WO2015016256A1 - Comprimé - Google Patents

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Publication number
WO2015016256A1
WO2015016256A1 PCT/JP2014/070047 JP2014070047W WO2015016256A1 WO 2015016256 A1 WO2015016256 A1 WO 2015016256A1 JP 2014070047 W JP2014070047 W JP 2014070047W WO 2015016256 A1 WO2015016256 A1 WO 2015016256A1
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WO
WIPO (PCT)
Prior art keywords
tablet
particle group
mass
component
particle
Prior art date
Application number
PCT/JP2014/070047
Other languages
English (en)
Japanese (ja)
Inventor
政明 立花
大輔 金島
大佑 小林
晃子 稲田
明希 尾谷
高士 小林
Original Assignee
ライオン株式会社
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 ライオン株式会社 filed Critical ライオン株式会社
Priority to JP2015529590A priority Critical patent/JP6304896B2/ja
Priority to KR1020157022575A priority patent/KR101890649B1/ko
Publication of WO2015016256A1 publication Critical patent/WO2015016256A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a tablet.
  • This application claims priority on July 30, 2013 based on Japanese Patent Application No. 2013-157823 for which it applied to Japan, and uses the content here.
  • the dispersibility of the drug in the stomach after taking is one of the important factors affecting the bioavailability of the drug.
  • the drug is a poorly water-soluble drug
  • the poorly water-soluble drug is more likely to aggregate in a polar solution than the water-soluble drug, and the transition from the stomach to the intestine is considered to be delayed.
  • a poorly water-soluble drug often aggregates once, it is often difficult to redissolve in the solution. Therefore, in a preparation containing a poorly water-soluble drug, the quality of the dispersibility of the drug greatly affects the bioavailability of the drug. . Therefore, improving the dispersibility of a drug in a preparation containing a poorly water-soluble drug is important for increasing the bioavailability of the drug.
  • Patent Documents 1 and 2 disclose formulations that improve the dispersibility of drugs.
  • Patent Document 1 discloses a dispersion containing a non-steroidal anti-inflammatory drug such as naproxen.
  • Patent Document 1 shows that when a hygroscopic sugar and sodium lauryl sulfate are used in combination, the redispersibility of the drug is synergistically high.
  • Patent Document 2 discloses a nanoparticle composition containing an active drug having low solubility.
  • Patent Document 2 when nanoparticle composition containing active drug particles having a polymer surface stabilizer such as polyvinylpyrrolidone (PVP) adsorbed on the surface thereof, dioctyl sodium sulfosuccinate (DOSS) is contained, It has been shown that the dispersibility of the active drug is excellent.
  • PVP polyvinylpyrrolidone
  • DOSS dioctyl sodium sulfosuccinate
  • an object of this invention is to provide the tablet with which the dispersibility of the poorly water-soluble drug was improved more.
  • the tablet of the present invention comprises a particle group (A) containing a particle group of a poorly water-soluble drug, and at least one particle group (B) selected from a carbonate particle group and a bicarbonate particle group. It is characterized by including.
  • the average particle size of the particle group of the poorly water-soluble drug is less than 10 ⁇ m.
  • a tablet containing a poorly water-soluble drug that exhibits good dispersibility can be provided.
  • the tablet of the present invention is a particle group (a1) of a poorly water-soluble drug (also referred to herein as “(a1) component”.
  • “(A1) component” refers to the component itself of the particle group (a1)).
  • a particle group (A) also referred to simply as “particle group (A)” in this specification
  • a carbonate particle group and a hydrogen carbonate particle group containing a carbonate particle group and a hydrogen carbonate particle group.
  • B also simply referred to as “particle group (B)” in this specification.
  • the average particle size of the poorly water-soluble drug particle group is preferably less than 10 ⁇ m.
  • the tablet includes an optional component such as a surfactant (C), a water-soluble excipient (D) or a disintegrant (E) (in this specification, , Also referred to as “pharmaceutically acceptable carrier”).
  • a surfactant C
  • D water-soluble excipient
  • E disintegrant
  • One aspect of the tablet of the present invention includes a particle group (A) and a particle group (B), and the particle group (A) includes a plurality of particles (A ′) including particles (a1 ′) of a poorly water-soluble drug.
  • the particle group (B) is composed of a plurality of at least one kind of particles (B ′) selected from carbonate particles and hydrogen carbonate particles.
  • the hardly water-soluble drug particle group (a1) is composed of a plurality of the hardly water-soluble drug particles (a1 ′), and the particle group (a1) has an average particle size of less than 10 ⁇ m. preferable.
  • One side of the average particle diameter of the particle group (a1) is 0.01 ⁇ m or more and less than 10 ⁇ m, and the other side is 0.1 ⁇ m or more and 2 ⁇ m or less.
  • Another aspect of the tablet of the present invention includes the particle group (A) and the particle group (B), and constitutes a plurality of particles (A ′) and the particle group (B) constituting the particle group (A).
  • Each of the plurality of particles (B ′) having a discontinuous interface (also referred to as an interface in the present specification) with other particles or components is a tablet.
  • Another aspect of the tablet of the present invention includes the particle group (A) and the particle group (B), and the particle group (A) and the particle group (B) are compression molded (in this specification, “compression molding”). "Is sometimes referred to as” tablet ").
  • a pharmaceutically acceptable carrier such as E) is a compressed tablet.
  • Another aspect of the tablet of the present invention is a tablet having a tablet hardness of 3 kgf to 15 kgf, another aspect is a tablet having a tablet hardness of 4 kgf to 12 kgf, and still another aspect is a tablet hardness. Is a tablet of 6 kgf to 7 kgf.
  • the tablet hardness can be measured using a tablet hardness measuring device PTB-301 (manufactured by Pharma Test).
  • a tablet hardness measuring device PTB-301 manufactured by Pharma Test.
  • Another aspect of the tablet of the present invention is a tablet in which a plurality of particles (a1 ′) constituting the poorly water-soluble drug particle group (a1) are contained while maintaining the particle diameter before compression molding.
  • the dispersion ratio of the poorly water-soluble drug 10 minutes after the addition of the tablet to the gastric model solution is 40% or more, preferably 60% or more, more preferably 80% or more, and still more preferably 90%. It is the tablet which is above.
  • Yet another aspect of the tablet of the present invention is a tablet having a dispersion reduction value of 0 to 10%, more preferably 0 to 7%, and 0 to 3%.
  • the dispersion rate reduction value is a value obtained by subtracting the dispersion rate after 30 minutes from the dispersion rate after 10 minutes from the addition of the tablet to the stomach model solution in the dispersibility evaluation test. The dispersibility evaluation test will be described later.
