquid in which LHPC and MCC were dispersed in a 1% aqueous solution of HPMC to a concentration shown in Table 3 was used. The tablets were then manufactured and evaluated. The results are shown in Table 3.
Figure JPOXMLDOC01-appb-T000003
　表３に示すように、Ｎｏ．４、Ｎｏ．５およびＮｏ．６の錠剤はいずれも、５．０ｋｇｆ以上の適切（○）な錠剤硬度を備えるとともに、崩壊時間は３０秒以下と短く、口腔内崩壊錠として好適（◎）であった。この結果から、口腔内崩壊錠に用いるエリスリトール顆粒に含有させる崩壊剤として、ＬＨＰＣおよびＭＣＣは併用可能であることが明らかになった。 As shown in Table 3, no. 4, no. 5 and No. The tablets of No. 6 all had suitable (o) tablet hardnesses of 5.0 kgf or more, and the disintegration time was as short as 30 seconds or less, and were suitable as orally disintegrating tablets (o). From this result, it has become clear that LHPC and MCC can be used in combination as a disintegrant to be contained in erythritol granules used for orally disintegrating tablets.
＜実施例２＞噴霧液における崩壊剤用途の添加物の量の検討
　造粒装置に、基質として粉末状のエリスリトール１８０ｇとＣＰＶＰ３０ｇとを仕込み、噴霧液１５０ｍＬを噴霧しながら造粒を行った。噴霧液は、ＨＰＭＣ１％水溶液にＭＣＣを１．３％、３．３％、６．７％または１０．０％となるよう分散した水性液体を用いた。その後、錠剤を製造して評価した。その結果を表４に示す。
Figure JPOXMLDOC01-appb-T000004
 Example 2 Examination of Amount of Additive for Use in Disintegrating Agent in Spray Liquid Into a granulation apparatus, 180 g of powdered erythritol and 30 g of CPVP were charged as a substrate, and granulation was carried out while spraying 150 mL of the spray liquid. The spray liquid used was an aqueous liquid in which MCC was dispersed in a 1% aqueous solution of HPMC so as to be 1.3%, 3.3%, 6.7% or 10.0%. The tablets were then manufactured and evaluated. The results are shown in Table 4.
Figure JPOXMLDOC01-appb-T000004
　表４に示すように、Ｎｏ．７、Ｎｏ．８、Ｎｏ．９およびＮｏ．１０の錠剤はいずれも、５．０ｋｇｆ以上の適切（○）な錠剤硬度を備えるとともに、崩壊時間は３０秒以下と短く、口腔内崩壊錠として好適（◎）であった。この結果から、口腔内崩壊錠に用いるエリスリトール顆粒において、ＬＨＰＣおよび／またはＭＣＣの量は、１８０重量部のエリスリトールに対して、２重量部以上１５重量部以下が好ましいことが明らかになった。また、当該エリスリトール顆粒の製造工程では、噴霧液におけるＬＨＰＣおよび／またはＭＣＣの濃度は、１．３％以上１０．０％以下が好ましいことが明らかになった。 As shown in Table 4, no. 7, No. 8, No. 9 and No. Each of the 10 tablets had an appropriate (o) tablet hardness of 5.0 kgf or more, and the disintegration time was as short as 30 seconds or less, and was suitable as an orally disintegrating tablet (o). From these results, it was revealed that the amount of LHPC and / or MCC in the erythritol granules used for the orally disintegrating tablet is preferably 2 parts by weight or more and 15 parts by weight or less with respect to 180 parts by weight of erythritol. Moreover, in the manufacturing process of the said erythritol granule, it became clear that the density | concentration of LHPC and / or MCC in a spray liquid has preferable 1.3% or more and 10.0% or less.
