JP6304896B2 - tablet - Google Patents

Description

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.

In drug-containing preparations, the dispersibility of the drug in the stomach after taking is one of the important factors affecting the bioavailability of the drug. In particular, when 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. In addition, since 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.

For example, 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. In 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.

Japanese Patent No. 3710818 JP-T-2004-513886

However, in order to further increase the bioavailability of the drug, a new means for improving the dispersibility of the drug is desired.
Then, 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.
Preferably, the average particle size of the particle group of the poorly water-soluble drug is less than 10 μm.

  ADVANTAGE OF THE INVENTION According to this invention, the tablet containing the poorly water-soluble drug which shows favorable dispersibility can be provided.

≪Tablet≫
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) containing a carbonate particle group and a hydrogen carbonate particle group. And at least one kind of 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 μm.
In addition to the particle group (A) and the particle group (B), 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”).
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 μm. preferable.
One side of the average particle diameter of the particle group (a1) is 0.01 μm or more and less than 10 μm, and the other side is 0.1 μm or more and 2 μm 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 ").
In another aspect of the tablet of the present invention, in addition to the particle group (A) and the particle group (B), a surfactant (C), a water-soluble excipient (D) or a disintegrant (E ) And the like, and the particles (A) and (B), and optionally included surfactant (C), water-soluble excipient (D) or disintegrant ( 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.
In this specification, tablet hardness can be measured using a tablet hardness measuring instrument 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.
In another aspect of the tablet of the present invention, 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.

<Particle group (A)>
The particle group (A) is a particle group containing a particle group (a1) of a poorly water-soluble drug.
In addition to the component (a1), 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) In the specification, it is 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.
In one aspect of the present invention, the particle group (A) is composed of a plurality of particles (A ′) including particles (a1 ′) of poorly water-soluble drugs.
In another aspect of the present invention, 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.
When 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. When coexisting, 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).

((A1) component)
The particle group (A) contains the component (a1).
In one aspect of the present invention, the hardly water-soluble drug particle group (a1) is composed of a plurality of the hardly water-soluble drug particles (a1 ′). In the present specification, 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. Applied.
In the present specification, the 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. of 0 to 10 mg / mL, more preferably 0 to 5 mg / mL, more preferably 0 to 1 mg / mL, and most preferably 0 to 0.35 mg / mL. preferable.
In the present specification, 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. For example, ibuprofen, aspirin, naproxen, ketoprofen, indomethacin, bufexamac, diclofenac, alclofenac, etodolac, flurbiprofen, Nonsteroidal anti-inflammatory drugs such as ketoprofen, mefenamic, meclofenamic, and piroxicam; hypnotics and sedatives such as nitrazepam, triazolam, phenobarbital, amibarbital, allylisopropylpropyrea, etc .; 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; Arrhythmic agents such as pindolol and disopyramide; Diuretics such as hydrochlorothiazide, spironolactone, triamterene, furosemide, and bumetanide; Antihypertensive agents such as prazosin hydrochloride; Crowns such as isosorbide nitrate, nifedipine, and dipyridamole Vasodilators; antitussives such as noscapine, turopterol, tranilast; expectorants such as bromhexine hydrochloride; antibiotics such as erythromycin, josamycin, chloramphenicol, rifampicin, griseofulvin; antihistamines such as clemastine fumarate; dexamethasone, betamethasone, prednisolone, Steroids such as danazol and chlormadinone acetate; vitamins such as vitamin A and folic acid (vitamin M); famotidine, metoclopramide, ome Razoru, Torepibuton, digestive system diseases agents such as sucralfate; clofibrate, mercaptopurine, methotrexate, mesylate dihydroergotamine, aluminum hydroxide, synthetic hydrotalcite, magnesium oxide, and magnesium hydroxide. Non-steroidal anti-inflammatory agents can obtain the effects of the present invention particularly remarkably, and ibuprofen can be obtained more remarkably.
In the component (a1), one poorly water-soluble drug may be used alone, or two or more may be used in combination.

