KR101890649B1 - Tablet - Google Patents

Abstract

A tablet comprising a particle group (A) containing particles of a water-soluble drug, and at least one particle group (B) selected from a group of particles of carbonate and a group of particles of bicarbonate.

Description

Tablets {TABLET}

The present invention relates to tablets.

The present application claims priority based on Japanese Patent Application No. 2013-157823 filed on July 30, 2013, the contents of which are incorporated herein by reference.

In drug-containing preparations, the dispersibility of the drug in the stomach after administration is one of the important factors affecting the bioavailability of the drug. In particular, when the drug is a poorly water-soluble drug, it is considered that the poorly water-soluble drug is more likely to flocculate in the polar solution than the water-soluble drug, and the transition from the top to the intestine is delayed. In addition, since the water-soluble drug can hardly be redissolved in the solution once it is flocculated, the good or badness of the drug dispersibility in the preparation containing the water-soluble drug greatly affects the bioavailability of the drug.

Therefore, it is important to improve the dispersibility of a drug in a formulation containing a poorly soluble drug, in order to increase the bioavailability of the drug.

For example, Patent Documents 1 and 2 disclose preparations for improving 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 the hygroscopic saccharide and sodium lauryl sulfate are used in combination, the redispersibility of the drug increases synergistically.

Patent Document 2 discloses a nanoparticle composition comprising an active drug with low solubility. Patent Document 2 discloses that when dioctyl sodium sulfosuccinate (DOSS) is incorporated into a nanoparticle composition containing active drug particles on the surface of which a polymer surface stabilizer such as polyvinylpyrrolidone (PVP) is adsorbed, It is shown that acidity is excellent.

Japanese Patent No. 3710818 Japanese Patent Publication No. 2004-513886

However, in order to further increase the bioavailability of the drug, a new means for improving the dispersibility of the drug is required.

Therefore, it is an object of the present invention to provide tablets having higher dispersibility of water-miscible drugs.

The tablet of the present invention is characterized in that it comprises a particle group (A) containing a particle group of a water-insoluble drug and at least one particle group (B) selected from a particle group of a carbonate and a particle group of a bicarbonate .

Preferably, the average particle diameter of the particle group of the water-insoluble drug is less than 10 mu m.

(Effects of the Invention)

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a tablet containing a poorly soluble drug showing good dispersibility.

«Tablets»

The tablet of the present invention is also referred to as a particle group a1 of the water-insoluble drug (also referred to as " component (a1) " in this specification). The component (a1) may also represent the component itself of the particle group (a1). ) (Hereinafter also referred to simply as "particle group (A)") and at least one kind of particle group (B) selected from the group of particles of carbonate and the group of particles of bicarbonate (B) " in this specification).

The average particle diameter of the particles of the water-insoluble drug is preferably less than 10 mu m.

In addition, the above-mentioned tablet may contain an optional component such as a surfactant (C), a water-soluble excipient (D) or a disintegrant (E) in addition to the particle group (A) Quot; carrier ").

One aspect of the tablet of the present invention comprises a group of particles (A) and a group of particles (B), wherein said group of particles (A) comprises a plurality of particles (A ') comprising particles , And the particle group (B) is composed of a plurality of particles of carbonate and at least one kind of particles (B ') selected from particles of hydrogencarbonate.

The particle group (a1) of the water-insoluble drug is composed of a plurality of particles (a1 ') of the water-insoluble drug, and the average particle diameter of the particle group (a1) is preferably less than 10 m.

One side of the average particle diameter of the particle group (a1) is 0.01 占 퐉 or more and less than 10 占 퐉, and the other side is 0.1 占 퐉 or more and 2 占 퐉 or less.

Another aspect of the tablet of the present invention is that the tablet contains the particle group (A) and the particle group (B), and constitutes a plurality of particles (A ') and a particle group (B) And the plurality of particles (B ') each have a discontinuous interface (also referred to as an interface in this specification) between different particles or components.

Another aspect of the tablet of the present invention includes the above-mentioned particle group (A) and the above-mentioned particle group (B), wherein the particle group (A) and the particle group (B) Tablet ").

