WO2023145867A1 - Polyalkylene oxide granules for pharmaceutical preparation, composition for pharmaceutical use, pharmaceutical preparation composition, and pharmaceutical preparation - Google Patents

Polyalkylene oxide granules for pharmaceutical preparation, composition for pharmaceutical use, pharmaceutical preparation composition, and pharmaceutical preparation Download PDF

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WO2023145867A1
WO2023145867A1 PCT/JP2023/002608 JP2023002608W WO2023145867A1 WO 2023145867 A1 WO2023145867 A1 WO 2023145867A1 JP 2023002608 W JP2023002608 W JP 2023002608W WO 2023145867 A1 WO2023145867 A1 WO 2023145867A1
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oxide particles
polyalkylene oxide
mass
particles
sieve
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PCT/JP2023/002608
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French (fr)
Japanese (ja)
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直輝 西能
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住友精化株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods

Definitions

  • the present invention relates to pharmaceutical polyalkylene oxide particles, pharmaceutical compositions, pharmaceutical compositions and formulations.
  • Patent Literature 1 discloses polyalkylene oxide particles having improved miscibility with various powder components contained in pharmaceutical formulations.
  • polyalkylene oxide particles used for pharmaceutical formulations are excellent in compression moldability, they are also widely used as binders for tablets, for example.
  • the present invention has been made in view of the above, and polyalkylene oxide particles suitably used for forming a formulation having high tablet hardness, a pharmaceutical composition containing the polyalkylene oxide particles, and the pharmaceutical composition
  • An object of the present invention is to provide a pharmaceutical composition comprising a substance.
  • the inventors of the present invention have conducted intensive studies to achieve the above objects, and found that polyalkylene oxide particles having a specific bulk density, spatula angle and particle size distribution can achieve the above objects. Arrived.
  • Item 1 Loose bulk density is 0.43 g / mL or more and 0.49 g / mL or less, Firm bulk density is 0.51 g / mL or more, The spatula angle is 35.0° or more and 55.0° or less, Polyalkylene oxide particles for formulation, wherein the content of particles less than 150 ⁇ m is 46% by mass or more.
  • Item 2 Item 2.
  • Item 3 Item 2.
  • the polyalkylene oxide particles for formulation according to Item 1 which have a 1% by mass aqueous solution viscosity of less than 40 mPa ⁇ s and a 5% by mass aqueous solution viscosity of 30 to 50000 mPa ⁇ s.
  • Item 4 A pharmaceutical composition comprising the pharmaceutical polyalkylene oxide particles according to any one of Items 1 to 3.
  • Item 5 Item 5.
  • a pharmaceutical composition comprising the pharmaceutical composition of Item 4.
  • Item 6 A formulation comprising the pharmaceutical composition of Item 5.
  • Item 7 Item 7.
  • the polyalkylene oxide particles of the present invention are suitably used as raw materials for forming formulations with high tablet hardness.
  • the pharmaceutical composition of the present invention contains the polyalkylene oxide particles, it can be suitably used as a raw material for forming a formulation having high tablet hardness.
  • the upper limit or lower limit of the numerical range at one stage can be arbitrarily combined with the upper limit or lower limit of the numerical range at another stage.
  • the upper and lower limits of the numerical ranges may be replaced with values shown in Examples or values that can be uniquely derived from Examples.
  • a numerical value connected with "-" means a numerical range including numerical values before and after "-" as lower and upper limits.
  • compositions of the present invention have a loose bulk density of 0.43 g/mL or more. , 0.49 g/mL or less, a bulk density of 0.51 g/mL or more, a spatula angle of 35.0° or more and 55.0° or less, and a content of particles of less than 150 ⁇ m of 46 It is mass % or more.
  • Such polyalkylene oxide particles when used as a binder (excipient) for forming a formulation having a dosage form such as a tablet, can impart high hardness to the formulation, preventing chipping and cracking. can be made less likely. Therefore, the polyalkylene oxide particles of the present invention are preferably used to form formulations having high hardness, especially tablets.
  • the polyalkylene oxide particles have a loose bulk density of 0.43 g/mL or more and 0.49 g/mL or less, so that the formulation can have high hardness.
  • the loose bulk density of the polyalkylene oxide particles is less than 0.43 g/mL, problems such as reduced fluidity occur. If the loose bulk density of the polyalkylene oxide particles exceeds 0.49 g/mL, the hardness of the formulation will be low and it will be difficult to form the desired tablets.
  • the loose bulk density of the polyalkylene oxide particles is preferably 0.45 g/mL or more and preferably 0.48 g/mL or less.
  • the loose bulk density of polyalkylene oxide particles means a value measured using "Powder Tester PT-X” manufactured by Hosokawa Micron Co., Ltd. according to the procedure displayed on the device and the standard conditions recommended by the device.
  • the polyalkylene oxide particles have a bulk density of 0.51 g/mL or more, so that they can impart high hardness to the formulation.
  • the bulk density of the polyalkylene oxide particles is less than 0.51 g/mL, the hardness of the formulation becomes low, making it difficult to form desired tablets.
  • the bulk density of the polyalkylene oxide particles is preferably 0.52 g/mL or more and preferably 0.60 g/mL or less.
  • the bulk density of polyalkylene oxide particles means a value measured using "Powder Tester PT-X” manufactured by Hosokawa Micron Co., Ltd. according to the procedure displayed on the device and the standard conditions recommended by the device. However, when measuring the bulk density, the number of tapping is 180 times.
  • the polyalkylene oxide particles have a spatula angle of 35.0° or more and 55.0° or less, so that the formulation can have high hardness.
  • spatula angle of the polyalkylene oxide particles is less than 35.0°, the hardness of the formulation will be low, making it difficult to form desired tablets. If the spatula angle of the polyalkylene oxide particles exceeds 55.0°, problems such as reduced fluidity will occur.
  • the spatula angle of the polyalkylene oxide particles is preferably 38.0° or more and preferably 50.0° or less.
  • the spatula angle of polyalkylene oxide particles means a value measured using Hosokawa Micron Corporation's "Powder Tester PT-X" according to the procedure displayed on the device and the standard conditions recommended by the device.
  • the polyalkylene oxide particles contain 46% by mass or more of particles having a particle diameter of less than 150 ⁇ m. That is, the polyalkylene oxide particles of the present invention are particles having a specific particle size distribution. This allows the polyalkylene oxide particles to provide greater hardness to the formulation.
  • the content of particles having a particle diameter of less than 150 ⁇ m is preferably 48% by mass or more, more preferably 50% by mass or more, and even more preferably 55% by mass or more.
  • the upper limit of the content of particles having a particle diameter of less than 150 ⁇ m is not particularly limited, and may be, for example, 100% by mass.
  • the content of polyalkylene oxide particles having a particle diameter of less than 150 ⁇ m can be calculated by classifying the polyalkylene oxide particles with a sieve having an opening of 150 ⁇ m (JIS Z 8801-1 standard sieve). can. Specifically, the polyalkylene oxide particles are classified with a sieve having an opening of 150 ⁇ m, the mass of the polyalkylene oxide particles that pass through the sieve is measured, and the ratio of the total mass of the polyalkylene oxide particles used for classification is calculated. , the content of polyalkylene oxide particles having a particle size of less than 150 ⁇ m can be obtained.
  • "polyalkylene oxide particles having a particle diameter of less than 150 ⁇ m” means particles obtained by classifying polyalkylene oxide particles with a sieve having an opening of 150 ⁇ m and passing through the sieve.
  • the method of adjusting various physical properties such as loose bulk density, hard bulk density, spatula angle and particle size distribution of polyalkylene oxide particles is not particularly limited, and for example, a wide range of known methods can be adopted.
  • various physical properties of the polyalkylene oxide particles can be adjusted by selecting polymerization conditions for obtaining the polyalkylene oxide particles. Specifically, the type and amount of catalyst used to produce polyalkylene oxide particles, the type and amount of monomer used, the type and amount of solvent used, various conditions such as polymerization temperature and polymerization time, and polymerization Various physical properties of the polyalkylene oxide particles can be adjusted by appropriately selecting the drying conditions for the particles obtained in .
  • the polyalkylene oxide particles obtained by polymerization by classifying the polyalkylene oxide particles obtained by polymerization to prepare two or more kinds of polyalkylene oxide particles having different particle sizes and mixing them in a predetermined ratio, the polyalkylene oxide particles are loosened and bulky.
  • Various physical properties such as density, firm bulk density, spatula angle and particle size distribution can be adjusted.
  • polyalkylene oxide particles obtained by polymerization are subjected to a 300 ⁇ m sieve, a 250 ⁇ m sieve, a 180 ⁇ m sieve, a 150 ⁇ m sieve, a 106 ⁇ m sieve, and a 75 ⁇ m sieve.
  • the polyethylene oxide particles are placed on the tray in this order, and placed on the uppermost sieve with an opening of 500 ⁇ m.
  • the polyethylene oxide particles are classified by shaking the sieves with a low-tap shaker for 20 minutes, and after the classification, a predetermined amount of the polyethylene oxide particles remaining on each sieve and the tray are arbitrarily collected and mixed. do.
  • Various physical properties of the polyalkylene oxide particles such as loose bulk density, hard bulk density, spatula angle and particle size distribution can be adjusted by appropriately selecting the mixing ratio at this time.
  • the particles remaining in the sieve with an opening of 300 ⁇ m, the sieve with an opening of 250 ⁇ m, the sieve with an opening of 180 ⁇ m, the sieve with an opening of 150 ⁇ m, the sieve with an opening of 106 ⁇ m, the sieve with an opening of 75 ⁇ m, and the particles remaining in the tray were respectively P (300 ), P(250), P(180), P(150), P(106), P(75) and P(D).
  • P (300) is 0 to 15% by mass
  • P (250) is 0 to 20% by mass
  • P (180) is 0 to 40% by mass
  • P (150) is 0 to 30% by mass
  • the particle size distribution of the polyalkylene oxide particles can be adjusted by classifying polyalkylene oxide particles obtained by a known production method or commercially available polyalkylene oxide particles using a sieve with an appropriate opening. .
  • a sieve with an appropriate opening.
  • the content of polyalkylene oxide particles having a particle size of less than 150 ⁇ m can be adjusted.
  • the polyalkylene oxide particles are particles of polyalkylene oxide.
  • the type of polyalkylene oxide is not particularly limited, and for example, a wide range of known polyalkylene oxides can be exemplified.
  • the number of carbon atoms in the alkylene moiety in the polyalkylene oxide is, for example, preferably 2 or more, and preferably 4 or less. From the viewpoint that the effects of the present invention are likely to be exhibited, it is particularly preferable that the number of carbon atoms in the alkylene moiety is 2, that is, the polyalkylene oxide is polyethylene oxide.
  • polyalkylene oxides other than polyethylene oxide include polypropylene oxide, polybutylene oxide, ethylene oxide/propylene oxide copolymers, and ethylene oxide/butylene oxide copolymers.
  • the polyalkylene oxide is usually a homopolymer, but is not limited to this and may be a copolymer.
  • the polyalkylene oxide is a copolymer, the polyalkylene oxide has, for example, two or more structural units with different carbon numbers in the alkylene moieties.
  • the alkylene portion of the polyalkylene oxide particles preferably contains at least an ethylene oxide unit in that it is easy to manufacture and can impart high hardness to the formulation. That is, in the polyalkylene oxide particles, the polyalkylene oxide is preferably polyethylene oxide, or a copolymer of ethylene oxide units and other units (for example, the above-mentioned ethylene oxide/propylene oxide copolymer, ethylene oxide/butylene oxide copolymer).
  • the polyalkylene oxide particles can contain only one type of polyalkylene oxide, or can contain two or more types of polyalkylene oxides.
  • the aqueous solution viscosity of the polyalkylene oxide particles is not particularly limited.
  • the viscosity of a 1% by mass aqueous solution of polyalkylene oxide particles can be 20000 mPa ⁇ s or less.
  • the polyalkylene oxide particles preferably have a 1% by mass aqueous solution viscosity of 40 to 20,000 mPa ⁇ s in that they easily provide high hardness to the formulation.
  • the 1% by mass aqueous solution viscosity of the polyalkylene oxide particles is more preferably 1000 mPa s or more, more preferably 5000 mPa s or more, and more preferably 15000 mPa s or less, and 10000 mPa s.
  • the 1% by mass aqueous solution viscosity of the polyalkylene oxide particles and the 5% by mass aqueous solution viscosity described later can be measured using a rotational viscometer ("RV DVII+" manufactured by BROOK FIELD).
  • the 1% by mass aqueous solution viscosity of the polyalkylene oxide particles may be less than 40 mPa ⁇ s, provided that the 5% by mass aqueous solution viscosity is 30 to 50000 mPa ⁇ s in this case. That is, as one aspect of the polyalkylene oxide particles of the present invention, the 1% by mass aqueous solution viscosity may be less than 40 mPa ⁇ s and the 5% by mass aqueous solution viscosity may be 30 to 50000 mPa ⁇ s. This also allows the polyalkylene oxide particles to provide high hardness to the formulation.
  • the 5% by mass aqueous solution viscosity of the polyalkylene oxide particles is more preferably 50 mPa s or more, more preferably 100 mPa s or more, and more preferably 40,000 mPa s or less, and 20,000 mPa s. More preferably:
  • the mass average molecular weight of the polyalkylene oxide particles is not particularly limited.