In the present invention, the volume average particle size of the component (a1) (sometimes referred to simply as “average particle size” in this specification) is a 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 μm, more preferably 5 μm or less, and even more preferably 2 μm or less. Moreover, 0.01 micrometer or more is preferable, More preferably, it is 0.1 micrometer or more. That is, the average particle diameter of the component (a1) is preferably 0.01 μm or more and less than 10 μm, more preferably 0.1 μm or more and 5 μm or less, further preferably 0.1 μm or more and 2 μm or less, and further more preferably 0.2 μm or more and 2 μm or less. preferable.
In one aspect of the present invention, 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.
In another aspect of the present invention, 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. ing.
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. If the average particle size 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. Moreover, if it is more than the said lower limit, the particle | grains of (a1) component cannot aggregate easily, and the further improvement of the dispersibility of a poorly water-soluble drug can be aimed at.

As for the compounding quantity of the (a1) component in particle group (A), 5-90 mass% is preferable with respect to the total mass of particle group (A), More preferably, it is 10-80 mass%, More preferably, it is 20 -70 mass%.
In one aspect of the present invention, 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 ′). 5-90 mass% is preferable, More preferably, it is 10-80 mass%, More preferably, it is 20-70 mass%, More preferably, it is 47.8-66.2 mass%.
If it is at least the lower limit, the amount of additives other than drugs can be reduced, so that the dose per dose can be reduced, the dosage is good, and if it is not more than the upper limit, The dispersibility of the poorly water-soluble drug can be further improved.
The blending amount of the component (a1) in the tablet is preferably from 0.25 to 81% by mass, more preferably from 2 to 72% by mass, still more preferably from 4 to 56% by mass, based on the total mass of one tablet. Yes, even more preferably 8.8 to 18.8% by mass.
If it is at least the lower limit, the amount of additives other than drugs can be reduced, so that the dose per dose can be reduced, the dosage is good, and if it is not more than the upper limit, The dispersibility of the poorly water-soluble drug can be further improved.
In one aspect of the present invention, 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.

(Water-soluble binder (a2))
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).
In one aspect of the present invention, each of the plurality of particles (A ′) constituting the particle group (A) may contain a component (a2).
Examples of 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). 5-5 mass% is still more preferable, and 2.0-4.0 mass% is the most preferable.
In one aspect of the present invention, 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.
If it is at least the lower limit value, 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 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 with respect to the total mass of one tablet. Is more preferable, and 0.10 to 1.3% by mass is most preferable.
If it is at least the lower limit value, 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.
In one aspect of the present invention, 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.

(Water-soluble compound particle group (a3))
The particle group (A) may contain a component (a3). The component (a3) is a water-soluble compound particle group.
In one aspect of the present invention, the water-soluble compound particle group (a3) is composed of one or more of the water-soluble compound particles (a3 ′). In the present specification, 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. Applied.
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). You may mix with an ingredient.
In one aspect of the present invention, 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.
In another aspect of the present invention, 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.
In another aspect of the present invention, 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.
In still another aspect of the present invention, 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. . In addition, a water-soluble active agent such as acetaminophen, anhydrous caffeine or a hydrate thereof may be used. Of these, mannitol and acetaminophen are preferable.

10-90 mass% is preferable with respect to the total mass of particle group (A), and, as for the compounding quantity of (a3) component in particle group (A), 20-70 mass% is more preferable, and 30-50 mass% is. More preferably, 34.7-47.8 mass% is still more preferable.
In one aspect of the present invention, 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 ′). 10-90 mass% is preferable, 20-70 mass% is more preferable, 30-50 mass% is still more preferable, 34.7-47.8 mass% is still 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. 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, and still more preferably 1.5 to 45% by mass with respect to the total mass of one tablet. 2.7 to 18.5 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. 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.
In one aspect of the present invention, 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.

In this invention, 5-500 micrometers is preferable and, as for the average particle diameter of (a3) component, 10-300 micrometers is more preferable.
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 by using a laser diffraction / scattering particle size distribution measuring device “LA-920” (manufactured by Horiba, Ltd.), and other components by laser diffraction / scattering. Measure before mixing with.
In one aspect of the present invention, 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.
In another aspect of the present invention, 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.
In one aspect of the present invention, 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. Less than 33 is preferable, 0.015 or more and less than 0.23 is more preferable, 0.03 or more and less than 0.12 is more preferable, and 0.0462 to 0.1154 or less is even more preferable.
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.