＜実施例３＞噴霧液における結合剤用途の添加物の検討
　造粒装置に、基質として粉末状のエリスリトール１８０ｇとＣＰＶＰ３０ｇとを仕込み、噴霧液１５０ｍＬを噴霧しながら造粒を行った。噴霧液は、水にＨＰＭＣを０．０％、０．５％、１．０％、２．５％または５．０％となるよう溶解し、さらに、ＬＨＰＣを１．３％およびＭＣＣ（（１）平均粒子径が５０μｍで安息角が５７度のもの、または（２）平均粒子径が５０μｍで安息角が４５度のもの）を５．３％となるよう分散した水性液体を用いた。その後、錠剤を製造して評価した。その結果を表５に示す。なお、Ｎｏ．１４－１はＭＣＣ（１）を、Ｎｏ．１４－２はＭＣＣ（２）を、それぞれ用いた。
Figure JPOXMLDOC01-appb-T000005
 <Example 3> Examination of Additives for Binder Application in Spray Liquid Into a granulation apparatus, 180 g of powdered erythritol and 30 g of CPVP were charged as a substrate, and granulation was carried out while spraying 150 mL of the spray liquid. The spray solution dissolves HPMC in water to 0.0%, 0.5%, 1.0%, 2.5% or 5.0%, and further, 1.3% LHPC and MCC (( 1) An aqueous liquid having an average particle size of 50 μm and a repose angle of 57 degrees, or (2) an average particle size of 50 μm and a repose angle of 45 degrees) dispersed to 5.3% was used. The tablets were then manufactured and evaluated. The results are shown in Table 5. No. No. 14-1 has MCC (1). 14-2 used MCC (2), respectively.
Figure JPOXMLDOC01-appb-T000005
　表５に示すように、Ｎｏ．１１～１５の錠剤はいずれも、５．０ｋｇｆ以上の適切（○）な錠剤硬度を備えていた。そして、Ｎｏ．１１～１３の錠剤の崩壊時間は３０秒以下と短く、口腔内崩壊錠として好適（◎）であった。Ｎｏ．１４－１の錠剤の崩壊時間は３２．１秒前後、Ｎｏ．１４－２の錠剤の崩壊時間は３８秒前後で、口腔内崩壊錠として適する（○）ものであった。Ｎｏ．１５の錠剤の崩壊時間も、口腔内崩壊錠として適する（○）ものの、５２．７秒前後と比較的長かった。この結果から、口腔内崩壊錠に用いるエリスリトール顆粒において、ＨＰＭＣの量は、１８０重量部のエリスリトールに対して、７．５重量部以下が好ましく、３．８重量部以下がより好ましいことが明らかになった。また、当該エリスリトール顆粒の製造工程では、噴霧液におけるＨＰＭＣの濃度は、５．０％以下が好ましく、２．５％以下がより好ましいことが明らかになった。 As shown in Table 5, no. All of the 11 to 15 tablets had an appropriate (o) tablet hardness of 5.0 kgf or more. And No. The disintegration time of the tablets of 11 to 13 was as short as 30 seconds or less, and it was suitable as an orally disintegrating tablet ((). No. The disintegration time of the tablet of 14-1 is about 32.1 seconds, No. The disintegration time of the tablet 14-2 was around 38 seconds, and it was suitable as an orally disintegrating tablet (o). No. The disintegration time of 15 tablets was also relatively long, around 52.7 seconds, although it was suitable as an orally disintegrating tablet (o). From these results, it is apparent that in the erythritol granules used in the orally disintegrating tablet, the amount of HPMC is preferably 7.5 parts by weight or less and more preferably 3.8 parts by weight or less with respect to 180 parts by weight of erythritol. became. Moreover, in the manufacturing process of the said erythritol granule, it became clear that 5.0% or less is preferable and 2.5% or less of the density | concentration of HPMC in a spray liquid is more preferable.
