WO2009157564A1 - Composition de cellulose - Google Patents

Composition de cellulose Download PDF

Info

Publication number
WO2009157564A1
WO2009157564A1 PCT/JP2009/061779 JP2009061779W WO2009157564A1 WO 2009157564 A1 WO2009157564 A1 WO 2009157564A1 JP 2009061779 W JP2009061779 W JP 2009061779W WO 2009157564 A1 WO2009157564 A1 WO 2009157564A1
Authority
WO
WIPO (PCT)
Prior art keywords
cellulose
less
bulk density
composition
dry
Prior art date
Application number
PCT/JP2009/061779
Other languages
English (en)
Japanese (ja)
Inventor
真幸 垣澤
義仁 柳沼
俊一 五味
Original Assignee
旭化成ケミカルズ株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 旭化成ケミカルズ株式会社 filed Critical 旭化成ケミカルズ株式会社
Priority to JP2010518085A priority Critical patent/JP5442609B2/ja
Publication of WO2009157564A1 publication Critical patent/WO2009157564A1/fr

Links

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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a cellulose composition.
  • the cellulose composition used for tableting needs to have moldability for imparting the tablet with a hardness that prevents the tablet from being worn out or broken.
  • the powder needs to be filled in a uniform amount in a die of a tableting machine. Therefore, the cellulose composition needs to have sufficient filling property (fluidity) in addition to moldability.
  • a direct tableting method in which a powder containing a drug and a cellulose composition is directly filled in a mortar and then compression-molded to obtain a tablet, and the drug and the cellulose composition are mixed with water or an organic solvent.
  • a wet granulation method or the like is generally used in which a granule is granulated using a binding solution dissolved in a powder, the resulting granule is filled in a mortar, and then compressed to obtain a tablet.
  • the size of these tablets is usually about 5 to 20 mm.
  • Non-Patent Document 1 discloses a method of performing spray drying (spray drying), and lactose for direct hitting is disclosed as an example of improving moldability and fillability by the spray drying method.
  • spray drying spray drying
  • lactose for direct hitting is disclosed as an example of improving moldability and fillability by the spray drying method.
  • direct lactose has higher moldability than crystalline lactose, moldability is still not sufficient.
  • Patent Document 1 discloses an average L / D (major axis / minor axis ratio) of particles having an average degree of polymerization of 150 to 450 and 75 ⁇ m or less. 2.0-4.5, average particle size 20-250 ⁇ m, apparent specific volume 4.0-7.0 cm 3 / g, apparent tapping specific volume 2.4-4.5 cm 3 / g, angle of repose
  • a cellulose powder (crystalline cellulose) characterized by being 55 degrees or less is disclosed.
  • Patent Document 1 when the L / D of the crystalline cellulose particles is increased to improve the moldability, the bulk density of the powder of the cellulose composition is reduced, and the fluidity is impaired. In addition, there is a problem that the filling variation becomes large.
  • Patent Document 2 has a secondary aggregation structure in which cellulose primary particles are aggregated, has an intraparticle pore volume of 0.265 to 2.625 cm 3 / g, contains type I crystals, and has an average particle size.
  • a porous cellulose aggregate having a diameter exceeding 30 ⁇ m and not more than 250 ⁇ m, a specific surface area of 1.3 to 20 m 2 / g, an angle of repose of 25 degrees or more and less than 44 degrees and having a property of collapsing in water is disclosed.
  • the particles having a secondary aggregation structure disclosed in Patent Document 2 are characterized by high moldability and good fluidity as compared with conventional crystalline cellulose, and are usually 5 to 20 mm in size.
  • the cellulose composition has sufficient moldability and fluidity.
  • the filling volume of the particles becomes small, so that particles with a small bulk density have a problem of poor filling properties and large filling variation.
  • Non-Patent Document 2 discloses a basic structure of a dry-coated tablet and a manufacturing method thereof.
  • the dry-coated tablet is filled with the outer layer powder in the die by the first feeder, and then the pre-prepared inner core tablet is supplied to the center of the die using a dedicated feeder, and further the second feeder.
  • the outer layer powder is supplied to the side and upper part of the inner core tablet, the whole is compression-molded, and the tablet is composed of two layers of the inner core part and the outer layer part.
  • the cellulose composition used for the outer layer portion of the dry-coated tablet is required to have both high moldability and fillability.
  • the dry-coated tablet since the central lock is present in the center portion, pressure transmission is likely to be hindered during tableting, and the tableting pressure may not be sufficiently transmitted to the entire outer layer portion.
  • the thickness of the outer layer of the displaced portion (clearance between the inner core tablet and the mortar wall) becomes thin, and the strength may be insufficient.
  • a high tableting pressure is applied during tableting of the dry-coated tablet, the inner core is deformed and bites into the outer layer portion, resulting in a portion where the thickness of the outer layer portion is reduced, resulting in insufficient strength. Therefore, when the moldability of the cellulose composition used for the outer layer portion of the dry-coated tablet is low, the tablet may crack or crack immediately after tableting or during storage.
  • the thickness of the outer layer (clearance between the inner core tablet and the die) is determined by the size of the inner core tablet and the final tablet size, but is usually about 0.5 to 3 mm. If the fluidity of the cellulose composition used for the outer layer is not sufficient, the cellulose composition cannot enter the side surface (outer layer side surface portion) of the outer layer having a width of 0.5 to 3 mm, resulting in a rough filling state. Even when the moldability of the cellulose composition itself is high, if the cellulose composition is roughly filled, the amount of the cellulose composition particles is small, so that sufficient strength cannot be obtained during compression.
  • the cellulose composition used for the outer layer of the dry-coated tablet is required to have good filling properties in addition to high moldability.
  • the outer layer portion is also required to have a fast disintegrating property.
  • a microtablet is a method in which particles having a diameter of about 1 to 3 mm are filled into a fine mortar having a diameter of 1 to 3 mm, and then the powder is compressed and molded, as in the case of tablet compression. It is obtained.
  • a microtablet containing a drug and a cellulose composition it is filled into a capsule as it is, or after being applied with a bitterness mask or a coating for controlling the release of the drug, it is filled into a capsule.
  • the diameter of the die is 3 mm or less, and the filling volume is smaller than that of a normal tablet. Therefore, as the properties of the cellulose composition used for the microtablet, it is necessary to have a filling property that allows the cellulose composition to be sufficiently filled in the die and a moldability for imparting strength when compressed.
  • Patent Document 3 discloses a tablet comprising a combination of crystalline cellulose, hydroxypropylcellulose, light anhydrous silicic acid, lactose and a drug (water-soluble azulene and L-glutamic acid) that easily releases the drug in the stomach after taking.
  • Patent Document 4 discloses an orally disintegrating tablet composed of a combination of crystalline cellulose, hydroxypropylcellulose, calcium silicate, lactose and a drug (epiepipine).
  • the techniques disclosed in Patent Documents 3 and 4 are techniques related to general tablets, and Patent Documents 3 and 4 have no description regarding dry-coated tablets and microtablets.
  • Patent Document 5 and Non-patent Document 2 contain polyethylene oxide in the outer layer granules of the dry-coated tablet as a technology related to dry-coated tablets to reduce cracking defects when the dry-coated tablet is compressed. Is disclosed.
  • Patent Document 6 discloses, as outer layer components of dry-coated tablets, crystalline cellulose, low-viscosity hydroxypropyl cellulose, and high-viscosity hydroxypropyl cellulose (low-viscosity hydroxypropylcellulose and high-viscosity hydroxypropylcellulose).
  • the drug release time controlled solid preparation is characterized in that the release time of the drug is controlled from the core layer containing the drug by using a mixed powder consisting of 10/0 to 0/10) It is disclosed.
  • Patent Document 7 discloses a technique of a dry-coated tablet using hydroxypropylcellulose as an outer layer, which is a technique for gradually releasing a drug by gelling the outer layer.
  • the direct compression lactose as disclosed in Non-Patent Document 1 has a certain degree of filling property but has a low moldability, so that it can be used as an outer layer of a dry-coated tablet or a cellulose composition for a microtablet. Do not mold when it is.
  • the cellulose powder as disclosed in Patent Document 1 has poor fluidity, it cannot be filled into a narrow space when used as an outer layer of a dry-coated tablet or as a cellulose composition of a microtablet. Therefore, even if the moldability of the cellulose composition itself is high, the moldability of the outer layer of the dry-coated tablet or the microtablet cannot be increased.
  • the porous cellulose aggregate disclosed in Patent Document 2 has good moldability and fluidity of the particles, there is a drawback that the bulk density of the particles is small.
  • a general tablet even if it is a powder with a small bulk density, it is possible to secure the filling amount and to give the strength of the tablet by increasing the filling depth (volume) of the die. .
  • the volume of the outer layer side surface is determined from the diameter of the inner core tablet and the final tablet and the thickness of the inner core tablet, and the volume that can be filled is limited. Therefore, since the powder with a small bulk density has a small amount of powder that can be filled in the volume of the side surface portion of the outer layer, it is difficult to impart sufficient strength to the outer layer portion.
  • Patent Document 3 is a technique for producing an easily disintegrating tablet having a general size (diameter 9 mm).
  • the powder is granulated with a binding liquid and then dried.
  • a so-called wet granulation method using the passed granules is used.
  • the particle diameter of the granule is usually larger than 100 ⁇ m for the purpose of improving fluidity. If this granule is used in a dry-coated tablet, the width of the side surface of the outer layer is as narrow as 0.5 to 3 mm, so that it is difficult for the granule to enter, and it is difficult to impart sufficient strength to the outer layer part due to insufficient filling.
  • Patent Document 4 is a technique for producing an orally disintegrating tablet having a general size, and is characterized by being disintegrated within 60 seconds. Therefore, there is a description that hydroxypropyl cellulose can be blended as a binder, and there is no specific rule regarding the blending amount, but in order to achieve a short disintegration time, hydroxypropyl cellulose should be included. A smaller amount is preferable, and there is no description in the examples.
  • Patent Document 6 is a technique of blending crystalline cellulose / hydroxypropyl cellulose in the outer layer of the dry-coated tablet, but there is no provision regarding the ratio of crystalline cellulose / hydroxypropyl cellulose, and the ratio is only in the examples. There is a description, and the blending ratio of crystalline cellulose / hydroxypropyl cellulose is all 49/50.