(Average particle diameter of particle group (A))
In the present invention, 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 measuring device “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 μm, more preferably 700 μm or less, and still more preferably 600 μm or less. Moreover, 1 micrometer or more is preferable, More preferably, it is 10 micrometers or more. That is, the average particle size of the particle group (A) is preferably 1 μm or more and less than 800 μm, more preferably 10 μm or more and 700 μm or less, and further preferably 10 μm or more and 600 μm or less.
In one aspect of the present invention, 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.
In another aspect of the present invention, 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.

(Structure of particle group (A))
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).
In one aspect of the present invention, each particle of the plurality of particles (A ′) constituting the particle group (A) is configured to include one or more particles (a1 ′).
In another aspect of the present invention, 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.
In another aspect of the present invention, 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.
In still another aspect of the present invention, 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.

(Blending amount of particle group (A))
As for the compounding quantity of the particle group (A) in a tablet, 5-90 mass% is preferable with respect to the total mass of one tablet, More preferably, it is 20-80 mass%.
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.
In one aspect of the present invention, 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.

<Particle group (B)>
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.
In one aspect of the present invention, the particle group (B) is composed of a plurality of carbonate or hydrogen carbonate particles (B ′).
In the present specification, 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. This is because carbon dioxide gas can be generated with hydrogen ions.
Of these, sodium hydrogen carbonate and potassium hydrogen carbonate are preferable. Of these, sodium bicarbonate having a low hygroscopic property is more preferable.
The particle group (B) can contain one or more of these carbonates and bicarbonates.

(Average particle diameter of particle group (B))
The average particle size (volume average particle size) 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 laser diffraction / scattering method. Measure before mixing with ingredients.
10-800 micrometers is preferable, as for the average particle diameter of particle group (B), 30-600 micrometers is more preferable, More preferably, it is 50-300 micrometers. If it is 10 μm or more, no dust is generated during production, and if it is 30 μm or more, the fluidity is good, and if it is 50 μm or more, the fluidity is further improved and the handling property during production is good. Moreover, if it is 800 micrometers or less, the further improvement of a dispersibility can be aimed at.
In one aspect of the present invention, 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.
In another aspect of the present invention, 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.

(Blending amount of particle group (B))
The blending amount of the particle group (B) in the tablet is not particularly limited. As a compounding quantity of particle group (B), 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.
Moreover, as a compounding quantity of the particle group (B) in a tablet, 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.
In general, 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. Since the particle group (B) is an alkaline substance, it has an unpleasant taste such as a bitter taste or a salty taste. Therefore, it is easy to avoid such disadvantages as long as the upper limit is reached.
In one aspect of the present invention, 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. As said mass ratio, 8.5 or less are preferable, More preferably, it is 1.2 or less, More preferably, it is 0.65 or less.
That is, 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.
In one aspect of the present invention, 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.
In another aspect of the present invention, 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.

<Optional component>
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). E), an optional component (also referred to as a pharmaceutically acceptable carrier) such as a binder, a lubricant, a fragrance, and a corrigent (such as a sweetener and a sour agent) may be included.

(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 | blending component, the further improvement of the dispersibility of the poorly water-soluble drug which is the effect of this invention can be aimed at.

Examples of the component (C) include anionic surfactants, cationic surfactants, nonionic surfactants, and amphoteric surfactants.
Examples of the anionic surfactant include alkyl sulfate salts such as sodium lauryl sulfate, alkyl ether sulfates, alkyl ether carboxylates, N-acyl sarcosine salts, N-acyl glutamates, N-acyl-N-methyl β-alanines. N-acyl amino acid salts such as salts, alkyl polyoxyethylene sulfate, α-olefin sulfonate, N-acyl-N-methyl taurate, alkyl sulfosuccinate, alkyl phosphate, polyoxyethylene alkyl ether phosphorus Examples include acid salts.
Examples of the cationic surfactant include N-acylaminoethyl diethylamine salt, N-acylguanidine salt, alkyltrimethylammonium salt, dialkyldimethylammonium salt, alkylbenzyldimethylammonium salt and the like.
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, hydrogenated sterol, polyethylene glycol (1) fatty acid ester, Polyethylene glycol (2) fatty acid ester, polyethylene glycol (4) fatty acid ester, polyethylene glycol (10) fatty acid ester, polyethylene Glycol (25) fatty acid ester, polyethylene glycol (40) fatty acid ester, polyoxyethylene lanolin, polyoxyethylene lanolin alcohol, polyoxyethylene (6) beeswax derivative, polyoxyethylene (20) beeswax derivative, polyoxyethylene (5 ) Alkylamine, polyoxyethylene (10) alkylamine, polyoxyethylene (15) alkylamine, polyoxyethylene (5) fatty acid amide, polyoxyethylene (10) fatty acid amide, polyoxyethylene (15) fatty acid amide, alkyl Examples include diethanolamine, alkyl glucoside, alkyl maltoside, alkyl polyglucoside, sucrose fatty acid ester, methyl glucoside ester, and methyl glucamide.
In addition, the numerical value in the bracket | parenthesis in the description of the nonionic activator of the said illustration represents the average addition mole number of ethylene oxide (EO).
Among these, an anionic surfactant is preferable.
Among the anionic surfactants, sodium lauryl sulfate is preferable in order to produce good wettability with the drug.