  • the particle group (A) is a particle group containing a particle group (a1) of a poorly water-soluble drug.
  • the particle group (A) includes a water-soluble binder (a2) (also referred to herein as “component (a2)”), a water-soluble compound particle group (a3) (present)
  • component (a3) also referred to as “component (a3)”
  • surfactant (C) an optional component usually used in a pharmaceutical formulation (also referred to herein as “pharmaceutically acceptable carrier”). It can be included.
  • the particle group (A) is composed of a plurality of particles (A ′) including particles (a1 ′) of poorly water-soluble drugs.
  • the particle group (A) includes, in addition to the poorly water-soluble drug particles (a1 ′), optionally, a water-soluble binder (a2), water-soluble compound particles (a3 ′), an interface. It is composed of a plurality of particles (A ′) containing an active agent (C) or a pharmaceutically acceptable carrier.
  • the poorly water-soluble drug particles (a1 ′) and the particles (B ′) are allowed to coexist in the same granule (also referred to as particles), that is, the poorly water-soluble drug component and the carbonate or hydrogencarbonate are contained in the same granule.
  • the particles (B ′) react with the particles (a1 ′) to make the particles (a1 ′) unstable, or change the physical properties of the powder to adhere to the container or apparatus during production. It may cause. For this reason, it is preferable that the poorly water-soluble drug component and the carbonate or bicarbonate are not allowed to coexist in the same granule (also referred to as particle).
  • the particle group (A) contains the component (a1).
  • the hardly water-soluble drug particle group (a1) is composed of a plurality of the hardly water-soluble drug particles (a1 ′).
  • the description and illustration of the particle group (a1), that is, the component (a1) are also applied to each particle of the plurality of particles (a1 ′) constituting the particle group (a1) unless otherwise specified.
  • a poorly water-soluble drug refers to a drug having a solubility in water at 20 ° C. of 0 to 13 mg / mL.
  • the poorly water-soluble drug is preferably a drug having a solubility in water at 20 ° C.
  • the method for measuring solubility is a test according to the 16th Japanese Pharmacopoeia. Specifically, when a drug is put into water at 20 ° C. and shaken strongly every 5 minutes for 30 seconds, the ratio of the mass of the drug dissolved within 30 minutes to the volume of water is measured.
  • the kind of poorly water-soluble drug used for the component (a1) is not particularly limited.
  • Non-steroidal anti-inflammatory drugs such as ketoprofen, mefenamic, meclofenamic, and piroxicam; hypnotics and sedatives such as nitrazepam, triazolam, phenobarbital, amibarbital, allylisopropylpropyrea, phenytoin, primidone, clonazepam, carbamazepine, valpro Antiepileptics such as acids; Antidepressants such as meclizine hydrochloride and dimenhydrinate; Psychiatric and neurological agents such as haloperidol, chlordiazepoxide, diazebam and sulpiride; Antispasmodic agents such as digoxin; Ar
  • the volume average particle size of the component (a1) (sometimes referred to simply as “average particle size” in this specification) is the laser diffraction / scattering particle size distribution analyzer “LA-920” (( Measured before mixing with other particles by the manual flow cell measurement method or after the pulverization step.
  • the average particle size of the component (a1) is preferably less than 10 ⁇ m, more preferably 5 ⁇ m or less, and even more preferably 2 ⁇ m or less. Moreover, 0.01 micrometer or more is preferable, More preferably, it is 0.1 micrometer or more.
  • the average particle diameter of the component (a1) is preferably 0.01 ⁇ m or more and less than 10 ⁇ m, more preferably 0.1 ⁇ m or more and 5 ⁇ m or less, further preferably 0.1 ⁇ m or more and 2 ⁇ m or less, and further more preferably 0.2 ⁇ m or more and 2 ⁇ m or less. preferable.
  • the average particle size of the component (a1) means the average particle size before mixing with other particles or after the pulverization step, but the particles giving the average particle size (a1 ′) The particle diameter of at least some of the particles is maintained even after tableting.
  • the plurality of particles (a1 ′) constituting the hardly water-soluble drug particle group (a1) have an interface with other particles or components in the tablet of the present invention.
  • the peristaltic movement of the stomach after taking a tablet has individual differences in time, intensity, frequency and duration until the peristaltic movement is started. Even if the drug is quickly dispersed, the above-described factors vary, and the time until the drug moves to the intestine is delayed. If the drug re-aggregates and precipitates during that time, the amount and rate of drug transfer to the intestine will decrease, leading to a decrease in effectiveness.
  • the dispersibility of the component (a1) is less than or equal to the above upper limit value, the dispersibility can be further improved, and the dispersed state is maintained even 30 minutes after dispersion, so that stable even if the gastric peristalsis varies.
  • the medicinal effect is obtained.
  • grains of (a1) component cannot aggregate easily, and the further improvement of the dispersibility of a poorly water-soluble drug can be aimed at.
  • the blending amount of the component (a1) in the particle group (A) is preferably 5 to 90% by mass, more preferably 10 to 80% by mass, still more preferably 20%, based on the total mass of the particle group (A). -70% by mass.
  • the blending amount of the particles (a1 ′) in each particle of the plurality of particles (A ′) constituting the particle group (A) is based on the mass of each particle (A ′). 5 to 90% by mass is preferable, more preferably 10 to 80% by mass, still more preferably 20 to 70% by mass, and still more preferably 47.8 to 66.2% by mass.
  • the blending amount of the component (a1) in the tablet is preferably 0.25 to 81% by mass, more preferably 2 to 72% by mass, and further preferably 4 to 56% by mass with respect to the total mass of one tablet. It is even more preferably 8.8 to 18.8% by mass.
  • the blending amount of the component (a1) in one tablet is the total of the components (a1) used in the manufacture of all the tablets with respect to the mass of all the tablets manufactured in one manufacture. Expressed as a percentage of mass.
  • the particle group (A) may contain a component (a2).
  • the component (a2) is a water-soluble binder and is blended as a binder for the component (a1).
  • each of the plurality of particles (A ′) constituting the particle group (A) may contain a component (a2).
  • the component (a2) include polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, methyl cellulose, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like. Among these, hydroxypropyl cellulose and methyl cellulose are preferable for improving the wettability of the component (a1) and further improving dispersibility.
  • the wettability is the affinity of the solid surface for the liquid and is evaluated by the contact angle.
  • the wettability in the present invention indicates affinity for water.
  • the blending amount of the component (a2) in the particle group (A) is preferably 0.2 to 30% by mass, more preferably 0.8 to 10% by mass with respect to the total mass of the particle group (A). 5 to 5% by mass is even more preferable, and 2.0 to 4.0% by mass is most preferable.