  • the purpose of this technique is to gel the outer layer of the dry-coated tablet and control the release time of the drug contained in the inner core for 80 minutes or more. Therefore, in order to gel the outer layer, it is necessary to add about half of the outer layer of hydroxypropyl cellulose.
  • Patent Document 7 is also a technique of a dry-coated tablet using crystalline cellulose and hydroxypropyl cellulose for the outer layer, but this technique is also a technique for gradually releasing the drug by gelling the outer layer.
  • the amount of water-insoluble particles containing crystalline cellulose is 1 to 50%.
  • the technique disclosed in Patent Documents 6 and 7 cannot be realized in order to obtain an immediate-release preparation that exhibits moderately fast disintegration without gelling the outer layer.
  • the problem to be solved by the present invention is to provide a cellulose composition that imparts high fillability and moldability during tableting, particularly tableting under conditions where the powder filling volume is small.
  • the present invention is as follows. [1] 55 to 75% by mass of crystalline cellulose [A] having an average particle size of 80 to 150 ⁇ m, a loose bulk density of 0.30 to 0.50 g / cm 3 and an angle of repose of 40 degrees or less, 17.5 to 37.5% by mass of a water-soluble cellulose derivative [B] in which the viscosity of a 20 ° C.
  • aqueous solution having an average particle size of 80 ⁇ m or less and 2% by mass is 10 mPa ⁇ s 5
  • Excipients [D] having 0.01 to 0.5% by mass of a fluidizing agent [C], an average particle size of 150 ⁇ m or less, and a loose bulk density of 0.60 to 1.00 g / cm 3 Up to 20% by weight,
  • the content ratio of [D] and [B] ([D] / [B]) is less than 1.0, [A], [B], [C], and [D] are all included in a powder state, the average particle size is 100 ⁇ m or less, the loose bulk density is 0.47 g / cm 3 or more, and the angle of repose is 35.
  • [11] Mixing the component containing [A] and [C] in a container-fixed mixer, and adding [B] and [D] to the mixture of [A] and [C].
  • aqueous solution having a viscosity of 10 mPa ⁇ s or less, 5 Excipients [D] having 0.01 to 0.5% by mass of a fluidizing agent [C], an average particle size of 150 ⁇ m or less, and a loose bulk density of 0.60 to 1.00 g / cm 3
  • an outer layer containing The ratio of [D] to [B] ([D] / [B]) is less than 1.0;
  • a dry-coated tablet having a thickness of a side surface portion of the outer layer of 2 mm or less and a disintegration time of 30 minutes or less.
  • the cellulose composition of the present invention exhibits good filling properties and moldability.
  • a tablet with high strength can be obtained.
  • a high-strength dry-coated tablet or microcapsule can be obtained.
  • the present embodiment a mode for carrying out the present invention (hereinafter referred to as “the present embodiment”) will be described in detail.
  • this invention is not limited to the following embodiment, It can implement by changing variously within the range of the summary.
  • the cellulose composition of the present embodiment contains 55 to 75 crystalline cellulose [A] having an average particle size of 80 to 150 ⁇ m, a loose bulk density of 0.30 to 0.50 g / cm 3 , and an angle of repose of 40 degrees or less. 17.5 to 37.5% by mass of a water-soluble cellulose derivative [B] in which the viscosity of a 20% aqueous solution of 2% by mass and an average particle size of 80 ⁇ m or less is 10 mPa ⁇ s or less, and a fluidizing agent [ C] in an amount of 0.01 to 0.5% by mass, 5 to 20% by mass of excipient [D] having an average particle size of 150 ⁇ m or less and a loose bulk density of 0.60 to 1.00 g / cm 3
  • the content ratio of [D] to [B] ([D] / [B]) is less than 1.0, and [A], [B], [C], and [D ] In a powder state, and the average particle size is 100 ⁇ m or less
  • the crystalline cellulose [A] used in the present embodiment is crystalline cellulose having an average particle size of 80 to 150 ⁇ m, a loose bulk density of 0.30 to 0.50 g / cm 3 , and an angle of repose of 40 degrees or less.
  • the crystalline cellulose is cellulose having an average degree of polymerization of 60 to 375 obtained by hydrolyzing pulp, and is consistent with crystalline cellulose according to the 15th revised Japanese pharmacopoeia.
  • the average particle size of crystalline cellulose is 80 to 150 ⁇ m.
  • the average particle size is 80 ⁇ m or more, a cellulose composition having excellent fluidity can be obtained.
  • the surface area of crystalline cellulose is increased, the contact area with the water-soluble cellulose derivative [B] is increased, and deterioration of moldability due to a decrease in the bond between the water-soluble cellulose derivatives [B] during compression is prevented. Can do.
  • the average particle size is 150 ⁇ m or less, the cellulose composition can be filled in a very narrow space of 3 mm or less of the outer layer of the dry-coated tablet or the microtablet.
  • the average particle size of the crystalline cellulose is preferably 85 to 135 ⁇ m.
  • the loose bulk density of crystalline cellulose is 0.30 to 0.50 g / cm 3 .
  • the loose bulk density is 0.30 g / cm 3 or more, the number of particles that can be filled in the outer layer of the dry-coated tablet or the narrow space of the microtablet increases, and the compression moldability of the cellulose composition can be improved.
  • the loose bulk density is 0.50 g / cm 3 or less, it is possible to obtain a cellulose composition having excellent fillability and high compression moldability due to the moldability of crystalline cellulose itself.
  • the loose bulk density of crystalline cellulose is preferably 0.35 g / cm 3 or more, and more preferably 0.40 g / cm 3 or more.
  • the angle of repose of crystalline cellulose is 40 degrees or less. When the angle of repose is 40 degrees or less, the cellulose composition has excellent fluidity, and therefore, the cellulose composition can be filled into the outer layer of the dry-coated tablet or the narrow space of the microtablet.
  • the angle of repose of crystalline cellulose is preferably 38 degrees or less, and more preferably 32 to 38 degrees. By setting the angle of repose to 32 degrees or more, a cellulose composition having high compression moldability can be obtained, which is preferable.
  • the average particle diameter, loose bulk density, and angle of repose of crystalline cellulose can be measured by the methods described in the following examples.
  • the blending amount of the crystalline cellulose is 55 to 75% by mass, preferably 57.5 to 72.5% by mass.
  • the blending amount is 55% by mass or more, the bulk density of the whole cellulose composition can be increased and a cellulose composition having excellent fluidity can be obtained.
  • the blending amount is 75% by mass or less, a sufficient amount of the water-soluble cellulose derivative [B] can be blended as a relative amount, and a cellulose composition having high moldability can be obtained.
  • the water-soluble cellulose derivative [B] used in the present embodiment has an average particle size of 80 ⁇ m or less, and the viscosity of a 2 mass% 20 ° C. aqueous solution is 10 mPa ⁇ s or less.
  • the water-soluble cellulose derivative is not particularly limited as long as it is a water-soluble cellulose derivative used as a pharmaceutical additive. Examples thereof include hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), hydroxyethylcellulose, hydroxyethylmethylcellulose, and methylcellulose. . Among them, hydroxypropyl cellulose having an average particle diameter of 80 ⁇ m or less and a 2 mass% 20 ° C.
  • hydroxypropylcellulose is a hydroxypropyl ether of cellulose containing 53.4-77.5% of hydroxypropoxyl groups (—OCH 3 H 5 OH) with respect to the hydroxyl groups of cellulose.
  • the average particle size of the water-soluble cellulose derivative is 80 ⁇ m or less.
  • the average particle size is 80 ⁇ m or less, the surface area of the water-soluble cellulose derivative is reduced, and at the time of compression molding, the water-soluble cellulose derivative particles or the bonding portion between the water-soluble cellulose derivative particles and the crystalline cellulose particles is reduced. Moreover, the fall of the moldability of a cellulose composition can be prevented.
  • the average particle size of the water-soluble cellulose derivative is preferably 20 to 70 ⁇ m.
  • the viscosity of a 2% by weight aqueous solution of 20 ° C. of a water-soluble cellulose derivative is 10 mPa ⁇ s or less.
  • a water-soluble cellulose derivative having a viscosity of 2% by mass of a 20 ° C. aqueous solution of greater than 10 mPa ⁇ s for example, Nisso HPC-M, which is hydroxypropyl cellulose and the viscosity of a 2% by mass of 20 ° C. aqueous solution is greater than 10 mPa ⁇ s, In the case of HPC-H), the viscosity when dissolved is very high.
  • the moldability is unexpectedly low, and the moldability of the cellulose composition cannot be sufficiently obtained.
  • Tend. In the case of a water-soluble cellulose derivative in which the viscosity of a 2% by mass aqueous solution at 20 ° C. is 10 mPa ⁇ s or less, the gelation tendency when water is contained is reduced. A formulation can be obtained. It is preferable that the viscosity of a 2 mass% 20 degreeC aqueous solution of a water-soluble cellulose derivative is 6 mPa * s or less.
  • the average particle diameter of the water-soluble cellulose derivative and the viscosity of a 2 mass% 20 ° C. aqueous solution can be measured by the method described in the following examples.
  • HPC-SL is preferable because it has a particularly low viscosity and a fine powder type is available.
  • the compounding amount of the water-soluble cellulose derivative is 17.5 to 37.5% by mass, preferably 20 to 35% by mass.
  • the blending amount is 17.5% by mass or more, a cellulose composition having high moldability can be obtained by sufficiently exhibiting the binding strength of the water-soluble cellulose derivative.
  • the loose bulk density of the water-soluble cellulose derivative itself is smaller than that of crystalline cellulose [A], and the angle of repose is also large.
  • the blending amount is 37.5% by mass or less, a decrease in bulk density of the cellulose composition and deterioration of fluidity can be prevented, and a cellulose composition having excellent formability and high moldability is obtained. be able to.
  • the fluidizing agent [C] used in the cellulose composition of the present embodiment is obtained by dispersing particles on the surface of the crystalline cellulose [A] and the water-soluble cellulose derivative [B]. By increasing the bulk density and improving the fluidity, it is a substance to be blended in order to improve the filling property and moldability of the cellulose composition even under limited conditions where the filling volume is extremely small.
  • the fluidizing agent include light anhydrous silicic acid, hydrous silicic acid, magnesium aluminate metasilicate, calcium silicate, and the like, among which silicic acid such as light anhydrous silicic acid and hydrous silicic acid is preferable.
  • Light anhydrous silicic acid is preferable in that the primary particle size is small and the fluidization effect is high, and specific examples include Aerosil 200 or Aerosil 200CF sold by Nippon Aerosil Co., Ltd.
  • the blending amount of the fluidizing agent is 0.01 to 0.5% by mass, preferably 0.01 to 0.35% by mass.
  • the blending amount is 0.01 mass or more, the effect of the fluidizing agent can be sufficiently exhibited in the cellulose composition.
  • the blending amount is 0.5% by mass or less, a sufficient amount of fluidizing agent particles can be blended, and a cellulose composition having an appropriate loose bulk density can be obtained.
