WO2009133774A1 - Spherical granules and method of producing the same - Google Patents

Spherical granules and method of producing the same Download PDF

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Publication number
WO2009133774A1
WO2009133774A1 PCT/JP2009/057673 JP2009057673W WO2009133774A1 WO 2009133774 A1 WO2009133774 A1 WO 2009133774A1 JP 2009057673 W JP2009057673 W JP 2009057673W WO 2009133774 A1 WO2009133774 A1 WO 2009133774A1
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WO
WIPO (PCT)
Prior art keywords
sugar
spherical
granule
spherical granules
core particles
Prior art date
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PCT/JP2009/057673
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French (fr)
Japanese (ja)
Inventor
照美 高橋
Original Assignee
フロイント産業株式会社
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Application filed by フロイント産業株式会社 filed Critical フロイント産業株式会社
Publication of WO2009133774A1 publication Critical patent/WO2009133774A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug

Definitions

  • the present invention relates to a spherical granule suitable as a base material for pharmaceuticals and the like and an efficient production method thereof.
  • Nonparell registered trademark
  • the spherical granule is used as a preparation having a surface coated with various physiologically active substances, or a preparation having a functional coating layer formed on the surface thereof, or a preparation encapsulated in a capsule.
  • this spherical granule is used as a core particle to form a bioactive substance coating or a functional coating layer, the spherical granule may be damaged during the process if it is brittle.
  • a spherical granule having a strength capable of withstanding the processing in the apparatus in each process is required.
  • the shape of the spherical granule is true from the viewpoint of controlling the release of the physiologically active substance, for example, the release time as accurately as possible. It is required to be closer to a sphere and have a sharp particle size distribution.
  • a centrifugal fluid granulating device As a method for producing the spherical granule, a centrifugal fluid granulating device, an onion type pan coating device, or the like is used, and a liquid or powder containing sugar in particles serving as the core of the spherical granule (hereinafter referred to as “nuclear particle”).
  • a method of producing by granulating while supplying is known.
  • the obtained granule has a low sphericity and a spherical granule suitable for a preparation with controlled release of the physiologically active substance cannot be obtained. .
  • the spherical granules are granulated with a centrifugal fluidizing granulator, it is possible to produce granules having a higher sphericity than those granulated with an onion type pan coating apparatus. More specifically, granulated sugar crystals are charged as the core particles in the centrifugal flow granulator, and the sucrose fine particles or fine powder are dispersed while spraying an aqueous solution of sucrose as a binder on the surface of the core particles.
  • a method of forming spherical granules by forming a coating layer of the sucrose on the granulated sugar crystals see paragraph [0004] of Patent Document 1).
  • spherical granules with high sphericity can be obtained.
  • the present invention improves the friability and granule hardness to a sufficiently high level, has a high sphericity, and is coated with a physiologically active substance that can be taken orally on its surface and applied to the formulation. It is an object of the present invention to provide a high-quality spherical granule excellent in the release controllability of a physiologically active substance, and a method capable of efficiently and easily producing the spherical granule.
  • a coating layer is formed by spraying a liquid containing solids on the core particles without spraying the powder component while rolling by rotating a rotating dish in which the core particles containing sugar are horizontally installed.
  • a process for producing spherical granules comprising the step of forming In the method for producing spherical particles, since the core particles are rolled and granulated, the obtained spherical granules have a high sphericity. Further, at the time of granulation, the liquid is sprayed on the surface of the core particles while rolling, and a coating layer made of sugar or the like dissolved or dispersed in the liquid is formed on the surface of the core particles.
  • the spherical granules thus obtained have a high sphericity, excellent friability and granule hardness.
  • ⁇ 2> The method for producing a spherical granule according to ⁇ 1>, wherein the liquid containing solid content is an aqueous solution or suspension containing sugar.
  • ⁇ 3> The method for producing a spherical granule according to any one of ⁇ 1> to ⁇ 2>, wherein the core particles are sugar crystals or spray-dried particles of sugar and starch or a derivative thereof.
  • ⁇ 4> The nuclear particles according to any one of ⁇ 1> to ⁇ 3>, wherein the core particles are floated and flowed by blowing air into the rolling particles in addition to rolling by rotating a horizontally disposed rotating dish.
  • ⁇ 5> The spherical shape according to any one of ⁇ 1> to ⁇ 4>, further comprising spraying an aqueous solution of sugar and / or sugar alcohol on the surface of the obtained spherical granule to form a surface coating layer. It is a manufacturing method of a granule.
  • ⁇ 6> The method for producing a spherical granule according to any one of ⁇ 1> to ⁇ 5>, wherein the obtained spherical granule has a particle size of 75 to 1,000 ⁇ m as measured by a sieving method. . ⁇ 7> A spherical granule produced by the method for producing a spherical granule according to any one of ⁇ 1> to ⁇ 6>. ⁇ 8> A method for producing a preparation obtained by coating the surface of the spherical granule according to ⁇ 7> with a component containing a physiologically active substance that can be taken orally.
  • the above-mentioned problems in the prior art can be solved, and the friability and granule hardness are improved to a sufficiently high level. It is possible to provide a high-quality spherical granule excellent in the release controllability of a physiologically active substance, and a method capable of efficiently and easily producing the spherical granule.
  • the method for producing a spherical granule of the present invention includes at least a granulation step in which a spherical granule is granulated by rotating by rotating a rotating dish in which the core particles are horizontally installed and spraying a liquid on the core particles.
  • a granulation step in which a spherical granule is granulated by rotating by rotating a rotating dish in which the core particles are horizontally installed and spraying a liquid on the core particles.
  • other processes appropriately selected as necessary are included.
  • the spherical granules of the present invention are produced by the method for producing spherical granules of the present invention.
  • the granulation step rolls by rotating a rotating dish in which the core particles are horizontally installed, and sprays a liquid containing solids on the core particles without spraying powder components on the core particles.
  • spherical granules are formed by forming a coating layer.
  • the core particle can be appropriately selected according to the use and purpose of the spherical granule, and can be appropriately selected from known ones. In the present invention, it only needs to contain at least a sugar. In addition to sugar, other components may be contained.
  • a commercially available crystal grain or granulated product may be used as it is, or the crystal grain may be used after being polished, pulverized, or obtained by granulating a powder or the like. May be used.
  • the particle size of the core particle is not particularly limited and can be appropriately selected depending on the use and purpose of the spherical granule.
  • the particle size measured by a sieving method is preferably 50 to 850 ⁇ m. 75 to 500 ⁇ m is more preferable.
  • the particle size of the core particles exceeds 850 ⁇ m, the spherical particles obtained have a particle size of about 1,000 ⁇ m or more. Is likely to occur.
  • it is less than 50 ⁇ m aggregation may easily occur when spherical granules are formed or when a coating layer is formed on the surface of the obtained spherical granules.
  • sugar there is no restriction
  • the other components are not particularly limited as long as they can be taken orally, and can be appropriately selected according to the purpose. Examples thereof include sugar alcohols, organic acids and salts thereof, inorganic substances, starches and derivatives thereof, celluloses and the like.
  • Examples thereof include cellulose derivatives and synthetic polymers.
  • physiologically active substances are not used as other components. These may be used individually by 1 type and may use 2 or more types together. There are no particular restrictions on how to use them, and examples thereof include a method of granulating together with the above-mentioned sugar and coating the component on sugar crystal grains.
  • the sugar alcohol include mannitol, xylitol, erythritol, and the like.
  • Examples of the organic acid include citric acid, tartaric acid, ascorbic acid, and the like.
  • the salt of the organic acid include sodium salt, calcium salt, potassium salt and the like.
  • As said inorganic substance, salt, a titanium oxide, silicon dioxide etc. are mentioned, for example.
  • starch and derivatives thereof include corn starch, wheat starch, rice starch, and derivatives thereof.
  • cellulose and cellulose derivative include crystalline cellulose, powdered cellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, and the like.
  • synthetic polymer include polyvinyl pyrrolidone, poly (meth) acrylic acid and esters thereof, polyvinyl alcohol and derivatives thereof.
  • the liquid containing the solid content can be appropriately selected according to the use and purpose of the spherical granule, and can be appropriately selected from known ones.
  • the aqueous solution containing sugar Or suspension There is no restriction
  • this sugar 1 type may be used individually and 2 or more types may be used together. Depending on the kind of the sugar, since it has a binder effect, when the coating layer is formed on the surface of the core particle, the adhesive strength between the coating layer and the core particle is excellent.
  • the content of the sugar in the liquid containing the solid content is not particularly limited, and may be adjusted to a concentration according to the solubility of the sugar.
  • a concentration according to the solubility of the sugar For example, in the case of sucrose, 20 to 60% by weight is preferable. If the sugar content is less than 20% by weight, it is assumed that the production efficiency is lowered due to the extension of the process time for spraying the liquid, and if it exceeds 60% by weight, aggregation occurs due to the binder effect of sucrose. There is. Moreover, it is preferable that the whole amount of sugar is dissolved in the liquid.
  • the additive component other than the sugar contained in the liquid containing the solid content is not particularly limited as long as it can be taken orally, sugar alcohol, organic acid and salt thereof, inorganic substance, starch and derivative thereof, cellulose.
  • examples thereof include derivatives and synthetic polymers.
  • examples of the sugar alcohol, the organic acid and salt thereof, the starch and derivative thereof, the cellulose and cellulose derivative, and the synthetic polymer include those described above.
  • the physiologically active substance is not contained as a solid content.
  • the content of the dispersoid is preferably 30% by weight or less, and more preferably 20% by weight or less. If the content of the additive component exceeds 30% by weight, the viscosity may be high, depending on the properties of the component to be added, and sprayability may be deteriorated or aggregation may easily occur.
  • the solvent contained in the liquid include water. There is no restriction
  • the organic solvent etc. may be contained in the range which does not injure the objective of this invention other than water.
  • the organic solvent alcohol, such as ethanol, etc. are mentioned suitably, for example. If the liquid contains the organic solvent, the solubility may be improved and the drying time may be shortened.
  • the solubility may be improved and the drying time may be shortened.
  • the objective it can select suitably.
  • the method for preparing the liquid containing the solid content is not particularly limited, and can be prepared according to a known method according to the purpose.
  • the sugar, additional components other than the sugar are added to water, or as necessary.
  • the method for spraying the liquid containing the solid content onto the core particles is not particularly limited and can be appropriately selected depending on the purpose.
  • spray means provided in the granulating apparatus to be used for example, A method of spraying from a spray gun, a spray nozzle or the like is preferable.
  • the spraying conditions are not particularly limited, and publicly known conditions can be adopted.
  • the spraying amount, the size of sprayed mist particles (mist), the spraying time, and the like are determined according to the purpose. It can be selected appropriately.
  • the spray air pressure is preferably about 0.1 MPa to 0.5 MPa, for example.
  • the granulator is not particularly limited as long as it can roll the core particles in the present invention, and can be appropriately selected from known ones according to the purpose.
  • Centrifugal flow type coating granulator for example, “CF Granulator” manufactured by Freund Sangyo Co., Ltd.
  • composite type granulating coating device for example, “Spiraflow” manufactured by Freund Sangyo Co., Ltd.
  • centrifugal rolling granulation coating A device for example, “Granurex” manufactured by Freund Sangyo Co., Ltd.
  • Gnurex manufactured by Freund Sangyo Co., Ltd.
  • the powder such as sugar is sprayed from a powder spraying device to the core particles during the spraying.
  • the friability and granule hardness could not be sufficiently improved.
  • the friability and granule hardness were sufficiently high. In order to obtain high-quality spherical granules with improved levels, the powder is not applied to the core particles during the application.
  • the rolling is also referred to as “centrifugal flow” or “centrifugal rolling”, and a rotating plate (rotor) installed horizontally inside a cylindrical fixed wall (stator) rotates, It means that the core particles roll on the rotor while introducing slit air supplied from a constant clearance provided between the rotors.
  • the core particles are formed into a spherical shape while a coating layer made of the liquid containing the solid content is formed on the surface thereof.
  • the method of using the well-known granulator provided with the rotor and stator which can rotate etc. is mentioned suitably.
  • the granulator is not particularly limited and may be appropriately selected depending on the intended purpose.
  • examples thereof include a centrifugal flow type coating granulator (for example, “CF Granulator” manufactured by Freund Sangyo Co., Ltd.), a composite Preferred examples include a mold granulation coating apparatus (for example, “Spiraflow” manufactured by Freund Sangyo Co., Ltd.), a centrifugal rolling granulation coating apparatus (for example, “Granurex” manufactured by Freund Sangyo Co., Ltd.), and the like.
  • the rolling condition is not particularly limited and may be appropriately selected depending on the purpose. However, the rotational speed of the rotor may vary depending on the apparatus diameter, but may vary depending on the device diameter, but may be about 50 to 1,000 rpm. Is preferred.
  • the temperature at the time of rolling is not particularly limited and may be appropriately selected depending on the kind of the core particles, the composition of the liquid, and the like, but the product temperature is preferably about 20 to 50 ° C.
  • a screen that does not allow the passage of nuclear particles but allows air to pass through is provided on the rotating dish, and floating air is introduced by blowing air toward the rolling particles from below the rotating dish, or near the rotating dish from above the rotating dish.
  • Floating fluid air can be introduced toward the rolling particles by the provided tubular air supply means.
  • the air volume of the slit air and the floating fluid air can be appropriately selected according to the purpose such as the capacity of the apparatus.
  • the rolling floating flow method is not particularly limited, and a method using a known granulator equipped with a rotatable rotor and slit air and a floating flow air path is preferable.
  • the granulator is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a composite granulation coating apparatus (for example, “Spiraflow” manufactured by Freund Sangyo Co., Ltd.), centrifugal rolling, etc.
  • a granulating and coating apparatus for example, “Granurex” manufactured by Freund Sangyo Co., Ltd.) and the like are preferable.