  If component (C) is contained in the tablet, 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).

When (C) component is mix | blended with particle group (A), the compounding quantity of (C) component in particle group (A) is 0.1-50 mass% with respect to the gross mass of particle group (A). Preferably, it is 0.5 to 25% by mass. Moreover, 0.005-45 mass% is preferable with respect to the total mass of one tablet, and, as for the compounding quantity of (C) component in a tablet, More preferably, it is 0.025-22.5 mass%.
1 aspect of this invention WHEREIN: The compounding quantity of (C) component in each particle | grains of several particle | grains (A ') which comprises particle group (A) is 0. 0 with respect to the mass of each particle | grain (A'). 1-50 mass% is preferable, More preferably, it is 0.5-25 mass%.
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.
In another aspect of the present invention, 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.
In another aspect of the present invention, 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.

When the component (C) is added to the tablet of the present invention in addition to the particle group (A), the amount of the component (C) in the tablet excluding the component (C) in the particle group (A) is 0.1. -20 mass% is preferable.
In one aspect of the present invention, 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. When 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.

When the component (C) is added as a powder, the average particle size of (C) is preferably 1 to 300 μm.
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 diameter (volume average particle diameter) of the particle group (C) is determined by another laser diffraction / scattering method using a laser diffraction / scattering particle size distribution measuring device “LA-920” (manufactured by Horiba, Ltd.). Measure before mixing with ingredients.
In one aspect of the present invention, when the component (C) is added as a powder, 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.
In another aspect of the present invention, the particles of the component (C) have an interface with other particles or components in the tablet of the present invention.

(Water-soluble excipient)
The water-soluble excipient (referred to herein as “component (D)”) 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. . Among them, 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.
In one aspect of the present invention, the component (D) is blended outside each particle of the particle (A ′). In this case, 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, based on the total mass of one tablet. It is.
Since the dispersibility of a poorly water-soluble drug can be further improved if the amount is not less than the lower limit value, and the amount of additives other than the drug can be reduced if the amount is not more than the upper limit value, the dose per dose Can be reduced, and the dosage becomes better.
In one aspect of the present invention, 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.

(Disintegrant)
Examples of the disintegrant (hereinafter referred to as “component (E)”) include carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, partial α 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.
In one aspect of the present invention, 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.

(Other optional ingredients)
As the binder, crystalline cellulose, anhydrous calcium hydrogen phosphate, hydroxypropyl cellulose, polovinylpyrrolidone, or the like can be used.
As the 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.
As the fragrance, for example, menthol, limonene, plant essential oil (mint oil, mint oil, lychee oil, orange oil, lemon oil, etc.) can be used.
As the sweetener, for example, saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose and the like can be used.
As the acidulant, for example, citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, or a salt thereof can be used.

<< Method for producing tablet of the present invention >>
The tablet production method of the present invention comprises a granulation step and a tableting step.

<Granulation process>
A granulation process is a process of producing a particle group (A).
As the granulation step of the present invention, it is sufficient that a particle group containing the component (a1) is obtained.
For example, 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.
As a dispersion containing the component (a1), if there is a commercial product of the component (a1) having a desired average particle size, the commercial product of the component (a1) may be dispersed in the solution as it is to obtain a dispersion. As the 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. When pulverizing the dispersion with a bead mill, general beads can be used. For example, beads made of zirconia, polystyrene, polyurethane, glass, and stainless steel can be used, and beads having a bead diameter of 0.015 μm 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. In particular, 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 μm, more preferably 10 to 300 μm. 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 Coarseness is less likely to occur.
Spraying of 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). Is preferable, more preferably 10 to 80% by mass, and still 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.