＜実施例４＞基質における崩壊剤用途の添加物の検討
　造粒装置に、基質として粉末状のエリスリトール１８０ｇのみ、または粉末状のエリスリトール１８０ｇと、崩壊剤用途の添加物２０ｇとを仕込み、噴霧液１５０ｍＬを噴霧しながら造粒を行った。基質における崩壊剤用途の添加物としては、表６に示すように、ＣＰＶＰ、コーンスターチ（ＣＳ）、クロスカルメロースナトリウム（ＣＭＣ－Ｎａ）またはＭＣＣを用いた。噴霧液は、ＨＰＭＣ１％水溶液に、ＬＨＰＣを１．３％およびＭＣＣを５．３％となるよう分散した水性液体を用いた。その後、錠剤を製造して評価した。その結果を表６に示す。
Figure JPOXMLDOC01-appb-T000006
 <Example 4> Examination of additive for use as disintegrant in a substrate In a granulating apparatus, 180 g of powdered erythritol alone or 180 g of powdered erythritol and 20 g of additive for disintegrant are charged as a substrate, and a spray liquid is prepared. Granulation was performed while spraying 150 mL. CPVP, corn starch (CS), croscarmellose sodium (CMC-Na) or MCC were used as additives for disintegrant use in the substrate as shown in Table 6. The spray liquid used was an aqueous liquid in which 1% of LHPC and 1% of MCC were dispersed in a 1% aqueous solution of HPMC. The tablets were then manufactured and evaluated. The results are shown in Table 6.
Figure JPOXMLDOC01-appb-T000006
　表６に示すように、Ｎｏ．１６、Ｎｏ．１８、Ｎｏ．１９およびＮｏ．２０の錠剤は、いずれも崩壊時間が６０秒より長く、口腔内崩壊錠としてやや不適（△）であった。これに対して、Ｎｏ．１７の錠剤は、５．０ｋｇｆ以上の適切（○）な錠剤硬度を備えるとともに、崩壊時間は１９．２秒前後と短く、口腔内崩壊錠として好適（◎）であった。この結果から、ＣＰＶＰを含有させることにより、口腔内崩壊錠に好適なエリスリトール顆粒を製造できることが明らかになった。また、当該エリスリトール顆粒の製造工程では、基質にＣＰＶＰを含有させることが好ましいことが明らかになった。 As shown in Table 6, no. 16, no. 18, no. 19 and No. Each of the 20 tablets had a disintegration time of more than 60 seconds and was somewhat unsuitable (不) as an orally disintegrating tablet. On the other hand, no. The 17 tablets had an appropriate (o) tablet hardness of 5.0 kgf or more, a short disintegration time of around 19.2 seconds, and were suitable as orally disintegrating tablets (o). From this result, it was revealed that the inclusion of CPVP makes it possible to produce erythritol granules suitable for orally disintegrating tablets. Moreover, it became clear that it is preferable to make a board | substrate contain CPVP in the manufacturing process of the said erythritol granule.
＜実施例５＞基質における崩壊剤用途の添加物の量の検討
　造粒装置に、基質として、粉末状のエリスリトール１８０ｇと、ＣＰＶＰ０ｇ、５ｇ、１０ｇ、２０ｇ、３０ｇ、４０ｇまたは５０ｇとを仕込み、噴霧液１５０ｍＬを噴霧しながら造粒を行った。噴霧液は、ＨＰＭＣ１％水溶液に、ＬＨＰＣを１．３％およびＭＣＣを５．３％となるよう分散した水性液体を用いた。その後、錠剤を製造して評価した。その結果を表７に示す。
Figure JPOXMLDOC01-appb-T000007
 Example 5 Examination of Amount of Additive for Use in Disintegrant in Substrate In a granulating apparatus, 180 g of powdered erythritol and 0 g, 5 g, 10 g, 20 g, 30 g, 40 g or 50 g of CPVP as a substrate are charged and sprayed. Granulation was performed while spraying 150 mL of the solution. The spray liquid used was an aqueous liquid in which 1% of LHPC and 1% of MCC were dispersed in a 1% aqueous solution of HPMC. The tablets were then manufactured and evaluated. The results are shown in Table 7.