  • a coating layer made of the liquid containing the solid content is formed on the surface of the core particles, and the spherical granules of the present invention are granulated.
  • the coating amount of the coating layer is not particularly limited and can be appropriately selected according to the use and purpose of the spherical granule.
  • the sugar contained in the liquid with respect to the core particles The solid content is preferably about 50 to 1,500% by weight, more preferably about 100 to 1,000% by weight.
  • the particle size of the spherical granule is not particularly limited and can be appropriately selected depending on the use and purpose of the spherical granule.
  • the particle size measured by a sieving method is 75 to 1,000 ⁇ m. It is preferably 150 to 850 ⁇ m.
  • the particle diameter of the spherical granule exceeds 1,000 ⁇ m, there are cases where problems such as a poor feeling of taking of the preparation are likely to occur when formulated using the obtained spherical granule, whereas the particle diameter is less than 75 ⁇ m. When it exists, it may become easy to raise
  • the sphericity of the spherical granules thus obtained is preferably 0.85 or more, more preferably 0.90 or more.
  • the solubility of the physiologically active substance in the preparation in the body is not uniform, and the drug delivery Quality as a system-applied formulation may be insufficient.
  • it is 0.85 or more when a coating layer containing a physiologically active substance or the like is formed on the surface of the spherical granule, the physiologically active substance can be uniformly coated and the release of the physiologically active substance This is advantageous in that the speed can be controlled more accurately.
  • the spherical granules have high sphericity because they are granulated by rolling the core particles.
  • the liquid is sprayed and components such as sugar dissolved or dispersed in the liquid form a coating layer on the surface of the core particles, so that the spherical granules have a friability.
  • the surface coating layer forming step is a step of forming a surface coating layer on the surface of the spherical granule obtained in the granulation step.
  • the spherical granule of the present invention may be one in which the surface coating layer is not formed, or one in which the surface coating layer is formed.
  • the spherical granules having the surface coating layer are improved in their friability, granule hardness, and the like as compared with the case where the surface coating layer is not formed.
  • the method for forming the surface coating layer is not particularly limited and can be appropriately selected according to the purpose.
  • the method etc. which are performed by spraying a surface coating layer forming liquid are mentioned.
  • limiting in particular as said surface coating layer forming liquid although it can select suitably according to the objective, The thing similar to the liquid containing the said solid content mentioned above is mentioned suitably.
  • the liquid may be either an aqueous solution or a suspension.
  • the surface coating layer forming liquid may be used in terms of the degree of friability of the resulting spherical granules, improvement in granule hardness, and the like. From an aqueous solution is preferred over a suspension. In the present invention, an aqueous solution of the sugar and / or sugar alcohol is particularly preferable.
  • the coating amount of the surface coating layer is not particularly limited and can be appropriately selected depending on the use and purpose of the spherical granule. For example, it is contained in the surface coating layer forming liquid for the core particles.
  • the ratio of the solids such as sugar is preferably about 1 to 200% by weight, more preferably about 10 to 100% by weight.
  • the centrifugal rolling granulation coating apparatus “Granurex” (manufactured by Freund Sangyo Co., Ltd.) includes a granulation chamber capable of granulating spherical granules while rolling the core particles.
  • the granulation chamber has a space having a circular cross section on the installation surface, and a circular rotating plate (rotor) in which the plate surface is installed horizontally with respect to the installation surface in the space. ).
  • the rotor has a shape in which the outer peripheral edge portion is gradually inclined upward. When the rotor is rotated around the rotation axis, the core particles can roll on the dish surface.
  • a predetermined clearance is formed between the outer peripheral end of the rotor and the inner wall of the granulation chamber.
  • the granulation chamber is provided with a thermometer such as a thermocouple for measuring the temperature in the space.
  • the granulation chamber is also provided with a spraying device so that the liquid for forming the coating layer on the surface of the core particles can be sprayed into the granulation chamber.
  • the spraying device is provided above the rotor and in the vicinity of the outer peripheral edge thereof, and a pipe and a pump for feeding the liquid, and the liquid can be sprayed into the space.
  • a spray nozzle is provided in the granulation chamber, an air chamber is formed below the rotor, and air can be pumped into the air chamber, and the inside of the granulation chamber (inside the space) from the clearance portion. ) Slit air can be introduced.
  • the core particles when the core particles are introduced while the rotor is rotated and slit air is introduced, the core particles roll. Next, when the liquid containing the solid content for forming the coating layer is sprayed, the surface of the core particles is coated with the components such as the sugar contained in the liquid containing the solid content to form spherical granules. .
  • the spherical granules obtained in this way can be taken out from the centrifugal rolling coating device and transferred to a fluidized bed device or the like, and further subjected to a drying process, etc.
  • the particles In the granulation chamber, the particles can be rolled and floated by feeding air into the rolling particles. Therefore, since this floating fluidized air is introduced during granulation, the drying efficiency is improved, so that granulation can be performed more efficiently.
  • the spherical granule obtained by the method for producing a spherical granule of the present invention is the spherical granule of the present invention, and the spherical granule can be suitably used as a spherical granule for preparation. Since the spherical granule has improved friability and granule hardness, the spherical granule is coated with the physiologically active substance on the surface thereof to produce a defective product due to damage of the spherical granule. The rate is also low.
  • the physiologically active substance when the surface is coated with the physiologically active substance or the like to form a preparation, the physiologically active substance can be uniformly dissolved in the body and is suitable for a drug delivery system or the like. It can be a high quality formulation.
  • a preparation using the spherical granule of the present invention there is no particular limitation on the method of preparing a preparation by forming a coating layer containing a physiologically active substance on the surface of the spherical granule.
  • a powder containing a physiologically active substance is supplied while spraying a binding solution to perform coating. It can be carried out under known conditions such as powder coating granulation, spray coating method in which a solution in which a physiologically active substance or binder is dissolved or suspended is sprayed to coat.
  • the component constituting the bioactive substance-containing coating layer is not particularly limited and can be appropriately selected according to the purpose.
  • a pharmaceutical additive or a food additive is used. Also good. These may be used individually by 1 type and may use 2 or more types together.
  • the physiologically active substance is not particularly limited as long as it can be taken orally, and can be appropriately selected according to the purpose.
  • hypnosis / sedation antipyretic analgesic / antiinflammatory agent, neuropsychiatric agent, autonomic nerve Preparations, antiparkinsonian agents, antihistamines, cardiotonic agents, diuretics, antihypertensive agents, vasoconstrictors, arteriosclerotic agents, antitussive expectorants, vitamins, nourishing tonics, antibiotics, gastrointestinals, and the like.
  • the pharmaceutical additive and the food additive are not particularly limited as long as they can be taken orally, and can be appropriately selected according to the purpose.
  • a functional coating layer may be formed in addition to the physiologically active substance-containing coating layer.
  • the functional coating layer is a layer formed for the purpose of controlling the release rate of the physiologically active substance such as sustained release, gastric solubility, entericity, etc., or for the purpose of moisture proofing, light shielding, bitterness and odor masking.
  • the functional coating layer may be formed under known conditions depending on the purpose of the preparation.
  • the component for forming the functional coating layer is not particularly limited as long as it can be taken orally, and examples thereof include natural polymers and synthetic polymers. As described above, various preparations can be obtained.
  • the obtained spherical granule has a minor axis and a major axis, and is a value represented by a ratio of the minor axis / major axis.
  • the ratio of the minor axis / major axis means the ratio between the minor axis and the major axis of the spherical granule, and is a standard indicating the sphericity.
  • the ratio of the minor axis to the major axis is determined by randomly placing the obtained spherical granules on a sample stage, taking a photograph, and measuring the length of the major axis (major axis) of the 50 spherical granules at the midpoint of the major axis.
  • the lengths of the minor axes perpendicular to each other (minor axis) are measured, the ratio of the minor axis to the major axis is determined for each, and the average value of 50 is shown.
  • the evaluation criteria for sphericity are as follows. ⁇ ⁇ ⁇ ⁇ Sphericality 0.90 or more ⁇ ⁇ ⁇ Sphericality 0.85 or more and less than 0.90 ⁇ ⁇ ⁇ ⁇ Sphericality less than 0.85
  • Friction degree (%) (Wt ⁇ Ws) / Wt ⁇ 100 (i)
  • Friction degree (%) (Wt ⁇ Ws) / Wt ⁇ 100 (i)
  • Example 1 Using a composite granulation coating apparatus (Freund Sangyo Co., Ltd., “Spiraflow”, SFC-5), suspensions of the formulations shown in Table 2 below are prepared as core particles (particle size is 150 to 212 ⁇ m).
  • the weight of the sucrose and corn starch in the suspension is 700% by weight with respect to the weight of the granulated sugar crystals (sucrose crystals, manufactured by Shisui Minato Seika Co., Ltd.).
  • Spherical granules were granulated by covering the surface of core particles (granulated sugar crystals).
  • the operating conditions of the composite granulation coating apparatus include a total air volume (floating air flow amount + slit air amount) of 3.4 m 3 / min (80 ° C. setting), a rotor rotational speed of 300 rpm, and a spray air pressure.
  • a total air volume floating air flow amount + slit air amount
  • a rotor rotational speed 300 rpm
  • a spray air pressure 300 rpm
  • the composite granulation coating apparatus includes the granulation chamber described above, and a rotatable rotor is provided in the granulation chamber. Further, the inner wall of the granulation chamber is provided with a spraying device (spray gun) capable of spraying the suspension toward the core particles near and above the outer peripheral edge of the rotor. Yes. In addition, a slight clearance is provided between the outer peripheral edge of the rotor and the inner wall of the granulation chamber, so that slit air can pass through the clearance from below and be introduced into the granulation chamber. Yes. Further, a part of the rotor is a screen that allows ventilation, and floating fluid air can be introduced from this screen portion.
  • a spraying device spray gun
  • the core particles when the core particles are introduced while the rotor is rotated and the slit air is introduced into the granulation chamber, the core particles cause the rolling.
  • the rolling floating flow is generated.
  • the resulting spherical granules have a sphericity of 0.87, a friability of 1.08%, a granule hardness of 169 g, and a yield of about 88 when screened with a particle size of 355 to 500 ⁇ m. %Met.
  • the sphericity, the friability, and the granule hardness were measured and evaluated by the methods described above.
  • the yield is a value calculated by a sieving method.
  • Example 2 After granulating the spherical granules under the same formulation and conditions as in Example 1, the solution of the formulation shown in Table 2 (the surface coating layer forming solution) was further added to the weight of the core particles with respect to the sucrose content in the solution. Spherical granules were granulated in the same manner as in Example 1 except that the surface of the spherical granules was coated (sprayed) to form a coating amount of 50% by weight in terms of solid content.
  • the resulting spherical granule has a sphericity of 0.88, a friability of 0.18%, a granule hardness of 190 g, and a yield of about 88 when screened with a particle size of 355 to 500 ⁇ m. %Met.
  • Example 3 Spherical granules were obtained in the same manner as in Example 1 except that the particle size of granulated sugar as the core particle was changed to 212 to 300 ⁇ m and the coating amount by coating was changed from 700% by weight to 900% by weight. The same evaluation as in Example 1 was performed.
  • the obtained spherical granule has a sphericity of 0.90, a friability of 1.33%, a granule hardness of 345 g, and a yield of about 96 when the particle size is 500 to 710 ⁇ m. %Met.
  • Example 4 In Example 3, after changing the composition of the suspension to the formulation shown in Table 2 and granulating spherical granules in the same manner as in Example 3, the solution having the formulation shown in Table 2 (the surface coating layer forming solution) Except that the surface coating layer is formed by coating (spraying) the surface of the spherical granules so that the coating amount is 50% by weight with respect to the weight of the core particles. Were granulated in the same manner as in Example 3. The resulting spherical granule has a sphericity of 0.90, a friability of 0.45%, a granule hardness of 360 g, and a yield of about 95 when screened with a particle size of 500-710 ⁇ m. %Met.
  • Example 5 In Example 4, a centrifugal tumbling granulation coating apparatus (manufactured by Freund Sangyo Co., Ltd., “Granurex”, GX-40) was used instead of the composite granulation coating apparatus, and the formulation shown in Table 2 Spherical granules were granulated in the same manner as in Example 4 except that the above suspension was used.
  • the operating conditions of the centrifugal rolling granulation coating apparatus are as follows: the total air volume (floating air flow amount + slit air amount) is 2.5 m 3 / min (80 ° C.
  • the obtained spherical granule has a sphericity of 0.91, a friability of 0.49%, a granule hardness of 341 g, and a yield of about 91 when screened with a particle size of 500 to 710 ⁇ m. %Met.
  • the operating conditions of the composite granulation coating apparatus include a total air volume (floating air flow amount + slit air amount) of 3.0 m 3 / min (70 ° C.
  • the spray rate of the liquid was adjusted so that the air pressure was 0.4 MPa and the exhaust temperature was around 43 ° C.
  • the resulting spherical granules have a sphericity of 0.98, a friability of 0.05%, a granule hardness of 42 g, and a yield of about 73 when sieved with a particle size of 150-250 ⁇ m. %Met.
  • the obtained granules were evaluated in the same manner as in Example 1.
  • the operating conditions of the centrifugal flow type coating granulator are as follows: the slit air amount is 0.18 m 3 / min, the rotor rotational speed is 160 rpm, the spray air pressure is 0.1 MPa, and the liquid speed is 5 to 10 mL / min. It was set to min.
  • the amount of the mixed powder applied was adjusted between 20 and 70 g / min.
  • the obtained spherical granules had a sphericity of 0.93, a friability of 1.49%, a granule hardness of 93 g, and a yield when sieved with a particle size of 355 to 500 ⁇ m.
  • the obtained granules were evaluated in the same manner as in Example 1.