  • the blending amount of the component (a2) in each particle of the plurality of particles (A ′) constituting the particle group (A) is 0 with respect to the mass of each particle (A ′). 0.2 to 30% by mass is preferable, 0.8 to 10% by mass is more preferable, 1.5 to 5.0% by mass is even more preferable, and 2.0 to 4.0% by mass is most preferable.
  • the tablet is provided with sufficient hardness and wettability to improve dispersibility, and if it is not more than the upper limit value, the powder adheres to the device during granulation or tableting.
  • the blending amount of the component (a2) in the tablet is preferably 0.01 to 27% by mass, more preferably 0.04 to 9% by mass, and 0.075 to 4.5% by mass based on the total mass of one tablet. Is more preferable, and 0.10 to 1.3% by mass is most preferable.
  • the tablet is provided with sufficient hardness and wettability to improve dispersibility, and if it is not more than the upper limit value, the powder adheres to the device during granulation or tableting. Reduce.
  • the blending amount of the component (a2) in one tablet is the total amount of the component (a2) used in the production of all the tablets with respect to the mass of all the tablets produced in one production. Expressed as a percentage of mass.
  • the particle group (A) may contain a component (a3).
  • the component (a3) is a water-soluble compound particle group.
  • the water-soluble compound particle group (a3) is composed of one or more of the water-soluble compound particles (a3 ′).
  • the description and illustration of the particle group (a3), that is, the component (a3) are also applied to each particle of the plurality of particles (a3 ′) constituting the particle group (a3) unless otherwise specified.
  • the component (a1) may be present in the particle group (A) in a state of adhering to the surface of the particle (a3 ′) constituting the component (a3), or (a3) in the particle group (A).
  • each particle of the plurality of particles (A ′) constituting the particle group (A) has one or more particles (a2) as a binder on the surface of the particle (a3 ′) ( a1 ′) containing particles attached.
  • each particle of the plurality of particles (A ′) constituting the particle group (A) includes one or more particles (a3 ′) and one or more particles (a1 ′). Includes particles aggregated with each other.
  • each particle of the plurality of particles (A ′) constituting the particle group (A) includes one or more dispersed particles (a3 ′) and one or more particles (a1). ') And.
  • each particle of the plurality of particles (A ′) constituting the particle group (A) is one or more particles using the component (a2) as a binder on the surface of the particle (a3 ′). Particles to which (a1 ′) is attached; particles in which one or more particles (a3 ′) and one or more particles (a1 ′) are aggregated together; and one or more particles (a3 ′) in which they are dispersed And at least one particle selected from the group consisting of one or two or more particles (a1 ′), and the particles may be mixed in the particles (A ′).
  • the water-soluble compound used for the component (a3) is a substance having a solubility in water at 20 ° C. of greater than 13 mg / mL.
  • examples include mannitol, lactose or hydrates thereof, sugars such as sucrose and fructose, sugar alcohols such as erythritol, xylitol, and sorbitol, inorganic salts such as anhydrous potassium dihydrogen phosphate, sodium chloride, and potassium chloride.
  • a water-soluble active agent such as acetaminophen, anhydrous caffeine or a hydrate thereof may be used. Of these, mannitol and acetaminophen are preferable.
  • the blending amount of the component (a3) in the particle group (A) is preferably 10 to 90% by mass, more preferably 20 to 70% by mass, and more preferably 30 to 50% by mass with respect to the total mass of the particle group (A). More preferably, 34.7 to 47.8% by mass is even more preferable.
  • the blending amount of the particles (a3 ′) in each particle of the plurality of particles (A ′) constituting the particle group (A) is based on the mass of each particle (A ′). 10 to 90% by mass is preferable, 20 to 70% by mass is more preferable, 30 to 50% by mass is further preferable, and 34.7 to 47.8% by mass is even more preferable.
  • the compounding amount of the component (a3) is not less than the lower limit, the wettability of the tablet can be improved and the dispersibility can be improved. Moreover, if it is below the said upper limit, since the compounding quantity of additives other than a drug can be reduced, the dosage per time can be reduced and taking property becomes favorable.
  • the blending amount of the component (a3) in the tablet is preferably 0.5 to 81% by mass, more preferably 1 to 63% by mass, still more preferably 1.5 to 45% by mass, based on the total mass of one tablet. 2.7 to 18.5% by mass is even more preferable. If the compounding amount of the component (a3) is not less than the lower limit, the wettability of the tablet can be improved and the dispersibility can be improved.
  • the blending amount of the component (a3) in one tablet is the total amount of the component (a3) used in the production of all the tablets with respect to the mass of all the tablets produced in one production. Expressed as a percentage of mass.
  • the average particle size of the component (a3) is preferably 5 to 500 ⁇ m, more preferably 10 to 300 ⁇ m. If it is at least the lower limit value, the fluidity of the powder will be good and handling at the time of production will be improved, and if it is not more than the upper limit value, the dispersibility will be good and the particle size after granulation will be improved. It is difficult for coarsening to occur.
  • the average particle diameter (volume average particle diameter) of the component (a3) is determined using a laser diffraction / scattering method using a laser diffraction / scattering particle size distribution analyzer “LA-920” (manufactured by Horiba, Ltd.). Measure before mixing with.
  • the average particle size of the component (a3) means an average particle size before mixing with other components, but at least one of the particles (a3 ′) giving the average particle size.
  • the particle diameter of the part of the particles is maintained even after tableting.
  • the plurality of particles (a3 ′) constituting the particle group (a3) of the water-soluble compound have an interface with other particles or components in the tablet of the present invention. ing.
  • Mass ratio of component (a2) to component (a3) By containing the particle group (A) and the particle group (B) in the tablet of the present invention, a tablet having sufficiently good dispersibility of the poorly water-soluble drug can be obtained, but (a2) with respect to the component (a2) ) By adjusting the blending ratio of the components (a2 / a3 ratio), it is possible to obtain a tablet with a better dispersibility of the poorly water-soluble drug.
  • the a2 / a3 ratio is a mass ratio represented by the formula “(a2) component / (a3) component”.
  • the a2 / a3 ratio is preferably 0.0001 or more and less than 0.33, more preferably 0.015 or more and less than 0.23, still more preferably 0.03 or more and less than 0.12, and 0.0462 to 0.1154 or less. Even more preferred.