Figure JPOXMLDOC01-appb-T000007
　表７に示すように、Ｎｏ．２１、Ｎｏ．２２、Ｎｏ．２３、Ｎｏ．２４、Ｎｏ．２５およびＮｏ．２６の錠剤はいずれも、５．０ｋｇｆ以上の好適（○）な錠剤硬度を備えるとともに、崩壊時間は６０秒以下と短く、口腔内崩壊錠として適（○）する、または好適（◎）なものであった。この結果から、口腔内崩壊錠に用いるエリスリトール顆粒において、ＣＰＶＰの量は、１８０重量部のエリスリトールに対して、５重量部以上５０重量部以下が好ましいことが明らかになった。また、当該エリスリトール顆粒の製造工程では、基質におけるＣＰＶＰの量は、１８０重量部のエリスリトールに対して、５重量部以上５０重量部以下が好ましいことが明らかになった。 As shown in Table 7, no. 21, no. 22, no. 23, no. 24, no. 25 and no. Each of the 26 tablets has a suitable (o) tablet hardness of 5.0 kgf or more, a short disintegration time of 60 seconds or less, and is suitable as an orally disintegrating tablet (o) or suitable (o) Met. From these results, it has become clear that, in the erythritol granules used for the orally disintegrating tablet, the amount of CPVP is preferably 5 parts by weight or more and 50 parts by weight or less with respect to 180 parts by weight of erythritol. In addition, in the production process of the erythritol granules, it has been revealed that the amount of CPVP in the substrate is preferably 5 parts by weight or more and 50 parts by weight or less with respect to 180 parts by weight of erythritol.
＜実施例６＞口腔内崩壊錠（解熱・鎮痛薬）の製造
　造粒装置に、基質として粉末状のエリスリトール１８０ｇとＣＰＶＰ３０ｇとを仕込み、噴霧液１５０ｍＬを噴霧しながら造粒を行ってＥＲＴ顆粒を製造した。噴霧液は、水にＨＰＭＣを０．５％となるよう溶解し、さらに、ＬＨＰＣを１．３％およびＭＣＣを５．３％となるよう分散した水性液体を用いた。このＥＲＴ顆粒８０～９５重量部と、アセトアミノフェン（アセトアミノフェン＜ハチ＞、東洋製薬化成、１ｇ中　日本薬局方アセトアミノフェン１ｇ含有、白色の結晶又は結晶性の粉末）５～２０重量部との混合物１００重量部に対して、滑沢剤としてステアリン酸マグネシウム１重量部を添加した後、＜試験方法＞（３）に記載の方法により錠剤を製造した。その後、＜試験方法＞（４）に記載の方法により錠剤を評価した。口腔内崩壊時間の評価結果を表８に示す。
Figure JPOXMLDOC01-appb-T000008
 <Example 6> Production of orally disintegrating tablet (antipyretic and analgesic drug) In a granulating apparatus, 180 g of powdered erythritol and 30 g of CPVP were charged as a substrate, and granulation was carried out while spraying 150 mL of spray liquid to obtain ERT granules. Manufactured. The spray liquid was an aqueous liquid in which HPMC was dissolved to 0.5% in water, and 1.3% LHPC and 5.3% MCC were dispersed. 80 to 95 parts by weight of this ERT granule and 5 to 20 parts by weight of acetaminophen (acetaminophen <Bee>, in 1 g, containing 1 g of acetaminophen of Toyo Pharma Chemical Co., Ltd., white powder or crystalline powder) To 1 part by weight of magnesium stearate as a lubricant was added with respect to 100 parts by weight of the mixture thereof, and then tablets were produced by the method described in <Test method> (3). Thereafter, the tablets were evaluated by the method described in <Test method> (4). The evaluation results of the oral disintegration time are shown in Table 8.
Figure JPOXMLDOC01-appb-T000008
　Ｎｏ．２７～２９の錠剤はいずれも、５．０ｋｇｆ以上の好適（○）な錠剤硬度を備えていた。また、表８に示すように、Ｎｏ．２７～２９の錠剤はいずれも、崩壊時間が２２秒以下と顕著に短く、口腔内崩壊錠として好適（◎）なものであった。この結果から、本発明に係るエリスリトール顆粒と薬効成分や食品材料との混合物を直打法により打錠することにより、適切な錠剤硬度と短い口腔内崩壊時間とを兼ね備えた口腔内崩壊錠を製造できることが明らかになった。 No. All of the 27 to 29 tablets had a suitable (o) tablet hardness of 5.0 kgf or more. In addition, as shown in Table 8, No. All of the tablets of 27 to 29 had a remarkably short disintegration time of 22 seconds or less and were suitable as orally disintegrating tablets ((). From this result, an orally disintegrating tablet having appropriate tablet hardness and short intraoral disintegration time is manufactured by directly tableting the mixture of the erythritol granules according to the present invention and the medicinal ingredients and food materials by a direct compression method. It has become clear what can be done.