  • the operating conditions of the centrifugal flow type coating granulator are as follows: the slit air amount is 0.18 m 3 / min, the rotor rotational speed is 160 rpm, the spray air pressure is 0.1 MPa, and the liquid speed is 5 to 10 mL / min. It was set to min.
  • the amount of the mixed powder applied was adjusted between 20 and 70 g / min.
  • the obtained spherical granule has a sphericity of 0.94, a friability of 1.85%, a granule hardness of 152 g, and a yield when sieved with a particle size of 500 to 710 ⁇ m.
  • the obtained spherical granules were evaluated in the same manner as in Example 1.
  • the operating conditions of the centrifugal flow type coating granulator are as follows: the slit air amount is 0.18 m 3 / min, the rotor rotational speed is 160 rpm, the spray air pressure is 0.1 MPa, and the liquid speed is 5 to 10 mL / min. It was set to min. The amount of the mixed powder applied was adjusted between 20 and 70 g / min.
  • the obtained spherical granule has a sphericity of 0.93, a friability of 0.36%, a granule hardness of 13 g, and a yield when sieved with a particle size of 150 to 250 ⁇ m. Was about 61%.
  • the spherical granule obtained in Example 6 having the same particle size with the spherical granule obtained in Comparative Example 3, the spherical granule obtained in Example 6 is more granular than the spherical granule of Comparative Example 3. An increase in hardness and a decrease in friability were confirmed.
  • the method for producing spherical granules of the present invention while using a method in which only the liquid is sprayed on the core particles composed of crystal grains, the sphericity granules are excellent in friability and granule hardness compared to spherical granules granulated by powder coating. Since a high-quality spherical granule with high sphericity is obtained, the method for producing a spherical granule of the present invention is suitable for producing a spherical granule suitable as a core particle for a preparation used for efficiently producing a high-quality preparation. Can be used.
  • the spherical granule of the present invention is more suitable as a core particle for pharmaceutical preparations used in controlled release preparations and the like because it is superior in friability, granule hardness, high sphericity and high quality than spherical granules granulated by powder coating. Can be used.

Abstract

Provided are spherical granules, which have been improved in abrasiveness and granular hardness each to a sufficiently high level and have a high sphericity and, in the case of being surface-coated with a physiologically active substance or the like and employed in a medicinal preparation, which show an excellent ability to control the release of the physiologically active substance; and a method whereby the above-described spherical granules can be efficiently and conveniently produced. A method of producing spherical granules characterized by comprising while tumbling sugar-containing core grains by rotating a rotary plate that is located horizontally, spraying a liquid containing solid matters onto the core grains without dusting a powdery component. Preferred are a mode wherein the above-described liquid is an aqueous solution or suspension containing a sugar, a mode wherein the above-described core grains contain sugar crystals or spray-dried grains of a sugar, starch of a derivative of the same, and a mode wherein an aqueous solution containing a sugar and/or a sugar alcohol is further sprayed onto the surface of the spherical granules obtained above to thereby form a surface coating layer. Spherical granules characterized by being produced by the above-described method of producing spherical granules.

Description

球形顆粒及びその製造方法Spherical granule and method for producing the same
　本発明は、医薬品等の基材として好適な球形顆粒及びその効率的な製造方法に関する。 The present invention relates to a spherical granule suitable as a base material for pharmaceuticals and the like and an efficient production method thereof.
　従来より、医薬品や食品等の基材として使用される球形顆粒が各種提供されており、その市販品としては、フロイント産業株式会社製「ノンパレル（登録商標）」などが知られている（非特許文献１参照）。前記球形顆粒は、その表面に各種の生理活性物質を被覆した製剤として使用されたり、あるいは更にその表面に機能性コーティング層が形成された製剤、あるいはカプセルに内包された製剤として使用される。この球形顆粒を核粒子に用いて生理活性物質の被覆や機能性コーティング層を形成する場合、該球形顆粒が脆弱なものであると工程中に破損してしまう事がある。そのため、各工程における装置内での加工に耐えうる強度を持った球形顆粒が求められる。また、ドラッグ・デリバリー・システム（ＤＤＳ）に好適な製剤として使用される場合、該生理活性物質の放出性、例えば放出時間を可能な限り正確に制御する観点からは、前記球形顆粒の形状が真球により近い、粒度分布がシャープであることなどが求められる。 Conventionally, various spherical granules used as a base material for pharmaceuticals and foods have been provided, and “Nonparell (registered trademark)” manufactured by Freund Sangyo Co., Ltd. is known as a commercially available product (non-patent) Reference 1). The spherical granule is used as a preparation having a surface coated with various physiologically active substances, or a preparation having a functional coating layer formed on the surface thereof, or a preparation encapsulated in a capsule. When this spherical granule is used as a core particle to form a bioactive substance coating or a functional coating layer, the spherical granule may be damaged during the process if it is brittle. Therefore, a spherical granule having a strength capable of withstanding the processing in the apparatus in each process is required. In addition, when used as a preparation suitable for a drug delivery system (DDS), the shape of the spherical granule is true from the viewpoint of controlling the release of the physiologically active substance, for example, the release time as accurately as possible. It is required to be closer to a sphere and have a sharp particle size distribution.
　前記球形顆粒の製造方法としては、遠心流動造粒装置やオニオン型パンコーティング装置などを用い、前記球形顆粒の核となる粒子（以下「核粒子」という）に、糖を含有する液や粉末等を供給しながら造粒することにより製造する方法が知られている。オニオン型パンコーティング装置により前記球形顆粒を造粒した場合、得られる顆粒の真球度が低く、前記生理活性物質の放出性を制御した製剤に好適な球形顆粒が得られないという問題があった。 As a method for producing the spherical granule, a centrifugal fluid granulating device, an onion type pan coating device, or the like is used, and a liquid or powder containing sugar in particles serving as the core of the spherical granule (hereinafter referred to as “nuclear particle”). A method of producing by granulating while supplying is known. When the spherical granule is granulated by an onion type pan coating apparatus, there is a problem that the obtained granule has a low sphericity and a spherical granule suitable for a preparation with controlled release of the physiologically active substance cannot be obtained. .
　一方、遠心流動造粒装置で前記球形顆粒を造粒した場合、オニオン型パンコーティング装置で造粒した顆粒と比較して真球度の高い顆粒の製造が可能である。より具体的には、遠心流動造粒装置内に、前記核粒子としてグラニュー糖の結晶を仕込み、該核粒子の表面にバインダーとして蔗糖の水溶液を噴霧しつつ、蔗糖の微粒子乃至微粉末を散布することにより、前記グラニュー糖の結晶上に前記蔗糖による被覆層を形成して、球形顆粒を造粒する方法が知られている（特許文献１の段落〔０００４〕参照）。この方法により製造した場合、真球度の高い球形顆粒が得られる。 On the other hand, when the spherical granules are granulated with a centrifugal fluidizing granulator, it is possible to produce granules having a higher sphericity than those granulated with an onion type pan coating apparatus. More specifically, granulated sugar crystals are charged as the core particles in the centrifugal flow granulator, and the sucrose fine particles or fine powder are dispersed while spraying an aqueous solution of sucrose as a binder on the surface of the core particles. Thus, there is known a method of forming spherical granules by forming a coating layer of the sucrose on the granulated sugar crystals (see paragraph [0004] of Patent Document 1). When manufactured by this method, spherical granules with high sphericity can be obtained.
　しかしながら、この製造方法により球形顆粒を造粒する場合、真球度が高い球形顆粒は得られる一方で、顆粒硬度が十分でない場合が多い。さらに、この製造方法により小粒径の球形顆粒を造粒する場合には、造粒中に凝集が発生し易く回収率が低くなるなどの問題がある。近時は、得られる球形顆粒について、その摩損度、顆粒硬度の改善が望まれてきており、球形顆粒の摩損度、硬度の更なる向上が重要な技術的課題となってきている。 However, when a spherical granule is granulated by this production method, a spherical granule having a high sphericity can be obtained, but the granule hardness is often insufficient. Further, when spherical granules having a small particle diameter are granulated by this production method, there is a problem that agglomeration is likely to occur during granulation and the recovery rate is lowered. Recently, it has been desired to improve the friability and granule hardness of the obtained spherical granules, and further improvement of the sphericity and hardness of the spherical granules has become an important technical issue.
特開２００４－６７６７０号公報JP 2004-67670 A
　本発明は、従来における前記問題を解決し、以下の目的を達成することを課題とする。即ち、本発明は、摩損度、顆粒硬度が十分高いレベルに改善され、真球度が高く、その表面に経口摂取可能な生理活性物質等を被覆して製剤に応用した場合に該製剤における該生理活性物質の放出制御性に優れた高品質の球形顆粒、及び、該球形顆粒を効率的かつ簡便に製造することができる方法を提供することを目的とする。 This invention makes it a subject to solve the said problem in the past and to achieve the following objectives. That is, the present invention improves the friability and granule hardness to a sufficiently high level, has a high sphericity, and is coated with a physiologically active substance that can be taken orally on its surface and applied to the formulation. It is an object of the present invention to provide a high-quality spherical granule excellent in the release controllability of a physiologically active substance, and a method capable of efficiently and easily producing the spherical granule.
　前記課題を解決するための手段は、以下の通りである。即ち、
＜１＞　糖を含有する核粒子を水平に設置した回転皿を回転させることにより転動させながら、粉末成分を散布することなく、該核粒子に固形分を含有する液を噴霧して被覆層を形成する工程を含むことを特徴とする球形顆粒の製造方法である。
　該球形粒子の製造方法においては、前記核粒子を転動して造粒するため、得られる球形顆粒は、真球度が高い。また、造粒の際に、前記核粒子が転動しながらその表面に前記液が噴霧され、該液中に溶解乃至分散された糖等による被覆層が該核粒子の表面に形成される。このようにして得られる球形顆粒の真球度は高く、摩損度、顆粒硬度も優れている。
＜２＞　固形分を含有する液が、糖を含有する水溶液乃至懸濁液である前記＜１＞に記載の球形顆粒の製造方法である。
＜３＞　核粒子が、糖の結晶、又は、糖及びデンプン若しくはその誘導体の噴霧乾燥粒子からなる前記＜１＞から＜２＞のいずれかに記載の球形顆粒の製造方法である。
＜４＞　核粒子が、水平に設置した回転皿を回転させることによる転動に加え、転動粒子にエアーを吹き込むことにより浮遊流動される前記＜１＞から＜３＞のいずれかに記載の球形顆粒の製造方法である。
＜５＞　更に、得られた球形顆粒の表面に、糖及び／又は糖アルコールの水溶液を噴霧して表面被覆層を形成することを含む前記＜１＞から＜４＞のいずれかに記載の球形顆粒の製造方法である。
＜６＞　得られる球形顆粒の粒径が、篩い分け法により測定される粒径で７５～１，０００μｍである前記＜１＞から＜５＞のいずれかに記載の球形顆粒の製造方法である。
＜７＞　前記＜１＞から＜６＞のいずれかに記載の球形顆粒の製造方法により製造されることを特徴とする球形顆粒である。
＜８＞　前記＜７＞に記載の球形顆粒の表面に経口摂取可能な生理活性物質を含有する成分を被覆して得られる製剤の製造方法である。 Means for solving the above problems are as follows. That is,
<1> A coating layer is formed by spraying a liquid containing solids on the core particles without spraying the powder component while rolling by rotating a rotating dish in which the core particles containing sugar are horizontally installed. A process for producing spherical granules, comprising the step of forming
In the method for producing spherical particles, since the core particles are rolled and granulated, the obtained spherical granules have a high sphericity. Further, at the time of granulation, the liquid is sprayed on the surface of the core particles while rolling, and a coating layer made of sugar or the like dissolved or dispersed in the liquid is formed on the surface of the core particles. The spherical granules thus obtained have a high sphericity, excellent friability and granule hardness.
<2> The method for producing a spherical granule according to <1>, wherein the liquid containing solid content is an aqueous solution or suspension containing sugar.
<3> The method for producing a spherical granule according to any one of <1> to <2>, wherein the core particles are sugar crystals or spray-dried particles of sugar and starch or a derivative thereof.
<4> The nuclear particles according to any one of <1> to <3>, wherein the core particles are floated and flowed by blowing air into the rolling particles in addition to rolling by rotating a horizontally disposed rotating dish. A method for producing spherical granules.
<5> The spherical shape according to any one of <1> to <4>, further comprising spraying an aqueous solution of sugar and / or sugar alcohol on the surface of the obtained spherical granule to form a surface coating layer. It is a manufacturing method of a granule.
<6> The method for producing a spherical granule according to any one of <1> to <5>, wherein the obtained spherical granule has a particle size of 75 to 1,000 μm as measured by a sieving method. .
<7> A spherical granule produced by the method for producing a spherical granule according to any one of <1> to <6>.
<8> A method for producing a preparation obtained by coating the surface of the spherical granule according to <7> with a component containing a physiologically active substance that can be taken orally.
　本発明によると、従来における前記問題を解決することができ、摩損度、顆粒硬度が十分高いレベルに改善され、その表面に生理活性物質等を被覆して製剤に応用した場合に該製剤における該生理活性物質の放出制御性に優れた高品質の球形顆粒、及び、該球形顆粒を効率的かつ簡便に製造することができる方法を提供することができる。 According to the present invention, the above-mentioned problems in the prior art can be solved, and the friability and granule hardness are improved to a sufficiently high level. It is possible to provide a high-quality spherical granule excellent in the release controllability of a physiologically active substance, and a method capable of efficiently and easily producing the spherical granule.