  • the weight average molecular weight of the polyalkylene oxide particles is, for example, preferably 100,000 or more, and preferably 15,000,000 or less.
  • the mass average molecular weight of the polyalkylene oxide particles is more preferably 200,000 to 12,000,000, more preferably 2,000,000 to 10,000,000, and even more preferably 3,000,000 to 8,000,000.
  • the mass-average molecular weight of polyalkylene oxide P as used herein means a value measured by gel permeation chromatography, and particularly means a value calculated from a calibration curve prepared using a known polyethylene oxide standard sample.
  • the shape of the polyalkylene oxide particles is not particularly limited, and may be spherical, ellipsoidal, irregular, or the like, for example.
  • the polyalkylene oxide particles of the present invention are used as an excipient for a formulation, it is possible to prevent abrasion of the formulation in the manufacturing process without changing the composition of the formulation, and industrially stabilize the formulation having high hardness. can be manufactured.
  • the polyalkylene oxide particles of the present invention can be suitably used as raw materials, particularly excipients, for producing formulations having high hardness. It is suitable for pharmaceutical use, and particularly suitable as an excipient for tablets.
  • the method for producing the polyalkylene oxide particles of the present invention is not particularly limited, and for example, widely known methods for producing polyalkylene oxide particles can be employed.
  • polyalkylene oxide particles can be obtained by polymerizing alkylene oxide in the presence of an alkali or metal catalyst.
  • Alkylene oxides used herein include, for example, aliphatic alkylene oxides, specifically ethylene oxide, propylene oxide and butylene oxide, with ethylene oxide or propylene oxide being preferred, and ethylene oxide being particularly preferred.
  • One type of alkylene oxide can be used alone, or two or more types can be used.
  • the metal catalyst for example, a wide range of metal catalysts that have been conventionally used in the production of polyalkylene oxides can be used, and among them, an organic zinc catalyst is preferable.
  • the organozinc catalyst can be obtained by a known production method, and is preferably obtained by a step of reacting an organozinc compound with an aliphatic polyhydric alcohol and a monohydric alcohol to produce a particulate reaction product.
  • the metal catalyst can be used in a catalytic amount, preferably 0.00005 mol or more per 1 mol of alkylene oxide.
  • amount of the catalyst used is within this range, the decrease in the polymerization reaction rate is easily suppressed, and the polymerization time can be controlled to be shorter.
  • the polymerization reaction of alkylene oxide can be carried out in a solvent.
  • Solvents used in known polyalkylene oxide production methods can be widely used, for example, 2-methylpentane, n-pentane, n-hexane, n-heptane, isopentane and cyclohexane.
  • At least one hydrocarbon solvent selected from the group consisting of n-hexane or n-pentane is preferably used because it is easily available industrially and because it has a boiling point lower than the melting point of the resulting polyalkylene oxide and is easy to remove after the polymerization reaction.
  • the amount of the polymerization solvent used is preferably 100 to 10,000 parts by mass, preferably 200 to 2,000 parts by mass, relative to 100 parts by mass of the alkylene oxide, in terms of removing the heat of polymerization and facilitating control of the polymerization reaction. is more preferable, and 400 to 600 parts by mass is even more preferable.
  • a chain transfer agent can be used as in the known method for producing polyalkylene oxide particles.
  • Conditions such as temperature for the polymerization reaction of alkylene oxide are not particularly limited, and can be the same as known conditions.
  • the polyalkylene oxide obtained by the above polymerization reaction can be subjected, if necessary, to drying treatment, classification treatment, and the like.
  • drying treatment classification treatment
  • a wide range of known methods can be employed for the drying treatment and classification treatment.
  • composition of the present invention comprises the aforementioned pharmaceutical polyalkylene oxide particles of the present invention. Therefore, when the pharmaceutical composition of the present invention is used as an excipient for forming a formulation having a dosage form such as a tablet, it is a raw material, particularly an excipient, for producing a formulation having a high hardness. can be preferably used as. That is, the pharmaceutical composition of the present invention is suitable as a raw material for preparing pharmaceutical compositions.
  • the pharmaceutical composition of the present invention may contain only the polyalkylene oxide particles, or may contain components other than the polyalkylene oxide particles.
  • composition of the present invention includes the aforementioned pharmaceutical composition of the present invention.
  • the pharmaceutical composition of the present invention can contain the polyalkylene oxide particles and components other than the polyalkylene oxide particles.
  • components other than polyalkylene oxide particles for example, various components contained in known pharmaceutical compositions can be widely applied.
  • specific examples of other components include active ingredients, fillers, excipients other than polyalkylene oxide particles, diluents, lubricants, dyes, pigments, and osmotic pressure inducers.
  • the pharmaceutical composition of the present invention can contain silica as the polyalkylene oxide particles and filler.
  • the pharmaceutical composition of the present invention contains the polyalkylene oxide particles and silica
  • the pharmaceutical composition of the present invention contains 3.0 parts by mass or less of silica with respect to 100 parts by mass of the polyalkylene oxide particles. is preferred.
  • the content of silica relative to 100 parts by mass of the polyalkylene oxide particles is, for example, more preferably 2.0 parts by mass or less, and even more preferably 1.5 parts by mass or less.
  • the content of silica relative to 100 parts by mass of the polyalkylene oxide particles is more preferably, for example, 0.1 parts by mass or more in terms of easily improving fluidity and the like.
  • the content of the polyalkylene oxide particles in the pharmaceutical composition is not particularly limited.
  • the formulation composition contains 20 of the polyalkylene oxide particles with respect to the total mass of the polyalkylene oxide particles and the other components (or the total mass of the formulation composition).
  • the content is preferably 30% by mass or more, more preferably 40% by mass or more, and even more preferably 50% by mass or more.
  • the polyalkylene oxide particles are contained in an amount of 90% by mass or less based on the total mass of the polyalkylene oxide particles and the other components (or the total mass of the pharmaceutical composition).
  • the pharmaceutical composition of the present invention is excellent in compression moldability by containing the polyalkylene oxide particles, and can be easily obtained into a compression molded product.
  • the method for obtaining the compression-molded body is not particularly limited, and for example, a wide range of known compression-molding methods can be employed.
  • the method for preparing the pharmaceutical composition of the present invention is not particularly limited, and can be, for example, the same as the known method for preparing pharmaceutical compositions.
  • a pharmaceutical composition can be prepared by mixing polyalkylene oxide particles and optionally optional ingredients.
  • formulations can be prepared using the pharmaceutical composition of the present invention.
  • Such formulations have a high hardness because they contain the pharmaceutical composition of the present invention, ie because they contain the polyalkylene oxide particles.
  • the formulation of the present invention can contain a compression molded body of the pharmaceutical composition.
  • the formulation can be made into various dosage forms including compression moldings, for example, tablets.
  • the reaction solution in the container was diluted with n-hexane so that the concentration of the organozinc catalyst was 3% by mass to obtain a dispersion containing the organozinc catalyst.
  • the organic zinc catalyst and n-hexane were added to the nitrogen-purged pressure vessel so that the concentration of the organic zinc catalyst in terms of zinc to n-hexane was 0.0022 mol / L in terms of zinc, and dispersed uniformly. .
  • ethylene oxide was added so as to have a concentration of 3.84 mol/L with respect to hexane, and the mixture was sealed and polymerized with stirring in a constant temperature bath at 40°C. After completion of the polymerization, the white product was taken out by filtration and dried with stirring at a temperature of 40°C or less. , JIS Z 8801-1 standard sieve (500 ⁇ m) to obtain polyethylene oxide particles A that passed through.
  • the reaction solution in the container was diluted with n-hexane so that the concentration of the organozinc catalyst was 3% by mass to obtain a dispersion containing the organozinc catalyst.
  • the organozinc catalyst and n-hexane were added to the nitrogen-purged pressure vessel so that the concentration of the organozinc catalyst in terms of zinc to n-hexane was 0.0011 mol / L in terms of zinc, and dispersed uniformly. .
  • ethylene oxide was added so as to give a concentration of 4.18 mol/L with respect to hexane, and the mixture was sealed and polymerized with stirring in a constant temperature bath at 40°C.
  • the white product is filtered out and dried under reduced pressure while stirring at a temperature of 40° C. or less, and 1% by mass of amorphous silica (Aerosil, manufactured by Nippon Aerosil Co., Ltd.) is mixed with the obtained dry particles. and transferred to a JIS Z 8801-1 standard sieve (500 ⁇ m) to obtain polyethylene oxide particles B that passed through.
  • the temperature inside the container was raised to 80° C., and distillation was performed.
  • the reaction solution in the container was diluted with n-hexane so that the concentration of the organozinc catalyst was 3% by mass to obtain a dispersion containing the organozinc catalyst.
  • the organozinc catalyst and n-hexane were added to the nitrogen-purged pressure vessel so that the concentration of the organozinc catalyst in terms of zinc to n-hexane was 0.0004 mol/L in terms of zinc, and dispersed uniformly. .
  • ethylene oxide was added so as to give a concentration of 2.52 mol/L with respect to hexane, and the mixture was sealed and polymerized with stirring in a constant temperature bath at 40°C.
  • the white product was filtered out and dried at 40° C. under reduced pressure, and 1% by mass of amorphous silica (Aerosil, manufactured by Nippon Aerosil Co., Ltd.) was mixed with the obtained dry particles, and JIS Z 8801- No. 1 standard sieve (500 ⁇ m) to obtain polyethylene oxide particles C which passed through.
  • the polyethylene oxide particles A obtained in Production Example 1 are used as JIS Z 8801-1 standard sieves, with a 300 ⁇ m mesh sieve, a 250 ⁇ m mesh sieve, a 180 ⁇ m mesh sieve, a 150 ⁇ m mesh sieve, and a 106 ⁇ m mesh sieve. A sieve and a sieve with an opening of 75 ⁇ m were superimposed on the tray in this order from the top. Polyethylene oxide particles were placed in a sieve with a mesh size of 500 ⁇ m placed on the uppermost stage. The polyethylene oxide particles were classified by shaking the sieve for 20 minutes using a low-tap shaker. After classification, the mass of polyethylene oxide particles remaining on each sieve was measured, and the percentage of each mass relative to the total mass (particle size distribution) was calculated.
  • Example 1 As shown in Table 1, the proportions of 106 ⁇ m sieve particles, 75 ⁇ m sieve particles, and particles on the tray of the polyethylene oxide particles A after classification are 21% by mass, 12% by mass, and 67% by mass, respectively. %, polyethylene oxide particles D were obtained.
  • Example 2 As shown in Table 1, 300 ⁇ m on-sieve particles, 250 ⁇ m on-sieve particles, 180 ⁇ m on-sieve particles, 150 ⁇ m on-sieve particles, 106 ⁇ m on-sieve particles, 75 ⁇ m on-sieve particles, and particles on the tray of polyethylene oxide particles A after classification By uniformly mixing so that the proportions of the total particles are 4% by mass, 2% by mass, 25% by mass, 13% by mass, 12% by mass, 6% by mass, and 38% by mass, polyethylene oxide Particles E were obtained.
  • the percentage of particles in Examples and Comparative Examples is a numerical value rounded to the first decimal place. Therefore, the sum of these may not be 100% by mass.
  • This aqueous solution is kept at 25 ° C., and the viscosity is measured using a rotational viscometer ("RV DVII+” manufactured by BROOK FIELD) (spindle: RV-2, rotation speed: 2 rpm). bottom.
  • RV DVII+ manufactured by BROOK FIELD
  • This aqueous solution was kept at 25° C., and the viscosity was measured using a rotational viscometer (“RV DVII+” manufactured by BROOK FIELD), and this value was taken as the viscosity of the 5% by mass aqueous solution.
  • the particle size distribution of polyethylene oxide particles was measured and calculated by a dry sieving test.
  • a mixture was prepared by mixing polyethylene oxide particles with 1% by mass of amorphous silica (Aerosil, manufactured by Nippon Aerosil Co., Ltd.) as a lubricant.
  • JIS Z 8801-1 standard sieves include a 500 ⁇ m sieve, a 300 ⁇ m sieve, a 250 ⁇ m sieve, a 180 ⁇ m sieve, a 150 ⁇ m sieve, a 106 ⁇ m sieve and a 75 ⁇ m sieve. were superimposed on the saucer in this order from the top side.
  • the mixture was put into a sieve with a mesh size of 500 ⁇ m arranged on the uppermost stage, and the mixture was classified by shaking the sieve for 20 minutes using a low-tap shaker. After classification, the mass of the polyalkylene oxide particles remaining on each sieve was measured, and the calculated percentage of each mass to the total amount was taken as the particle size distribution of the polyalkylene oxide particles.
  • tablette hardness measurement Using the polyethylene oxide particles obtained in each example and comparative example as the polyalkylene oxide particles for formulation, tablet hardness was measured. 426 mg of polyalkylene oxide particles for formulation are charged into a general-purpose punch and die for autograph ( ⁇ 11, flat type), and are struck using an autograph (AGS-T manufactured by Shimadzu Corporation) at a compression speed of 10 mm / min at a predetermined test force. It was tableted to obtain a single tablet of polyethylene oxide particles. The test force was set to 7 kN, and polyethylene oxide particle single tablets were produced at each test force.