  • the fluidizing agent appropriately covers the particle surface of the crystalline cellulose [A] or the water-soluble cellulose derivative [B], and the cellulose composition has a sufficient binding force. It can be demonstrated.
  • the excipient [D] used in the present embodiment has an average particle size of 150 ⁇ m or less and a loose bulk density of 0.60 to 1.00 g / cm 3 .
  • the average particle size of the excipient is 150 ⁇ m or less, the cellulose composition is sufficiently filled in the outer layer of the dry-coated tablet and the very narrow space of 3 mm or less of the microtablet.
  • the average particle size of the excipient [D] is preferably 30 to 100 ⁇ m from the viewpoint of the bulk density of the cellulose composition.
  • the loose bulk density of the excipient [D] is 0.60 to 1.00 g / cm 3 .
  • the loose bulk density of the cellulose composition can be increased.
  • the loose bulk density is 1.00 g / cm 3 or less, a cellulose composition having high moldability can be obtained.
  • the loose bulk density of the excipient [D] is preferably 0.70 to 0.95 cm 3 or more.
  • the blending amount of the excipient [D] is 5 to 20% by mass or less, preferably 6 to 18% by mass, and more preferably 8 to 15% by mass.
  • the blending amount is 5% by mass or more, the bulk density of the cellulose composition can be increased.
  • the blending amount is 20% by mass or less, a cellulose composition having high moldability can be obtained.
  • the average particle size and loose bulk density of the excipient can be measured by the methods described in the following examples.
  • the ratio [D] / [B] of the excipient [D] and the water-soluble cellulose derivative [B] is less than 1.0.
  • the ratio [D] / [B] is less than 1.0, that is, the blending amount of the excipient is less than the blending amount of the water-soluble cellulose derivative, the moldability of the water-soluble cellulose derivative can be exhibited. It can be set as the cellulose composition which has high moldability.
  • excipient [D] for example, sugars such as sucrose, glucose, lactose, trehalose, sugar alcohols such as mannitol, erythritol, sorbitol, maltitol, xylitol, magnesium silicate, calcium hydrogen phosphate, anhydrous hydrogen phosphate
  • examples include inorganic compounds such as calcium, calcium dihydrogen phosphate, talc, titanium oxide, and calcium carbonate.
  • commercially available spray-dried lactose, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate are available.
  • anhydrous calcium hydrogen phosphate having a looser bulk density is more preferable.
  • Commercially available products include anhydrous calcium hydrogen phosphate heavy grade, GS grade (manufactured by Kyowa Chemical Industry Co., Ltd.) and the like.
  • the cellulose composition of the present embodiment contains crystalline cellulose [A], a water-soluble cellulose derivative [B], a fluidizing agent [C], and an excipient [D], all in a powder state.
  • “all in the state of powder” is a product that has undergone a mixing process as described later in the manufacturing process, and [A], [B], [C], and It means that the particles of [D] are not combined into granules.
  • a water-soluble cellulose derivative particularly, hydroxypropyl cellulose
  • the water-soluble cellulose derivative is dissolved in a solvent.
  • the cellulose derivative becomes a film when the solvent is dried, and other powders are bonded through this film to form granules.
  • the size of the granule is generally larger than 100 ⁇ m. In this case, the flowability is improved, but in a narrow space such as the outer layer of a dry-coated tablet or a microtablet. It is difficult to fill with powder.
  • wet granulation methods fluidized bed granulation and stirring granulation, but fluidized bed granulation is difficult to produce granules with a loose bulk density of 0.47 g / cm 3 or more.
  • the agitation granulation method may be able to produce granules having a loose bulk density of 0.47 g / cm 3 or more, but in this case, the granules become hard and thus have poor compression moldability, which is sufficient at the time of compression molding. Can not give strength.
  • the average particle size of the cellulose composition of the present embodiment is 100 ⁇ m or less, preferably 30 to 100 ⁇ m.
  • the cellulose composition is sufficiently filled into the outer layer of the dry-coated tablet and the very narrow space of 3 mm or less of the microtablet.
  • An average particle size of 30 ⁇ m or less is preferable because a cellulose composition having excellent filling properties can be obtained.
  • the repose angle of the cellulose composition of the present embodiment is 35 degrees or less, preferably 32 to 35 degrees.
  • the angle of repose is 35 degrees or less, the cellulose composition has sufficient fluidity, the filling volume is extremely small, and the outer layer of the dry-coated tablet or the narrow space of the microtablet having a filling width of 3 mm or less. Easy to be filled with particles. Therefore, there is no variation in the filling weight of the outer layer of the dry-coated tablet or the microtablet, and a sufficient filling weight is obtained, so that moldability during compression can be obtained.
  • a repose angle of 32 degrees or less is preferable because a cellulose composition having high compression moldability can be obtained.
  • the loose bulk density of the cellulose composition of the present embodiment is 0.47 g / cm 3 or more, preferably 0.47 to 0.56 g / cm 3 .
  • the tapping bulk density of the cellulose composition is 0.60 g / cm 3 or more, preferably 0.60 to 0.80 g / cm 3 .
  • a loose bulk density of 0.56 g / cm 3 or less or a tapping bulk density of 0.80 g / cm 3 or less is preferable because a cellulose composition having high compression moldability can be obtained.
  • volume strength of the compression molded body of the cellulose composition in the present embodiment is preferably 80 ⁇ 115N / cm 3, more preferably 82.5 ⁇ 110N / cm 3.
  • the volume strength [N / cm 3 ] of the compression molded body is a physical property calculated by the following formula when the cellulose composition is a compression molded body.
  • Volume strength of compression molded product [N / cm 3 ] tensile strength at break of compression molded product [N] / powder volume [cm 3 ]
  • Powder volume [cm 3 ] 0.15 [g] / Loose bulk density [g / cm 3 ]
  • a method for obtaining the tensile breaking strength of the compression molded body will be described. Weigh accurately 150 mg of the cellulose composition. Then, when placed in the bottom area of 1 cm 2 circular die (diameter 11.3Mmfai), the bottom area is compressed by the compression rate 20 cm / min in a circular flat punch of 1 cm 2, the compression force reaches 2 kN, 10 seconds A compression molded body is created by maintaining the compression force. The thickness of the compression molded body obtained at this time is about 1.0 to 1.5 mm. Next, the tensile fracture strength of the obtained compression molded body is measured. For the measurement, a creep meter (Yamaden Co., Ltd., RE-33005, 20 kgf load cell) is used.
  • the compression molded body is left so that the central portion can be seen by 1 mm, and is fixed by sandwiching the upper and lower portions with a dedicated jig. Thereafter, with the upper part fixed, the compression molded body is pulled at the lower part at a tensile speed of 0.1 mm / s, and the strength when it is broken is defined as tensile breaking strength [N].
  • the volume strength of the compression-molded body is an index that represents the physical properties of powder that has not existed before.
  • mass strength the strength per mass of powder in which the mass of the compression molded product is evaluated to be constant.
  • the filling volume is changed to set the mass to the target value (for example, 200 mg), and whether or not the strength at that time is sufficient As long as the excipient was determined. Therefore, there was no concept of volume strength.
  • the cellulose composition of the present embodiment is used for applications where it is very difficult to change the volume of the filled portion, such as the outer layer part of the dry-coated tablet or the microtablet, as the cellulose composition for compression molding.
  • the strength of the compression-molded body is evaluated not by the mass of the powder but by the tensile breaking strength per volume, and thus it is difficult to change the volume in which the powder can be filled. It was possible to find a cellulose composition suitable for the outer layer of a dry-coated tablet or for compression molding of a microtablet.
  • the cellulose composition has a specific average particle size, loose bulk density, angle of repose, tapping bulk density, and the volume strength of the compression molded product of the cellulose composition is 80 N / cm 3 or more
  • an ordinary tablet it is possible to give sufficient strength even when the volume of the portion to be filled, such as the outer layer part of a dry-coated tablet or a micro tablet, is small. Is preferable. Thereby, in the case of a dry-coated tablet, it is possible to prevent the tablet from being cracked or cracked during tableting, and the inner core from being deformed and biting into the outer layer.
  • the outer layer may crack without being able to withstand the deformation force, or when stored in a bottle, it may be cracked by impact force during transportation.
  • the compression molded body has a volume strength of 80 N / cm 3 or more, these problems can be prevented.
  • cellulose compositions are mostly powders with high moldability and low bulk density, or powders with low moldability and high bulk density. Is less than 80 N / cm 3 , and the above problem cannot be sufficiently prevented.
  • the volume strength of the compression molded product may be greater than 115 N / cm 3 .
  • gelation occurs when water is included, and the disintegration property is very poor. Therefore, when used for the outer layer of a dry-coated tablet, the tablet does not disintegrate within 30 minutes and cannot be used as an immediate release preparation.
  • the disintegration time in the compression molded product of the cellulose composition of the present embodiment is preferably 1 to 20 minutes, and more preferably 1 to 15 minutes.
  • the method for obtaining the disintegration time of the compression molded product of the cellulose composition will be described. Weigh accurately 150 mg of the cellulose composition. Then, when placed in the bottom area of 1 cm 2 circular die (diameter 11.3Mmfai), the bottom area is compressed by the compression rate 20 cm / min in a circular flat punch of 1 cm 2, the compression force reaches 2 kN, 10 seconds A compression molded body is created by maintaining the compression force. The thickness of the compression molded body obtained at this time is about 1.0 to 1.5 mm. Next, the disintegration time of the obtained compression molded body is measured.
  • the measurement is performed according to the 15th revised Japanese Pharmacopoeia, tablet disintegration test method.
  • the compression molded product obtained from the cellulose composition is determined as a disintegration time in 37 ° C. pure water using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd., NT-40HS type, with disk). The value is the number average of 6 samples.
  • the disintegration time of the compression molded product is 20 minutes or less, and when the cellulose composition is mainly used for the dry-coated tablet, the disintegration test described in the 15th revised Japanese Pharmacopoeia is performed on the dry-coated tablet Furthermore, it is possible to obtain a dry-coated tablet that disintegrates in 30 minutes or less and is suitable as an immediate release preparation.