Claims (5)

  1. 　１８０重量部のエリスリトールに対して、
    　５重量部以上５０重量部以下のクロスポビドン、ならびに、
    　２重量部以上１５重量部以下の低置換度ヒドロキシプロピルセルロースおよび／または結晶セルロース
    　を含有する、口腔内崩壊錠用エリスリトール顆粒。     For 180 parts by weight of erythritol,
    5 to 50 parts by weight of crospovidone, and
    An erythritol granule for orally disintegrating tablets, comprising 2 parts by weight or more and 15 parts by weight or less of low-substituted hydroxypropyl cellulose and / or crystalline cellulose.
  2. 　前記口腔内崩壊錠用エリスリトール顆粒は、前記口腔内崩壊錠用エリスリトール顆粒１００重量部に対してステアリン酸マグネシウムを１重量部の割合で添加した後、乾式直接打錠法により１５．０ｋＮ未満の打錠圧で打錠して、直径が８ｍｍで１錠当たり２００ｍｇの錠剤に成型した場合に、当該錠剤の口腔内崩壊時間が３０秒以下となる物性を有する、請求項１に記載の口腔内崩壊錠用エリスリトール顆粒。 The erythritol granules for orally disintegrating tablets are added in a proportion of 1 part by weight of magnesium stearate to 100 parts by weight of the erythritol granules for orally disintegrating tablets and then beaten less than 15.0 kN by dry direct tableting method The oral disintegration according to claim 1, having physical properties such that the oral disintegration time of the tablet is 30 seconds or less when the tablet is tableted by a tableting pressure and formed into a tablet having a diameter of 8 mm and a tablet of 200 mg per tablet. Erythritol granules for tablets.
  3. 　エリスリトールの粉末およびクロスポビドンからなる基質を流動または攪拌しながら、当該基質に、低置換度ヒドロキシプロピルセルロースおよび／または結晶セルロースを含有する噴霧液を噴霧した後に乾燥させる造粒工程を有する、口腔内崩壊錠用エリスリトール顆粒の製造方法。 An intraoral cavity having a granulating step of spraying a spray solution containing low substituted hydroxypropyl cellulose and / or crystalline cellulose onto a matrix consisting of erythritol powder and crospovidone while the matrix is flowing or stirring and then drying it. Process for producing erythritol granules for disintegrating tablets.
  4. 　前記基質が、エリスリトール１８０重量部に対してクロスポビドンを５重量部以上５０重量部以下含有するものであり、
    　前記噴霧液において、低置換度ヒドロキシプロピルセルロースおよび／または結晶セルロースの濃度が１．３質量％以上１０．０質量％以下である、
    　請求項３に記載の製造方法。     The substrate contains 5 to 50 parts by weight of crospovidone based on 180 parts by weight of erythritol,
    In the spray solution, the concentration of low substituted hydroxypropyl cellulose and / or crystalline cellulose is 1.3% by mass or more and 10.0% by mass or less.
    The method according to claim 3.
  5. 　請求項１または請求項２に記載の口腔内崩壊錠用エリスリトール顆粒と薬効成分または食品材料とを含むことを特徴とする、口腔内崩壊錠。 An orally disintegrating tablet comprising the erythritol granules for orally disintegrating tablet according to claim 1 or 2 and a medicinal ingredient or a food material.
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JPH1143429A (en) * 1997-05-27 1999-02-16 Takeda Chem Ind Ltd Solid preparation
JP2000016930A (en) * 1998-04-27 2000-01-18 Taisho Pharmaceut Co Ltd Oral rapid disintegration tablet and its production
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JP7486258B2 (en) 2019-12-26 2024-05-17 物産フードサイエンス株式会社 Granules for orally disintegrating tablets, their manufacturing method and orally disintegrating tablets

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