<Mixing process>
In the mixing step, 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 and mixed powder It is the process of obtaining.
The component (C) can also be included in the particle group (A) in the granulation step. In the mixing step, the particle group (A), the particle group (B), and, if desired, the component (D) , (E) can also be mixed. In any case, the dispersibility of the poorly water-soluble drug can be further improved.
For mixing, 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.

<Tabletting process>
The tableting step is a step of tableting the mixed powder produced in the mixing step to obtain a tablet.
As an example, 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 Kogyo) or the like.
In one aspect of the present invention, 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.
In another aspect of the present invention, the tableting pressure in the compression molding is 400 to 1800 kgf, more preferably 600 to 1400 kgf.

<Coating process>
Thereafter, the tablets to be produced may be coated with a coating agent as necessary for the purpose of improving stability or the like.
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.
As 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. Specifically, 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. In addition, commercially available premix products such as Opadry (manufactured by Nippon Colorcon LLC) may be used as long as the dispersibility is not significantly impaired.
These coating agents may be used individually by 1 type, and may be used in combination of 2 or more type.
It is preferable that the usage-amount of a coating agent shall be about 0.1-20 mass parts with respect to 100 mass parts of tablets.

  According to the present invention, since the particle group (A) and the particle group (B) are included, a tablet containing a poorly water-soluble drug that exhibits good dispersibility can be provided.

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.
Moreover, as a tablet of this invention, the compounding quantity of (a1) component in a tablet is 4-56 mass% with respect to the total mass of one tablet, and the compounding quantity of (a2) component in a tablet is, for example. 0.075 to 4.5% by mass with respect to the total mass of one tablet, and the blending amount of the component (a3) in the tablet is 1.4 to 45% by mass with respect to the total mass of one tablet. The tablet which the compounding quantity of (C) component in a tablet is 0.025-22.5 mass% with respect to the total mass of one tablet can be mentioned. Moreover, the compounding quantity of the (a1) component in a tablet is 4-56 mass% with respect to the total mass of one tablet, and the compounding quantity of the (a2) component in a tablet is with respect to the total mass of one tablet, 0.075 to 4.5% by mass, and 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, and 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, and 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. Can be mentioned tablets. However, the sum total of the said compounding quantity does not exceed 100 mass%.
As the tablet of the present invention, for example, 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.
Examples of 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%.

  Hereinafter, the present invention will be described in more detail using examples, but the present invention is not limited to these examples. Further, “parts” and “%” in the examples are solid contents excluding water unless otherwise specified, and indicate mass parts and mass%, respectively.

"material"
The main materials used in this example are shown below.
・ Ibuprofen "Ibuprofen 25" (BASF)
・ Hydroxypropyl cellulose “HPC-SSL” (manufactured by Nippon Soda Co., Ltd.)
・ Mannitol "Pairitol 50C" (Made by Rocket)
・ Mannitol "Pairitol 200SD" (manufactured by Rocket)
・ Sodium bicarbonate "Sodium bicarbonate KF" (Asahi Glass Co., Ltd.)
・ Sodium bicarbonate "Sodium bicarbonate KP" (Asahi Glass Co., Ltd.)
・ Potassium hydrogen carbonate “Potassium hydrogen carbonate” (Wako Pure Chemical Industries, Ltd.)
・ Sodium carbonate "Sodium carbonate" (Wako Pure Chemical Industries, Ltd.)
・ Calcium carbonate "Calcium carbonate" (Asahi Glass Co., Ltd.)
・ Sodium lauryl sulfate “SLS” (manufactured by Nikko Chemicals Co., Ltd.)
・ Crospovidone "Kollidon CL-SF" (BASF)
・ Magnesium stearate “Magnesium stearate” (manufactured by Taihei Chemical Industry Co., Ltd.)
・ Acetaminophen "Piretinol" (Iwaki Pharmaceutical Co., Ltd.)
・ Allyl isopropyl acetyl urea “Alipronal Congo” (manufactured by Kongo Chemical Co., Ltd.)
* Etodolac "Etodlac micronized" (manufactured by LONZA)

"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.
After dissolution, the solution was filtered through a 0.45 μm 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.

In this example, 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 for 10 minutes after addition of tablet) − (dispersion rate of drug for 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.