Another aspect of the tablets of the present invention is that they are pharmaceutically acceptable for the surfactants (C), water-soluble excipients (D) or disintegrants (E) (C), water-soluble excipient (D) or disintegrant (E), which are contained in the particle group (A) and the particle group (B) The carrier that can be used is a compression molded tablet.

Another aspect of the tablet of the present invention is a tablet having a tablet hardness of 3 kgf or more and 15 kgf or less and a tablet having a tablet hardness of 4 kgf or more and 12 kgf or less on the other side and a tablet having a tablet hardness of 6 kgf or more and 7 kgf or less.

In the present specification, the tablet hardness can be measured using a tablet hardness tester PTB-301 (manufactured by Pharmac Co.).

Another aspect of the tablet of the present invention is a tablet in which a plurality of particles (a1 ') constituting the particle group (a1) of the water-insoluble drug are contained while retaining the particle diameter before compression molding.

Another aspect of the tablet of the present invention is that the dispersion ratio of the water-insoluble drug after 10 minutes from the above model solution is 40% or more, preferably 60% or more, more preferably 80% or more, still more preferably 90% Or more.

Yet another aspect of the tablet of the present invention is a tablet having a dispersion lowering value of 0 to 10%, more preferably 0 to 7%, and 0 to 3%. The dispersion lowering value is a value obtained by subtracting the dispersion ratio after 30 minutes from the dispersion ratio after 10 minutes from the addition of the tablet to the above model solution in the dispersibility evaluation test. The dispersibility evaluation test will be described later.

≪ Particle group (A) >

The particle group (A) is a group of particles containing the particle group (a1) of the water-insoluble drug.

The water-soluble compound particles (a3) (in this specification, the "component (a3)") and the water-soluble compound (a2) ), A surfactant (C), and an optional ingredient (also referred to as a " pharmaceutically acceptable carrier " in the present specification) commonly used in pharmaceutical preparations.

In one aspect of the present invention, the particle group (A) is composed of a plurality of particles (A ') comprising particles (a1') of the water-insoluble drug.

In another aspect of the present invention, the particle group (A) may contain a water-soluble binder (a2), a water-soluble compound particle (a3 '), a surfactant (C) And consists of a plurality of particles (A ') comprising a pharmaceutically acceptable carrier.

When the particles (a1 ') and the particles (B') of the water-soluble drug are coexisted in the same granules (also referred to as particles), that is, when the component of the water-insoluble drug and the carbonate or bicarbonate are coexisted in the same granule, 'May react with the particles (a1') to cause the particles (a1 ') to become unstable, or the physical properties of the powder may be changed to cause adhesion to the container or apparatus at the time of production. Therefore, it is preferable that the components of the water-miscible drug and the carbonate or hydrogencarbonate do not coexist in the same granules (also referred to as particles).

(component (a1))

The particle group (A) contains the component (a1).

In one aspect of the present invention, the particle group (a1) of the water-insoluble drug is composed of a plurality of particles (a1 ') of the water-insoluble drug. The description and illustration of the particle group (a1), that is, the component (a1) is applied to each particle of the plurality of particles (a1 ') constituting the particle group (a1) unless otherwise specified.

In the present specification, the water-insoluble drug refers to a drug having a solubility of 0 to 13 mg / mL in water at 20 ° C. The water-soluble drug is preferably a drug having a solubility of 0 to 10 mg / mL in water at 20 캜, more preferably 0 to 5 mg / mL, more preferably 0 to 1 mg / mL, and 0 to 0.35 mg / mL Most preferred.

In the present specification, the method for measuring the solubility is a test according to the Japanese Pharmacopoeia of the 16th State. Specifically, when the drug is added to water at 20 ° C and shaken strongly for 30 seconds every 5 minutes, the ratio of the mass of the drug dissolved within 30 minutes to the volume of water is measured.