（球形顆粒及びその製造方法）
　本発明の球形顆粒の製造方法においては、核粒子を水平に設置した回転皿を回転させることにより転動させ、該核粒子に液を噴霧して球形顆粒を造粒する造粒工程を少なくとも含み、更に必要に応じて適宜選択したその他の工程を含む。
　本発明の球形顆粒は、本発明の前記球形顆粒の製造方法により製造される。 (Spherical granules and production method thereof)
The method for producing a spherical granule of the present invention includes at least a granulation step in which a spherical granule is granulated by rotating by rotating a rotating dish in which the core particles are horizontally installed and spraying a liquid on the core particles. In addition, other processes appropriately selected as necessary are included.
The spherical granules of the present invention are produced by the method for producing spherical granules of the present invention.
＜造粒工程＞
　前記造粒工程は、前記核粒子を水平に設置した回転皿を回転させることにより転動させ、該核粒子に粉末成分を散布することなく、該核粒子に固形分を含有する液を噴霧して被覆層を形成することにより球形顆粒を造粒する工程である。 <Granulation process>
The granulation step rolls by rotating a rotating dish in which the core particles are horizontally installed, and sprays a liquid containing solids on the core particles without spraying powder components on the core particles. In this step, spherical granules are formed by forming a coating layer.
－核粒子－
　前記核粒子としては、前記球形顆粒の用途、目的に応じて適宜選択することができ、公知のものの中から適宜選択することができるが、本発明においては、少なくとも糖を含有していればよく、糖以外にその他の成分を含有していてもよい。
　前記核粒子としては、市販の結晶粒や造粒物をそのまま使用してもよいし、該結晶粒を研磨、粉砕等して使用してもよいし、粉末等を造粒して得たものを使用してもよい。
　前記核粒子の形状としては、特に制限はなく、目的に応じて適宜選択することができるが、真球度の高い前記顆粒を得る観点からは、立方に近い形や球状である方が好ましい。 -Nuclear particles-
The core particle can be appropriately selected according to the use and purpose of the spherical granule, and can be appropriately selected from known ones. In the present invention, it only needs to contain at least a sugar. In addition to sugar, other components may be contained.
As the core particle, a commercially available crystal grain or granulated product may be used as it is, or the crystal grain may be used after being polished, pulverized, or obtained by granulating a powder or the like. May be used.
There is no restriction | limiting in particular as a shape of the said core particle, Although it can select suitably according to the objective, From the viewpoint of obtaining the said granule with high sphericity, the shape close | similar to a cube or a spherical shape is preferable.
　前記核粒子の粒径としては、特に制限はなく、前記球形顆粒の用途、目的等に応じて適宜選択することができ、例えば、篩い分け法により測定される粒径が、５０～８５０μｍが好ましく、７５～５００μｍがより好ましい。
　前記核粒子の粒径が８５０μｍを超えると、得られる球形顆粒の粒径が１，０００μｍ程度、あるいはそれ以上の粒径となるため、製剤化した際に製剤の服用感が悪くなるなどの問題が生じやすくなる。また、５０μｍ未満であると、球形顆粒を造粒する際や得られた球形顆粒の表面に被覆層を形成する際に凝集を起こし易くなることがある。 The particle size of the core particle is not particularly limited and can be appropriately selected depending on the use and purpose of the spherical granule. For example, the particle size measured by a sieving method is preferably 50 to 850 μm. 75 to 500 μm is more preferable.
When the particle size of the core particles exceeds 850 μm, the spherical particles obtained have a particle size of about 1,000 μm or more. Is likely to occur. Moreover, when it is less than 50 μm, aggregation may easily occur when spherical granules are formed or when a coating layer is formed on the surface of the obtained spherical granules.
　前記糖としては、特に制限はなく、公知のものの中から適宜選択することができ、例えば、ブドウ糖、果糖、蔗糖、乳糖、麦芽糖などが挙げられる。これらは、核粒子を造粒して調製する場合には１種単独で使用してもよいし、２種以上を併用してもよい。結晶粒をそのまま核粒子として用いる場合には、得られた球形顆粒の組成の均一性を高める面で、1種単独で使用するのが好ましい。
　前記その他の成分としては、経口摂取可能なものであれば特に制限はなく、目的に応じて適宜選択することができ、例えば糖アルコール、有機酸及びその塩、無機物、デンプン及びその誘導体、セルロース及びセルロース誘導体、合成高分子などが挙げられる。但し、本発明では生理活性物質をその他の成分として用いない。これらは、１種単独で使用してもよいし、２種以上を併用してもよい。これらの使用法は特に制限は無いが、前述の糖と共に造粒する、糖の結晶粒に該成分をコーティングするなどの手法が挙げられる。
　前記糖アルコールとしては、例えば、マンニトール、キシリトール、エリスリトールなどが挙げられる。前記有機酸としては、例えば、クエン酸、酒石酸、アスコルビン酸などが挙げられる。該有機酸の塩としては、例えば、ナトリウム塩、カルシウム塩、カリウム塩などが挙げられる。前記無機物としては、例えば、食塩、酸化チタン、二酸化ケイ素などが挙げられる。前記デンプン及びその誘導体としては、例えば、コーンスターチ、コムギデンプン、コメデンプン、これらの誘導体などが挙げられる。前記セルロース及びセルロース誘導体としては、例えば、結晶セルロース、粉末セルロース、メチルセルロース、エチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルメチルセルロースアセテートサクシネートなどが挙げられる。前記合成高分子としては、ポリビニルピロリドン、ポリ(メタ)アクリル酸及びそのエステル、ポリビニルアルコール及びその誘導体などが挙げられる。
　本発明では蔗糖の結晶であるグラニュー糖を使用することがより好ましい。また、造粒した粒子を使用する場合は、噴霧乾燥造粒により得られる粒子は球形に近いため好ましく、糖及びデンプン若しくはその誘導体を噴霧乾燥した粒子であることがより好ましい。 There is no restriction | limiting in particular as said sugar, It can select suitably from well-known things, For example, glucose, fructose, sucrose, lactose, maltose etc. are mentioned. These may be used alone or in combination of two or more in the case of preparing by granulating the core particles. When crystal grains are used as core particles as they are, it is preferable to use one kind alone in terms of improving the uniformity of the composition of the obtained spherical granules.
The other components are not particularly limited as long as they can be taken orally, and can be appropriately selected according to the purpose. Examples thereof include sugar alcohols, organic acids and salts thereof, inorganic substances, starches and derivatives thereof, celluloses and the like. Examples thereof include cellulose derivatives and synthetic polymers. However, in the present invention, physiologically active substances are not used as other components. These may be used individually by 1 type and may use 2 or more types together. There are no particular restrictions on how to use them, and examples thereof include a method of granulating together with the above-mentioned sugar and coating the component on sugar crystal grains.
Examples of the sugar alcohol include mannitol, xylitol, erythritol, and the like. Examples of the organic acid include citric acid, tartaric acid, ascorbic acid, and the like. Examples of the salt of the organic acid include sodium salt, calcium salt, potassium salt and the like. As said inorganic substance, salt, a titanium oxide, silicon dioxide etc. are mentioned, for example. Examples of the starch and derivatives thereof include corn starch, wheat starch, rice starch, and derivatives thereof. Examples of the cellulose and cellulose derivative include crystalline cellulose, powdered cellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, and the like. Examples of the synthetic polymer include polyvinyl pyrrolidone, poly (meth) acrylic acid and esters thereof, polyvinyl alcohol and derivatives thereof.
In the present invention, it is more preferable to use granulated sugar which is a sucrose crystal. When granulated particles are used, the particles obtained by spray-drying granulation are preferable because they are nearly spherical, and more preferably particles obtained by spray-drying sugar and starch or derivatives thereof.
－固形分を含有する液－
　前記固形分を含有する液としては、前記球形顆粒の用途、目的に応じて適宜選択することができ、公知のものの中から適宜選択することができるが、本発明においては、糖を含有する水溶液乃至懸濁液が挙げられる。
　前記糖としては、特に制限はなく、目的に応じて適宜選択することができ、上述したものなどが好適に挙げられ、蔗糖が特に好適に挙げられる。該糖としては、１種単独で使用してもよいし、２種以上を併用してもよい。該糖の種類によっては、バインダー効果を有するため、前記核粒子の表面で被覆層を形成した際、該被覆層と前記核粒子との接着強度に優れる。 -Liquid containing solids-
The liquid containing the solid content can be appropriately selected according to the use and purpose of the spherical granule, and can be appropriately selected from known ones. In the present invention, the aqueous solution containing sugar Or suspension.
There is no restriction | limiting in particular as said sugar, According to the objective, it can select suitably, What was mentioned above etc. is mentioned suitably, and sucrose is mentioned especially suitably. As this sugar, 1 type may be used individually and 2 or more types may be used together. Depending on the kind of the sugar, since it has a binder effect, when the coating layer is formed on the surface of the core particle, the adhesive strength between the coating layer and the core particle is excellent.
　前記固形分を含有する液における前記糖の含有量としては、特に制限はなく、糖の溶解度に応じた濃度に調製すればよい。例えば蔗糖の場合では、２０～６０重量％が好ましい。前記糖の含有量が、２０重量％未満であると、液を噴霧する工程時間の延長による製造効率の低下が想定され、６０重量％を超えると、蔗糖の持つバインダー効果により凝集発生を生じることがある。また、糖は液中で全量溶解しているのが好ましい。 The content of the sugar in the liquid containing the solid content is not particularly limited, and may be adjusted to a concentration according to the solubility of the sugar. For example, in the case of sucrose, 20 to 60% by weight is preferable. If the sugar content is less than 20% by weight, it is assumed that the production efficiency is lowered due to the extension of the process time for spraying the liquid, and if it exceeds 60% by weight, aggregation occurs due to the binder effect of sucrose. There is. Moreover, it is preferable that the whole amount of sugar is dissolved in the liquid.
　前記固形分を含有する液に含有される前記糖以外の添加成分としては、経口摂取可能なものであれば特に制限はなく、糖アルコール、有機酸及びその塩、無機物、デンプン及びその誘導体、セルロース誘導体、合成高分子などが挙げられる。前記糖アルコール、前記有機酸及びその塩、前記デンプン及びその誘導体、前記セルロース及びセルロース誘導体、前記合成高分子としては、上述したものと同様のものが挙げられる。但し、本発明では、生理活性物質は固形分として含有されない。
　なお、前記添加成分が溶媒に対して溶解性の場合には、該液は水溶液となり、不溶性乃至難溶性の場合には、該液は懸濁液となる。
　前記固形分を含有する液における前記添加成分の含有量としては、特に制限はなく、粘度、噴霧性等を考慮して目的に応じて適宜選択することができる。懸濁液の場合、分散質の含有量は３０重量％以下が好ましく、２０重量％以下がより好ましい。前記添加成分の含有量が、３０重量％を超えると、添加する成分の性質にもよるが粘度が高くなり、噴霧性が悪くなったり、凝集が発生し易くなったりすることがある。 The additive component other than the sugar contained in the liquid containing the solid content is not particularly limited as long as it can be taken orally, sugar alcohol, organic acid and salt thereof, inorganic substance, starch and derivative thereof, cellulose. Examples thereof include derivatives and synthetic polymers. Examples of the sugar alcohol, the organic acid and salt thereof, the starch and derivative thereof, the cellulose and cellulose derivative, and the synthetic polymer include those described above. However, in the present invention, the physiologically active substance is not contained as a solid content.
When the additive component is soluble in the solvent, the liquid becomes an aqueous solution, and when it is insoluble or hardly soluble, the liquid becomes a suspension.
There is no restriction | limiting in particular as content of the said additional component in the liquid containing the said solid content, It can select suitably according to the objective in consideration of a viscosity, sprayability, etc. In the case of a suspension, the content of the dispersoid is preferably 30% by weight or less, and more preferably 20% by weight or less. If the content of the additive component exceeds 30% by weight, the viscosity may be high, depending on the properties of the component to be added, and sprayability may be deteriorated or aggregation may easily occur.
　前記液に含有される溶媒としては、水が好適に挙げられる。前記液における水の含有量としては、特に制限はなく、目的に応じて適宜選択することができる。 Favorable examples of the solvent contained in the liquid include water. There is no restriction | limiting in particular as content of the water in the said liquid, According to the objective, it can select suitably.
　また、前記固形分を含有する液に含有される溶媒としては、水以外に、本発明の目的を害さない範囲で、有機溶媒などを含有していてもよい。前記有機溶媒としては、例えば、エタノール等のアルコールなどが好適に挙げられる。前記液が前記有機溶媒を含有していると、溶解性の向上、乾燥時間の短縮が可能となる場合がある。
　前記固形分を含有する液における前記有機溶媒の含有量としては、特に制限はなく、目的に応じて適宜選択することができる。 Moreover, as a solvent contained in the liquid containing the said solid content, the organic solvent etc. may be contained in the range which does not injure the objective of this invention other than water. As said organic solvent, alcohol, such as ethanol, etc. are mentioned suitably, for example. If the liquid contains the organic solvent, the solubility may be improved and the drying time may be shortened.
There is no restriction | limiting in particular as content of the said organic solvent in the liquid containing the said solid content, According to the objective, it can select suitably.
　前記固形分を含有する液の調製方法としては、特に制限はなく、目的に応じて公知の方法に従って調製することができ、例えば、前記糖、前記糖以外の添加成分を水、あるいは必要に応じて選択した前記有機溶媒と混合し、攪拌等する方法などが挙げられる。 The method for preparing the liquid containing the solid content is not particularly limited, and can be prepared according to a known method according to the purpose. For example, the sugar, additional components other than the sugar are added to water, or as necessary. And a method of mixing with the organic solvent selected above and stirring.