(Examples 1 to 10 and Comparative Example 1)
"Production of ibuprofen-containing particles"
In Examples 1 and 2, the above “ibuprofen 25” was used as it was as the particle group (A).
In this example, 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 μm. However, Examples 1 to 3 are reference examples.

The particle groups (A) in Examples 3 to 10 and Comparative Example 1 were prepared as follows.
680 mL of water was put into a container equipped with a stirrer, and stirring was started. In this, 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)).
In this example, the average particle size of the particles in the dispersion is 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.
As a result, the average particle diameter of the component (a1) in the dispersion was 0.5 μm.
In a dispersion of the ibuprofen particle group, 14 g of sodium lauryl sulfate “SLS” corresponding to component (C) was dissolved.

Next, powder mannitol “Pairitol 50C” (component (a3)) having an average particle diameter of 50 μm 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 μm. 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.

  In Examples 1 to 10 and Comparative Example 1, sodium bicarbonate “sodium bicarbonate KF” having an average particle size of 120 μm 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.

"Production of mixed powder"
In a blender (“Bole Container Mixer LM20” manufactured by Kotobuki Kogyo Co., Ltd., Container “MC20” manufactured by Kotobuki Kogyo Co., Ltd.), the particle group (A ), Particle group (B) and optional components were added. The total amount of powder charged was about 2 kg. As the optional components mannitol, crospovidone, and magnesium stearate, the above-mentioned “Pairitol 200SD”, “Kollidon CL-SF”, and “Magnesium stearate” were used, respectively. After the addition, mixing was performed at a rotation speed of 21 rpm for 20 minutes to obtain a mixed powder (mixing step).

"Manufacture of tablets"
From the mixed powder, a rotary tableting machine “Collect 12 HUK” (manufactured by Kikusui Seisakusho Co., Ltd.)) is used to prepare a tableting pressure so that the tablet hardness is 6 to 7 kgf. A 10-mm diameter tablet was obtained (tablet process).

  As shown in Table 1, the compounding amount of each component and the tablet weight per tablet of Examples 1 to 10 and Comparative Example 1 were adjusted. In addition, the content rate (%) of each component shown in the parenthesis in Table 1 means mass%.

  Table 1 shows the results of the dispersibility evaluation test conducted using the tablets of Examples 1 to 10 and Comparative Example 1.

  As shown in Table 1, the tablet of Comparative Example 1 not containing sodium bicarbonate had an ibuprofen dispersion rate of 28% for 10 minutes after the addition of the tablet. On the other hand, the tablets of Examples 1 to 10 containing sodium bicarbonate showed a high dispersion rate of 62% or more.

(Examples 11 to 13)
About Examples 11-13, it replaces with sodium hydrogencarbonate in the said Example 6, and uses potassium hydrogen carbonate (average particle diameter of 130 micrometers), sodium carbonate (average particle diameter of 100 micrometers), or calcium carbonate (average particle diameter of 110 micrometers), respectively. 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 performed using the tablets of Examples 6 and 11 to 13 minutes after the addition of the tablets. In addition, the content rate (%) of each component shown in the parenthesis in Table 2 means mass%. However, Example 13 is a reference example.

As shown in Table 2, the tablets of Examples 6 and 11 to 13 containing potassium hydrogen carbonate, sodium carbonate or calcium carbonate all have a high dispersion value of 69% or more of ibuprofen for 10 minutes after the addition of the tablets. Indicated.
It was also found that tablets using hydrogen carbonate had a higher drug dispersion rate than carbonate.

(Examples 14 to 19)
For Examples 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. However, Example 19 is a reference example.

  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.

As shown in Table 3, the tablets of Examples 6 and 14 to 19 containing ibuprofen particles and hydrogen carbonate particles in the tablets had a dispersion ratio of ibuprofen of 10% or more after addition of the tablets of 83% or more. The dispersion was significantly higher than that of Example 1 (28%).
In particular, in Examples 6 and 14 to 18 in which the particle diameter of ibuprofen is less than 10 μm, the dispersion rate reduction value is 10% or less, and it was also found that the stability of dispersibility is high.