Examples of the water-insoluble drug to be used as the component (a1) include, but are not limited to, ibuprofen, aspirin, naproxen, ketoprofen, indomethacin, buffet, diclofenac, alclofenac, etodolac, Non-steroidal anti-inflammatory agents such as lebifropene, ketoprofen, mefenamic, meclofenamic, and piroxycam; Hypnotics and sedatives such as Nitrazam, Nitrazam, Triazolam, Phenobarbital, Amivarbital, and Allyl isopropylacetylurea; Antiepileptics such as phenytoin, primidone, clonazepam, carbamazepine and valproic acid; Antidepressants such as methicillin hydrochloride and dimenhydrinate; Psychotropic solvents such as halepellidol, chlorodiaxanthide, diazepam, and sulpiride; Antispasmodics such as atropine; Cardiac drugs such as digoxin; Arrhythmia agents such as pinoleilol and dysopyramide; Diuretics such as hydrochlorothiazide, spironolactone, triamterene, prochemide, and butanenide; Antihypertensive agents such as prazosin hydrochloride; Vascular vasodilators such as isosorbide nitrate, nifedipine, dipyridamole and the like; Such as nocarpine, tulobuterol, and tranilast; Expectorants such as bromohexane hydrochloride; Antibiotics such as erythromycin, irradiated mycin, chloramphenicol, rifampicin, and glyceoflavin; Antihistamines such as clemastine fumarate; Steroid agents such as dexamethasone, betamethasone, prednisolone, danazol, chlormadine acetate and the like; Vitamins such as vitamin A and folic acid (vitamin M class); Therapeutic agents for gastrointestinal diseases such as famotidine, metoclopramide, omeprazole, treadtone, and squalate; Mercaptopurine, methotrexate, mesyl dihydrogerthamine, aluminum hydroxide, synthetic hydrotalcite, magnesium oxide, magnesium hydroxide, and the like. The nonsteroidal anti-inflammatory agent is particularly remarkably obtained by the effect of the present invention, and among them, ibuprofen is more remarkably obtained.

In the component (a1), the water-miscible drugs may be used singly or in combination of two or more kinds.

In the present invention, the volume average particle diameter of the component (a1) (sometimes referred to simply as " average particle diameter " in this specification) is measured with a laser diffraction / scattering type particle size distribution measuring apparatus "LA-920" HORIBA SEISAKUSHO Co., Ltd.) before or after mixing with other particles according to the manual flow cell measurement method.

The average particle diameter of the component (a1) is preferably less than 10 mu m, more preferably not more than 5 mu m, and further preferably not more than 2 mu m. Further, it is preferably 0.01 탆 or more, and more preferably 0.1 탆 or more. That is, the average particle diameter of the component (a1) is preferably from 0.01 m or more to less than 10 m, more preferably from 0.1 m to 5 m, even more preferably from 0.1 m to 2 m, even more preferably from 0.2 m to 2 m Even more preferred.

In one aspect of the present invention, the average particle diameter of the component (a1) means the average particle diameter before mixing with the other particles or after the pulverizing step, but the average particle diameter of the particles (a1 ' Particle size of some particles is maintained even after tableting.

In another aspect of the present invention, the plurality of particles (a1 ') constituting the particle group (a1) of the water-insoluble drug have an interface between other particles or components in the tablets of the present invention.

There are individual differences in the time, strength, frequency, and duration until the peristalsis is initiated in the peristalsis after the tablet is taken. Even if the drug is rapidly dispersed, the aforementioned factors are deviated, and the time until the drug is transferred to the intestine is delayed. If the re-aggregation of the drug occurs and precipitates therebetween, the amount and speed of transfer of the drug to the intestine are lowered, leading to deterioration of effectiveness. When the average particle diameter of the component (a1) is not more than the upper limit value, the dispersibility can be further improved and the dispersed state can be maintained even after 30 minutes of dispersion. On the other hand, if it is not less than the above lower limit value, the particles of the component (a1) are hardly aggregated, and the dispersibility of the poorly soluble drug is further improved.

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, and still more preferably 20 To 70% by mass.

In one aspect of the present invention, the amount of the particles (a1 ') in each particle of the plurality of particles (A') constituting the particle group (A ' To 90% by mass, more preferably 10% to 80% by mass, still more preferably 20% to 70% by mass, still more preferably 47.8% to 66.2% by mass.

If the amount is above the lower limit value, the amount of the additive other than the drug is decreased, so that the dosage per one dose can be reduced and the dosage can be improved, and if it is not more than the upper limit, the dispersibility of the poorly water soluble drug can be further improved.