  • the hardness of the polyethylene oxide particle single tablet obtained in this way is measured using a "tablet hardness tester TBH-325" manufactured by ERWEKA at a sensitivity of 10 N, a measurement speed of 2.3 mm/s, and a pressing speed of 20 N/s. bottom.
  • Table 1 shows the particle size distribution, firm bulk density, loose bulk density, spatula angle, particle size distribution, and tablet hardness measurement results at each test force of the polyalkylene oxide particles for formulation produced in each example and comparative example. ing.

Abstract

Provided are: polyalkylene oxide particles, which are suitably used for forming a pharmaceutical preparation that can be formed into a tablet having a high hardness; a composition for pharmaceutical use containing said polyalkylene oxide particles; and a pharmaceutical preparation composition containing said composition for pharmaceutical use.　These polyalkylene oxide particles for a pharmaceutical preparation have a loose bulk density of 0.43 g/mL to 0.49 g/mL, a tapped bulk density of 0.51 g/mL or greater, an angle of spatula of 35.0° to 55.0°, and a content ratio of particles smaller than 150 μm of 46 mass% or greater.

Description

製剤用ポリアルキレンオキシド粒子、医薬用組成物、製剤用組成物及び製剤Pharmaceutical polyalkylene oxide particles, pharmaceutical compositions, pharmaceutical compositions and formulations
　本発明は、製剤用ポリアルキレンオキシド粒子、医薬用組成物、製剤用組成物及び製剤に関する。 The present invention relates to pharmaceutical polyalkylene oxide particles, pharmaceutical compositions, pharmaceutical compositions and formulations.
　従来、ポリエチレンオキシドに代表されるポリアルキレンオキシド粒子は、医薬用製剤等のバインダーとして用いられることが知られている。例えば、特許文献１には、医薬用製剤に含まれる各種粉末成分に対する混合性が改良されたポリアルキレンオキシド粒子が開示されている。 Conventionally, polyalkylene oxide particles typified by polyethylene oxide are known to be used as binders for pharmaceutical preparations and the like. For example, Patent Literature 1 discloses polyalkylene oxide particles having improved miscibility with various powder components contained in pharmaceutical formulations.
　また、医薬用製剤用として使用されるポリアルキレンオキシド粒子は、圧縮成形性に優れることから、例えば、錠剤用のバインダーとしても広く使用されている。 In addition, since polyalkylene oxide particles used for pharmaceutical formulations are excellent in compression moldability, they are also widely used as binders for tablets, for example.
国際公開第２０１２／１６５１９８号WO2012/165198
　しかしながら、錠剤等の製造工程においては、錠剤が摩擦等によって破損したり、錠剤同士の衝突などによって欠けや割れが発生したりする問題があり、これにより、歩留まりが悪くなるという問題があった。このため、錠剤硬度を高めて、歩留まりを改善することが求められている。この点、例えば、バインダーの種類や使用量、その他の製剤成分の種類及び量等を調整することで、錠剤硬度を向上させることは可能である。しかし、通常、薬物の種類及び量は目的とする製剤によって固有のものであるため、それらの選択で溶出速度を制御することは現実的ではなかった。 However, in the manufacturing process of tablets, etc., there are problems such as tablets being damaged by friction, etc., and chipping and cracking due to collisions between tablets, etc., resulting in a problem of poor yield. Therefore, it is required to improve the yield by increasing the tablet hardness. In this respect, for example, it is possible to improve the tablet hardness by adjusting the type and amount of binder used, the type and amount of other formulation components, and the like. However, since the type and amount of the drug are usually unique to the desired formulation, it was not realistic to control the dissolution rate by selecting them.
　また、製剤の形状や寸法の変更によって硬度を向上させることもできるが、この場合は溶出性への影響等を鑑みて生産工程から検討をやり直す必要があり、さらに、製剤化のための機器の変更を伴うこともあることから、大きな手間やコストが掛かるものであった。 It is also possible to improve the hardness by changing the shape and dimensions of the formulation, but in this case, it is necessary to reconsider the production process in consideration of the impact on dissolution, etc., and furthermore, the equipment for formulation will need to be reconsidered. Since it may be accompanied by changes, it takes a lot of time and effort and costs.
　本発明は、上記に鑑みてなされたものであり、高い錠剤硬度を有する製剤を形成するために好適に用いられるポリアルキレンオキシド粒子及び該ポリアルキレンオキシド粒子を含む医薬用組成物並びに該医薬用組成物を含む製剤用組成物を提供することを目的とする。 The present invention has been made in view of the above, and polyalkylene oxide particles suitably used for forming a formulation having high tablet hardness, a pharmaceutical composition containing the polyalkylene oxide particles, and the pharmaceutical composition An object of the present invention is to provide a pharmaceutical composition comprising a substance.
　本発明者らは、上記目的を達成すべく鋭意研究を重ねた結果、特定の嵩密度、スパチュラ角及び粒度分布を有するポリアルキレンオキシド粒子により上記目的を達成できることを見出し、本発明を完成するに至った。 The inventors of the present invention have conducted intensive studies to achieve the above objects, and found that polyalkylene oxide particles having a specific bulk density, spatula angle and particle size distribution can achieve the above objects. Arrived.
　すなわち、本発明は、例えば、以下の項に記載の主題を包含する。
項１
ゆるめ嵩密度が０．４３ｇ／ｍＬ以上、０．４９ｇ／ｍＬ以下であり、
かため嵩密度が０．５１ｇ／ｍＬ以上であり、
スパチュラ角が３５．０°以上、５５．０°以下であり、
１５０μｍ未満の粒子の含有割合が４６質量％以上である、製剤用ポリアルキレンオキシド粒子。
項２
１質量％水溶液粘度が４０～２００００ｍＰａ・ｓである、項１に記載の製剤用ポリアルキレンオキシド粒子。
項３
１質量％水溶液粘度が４０ｍＰａ・ｓ未満、かつ、５質量％水溶液粘度が３０～５００００ｍＰａ・ｓである、項１に記載の製剤用ポリアルキレンオキシド粒子。
項４
項１～３のいずれか１項に記載の製剤用ポリアルキレンオキシド粒子を含む、医薬用組成物。
項５
項４に記載の医薬用組成物を含む、製剤用組成物。
項６
項５に記載の製剤用組成物を含む、製剤。
項７
前記製剤用組成物の圧縮成形体を含む、項６に記載の製剤。 That is, the present invention includes, for example, the subject matter described in the following sections.
Item 1
Loose bulk density is 0.43 g / mL or more and 0.49 g / mL or less,
Firm bulk density is 0.51 g / mL or more,
The spatula angle is 35.0° or more and 55.0° or less,
Polyalkylene oxide particles for formulation, wherein the content of particles less than 150 μm is 46% by mass or more.
Item 2
Item 2. The polyalkylene oxide particles for pharmaceutical preparations according to Item 1, having a 1% by mass aqueous solution viscosity of 40 to 20000 mPa·s.
Item 3
Item 2. The polyalkylene oxide particles for formulation according to Item 1, which have a 1% by mass aqueous solution viscosity of less than 40 mPa·s and a 5% by mass aqueous solution viscosity of 30 to 50000 mPa·s.
Item 4
A pharmaceutical composition comprising the pharmaceutical polyalkylene oxide particles according to any one of Items 1 to 3.
Item 5
Item 5. A pharmaceutical composition comprising the pharmaceutical composition of Item 4.
Item 6
A formulation comprising the pharmaceutical composition of Item 5.
Item 7
Item 7. The formulation according to Item 6, comprising a compression molded body of the pharmaceutical composition.
　本発明のポリアルキレンオキシド粒子は、高い錠剤硬度を有する製剤を形成するための原料として好適に用いられる。また、本発明の医薬用組成物は前記ポリアルキレンオキシド粒子を含むので、高い錠剤硬度を有する製剤を形成するための原料として好適に用いられる。 The polyalkylene oxide particles of the present invention are suitably used as raw materials for forming formulations with high tablet hardness. In addition, since the pharmaceutical composition of the present invention contains the polyalkylene oxide particles, it can be suitably used as a raw material for forming a formulation having high tablet hardness.
　以下、本発明の実施形態について詳細に説明する。なお、本明細書中において、「含有」及び「含む」なる表現については、「含有」、「含む」、「実質的にからなる」及び「のみからなる」という概念を含む。 Hereinafter, embodiments of the present invention will be described in detail. In this specification, the expressions "contain" and "include" include the concepts of "contain", "include", "substantially consist of" and "consist only of".
　本明細書に段階的に記載されている数値範囲において、ある段階の数値範囲の上限値又は下限値は、他の段階の数値範囲の上限値又は下限値と任意に組み合わせることができる。本明細書に記載されている数値範囲において、その数値範囲の上限値又は下限値は、実施例に示されている値又は実施例から一義的に導き出せる値に置き換えてもよい。また、本明細書において、「～」で結ばれた数値は、「～」の前後の数値を下限値及び上限値として含む数値範囲を意味する。 In the numerical ranges described stepwise in this specification, the upper limit or lower limit of the numerical range at one stage can be arbitrarily combined with the upper limit or lower limit of the numerical range at another stage. In the numerical ranges described herein, the upper and lower limits of the numerical ranges may be replaced with values shown in Examples or values that can be uniquely derived from Examples. Further, in this specification, a numerical value connected with "-" means a numerical range including numerical values before and after "-" as lower and upper limits.
　１．製剤用ポリアルキレンオキシド粒子
　本発明の製剤用ポリアルキレンオキシド粒子（以下単に「本発明のポリアルキレンオキシド粒子」又は「ポリアルキレンオキシド粒子」と表記する）は、ゆるめ嵩密度が０．４３ｇ／ｍＬ以上、０．４９ｇ／ｍＬ以下であり、かため嵩密度が０．５１ｇ／ｍＬ以上であり、スパチュラ角が３５．０°以上、５５．０°以下であり、１５０μｍ未満の粒子の含有割合が４６質量％以上である。 1. Pharmaceutical Polyalkylene Oxide Particles The pharmaceutical polyalkylene oxide particles of the present invention (hereinafter simply referred to as "polyalkylene oxide particles of the present invention" or "polyalkylene oxide particles") have a loose bulk density of 0.43 g/mL or more. , 0.49 g/mL or less, a bulk density of 0.51 g/mL or more, a spatula angle of 35.0° or more and 55.0° or less, and a content of particles of less than 150 µm of 46 It is mass % or more.
　斯かるポリアルキレンオキシド粒子は、例えば、錠剤等の剤形を有する製剤を形成するためのバインダー（賦形剤）として使用される場合に、製剤に高い硬度をもたらすことができ、欠け及び割れを起こりにくくすることができる。従って、本発明のポリアルキレンオキシド粒子は、高い硬度を有する製剤、とりわけ錠剤を形成するために好適に用いられる。 Such polyalkylene oxide particles, for example, when used as a binder (excipient) for forming a formulation having a dosage form such as a tablet, can impart high hardness to the formulation, preventing chipping and cracking. can be made less likely. Therefore, the polyalkylene oxide particles of the present invention are preferably used to form formulations having high hardness, especially tablets.
　ポリアルキレンオキシド粒子は、ゆるめ嵩密度が０．４３ｇ／ｍＬ以上、０．４９ｇ／ｍＬ以下であることで、製剤に高い硬度をもたらすことができる。 The polyalkylene oxide particles have a loose bulk density of 0.43 g/mL or more and 0.49 g/mL or less, so that the formulation can have high hardness.
　ポリアルキレンオキシド粒子のゆるめ嵩密度が０．４３ｇ／ｍＬを下回ると、流動性の低下等の問題が生じる。ポリアルキレンオキシド粒子のゆるめ嵩密度が０．４９ｇ／ｍＬを超過すると、製剤の硬度が低くなり、所望の錠剤を形成することが難しくなる。ポリアルキレンオキシド粒子のゆるめ嵩密度は、０．４５ｇ／ｍＬ以上であることが好ましく、また、０．４８ｇ／ｍＬ以下であることが好ましい。 When the loose bulk density of the polyalkylene oxide particles is less than 0.43 g/mL, problems such as reduced fluidity occur. If the loose bulk density of the polyalkylene oxide particles exceeds 0.49 g/mL, the hardness of the formulation will be low and it will be difficult to form the desired tablets. The loose bulk density of the polyalkylene oxide particles is preferably 0.45 g/mL or more and preferably 0.48 g/mL or less.
　本発明において、ポリアルキレンオキシド粒子のゆるめ嵩密度は、ホソカワミクロン株式会社製「パウダーテスターＰＴ－Ｘ」を用い、装置に表示される手順及び装置が推奨する標準条件に従って測定された値を意味する。 In the present invention, the loose bulk density of polyalkylene oxide particles means a value measured using "Powder Tester PT-X" manufactured by Hosokawa Micron Co., Ltd. according to the procedure displayed on the device and the standard conditions recommended by the device.
　ポリアルキレンオキシド粒子は、かため嵩密度が０．５１ｇ／ｍＬ以上であることで、製剤に高い硬度をもたらすことができる。 The polyalkylene oxide particles have a bulk density of 0.51 g/mL or more, so that they can impart high hardness to the formulation.