(Examples 20 to 24)
For Examples 20 to 24, tablets were obtained in the same manner as in Example 6 except that the average particle diameter of sodium hydrogen carbonate shown in Table 4 was used.
For Example 20, sodium bicarbonate “sodium bicarbonate KP” having an average particle size of 40 μm 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 hydrogencarbonate used in Examples 21 to 24 was produced by the following method.
1 kg of sodium hydrogen carbonate “sodium bicarbonate KF” having an average particle size of 120 μm was put into a stirring granulator (High Speed Mixer FS-10 (manufactured by Fukae Pautech Co., Ltd.). 50 g of water was added, and the agitator rotation speed was 300 rpm. The mixture was stirred and granulated at a chopper rotation speed of 1500 rpm, and the powder in the container was collected and dried in a constant temperature layer. Sodium hydride was obtained, and the average particle size was measured in the same manner as the average particle size of the dried particles.
Table 4 shows the results of the dispersibility evaluation test conducted using the tablets of Examples 6 and 20 to 24 for 10 minutes and 30 minutes after the addition of the tablets. However, Example 24 is a reference example.

  In the tablets of Examples 6, 20, and 21 having an average particle size of sodium hydrogen carbonate of 300 μm or less, the ibuprofen dispersion ratio of 10 minutes after the tablet addition was 92% or more, and Example 22 of 500 μm was 85% and 720 μm Example 23 was 72%, and Example 24 of 960 μm was 58%. In any of the Examples, the dispersibility of ibuprofen was higher than that of Comparative Example 1 (28%) not containing sodium bicarbonate.

(Examples 25 to 28)
About Examples 25-28, the tablet was produced like Example 6 except having adjusted the amount of preparation powder | flour so that it might become the composition shown in Table 5. When the particle diameter of the component (a1) after pulverizing the beads in Examples 25 to 28 was measured in the same manner as in Example 6, they were all 0.5 μm. The average particle size of the particle group (A) was 210 μm in Example 25, 220 μm in Example 26, 215 μm in Example 27, and 209 μm 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 performed using the tablets of Examples 6 and 25 to 28 for 10 minutes and 30 minutes after the addition of the tablets.

  In the tablets of Examples 6, 27, and 28 in which the blending amount of the component (a2) in the particle group (A) is 1.5 to 5% by mass, the ibuprofen dispersion rate after 10 minutes from the addition of the tablet was 92% or more. . In the tablet of Example 26 in which the blending amount of the component (a2) in the particle group (A) was 0.8 to 10% by mass, the ibuprofen dispersion rate after 10 minutes from the addition of the tablet was 84% or more. In the tablet of Example 25 in which the blending amount of the component (a2) in the particle group (A) is 0.2 to 30% by mass, the ibuprofen dispersion rate after 10 minutes from the tablet addition was as high as 76%.

(Examples 29 to 33)
About Examples 29-33, the amount of preparation powder was adjusted so that it might become a composition shown in Table 6, and the tablet was produced similarly to Example 6. FIG. When the particle diameter of the component (a1) after pulverizing the beads in Examples 29 to 33 was measured in the same manner as in Example 6, all were 0.5 μm. The average particle size of the particle group (A) was 211 μm in Example 29, 212 μm in Example 30, 215 μm in Example 31, 205 μm in Example 32, and 201 μm in Example 33. 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 6 shows the results of the dispersibility evaluation test conducted using the tablets of Examples 29 to 33 for 10 minutes and 30 minutes after the addition of the tablets.

In the tablets of Examples 31, 32, and 33 in which the blending amount of the component (a3) in the particle group (A) was 30 to 50% by mass, the ibuprofen dispersion rate after 10 minutes from the addition of the tablets was 92% or more. In the tablet of Example 30 in which the blending amount of the component (a3) in the particle group (A) was 20 to 70% by mass, the ibuprofen dispersion rate after 10 minutes from the addition of the tablet was 82%. In the tablet of Example 29 in which the blending amount of the component (a2) in the particle group (A) was 10 to 90% by mass, the ibuprofen dispersion rate after 10 minutes from the addition of the tablet was 72% or more. All the examples showed high dispersion ratio values.
In addition, in the tablets of Examples 30 to 33 in which the blending ratio of the component (a2) to the component (a3) is 0.03 or more and less than 0.12, the ibuprofen dispersion rate 10 minutes after the addition of the tablet was 82% or more. It was. In the tablet of Example 29 in which the blending ratio of the component (a2) to the component (a3) was 0.0001 or more and less than 0.33, the ibuprofen dispersion rate after 10 minutes from the addition of the tablet was 72% or more.