The amount of the component (a1) in the tablet is preferably 0.25 to 81% by mass, more preferably 2 to 72% by mass, still more preferably 4 to 56% by mass, relative to the total mass of the tablet And more preferably 8.8 to 18.8 mass%.

If the amount is above the lower limit value, the dosage per one dose can be reduced to reduce the amount of the additive other than the drug, and the dosage can be improved. If the amount is below 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 such that the total mass of the component (a1) used in the production of all of the tablets, .

(Water-soluble binder (a2))

The particle group (A) may contain the component (a2). The component (a2) is a water-soluble binder and is compounded as a binder of the component (a1).

In one aspect of the present invention, the plurality of particles (A ') constituting the particle group (A) may each contain the component (a2).

Examples of the component (a2) include polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, methylcellulose, hypromelose, hydroxyethylcellulose, hydroxypropylcellulose and the like.

Among them, hydroxypropylcellulose and methylcellulose are preferable in order to improve the wettability of the component (a1) and further improve the dispersibility. Wettability is the affinity of a solid surface for a liquid and is evaluated as 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, and more preferably 1.5 to 5% by mass relative to the total mass of the particle group (A) , And most preferably 2.0 to 4.0 mass%.

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) , More preferably from 0.8 to 10 mass%, even more preferably from 1.5 to 5.0 mass%, and most preferably from 2.0 to 4.0 mass%.

When the lower limit is not less than the lower limit, sufficient hardness and wettability are imparted to the tablet to improve dispersibility. When the content is not more than the upper limit, adhesion of the powder to the apparatus at the time of granulation or tableting is reduced.

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, still more preferably 0.075 to 4.5% by mass, more preferably 0.10 to 1.3% % By mass is most preferable.

If the lower limit value is not less than the lower limit value, sufficient hardness and wettability are imparted to the tablet to improve dispersibility, and if it is not more than the upper limit value, adhesion of the powder to the apparatus during assembly or treading is reduced.

In one aspect of the present invention, the blending amount of the component (a2) in one tablet is not more than the total mass of the component (a2) used in the production of all the tablets, .

(Water-soluble compound particle group (a3))

The particle group (A) may contain the component (a3). The component (a3) is a water-soluble compound particle group.

In one aspect of the present invention, the particle group (a3) of the water-soluble compound is composed of one or a plurality of particles (a3 ') of the water-soluble compound. In this specification, the description and examples of the particle group (a3), that is, the component (a3) are applied to each particle of a plurality of particles (a3 ') constituting the particle group (a3) unless otherwise specified.

The component (a1) may be present in the particle group (A) in the state of being attached to the surface of the particle (a3 ') constituting the component (a3) or may be mixed with the component (a3) in the particle group (A).

In one aspect of the present invention, each particle of the plurality of particles (A ') constituting the particle group (A') comprises one or more particles (a1 ') as a binder on the surface of the particle ').

In another aspect of the present invention, each particle of the plurality of particles (A ') constituting the particle group (A) is formed by aggregating one or more particles (a3') and one or more particles (a1 ' Particles.

In another aspect of the present invention, each particle of the plurality of particles (A ') constituting the particle group (A) comprises one or more particles (a3') dispersed and one or more particles (a1 ') .

In a still further aspect of the present invention, each particle of the plurality of particles (A ') constituting the particle group (A') comprises one or more particles (a2 ' a1 ') attached thereto; Particles in which one or more particles (a3 ') and one or more particles (a1') are aggregated with each other; And at least one particle selected from the group consisting of one or more dispersed particles (a3 ') and one or more particles (a1'), and the particles may be mixed in the particles (A ').

The water-soluble compound used in the component (a3) is a substance whose solubility in water at 20 ° C is higher than 13 mg / mL. Examples thereof include saccharides such as mannitol, lactose or its hydrate, sucrose and fructose, sugar alcohols such as erythritol, xylitol and sorbitol, and inorganic salts such as anhydrous potassium dihydrogenphosphate, sodium chloride and potassium chloride. Further, a water-soluble active agent such as acetaminophen, anhydrous caffeine or a hydrate thereof may be used. Among them, mannitol and acetaminophen are preferred.

The 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 relative to the total mass of the particle group (A) , Still more preferably from 34.7 to 47.8 mass%.