－噴霧－
　前記固形分を含有する液の前記核粒子への噴霧の方法としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、使用する造粒装置に設けられた噴霧手段、例えば、スプレーガン、噴霧ノズル等から噴霧する方法などが好適に挙げられる。
　なお、このとき、前記噴霧の条件としては、特に制限はなく、公知の条件を採用することができ、目的に応じてその噴霧量、噴霧する霧粒子（ミスト）の大きさ、噴霧時間などを適宜選択することができる。前記噴霧にスプレーガン等を使用する場合、そのスプレー空気圧としては、例えば、０．１ＭＰａ～０．５ＭＰａ程度が好ましい。
　前記造粒装置としては、本発明においては、前記核粒子を転動させることができるものであれば特に制限はなく、公知のものの中から目的に応じて適宜選択することができるが、例えば、遠心流動型コーティング造粒装置（例えばフロイント産業（株）製「ＣＦグラニュレーター」など）、複合型造粒コーティング装置（例えばフロイント産業（株）製「スパイラフロー」など）、遠心転動造粒コーティング装置（例えば、フロイント産業（株）製「グラニュレックス」など）、などが好適に挙げられる。 -Spraying-
The method for spraying the liquid containing the solid content onto the core particles is not particularly limited and can be appropriately selected depending on the purpose. For example, spray means provided in the granulating apparatus to be used, for example, A method of spraying from a spray gun, a spray nozzle or the like is preferable.
At this time, the spraying conditions are not particularly limited, and publicly known conditions can be adopted. The spraying amount, the size of sprayed mist particles (mist), the spraying time, and the like are determined according to the purpose. It can be selected appropriately. When a spray gun or the like is used for the spraying, the spray air pressure is preferably about 0.1 MPa to 0.5 MPa, for example.
The granulator is not particularly limited as long as it can roll the core particles in the present invention, and can be appropriately selected from known ones according to the purpose. Centrifugal flow type coating granulator (for example, “CF Granulator” manufactured by Freund Sangyo Co., Ltd.), composite type granulating coating device (for example, “Spiraflow” manufactured by Freund Sangyo Co., Ltd.), centrifugal rolling granulation coating A device (for example, “Granurex” manufactured by Freund Sangyo Co., Ltd.) and the like are preferable.
　なお、従来の球形顆粒の造粒方法では、前記噴霧の際に、前記核粒子に対して、粉末散布装置から前記糖等の粉末を散布することが一般的に行われている。しかし、本発明者が鋭意検討したところ、前記粉末の散布を行うと、摩損度、顆粒硬度の向上が十分に図れないことを見出した結果、本発明においては、摩損度、顆粒硬度が十分高いレベルに改善された高品質の球形顆粒を得る目的で、前記散布の際に、前記核粒子に対し前記粉末を散布することは行わない。 In addition, in the conventional granulation method for spherical granules, it is generally performed that the powder such as sugar is sprayed from a powder spraying device to the core particles during the spraying. However, as a result of intensive studies by the present inventors, it was found that when the powder was dispersed, the friability and granule hardness could not be sufficiently improved. As a result, in the present invention, the friability and granule hardness were sufficiently high. In order to obtain high-quality spherical granules with improved levels, the powder is not applied to the core particles during the application.
－転動－
　本発明において、前記転動は、「遠心流動」や「遠心転動」とも称され、円筒状の固定壁（ステーター）の内側に水平に設置された回転皿（ローター）が回転し、ステーターとローターの間に一定に設けられたクリアランスから供給されるスリットエアーを導入しながら、前記核粒子が該ローター上を転がり動くことを意味する。該転動により、前記核粒子はその表面に前記固形分を含有する液による被覆層が形成されつつ球形に成形される。
　前記転動の方法としては、特に制限はなく、回転可能なローター及びステーターを備えた公知の造粒装置を用いる方法などが好適に挙げられる。前記造粒装置としては、特に制限はなく、目的に応じて適宜選択することができるが、例えば、遠心流動型コーティング造粒装置（例えばフロイント産業（株）製「ＣＦグラニュレーター」など）、複合型造粒コーティング装置（例えばフロイント産業（株）製「スパイラフロー」など）、遠心転動造粒コーティング装置（例えば、フロイント産業（株）製「グラニュレックス」など）、などが好適に挙げられる。
　前記転動の条件としては、特に制限はなく、目的に応じて適宜選択することができるが、前記ローターの回転数としては、装置径の違いにより設定に差はあるが５０～１，０００ｒｐｍ程度が好ましい。また、前記転動の際の温度としては、特に制限はなく、前記核粒子の種類、前記液の組成等に応じて適宜選択することができるが、製品温度として２０～５０℃程度が好ましい。 -Rolling-
In the present invention, the rolling is also referred to as “centrifugal flow” or “centrifugal rolling”, and a rotating plate (rotor) installed horizontally inside a cylindrical fixed wall (stator) rotates, It means that the core particles roll on the rotor while introducing slit air supplied from a constant clearance provided between the rotors. By the rolling, the core particles are formed into a spherical shape while a coating layer made of the liquid containing the solid content is formed on the surface thereof.
There is no restriction | limiting in particular as the method of the said rolling, The method of using the well-known granulator provided with the rotor and stator which can rotate etc. is mentioned suitably. The granulator is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a centrifugal flow type coating granulator (for example, “CF Granulator” manufactured by Freund Sangyo Co., Ltd.), a composite Preferred examples include a mold granulation coating apparatus (for example, “Spiraflow” manufactured by Freund Sangyo Co., Ltd.), a centrifugal rolling granulation coating apparatus (for example, “Granurex” manufactured by Freund Sangyo Co., Ltd.), and the like.
The rolling condition is not particularly limited and may be appropriately selected depending on the purpose. However, the rotational speed of the rotor may vary depending on the apparatus diameter, but may vary depending on the device diameter, but may be about 50 to 1,000 rpm. Is preferred. The temperature at the time of rolling is not particularly limited and may be appropriately selected depending on the kind of the core particles, the composition of the liquid, and the like, but the product temperature is preferably about 20 to 50 ° C.
－浮遊流動－
　本発明において、前記核粒子を転動させて造粒を行う際に、更に、前記核粒子が転動している状態にエアーを吹き込むことにより浮遊流動させること（以下、「転動」と「浮遊流動」とを組み合わせた状態のことを「転動浮遊流動」という）が好ましい。前記転動に加えて、前記浮遊流動を組み合わせた転動浮遊流動を行うと、乾燥効率が高くなるため作業効率が向上するなどの利点が得られる。
　前記転動に加えて前記浮遊流動を生じさせるためには、スリットエアーとは別経路からのエアー（浮遊流動エアー）の導入が必要となる。例えば、核粒子は通過できないがエアーは通過できるスクリーンを回転皿に設け、回転皿下方から転動粒子に向けてエアーを吹き込むことにより浮遊流動エアーを導入したり、回転皿上方より回転皿近傍に設けられた管状のエアー供給手段により転動粒子に向けて浮遊流動エアーを導入したりすることができる。スリットエアー及び浮遊流動エアーの風量は、装置の容量などの目的に応じて適宜選択することができる。 -Floating flow-
In the present invention, when granulation is performed by rolling the core particles, the core particles are further floated by blowing air into a state where the core particles are rolling (hereinafter referred to as “rolling” and “rolling”). A state in which “floating flow” is combined is referred to as “rolling floating flow”). In addition to the rolling, when rolling floating flow combining the floating flow is performed, advantages such as improvement in work efficiency can be obtained because drying efficiency is increased.
In order to generate the floating flow in addition to the rolling, it is necessary to introduce air (floating flowing air) from a different path from the slit air. For example, a screen that does not allow the passage of nuclear particles but allows air to pass through is provided on the rotating dish, and floating air is introduced by blowing air toward the rolling particles from below the rotating dish, or near the rotating dish from above the rotating dish. Floating fluid air can be introduced toward the rolling particles by the provided tubular air supply means. The air volume of the slit air and the floating fluid air can be appropriately selected according to the purpose such as the capacity of the apparatus.
　前記転動浮遊流動の方法としては、特に制限はなく、回転可能なローター及びスリットエアーと浮遊流動エアー経路を備えた公知の造粒装置を用いる方法などが好適に挙げられる。前記造粒装置としては、特に制限はなく、目的に応じて適宜選択することができるが、例えば、複合型造粒コーティング装置（例えばフロイント産業（株）製「スパイラフロー」など）、遠心転動造粒コーティング装置（例えば、フロイント産業（株）製「グラニュレックス」など）、などが好適に挙げられる。 The rolling floating flow method is not particularly limited, and a method using a known granulator equipped with a rotatable rotor and slit air and a floating flow air path is preferable. The granulator is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a composite granulation coating apparatus (for example, “Spiraflow” manufactured by Freund Sangyo Co., Ltd.), centrifugal rolling, etc. A granulating and coating apparatus (for example, “Granurex” manufactured by Freund Sangyo Co., Ltd.) and the like are preferable.
－球形顆粒－
　以上の造粒工程により、前記核粒子の表面に前記固形分を含有する液による被覆層が形成されて本発明の球形顆粒が造粒される。
　前記被覆層の被覆量としては、特に制限はなく、前記球形顆粒の用途、目的等に応じて適宜選択することができるが、例えば、前記核粒子に対する前記液中に含有される前記糖等の固形分の割合で、５０～１，５００重量％程度が好ましく、１００～１，０００重量％程度がより好ましい。 -Spherical granules-
Through the above granulation step, a coating layer made of the liquid containing the solid content is formed on the surface of the core particles, and the spherical granules of the present invention are granulated.
The coating amount of the coating layer is not particularly limited and can be appropriately selected according to the use and purpose of the spherical granule. For example, the sugar contained in the liquid with respect to the core particles The solid content is preferably about 50 to 1,500% by weight, more preferably about 100 to 1,000% by weight.
　前記球形顆粒の粒径としては、特に制限はなく、該球形顆粒の用途、目的等に応じて適宜選択することができ、例えば、篩い分け法により測定される粒径が、７５～１，０００μｍが好ましく、１５０～８５０μｍがより好ましい。
　前記球形顆粒の粒径が１，０００μｍを超えると、得られた球形顆粒を用いて製剤化した際に製剤の服用感が悪くなるなどの問題が生じやすくなることがあり、対して７５μｍ未満であると、製剤化の際に凝集を起こし易くなることがある。
　こうして得られた球形顆粒の真球度としては、０．８５以上が好ましく、０．９０以上がより好ましい。前記真球度が、０．８５未満であると、該球形顆粒を製剤用核粒子として使用した場合に、該製剤における前記生理活性物質の体内での溶解性が均一ではなく、ドラッグ・デリバリー・システム適用の製剤としての品質が不十分となることがある。一方、０．８５以上であると、該球形顆粒の表面に、生理活性物質等を含有する被覆層を形成した際、該生理活性物質を均一にコートすることができ、該生理活性物質の放出速度をより正確に制御できる点で有利である。 The particle size of the spherical granule is not particularly limited and can be appropriately selected depending on the use and purpose of the spherical granule. For example, the particle size measured by a sieving method is 75 to 1,000 μm. It is preferably 150 to 850 μm.
When the particle diameter of the spherical granule exceeds 1,000 μm, there are cases where problems such as a poor feeling of taking of the preparation are likely to occur when formulated using the obtained spherical granule, whereas the particle diameter is less than 75 μm. When it exists, it may become easy to raise | generate aggregation in the case of formulation.
The sphericity of the spherical granules thus obtained is preferably 0.85 or more, more preferably 0.90 or more. When the sphericity is less than 0.85, when the spherical granule is used as a core particle for a preparation, the solubility of the physiologically active substance in the preparation in the body is not uniform, and the drug delivery Quality as a system-applied formulation may be insufficient. On the other hand, when it is 0.85 or more, when a coating layer containing a physiologically active substance or the like is formed on the surface of the spherical granule, the physiologically active substance can be uniformly coated and the release of the physiologically active substance This is advantageous in that the speed can be controlled more accurately.
　前記球形顆粒は、前記核粒子を転動して造粒されるため、真球度が高い。また、該造粒の際に、前記液を噴霧して該液中に溶解乃至分散された糖等の成分が該核粒子の表面に被覆層を形成するため、該球形顆粒は、摩損度が低く、顆粒硬度が高い。 The spherical granules have high sphericity because they are granulated by rolling the core particles. In addition, during the granulation, the liquid is sprayed and components such as sugar dissolved or dispersed in the liquid form a coating layer on the surface of the core particles, so that the spherical granules have a friability. Low and high granule hardness.
＜その他の工程＞
　前記その他の工程としては、特に制限はなく、目的に応じて適宜選択することができるが、例えば、表面被覆層形成工程などが好適に挙げられる。
　前記表面被覆層形成工程は、前記造粒工程において得られた前記球形顆粒の表面に表面被覆層を形成する工程である。本発明の球形顆粒は、前記表面被覆層が形成されていないものであってもよいし、該表面被覆層が形成されたものであってもよい。該表面被覆層が形成された前記球形顆粒は、該表面被覆層が形成されていない場合に比し、一般的にはその摩損度、顆粒硬度等が良化する。 <Other processes>
There is no restriction | limiting in particular as said other process, Although it can select suitably according to the objective, For example, a surface coating layer formation process etc. are mentioned suitably.
The surface coating layer forming step is a step of forming a surface coating layer on the surface of the spherical granule obtained in the granulation step. The spherical granule of the present invention may be one in which the surface coating layer is not formed, or one in which the surface coating layer is formed. In general, the spherical granules having the surface coating layer are improved in their friability, granule hardness, and the like as compared with the case where the surface coating layer is not formed.