　ポリアルキレンオキシド粒子のかため嵩密度が０．５１ｇ／ｍＬを下回ると、製剤の硬度が低くなり、所望の錠剤を形成することが難しくなる。ポリアルキレンオキシド粒子のかため嵩密度は、０．５２ｇ／ｍＬ以上であることが好ましく、また、０．６０ｇ／ｍＬ以下であることが好ましい。 When the bulk density of the polyalkylene oxide particles is less than 0.51 g/mL, the hardness of the formulation becomes low, making it difficult to form desired tablets. The bulk density of the polyalkylene oxide particles is preferably 0.52 g/mL or more and preferably 0.60 g/mL or less.
　本発明において、ポリアルキレンオキシド粒子のかため嵩密度は、ホソカワミクロン株式会社製「パウダーテスターＰＴ－Ｘ」を用い、装置に表示される手順及び装置が推奨する標準条件に従って測定された値を意味する。ただし、かため嵩密度を測定するにあたって、タッピング回数は１８０回とする。 In the present invention, the bulk density of polyalkylene oxide particles means a value measured using "Powder Tester PT-X" manufactured by Hosokawa Micron Co., Ltd. according to the procedure displayed on the device and the standard conditions recommended by the device. However, when measuring the bulk density, the number of tapping is 180 times.
　ポリアルキレンオキシド粒子は、スパチュラ角が３５．０°以上、５５．０°以下であることで、製剤に高い硬度をもたらすことができる。 The polyalkylene oxide particles have a spatula angle of 35.0° or more and 55.0° or less, so that the formulation can have high hardness.
　ポリアルキレンオキシド粒子のスパチュラ角が３５．０°を下回ると、製剤の硬度が低くなり、所望の錠剤を形成することが難しくなる。ポリアルキレンオキシド粒子のスパチュラ角が５５．０°を超過すると、流動性の低下等の問題が生じる。ポリアルキレンオキシド粒子のスパチュラ角は、３８．０°以上であることが好ましく、また、５０．０°以下であることが好ましい。 If the spatula angle of the polyalkylene oxide particles is less than 35.0°, the hardness of the formulation will be low, making it difficult to form desired tablets. If the spatula angle of the polyalkylene oxide particles exceeds 55.0°, problems such as reduced fluidity will occur. The spatula angle of the polyalkylene oxide particles is preferably 38.0° or more and preferably 50.0° or less.
　本発明において、ポリアルキレンオキシド粒子のスパチュラ角は、ホソカワミクロン株式会社製「パウダーテスターＰＴ－Ｘ」を用い、装置に表示される手順及び装置が推奨する標準条件に従って測定された値を意味する。 In the present invention, the spatula angle of polyalkylene oxide particles means a value measured using Hosokawa Micron Corporation's "Powder Tester PT-X" according to the procedure displayed on the device and the standard conditions recommended by the device.
　ポリアルキレンオキシド粒子は、１５０μｍ未満の粒子径を有する粒子の含有割合が４６質量％以上である。すなわち、本発明のポリアルキレンオキシド粒子は、特定の粒度分布を有する粒子群である。これにより、ポリアルキレンオキシド粒子は、製剤により高い硬度をもたらすことができる。 The polyalkylene oxide particles contain 46% by mass or more of particles having a particle diameter of less than 150 μm. That is, the polyalkylene oxide particles of the present invention are particles having a specific particle size distribution. This allows the polyalkylene oxide particles to provide greater hardness to the formulation.
　ポリアルキレンオキシド粒子は、１５０μｍ未満の粒子径を有する粒子の含有割合が４８質量％以上であることが好ましく、５０質量％以上であることがより好ましく、５５質量％以上であることがさらに好ましい。ポリアルキレンオキシド粒子は、１５０μｍ未満の粒子径を有する粒子の含有割合上限は特に制限はなく、例えば、１００質量％であってもよい。 In the polyalkylene oxide particles, the content of particles having a particle diameter of less than 150 μm is preferably 48% by mass or more, more preferably 50% by mass or more, and even more preferably 55% by mass or more. Regarding the polyalkylene oxide particles, the upper limit of the content of particles having a particle diameter of less than 150 μm is not particularly limited, and may be, for example, 100% by mass.
　ポリアルキレンオキシド粒子において、１５０μｍ未満の粒子径を有するポリアルキレンオキシド粒子の含有割合は、目開き１５０μｍの篩（ＪＩＳ　Ｚ　８８０１－１標準篩）でポリアルキレンオキシド粒子を分級することで算出することができる。具体的には、目開き１５０μｍの篩でポリアルキレンオキシド粒子を分級して篩を通過したポリアルキレンオキシド粒子の質量を計測し、分級に使用したポリアルキレンオキシド粒子の全質量に対する割合を算出することで、１５０μｍ未満の粒子径を有するポリアルキレンオキシド粒子の含有割合を求めることができる。なお、当該説明から明らかなように、「１５０μｍ未満の粒子径を有するポリアルキレンオキシド粒子」とは、ポリアルキレンオキシド粒子を目開き１５０μｍの篩で分級して篩を通過した粒子を意味する。 Among the polyalkylene oxide particles, the content of polyalkylene oxide particles having a particle diameter of less than 150 μm can be calculated by classifying the polyalkylene oxide particles with a sieve having an opening of 150 μm (JIS Z 8801-1 standard sieve). can. Specifically, the polyalkylene oxide particles are classified with a sieve having an opening of 150 μm, the mass of the polyalkylene oxide particles that pass through the sieve is measured, and the ratio of the total mass of the polyalkylene oxide particles used for classification is calculated. , the content of polyalkylene oxide particles having a particle size of less than 150 μm can be obtained. As is clear from the description, "polyalkylene oxide particles having a particle diameter of less than 150 µm" means particles obtained by classifying polyalkylene oxide particles with a sieve having an opening of 150 µm and passing through the sieve.
　ポリアルキレンオキシド粒子のゆるめ嵩密度、かため嵩密度、スパチュラ角及び粒度分布等の各種物性を調節する方法は特に限定されず、例えば、公知の方法を広く採用することができる。例えば、ポリアルキレンオキシド粒子を得るための重合条件の選択により、ポリアルキレンオキシド粒子の各種物性を調節することができる。具体的には、ポリアルキレンオキシド粒子を製造するために使用する触媒の種類及び使用量、モノマーの種類及び使用量、溶媒の種類及び使用量、その他、重合温度、重合時間等の各種条件、重合で得られた粒子の乾燥条件を適宜選択することで、ポリアルキレンオキシド粒子の各種物性を調節することができる。 The method of adjusting various physical properties such as loose bulk density, hard bulk density, spatula angle and particle size distribution of polyalkylene oxide particles is not particularly limited, and for example, a wide range of known methods can be adopted. For example, various physical properties of the polyalkylene oxide particles can be adjusted by selecting polymerization conditions for obtaining the polyalkylene oxide particles. Specifically, the type and amount of catalyst used to produce polyalkylene oxide particles, the type and amount of monomer used, the type and amount of solvent used, various conditions such as polymerization temperature and polymerization time, and polymerization Various physical properties of the polyalkylene oxide particles can be adjusted by appropriately selecting the drying conditions for the particles obtained in .
　また、重合によって得られたポリアルキレンオキシド粒子を分級して、粒子径の異なる２種以上のポリアルキレンオキシド粒子を調製し、それらを所定の割合で混合することで、ポリアルキレンオキシド粒子のゆるめ嵩密度、かため嵩密度、スパチュラ角及び粒度分布等の各種物性を調節することができる。 In addition, by classifying the polyalkylene oxide particles obtained by polymerization to prepare two or more kinds of polyalkylene oxide particles having different particle sizes and mixing them in a predetermined ratio, the polyalkylene oxide particles are loosened and bulky. Various physical properties such as density, firm bulk density, spatula angle and particle size distribution can be adjusted.
　例えば、重合によって得られたポリアルキレンオキシド粒子を、目開き３００μｍの篩、目開き２５０μｍの篩、目開き１８０μｍの篩、目開き１５０μｍの篩、目開き１０６μｍの篩、目開き７５μｍの篩を上段からこの順で受け皿の上に重ね合わせ、最上段に配置された目開き５００μｍの篩に、ポリエチレンオキシド粒子を入れる。篩をロータップ式振とう器を用いて２０分間振とうさせることにより、ポリエチレンオキシド粒子を分級し、分級後、各篩及び受け皿上に残ったポリエチレンオキシド粒子を任意に所定量採取し、それらを混合する。このときの混合割合を適宜選択することで、ポリアルキレンオキシド粒子のゆるめ嵩密度、かため嵩密度、スパチュラ角及び粒度分布等の各種物性を調節することができる。 For example, polyalkylene oxide particles obtained by polymerization are subjected to a 300 μm sieve, a 250 μm sieve, a 180 μm sieve, a 150 μm sieve, a 106 μm sieve, and a 75 μm sieve. The polyethylene oxide particles are placed on the tray in this order, and placed on the uppermost sieve with an opening of 500 μm. The polyethylene oxide particles are classified by shaking the sieves with a low-tap shaker for 20 minutes, and after the classification, a predetermined amount of the polyethylene oxide particles remaining on each sieve and the tray are arbitrarily collected and mixed. do. Various physical properties of the polyalkylene oxide particles such as loose bulk density, hard bulk density, spatula angle and particle size distribution can be adjusted by appropriately selecting the mixing ratio at this time.
　ここで、目開き３００μｍの篩、目開き２５０μｍの篩、目開き１８０μｍの篩、目開き１５０μｍの篩、目開き１０６μｍの篩、目開き７５μｍの篩及び受け皿に残った粒子をそれぞれ、Ｐ（３００）、Ｐ（２５０）、Ｐ（１８０）、Ｐ（１５０）、Ｐ（１０６）、Ｐ（７５）及びＰ（Ｄ）とする。このとき、ポリアルキレンオキシド粒子全質量に対し、Ｐ（３００）が０～１５質量％、Ｐ（２５０）が０～２０質量％、Ｐ（１８０）が０～４０質量％、Ｐ（１５０）が０～３０質量％、Ｐ（１０６）が５～３０質量％、Ｐ（７５）が５～３０質量％、Ｐ（Ｄ）が１５～７０質量％であることが好ましい。これにより、所望のゆるめ嵩密度、かため嵩密度、スパチュラ角及び粒度分布を有しやすい。 Here, the particles remaining in the sieve with an opening of 300 μm, the sieve with an opening of 250 μm, the sieve with an opening of 180 μm, the sieve with an opening of 150 μm, the sieve with an opening of 106 μm, the sieve with an opening of 75 μm, and the particles remaining in the tray were respectively P (300 ), P(250), P(180), P(150), P(106), P(75) and P(D). At this time, with respect to the total mass of the polyalkylene oxide particles, P (300) is 0 to 15% by mass, P (250) is 0 to 20% by mass, P (180) is 0 to 40% by mass, P (150) is 0 to 30% by mass, 5 to 30% by mass of P(106), 5 to 30% by mass of P(75), and 15 to 70% by mass of P(D). This makes it easier to have desired loose bulk density, firm bulk density, spatula angle and particle size distribution.
　また、ポリアルキレンオキシド粒子の粒度分布は、公知の製造方法で得られたポリアルキレンオキシド粒子、又は市販のポリアルキレンオキシド粒子を適宜の目開きの篩を用いた分級処理により、調節することができる。一例として、目開き１５０μｍの篩（ＪＩＳ　Ｚ　８８０１－１標準篩）でポリアルキレンオキシド粒子を分級し、篩上に残った粒子と、篩を通過した粒子とを所定の割合で混合することにより、１５０μｍ未満の粒子径を有するポリアルキレンオキシド粒子の含有割合を調節することができる。 In addition, the particle size distribution of the polyalkylene oxide particles can be adjusted by classifying polyalkylene oxide particles obtained by a known production method or commercially available polyalkylene oxide particles using a sieve with an appropriate opening. . As an example, by classifying the polyalkylene oxide particles with a 150 μm sieve (JIS Z 8801-1 standard sieve) and mixing the particles remaining on the sieve and the particles that have passed through the sieve in a predetermined ratio, The content of polyalkylene oxide particles having a particle size of less than 150 μm can be adjusted.
　ポリアルキレンオキシド粒子は、ポリアルキレンオキシドが粒子状に形成されたものである。ポリアルキレンオキシドの種類は特に限定されず、例えば、公知のポリアルキレンオキシドを広く例示することができる。 The polyalkylene oxide particles are particles of polyalkylene oxide. The type of polyalkylene oxide is not particularly limited, and for example, a wide range of known polyalkylene oxides can be exemplified.
　ポリアルキレンオキシドにおけるアルキレン部位の炭素数は、例えば、２以上が好ましく、また、４以下であることが好ましい。本発明の効果が発揮されやすいという点で、アルキレン部位の炭素数は２であること、即ち、ポリアルキレンオキシドは、ポリエチレンオキシドであることが特に好ましい。ポリエチレンオキシド以外のポリアルキレンオキシドの具体例としては、ポリプロピレンオキシド、ポリブチレンオキシド、エチレンオキシド／プロピレンオキシド共重合体、エチレンオキシド／ブチレンオキシド共重合体等も挙げられる。 The number of carbon atoms in the alkylene moiety in the polyalkylene oxide is, for example, preferably 2 or more, and preferably 4 or less. From the viewpoint that the effects of the present invention are likely to be exhibited, it is particularly preferable that the number of carbon atoms in the alkylene moiety is 2, that is, the polyalkylene oxide is polyethylene oxide. Specific examples of polyalkylene oxides other than polyethylene oxide include polypropylene oxide, polybutylene oxide, ethylene oxide/propylene oxide copolymers, and ethylene oxide/butylene oxide copolymers.