  • the a2 / a3 ratio is represented by the total mass of the water-soluble binder / the total mass of the water-soluble compound in one tablet, and the a2 / a3 ratio is 0.0001 or more and 0.00. It is preferably less than 33, more preferably from 0.015 to less than 0.23, even more preferably from 0.03 to less than 0.12, and even more preferably from 0.0462 to 0.1154. If it is more than the said lower limit, sufficient hardness can be given to a tablet, and if it is less than the said upper limit, adhesion of the powder to an apparatus will be reduced.
  • the average particle size (volume average particle size) of the particle group (A) is determined by laser diffraction / scattering using a laser diffraction / scattering particle size distribution analyzer “LA-920” (manufactured by Horiba, Ltd.). Measure before mixing with other ingredients by the method.
  • the average particle size of the particle group (A) is preferably less than 800 ⁇ m, more preferably 700 ⁇ m or less, and still more preferably 600 ⁇ m or less. Moreover, 1 micrometer or more is preferable, More preferably, it is 10 micrometers or more.
  • the average particle size of the particle group (A) is preferably 1 ⁇ m or more and less than 800 ⁇ m, more preferably 10 ⁇ m or more and 700 ⁇ m or less, and further preferably 10 ⁇ m or more and 600 ⁇ m or less.
  • the average particle size of the particle group (A) means an average particle size before tableting, but at least some of the particles (A ′) that give the average particle size. The particle size is maintained even after tableting.
  • the plurality of particles (A ′) constituting the particle group (A) have an interface with other particles or components in the tablet of the present invention.
  • the particle group (A) may contain the component (a1).
  • the particle group (A) may be, for example, an aggregate in which the component (a1) is mixed with one or more arbitrary components selected from the component (a2), the component (a3), and the component (C).
  • the particle group (A) may be an aggregate of the component (a1) attached to the surface of the component (a3) or the like. Furthermore, it may be an aggregate in which one or more optional components selected from the group consisting of the component (a2) and the component (C) are attached to the surface of the component (a3) and the like in addition to the component (a1).
  • each particle of the plurality of particles (A ′) constituting the particle group (A) is configured to include one or more particles (a1 ′).
  • each particle of the plurality of particles (A ′) constituting the particle group (A) is a mixture of particles (a1 ′), (a2) component, particles (a3 ′) and ( C) At least one component or particle selected from the group consisting of components is included.
  • each particle of the plurality of particles (A ′) constituting the particle group (A) is a particle in which one or more particles (a1 ′) are attached to the surface of the particle (a3 ′). It is comprised so that it may contain.
  • each particle of the plurality of particles (A ′) constituting the particle group (A) has one or more particles (a1 ′) attached to the surface of the particle (a3 ′). Furthermore, it is configured to include particles to which at least one component selected from the group consisting of the component (a2), the particles (a3 ′) and the component (C) or particles are attached, as desired.
  • the blending amount of the particle group (A) in the tablet is preferably 5 to 90% by mass, more preferably 20 to 80% by mass with respect to the total mass of one tablet. If the amount is not less than the lower limit, the amount of additives other than drugs can be reduced, so that the dose per dose can be reduced, and the dosage is good. The dispersibility of the soluble drug can be further improved.
  • the compounding amount of the particle group (A) in one tablet is the particle group (A) used for the production of all the tablets with respect to the mass of all the tablets produced in one production. It is expressed as a percentage of the total mass.
  • the particle group (B) is at least one particle group selected from a carbonate particle group and a hydrogen carbonate particle group.
  • the particle group (B) mainly functions as a dispersant by reacting with gastric acid and generating carbon dioxide gas.
  • the particle group (B) is composed of a plurality of carbonate or hydrogen carbonate particles (B ′).
  • the description and illustration of the particle group (B) are also applied to each particle of the plurality of particles (B ′) constituting the particle group (B) unless otherwise specified.
  • Carbonate, bicarbonate examples of the carbonate used in the present invention include metal carbonates such as potassium carbonate, sodium carbonate, magnesium carbonate, and calcium carbonate. Of these, sodium carbonate is preferable.
  • Examples of the hydrogen carbonate used in the present invention include metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, hydrogen carbonates other than metal hydrogen carbonate such as ammonium hydrogen carbonate, and the like. Of the carbonates and bicarbonates, bicarbonates are more preferred in order to further improve the dispersibility of the poorly water-soluble drug. In order for carbonates to react with gastric acid to produce carbon dioxide, two molecules of hydrogen ions are required for one molecule of carbonate, but one molecule of bicarbonate is one molecule of one molecule of bicarbonate.
  • the particle group (B) can contain one or more of these carbonates and bicarbonates.
  • the average particle diameter (volume average particle diameter) of the particle group (B) can be determined by using a laser diffraction / scattering particle size distribution measuring device “LA-920” (manufactured by Horiba, Ltd.) by using a laser diffraction / scattering method. Measure before mixing with ingredients.
  • the average particle size of the particle group (B) is preferably 10 to 800 ⁇ m, more preferably 30 to 600 ⁇ m, and still more preferably 50 to 300 ⁇ m.
  • the average particle size of the particle group (B) means an average particle size before tableting, but at least some of the particles (B ′) that give the average particle size. The particle size is maintained even after tableting.
  • the plurality of particles (B ′) constituting the particle group (B) have an interface with other particles or components in the tablet of the present invention.
  • the blending amount of the particle group (B) in the tablet is not particularly limited.
  • 0.1 mass% or more is preferable with respect to the total mass of one tablet, More preferably, it is 2 mass% or more, More preferably, it is 5 mass% or more. If the lower limit is exceeded, the dispersibility of the poorly water-soluble drug can be further improved.
  • 85 mass% or less is preferable with respect to the total mass of one tablet, More preferably, it is 40 mass% or less, More preferably, it is 20 mass% or less. is there.
  • the blending amount of the particles (B) in the tablet is preferably 0.1% by mass or more and 85% by mass or less, more preferably 2% by mass or more and 40% by mass or less with respect to the total mass of one tablet, and 5% by mass or more. 20 mass% or less is further more preferable, and 8.4 mass% or more and 14.3 mass% or less are the most preferable.
  • the particle group (B) is often hard particles, that is, the compression molding property is not good, and therefore, when the particle group (B) is made into a tablet, it is difficult to obtain hardness. Moreover, when the particle group (B) is contained in a large amount, the stability of the drug may be deteriorated.
  • the compounding amount of the particle group (B) in one tablet is the particle group (B) used for the production of all the tablets with respect to the mass of all the tablets produced in one production. It is expressed as a percentage of the total mass.
  • the mass ratio (B / A ratio) of the particle group (B) to the particle group (A) represented by “particle group (B) / particle group (A)” is preferably 0.001 or more, and more preferably. Is 0.06 or more, more preferably 0.15 or more.