　前記表面被覆層の形成方法としては特に制限はなく、目的に応じて適宜選択することができ、例えば、前記造粒工程と同様に、上述した造粒装置を用い、適宜選択した条件にて、表面被覆層形成液を噴霧することにより行う方法などが挙げられる。なお、前記表面被覆層形成液としては、特に制限はなく、目的に応じて適宜選択することができるが、上述した前記固形分を含有する液と同様のものが好適に挙げられる。
　なお、本発明においては、前記液としては、水溶液、懸濁液のいずれであってもよいが、前記表面被覆層形成液としては、得られる球形顆粒の摩損度、顆粒硬度の向上等の観点からは、懸濁液よりも水溶液の方が好ましい。
　本発明では、特に前記糖及び／又は糖アルコールの水溶液であることが好ましい。 The method for forming the surface coating layer is not particularly limited and can be appropriately selected according to the purpose. For example, in the same manner as the granulation step, using the above-described granulation apparatus, under appropriately selected conditions, The method etc. which are performed by spraying a surface coating layer forming liquid are mentioned. In addition, there is no restriction | limiting in particular as said surface coating layer forming liquid, Although it can select suitably according to the objective, The thing similar to the liquid containing the said solid content mentioned above is mentioned suitably.
In the present invention, the liquid may be either an aqueous solution or a suspension. However, the surface coating layer forming liquid may be used in terms of the degree of friability of the resulting spherical granules, improvement in granule hardness, and the like. From an aqueous solution is preferred over a suspension.
In the present invention, an aqueous solution of the sugar and / or sugar alcohol is particularly preferable.
　前記表面被覆層の被覆量としては、特に制限はなく、前記球形顆粒の用途、目的等に応じて適宜選択することができるが、例えば、前記核粒子に対する前記表面被覆層形成液中に含有される前記糖等の固形分の割合で、１～２００重量％程度が好ましく、１０～１００重量％程度がより好ましい。 The coating amount of the surface coating layer is not particularly limited and can be appropriately selected depending on the use and purpose of the spherical granule. For example, it is contained in the surface coating layer forming liquid for the core particles. The ratio of the solids such as sugar is preferably about 1 to 200% by weight, more preferably about 10 to 100% by weight.
＜球形顆粒の製造例＞
　ここで、前記球形顆粒（前記核粒子の表面に前記被覆層が形成されたもの）、乃至、前記表面被覆層が形成された前記球形顆粒の製造例として、例えば、遠心転動造粒コーティング装置を用いた場合について以下に説明する。 <Examples of spherical granules>
Here, as an example of manufacturing the spherical granule (with the coating layer formed on the surface of the core particle) or the spherical granule having the surface coating layer formed thereon, for example, a centrifugal rolling granulation coating apparatus The case where is used will be described below.
　前記遠心転動造粒コーティング装置「グラニュレックス」（フロイント産業株式会社製）は、前記核粒子を転動させながら球形顆粒に造粒可能な造粒室を備える。
　前記造粒室は、設置面に水平な断面形状が円形の空間を有しており、該空間内に、前記設置面に対し水平に皿面が設置され、回転可能な円形の回転皿（ローター）を備えてなる。なお、前記ローターは、その外周縁部が徐々に上方に傾斜した形状となっていて、回転軸を中心に回転されると、その皿面上で前記核粒子を転動可能である。
　該造粒室においては、前記ローターの外周端と該造粒室の内壁との間に所定のクリアランスが形成されている。また、前記造粒室の内部には、前記空間内の温度を測定するための熱電対などの温度計が備えられている。 The centrifugal rolling granulation coating apparatus “Granurex” (manufactured by Freund Sangyo Co., Ltd.) includes a granulation chamber capable of granulating spherical granules while rolling the core particles.
The granulation chamber has a space having a circular cross section on the installation surface, and a circular rotating plate (rotor) in which the plate surface is installed horizontally with respect to the installation surface in the space. ). The rotor has a shape in which the outer peripheral edge portion is gradually inclined upward. When the rotor is rotated around the rotation axis, the core particles can roll on the dish surface.
In the granulation chamber, a predetermined clearance is formed between the outer peripheral end of the rotor and the inner wall of the granulation chamber. The granulation chamber is provided with a thermometer such as a thermocouple for measuring the temperature in the space.
　前記造粒室には、噴霧装置も設けられており、前記核粒子の表面の前記被覆層を形成するための前記液を、前記造粒室の内部に噴霧可能になっている。なお、前記噴霧装置は、前記ローターの上方であって、かつその外周縁部近傍に設けられており、前記液を送液するための管及びポンプと、該液を前記空間内に噴霧可能なスプレーノズルとを備える。
　また、前記造粒室においては、前記ローターの下方にエアチャンバが形成されていて、該エアチャンバ内に空気を圧送可能になっており、前記クリアランス部分から前記造粒室の内部（前記空間内）にスリットエアーが導入可能になっている。 The granulation chamber is also provided with a spraying device so that the liquid for forming the coating layer on the surface of the core particles can be sprayed into the granulation chamber. The spraying device is provided above the rotor and in the vicinity of the outer peripheral edge thereof, and a pipe and a pump for feeding the liquid, and the liquid can be sprayed into the space. A spray nozzle.
Further, in the granulation chamber, an air chamber is formed below the rotor, and air can be pumped into the air chamber, and the inside of the granulation chamber (inside the space) from the clearance portion. ) Slit air can be introduced.
　この遠心転動造粒コーティング装置において、前記ローターを回転させてスリットエアーを導入した状態で前記核粒子を投入すると、前記核粒子が転動する。次に前記被覆層を形成するための前記固形分を含有する液を噴霧すると、前記核粒子の表面が前記固形分を含有する液に含まれる前記糖等の成分で被覆され、球形顆粒となる。こうして得られた球形顆粒は、前記遠心転動コーティング装置から取り出し、流動層装置などの装置に移し変えて、更に乾燥工程等を行うこともできるが、前記グラニュレックスでは自動昇降式の給気システムを造粒室内に有しており、転動している粒子内にエアーを送り込むことにより、粒子を転動浮遊流動させることが可能となる。よって造粒中にこの浮遊流動エアーを導入することにより乾燥効率が向上するため、さらに効率よく造粒が可能となる。 In this centrifugal rolling granulation coating apparatus, when the core particles are introduced while the rotor is rotated and slit air is introduced, the core particles roll. Next, when the liquid containing the solid content for forming the coating layer is sprayed, the surface of the core particles is coated with the components such as the sugar contained in the liquid containing the solid content to form spherical granules. . The spherical granules obtained in this way can be taken out from the centrifugal rolling coating device and transferred to a fluidized bed device or the like, and further subjected to a drying process, etc. In the granulation chamber, the particles can be rolled and floated by feeding air into the rolling particles. Therefore, since this floating fluidized air is introduced during granulation, the drying efficiency is improved, so that granulation can be performed more efficiently.
　以上、本発明の球形顆粒の製造方法により得られた球形顆粒が本発明の球形顆粒であり、該球形顆粒は、製剤用球形顆粒として好適に使用することができる。該球形顆粒は、その摩損度及び顆粒硬度が良化されているので、該球形顆粒の表面に前記生理活性物質を被覆して製剤化する際に、前記球形顆粒の破損等による不良品の発生率も低くなる。また該球形顆粒は真球度が高いので、その表面に前記生理活性物質等を被覆して製剤とすると、該生理活性物質が均一に体内で溶解可能となり、ドラッグ・デリバリー・システム等に好適な高品質の製剤とすることができる。 As described above, the spherical granule obtained by the method for producing a spherical granule of the present invention is the spherical granule of the present invention, and the spherical granule can be suitably used as a spherical granule for preparation. Since the spherical granule has improved friability and granule hardness, the spherical granule is coated with the physiologically active substance on the surface thereof to produce a defective product due to damage of the spherical granule. The rate is also low. Further, since the spherical granules have a high sphericity, when the surface is coated with the physiologically active substance or the like to form a preparation, the physiologically active substance can be uniformly dissolved in the body and is suitable for a drug delivery system or the like. It can be a high quality formulation.
＜本発明の球形顆粒を用いた製剤の製造＞
　前記球形顆粒の表面に、生理活性物質含有被覆層を形成して製剤とする方法としては特に制限はなく、例えば、結合液を噴霧しながら生理活性物質を含有する粉末を供給して被覆を行う粉末被覆造粒や、生理活性物質や結合剤を溶解乃至懸濁させた液を噴霧して被覆するスプレーコーティング法などの公知の条件にて行うことができる。
　前記生理活性物質含有被覆層を構成する成分としては特に制限はなく、目的に応じて適宜選択することができ、経口摂取可能な生理活性物質に加えて医薬品添加物や食品添加物などを用いてもよい。これらは、１種単独で使用してもよいし、２種以上を併用してもよい。 <Manufacture of a preparation using the spherical granule of the present invention>
There is no particular limitation on the method of preparing a preparation by forming a coating layer containing a physiologically active substance on the surface of the spherical granule. For example, a powder containing a physiologically active substance is supplied while spraying a binding solution to perform coating. It can be carried out under known conditions such as powder coating granulation, spray coating method in which a solution in which a physiologically active substance or binder is dissolved or suspended is sprayed to coat.
The component constituting the bioactive substance-containing coating layer is not particularly limited and can be appropriately selected according to the purpose. In addition to a bioactive substance that can be taken orally, a pharmaceutical additive or a food additive is used. Also good. These may be used individually by 1 type and may use 2 or more types together.
　前記生理活性物質としては、経口摂取可能なものであれば特に制限はなく、目的に応じて適宜選択することができ、例えば、催眠・鎮静剤、解熱鎮痛消炎剤、精神神経用剤、自律神経用剤、抗パーキンソン剤、抗ヒスタミン剤、強心剤、利尿剤、血圧降下剤、血管収縮剤、動脈硬化用剤、鎮咳去痰剤、ビタミン剤、滋養強壮薬、抗生物質、胃腸薬、などが挙げられる。
　前記医薬品添加物及び前記食品添加物としては、経口摂取可能なものであれば特に制限はなく、目的に応じて適宜選択することができ、例えば、糖、糖アルコール、デンプン及びその誘導体、有機酸及びその塩、無機物、セルロース及びその誘導体、非セルロース多糖類、合成高分子などが挙げられる。 The physiologically active substance is not particularly limited as long as it can be taken orally, and can be appropriately selected according to the purpose. For example, hypnosis / sedation, antipyretic analgesic / antiinflammatory agent, neuropsychiatric agent, autonomic nerve Preparations, antiparkinsonian agents, antihistamines, cardiotonic agents, diuretics, antihypertensive agents, vasoconstrictors, arteriosclerotic agents, antitussive expectorants, vitamins, nourishing tonics, antibiotics, gastrointestinals, and the like.
The pharmaceutical additive and the food additive are not particularly limited as long as they can be taken orally, and can be appropriately selected according to the purpose. For example, sugar, sugar alcohol, starch and derivatives thereof, organic acid And salts thereof, inorganic substances, cellulose and derivatives thereof, non-cellulose polysaccharides, synthetic polymers, and the like.
　さらに製剤としての機能性を高めるために、前記生理活性物質含有被覆層に加えて機能性コーティング層を形成してもよい。機能性コーティング層とは、徐放性、胃溶性、腸溶性などの前記生理活性物質の放出速度をコントロールするためや、防湿、遮光、苦味や臭いのマスキングを目的として形成する層である。該機能性コーティング層を形成する方法としては、製剤の目的に応じて公知の条件にて行えばよい。該機能性コーティング層を形成する成分としては、経口摂取可能なものであれば特に制限はなく、例えば天然高分子や合成高分子などが挙げられる。
　以上により、各種の製剤が得られる。 Further, in order to enhance the functionality as a preparation, a functional coating layer may be formed in addition to the physiologically active substance-containing coating layer. The functional coating layer is a layer formed for the purpose of controlling the release rate of the physiologically active substance such as sustained release, gastric solubility, entericity, etc., or for the purpose of moisture proofing, light shielding, bitterness and odor masking. The functional coating layer may be formed under known conditions depending on the purpose of the preparation. The component for forming the functional coating layer is not particularly limited as long as it can be taken orally, and examples thereof include natural polymers and synthetic polymers.
As described above, various preparations can be obtained.
　以下に、本発明の実施例について説明するが、本発明はこれらの実施例に何ら限定されるものではない。なお、以下の実施例において得られた球形顆粒については、真球度、摩損度、顆粒硬度を以下のように測定した。 Examples of the present invention will be described below, but the present invention is not limited to these examples. In addition, about the spherical granule obtained in the following Examples, the sphericity, the friability, and the granule hardness were measured as follows.
＜真球度＞
　得られた球形顆粒につき、その短径及び長径を測定し、その短径／長径の比で表した値である。この短径／長径の比とは、前記球形顆粒の短軸と長軸との比を意味し、真球度を示す目安となる。
　前記短径及び長径の比は、得られた前記球形顆粒を試料台にランダムに置き、写真撮影し、５０個の球形顆粒についてその長軸の長さ（長径）と、長軸の中点に直交する短軸の長さ（短径）とを、各々測定し、各々について長径に対する短径の比を求め、５０個の平均値で示したものである。
　なお、真球度の評価基準は以下のとおりである。
　　◎・・・真球度０．９０以上
　　○・・・真球度０．８５以上０．９０未満
　　×・・・真球度０．８５未満 <Sphericality>
The obtained spherical granule has a minor axis and a major axis, and is a value represented by a ratio of the minor axis / major axis. The ratio of the minor axis / major axis means the ratio between the minor axis and the major axis of the spherical granule, and is a standard indicating the sphericity.
The ratio of the minor axis to the major axis is determined by randomly placing the obtained spherical granules on a sample stage, taking a photograph, and measuring the length of the major axis (major axis) of the 50 spherical granules at the midpoint of the major axis. The lengths of the minor axes perpendicular to each other (minor axis) are measured, the ratio of the minor axis to the major axis is determined for each, and the average value of 50 is shown.
The evaluation criteria for sphericity are as follows.