　ポリアルキレンオキシドは、通常、ホモポリマーであるが、これに限定されず、コポリマーであってもよい。ポリアルキレンオキシドがコポリマーである場合、ポリアルキレンオキシドは、例えば、アルキレン部位の炭素数が異なる二以上の構造単位を有する。 The polyalkylene oxide is usually a homopolymer, but is not limited to this and may be a copolymer. When the polyalkylene oxide is a copolymer, the polyalkylene oxide has, for example, two or more structural units with different carbon numbers in the alkylene moieties.
　ポリアルキレンオキシド粒子のアルキレン部位は、製造が容易であって、製剤に高い硬度をもたらすことができる点で、エチレンオキシド単位を少なくとも含むことが好ましい。すなわち、ポリアルキレンオキシド粒子において、ポリアルキレンオキシドは、ポリエチレンオキシドであることが好ましく、あるいは、エチレンオキシド単位と他の単位との共重合体（例えば、前述のエチレンオキシド／プロピレンオキシド共重合体、エチレンオキシド／ブチレンオキシド共重合体）であることが好ましい。 The alkylene portion of the polyalkylene oxide particles preferably contains at least an ethylene oxide unit in that it is easy to manufacture and can impart high hardness to the formulation. That is, in the polyalkylene oxide particles, the polyalkylene oxide is preferably polyethylene oxide, or a copolymer of ethylene oxide units and other units (for example, the above-mentioned ethylene oxide/propylene oxide copolymer, ethylene oxide/butylene oxide copolymer).
　ポリアルキレンオキシド粒子は、１種のみのポリアルキレンオキシドを含むことができ、あるいは、２種以上のポリアルキレンオキシドを含むこともできる。 The polyalkylene oxide particles can contain only one type of polyalkylene oxide, or can contain two or more types of polyalkylene oxides.
　ポリアルキレンオキシド粒子の水溶液粘度は特に限定されない。例えば、ポリアルキレンオキシド粒子の１質量％水溶液粘度は、２００００ｍＰａ・ｓ以下とすることができる。 The aqueous solution viscosity of the polyalkylene oxide particles is not particularly limited. For example, the viscosity of a 1% by mass aqueous solution of polyalkylene oxide particles can be 20000 mPa·s or less.
　製剤に対して高い硬度をもたらしやすい点で、ポリアルキレンオキシド粒子は、１質量％水溶液粘度が４０～２００００ｍＰａ・ｓであることが好ましい。ポリアルキレンオキシド粒子の１質量％水溶液粘度は、１０００ｍＰａ・ｓ以上であることがより好ましく、５０００ｍＰａ・ｓ以上であることがさらに好ましく、また、１５０００ｍＰａ・ｓ以下であることがより好ましく、１００００ｍＰａ・ｓ以下であることがさらに好ましい。ポリアルキレンオキシド粒子の１質量％水溶液粘度及び後記する５質量％水溶液粘度は、回転粘度計（ＢＲＯＯＫ　ＦＩＥＬＤ製「ＲＶ　ＤＶＩＩ＋」）を用いて測定することができる。 The polyalkylene oxide particles preferably have a 1% by mass aqueous solution viscosity of 40 to 20,000 mPa·s in that they easily provide high hardness to the formulation. The 1% by mass aqueous solution viscosity of the polyalkylene oxide particles is more preferably 1000 mPa s or more, more preferably 5000 mPa s or more, and more preferably 15000 mPa s or less, and 10000 mPa s. More preferably: The 1% by mass aqueous solution viscosity of the polyalkylene oxide particles and the 5% by mass aqueous solution viscosity described later can be measured using a rotational viscometer ("RV DVII+" manufactured by BROOK FIELD).
　一方、ポリアルキレンオキシド粒子の１質量％水溶液粘度が４０ｍＰａ・ｓ未満であってもよく、ただし、この場合は、５質量％水溶液粘度が３０～５００００ｍＰａ・ｓである。すなわち、本発明のポリアルキレンオキシド粒子の一態様として、１質量％水溶液粘度が４０ｍＰａ・ｓ未満、かつ、５質量％水溶液粘度が３０～５００００ｍＰａ・ｓであってもよい。これによっても、ポリアルキレンオキシド粒子は、製剤に高い硬度をもたらすことができる。ポリアルキレンオキシド粒子の５質量％水溶液粘度は、５０ｍＰａ・ｓ以上であることがより好ましく、１００ｍＰａ・ｓ以上であることがさらに好ましく、また、４００００ｍＰａ・ｓ以下であることがより好ましく、２００００ｍＰａ・ｓ以下であることがさらに好ましい。 On the other hand, the 1% by mass aqueous solution viscosity of the polyalkylene oxide particles may be less than 40 mPa·s, provided that the 5% by mass aqueous solution viscosity is 30 to 50000 mPa·s in this case. That is, as one aspect of the polyalkylene oxide particles of the present invention, the 1% by mass aqueous solution viscosity may be less than 40 mPa·s and the 5% by mass aqueous solution viscosity may be 30 to 50000 mPa·s. This also allows the polyalkylene oxide particles to provide high hardness to the formulation. The 5% by mass aqueous solution viscosity of the polyalkylene oxide particles is more preferably 50 mPa s or more, more preferably 100 mPa s or more, and more preferably 40,000 mPa s or less, and 20,000 mPa s. More preferably:
　ポリアルキレンオキシド粒子の質量平均分子量は特に限定されない。ポリアルキレンオキシド粒子の質量平均分子量は、例えば、１０万以上であることが好ましく、また、１５００万以下であることが好ましい。ポリアルキレンオキシド粒子の質量平均分子量は、２０万～１２００万がより好ましく、２００万～１０００万がさらに好ましく、３００万～８００万がよりさらに好ましい。ここでいうポリアルキレンオキシドＰの質量平均分子量はゲル浸透クロマトグラフィーによる測定値を意味し、特に、既知のポリエチレンオキシド標準試料を用いて作製した検量線から算出した値を意味する。 The mass average molecular weight of the polyalkylene oxide particles is not particularly limited. The weight average molecular weight of the polyalkylene oxide particles is, for example, preferably 100,000 or more, and preferably 15,000,000 or less. The mass average molecular weight of the polyalkylene oxide particles is more preferably 200,000 to 12,000,000, more preferably 2,000,000 to 10,000,000, and even more preferably 3,000,000 to 8,000,000. The mass-average molecular weight of polyalkylene oxide P as used herein means a value measured by gel permeation chromatography, and particularly means a value calculated from a calibration curve prepared using a known polyethylene oxide standard sample.
　ポリアルキレンオキシド粒子の形状は特に限定されず、例えば、真球状、楕円球状、不定形状等であってもよい。 The shape of the polyalkylene oxide particles is not particularly limited, and may be spherical, ellipsoidal, irregular, or the like, for example.
　本発明のポリアルキレンオキシド粒子を製剤の賦形剤として利用した場合に、製剤の組成を変更することなく製造工程において製剤の摩損を防止することができ、高い硬度を有する製剤を工業的に安定製造することができる。 When the polyalkylene oxide particles of the present invention are used as an excipient for a formulation, it is possible to prevent abrasion of the formulation in the manufacturing process without changing the composition of the formulation, and industrially stabilize the formulation having high hardness. can be manufactured.
　よって、本発明のポリアルキレンオキシド粒子は、高い硬度を有する製剤を製造するための原料、特に賦形剤として好適に使用することができ、すなわち、本発明のポリアルキレンオキシド粒子は、医薬用、製剤用として好適であり、特に錠剤用の賦形剤として好適である。 Therefore, the polyalkylene oxide particles of the present invention can be suitably used as raw materials, particularly excipients, for producing formulations having high hardness. It is suitable for pharmaceutical use, and particularly suitable as an excipient for tablets.
　本発明のポリアルキレンオキシド粒子の製造方法は特に限定されず、例えば、公知のポリアルキレンオキシド粒子の製造方法を広く採用することができる。例えば、アルカリまたは金属触媒の存在下、アルキレンオキシドの重合反応により、ポリアルキレンオキシド粒子を得ることができる。ここで使用するアルキレンオキシドは、例えば、脂肪族アルキレンオキシドが挙げられ、具体的には、エチレンオキシド、プロピレンオキシドおよびブチレンオキシドが挙げられ、エチレンオキシドまたはプロピレンオキシドが好ましく、エチレンオキシドが特に好ましい。アルキレンオキシドは、１種単独で使用することができ、あるいは、２種以上を使用することができる。 The method for producing the polyalkylene oxide particles of the present invention is not particularly limited, and for example, widely known methods for producing polyalkylene oxide particles can be employed. For example, polyalkylene oxide particles can be obtained by polymerizing alkylene oxide in the presence of an alkali or metal catalyst. Alkylene oxides used herein include, for example, aliphatic alkylene oxides, specifically ethylene oxide, propylene oxide and butylene oxide, with ethylene oxide or propylene oxide being preferred, and ethylene oxide being particularly preferred. One type of alkylene oxide can be used alone, or two or more types can be used.
　前記金属触媒は、例えば、ポリアルキレンオキシドの製造において従来から使用されている金属触媒を広く使用することができ、中でも、有機亜鉛触媒であることが好ましい。有機亜鉛触媒は、公知の製造方法で得ることができ、中でも、有機亜鉛化合物を脂肪族多価アルコール及び一価アルコールと反応させて粒子状の反応生成物を生成させる工程によって得ることが好ましい。 For the metal catalyst, for example, a wide range of metal catalysts that have been conventionally used in the production of polyalkylene oxides can be used, and among them, an organic zinc catalyst is preferable. The organozinc catalyst can be obtained by a known production method, and is preferably obtained by a step of reacting an organozinc compound with an aliphatic polyhydric alcohol and a monohydric alcohol to produce a particulate reaction product.
　前記金属触媒は、触媒量使用することができ、中でも、アルキレンオキシド１モルに対して０．００００５モル以上使用することが好ましい。触媒の使用量が斯かる範囲であることにより、重合反応速度の低下が抑制されやすく、重合時間をより短く制御することができる。 The metal catalyst can be used in a catalytic amount, preferably 0.00005 mol or more per 1 mol of alkylene oxide. When the amount of the catalyst used is within this range, the decrease in the polymerization reaction rate is easily suppressed, and the polymerization time can be controlled to be shorter.
　アルキレンオキシドの重合反応は、溶媒中で行うことができる。斯かる溶媒は、公知のポリアルキレンオキシドの製造方法で使用されている溶媒を広く使用することができ、例えば、２－メチルペンタン、ｎ－ペンタン、ｎ－ヘキサン、ｎ－ヘプタン、イソペンタン及びシクロヘキサンからなる群より選ばれる少なくとも１種の炭化水素溶媒を挙げることができる。工業的に入手が容易である点、並びに、得られるポリアルキレンオキシドの融点より沸点が低く、重合反応後の除去が容易である点から、ｎ－ヘキサン又はｎ－ペンタンが好適に用いられる。重合溶媒の使用量は、重合熱を除去し、重合反応を制御しやすい点から、アルキレンオキシド１００質量部に対して、１００～１００００質量部であることが好ましく、２００～２０００質量部であることがより好ましく、４００～６００質量部であることがさらに好ましい。 The polymerization reaction of alkylene oxide can be carried out in a solvent. Solvents used in known polyalkylene oxide production methods can be widely used, for example, 2-methylpentane, n-pentane, n-hexane, n-heptane, isopentane and cyclohexane. At least one hydrocarbon solvent selected from the group consisting of n-hexane or n-pentane is preferably used because it is easily available industrially and because it has a boiling point lower than the melting point of the resulting polyalkylene oxide and is easy to remove after the polymerization reaction. The amount of the polymerization solvent used is preferably 100 to 10,000 parts by mass, preferably 200 to 2,000 parts by mass, relative to 100 parts by mass of the alkylene oxide, in terms of removing the heat of polymerization and facilitating control of the polymerization reaction. is more preferable, and 400 to 600 parts by mass is even more preferable.
　アルキレンオキシドの重合反応を行うにあたって、例えば、公知のポリアルキレンオキシド粒子の製造方法と同様、連鎖移動剤を使用することができる。 In carrying out the polymerization reaction of alkylene oxide, for example, a chain transfer agent can be used as in the known method for producing polyalkylene oxide particles.
　アルキレンオキシドの重合反応の温度等の条件は特に限定されず、公知の条件と同様とすることができる。 Conditions such as temperature for the polymerization reaction of alkylene oxide are not particularly limited, and can be the same as known conditions.
　上記重合反応によって得られたポリアルキレンオキシドには、必要に応じて、乾燥処理、分級処理等を行うことができる。乾燥処理及び分級処理は、公知の方法を広く採用することができる。 The polyalkylene oxide obtained by the above polymerization reaction can be subjected, if necessary, to drying treatment, classification treatment, and the like. A wide range of known methods can be employed for the drying treatment and classification treatment.