  • a shorter disintegration time of the compression molded article is advantageous as an immediate release preparation, but it is usually difficult to increase the volume strength to 80 N / cm 3 or more.
  • the collapse time of the compression molded body is preferably 1 minute or longer.
  • the cellulose composition of the present embodiment is prepared by the above-described crystalline cellulose [A], water-soluble cellulose derivative [B], fluidizing agent [C], emulsifying agent, and the like when producing ordinary tablets, dry-coated tablets, microtablets and the like. It may be used together with other additives other than the form [D], such as croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, low substituted hydroxypropylcellulose, etc.
  • Cellulose sodium carboxymethyl starch, hydroxypropyl starch, rice starch, wheat starch, corn starch, potato starch, partially pregelatinized starch, crospovidone and other disintegrants, magnesium stearate, calcium stearate, stearic acid, sucrose Lubricants such as fatty acid esters, glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, 1-menthol and other flavoring agents, orange, vanilla, strawberry, menthol Fragrances such as fennel oil, cinnamon oil, spruce oil, peppermint oil, green tea powder, edible pigments such as edible red No. 3, edible yellow No. 5, edible blue No.
  • colorants such as copper chlorophyllin sodium, titanium oxide, riboflavin Sweeteners such as aspartame, saccharin, dipotassium glycyrrhizinate, stevia, starch syrup, and amacha powder
  • surfactants such as phospholipids, glycerin fatty acid esters, polyethylene glycol fatty acid esters, sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, etc. Can be mentioned.
  • the cellulose composition of the present embodiment may be used together with active ingredients such as drugs, agricultural chemicals, fertilizers, feeds, foods, cosmetics, and the like as antipyretic analgesic anti-inflammatory drugs, hypnotic sedatives, sleepiness prevention drugs.
  • active ingredients such as drugs, agricultural chemicals, fertilizers, feeds, foods, cosmetics, and the like as antipyretic analgesic anti-inflammatory drugs, hypnotic sedatives, sleepiness prevention drugs.
  • active ingredients such as drugs, agricultural chemicals, fertilizers, feeds, foods, cosmetics, and the like as antipyretic analgesic anti-inflammatory drugs, hypnotic sedatives, sleepiness prevention drugs.
  • active ingredients such as drugs, agricultural chemicals, fertilizers, feeds, foods, cosmetics, and the like as antipyretic analgesic anti-inflammatory drugs, hypnotic sedatives, sleepiness prevention drugs.
  • Antipruritic pediatric analgesic, stomachic, antacid, digestive, cardiotonic, arrhythmic, antihypertens
  • additives and active ingredients added to the cellulose composition of the present embodiment have a loose bulk density and a low moldability, so that the blending amount does not impair the advantages of the cellulose composition. It is preferable.
  • the thickness of the outer layer of a normal tablet having a diameter of 5 to 20 mm or a dry-coated tablet is relatively large, or the size of the microtablet is relatively large, the above-mentioned other additives or active ingredients may be incorporated in a relatively large amount.
  • the smaller the outer layer thickness of the dry-coated tablet or the smaller the size of the microtablet the smaller the amount of other pharmaceutical additives or active ingredients that can be added.
  • the amount of other additives and active ingredients is preferably 20 parts by mass or less, more preferably 10 parts by mass or less, and more preferably 5 parts by mass or less with respect to 100 parts by mass of the cellulose composition. Is more preferable.
  • cellulose composition of the present embodiment components containing at least crystalline cellulose [A] and a fluidizing agent [C] are first mixed in a container-fixed mixer, and then the remaining components are added to add any optional components. It is preferable to mix with a mixer.
  • At least the crystalline cellulose [A] and the fluidizing agent [C] may contain only the crystalline cellulose [A] and the fluidizing agent [C], or the crystalline cellulose [A], the fluidizing agent [C] and the water-soluble Cellulose derivative [B] may be included, crystalline cellulose [A], fluidizing agent [C] and excipient [D] may be included, crystalline cellulose [A], fluidizing agent [C] and water-soluble Cellulose derivative [B] and excipient [D], crystalline cellulose [A], fluidizing agent [C], water-soluble cellulose derivative [B], excipient [D] and the other Meaning that it may contain other pharmaceutical additives and active ingredients.
  • crystalline cellulose [A] and fluidizing agent [C] are mixed in a container-fixed mixer, and further water-soluble cellulose derivative [B] and excipient [D], and further if necessary.
  • other pharmaceutical additives and active ingredients are added to the mixture of [A] and [C] and mixed in an arbitrary mixer.
  • the container-fixing type mixer is a general term for a container in which a container is fixed and a stirring blade for promoting mixing by giving motion to the powder charged in the container is mounted in the container. It is also called a mechanical stirring mixer.
  • the container-fixed mixer forcibly gives shearing force and diffusing force by the rotation of the stirring blades, and the mixing flow is promoted by adding a circulating flow of powder particles in the vessel.
  • mixers such as ribbon type mixers, screw type mixers, paddle type mixers, planetary motion type (Nauter mixer), etc.
  • high-speed stirring type mixers Can be used.
  • Specific devices of the high-speed agitating mixer include mechano mill (Okada Seiko Co., Ltd.), vertical granulator (Powrec Co., Ltd.), high speed mixer (Fukae Kogyo Co., Ltd.), laboratory matrix (( Nara Machinery Co., Ltd.).
  • a mixer called a container rotation type mixer a horizontal cylindrical mixer, a V type mixer, a tumbler type mixer, a double cone type mixer, and the like can be given.
  • the container-fixed mixer is a mixing method in which the stirring blade in the container directly gives shear to the powder as compared with the container rotating mixer, and the crystalline cellulose [A], which is a component of the cellulose composition, and the fluidizing agent
  • the dispersion of [C] proceeds more uniformly. Therefore, the fluidizing agent tends to adhere uniformly to the surface of the crystalline cellulose, and the loose bulk density and tapping bulk density of the mixture are larger than when a container-fixed mixer is used.
  • the method of mixing the crystalline cellulose [A] and the fluidizing agent [C] with a container-fixed mixer first is because the fluidizing agent [C] is dispersed on the surface of the crystalline cellulose [A] having the largest blending amount.
  • the effect of increasing the loose bulk density and the tapping bulk density is large, and crystalline cellulose [A] is preferable because the compression moldability is not easily lowered even when the fluidizing agent [C] adheres to the surface.
  • the fluidizing agent [C] when the fluidizing agent [C] is mixed under a condition not containing crystalline cellulose [A] and then the crystalline cellulose [A] is added, that is, the fluidizing agent [C] and the water-soluble cellulose.
  • the fluidizing agent [B] When mixing is performed by a method in which the derivative [B] is first mixed and then the crystalline cellulose [A] is added and mixed, the fluidizing agent [B] is added to the surface of the water-soluble cellulose derivative [B]. If C] is uniformly dispersed and adhered, the binding portion of the water-soluble cellulose derivative [B] may be covered, and the compression moldability of the cellulose composition after mixing may be greatly reduced.
  • Crystalline cellulose [A] and fluidizing agent [C] are mixed in a container-fixed mixer, and then water-soluble cellulose derivative [B], excipient [D], and other components are added and mixed.
  • mixing may be performed with an arbitrary mixer, and the mixture may be subsequently added to the container-fixed mixer and mixed, or may be transferred to the container rotating mixer and mixed.
  • the mixing time can be appropriately selected depending on the type and size of the container-fixed mixer, the rotational speed of the stirring blade, and the like.
  • the bulk density, tapping bulk density, angle of repose, volume strength in the compression molded product, and disintegration time of the cellulose composition of the present embodiment are crystalline cellulose [A], water-soluble cellulose derivative [B], and fluidizing agent [C]. It can be achieved for the first time by blending the excipient [D] with the physical properties and blending amounts defined above.
  • the bulk density, tapping bulk density, and angle of repose of the cellulose composition can be measured by the methods described in the following examples.
  • the cellulose composition of the present embodiment can be tableted by tableting with an active ingredient and other additives using a known method.
  • the cellulose composition of the present embodiment is used for a normal tablet having a diameter of about 5 to 20 mm, the cellulose composition, the active ingredient, and other additives are mixed because the filling property and moldability are good.
  • the powder can be produced by a direct tableting method in which the powder is supplied to a known rotary tableting machine as it is for tableting. At this time, since the powder filling property and moldability are good, there is an advantage that a tablet with high mass production, small mass variation and high strength can be produced.
  • the cellulose composition of the present embodiment has a feature that the volume strength of the compression-molded body is high. Therefore, among tablets, so-called microtablets or powdered tablets for outer layer compression molding of dry-coated tablets are used. In applications where the volume for filling the body is small and it is difficult to change the volume, the moldability and fillability are significantly higher than conventional powders.
  • the outer layer compression molding application of the dry-coated tablet is a field suitable for applying the cellulose composition of the present embodiment, and among them, the outer-layer compression molding application of the rapid-release preparation of the dry-coated tablet is particularly suitable. .
  • the dry coated tablet produced using the cellulose composition of the present embodiment has an average particle size of 80 to 150 ⁇ m, a loose bulk density of 0.30 to 0.50 g / cm 3 , and an angle of repose of 40 degrees or less. 55-75% by mass of crystalline cellulose [A] and 17.5-37.
  • Excipient having 5% by mass, 0.01 to 0.5% by mass of fluidizing agent [C], an average particle size of 150 ⁇ m or less, and a loose bulk density of 0.60 to 1.00 g / cm 3
  • An outer layer containing 5 to 20% by mass of [D] The ratio of [D] to [B] ([D] / [B]) is less than 1.0, the thickness of the outer layer side surface portion is 2 mm or less, and the disintegration time is 30 minutes or less.
  • a commercially available dry-coated tablet press for example, AP-MS-C type dry tablet press (manufactured by Hata Iron Works Co., Ltd.), AQUARIUS DC type rotary type It can be manufactured using a nuclear tablet press (such as Kikusui Seisakusho Co., Ltd.).
  • the general manufacturing method of a dry-coated tablet is as follows. The first feeder is filled with a cellulose composition for an outer layer in a die, and then the pre-prepared inner core tablet is supplied to the center of the die using a dedicated feeder. Further, after the cellulose composition for the outer layer is supplied to the side surface and the upper part of the inner core tablet by the second feeder, the whole is compression-molded.