In one aspect of the present invention, the amount of the particles (a3 ') in each particle of the plurality of particles (A') constituting the particle group (A ') is 10 To 90% by mass, more preferably 20% to 70% by mass, still more preferably 30% to 50% by mass, still more preferably 34.7% to 47.8% by mass.

When the compounding amount of the component (a3) is the lower limit value or more, the wettability of the tablet is improved and the dispersibility can be improved. If the upper limit is not more than the upper limit, the amount of the additive other than the drug is decreased, so that the dose per dose can be reduced, and the dosage can be improved.

The amount of the component (a3) in the tablet is preferably 0.5 to 81 mass%, more preferably 1 to 63 mass%, further preferably 1.5 to 45 mass%, and most preferably 2.7 to 18.5 mass% % By mass is still more preferable.

When the compounding amount of the component (a3) is the lower limit value or more, the wettability of the tablet is improved and the dispersibility can be improved. If the upper limit is not more than the upper limit, the amount of the additive other than the drug is decreased, so that the dose per dose can be reduced, and the dosage can be improved.

In one aspect of the present invention, the blending amount of the component (a3) in one tablet is such that the total mass of the component (a3) used in the production of all of the tablets with respect to the mass of all the tablets produced in one preparation .

In the present invention, the average particle diameter of the component (a3) is preferably 5 to 500 mu m, more preferably 10 to 300 mu m.

If the ratio is not less than the lower limit value, the fluidity of the powder becomes good and the handling property at the time of production is improved. If the upper limit is not more than the upper limit value, the dispersibility becomes good and coarsening of the particle diameter after the granulation is difficult to occur.

The average particle diameter (volume average particle diameter) of the component (a3) was measured by a laser diffraction / scattering particle size distribution analyzer " LA-920 " (Horiba Seisakusho Co., Ltd.) Measure before mixing.

In one aspect of the present invention, the average particle diameter of the component (a3) means the average particle diameter before mixing with the other components, but the average particle diameter of the particles (a3 ' 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 between the other particles or components in the tablets of the present invention.

The mass ratio of the component (a2) to the component (a3)

The tablets of the present invention contain a particle group (A) and a particle group (B), whereby tablets having sufficiently good dispersibility of the water-insoluble drug can be obtained. The compounding ratio of the component (a2) a2 / a3 ratio), it is possible to obtain tablets with better dispersibility of the water-insoluble drug.

The a2 / a3 ratio is a mass ratio represented by the formula "component (a2) / component (a3)". The ratio a2 / a3 is preferably from 0.0001 to less than 0.33, more preferably from 0.015 to less than 0.23, still more preferably from 0.03 to less than 0.12, and still more preferably from 0.0462 to 0.1154 or less.

In one aspect of the present invention, the a2 / a3 ratio is represented by the total mass of the water-soluble binding agent / total mass of the water-soluble compound in one tablet, and the a2 / a3 ratio is preferably from 0.0001 to less than 0.33, More preferably less than 0.23, still more preferably 0.03 or more but less than 0.12, and still more preferably 0.0462 to 0.1154 or less.

If the lower limit value is not less than the lower limit value, sufficient hardness can be imparted to the tablet, and if it is less than the upper limit value, adhesion of the powder to the apparatus is alleviated.

(Average particle diameter of the particle group (A))

In the present invention, the average particle diameter (volume average particle diameter) of the particle group (A) was measured by a laser diffraction / scattering particle size distribution measuring apparatus "LA-920" (Horiba Seisakusho Co., Ltd.) Measure before mixing with other ingredients by the method.

The average particle diameter of the particle group (A) is preferably less than 800 mu m, more preferably not more than 700 mu m, and further preferably not more than 600 mu m. It is preferably at least 1 mu m, more preferably at least 10 mu m. That is, the average particle diameter of the particle group (A) is preferably 1 占 퐉 or more and less than 800 占 퐉, more preferably 10 占 퐉 to 700 占 퐉, and still more preferably 10 占 퐉 to 600 占 퐉.