◎ ・ ・ ・ Sphericality 0.90 or more ○ ・ ・ ・ Sphericality 0.85 or more and less than 0.90 × ・ ・ ・ Sphericality less than 0.85
＜摩損度＞
　得られた球形顆粒を、篩を用いてそれぞれ下表に示す粒子径に篩別した後、その約１０ｇを精密に量りとり（Ｗｔ）、内径３２ｍｍ×深さ６５ｍｍのステンレス製円筒容器に入れ、ミキサーミル（ＳＰＥＸ社製）にて、１０分間振とうを行った。振とう終了後、下表に示す目開きの篩に移して微粉を除去し、篩い上の残留分（Ｗｓ）を精密に秤量し、次式（ｉ）により摩損度を算出した。
　摩損度（％）＝（Ｗｔ－Ｗｓ）／Ｗｔ×１００　・・・（ｉ）
　なお、一般的に同じ成分を持つ顆粒の場合、粒子径が大きくなるにつれ摩損度は大きくなる傾向がある。この理由から、摩損度については同じ粒子径の顆粒を用いて比較を行った。 <Degree of wear>
After sieving the obtained spherical granules to the particle sizes shown in the table below using a sieve, about 10 g thereof was accurately weighed (Wt) and placed in a stainless steel cylindrical container having an inner diameter of 32 mm and a depth of 65 mm, The mixture was shaken for 10 minutes with a mixer mill (SPEX). After completion of the shaking, the mixture was transferred to a sieve with openings shown in the following table, fine powder was removed, the residue (Ws) on the sieve was accurately weighed, and the friability was calculated by the following equation (i).
Friction degree (%) = (Wt−Ws) / Wt × 100 (i)
In general, in the case of granules having the same components, the friability tends to increase as the particle diameter increases. For this reason, the friability was compared using granules having the same particle size.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
＜顆粒硬度＞
　得られた球形顆粒のうち摩損度測定と同様の粒子径の顆粒を用いて顆粒硬度測定装置（ＧＲＡＮＯ、岡田精工（株）製）を用い、測定加重１ｋｇ、測定速度１００μｍ/ｓｅｃ、先端チップ径３ｍｍφの条件にて顆粒硬度を測定し、２０粒の平均値を該顆粒硬度とした。なお、一般的に同じ成分を持つ顆粒の場合、粒子径が大きくなるにつれ顆粒硬度は大きくなる傾向がある。この理由から、顆粒硬度については同じ粒子径の顆粒を用いて比較を行った。 <Granule hardness>
Of the obtained spherical granules, granules having the same particle diameter as that of friability measurement were used, and a granule hardness measuring device (GRANO, manufactured by Okada Seiko Co., Ltd.) was used. Measurement weight 1 kg, measurement speed 100 μm / sec, tip diameter The granule hardness was measured under the condition of 3 mmφ, and the average value of 20 grains was defined as the granule hardness. In general, in the case of granules having the same components, the hardness of the granules tends to increase as the particle diameter increases. For this reason, the granule hardness was compared using granules having the same particle size.
（実施例１）
　複合型造粒コーティング装置（フロイント産業（株）製、「スパイラフロー」、ＳＦＣ－５）を用いて、下記表２に示す処方の懸濁液を、核粒子（粒径が１５０～２１２μｍであるグラニュー糖の結晶（蔗糖の結晶、塩水港精糖（株）製））の重量に対して、該懸濁液中の蔗糖及びコーンスターチの固形分重量で、７００重量％の被覆量となるように該核粒子（グラニュー糖の結晶）の表面に被覆して、球形顆粒を造粒した。
　該複合型造粒コーティング装置の運転条件としては、総風量（浮遊流動エアー量＋スリットエアー量）が３．４ｍ３／ｍｉｎ（８０℃設定）であり、ローター回転数が３００ｒｐｍであり、スプレー空気圧が０．４ＭＰａとし、排気温度が４０℃前後となるように、液の噴霧速度を調整した。 Example 1
Using a composite granulation coating apparatus (Freund Sangyo Co., Ltd., “Spiraflow”, SFC-5), suspensions of the formulations shown in Table 2 below are prepared as core particles (particle size is 150 to 212 μm). The weight of the sucrose and corn starch in the suspension is 700% by weight with respect to the weight of the granulated sugar crystals (sucrose crystals, manufactured by Shisui Minato Seika Co., Ltd.). Spherical granules were granulated by covering the surface of core particles (granulated sugar crystals).
The operating conditions of the composite granulation coating apparatus include a total air volume (floating air flow amount + slit air amount) of 3.4 m 3 / min (80 ° C. setting), a rotor rotational speed of 300 rpm, and a spray air pressure. Was 0.4 MPa, and the spray rate of the liquid was adjusted so that the exhaust temperature was about 40 ° C.
　該複合型造粒コーティング装置は、上述した造粒室を備えており、該造粒室内に回転可能なローターが備えられている。また、該造粒室の内壁には、前記ローターの外周縁部の近傍であってかつ上方に、前記懸濁液を前記核粒子に向けて噴霧可能な噴霧装置（スプレーガン）を備えられている。また、該ローターの外周縁部と前記造粒室の内壁との間には僅かなクリアランスが設けられており、下方からスリットエアーが該クリアランスを通過して該造粒室内に導入可能になっている。また、ローターの一部は通風が可能なスクリーンになっており、このスクリーン部分から浮遊流動エアーを導入することが可能である。
　このため、複合型造粒コーティング装置において、該ローターを回転させ、前記スリットエアーを前記造粒室内に導入した状態で前記核粒子を投入すると、該核粒子が前記転動を生じる。また、この転動の際に、浮遊流動エアーを前記造粒室内に導入させると、前記転動浮遊流動が生ずる。こうして、該複合型造粒コーティング装置を用いて前記造粒工程を行うことにより、以下の球形顆粒が造粒された。
　得られた球形顆粒の、真球度は０．８７であり、摩損度は１．０８％であり、顆粒硬度は１６９ｇであり、粒径３５５～５００μｍで篩い分けた際の収率は約８８％であった。なお、前記真球度、前記摩損度、前記顆粒硬度は、前述の方法にて測定し、評価した。前記収率は、篩い分け法により算出した値である。 The composite granulation coating apparatus includes the granulation chamber described above, and a rotatable rotor is provided in the granulation chamber. Further, the inner wall of the granulation chamber is provided with a spraying device (spray gun) capable of spraying the suspension toward the core particles near and above the outer peripheral edge of the rotor. Yes. In addition, a slight clearance is provided between the outer peripheral edge of the rotor and the inner wall of the granulation chamber, so that slit air can pass through the clearance from below and be introduced into the granulation chamber. Yes. Further, a part of the rotor is a screen that allows ventilation, and floating fluid air can be introduced from this screen portion.
For this reason, in the composite granulation coating apparatus, when the core particles are introduced while the rotor is rotated and the slit air is introduced into the granulation chamber, the core particles cause the rolling. In addition, when floating air is introduced into the granulation chamber during the rolling, the rolling floating flow is generated. Thus, the following spherical granules were granulated by performing the granulation step using the composite granulation coating apparatus.
The resulting spherical granules have a sphericity of 0.87, a friability of 1.08%, a granule hardness of 169 g, and a yield of about 88 when screened with a particle size of 355 to 500 μm. %Met. The sphericity, the friability, and the granule hardness were measured and evaluated by the methods described above. The yield is a value calculated by a sieving method.
（実施例２）
　実施例１と同様の処方及び条件で球形顆粒を造粒した後、更に表２に示す処方の液（前記表面被覆層形成液）を前記核粒子の重量に対して、該液中の蔗糖の固形分重量で、５０重量％の被覆量となるように該球形顆粒の表面に被覆（噴霧）し前記表面被覆層を形成した以外は、実施例１と同様として球形顆粒を造粒した。
　得られた球形顆粒の、真球度は０．８８であり、摩損度は０．１８％であり、顆粒硬度は１９０ｇであり、粒径３５５～５００μｍで篩い分けた際の収率は約８８％であった。 (Example 2)
After granulating the spherical granules under the same formulation and conditions as in Example 1, the solution of the formulation shown in Table 2 (the surface coating layer forming solution) was further added to the weight of the core particles with respect to the sucrose content in the solution. Spherical granules were granulated in the same manner as in Example 1 except that the surface of the spherical granules was coated (sprayed) to form a coating amount of 50% by weight in terms of solid content.
The resulting spherical granule has a sphericity of 0.88, a friability of 0.18%, a granule hardness of 190 g, and a yield of about 88 when screened with a particle size of 355 to 500 μm. %Met.
（実施例３）
　実施例１において、核粒子であるグラニュー糖の粒径を２１２～３００μｍに変更したこと、及びコーティングによる被覆量を７００重量％から９００重量％に変更した以外は、実施例１と同様として球形顆粒を造粒し、実施例１と同様の評価を行った。
　得られた球形顆粒の、真球度は０．９０であり、摩損度は１．３３％であり、顆粒硬度は３４５gであり、粒径５００～７１０μｍで篩い分けた際の収率は約９６％であった。 (Example 3)
Spherical granules were obtained in the same manner as in Example 1 except that the particle size of granulated sugar as the core particle was changed to 212 to 300 μm and the coating amount by coating was changed from 700% by weight to 900% by weight. The same evaluation as in Example 1 was performed.
The obtained spherical granule has a sphericity of 0.90, a friability of 1.33%, a granule hardness of 345 g, and a yield of about 96 when the particle size is 500 to 710 μm. %Met.
（実施例４）
　実施例３において、懸濁液の組成を表２に示す処方に変更して実施例３と同様として球形顆粒を造粒した後、更に表２に示す処方の液（前記表面被覆層形成液）を前記核粒子の重量に対して、該液中の蔗糖の固形分重量で、５０重量％の被覆量となるように該球形顆粒の表面に被覆（噴霧）し前記表面被覆層を形成した以外は、実施例３と同様として球形顆粒を造粒した。
　得られた球形顆粒の、真球度は０．９０であり、摩損度は０．４５％であり、顆粒硬度は３６０gであり、粒径５００～７１０μｍで篩い分けた際の収率は約９５％であった。 Example 4
In Example 3, after changing the composition of the suspension to the formulation shown in Table 2 and granulating spherical granules in the same manner as in Example 3, the solution having the formulation shown in Table 2 (the surface coating layer forming solution) Except that the surface coating layer is formed by coating (spraying) the surface of the spherical granules so that the coating amount is 50% by weight with respect to the weight of the core particles. Were granulated in the same manner as in Example 3.
The resulting spherical granule has a sphericity of 0.90, a friability of 0.45%, a granule hardness of 360 g, and a yield of about 95 when screened with a particle size of 500-710 μm. %Met.
（実施例５）
　実施例４において、複合型造粒コーティング装置に代えて遠心転動造粒コーティング装置（フロイント産業（株）製、「グラニュレックス」、ＧＸ－４０）を用いたこと、及び、表２に示す処方の懸濁液を使用したこと以外は、実施例４と同様として球形顆粒を造粒した。
　該遠心転動造粒コーティング装置の運転条件としては、総風量（浮遊流動エアー量＋スリットエアー量）が２．５ｍ３／ｍｉｎ（８０℃設定）であり、ローター回転数が２５０ｒｐｍであり、スプレー空気圧が０．４ＭＰａとし、排気温度が４０℃前後となるように、液の噴霧速度を調整した。
　得られた球形顆粒の、真球度は０．９１であり、摩損度は０．４９％であり、顆粒硬度は３４１gであり、粒径５００～７１０μｍで篩い分けた際の収率は約９１％であった。 (Example 5)
In Example 4, a centrifugal tumbling granulation coating apparatus (manufactured by Freund Sangyo Co., Ltd., “Granurex”, GX-40) was used instead of the composite granulation coating apparatus, and the formulation shown in Table 2 Spherical granules were granulated in the same manner as in Example 4 except that the above suspension was used.
The operating conditions of the centrifugal rolling granulation coating apparatus are as follows: the total air volume (floating air flow amount + slit air amount) is 2.5 m 3 / min (80 ° C. setting), the rotor rotational speed is 250 rpm, spraying The spraying speed of the liquid was adjusted so that the air pressure was 0.4 MPa and the exhaust temperature was about 40 ° C.
The obtained spherical granule has a sphericity of 0.91, a friability of 0.49%, a granule hardness of 341 g, and a yield of about 91 when screened with a particle size of 500 to 710 μm. %Met.
（実施例６）
　複合型造粒コーティング装置（フロイント産業（株）製、「スパイラフロー」、ＳＦＣ－５）を用いて、蔗糖：コーンスターチ＝８：２の懸濁液を噴霧乾燥して得られた噴霧乾燥品を、粒径１０６～１８０μｍに分級したものを核粒子とし、表２に示す処方の溶液を、核粒子の重量に対して該液の蔗糖の固形分重量で２５０重量％の被覆量となるように噴霧して球形顆粒を造粒した。
　なお、複合型造粒コーティング装置の運転条件としては、総風量（浮遊流動エアー量＋スリットエアー量）が３．０ｍ３／ｍｉｎ（７０℃設定）であり、ローター回転数が３００ｒｐｍであり、スプレー空気圧が０．４ＭＰａとし、排気温度が４３℃前後となるように、液の噴霧速度を調整した。
　得られた球形顆粒の、真球度は０．９８であり、摩損度は０．０５％であり、顆粒硬度は４２gであり、粒径１５０～２５０μｍで篩い分けた際の収率は約７３％であった。 (Example 6)
A spray-dried product obtained by spray-drying a suspension of sucrose: corn starch = 8: 2 using a composite granulation coating apparatus (Freund Sangyo Co., Ltd., “Spiraflow”, SFC-5) The particles classified into particle sizes of 106 to 180 μm are used as core particles, and the solution having the formulation shown in Table 2 is coated with a solid content weight of sucrose of 250% by weight with respect to the weight of the core particles. The spherical granules were granulated by spraying.
The operating conditions of the composite granulation coating apparatus include a total air volume (floating air flow amount + slit air amount) of 3.0 m 3 / min (70 ° C. setting), a rotor rotational speed of 300 rpm, The spray rate of the liquid was adjusted so that the air pressure was 0.4 MPa and the exhaust temperature was around 43 ° C.