  • the thickness of the outer layer side surface portion of the dry-coated tablet may be appropriately determined from the final tablet size and the inner core tablet size, but the thinner the outer layer side surface portion, the thinner the cellulose composition of the present embodiment has.
  • the effect of high volume strength is more exhibited.
  • the thickness of the outer layer side surface portion can be reduced accordingly, but the thinner the outer layer side surface portion of the dry coated tablet, the higher the moldability of the excipient used for the outer layer. And high filling properties are required. Therefore, the effect of the high volume strength which the cellulose composition of this Embodiment has is further exhibited.
  • the dry-coated tablet press disclosed in International Publication No. 2001/098067 pamphlet
  • the displacement can be further suppressed and the side surface of the outer layer can be made extremely thin, and can be made 1 mm or less. Therefore, the composition used for the outer layer is required to have both extremely high moldability and filling property, and the effect of high volume strength possessed by the cellulose composition of the present embodiment is most exhibited.
  • the thickness of the side surface portion of the outer layer is preferably 2 mm or less, and more preferably 1.5 mm or less.
  • the dry-coated tablet using the cellulose composition of the present embodiment for the outer layer is preferably used as an immediate-release preparation that does not suppress the release of the drug in the outer layer portion, and therefore the collapse of the dry-coated tablet
  • the time is preferably within 30 minutes in the disintegration test described in the 15th revised Japanese Pharmacopoeia, which is suitable as an immediate release formulation.
  • the hardness of the dry-coated tablet is preferably 40N or more, and more preferably 50N or more, so as not to cause chipping or abrasion during transportation and transportation. Since the disintegration time may be delayed if the hardness of the dry coated tablet is too high, it is preferably 200 N or less, and more preferably 150 N or less.
  • the cellulose composition of the present embodiment since it has a high volume strength, it can impart sufficient strength even when the thickness of the outer layer of the dry-coated tablet is reduced, so that the hardness of 40 N or more It is possible to produce a dry-coated tablet having an appropriate compressive force. Therefore, the inner core is not crushed and the film-coated granules are not damaged.
  • the microtablet can also be manufactured using a known method.
  • a general method for manufacturing a microtablet will be described below.
  • For the microtablet use is made of an original gutter having a plurality of thin ridges having a diameter of 1 to 3 mm and a mortar having a plurality of small holes having a diameter of 1 to 3 mm in accordance with the shape of the ridge. Marshal and mortar can be set in a normal tableting machine, and can be manufactured using a general tableting machine that supplies powder to a tableting machine from a hopper and compresses it.
  • Microtablets are cylindrical and have flat or convex upper and lower surfaces, and both the diameter and thickness can be varied independently of each other, but usually the thickness is adjusted to the diameter, In many cases, the thicknesses are approximately the same. Conditions such as tableting rotation speed and pressure can be set as appropriate depending on the size of the microtablet and the required physical properties of the microtablet. If it is high, there is a risk of breakage. Therefore, it is necessary to lower the tableting pressure as compared with normal tableting. In addition, since the diameter of the mortar is small, the powder used for tableting is required to have good filling properties.
  • the cellulose composition of the present embodiment Since the cellulose composition of the present embodiment has good filling properties, it can be filled even in a mortar having a small diameter without variation. In addition, since the cellulose composition of the present embodiment has high moldability, the tableting pressure can be kept low, and the risk of breakage can be reduced. Since the microtablets obtained in this way have high strength and abrasion resistance, they can be directly filled into capsules with a normal filling machine, and using a known coating technique, It is also possible to apply a coating treatment to the surface of the microtablet.
  • Average particle size [ ⁇ m] The particle size distribution was measured by sieving 30 g of a sample for 15 minutes using a JIS standard sieve (Z8801-1987) using a low-tap sieve shaker (manufactured by Heiko Seisakusho Co., Ltd., sieve shaker A type). A particle size of 50% by mass was measured as an average particle size. The measurement was repeated three times, and the average value was taken as the average particle size.
  • Tapping bulk density [g / cm 3 ] A sample of 30 g was loosely packed into a 100 cm 3 glass graduated cylinder and tapped by hand on a low impact table such as a desk with a rubber plate. The tapping was performed by dropping from a height of several centimeters perpendicular to the table until the compaction of the sample stopped. After completion of the tapping, the volume [cm 3 ] of the sample layer was read, and the mass of the sample 30 [g] / volume of the sample layer [cm 3 ] was measured. The measurement was repeated three times, and the average value was defined as the tapping bulk density.
  • volume strength [N / cm 3 ] The volume strength of the compression molded body was measured according to the method described above.
  • the disintegration test was conducted according to the 15th revision Japanese Pharmacopoeia, the disintegration test method for tablets.
  • the compression molding of the cellulose composition or the dry-coated tablet was determined as a disintegration time in 37 ° C. pure water using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd., NT-40HS type, with disk). The measurement was repeated 6 times, and the average value was taken as the disintegration time.
  • Example 1 1 kg of commercially available DP pulp is shredded, hydrolyzed under pressure in a 0.3% hydrochloric acid solution at 110 ° C. for 25 minutes, and the resulting acid-insoluble residue is filtered and washed, and then a 18% by weight solid content slurry It was. Using a two-fluid nozzle, the slurry was spray-dried under the conditions of a flow rate of 5 L / h, a hot air temperature of 180 ° C., and an exhaust air outlet temperature of 86 ° C. to obtain an average particle size of 98 ⁇ m and a loose bulk density of 0.445 g / cm 3. Crystalline cellulose [A] having an angle of repose of 37 degrees was obtained.
  • an excipient [D] 50 g of anhydrous calcium hydrogen phosphate (GS grade, manufactured by Kyowa Chemical Industry Co., Ltd.) having an average particle diameter of 75 ⁇ m, a loose bulk density of 0.775 g / cm 3 and an angle of repose of 38 degrees.
  • the mixture was added to a V-type mixer and mixed for 30 minutes to obtain a cellulose composition (I).
  • the physical properties of the obtained cellulose composition (I) are shown in Table 1.
  • the average particle size is 72 ⁇ m
  • the angle of repose is 35 degrees
  • the loose bulk density is 0.478 g / cm 3
  • the tapping bulk density is 0.616 g / cm 3
  • the volume strength is 90.1 N / cm 3
  • the disintegration time is 14.2. Minutes.
  • Example 2 Using the same crystalline cellulose [A], water-soluble cellulose derivative [B], fluidizing agent [C] and excipient [D] as in Example 1, 21 kg of crystalline cellulose [A] and water-soluble cellulose derivative [B] 10 4125 kg and fluidizing agent [C] 87.5 g were added to a Nauter mixer (NX-1 type, manufactured by Hosokawa Micron Corporation) and mixed for 30 minutes. 10.8 kg of the mixed powder is put into a tumbler type mixer (TM-50S type, manufactured by Tokuju Seisakusho Co., Ltd.), and further 1.2 kg of excipient [D] is added and mixed for 30 minutes. A cellulose composition (II) was obtained. Table 1 shows the physical properties of the obtained cellulose composition (II).
  • the average particle size is 72 ⁇ m, the angle of repose is 35 degrees, the loose bulk density is 0.483 g / cm 3 , the tapping bulk density is 0.621 g / cm 3 , the volume strength is 84.0 N / cm 3 , and the disintegration time is 9.2. Minutes.
  • Example 3 Except for using as an excipient [D] lactose for direct hitting (SUPER-TAB, sold by Asahi Kasei Chemicals Corporation) having an average particle size of 110 ⁇ m, a loose bulk density of 0.630 g / cm 3 and an angle of repose of 35 degrees,
  • a cellulose composition (III) was obtained.
  • Table 1 shows the physical properties of the obtained cellulose composition (III). The average particle size is 83 ⁇ m, the angle of repose is 34 degrees, the loose bulk density is 0.481 g / cm 3 , the tapping bulk density is 0.616 g / cm 3 , the volume strength is 87.3 N / cm 3 , and the disintegration time is 11.6. Minutes.
  • Example 4 Using the same crystalline cellulose [A], water-soluble cellulose derivative [B], fluidizing agent [C] and excipient [D] as in Example 1, 350 g of crystalline cellulose [A] and water-soluble cellulose derivative [B] was obtained in the same manner as in Example 1, except that 98.75 g, fluidizing agent [C] was 1.25 g, and excipient [D] was 50 g. Table 1 shows the physical properties of the cellulose composition (IV) obtained.
  • the average particle size is 78 ⁇ m, the angle of repose is 35 degrees, the loose bulk density is 0.477 g / cm 3 , the tapping bulk density is 0.643 g / cm 3 , the volume strength is 83.4 N / cm 3 , and the disintegration time is 0.9. Minutes.
  • Example 5 Using the same crystalline cellulose [A], water-soluble cellulose derivative [B], fluidizing agent [C] and excipient [D] as in Example 1, 275 g of crystalline cellulose [A] and water-soluble cellulose derivative [B] was obtained in the same manner as in Example 1 except that 123.75 g, fluidizing agent [C] was 1.25 g, and excipient [D] was 100 g. Table 1 shows the physical properties of the obtained cellulose composition (V).
  • the average particle size is 63 ⁇ m, the angle of repose is 35 degrees, the loose bulk density is 0.499 g / cm 3 , the tapping bulk density is 0.618 g / cm 3 , the volume strength is 81.7 N / cm 3 , and the disintegration time is 4.4. Minutes.
  • Example 1 According to Example 1 of WO 02/02643 pamphlet, 2 kg of commercially available SP pulp (polymerization degree 1030, level-off polymerization degree 220) is shredded and placed in 30 L of 4N hydrochloric acid aqueous solution. Hydrolysis was performed at 60 ° C. for 72 hours while stirring (stirring speed: 10 rpm) with a 30 LGL reactor (manufactured by Co., Ltd., blade diameter: about 30 cm). The obtained acid-insoluble residue was filtered using a Nutsche, and the filtered residue was further washed 4 times with 70 L of pure water.
  • composition (a) After neutralizing the filtration residue with aqueous ammonia, put it in a 90-liter plastic bucket, add pure water, and concentrate with stirring (stirring speed 100 rpm) with a three-one motor (made by HEIDON, type 1200G, 8M / M, blade diameter about 5 cm). A 10% by mass cellulose dispersion was prepared (pH; 6.7, IC; 45 ⁇ S / cm). This was spray-dried (liquid supply rate 6 L / hr, inlet temperature 180 to 220 ° C., outlet temperature 50 to 70 ° C.) to obtain crystalline cellulose, which was designated as composition (a). Table 2 shows the physical properties of the resulting composition (a).
  • the average particle size is 45 ⁇ m, the angle of repose is 49 degrees, the loose bulk density is 0.220 g / cm 3 , the tapping bulk density is 0.358 g / cm 3 , the volume strength is 51.2 N / cm 3 , and the disintegration time is 2.5. Minutes.