(Examples 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. As the poorly water-soluble drug (a1) component, etodolac was used in Example 34, and allylisopropylacetylurea was used in Example 35. When 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 μm. The average particle size of the particle group (A) was 211 μm in Example 34 and 225 μm 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. However, Example 35 is a reference example.

  In the tablets of Examples 34 and 35 using a poorly water-soluble drug other than ibuprofen as the poorly water-soluble drug (a1) component, the dispersion ratio of the poorly water-soluble drug 10 minutes after the addition of the tablet was 62% or more.

(Summary)
From these results, if a tablet contains a combination of a particle group containing a particle group of a poorly water-soluble drug and a carbonate particle group or a hydrogen carbonate particle group, the preparation has good dispersibility of the poorly water-soluble drug. Can understand.
Further, when the average particle diameter of the particle group of the poorly water-soluble drug contained in the particle group (A) is less than 10 μm, the dispersibility of the poorly water-soluble drug and the stability of the dispersibility of the poorly water-soluble drug are particularly good. Become.

  ADVANTAGE OF THE INVENTION According to this invention, the tablet containing the poorly water-soluble drug which shows favorable dispersibility can be provided. Therefore, the present invention can be suitably used for “tablets” and is extremely important in industry.

Claims (9)

A particle group (A) containing a particle group of a poorly water-soluble drug;
At least one particle group (B) selected from a particle group of sodium carbonate, a particle group of sodium bicarbonate and a particle group of potassium bicarbonate ;
A tablet, including,
The poorly water-soluble drug is a non-steroidal anti-inflammatory agent;
The average particle size of the particle group of the poorly water-soluble drug contained in the particle group (A) is 0.01 μm or more and less than 10 μm,
The average particle diameter of the particle group (B) is 10 μm or more and 800 μm or less,
The mass ratio of the particle group (B) to the particle group (A) is 0.0229 or more and 0.917 or less,
The tablet whose compounding quantity of the particle group (B) contained in a tablet is 5-20 mass% with respect to the total mass of one tablet . The non-steroidal anti-inflammatory agent is at least one selected from ibuprofen, aspirin, naproxen, ketoprofen, indomethacin, bufexamac, diclofenac, alclofenac, etodolac, flurbiprofen, mefenamic, meclofenamic, and piroxicam. The tablet according to claim 1. The tablet of Claim 1 or 2 whose compounding quantity of the said particle group (A) is 5-90 mass% with respect to the total mass of one tablet.   The amount of the poorly water-soluble drug contained in the particle group (A) is 5 to 90% by mass with respect to the total mass of the particle group (A). tablet. The particle group (A) is a particle containing a water-soluble binder (a2), a water-soluble compound particle group (a3), and a surfactant (C), and the amount of component (a2) in the tablet is It is 0.01-27 mass% with respect to one total mass, and the compounding quantity of (a3) component in a tablet is 0.5-81 mass% with respect to one gross mass of a tablet, and is in a tablet. the amount of component (C), for one of the total weight tablet, a 0.005 to 45 mass%, the does not exceed 100 weight% total of the amount of each component, according to claim 1-4 The tablet of any one of these. The tablet according to claim 5 , wherein a mass ratio of the component (a2) to the component (a3) is 0.0001 or more and less than 0.33. The component (a2) is at least one selected from polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, methyl cellulose, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose,
  The component (a3) is mannitol, lactose or a hydrate thereof, sucrose, fructose, erythritol, xylitol, sorbitol, anhydrous potassium dihydrogen phosphate, sodium chloride, potassium chloride, acetaminophen, anhydrous caffeine or water thereof One or more selected from Japanese,
  The tablet according to claim 5 or 6, wherein the component (C) is at least one selected from an anionic surfactant, a cationic surfactant, a nonionic surfactant, and an amphoteric surfactant. In the particle group (A), the poorly water-soluble drug (a1) and the surfactant (C) are attached to the surface of the water-soluble compound particle group (a3) using the water-soluble binder (a2) as a binder. The tablet according to any one of claims 5 to 7, wherein: The tablet according to any one of claims 1 to 8 , wherein the dispersion rate of the poorly water-soluble drug 10 minutes after the addition of the tablet to the gastric model solution is 80 % or more.