  • the mass ratio (B / A ratio) is preferably 0.001 to 8.5, more preferably 0.06 to 1.2, still more preferably 0.15 to 0.65, and 0.221. More preferably, it is 0.459 or less.
  • the B / A ratio is represented by the total mass of components constituting the particle group (B) / total mass of components constituting the particle group (A) in one tablet, and the B The / A ratio is preferably 0.001 or more and 8.5 or less, more preferably 0.06 or more and 1.2 or less, and further preferably 0.15 or more and 0.65 or less.
  • the B / A ratio in one tablet is the mass of all particle groups (B) used in one production and the mass of all particle groups (A) used in one production. It is expressed by the ratio of If it is more than the said lower limit, the further improvement of a dispersibility can be aimed at. In addition, if the amount is less than the above upper limit, the amount of additives other than drugs can be reduced, so the dose per dose can be reduced, so that the dosage is good and the above disadvantages are avoided. It's easy to do.
  • the tablet of the present invention may contain other raw materials, for example, a surfactant (C), a water-soluble excipient (D), a disintegrant (in addition to the above-described particle group (A) and particle group (B).
  • a surfactant C
  • D water-soluble excipient
  • D disintegrant
  • an optional component also referred to as a pharmaceutically acceptable carrier
  • a binder such as a lubricant, a fragrance, and a corrigent (such as a sweetener and a sour agent)
  • a corrigent such as a sweetener and a sour agent
  • a surfactant (C) In order to improve the wettability of the component (a1), a surfactant (C) (also referred to as “component (C)” in this specification) may be further included. (C) By mix
  • Examples of the component (C) include anionic surfactants, cationic surfactants, nonionic surfactants, and amphoteric surfactants.
  • Anionic surfactants include alkyl sulfates such as sodium lauryl sulfate, alkyl ether sulfates, alkyl ether carboxylates, N-acyl sarcosine salts, N-acyl glutamates, N-acyl-N-methyl ⁇ -alanines N-acyl amino acid salts such as salt, alkyl polyoxyethylene sulfate, ⁇ -olefin sulfonate, N-acyl-N-methyl taurate, alkyl sulfosuccinate, alkyl phosphate, polyoxyethylene alkyl ether phosphorus Examples include acid salts.
  • Nonionic surfactants include polyoxyethylene (2) alkyl ether, polyoxyethylene (9) alkyl ether, polyoxyethylene (21) alkyl ether, polyoxyethylene (25) alkyl ether, polyoxyethylene (5) alkyl.
  • Phenyl ether polyoxyethylene (10) alkylphenyl ether, polyoxyethylene (15) alkylphenyl ether, polyoxyethylene (10) polyoxypropylene (4) alkyl ether, polyoxyethylene (40) castor oil, polyoxyethylene (60) castor oil, polyoxyethylene (80) castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (80) hydrogenated castor oil, polyoxyethylene Nglycerin fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene (10) sorbitan fatty acid ester, polyoxyethylene (20) sorbitan fatty acid ester, polyoxyethylene (30) sorbit fatty acid ester, polyoxyethylene (40) Sorbit fatty acid ester, polyoxyethylene (60) sorbite fatty acid ester, polyoxyethylene (10) sterol, polyoxyethylene (20) sterol, polyoxyethylene (30) sterol
  • parenthesis in the description of the nonionic activator of the said illustration represents the average addition mole number of ethylene oxide (EO).
  • EO ethylene oxide
  • an anionic surfactant is preferable.
  • sodium lauryl sulfate is preferable in order to produce good wettability with the drug.
  • the dispersibility of the poorly water-soluble drug can be improved.
  • the component (C) may be mixed with the particle group (A) and tableted to obtain a tablet, or may be contained in the particles (A ′) constituting the particle group (A).
  • the amount of the component (C) in the particle group (A) is 0.1 to 50% by mass with respect to the total mass of the particle group (A). Preferably, it is 0.5 to 25% by mass.
  • the amount of component (C) in the tablet is preferably 0.005 to 45% by mass, more preferably 0.025 to 22.5% by mass, based on the total mass of one tablet.
  • WHEREIN The compounding quantity of (C) component in each particle
  • the compounding amount of the component (C) in each particle of the plurality of particles (A ′) constituting the particle group (A) is all the particle groups (A) manufactured by one manufacturing. It is represented by the ratio of the total mass of the component (C) used for the production of all the particle groups (A) to the mass of.
  • the blending amount of the component (C) in one tablet is the total amount of the component (C) used in the production of all the tablets with respect to the mass of all the tablets produced in one production. Expressed as a percentage of mass.
  • the amount of the component (C) in the tablet excluding the component (C) in the particle group (A) is 0.1. ⁇ 20% by weight is preferred.
  • the component (C) may be added to each particle of the plurality of particles (A ′) constituting the particle group (A), and the outside of each particle of the particle (A ′). Or may be blended so as to coexist with each particle of the particles (A ′) and the outside thereof.
  • the component (C) is blended outside the particles of the particles (A ′)
  • the blending amount of the component (C) existing outside the particles of the particles (A ′) is based on the total mass of one tablet. 0.1 to 20% by mass is preferable. If it is in the said range, favorable wettability will be produced with a poorly water-soluble drug, and the dispersibility can be further improved.
  • the average particle size of (C) is preferably 1 to 300 ⁇ m. If it is at least the lower limit, the fluidity of the powder is good and the effect that the handleability is good is obtained, and if it is within the upper limit, it causes better wettability to the poorly water-soluble drug, Dispersibility can be further improved.
  • the average particle size (volume average particle size) of the particle group (C) can be determined by using a laser diffraction / scattering particle size distribution measuring device “LA-920” (manufactured by Horiba, Ltd.) and other methods by laser diffraction / scattering method. Measure before mixing with ingredients.
  • the average particle size of the particles of the component (C) means the average particle size before tableting, but gives the average particle size.
  • the particle diameter of at least some of the particles of the component (C) is maintained even after tableting.
  • the particles of the component (C) have an interface with other particles or components in the tablet of the present invention.
  • the water-soluble excipient refers to a substance having a solubility in water at 20 ° C. of greater than 13 mg / mL.
  • the water-soluble excipient preferably has a solubility in water at 20 ° C. of more than 33 mg / mL, more preferably a substance of more than 100 mg / mL.
  • Examples include lactose or hydrates thereof, sugars such as sucrose and fructose, sugar alcohols such as mannitol, erythritol, xylitol, and sorbitol, inorganic substances such as anhydrous potassium dihydrogen phosphate, sodium chloride, and potassium chloride. .