  • composition (b) a cellulose aggregate (crystalline cellulose), which was designated as composition (b).
  • Table 2 shows the physical properties of the obtained composition (b). The average particle size is 80 ⁇ m, the angle of repose is 37 degrees, the loose bulk density is 0.242 g / cm 3 , the tapping bulk density is 0.335 g / cm 3 , the volume strength is 38.3 N / cm 3 , and the disintegration time is 1.5. Minutes.
  • Table 2 shows the properties of “SUPER-TAB” (sold by Asahi Kasei Chemicals Corporation), which is a commercially available spray-dried lactose, as a composition (c).
  • the average particle size is 90 ⁇ m
  • the angle of repose is 33 degrees
  • the loose bulk density is 0.631 g / cm 3
  • the tapping bulk density is 0.750 g / cm 3
  • the volume strength is 24.8 N / cm 3
  • the disintegration time is 1.7. Minutes.
  • Table 2 shows the physical properties of “PROSOLV SMCC90” (manufactured by JRS RETTENMAINER & SOEHNE GmbH + Co), which is a commercially available crystalline cellulose / silicon dioxide spray-dried product, as a composition (d).
  • the average particle size is 90 ⁇ m
  • the angle of repose is 37 degrees
  • the loose bulk density is 0.300 g / cm 3
  • the tapping bulk density is 0.408 g / cm 3
  • the volume strength is 55.5 N / cm 3
  • the disintegration time is 1.1. Minutes.
  • Table 2 shows the properties of “Microcelac 100” (manufactured by Meggle Pharma), which is a commercially available crystalline cellulose / lactose spray-dried product, as a composition (e).
  • the average particle size is 154 ⁇ m
  • the angle of repose is 37 degrees
  • the loose bulk density is 0.486 g / cm 3
  • the tapping bulk density is 0.622 g / cm 3
  • the volume strength is 26.1 N / cm 3
  • the disintegration time is 0.8. Minutes.
  • composition (f) was obtained in the same manner as in Example 1, except that the amount of the agent [C] was 1.5 g and the excipient [D] was not added and mixed (0 g). .
  • Table 3 shows the physical properties of the resulting composition (f).
  • the average particle size is 75 ⁇ m
  • the angle of repose is 36 degrees
  • the loose bulk density is 0.461 g / cm 3
  • the tapping bulk density is 0.597 g / cm 3
  • the volume strength is 89.5 N / cm 3
  • the disintegration time is 14.7. Since the excipient [D] was not blended, the bulk density was small, the angle of repose was large, and the filling property was lowered.
  • the average particle size is 85 ⁇ m, the angle of repose is 35 degrees, the loose bulk density is 0.512 g / cm 3 , the tapping bulk density is 0.649 g / cm 3 , the volume strength is 62.1 N / cm 3 , and the disintegration time is 1.5. Since the amount of the excipient [D] was too large, the bulk density of the composition was increased, but the moldability was lowered and the volume strength was lowered.
  • the average particle size is 87 ⁇ m, the angle of repose is 34 degrees, the loose bulk density is 0.501 g / cm 3 , the tapping bulk density is 0.638 g / cm 3 , the volume strength is 59.8 N / cm 3 , and the disintegration time is 1.2.
  • the average particle size is 78 ⁇ m
  • the angle of repose is 35 degrees
  • the loose bulk density is 0.518 g / cm 3
  • the tapping bulk density is 0.651 g / cm 3
  • the volume strength is 72.8 N / cm 3
  • the disintegration time is 3.0. Since the blending amount of crystalline cellulose [A] was reduced and the blending amount of excipient [D] was increased excessively, the volume strength was lowered.
  • the average particle size is 73 ⁇ m, the angle of repose is 35 degrees, the loose bulk density is 0.513 g / cm 3 , the tapping bulk density is 0.649 g / cm 3 , the volume strength is 67.6 N / cm 3 , and the disintegration time is 0.2 minutes. Since the blending amount of the water-soluble cellulose derivative [B] was decreased and the blending amount of the parting agent [D] was excessively increased, the volume strength was lowered.
  • the average particle size is 90 ⁇ m, the angle of repose is 35 degrees, the loose bulk density is 0.478 g / cm 3 , the tapping bulk density is 0.612 g / cm 3 , the volume strength is 65.2 N / cm 3 , and the disintegration time is 0.2. Since the blending amount of the crystalline cellulose [A] was large and the blending amount of the water-soluble cellulose derivative [B] was small, the volume strength was lowered.
  • the average particle size is 68 ⁇ m
  • the angle of repose is 39 degrees
  • the loose bulk density is 0.455 g / cm 3
  • the tapping bulk density is 0.559 g / cm 3
  • the volume strength is 116.8 N / cm 3
  • the disintegration time is 31.6. Since the blending amount of crystalline cellulose [A] was small and the blending amount of water-soluble cellulose derivative [B] was large, the angle of repose of the composition was large, the loose bulk density was small, and the filling property was lowered. Moreover, since there were too many water-soluble cellulose derivatives, the volume strength of the compression molding body exceeded 115 N / cm ⁇ 3 >, it gelatinized, and the disintegration time of the composition became longer than 20 minutes.
  • the average particle size is 72 ⁇ m
  • the angle of repose is 42 degrees
  • the loose bulk density is 0.397 g / cm 3
  • the tapping bulk density is 0.577 g / cm 3
  • the volume strength is 74.0 N / cm 3
  • the disintegration time is 19.3. Since the fluidizing agent [C] was not added, the angle of repose of the composition was large, the bulk density was small, and the filling property was lowered.
  • the fluidizing agent [C] Since the amount of the fluidizing agent [C] was too much, the fluidizing agent [C] covered the surfaces of the crystalline cellulose [A] and the water-soluble cellulose derivative [B], and the volume strength of the cellulose of Example 1 Reduced compared to the composition.
  • Example 15 A composition (o) was obtained in the same manner as in Example 1 except that the crystalline cellulose obtained in Comparative Example 1 was used as the crystalline cellulose [A].
  • Table 4 shows the physical properties of the resulting composition (o). The average particle size is 48 ⁇ m, the angle of repose is 45 degrees, the loose bulk density is 0.332 g / cm 3 , the tapping bulk density is 0.465 g / cm 3 , the volume strength is 70.9 N / cm 3 , and the disintegration time is 14.2. Minutes.
  • What is the crystalline cellulose [A] used here? When compared with tablets of the same weight than the crystalline cellulose [A] used in Example 1, the moldability is high, but the bulk density is small and the angle of repose is large. Therefore, the bulk density of the composition (o) after mixing was small, the angle of repose was large, and the filling property was lowered. Furthermore, since the bulk density was small, the volume strength was lower than that of the cellulose composition of Example 1.
  • Example 16 A composition (p) was obtained in the same manner as in Example 1 except that the crystalline cellulose obtained in Comparative Example 2 was used as the crystalline cellulose [A].
  • Table 4 shows the physical properties of the resulting composition (p). The average particle size is 78 ⁇ m, the angle of repose is 34 degrees, the loose bulk density is 0.394 g / cm 3 , the tapping bulk density is 0.487 g / cm 3 , the volume strength is 68.8 N / cm 3 , and the disintegration time is 10.3. Minutes. What is the crystalline cellulose [A] used here? When compared with the same weight tablet than the crystalline cellulose [A] used in Example 1, the moldability is high and the angle of repose is similar. However, since the bulk density was small, the bulk density of the composition (p) after mixing was also small, and the filling property was lowered. Furthermore, since the bulk density was small, the volume strength was lower than that of the cellulose composition of Example 1.
  • Example 17 According to Example 1 of JP-A-53-127553, 1 kg of commercially available DP pulp is shredded, and the acid-insoluble residue obtained by hydrolysis in 10% hydrochloric acid solution at 105 ° C. for 20 minutes is filtered and washed. After air drying, the mixture was crushed with a normal hammer mill, and coarse particles were removed with a 50 mesh sieve to obtain crystalline cellulose having an average particle diameter of 35 ⁇ m, a loose bulk density of 0.359 g / cm 3 and an angle of repose of 38 degrees. A composition (q) was obtained in the same manner as in Example 1 except that the crystalline cellulose obtained here was used as the crystalline cellulose [A]. Table 4 shows the physical properties of the resulting composition (q).
  • the average particle size is 47 ⁇ m, the angle of repose is 38 degrees, the loose bulk density is 0.471 g / cm 3 , the tapping bulk density is 0.603 g / cm 3 , the volume strength is 68.2 N / cm 3 , and the disintegration time is 8.3. Minutes.
  • the crystalline cellulose used here has an average particle size smaller than that of the crystalline cellulose [A] used in Example 1, so that the surface area of the crystalline cellulose is increased, the contact area with the hydroxypropyl cellulose is increased, and the hydroxy is compressed during compression. Since the bond between propylcelluloses decreased and the moldability became low, the volume strength was lowered as compared with the cellulose composition of Example 1.
  • composition (r) was obtained in the same manner as in Example 1 except that. Table 4 shows the physical properties of the resulting composition (r).
  • the average particle size is 130 ⁇ m, the angle of repose is 35 degrees, the loose bulk density is 0.458 g / cm 3 , the tapping bulk density is 0.588 g / cm 3 , the volume strength is 82.2 N / cm 3 , and the disintegration time is 23.3. Minutes.
  • “Theolus” has an average particle size larger than that of crystalline cellulose [A] used in Example 1, and thus the average particle size of the obtained cellulose composition is more than 100 ⁇ m, and thus, dry-coated tablets and microtablets. The size was not suitable as a vehicle excipient. Moreover, the disintegration time was delayed because the surface area of the crystalline cellulose decreased and the contact between the hydroxypropyl celluloses during compression increased.
  • the average particle size is 76 ⁇ m
  • the angle of repose is 37 degrees
  • the loose bulk density is 0.471 g / cm 3
  • the tapping bulk density is 0.632 g / cm 3
  • the volume strength is 60.9 N / cm 3
  • the disintegration time is 89.5. Minutes.
  • composition (t) was obtained by the following method. 168.5 g of water-soluble cellulose derivative [B] and 1.5 g of fluidizing agent [C] were previously mixed for 5 minutes using a high-speed stirring type mixing granulator (NSK250, manufactured by Gohashi Seisakusho Co., Ltd.). The obtained powder was transferred to a V-type mixer (V-5 type, manufactured by Tokuju Seisakusho Co., Ltd.), and 300 g of crystalline cellulose [A] was further added and mixed for 30 minutes.
  • V-type mixer V-5 type, manufactured by Tokuju Seisakusho Co., Ltd.
  • the excipient [D] was added to a 50 g V-type mixer and further mixed for 30 minutes to obtain a composition (t).
  • Table 4 shows the physical properties of the resulting composition (t). The average particle size is 72 ⁇ m, the angle of repose is 36 degrees, the loose bulk density is 0.462 g / cm 3 , the tapping bulk density is 0.601 g / cm 3 , the volume strength is 75.1 N / cm 3 , and the disintegration time is 13.8. Minutes.
  • water-soluble cellulose derivative [B] and fluidizing agent [C] were mixed previously, fluidizing agent [C] is on the surface of water-soluble cellulose derivative [B]. Since it adhered and the binding strength of the water-soluble cellulose derivative [B] was lowered, the volume strength was lowered as compared with the cellulose composition of Example 1.