The resulting spherical granules have a sphericity of 0.98, a friability of 0.05%, a granule hardness of 42 g, and a yield of about 73 when sieved with a particle size of 150-250 μm. %Met.
Figure JPOXMLDOC01-appb-T000002
 　　＊　コーンスターチの略
　　表中「％」は重量％を意味する
Figure JPOXMLDOC01-appb-T000002
 * Abbreviation for corn starch “%” in the table means% by weight.
（比較例１）
　粒径が１５０～２１２μｍのグラニュー糖５００gを核粒子として用い、遠心流動型コーティング造粒装置ＣＦグラニュレーター（フロイント産業（株）製、ＣＦ－３６０ＥＸ）へ投入し、５０重量％蔗糖水溶液を該核粒子に噴霧しながら、蔗糖及びコーンスターチを重量比で３：１の割合で混合粉砕した混合粉２．５ｋｇを該核粒子に散布することにより、粉末レイヤリングした。即ち、前記核粒子の表面に、前記混合粉の散布と、前記蔗糖水溶液の噴霧とを行って、被覆層を形成して顆粒を造粒した。得られた顆粒について、実施例１と同様の評価を行った。
　該遠心流動型コーティング造粒装置の運転条件は、スリットエアー量が０．１８ｍ３／ｍｉｎであり、ローター回転数が１６０ｒｐｍであり、スプレー空気圧が０．１ＭＰａであり、液速度が５～１０ｍＬ／ｍｉｎとした。また、前記混合粉の散布量は、２０～７０g／ｍｉｎの間で調整した。
　その結果、得られた球形顆粒は、真球度が０．９３であり、摩損度が１．４９％であり、顆粒硬度が９３ｇであり、粒径３５５～５００μｍで篩い分けた際の収率が約７０％であった。
　比較例１で得られた球形顆粒と同じ粒子径である実施例１及び２で得られた本発明の球形顆粒とを比較すると、実施例１、２で得られた球形顆粒は比較例１の球形顆粒と比較して顆粒硬度の上昇及び摩損度の低下が確認された。 (Comparative Example 1)
Using 500 g of granulated sugar having a particle size of 150 to 212 μm as core particles, it was put into a centrifugal fluidized coating granulator CF granulator (CF-360EX, manufactured by Freund Sangyo Co., Ltd.), and a 50 wt% sucrose aqueous solution was added to the core. While spraying the particles, 2.5 kg of mixed powder obtained by mixing and pulverizing sucrose and corn starch at a ratio of 3: 1 by weight was sprayed on the core particles to perform powder layering. That is, the mixed powder and the sucrose aqueous solution were sprayed on the surface of the core particles to form a coating layer and granulate the granules. The obtained granules were evaluated in the same manner as in Example 1.
The operating conditions of the centrifugal flow type coating granulator are as follows: the slit air amount is 0.18 m 3 / min, the rotor rotational speed is 160 rpm, the spray air pressure is 0.1 MPa, and the liquid speed is 5 to 10 mL / min. It was set to min. The amount of the mixed powder applied was adjusted between 20 and 70 g / min.
As a result, the obtained spherical granules had a sphericity of 0.93, a friability of 1.49%, a granule hardness of 93 g, and a yield when sieved with a particle size of 355 to 500 μm. Was about 70%.
Comparing the spherical granules of the present invention obtained in Examples 1 and 2 having the same particle size as the spherical granules obtained in Comparative Example 1, the spherical granules obtained in Examples 1 and 2 are the same as those in Comparative Example 1. An increase in granule hardness and a decrease in friability were confirmed compared to spherical granules.
Figure JPOXMLDOC01-appb-T000003
 　　＊　核粒子の重量に対する、表面被覆層形成液中の蔗糖の固形分重量の割合（被覆量）
Figure JPOXMLDOC01-appb-T000003
 * Ratio of sucrose solid content in the surface coating layer forming liquid to the weight of core particles (coating amount)
（比較例２）
　粒径が２１２～３００μｍのグラニュー糖５００gを核粒子として用い、遠心流動型コーティング造粒装置ＣＦグラニュレーター（フロイント産業（株）製、ＣＦ－３６０ＥＸ）へ投入し、５０重量％蔗糖水溶液を該核粒子に噴霧しながら、蔗糖及びコーンスターチを重量比で３：１の割合で混合粉砕した混合粉２．５ｋｇを該核粒子に散布することにより、粉末レイヤリングした。即ち、前記核粒子の表面に、前記混合粉の散布と、前記蔗糖水溶液の噴霧とを行って、被覆層を形成して顆粒を造粒した。得られた顆粒について、実施例１と同様の評価を行った。
　該遠心流動型コーティング造粒装置の運転条件は、スリットエアー量が０．１８ｍ３／ｍｉｎであり、ローター回転数が１６０ｒｐｍであり、スプレー空気圧が０．１ＭＰａであり、液速度が５～１０ｍＬ／ｍｉｎとした。また、前記混合粉の散布量は、２０～７０g／ｍｉｎの間で調整した。
　その結果、得られた球形顆粒は、真球度が０．９４であり、摩損度が１．８５％であり、顆粒硬度が１５２ｇであり、粒径５００～７１０μｍで篩い分けた際の収率が約７０％であった。
　比較例２で得られた球形顆粒と同じ粒子径である実施例３、４及び５で得られた球形顆粒とを比較すると、実施例３、４、５で得られた球形顆粒は比較例２の球形顆粒と比較して顆粒硬度の上昇及び摩損度の低下が確認された。 (Comparative Example 2)
Using 500 g of granulated sugar having a particle size of 212 to 300 μm as core particles, it was put into a centrifugal fluidized coating granulator CF granulator (CF-360EX, manufactured by Freund Sangyo Co., Ltd.), and a 50 wt% sucrose aqueous solution was added to the core. While spraying the particles, 2.5 kg of mixed powder obtained by mixing and pulverizing sucrose and corn starch at a ratio of 3: 1 by weight was sprayed on the core particles to perform powder layering. That is, the mixed powder and the sucrose aqueous solution were sprayed on the surface of the core particles to form a coating layer and granulate the granules. The obtained granules were evaluated in the same manner as in Example 1.
The operating conditions of the centrifugal flow type coating granulator are as follows: the slit air amount is 0.18 m 3 / min, the rotor rotational speed is 160 rpm, the spray air pressure is 0.1 MPa, and the liquid speed is 5 to 10 mL / min. It was set to min. The amount of the mixed powder applied was adjusted between 20 and 70 g / min.
As a result, the obtained spherical granule has a sphericity of 0.94, a friability of 1.85%, a granule hardness of 152 g, and a yield when sieved with a particle size of 500 to 710 μm. Was about 70%.
When the spherical granules obtained in Examples 3, 4 and 5 having the same particle size as the spherical granules obtained in Comparative Example 2 were compared, the spherical granules obtained in Examples 3, 4, and 5 were compared with Comparative Example 2. As compared with the spherical granules, an increase in granule hardness and a decrease in friability were confirmed.
Figure JPOXMLDOC01-appb-T000004
 ＊表面被複層形成液の略
Figure JPOXMLDOC01-appb-T000004
 * Abbreviation for surface multilayer formation liquid
（比較例３）
　蔗糖：コーンスターチ＝８：２の液を噴霧乾燥して得られた噴霧乾燥品を粒径１０６～１８０μmで分級したもの１ｋｇを核粒子として用い、遠心流動型コーティング造粒装置ＣＦグラニュレーター（フロイント産業（株）製、ＣＦ－３６０ＥＸ）へ投入し、３０重量％蔗糖水溶液を該核粒子に噴霧しながら、蔗糖及びコーンスターチを９：１（重量比）の割合で混合粉砕した混合粉２ｋｇを該核粒子に散布することにより、粉末レイヤリングした。即ち、前記核粒子の表面に、前記混合粉の散布と、前記蔗糖水溶液の噴霧とを行って、被覆層を形成して顆粒を造粒した。得られた球形顆粒について、実施例１と同様の評価を行った。
　該遠心流動型コーティング造粒装置の運転条件は、スリットエアー量が０．１８ｍ３／ｍｉｎであり、ローター回転数が１６０ｒｐｍであり、スプレー空気圧が０．１ＭＰａであり、液速度が５～１０ｍＬ／ｍｉｎとした。また、前記混合粉の散布量は、２０～７０g／ｍｉｎの間で調整した。
　その結果、得られた球形顆粒は、真球度が０．９３であり、摩損度が０．３６％であり、顆粒硬度が１３ｇであり、粒径１５０～２５０μｍで篩い分けた際の収率が約６１％であった。
　比較例３で得られた球形顆粒と同じ粒子径である実施例６で得られた球形顆粒とを比較すると、実施例６で得られた球形顆粒は比較例３の球形顆粒と比較して顆粒硬度の上昇及び摩損度の低下が確認された。 (Comparative Example 3)
A spray-dried product obtained by spray-drying sucrose: corn starch = 8: 2 and classified by a particle size of 106-180 μm is used as a core particle, and a centrifugal fluid coating granulator CF granulator (Freund Sangyo) (CF Co., Ltd., CF-360EX), and spraying 30% by weight sucrose aqueous solution onto the core particles, mixing 2 kg of sucrose and corn starch at a ratio of 9: 1 (weight ratio), Powder layering was performed by spreading on the particles. That is, the mixed powder and the sucrose aqueous solution were sprayed on the surface of the core particles to form a coating layer and granulate the granules. The obtained spherical granules were evaluated in the same manner as in Example 1.
The operating conditions of the centrifugal flow type coating granulator are as follows: the slit air amount is 0.18 m 3 / min, the rotor rotational speed is 160 rpm, the spray air pressure is 0.1 MPa, and the liquid speed is 5 to 10 mL / min. It was set to min. The amount of the mixed powder applied was adjusted between 20 and 70 g / min.
As a result, the obtained spherical granule has a sphericity of 0.93, a friability of 0.36%, a granule hardness of 13 g, and a yield when sieved with a particle size of 150 to 250 μm. Was about 61%.
When comparing the spherical granule obtained in Example 6 having the same particle size with the spherical granule obtained in Comparative Example 3, the spherical granule obtained in Example 6 is more granular than the spherical granule of Comparative Example 3. An increase in hardness and a decrease in friability were confirmed.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　本発明の球形顆粒の製造方法によれば、結晶粒からなる核粒子に液のみを噴霧する手法を用いながらも、粉末被覆して造粒した球形顆粒よりも摩損度、顆粒硬度に優れ、真球度の高い高品質な球形顆粒が得られるので、本発明の球形顆粒の製造方法は、高品質の製剤を効率よく製造するために用いる製剤用核粒子として好適な球形顆粒の製造に好適に利用することができる。
　本発明の球形顆粒は、粉末被覆して造粒した球形顆粒よりも摩損度、顆粒硬度に優れ、真球度が高く、高品質であるため、放出制御製剤等に用いる製剤用核粒子として好適に利用することができる。 According to the method for producing spherical granules of the present invention, while using a method in which only the liquid is sprayed on the core particles composed of crystal grains, the sphericity granules are excellent in friability and granule hardness compared to spherical granules granulated by powder coating. Since a high-quality spherical granule with high sphericity is obtained, the method for producing a spherical granule of the present invention is suitable for producing a spherical granule suitable as a core particle for a preparation used for efficiently producing a high-quality preparation. Can be used.
The spherical granule of the present invention is more suitable as a core particle for pharmaceutical preparations used in controlled release preparations and the like because it is superior in friability, granule hardness, high sphericity and high quality than spherical granules granulated by powder coating. Can be used.

Claims (6)

  1. 　糖を含有する核粒子を水平に設置した回転皿を回転させることにより転動させながら、粉末成分を散布することなく、該核粒子に固形分を含有する液を噴霧して被覆層を形成する工程を含むことを特徴とする球形顆粒の製造方法。 While rotating by rotating a rotating dish in which sugar-containing core particles are horizontally installed, a coating layer is formed by spraying a liquid containing solids on the core particles without spraying powder components. The manufacturing method of the spherical granule characterized by including the process.
  2. 　固形分を含有する液が、糖を含有する水溶液乃至懸濁液である請求の範囲第１項に記載の球形顆粒の製造方法。 2. The method for producing spherical granules according to claim 1, wherein the liquid containing solids is an aqueous solution or suspension containing sugar.
  3. 　核粒子が、糖の結晶、又は、糖及びデンプン若しくはその誘導体の噴霧乾燥粒子からなる請求の範囲第１項から第２項のいずれかに記載の球形顆粒の製造方法。 3. The method for producing a spherical granule according to any one of claims 1 to 2, wherein the core particles are composed of sugar crystals or spray-dried particles of sugar and starch or a derivative thereof.
  4. 　核粒子が、水平に設置した回転皿を回転させることによる転動に加え、転動粒子にエアーを吹き込むことにより浮遊流動される請求の範囲第１項から第３項のいずれかに記載の球形顆粒の製造方法。 The spherical shape according to any one of claims 1 to 3, wherein the core particles are floated and flowed by blowing air into the rolling particles in addition to rolling by rotating a rotating dish installed horizontally. Granule manufacturing method.
  5. 　更に、得られた球形顆粒の表面に、糖及び／又は糖アルコールの水溶液を噴霧して表面被覆層を形成することを含む請求の範囲第１項から第４項のいずれかに記載の球形顆粒の製造方法。 The spherical granule according to any one of claims 1 to 4, further comprising spraying an aqueous solution of sugar and / or sugar alcohol on the surface of the obtained spherical granule to form a surface coating layer. Manufacturing method.
  6. 　請求の範囲第１項から第５項のいずれかに記載の球形顆粒の製造方法により製造されることを特徴とする球形顆粒。 A spherical granule produced by the method for producing a spherical granule according to any one of claims 1 to 5.
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