  • saccharides and sugar alcohols are preferable, and lactose or a hydrate thereof, erythritol, and mannitol are more preferable. If the component (D) is contained in the tablet of the present invention, the wettability of the tablet can be improved and the dispersibility of the poorly water-soluble drug can be further improved.
  • the blending amount of the component (D) in the tablet (excluding the component (a3) in the particle group (A)) is preferably 5 to 70% by mass, more preferably 10 to 65% by mass.
  • the component (D) is blended outside each particle of the particle (A ′).
  • the blending amount of the component (D) existing outside each particle (A ′) is preferably 5 to 70% by mass, more preferably 10 to 65% by mass with respect to the total mass of one tablet. It is.
  • the blending amount of the component (D) in one tablet is the mass of the component (D) used for manufacturing all the tablets with respect to the mass of all tablets manufactured in one manufacturing. It is expressed as a percentage.
  • component (E) examples include carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, partial ⁇ Modified starch, carboxymethyl starch sodium and the like can be used. Of these, low-substituted hydroxypropylcellulose and crospovidone are preferred. If (E) component is included in the tablet of this invention, the disintegration property of a tablet will increase and the further improvement of the dispersibility of a poorly water-soluble drug can be aimed at.
  • the blending amount of the component (E) in the tablet is preferably 0.5 to 10% by mass, more preferably 1 to 8% by mass, and further preferably 2 to 6% by mass with respect to the total mass of one tablet. . If it is in the said range, the disintegration property of a tablet can further be improved and the further improvement of the dispersibility of a poorly water-soluble drug can be aimed at.
  • the blending amount of the component (E) in one tablet is the mass of the component (E) used for the production of all the tablets with respect to the mass of all the tablets produced in one production. It is expressed as a percentage.
  • binder crystalline cellulose, anhydrous calcium hydrogen phosphate, hydroxypropyl cellulose, polovinylpyrrolidone, or the like can be used.
  • lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, talc, stearic acid, sucrose fatty acid ester and the like can be used. Among these, magnesium stearate is preferable.
  • fragrance for example, menthol, limonene, plant essential oil (mint oil, mint oil, lychee oil, orange oil, lemon oil, etc.) can be used.
  • sweetener for example, saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose and the like can be used.
  • acidulant for example, citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, or a salt thereof can be used.
  • the tablet production method of the present invention comprises a granulation step and a tableting step.
  • a granulation process is a process of producing a particle group (A).
  • a particle group containing the component (a1) is obtained.
  • a dispersion containing the component (a1) (adding optional components as necessary) is prepared, and then using a fluidized bed granulator “MP-01” (manufactured by POWREC Co., Ltd.) This dispersion can be sprayed on the component (a3) such as mannitol to perform granulation.
  • the commercial product of the component (a1) may be dispersed in the solution as it is to obtain a dispersion.
  • a dispersion containing the component (a1) a dispersion in which a poorly water-soluble drug is dispersed may be processed with a bead mill and pulverized until a desired average particle size is obtained.
  • pulverizing the dispersion with a bead mill general beads can be used.
  • beads made of zirconia, polystyrene, polyurethane, glass, and stainless steel can be used, and beads having a bead diameter of 0.015 ⁇ m to 20 mm can be used.
  • the optional component may be added to the dispersion in advance, or may be added by spraying as a spray liquid during granulation.
  • the component (C) is preferably added as a spray liquid during granulation from the viewpoint of further increasing the dispersibility of the poorly water-soluble drug.
  • the average particle size of the component (a3) coated with the dispersion is preferably 5 to 500 ⁇ m, more preferably 10 to 300 ⁇ m.
  • the fluidity of the powder will be good and handling at the time of production will be improved, and if it is not more than the upper limit value, the dispersibility will be good and the particle size after granulation will be improved. Coarseness is less likely to occur.
  • Spraying the dispersion containing the component (a1) is performed until the content of the component (a1) in the particle group (A) is 5 to 90% by mass with respect to the total mass of the particle group (A). More preferably, it is carried out until it becomes 10 to 80% by mass, more preferably 20 to 70% by mass. If the amount is not less than the lower limit, the amount of additives other than drugs can be reduced, and the dose per dose can be reduced. Moreover, if it is below the said upper limit, the coarsening of a granulated particle can be reduced.
  • the particle group (A) prepared in the granulation step, the particle group (B), and, if necessary, optional components such as the components (C) to (E) are mixed to obtain a mixed powder It is the process of obtaining.
  • the component (C) can also be included in the particle group (A) in the granulation step.
  • the particle group (A), the particle group (B), and, if desired, the component (D) , (E) can also be mixed.
  • the dispersibility of the poorly water-soluble drug can be further improved.
  • a commonly used mixer can be used.
  • Examples of the mixer include a Boule container mixer (manufactured by Kotobuki Industries Co., Ltd.), a V-type mixer (manufactured by Dalton Co., Ltd.), a ribbon mixer (manufactured by Dalton Co., Ltd.), and the like. All components can be charged into a mixing container and mixed, or after mixing some components, other components can be added and mixed sequentially.
  • the tableting step is a step of tableting the mixed powder produced in the mixing step to obtain a tablet.
  • the tablet of the present invention can be produced by tableting using a rotary tableting machine such as Libra (manufactured by Kikusui Seisakusho), type L-41 (manufactured by Hata Seisakusho), or the like.
  • the tableting step can be performed by compression molding 50 to 1500 mg, more preferably 150 to 500 mg of the mixed powder produced in the mixing step.
  • the tableting pressure in the compression molding is 400 to 1800 kgf, more preferably 600 to 1400 kgf.
  • the tablets to be produced may be coated with a coating agent as necessary for the purpose of improving stability or the like.
  • a coating agent As a device used for coating, a general device can be used. For example, pan-type coating equipment such as a high coater (manufactured by Freund Sangyo Co., Ltd.) and an aqua coater (manufactured by Freund Sangyo Co., Ltd.) can be used.
  • the coating agent it is preferable to select a coating agent that does not significantly impair the dispersibility of the poorly water-soluble drug (a1) in the body, which is the effect of the present invention. Among them, it is more preferable to select a hydrophilic polymer compound, a saccharide, or the like. preferable.
  • celluloses such as hydroxypropylcellulose, hydroxypropylmethylcellulose, low-substituted hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, ethylcellulose; gum arabic, carboxyvinyl polymer, polyvinylpyrrolidone, crospovidone, polyvinyl alcohol, polyacrylic acid Hydrophilic polymer compounds such as sugar (granulated sugar), lactose, maltose, xylose, lactose and hydrates thereof, starch syrup, isomerized sugar, oligosaccharide, sucrose, trehalose, reduced starch saccharified product (reduced starch degradation product) ), Sugars such as palatinit, sorbitol, lactitol, erythritol, xylitol, reduced starch saccharified product, maltitol, mannitol and the like.