  • composition (u) was obtained by the following method. 300 g of crystalline cellulose [A] and 1.25 g of fluidizing agent [C] were charged into a V-type mixer and mixed for 30 minutes. Next, 148.75 g of water-soluble loxypropylcellulose derivative [B] was added and mixed for another 30 minutes, and further 50 g of excipient [D] was added and mixed for 30 minutes to obtain composition (u). Table 4 shows the physical properties of the resulting composition (u).
  • the average particle size is 72 ⁇ m
  • the angle of repose is 37 degrees
  • the loose bulk density is 0.455 g / cm 3
  • the tapping bulk density is 0.581 g / cm 3
  • the volume strength is 79.1 N / cm 3
  • the disintegration time is 14.2. Minutes. Since only the V-type mixer, which is a container rotating type mixer having a weak mixing shear force, was used, the resulting composition had a smaller bulk density and a larger angle of repose than the cellulose composition of Example 1, and was filled. Decreased. Moreover, since the bulk density decreased, the volume strength also decreased.
  • composition (v) was obtained by the following method.
  • Crystalline cellulose [A] 720 g, water-soluble cellulose derivative [B] 177.5 g, fluidizing agent [C] 2.5 g, excipient [D] 100 g were mixed with a high-speed stirring and mixing granulator (vertical granulator VG-10). And then mixed for 3 minutes, then added with 300 g of water in 30 seconds, further mixed for 5 minutes, granulated powder, and a 60 ° C.
  • the bulk density was large, but the average particle greatly exceeded 100 ⁇ m.
  • the strength of the compression molded product was lowered, and as a result, the volume strength was lowered.
  • Example 6 1. Evaluation of Nucleated Tablets 1) Preparation of inner core tablet Granulated lactose (“SUPER-TAB”) 140 g, crystalline cellulose (“Theorus” PH-101, manufactured by Asahi Kasei Chemicals Corporation) 56 g, croscarmellose sodium (“Kickolate”) 4 g of ND-2HS, sold by Asahi Kasei Chemicals Corporation, was mixed by hand in a PE bag for 3 minutes. Next, 1 g of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd.) was further added and mixed by hand for 30 seconds.
  • SUPER-TAB inner core tablet Granulated lactose
  • crystalline PH-101 manufactured by Asahi Kasei Chemicals Corporation
  • croscarmellose sodium (“Kickolate”) 4 g of ND-2HS, sold by Asahi Kasei Chemicals Corporation
  • the filling method is A.
  • Table 5 shows the physical properties of the dry coated tablet (I-1).
  • Example 7 The steps 1) to 3) were carried out in the same manner as in Example 6. 4) Supplying the outer layer side surface and upper part While accurately weighing 150 mg of the cellulose composition (I) and slowly turning the die into the 11.3 mm diameter die centered on the 8.0 mm diameter inner core tablet Filled. Further, the surface of the powder was leveled with a spatula, and the side surface was sufficiently filled with the powder. (Filling method B) 5) Tableting Carried out in the same manner as in Example 6, to obtain a dry-coated tablet (I-2). 6) Evaluation The dry-coated tablet (I-2) obtained here had a hardness of 105 N and a disintegration time of 9.1 minutes. Table 5 shows the physical properties of the dry coated tablet (I-2).
  • Example 8 A dry-coated tablet (II-1) was obtained in the same manner as in Example 6 except that the cellulose composition (II) of Example 2 was used.
  • the dry coated tablet (II-1) had a hardness of 99 N and a disintegration time of 8.9 minutes.
  • Table 5 shows the physical properties of the dry coated tablet (II-1).
  • Example 9 A dry-coated tablet (II-2) was obtained in the same manner as in Example 7, except that the cellulose composition (II) in Example 2 was used.
  • the dry coated tablet (II-2) had a hardness of 101 N and a disintegration time of 8.7 minutes.
  • Table 5 shows the physical properties of the dry coated tablet (II-2).
  • Example 23 A dry-coated tablet (o-1) was obtained in the same manner as in Example 6 except that the composition (o) of Comparative Example 15 was used.
  • the dry coated tablet (o-1) had a hardness of 85 N and a disintegration time of 1.2 minutes. Table 6 shows the physical properties of the dry coated tablet (o-1).
  • Example 24 A dry-coated tablet (o-2) was obtained in the same manner as in Example 7, except that the composition (o) of Comparative Example 15 was used.
  • the dry coated tablet (o-2) had a hardness of 115 N and a disintegration time of 0.8 minutes.
  • Table 6 shows the physical properties of the dry coated tablet (o-2).
  • the composition (o) has a tensile breaking strength of 32.0 N
  • the cellulose composition (I) has a tensile breaking strength of 28.2 N. Therefore, the cellulose composition (I ) Is a cellulose composition having a higher tablet hardness.
  • the hardness of (o-2) is higher.
  • the dry-coated tablet (o-1) clearly has a lower hardness than the close-packed dry-coated tablet (o-2), and the dry-coated tablet (I-1 The hardness was lower than -1).
  • the composition (o) has a smaller bulk density and a smaller volume strength than the cellulose composition (I). Since the composition (o) is a powder having poor filling properties, it is difficult to fill the outer layer side surface of the dry-coated tablet, and in the absence of forced powder filling, it means that the strength of the side surface is weakened.
  • a dry-coated tablet (c-1) was obtained in the same manner as in Example 6 except that the composition (c) of Comparative Example 3 was used.
  • the dry coated tablet (c-1) had a hardness of 13 N and a disintegration time of 4.9 minutes.
  • Table 6 shows the physical properties of the dry coated tablet (c-1). Since the composition (c) has a large bulk density and a small angle of repose, the filling property is good, but since the volume strength is low, the hardness of the dry-coated tablet is also low.
  • Example 26 A dry-coated tablet (k-1) was obtained in the same manner as in Example 6 except that the composition (k) of Comparative Example 11 was used.
  • the dry coated tablet (k-1) had a hardness of 62 N and a disintegration time of 0.2 minutes.
  • Table 6 shows the physical properties of the dry coated tablet (k-1). Reflecting that the volume strength of the composition (k) was lower than that of the cellulose composition (I) of Example 1, the hardness of the dry-coated tablet was also lowered.
  • a dry-coated tablet (l-1) was obtained in the same manner as in Example 6 except that the composition (l) of Comparative Example 12 was used.
  • the dry-coated tablet (l-1) had a hardness of 122 N, a disintegration time of 32.7 minutes, and the disintegration time was delayed to 30 minutes or more, so that it did not pass as an immediate release preparation.
  • Table 6 shows the physical properties of the dry coated tablet (l-1). Since the composition (l) was mixed with about half of the water-soluble cellulose derivative [B], the outer layer was gelled, causing a delay in disintegration.
  • the filling time of the outer layer powder is shorter than that of this example, and the filling property and moldability of the outer layer powder are required. It can be expected to exhibit excellent effects.
  • the compositions of Comparative Examples 1 to 5 have either a high formability or a high filling property that is commercially available. As shown in Table 2, the angle of repose, the loose bulk density, and the tapping bulk. Since the density is outside the range suitable for use for compression molding and the volume strength is less than 80 N / cm 3, none has both the properties of high formability and travelability.
  • Comparative Example 11 with a small amount of [B] the angle of repose, the loose bulk density, and the tapping bulk density are sufficient, but the moldability itself is lowered, so that the volume strength is outside the range suitable for use for compression molding.
  • the comparative example 12 is a case where there are many compounding quantities of hydroxypropylcellulose [B], since the angle of repose is large, it is natural that it is inferior to a filling property, but the disintegration time of a compression molded object is larger than 20 minutes. Therefore, when used in the outer layer of a dry-coated tablet, the outer layer is gelled, the disintegration property is significantly deteriorated and the drug release is delayed, so that an immediate release preparation with a disintegration time of 30 minutes or less is obtained. I can't.
  • compositions of Comparative Examples 15 to 18 containing commercially available crystalline cellulose whose average particle diameter, loose bulk density, and repose angle are out of the range are the average particle diameter, repose angle, loose bulk density, and tapping bulk. Since either the density or the volume strength is outside the range suitable for use as compression molding, the moldability and filling when used in the outer layer of a dry-coated tablet with a small filling volume, or microcapsules It is inferior in nature.
  • the composition of Comparative Example 15 has a higher hardness than the tablets of the Examples when comparing the hardness of tablets of the same weight, and is generally a composition that can be said to have high moldability. When applied, the hardness is lower than in the examples, indicating that the volume strength can be an index.
  • Comparative Example 19 containing hydroxypropyl cellulose having a viscosity of 2% by mass of a 20 ° C. aqueous solution having a viscosity of 10 mPa ⁇ s or more gels when formed into a compression-molded product, and the disintegration time is more prominent than 20 minutes. Since it becomes slow, when used for the outer layer portion of the dry-coated tablet, the outer layer is gelled, the disintegration property is remarkably deteriorated, and the release of the drug is delayed, so that an immediate release preparation cannot be obtained.
  • Comparative Example 20 is a case where hydroxypropyl cellulose [B] and fluidizing agent [C] are first mixed in a container-fixing type mixer, but crystalline cellulose [A] and fluidizing agent [C] are mixed in a container. The volume strength is reduced as compared with the example mixed earlier in the stationary mixer, indicating that the fluidizing agent [C] needs to be mixed in a state containing at least crystalline cellulose [A]. .
  • Comparative Example 21 is a case where the components are mixed in a container rotating mixer having a weak mixing shear force, but the bulk density and angle of repose of the composition are outside the ranges suitable for use for compression molding.
  • Comparative Example 22 is a case where water is added to the ingredients and wet granulation is performed.
  • the average particle size of the composition is larger than the range of the present invention, the outer layer portion of the dry-coated tablet with a small filling volume In addition, when used for microcapsules, it becomes difficult to fill.
  • Comparative Examples 25 and 26 in Table 6 show the results when a composition having a volume strength of less than 80 N / cm 3 is applied to the dry-coated tablet. The tablet hardness was clearly lower and the side strength was weaker than when used for molding. Comparative Example 27 in Table 6 shows the results when a composition having a volume strength of over 115 N / cm 3 and a disintegration time of 20 minutes or more is applied to a dry-coated tablet. Although the hardness of the dry-coated tablet is high, the disintegration time exceeds 30 minutes and the drug release is delayed, so that an immediate release preparation cannot be obtained.
  • a tablet with high strength can be obtained by tableting using the cellulose composition of the present invention.
  • the cellulose composition of the present invention has industrial applicability as an outer layer part of a dry-coated tablet having a small filling volume and a cellulose composition for compression molding for microcapsules.