　２．医薬用組成物
　本発明の医薬用組成物は、前述の本発明の製剤用ポリアルキレンオキシド粒子を含む。従って、本発明の医薬用組成物は、錠剤等の剤形を有する製剤を形成するための賦形剤として使用される場合に、高い硬度を有する製剤を製造するための原料、特に賦形剤として好適に使用することができる。すなわち、本発明の医薬用組成物は、製剤用組成物を調製するための原料として適している。 2. Pharmaceutical Composition The pharmaceutical composition of the present invention comprises the aforementioned pharmaceutical polyalkylene oxide particles of the present invention. Therefore, when the pharmaceutical composition of the present invention is used as an excipient for forming a formulation having a dosage form such as a tablet, it is a raw material, particularly an excipient, for producing a formulation having a high hardness. can be preferably used as. That is, the pharmaceutical composition of the present invention is suitable as a raw material for preparing pharmaceutical compositions.
　本発明の医薬用組成物は、前記ポリアルキレンオキシド粒子のみを含むのであってもよいし、前記ポリアルキレンオキシド粒子以外の成分を含むこともできる。 The pharmaceutical composition of the present invention may contain only the polyalkylene oxide particles, or may contain components other than the polyalkylene oxide particles.
　３．製剤用組成物
　本発明の製剤用組成物は、前述の本発明の医薬用組成物を含む。具体的に本発明の医薬用組成物は、前記ポリアルキレンオキシド粒子と、前記ポリアルキレンオキシド粒子以外の成分を含むことができる。 3. Pharmaceutical composition The pharmaceutical composition of the present invention includes the aforementioned pharmaceutical composition of the present invention. Specifically, the pharmaceutical composition of the present invention can contain the polyalkylene oxide particles and components other than the polyalkylene oxide particles.
　ポリアルキレンオキシド粒子以外の成分（以下、他の成分という）は、例えば、公知の製剤用組成物に含まれる各種成分を広く適用することができる。他の成分の具体例としては、活性成分、フィラー、ポリアルキレンオキシド粒子以外の賦形剤、希釈剤、潤滑剤、染料、色素、浸透圧誘起剤等を挙げることができる。 For components other than polyalkylene oxide particles (hereinafter referred to as other components), for example, various components contained in known pharmaceutical compositions can be widely applied. Specific examples of other components include active ingredients, fillers, excipients other than polyalkylene oxide particles, diluents, lubricants, dyes, pigments, and osmotic pressure inducers.
　本発明の製剤用組成物は、前記ポリアルキレンオキシド粒子とフィラーとしてシリカを含むことができる。本発明の製剤用組成物が前記ポリアルキレンオキシド粒子とシリカとを含む場合、本発明の製剤用組成物は、前記ポリアルキレンオキシド粒子１００質量部に対し、シリカを３．０質量部以下含むことが好ましい。これにより、ポリアルキレンオキシド粒子の流動性等が向上しやすい。前記ポリアルキレンオキシド粒子１００質量部に対するシリカの含有量は、例えば、２．０質量部以下であることがより好ましく、１．５質量部以下であることがさらに好ましい。流動性等が向上しやすい点で、前記ポリアルキレンオキシド粒子１００質量部に対するシリカの含有量は、例えば、０．１質量部以上であることがより好ましい。 The pharmaceutical composition of the present invention can contain silica as the polyalkylene oxide particles and filler. When the pharmaceutical composition of the present invention contains the polyalkylene oxide particles and silica, the pharmaceutical composition of the present invention contains 3.0 parts by mass or less of silica with respect to 100 parts by mass of the polyalkylene oxide particles. is preferred. As a result, the fluidity and the like of the polyalkylene oxide particles are likely to be improved. The content of silica relative to 100 parts by mass of the polyalkylene oxide particles is, for example, more preferably 2.0 parts by mass or less, and even more preferably 1.5 parts by mass or less. The content of silica relative to 100 parts by mass of the polyalkylene oxide particles is more preferably, for example, 0.1 parts by mass or more in terms of easily improving fluidity and the like.
　製剤用組成物は、本発明の効果が阻害されない限り、前記ポリアルキレンオキシド粒子の含有割合は特に制限はない。製剤に特に高い硬度をもたらしやすい点で、製剤用組成物は、前記ポリアルキレンオキシド粒子と前記他の成分との総質量（又は製剤用組成物全質量）に対し、前記ポリアルキレンオキシド粒子を２０質量％以上含有することが好ましく、３０質量％以上含有することが好ましく、４０質量％以上含有することがより好ましく、５０質量％以上含有することがさらに好ましい。また、前記ポリアルキレンオキシド粒子と前記他の成分との総質量（又は製剤用組成物全質量）に対し、前記ポリアルキレンオキシド粒子を９０質量％以下含有することが好ましい。 As long as the effects of the present invention are not inhibited, the content of the polyalkylene oxide particles in the pharmaceutical composition is not particularly limited. In terms of easily providing a particularly high hardness to the formulation, the formulation composition contains 20 of the polyalkylene oxide particles with respect to the total mass of the polyalkylene oxide particles and the other components (or the total mass of the formulation composition). The content is preferably 30% by mass or more, more preferably 40% by mass or more, and even more preferably 50% by mass or more. In addition, it is preferable that the polyalkylene oxide particles are contained in an amount of 90% by mass or less based on the total mass of the polyalkylene oxide particles and the other components (or the total mass of the pharmaceutical composition).
　特に本発明の製剤用組成物は、前記ポリアルキレンオキシド粒子を含むことで、圧縮成形性に優れるものであり、容易に圧縮成形体を得ることができる。圧縮成形体を得る方法は特に限定されず、例えば、公知の圧縮成形方法を広く採用することができる。 In particular, the pharmaceutical composition of the present invention is excellent in compression moldability by containing the polyalkylene oxide particles, and can be easily obtained into a compression molded product. The method for obtaining the compression-molded body is not particularly limited, and for example, a wide range of known compression-molding methods can be employed.
　本発明の製剤用組成物の調製方法は特に限定されず、例えば、公知の製剤用組成物の調製方法と同様とすることができる。例えば、ポリアルキレンオキシド粒子と必要に応じて任意成分と混合することで、製剤用組成物を調製することができる。 The method for preparing the pharmaceutical composition of the present invention is not particularly limited, and can be, for example, the same as the known method for preparing pharmaceutical compositions. For example, a pharmaceutical composition can be prepared by mixing polyalkylene oxide particles and optionally optional ingredients.
　本発明の製剤用組成物を用いて、各種の製剤を調製することができる。斯かる製剤は、本発明の製剤用組成物を含むので、すなわち、前記ポリアルキレンオキシド粒子を含むので、高い硬度を有する。 Various formulations can be prepared using the pharmaceutical composition of the present invention. Such formulations have a high hardness because they contain the pharmaceutical composition of the present invention, ie because they contain the polyalkylene oxide particles.
　本発明の製剤は、前記製剤用組成物の圧縮成形体を含むことができる。この場合、製剤は圧縮成形体を含む各種剤形とすることができ、例えば、錠剤が挙げられる。 The formulation of the present invention can contain a compression molded body of the pharmaceutical composition. In this case, the formulation can be made into various dosage forms including compression moldings, for example, tablets.
　以下、実施例により本発明をより具体的に説明するが、本発明はこれら実施例の態様に限定されるものではない。 The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the embodiments of these examples.
　（製造例１；ポリアルキレンオキシド粒子Ａの製造）
　窒素置換された容器内に、亜鉛換算で０．６６モル／Ｌの濃度になるようにジエチル亜鉛をｎ－ヘキサンで希釈した。次いで、容器内を１０℃に冷却し、攪拌下で、ｎ－ヘキサンに対して１，４－ブタンジオールが０．５９モル／Ｌ、エタノールが２．５８モル／Ｌの濃度になるまで該容器内に添加した。添加終了後、容器内を３０℃まで昇温して、ジエチル亜鉛を１，４－ブタンジオール及びエタノールと１時間反応させ、次に、５０℃まで昇温して１時間反応を行った。その後、容器内を８０℃まで昇温して、蒸留を行った。冷却後、容器内の反応液を有機亜鉛触媒が３質量％の濃度となるようにｎ－ヘキサンで希釈し、有機亜鉛触媒を含む分散液を得た。
　次いで、窒素置換された耐圧容器に、ｎ－ヘキサンに対して有機亜鉛触媒が亜鉛換算で０．００２２ｍｏｌ／Ｌの濃度になるように有機亜鉛触媒とｎ－ヘキサンを添加し、均一に分散させた。次いで、ヘキサンに対して３．８４ｍｏｌ／Ｌの濃度になるようにエチレンオキシドを添加して密閉し、４０℃の恒温槽中で攪拌しながら重合させた。重合終了後、白色生成物を濾過して取り出し、４０℃以下の温度で撹拌しながら乾燥し、得られた乾燥粒子に非晶質シリカ（日本アエロジル株式会社製、アエロジル）を１質量％混合し、ＪＩＳ　Ｚ　８８０１－１標準篩（５００μｍ）に移し、通過したポリエチレンオキシド粒子Ａを得た。 (Production Example 1; Production of polyalkylene oxide particles A)
Diethylzinc was diluted with n-hexane in a container purged with nitrogen so as to have a concentration of 0.66 mol/L in terms of zinc. Next, the inside of the vessel was cooled to 10° C., and the vessel was stirred until the concentration of 1,4-butanediol and ethanol was 0.59 mol/L and 2.58 mol/L, respectively, with respect to n-hexane. added inside. After completion of the addition, the temperature inside the vessel was raised to 30° C. to react diethylzinc with 1,4-butanediol and ethanol for 1 hour, then the temperature was raised to 50° C. and the reaction was carried out for 1 hour. After that, the temperature inside the container was raised to 80° C., and distillation was performed. After cooling, the reaction solution in the container was diluted with n-hexane so that the concentration of the organozinc catalyst was 3% by mass to obtain a dispersion containing the organozinc catalyst.
Next, the organic zinc catalyst and n-hexane were added to the nitrogen-purged pressure vessel so that the concentration of the organic zinc catalyst in terms of zinc to n-hexane was 0.0022 mol / L in terms of zinc, and dispersed uniformly. . Then, ethylene oxide was added so as to have a concentration of 3.84 mol/L with respect to hexane, and the mixture was sealed and polymerized with stirring in a constant temperature bath at 40°C. After completion of the polymerization, the white product was taken out by filtration and dried with stirring at a temperature of 40°C or less. , JIS Z 8801-1 standard sieve (500 μm) to obtain polyethylene oxide particles A that passed through.
　（製造例２；ポリアルキレンオキシド粒子Ｂの製造）
　窒素置換された容器内に、亜鉛換算で０．６６モル／Ｌの濃度になるようにジエチル亜鉛をｎ－ヘキサンで希釈した。次いで、容器内を１０℃に冷却し、攪拌下で、ｎ－ヘキサンに対して１，４－ブタンジオールが０．５９モル／Ｌ、エタノールが４．２４モル／Ｌの濃度になるまで該容器内に添加した。添加終了後、容器内を３０℃まで昇温して、ジエチル亜鉛を１，４－ブタンジオール及びエタノールと１時間反応させ、次に、５０℃まで昇温して１時間反応を行った。その後、容器内を８０℃まで昇温して、蒸留を行った後、容器内を１３０℃まで昇温して、未反応のアルコールをｎ－ヘキサン共に系外に留去した。冷却後、容器内の反応液を有機亜鉛触媒が３質量％の濃度となるようにｎ－ヘキサンで希釈し、有機亜鉛触媒を含む分散液を得た。
　次いで、窒素置換された耐圧容器に、ｎ－ヘキサンに対して有機亜鉛触媒が亜鉛換算で０．００１１ｍｏｌ／Ｌの濃度になるように有機亜鉛触媒とｎ－ヘキサンを添加し、均一に分散させた。次いで、ヘキサンに対して４．１８ｍｏｌ／Ｌの濃度になるようにエチレンオキシドを添加して密閉し、４０℃の恒温槽中で攪拌しながら重合させた。重合終了後、白色生成物を濾過して取り出し、４０℃以下の温度で撹拌しながら減圧乾燥し、得られた乾燥粒子に非晶質シリカ（日本アエロジル株式会社製、アエロジル）を１質量％混合し、ＪＩＳ　Ｚ　８８０１－１標準篩（５００μｍ）に移し、通過したポリエチレンオキシド粒子Ｂを得た。 (Production Example 2; Production of polyalkylene oxide particles B)
Diethylzinc was diluted with n-hexane in a container purged with nitrogen so as to have a concentration of 0.66 mol/L in terms of zinc. Next, the inside of the vessel was cooled to 10° C., and the vessel was stirred until the concentration of 1,4-butanediol and ethanol became 0.59 mol/L and 4.24 mol/L, respectively, with respect to n-hexane. added inside. After completion of the addition, the temperature inside the vessel was raised to 30° C. to react diethylzinc with 1,4-butanediol and ethanol for 1 hour, then the temperature was raised to 50° C. and the reaction was carried out for 1 hour. After that, the inside of the vessel was heated to 80° C. for distillation, and then the inside of the vessel was heated to 130° C., and the unreacted alcohol was distilled out of the system together with n-hexane. After cooling, the reaction solution in the container was diluted with n-hexane so that the concentration of the organozinc catalyst was 3% by mass to obtain a dispersion containing the organozinc catalyst.