  • coating agents may be used individually by 1 type, and may be used in combination of 2 or more type.
  • the amount of the coating agent used is preferably about 0.1 to 20 parts by mass with respect to 100 parts by mass of the tablet.
  • the present invention since it contains the particle group (A) and the particle group (B), it is possible to provide a tablet containing a poorly water-soluble drug that exhibits good dispersibility.
  • Examples of the tablet of the present invention include a tablet in which the component (a1) is ibuprofen and the component constituting the particle group (B) is sodium hydrocarbon.
  • the compounding amount of the component (a1) in the tablet is 4 to 56% by mass relative to the total mass of one tablet
  • the compounding amount of the component (a2) in the tablet is 0.075 to 4.5% by mass with respect to the total mass of one tablet
  • the amount of component (a3) in the tablet is 1.4 to 45% by mass with respect to the total mass of one tablet
  • a tablet in which the blending amount of the component (C) in the tablet is 0.025 to 22.5% by mass relative to the total mass of one tablet can be mentioned.
  • the compounding amount of the component (a1) in the tablet is 4 to 56% by mass with respect to the total mass of one tablet
  • the compounding amount of the component (a2) in the tablet is based on the total mass of one tablet, 0.075 to 4.5% by mass
  • the compounding amount of component (a3) in the tablet is 1.4 to 45% by mass with respect to the total mass of one tablet
  • compounding of component (C) in the tablet The amount is 0.025 to 22.5% by mass with respect to the total mass of one tablet
  • the blending amount of the particle group (B) in the tablet is 5 to 20% by mass with respect to the total mass of one tablet.
  • the sum total of the said compounding quantity does not exceed 100 mass%.
  • the mass ratio (B / A ratio) of the particle group (B) to the particle group (A) is from 0.15 to 0.65, and the component (a2) relative to the component (a3)
  • the tablet whose mass ratio (a2 / a3 ratio) is 0.03 or more and less than 0.12 can be mentioned.
  • the tablet of the present invention include a tablet having a water-insoluble drug dispersion of 60% or more, more preferably 80% or more 10 minutes after adding the tablet to the gastric model solution.
  • examples of the tablet of the present invention include tablets having a dispersion rate reduction value of 0 to 10%, more preferably 0 to 7%, and 0 to 3%.
  • Dispersibility evaluation test Dispersibility evaluation was performed using a paddle dissolution tester (Toyama Sangyo Co., Ltd.). Add 2 tablets to 333 mL of stomach model solution (adjust sodium chloride 6.8 mmol / L, hydrochloric acid 16.3 mmol / L, adjust pH to 1.8) so that the stirring blades of the paddle are sufficiently hidden. Stir at 20 rpm. A part of the gastric model solution was collected and transferred to a vial so as to contain the dispersed poorly water-soluble drug 10 minutes and 30 minutes after the addition of 2 tablets to the gastric model solution.
  • a gastric model solution transferred to a vial was dissolved in a poorly water-soluble drug such as ibuprofen dispersed by adding acetonitrile and acetic acid.
  • the dispersed poorly water-soluble drug means a drug that is not dissolved in the stomach model solution but is suspended or dispersed in the solution, but the solution used for calculating the dispersion rate is dissolved in the stomach model solution. Drugs that are being used are also included.
  • the solution was filtered through a 0.45 ⁇ m filter, and the amount of poorly water-soluble drug was measured by high performance liquid chromatography. From the measurement result of the high performance liquid chromatography, the amount of the poorly water-soluble drug dispersed from the tablet in the stomach model solution was calculated backward.
  • the dispersion ratio of the drug for 10 minutes and 30 minutes after the addition of the tablet is determined by determining the ratio (%) of the mass of the poorly water-soluble drug dispersed from the tablet when the mass of the poorly water-soluble drug in the added tablet is 100%. Was calculated.
  • the dispersion ratio is sufficiently high if it is 40% or more 10 minutes after the addition of the tablet. Further, it can be said that it is remarkably high if it is 60% or more, more remarkably higher if it is 80% or more, and extremely remarkably high if it is 90% or more. Further, a value (%) (hereinafter referred to as “dispersion rate lowering value”) calculated by “(dispersion rate of drug 10 minutes after addition of tablet) ⁇ (dispersion rate of drug 30 minutes after addition of tablet)”. If it is small, the stability of the dispersibility of the drug is high. For example, if the dispersion rate lowering value is 10% or less, the stability of dispersibility is sufficiently high, and if it is 7% or less, the stability of dispersibility is remarkably high. It can be said that the stability of is extremely remarkably high.
  • Example 1 to 10 and Comparative Example 1 "Production of ibuprofen-containing particles"
  • the above “ibuprofen 25” was used as it was as the particle group (A).
  • the average particle size of the dried particles was measured by a laser diffraction / scattering method using a laser diffraction / scattering particle size distribution measuring device “LS230 type” (manufactured by Beckman Coulter). As a result, the average particle diameter of the ibuprofen 25 was 25 ⁇ m.
  • the particle group (A) in Examples 3 to 10 and Comparative Example 1 was prepared as follows. 680 mL of water was put into a container equipped with a stirrer, and stirring was started. Here, 14 g of hydroxypropylcellulose (component (a2)) “HPC-SSL” was dissolved, and then 300 g of ibuprofen was added and dispersed. This dispersion was treated with a bead mill “UAM015” (Koto Kogyo Co., Ltd.) to obtain a dispersion of ibuprofen particle group (component (a1)).
  • the average particle diameter of the particles in the dispersion was measured by a manual flow cell measurement method using a laser diffraction / scattering particle size distribution measuring device “LA-920” (manufactured by Horiba, Ltd.). went.
  • the average particle diameter of the component (a1) in the dispersion was 0.5 ⁇ m.
  • 14 g of sodium lauryl sulfate “SLS” corresponding to component (C) was dissolved.
  • powder mannitol “Pairitol 50C” (component (a3)) having an average particle size of 50 ⁇ m is charged into a fluidized bed granulator “MP-01” (Paulec Co., Ltd.), and air at 50 ° C. is supplied to the powder. I let my body flow. A dispersion in which the SLS was dissolved was sprayed on the powder to perform granulation (granulation step). After spraying the dispersion until the ibuprofen content in the granulated product reaches 60% by mass, the granulated product is dried until the exhaust temperature reaches 35 ° C., and particles corresponding to the particle group (A) of the present invention A group was obtained. The average particle diameter of the obtained particle group (A) was 200 ⁇ m. The measurement of the average particle diameter was performed in the same manner as the measurement of the average particle diameter of the dried particle group described above.