Landscapes

  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)

Abstract

L’invention concerne une composition de cellulose qui comprend : 55 à 75 % en masse de cellulose cristalline [A] qui a un diamètre de particule moyen de 80 à 150 µm, une densité apparente lâche de 0,30 à 0,50 g/cm3 et un angle de talus naturel de 40 degrés ou moins; 17,5 à 37,5 % en masse d’un dérivé de cellulose soluble dans l’eau [B] qui a un diamètre de particule moyen de 80 µm ou moins et peut être préparé sous la forme d’une solution aqueuse à 2 % en masse ayant une viscosité de 10 mPa·s ou moins à 20 °C; 0,01 à 0,5 % en masse d’un agent fluidisant [C]; et 5 à 20 % en masse d’un excipient [D] ayant un diamètre de particule moyen de 150 µm ou moins et une densité apparente lâche de 0,60 à 1,00 g/cm3. Dans la composition, le rapport entre la teneur du composant [D] et la teneur du composant [B] (c.-à-d. un rapport [D]/[B]) est inférieur à 1.0, et chacun des composants [A], [B], [C] et [D] est présent sous une forme pulvérulente. La composition a un diamètre de particule moyen de 100 µm ou moins, une densité apparente lâche de 0,47 g/cm3 ou plus, un angle de talus naturel de 35 degrés ou moins et une densité apparente tassée de 0,60 g/cm3 ou plus.
PCT/JP2009/061779 2008-06-26 2009-06-26 Composition de cellulose WO2009157564A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2010518085A JP5442609B2 (ja) 2008-06-26 2009-06-26 セルロース組成物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2008-167878 2008-06-26
JP2008167878 2008-06-26

Publications (1)

Publication Number Publication Date
WO2009157564A1 true WO2009157564A1 (fr) 2009-12-30

Family

ID=41444624

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2009/061779 WO2009157564A1 (fr) 2008-06-26 2009-06-26 Composition de cellulose

Country Status (2)

Country Link
JP (1) JP5442609B2 (fr)
WO (1) WO2009157564A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012074042A1 (fr) * 2010-12-03 2012-06-07 日本曹達株式会社 Hydroxyalkylcellulose
WO2013180246A1 (fr) * 2012-05-31 2013-12-05 旭化成ケミカルズ株式会社 Poudre de cellulose
WO2013180248A1 (fr) * 2012-05-31 2013-12-05 旭化成ケミカルズ株式会社 Poudre de cellulose
WO2013180249A1 (fr) * 2012-05-31 2013-12-05 旭化成ケミカルズ株式会社 Poudre de cellulose

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002284674A (ja) * 2001-01-19 2002-10-03 Takeda Chem Ind Ltd 錠剤フィルムコーティング用組成物
JP2005194225A (ja) * 2004-01-06 2005-07-21 Akiyama Jozai Kk 胃内崩壊性錠剤
JP2006143650A (ja) * 2004-11-19 2006-06-08 Asahi Kasei Chemicals Corp 付着性の高い薬物を含有する錠剤の製造方法
US20070059361A1 (en) * 2005-09-09 2007-03-15 University Of Manitoba Fast-disintegrating epinephrine tablets for buccal or sublingual administration
WO2007148786A1 (fr) * 2006-06-23 2007-12-27 Takeda Pharmaceutical Company Limited Préparation solide stabilisée
JP2008013489A (ja) * 2006-07-06 2008-01-24 Ohara Yakuhin Kogyo Kk ベシル酸アムロジピン含有錠剤
JP2008056702A (ja) * 2006-05-26 2008-03-13 Japan Tobacco Inc 窒素含有縮合環化合物含有医薬組成物
JP2008105971A (ja) * 2006-10-24 2008-05-08 Nof Corp 打錠用粉末の製造方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4983399A (en) * 1989-10-18 1991-01-08 Eastman Kodak Company Direct compression carrier composition
JP3534130B2 (ja) * 1994-03-01 2004-06-07 旭化成ケミカルズ株式会社 医薬品組成物
CN1296387C (zh) * 2000-07-05 2007-01-24 旭化成株式会社 纤维素粉末
US6592901B2 (en) * 2001-10-15 2003-07-15 Hercules Incorporated Highly compressible ethylcellulose for tableting
WO2007066646A1 (fr) * 2005-12-06 2007-06-14 Asahi Kasei Chemicals Corporation Procede de production de tablette par compression directe a grande vitesse

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002284674A (ja) * 2001-01-19 2002-10-03 Takeda Chem Ind Ltd 錠剤フィルムコーティング用組成物
JP2005194225A (ja) * 2004-01-06 2005-07-21 Akiyama Jozai Kk 胃内崩壊性錠剤
JP2006143650A (ja) * 2004-11-19 2006-06-08 Asahi Kasei Chemicals Corp 付着性の高い薬物を含有する錠剤の製造方法
US20070059361A1 (en) * 2005-09-09 2007-03-15 University Of Manitoba Fast-disintegrating epinephrine tablets for buccal or sublingual administration
JP2008056702A (ja) * 2006-05-26 2008-03-13 Japan Tobacco Inc 窒素含有縮合環化合物含有医薬組成物
WO2007148786A1 (fr) * 2006-06-23 2007-12-27 Takeda Pharmaceutical Company Limited Préparation solide stabilisée
JP2008013489A (ja) * 2006-07-06 2008-01-24 Ohara Yakuhin Kogyo Kk ベシル酸アムロジピン含有錠剤
JP2008105971A (ja) * 2006-10-24 2008-05-08 Nof Corp 打錠用粉末の製造方法

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012074042A1 (fr) * 2010-12-03 2012-06-07 日本曹達株式会社 Hydroxyalkylcellulose
CN103228676A (zh) * 2010-12-03 2013-07-31 日本曹达株式会社 羟烷基纤维素
WO2013180246A1 (fr) * 2012-05-31 2013-12-05 旭化成ケミカルズ株式会社 Poudre de cellulose
WO2013180248A1 (fr) * 2012-05-31 2013-12-05 旭化成ケミカルズ株式会社 Poudre de cellulose
WO2013180249A1 (fr) * 2012-05-31 2013-12-05 旭化成ケミカルズ株式会社 Poudre de cellulose
JPWO2013180246A1 (ja) * 2012-05-31 2016-01-21 旭化成ケミカルズ株式会社 セルロース粉末
JPWO2013180248A1 (ja) * 2012-05-31 2016-01-21 旭化成ケミカルズ株式会社 セルロース粉末
JPWO2013180249A1 (ja) * 2012-05-31 2016-01-21 旭化成ケミカルズ株式会社 セルロース粉末
US9592199B2 (en) 2012-05-31 2017-03-14 Asahi Kasei Chemicals Corporation Cellulose powder
JP2017165972A (ja) * 2012-05-31 2017-09-21 旭化成株式会社 セルロース粉末
JP2018028101A (ja) * 2012-05-31 2018-02-22 旭化成株式会社 セルロース粉末
JP2018172699A (ja) * 2012-05-31 2018-11-08 旭化成株式会社 セルロース粉末
JP2019049012A (ja) * 2012-05-31 2019-03-28 旭化成株式会社 セルロース粉末
US10662258B2 (en) 2012-05-31 2020-05-26 Asahi Kasei Chemicals Corporation Cellulose powder
US11390690B2 (en) 2012-05-31 2022-07-19 Asahi Kasei Chemicals Corporation Cellulose powder

Also Published As

Publication number Publication date
JPWO2009157564A1 (ja) 2011-12-15
JP5442609B2 (ja) 2014-03-12

Similar Documents

Publication Publication Date Title
FI117962B (fi) Menetelmä valmistaa suun kautta otettava kiinteä annosmuoto ja täyteaine
US9446137B2 (en) Composite particles which contain both cellulose and inorganic compound
JP5788056B2 (ja) 低置換度ヒドロキシプロピルセルロース水分散液を用いた湿式造粒打錠法
US9655851B2 (en) Granular material for dosage forms
JP5577241B2 (ja) 崩壊性に優れる加工澱粉粉末及びその製法
EP2674149B1 (fr) Procédé de préparation de granules composites comprenant de la cellulose hydroxypropyle faiblement substituée et préparation à libération rapide
JPH01250314A (ja) 徐放性製剤
JP6706245B2 (ja) 微結晶性セルロースを含む直接圧縮可能な組成物
KR101867621B1 (ko) 만니톨과 과립형 전분의 압축성 및 유동성 공응집체
EA022168B1 (ru) Способ получения уплотненного промежуточного продукта дималеата bibw 2992 и твердые таблетки, полученные из такого продукта
CN109069455B (zh) 对乙酰氨基酚制剂的制造方法
WO2003018034A1 (fr) Comprimes antiacides et laxatifs
JP5442609B2 (ja) セルロース組成物
JP3900245B2 (ja) 口腔内速崩壊型錠剤及びその製造方法
WO2007018057A1 (fr) Comprime se desintegrant rapidement dans la cavite buccale et son procede de fabrication
JP3884056B1 (ja) 口腔内速崩錠の製造方法
JP4753567B2 (ja) 付着性の高い薬物を含有する錠剤の製造方法
TW201124157A (en) Microcrystalline cellulose and calcium phosphate compositions useful as pharmaceutical excipients
TWI829920B (zh) 醫藥製劑及其之製造方法
JP2012051810A (ja) 口腔内崩壊錠およびその製造法
WO2022004871A1 (fr) Comprimé et son procédé de fabrication
EP2429501B1 (fr) Compositions à libération de médicament en rafale
CN102784115B (zh) 含有伊潘立酮的口服片剂及其制备方法
KR20140131987A (ko) 지속 방출 경구 고체 제제
JP2008189634A (ja) 口腔内速崩錠の製造方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09770274

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2010518085

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09770274

Country of ref document: EP

Kind code of ref document: A1