Next, the organozinc catalyst and n-hexane were added to the nitrogen-purged pressure vessel so that the concentration of the organozinc catalyst in terms of zinc to n-hexane was 0.0011 mol / L in terms of zinc, and dispersed uniformly. . Then, ethylene oxide was added so as to give a concentration of 4.18 mol/L with respect to hexane, and the mixture was sealed and polymerized with stirring in a constant temperature bath at 40°C. After completion of the polymerization, the white product is filtered out and dried under reduced pressure while stirring at a temperature of 40° C. or less, and 1% by mass of amorphous silica (Aerosil, manufactured by Nippon Aerosil Co., Ltd.) is mixed with the obtained dry particles. and transferred to a JIS Z 8801-1 standard sieve (500 μm) to obtain polyethylene oxide particles B that passed through.
　（製造例３；ポリアルキレンオキシド粒子Ｃの製造）
　窒素置換された容器内に、亜鉛換算で０．６０モル／Ｌの濃度になるようにジエチル亜鉛をｎ－ヘキサンで希釈した。次いで、容器内を１０℃に冷却し、攪拌下で、ｎ－ヘキサンに対して１，４－ブタンジオールが０．５４モル／Ｌ、エタノールが３．９７モル／Ｌの濃度になるまで該容器内に添加した。添加終了後、容器内を３０℃まで昇温して、ジエチル亜鉛を１，４－ブタンジオール及びエタノールと１時間反応させ、次に、５０℃まで昇温して１時間反応を行った。その後、容器内を８０℃まで昇温して、蒸留を行った。冷却後、容器内の反応液を有機亜鉛触媒が３質量％の濃度となるようにｎ－ヘキサンで希釈し、有機亜鉛触媒を含む分散液を得た。
　次いで、窒素置換された耐圧容器に、ｎ－ヘキサンに対して有機亜鉛触媒が亜鉛換算で０．０００４ｍｏｌ／Ｌの濃度になるように有機亜鉛触媒とｎ－ヘキサンを添加し、均一に分散させた。次いで、ヘキサンに対して２．５２ｍｏｌ／Ｌの濃度になるようにエチレンオキシドを添加して密閉し、４０℃の恒温槽中で攪拌しながら重合させた。重合終了後、白色生成物を濾過して取り出し、４０℃で減圧乾燥し、得られた乾燥粒子に非晶質シリカ（日本アエロジル株式会社製、アエロジル）を１質量％混合し、ＪＩＳ　Ｚ　８８０１－１標準篩（５００μｍ）に移し、通過したポリエチレンオキシド粒子Ｃを得た。 (Production Example 3; Production of polyalkylene oxide particles C)
Diethylzinc was diluted with n-hexane to a concentration of 0.60 mol/L in terms of zinc in a vessel purged with nitrogen. Next, the inside of the vessel was cooled to 10° C., and the vessel was stirred until the concentration of 1,4-butanediol and ethanol became 0.54 mol/L and 3.97 mol/L, respectively, with respect to n-hexane. added inside. After completion of the addition, the temperature inside the vessel was raised to 30° C. to react diethylzinc with 1,4-butanediol and ethanol for 1 hour, then the temperature was raised to 50° C. and the reaction was carried out for 1 hour. After that, the temperature inside the container was raised to 80° C., and distillation was performed. After cooling, the reaction solution in the container was diluted with n-hexane so that the concentration of the organozinc catalyst was 3% by mass to obtain a dispersion containing the organozinc catalyst.
Next, the organozinc catalyst and n-hexane were added to the nitrogen-purged pressure vessel so that the concentration of the organozinc catalyst in terms of zinc to n-hexane was 0.0004 mol/L in terms of zinc, and dispersed uniformly. . Then, ethylene oxide was added so as to give a concentration of 2.52 mol/L with respect to hexane, and the mixture was sealed and polymerized with stirring in a constant temperature bath at 40°C. After completion of the polymerization, the white product was filtered out and dried at 40° C. under reduced pressure, and 1% by mass of amorphous silica (Aerosil, manufactured by Nippon Aerosil Co., Ltd.) was mixed with the obtained dry particles, and JIS Z 8801- No. 1 standard sieve (500 μm) to obtain polyethylene oxide particles C which passed through.
　ポリエチレンオキシド粒子の分級
　（製造例４）
　製造例１で得られたポリエチレンオキシド粒子Ａを、ＪＩＳ　Ｚ　８８０１－１標準篩として、目開き３００μｍの篩、目開き２５０μｍの篩、目開き１８０μｍの篩、目開き１５０μｍの篩、目開き１０６μｍの篩、目開き７５μｍの篩を上段からこの順で受け皿の上に重ね合わせた。最上段に配置された目開き５００μｍの篩に、ポリエチレンオキシド粒子を入れた。篩をロータップ式振とう器を用いて２０分間振とうさせることにより、ポリエチレンオキシド粒子を分級した。分級後、各篩上に残ったポリエチレンオキシド粒子の質量を測定し、各質量の全量に対する百分率（粒度分布）を計算した。 Classification of polyethylene oxide particles (Production Example 4)
The polyethylene oxide particles A obtained in Production Example 1 are used as JIS Z 8801-1 standard sieves, with a 300 μm mesh sieve, a 250 μm mesh sieve, a 180 μm mesh sieve, a 150 μm mesh sieve, and a 106 μm mesh sieve. A sieve and a sieve with an opening of 75 μm were superimposed on the tray in this order from the top. Polyethylene oxide particles were placed in a sieve with a mesh size of 500 μm placed on the uppermost stage. The polyethylene oxide particles were classified by shaking the sieve for 20 minutes using a low-tap shaker. After classification, the mass of polyethylene oxide particles remaining on each sieve was measured, and the percentage of each mass relative to the total mass (particle size distribution) was calculated.
　（製造例５）
　ポリエチレンオキシド粒子Ａの代わりに製造例２で得られたポリアルキレンオキシド粒子Ｂに変更したこと以外は製造例４と同様の方法で分級し、各篩上に残ったポリエチレンオキシド粒子の質量を測定し、各質量の全量に対する百分率（粒度分布）を計算した。 (Production example 5)
Classification was performed in the same manner as in Production Example 4 except that the polyalkylene oxide particles B obtained in Production Example 2 were used instead of the polyethylene oxide particles A, and the mass of the polyethylene oxide particles remaining on each sieve was measured. , the percentage (particle size distribution) of each mass relative to the total weight was calculated.
　（製造例６）
　ポリエチレンオキシド粒子Ａの代わりに製造例３で得られたポリアルキレンオキシド粒子Ｃに変更したこと以外は製造例４と同様の方法で分級し、各篩上に残ったポリエチレンオキシド粒子の質量を測定し、各質量の全量に対する百分率（粒度分布）を計算した。 (Production example 6)
Classification was performed in the same manner as in Production Example 4 except that the polyalkylene oxide particles C obtained in Production Example 3 were used instead of the polyethylene oxide particles A, and the mass of the polyethylene oxide particles remaining on each sieve was measured. , the percentage (particle size distribution) of each mass relative to the total weight was calculated.
　（実施例１）
　表１に示すように、分級後のポリエチレンオキシド粒子Ａの１０６μｍ篩上粒子、７５μｍ篩上粒子、および受皿上の粒子の割合がそれぞれ、粒子全体に対し、２１質量％、１２質量％および６７質量％となるように均一に混合することで、ポリエチレンオキシド粒子Ｄを得た。 (Example 1)
As shown in Table 1, the proportions of 106 μm sieve particles, 75 μm sieve particles, and particles on the tray of the polyethylene oxide particles A after classification are 21% by mass, 12% by mass, and 67% by mass, respectively. %, polyethylene oxide particles D were obtained.
　（実施例２）
　表１に示すように、分級後のポリエチレンオキシド粒子Ａの３００μｍ篩上粒子、２５０μｍ篩上粒子、１８０μｍ篩上粒子、１５０μｍ篩上粒子、１０６μｍ篩上粒子、７５μｍ篩上粒子、および受皿上の粒子の割合がそれぞれ、粒子全体に対し、４質量％、２質量％、２５質量％、１３質量％、１２質量％、６質量％および３８質量％となるように均一に混合することで、ポリエチレンオキシド粒子Ｅを得た。 (Example 2)
As shown in Table 1, 300 μm on-sieve particles, 250 μm on-sieve particles, 180 μm on-sieve particles, 150 μm on-sieve particles, 106 μm on-sieve particles, 75 μm on-sieve particles, and particles on the tray of polyethylene oxide particles A after classification By uniformly mixing so that the proportions of the total particles are 4% by mass, 2% by mass, 25% by mass, 13% by mass, 12% by mass, 6% by mass, and 38% by mass, polyethylene oxide Particles E were obtained.
　（比較例１）
　表１に示すように、分級後のポリエチレンオキシド粒子Ａの受皿およびポリエチレンオキシド粒子Ｂの３００μｍ篩上粒子の割合がそれぞれ、粒子全体に対し、６０質量％および４０質量％となるように均一に混合することでポリエチレンオキシド粒子Ｆを得た。 (Comparative example 1)
As shown in Table 1, the proportions of the polyethylene oxide particles A after classification and the 300 μm sieve particles of the polyethylene oxide particles B are uniformly mixed to 60% by mass and 40% by mass of the total particles, respectively. Polyethylene oxide particles F were obtained by doing so.
　（比較例２）
　表１に示すように、分級後のポリエチレンオキシド粒子Ａの１０６μｍ篩上粒子および受皿上の粒子、並びに、ポリエチレンオキシド粒子Ｂの３００μｍ篩上粒子の割合がそれぞれ、粒子全体に対し、４０質量％、１０質量％および５０質量％となるように均一に混合することでポリエチレンオキシド粒子Ｇを得た。 (Comparative example 2)
As shown in Table 1, the ratio of the 106 μm sieve particles of the polyethylene oxide particles A after classification and the particles on the tray and the 300 μm sieve particles of the polyethylene oxide particles B are respectively 40% by mass and 40% by mass of the total particles. Polyethylene oxide particles G were obtained by uniformly mixing 10% by mass and 50% by mass.
　（比較例３）
　表１に示すように、分級後のポリエチレンオキシド粒子Ａの１０６μｍ篩上粒子、７５μｍ篩上粒子、および受皿上の粒子、並びに、ポリエチレンオキシド粒子Ｂの３００μｍ篩上の粒子の割合がそれぞれ、粒子全体に対し、１１質量％、６質量％、３６質量％および４６質量％となるように均一に混合することでポリエチレンオキシド粒子Ｈを得た。 (Comparative Example 3)
As shown in Table 1, the ratio of the 106 μm sieve particles, the 75 μm sieve particles, and the particles on the tray of polyethylene oxide particles A after classification, and the ratio of the 300 μm sieve particles of polyethylene oxide particles B to the total particle 11 mass %, 6 mass %, 36 mass %, and 46 mass % were uniformly mixed to obtain polyethylene oxide particles H.
　（比較例４）
　表１に示すように、分級後のポリエチレンオキシド粒子Ａの受皿上の粒子およびポリエチレンオキシド粒子Ｂの３００μｍ篩上粒子の割合がそれぞれ、粒子全体に対し、４５質量％、５５質量％となるように均一に混合することでポリエチレンオキシド粒子Ｉを得た。 (Comparative Example 4)
As shown in Table 1, the proportions of the polyethylene oxide particles A on the tray and the polyethylene oxide particles B on the 300 μm sieve after classification were 45% by mass and 55% by mass, respectively, of the total particles. Polyethylene oxide particles I were obtained by uniform mixing.
　（比較例５）
　表１に示すように、分級後のポリエチレンオキシド粒子Ａの１０６μｍ篩上粒子、７５μｍ篩上粒子、および受皿上の粒子、並びに、ポリエチレンオキシド粒子Ｂの３００μｍ篩上粒子の割合がそれぞれ、粒子全体に対し、７質量％、４質量％、２１質量％および６９質量％となるように均一に混合することでポリエチレンオキシド粒子Ｊを得た。 (Comparative Example 5)
As shown in Table 1, the ratio of 106 μm sieve particles, 75 μm sieve particles, and particles on the tray of polyethylene oxide particles A after classification, and 300 μm sieve particles of polyethylene oxide particles B to the whole particles On the other hand, polyethylene oxide particles J were obtained by uniformly mixing so as to obtain 7% by mass, 4% by mass, 21% by mass and 69% by mass.
　（比較例６）
　表１に示すように、分級後のポリエチレンオキシド粒子Ａの１０６μｍ篩上粒子、７５μｍ篩上粒子、および受皿上の粒子、並びに、ポリエチレンオキシド粒子Ｂの３００μｍ篩上粒子の割合がそれぞれ、粒子全体に対し、９質量％、５質量％、３０質量％および５６質量％となるように均一に混合することでポリエチレンオキシド粒子Ｋを得た。 (Comparative Example 6)
As shown in Table 1, the ratio of 106 μm sieve particles, 75 μm sieve particles, and particles on the tray of polyethylene oxide particles A after classification, and 300 μm sieve particles of polyethylene oxide particles B to the whole particles On the other hand, polyethylene oxide particles K were obtained by uniformly mixing so as to obtain 9% by mass, 5% by mass, 30% by mass and 56% by mass.