  • sodium bicarbonate “sodium bicarbonate KF” having an average particle diameter of 120 ⁇ m was used as the particle group (B).
  • the measurement of the average particle diameter was performed in the same manner as the measurement of the average particle diameter of the dried particle group described above.
  • Table 1 shows the results of dispersibility evaluation tests conducted using the tablets of Examples 1 to 10 and Comparative Example 1.
  • the tablet of Comparative Example 1 not containing sodium hydrogen carbonate had an ibuprofen dispersion rate of 28% for 10 minutes after the addition of the tablet.
  • the tablets of Examples 1 to 10 containing sodium bicarbonate showed a high dispersion rate of 62% or more.
  • Example 11 to 13 potassium hydrogen carbonate (average particle size 130 ⁇ m), sodium carbonate (average particle size 100 ⁇ m) or calcium carbonate (average particle size 110 ⁇ m) is used in place of sodium hydrogen carbonate in Example 6 above. Except for the above, tablets were obtained in the same manner as in Example 6. The measurement of the average particle diameter was performed in the same manner as the measurement of the average particle diameter of the dried particle group described above. Table 2 shows the results of a dispersibility evaluation test conducted using the tablets of Examples 6 and 11 to 13 for 10 minutes after the addition of the tablets. In addition, the content rate (%) of each component shown in the parenthesis in Table 2 means mass%.
  • Example 14 to 19 tablets were obtained in the same manner as in Example 6 except that the average particle size of ibuprofen shown in Table 3 was used.
  • Table 3 shows the results of the dispersibility evaluation test conducted using the tablets of Examples 6 and 14 to 19 for 10 minutes and 30 minutes after the addition of the tablets.
  • the tablets of Examples 6 and 14 to 19 containing ibuprofen particles and hydrogen carbonate particles in the tablets had an ibuprofen dispersion ratio of 83% or more for 10 minutes after the addition of the tablets.
  • the dispersion was significantly higher than that of Example 1 (28%).
  • the dispersion rate reduction value was 10% or less, and it was also found that the stability of dispersibility was high.
  • Example 20 to 24 tablets were obtained in the same manner as in Example 6 except that the average particle size of sodium bicarbonate shown in Table 4 was used.
  • Example 20 sodium bicarbonate “sodium bicarbonate KP” having an average particle size of 40 ⁇ m was used. The measurement of the average particle diameter was performed in the same manner as the measurement of the average particle diameter of the dried particle group described above.
  • the sodium hydrogen carbonate used in Examples 21 to 24 was produced by the following method. 1 kg of sodium bicarbonate “sodium bicarbonate KF” having an average particle size of 120 ⁇ m was put into a stirring granulator (High Speed Mixer FS-10 (manufactured by Fukae Pautech Co., Ltd.).
  • the ibuprofen dispersion ratio of 10 minutes after the tablet addition was 92% or more, and Example 22 of 500 ⁇ m was 85% and 720 ⁇ m Example 23 was 72%, and Example 24 of 960 ⁇ m was 58%.
  • the dispersibility of ibuprofen was higher than that of Comparative Example 1 (28%) not containing sodium bicarbonate.
  • Example 25 to 28 tablets were prepared in the same manner as in Example 6 except that the amount of charged powder was adjusted so that the composition shown in Table 5 was obtained.
  • the particle diameter of component (a1) after bead milling in Examples 25 to 28 was measured in the same manner as in Example 6. As a result, all were 0.5 ⁇ m.
  • the average particle size of the particle group (A) was 210 ⁇ m in Example 25, 220 ⁇ m in Example 26, 215 ⁇ m in Example 27, and 209 ⁇ m in Example 28. These average particle diameters were measured in the same manner as the above-described measurement of the average particle diameter of the dried particles.
  • Table 5 shows the results of the dispersibility evaluation test conducted using the tablets of Examples 6 and 25 to 28 for 10 minutes and 30 minutes after the addition of the tablets.
  • the ibuprofen dispersion rate after 10 minutes from the addition of the tablets was 92% or more.
  • the ibuprofen dispersion rate after 10 minutes from the addition of the tablets was 92% or more.
  • the ibuprofen dispersion rate after 10 minutes from the addition of the tablet was 84% or more.
  • the ibuprofen dispersion rate after 10 minutes from the tablet addition was as high as 76%.
  • the ibuprofen dispersion ratio after 10 minutes from the addition of the tablet was 82% or more. It was.
  • the ibuprofen dispersion rate after 10 minutes from the addition of the tablet was 72% or more.
  • Example 34 and 35 For Examples 34 and 35, the amount of charged powder was adjusted so that the composition shown in Table 7 was obtained, and tablets were prepared in the same manner as in Example 6 except that a different poorly water-soluble drug (a1) component was used.
  • a1 component As the poorly water-soluble drug (a1) component, etodolac was used in Example 34, and allylisopropylacetylurea was used in Example 35.
  • the particle diameter of the component (a1) after pulverizing the beads of Examples 34 and 35 was measured in the same manner as in Example 6, both were 0.5 ⁇ m.
  • the average particle size of the particle group (A) was 211 ⁇ m in Example 34 and 225 ⁇ m in Example 35. These average particle diameters were measured in the same manner as the above-described measurement of the average particle diameter of the dried particles.
  • Table 7 shows the results of the dispersibility evaluation test conducted using the tablets of Examples 34 and 35 for 10 minutes and 30 minutes after the addition of the tablets.
  • the dispersion ratio of the poorly water-soluble drug 10 minutes after the addition of the tablet was 62% or more.
  • a tablet containing a poorly water-soluble drug that exhibits good dispersibility can be provided. Therefore, the present invention can be suitably used for “tablets” and is extremely important in industry.

Abstract

La présente invention concerne un comprimé contenant un agrégat de particules (A) contenant un agrégat de particules d'un médicament faiblement soluble dans l'eau et au moins un type d'agrégat de particules (B) sélectionné parmi un agrégat de particules de carbonate et un agrégat de particules de bicarbonate.
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Publication number Priority date Publication date Assignee Title
WO2018124062A1 (fr) * 2016-12-26 2018-07-05 塩野義製薬株式会社 Méthode de production pour formulation ayant une uniformité de teneur améliorée
JP2019167319A (ja) * 2018-03-26 2019-10-03 株式会社親広産業 糖消費促進剤

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