　（比較例７）
　表１に示すように、分級後のポリエチレンオキシド粒子Ａの１０６μｍ篩上粒子、７５μｍ篩上粒子、および受皿上の粒子、並びに、ポリエチレンオキシド粒子Ｂの３００μｍ篩上粒子の割合がそれぞれ、粒子全体に対し、７質量％、４質量％、２２質量％および６７質量％となるように均一に混合することでポリエチレンオキシド粒子Ｌを得た。 (Comparative Example 7)
As shown in Table 1, the ratio of 106 μm sieve particles, 75 μm sieve particles, and particles on the tray of polyethylene oxide particles A after classification, and 300 μm sieve particles of polyethylene oxide particles B to the whole particles On the other hand, the polyethylene oxide particles L were obtained by uniformly mixing so as to obtain 7% by mass, 4% by mass, 22% by mass and 67% by mass.
　（比較例８）
　製造例３で得たポリエチレンオキシド粒子Ｃを用いた。 (Comparative Example 8)
The polyethylene oxide particles C obtained in Production Example 3 were used.
　（比較例９）
　表１に示すように、分級後のポリエチレンオキシド粒子Ｂの１０６μｍ篩上粒子の割合が１００％となるポリエチレンオキシド粒子Ｍを得た。 (Comparative Example 9)
As shown in Table 1, polyethylene oxide particles M were obtained in which the percentage of 106 μm sieve particles in polyethylene oxide particles B after classification was 100%.
　（比較例１０）
　表１に示すように、分級後のポリエチレンオキシド粒子Ｂの１８０μｍ篩上粒子が１００％となるポリエチレンオキシド粒子Ｎを得た。 (Comparative Example 10)
As shown in Table 1, polyethylene oxide particles N having 100% of the 180 μm sieve particles of polyethylene oxide particles B after classification were obtained.
　なお、実施例及び比較例における粒子の割合は小数点第１位を四捨五入した数値である。そのため、これらを合計すると１００質量％にならない場合もある。 The percentage of particles in Examples and Comparative Examples is a numerical value rounded to the first decimal place. Therefore, the sum of these may not be 100% by mass.
　（ポリアルキレンオキシドの１質量％水溶液粘度）
　１Ｌビーカーにポリエチレンオキシド粒子６ｇと、イソプロパノール１２５ｍＬを添加し、撹拌翼を用いて３５０ｒｐｍで攪拌しつつ、イオン交換水５９４ｇを添加し、１分間撹拌を行った。その後、撹拌回転数を６０ｒｐｍに変更して、さらに３時間攪拌を続けることで、ポリエチレンオキシドの１質量％水溶液を得た。この水溶液を２５℃に保持し、回転粘度計（ＢＲＯＯＫ　ＦＩＥＬＤ製「ＲＶ　ＤＶＩＩ＋」）を用いて粘度を測定（スピンドル：ＲＶ－２、回転数：２ｒｐｍ）し、この値を１質量％水溶液粘度とした。 (1% by mass aqueous solution viscosity of polyalkylene oxide)
6 g of polyethylene oxide particles and 125 mL of isopropanol were added to a 1 L beaker, and while stirring at 350 rpm using a stirring blade, 594 g of ion-exchanged water was added and stirred for 1 minute. After that, the stirring rotation speed was changed to 60 rpm, and stirring was continued for 3 hours to obtain a 1% by mass aqueous solution of polyethylene oxide. This aqueous solution is kept at 25 ° C., and the viscosity is measured using a rotational viscometer ("RV DVII+" manufactured by BROOK FIELD) (spindle: RV-2, rotation speed: 2 rpm). bottom.
　（ポリアルキレンオキシド粒子の５質量％水溶液粘度）
　１Ｌビーカーにポリエチレンオキシド３０ｇと、イソプロパノール１２５ｍＬを添加し、撹拌翼を用いて３００～４００ｒｐｍで攪拌しつつ、イオン交換水５７０ｇを添加し、１分間撹拌を行った。その後、撹拌回転数を６０ｒｐｍに変更して、さらに３時間攪拌を続けることで、ポリエチレンオキシドの５質量％水溶液を得た。この水溶液を２５℃に保持し、回転粘度計（ＢＲＯＯＫ　ＦＩＥＬＤ製「ＲＶ　ＤＶＩＩ＋」）を用いて粘度を測定し、この値を５質量％水溶液粘度とした。 (5% by mass aqueous solution viscosity of polyalkylene oxide particles)
30 g of polyethylene oxide and 125 mL of isopropanol were added to a 1 L beaker, and while stirring at 300 to 400 rpm using a stirring blade, 570 g of ion-exchanged water was added and stirred for 1 minute. After that, the stirring rotation speed was changed to 60 rpm, and the stirring was continued for 3 hours to obtain a 5% by mass aqueous solution of polyethylene oxide. This aqueous solution was kept at 25° C., and the viscosity was measured using a rotational viscometer (“RV DVII+” manufactured by BROOK FIELD), and this value was taken as the viscosity of the 5% by mass aqueous solution.
　（粒度分布（各篩上の粒子質量百分率）測定方法）
　ポリエチレンオキシド粒子の粒度分布は乾式ふるい分け試験により測定して算出した。まず、ポリエチレンオキシド粒子に、滑剤として非晶質シリカ（日本アエロジル株式会社製、アエロジル）を１質量％混合した混合物を調製した。ＪＩＳ　Ｚ　８８０１－１標準篩として、目開き５００μｍの篩、目開き３００μｍの篩、目開き２５０μｍの篩、目開き１８０μｍの篩、目開き１５０μｍの篩、目開き１０６μｍの篩及び目開き７５μｍの篩を上段側からこの順で受皿の上に重ね合わせた。最上段に配置された目開き５００μｍの篩に前記混合物を投入し、篩をロータップ式振とう器を用いて２０分間振とうさせることにより、混合物を分級した。分級後、各篩上に残ったポリアルキレンオキシド粒子の質量を測定し、各質量の全量に対する百分率の算出値をポリアルキレンオキシド粒子の粒度分布とした。 (Particle size distribution (particle mass percentage on each sieve) measurement method)
The particle size distribution of polyethylene oxide particles was measured and calculated by a dry sieving test. First, a mixture was prepared by mixing polyethylene oxide particles with 1% by mass of amorphous silica (Aerosil, manufactured by Nippon Aerosil Co., Ltd.) as a lubricant. JIS Z 8801-1 standard sieves include a 500 μm sieve, a 300 μm sieve, a 250 μm sieve, a 180 μm sieve, a 150 μm sieve, a 106 μm sieve and a 75 μm sieve. were superimposed on the saucer in this order from the top side. The mixture was put into a sieve with a mesh size of 500 μm arranged on the uppermost stage, and the mixture was classified by shaking the sieve for 20 minutes using a low-tap shaker. After classification, the mass of the polyalkylene oxide particles remaining on each sieve was measured, and the calculated percentage of each mass to the total amount was taken as the particle size distribution of the polyalkylene oxide particles.
　（錠剤の硬度測定）
　各実施例及び比較例で得られたポリエチレンオキシド粒子を製剤用ポリアルキレンオキシド粒子として用いて、錠剤の硬度測定を行った。製剤用ポリアルキレンオキシド粒子４２６ｍｇをオートグラフ用汎用杵臼（Φ１１、平型）に投入し、オートグラフ（島津製作所製ＡＧＳ－Ｔ）用いて、所定の試験力にて圧縮速度を１０ｍｍ／ｍｉｎとして打錠し、ポリエチレンオキシド粒子単独錠剤を得た。試験力は、７ｋＮとして、それぞれの試験力にてポリエチレンオキシド粒子単独錠剤を作製した。このように得られたポリエチレンオキシド粒子単独錠剤の硬度を、ＥＲＷＥＫＡ製の「錠剤硬度計ＴＢＨ－３２５」を用いて、感度１０Ｎ，測定速度２．３ｍｍ／ｓ，加圧速度２０Ｎ／ｓにて計測した。 (Tablet hardness measurement)
Using the polyethylene oxide particles obtained in each example and comparative example as the polyalkylene oxide particles for formulation, tablet hardness was measured. 426 mg of polyalkylene oxide particles for formulation are charged into a general-purpose punch and die for autograph (Φ11, flat type), and are struck using an autograph (AGS-T manufactured by Shimadzu Corporation) at a compression speed of 10 mm / min at a predetermined test force. It was tableted to obtain a single tablet of polyethylene oxide particles. The test force was set to 7 kN, and polyethylene oxide particle single tablets were produced at each test force. The hardness of the polyethylene oxide particle single tablet obtained in this way is measured using a "tablet hardness tester TBH-325" manufactured by ERWEKA at a sensitivity of 10 N, a measurement speed of 2.3 mm/s, and a pressing speed of 20 N/s. bottom.
　（ポリアルキレンオキシド粒子の嵩密度及びスパチュラ角〕
　ホソカワミクロン株式会社製「パウダーテスターＰＴ－Ｘ」を用い、装置に表示される手順及び装置が推奨する標準条件に従って、ポリアルキレンオキシド粒子のゆるめ嵩密度、かため嵩密度、及び、スパチュラ角を計測した。なお、かため嵩密度の測定ではタッピング回数は１８０回とした。 (Bulk density and spatula angle of polyalkylene oxide particles)
Using "Powder Tester PT-X" manufactured by Hosokawa Micron Co., Ltd., the loose bulk density, firm bulk density, and spatula angle of the polyalkylene oxide particles were measured according to the procedure displayed on the device and the standard conditions recommended by the device. . The number of tapping was set to 180 in the measurement of the bulk density.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　表１には、各実施例及び比較例で製造した製剤用ポリアルキレンオキシド粒子の粒度分布、かため嵩密度、ゆるめ嵩密度、スパチュラ角、粒度分布及び各試験力での錠剤硬度測定結果を示している。 Table 1 shows the particle size distribution, firm bulk density, loose bulk density, spatula angle, particle size distribution, and tablet hardness measurement results at each test force of the polyalkylene oxide particles for formulation produced in each example and comparative example. ing.
　表１に示される結果から、所定のゆるめ嵩密度、かため嵩密度、スパチュラ角及び粒度分布を有するポリアルキレンオキシド粒子から得られた錠剤は、高い硬度を有していた。従って、実施例で得られたポリアルキレンオキシド粒子は、高い硬度を有する製剤を形成するための原料として好適に用いられることがわかった。 From the results shown in Table 1, tablets obtained from polyalkylene oxide particles having predetermined loose bulk density, firm bulk density, spatula angle and particle size distribution had high hardness. Therefore, it was found that the polyalkylene oxide particles obtained in Examples can be suitably used as raw materials for forming formulations having high hardness.

Claims (7)

  1. ゆるめ嵩密度が０．４３ｇ／ｍＬ以上、０．４９ｇ／ｍＬ以下であり、
    かため嵩密度が０．５１ｇ／ｍＬ以上であり、
    スパチュラ角が３５．０°以上、５５．０°以下であり、
    １５０μｍ未満の粒子の含有割合が４６質量％以上である、製剤用ポリアルキレンオキシド粒子。     Loose bulk density is 0.43 g / mL or more and 0.49 g / mL or less,
    Firm bulk density is 0.51 g / mL or more,
    The spatula angle is 35.0° or more and 55.0° or less,
    Polyalkylene oxide particles for formulation, wherein the content of particles less than 150 μm is 46% by mass or more.
  2. １質量％水溶液粘度が４０～２００００ｍＰａ・ｓである、請求項１に記載の製剤用ポリアルキレンオキシド粒子。 2. The polyalkylene oxide particles for pharmaceutical preparations according to claim 1, having a 1% by mass aqueous solution viscosity of 40 to 20000 mPa·s.
  3. １質量％水溶液粘度が４０ｍＰａ・ｓ未満、かつ、５質量％水溶液粘度が３０～５００００ｍＰａ・ｓである、請求項１に記載の製剤用ポリアルキレンオキシド粒子。 2. The polyalkylene oxide particles for formulation according to claim 1, which have a 1% by mass aqueous solution viscosity of less than 40 mPa·s and a 5% by mass aqueous solution viscosity of 30 to 50000 mPa·s.
  4. 請求項１～３のいずれか１項に記載の製剤用ポリアルキレンオキシド粒子を含む、医薬用組成物。 A pharmaceutical composition comprising the pharmaceutical polyalkylene oxide particles according to any one of claims 1-3.
  5. 請求項４に記載の医薬用組成物を含む、製剤用組成物。 A pharmaceutical composition comprising the pharmaceutical composition of claim 4 .
  6. 請求項５に記載の製剤用組成物を含む、製剤。 A formulation comprising the pharmaceutical composition of claim 5 .
  7. 前記製剤用組成物の圧縮成形体を含む、請求項６に記載の製剤。 7. The formulation according to claim 6, comprising a compression molded body of the pharmaceutical composition.
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JP2005232185A (en) * 2003-03-06 2005-09-02 Astellas Pharma Inc Medicinal composition for regulating release and process for producing the same
JP2006124695A (en) * 2004-10-01 2006-05-18 Zepharma Inc Granular composition of anion exchange resin and method for producing the same
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