In one aspect of the present invention, the average particle diameter of the particle group (A) means the average particle diameter before the tableting, but the particle diameter of at least a part of each particle (A ' 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 between different particles or components in the tablets 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, a mixture in which the component (a1) is mixed with at least one optional component selected from the component (a2), the component (a3) and the component (C). The particle group (A) may be an aggregate of the component (a1) on which the component (a1) is adhered. The surface of the component (a3) may be an aggregate of one or more optional components selected from the group consisting of the components (a2) and (C) 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') contains particles (a1 ') and (a2), particles (a3' And at least one kind of component or particle selected from the group consisting of

In another aspect of the present invention, each particle of the plurality of particles (A ') constituting the particle group (A') includes particles having one or more particles (a1 ') attached to the surface of the particle (a3' .

In a still further aspect of the present invention, each particle of the plurality of particles (A ') constituting the particle group (A') adheres one or more particles (a1 ') to the surface of the particle (a3' And at least one component selected from the group consisting of the component (a2), the particles (a3 ') and (C), or the particles to which the particles are attached.

(The amount of the particles (A) to be blended)

The compounding amount of the particle group (A) in the tablet is preferably 5 to 90% by mass, more preferably 20 to 80% by mass, based on the total mass of the tablet.

If the amount is above the lower limit value, the amount of the additive other than the drug is decreased, so that the dose per dose can be reduced and the dosage can be improved. If the amount is less than the upper limit, the dispersibility of the poorly soluble drug is further improved.

In one aspect of the present invention, the blending amount of the particle group (A) in one tablet is determined by the mass of all the tablets (A) used in the production of all of the tablets, It is expressed as a ratio of total mass.

≪ Particle group (B) >

The particle group (B) is at least one kind of particle group selected from a group of carbonate particles and a group of particles of hydrogen carbonate. The particle group (B) functions mainly as a dispersant by reacting with gastric acid to generate carbon dioxide gas.

In one aspect of the present invention, the particle group (B) is composed of a plurality of particles of carbonate or bicarbonate (B ').

In this specification, the description and examples of the particle group (B) are applied to each particle of a 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. Among them, sodium carbonate is preferable.

Examples of the hydrogencarbonate used in the present invention include metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate, and hydrogencarbonates other than metal hydrogencarbonate such as ammonium hydrogencarbonate.

Among the carbonate and bicarbonate salts, hydrogen carbonate is more preferred in order to further improve the dispersibility of the water-soluble drug. In order for carbonate to react with stomach acid to produce carbon dioxide gas, two molecules of hydrogen ion are required for one molecule of carbonate. However, hydrogencarbonate can generate carbon dioxide gas with one molecule of hydrogen ion for one molecule of bicarbonate Because.

Among them, sodium hydrogencarbonate and potassium hydrogencarbonate are preferable. Of these, sodium hydrogencarbonate having low hygroscopicity is more preferable.

The particle group (B) may contain at least one of these carbonates and hydrogen carbonate salts.

(Average particle diameter of the particle group (B))

The average particle diameter (volume average particle diameter) of the particle group (B) was measured by a laser diffraction / scattering particle size distribution analyzer " LA-920 " (Horiba Seisakusho Co., Ltd.) ≪ / RTI >

The average particle diameter of the particle group (B) is preferably 10 to 800 占 퐉, more preferably 30 to 600 占 퐉, and further preferably 50 to 300 占 퐉. If it is 10 mu m or more, it does not oscillate at the time of production. If it is 30 mu m or more, the fluidity is good, and when it is 50 mu m or more, the fluidity is further improved and the handling property at the time of production becomes good. Further, when the thickness is 800 μm or less, further improvement in dispersibility is achieved.

In one aspect of the present invention, the average particle diameter of the particle group (B) means the average particle diameter before the tableting, but the particle diameter of at least some of the particles (B ' 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 between different particles or components in the tablets of the present invention.

(The amount of the particles (B)

The blending amount of the particle group (B) in the tablet is not particularly limited. The blending amount of the particle group (B) is preferably 0.1% by mass or more, more preferably 2% by mass or more, further preferably 5% by mass or more based on the total mass of the tablet. When the lower limit is set, the dispersibility of the poorly water-soluble drug can be further improved.

The blending amount of the particle group (B) in the tablet is preferably 85% by mass or less, more preferably 40% by mass or less, further preferably 20% by mass or less based on the total mass of the tablet.

The amount of the particles (B) in the tablet is preferably from 0.1 to 85 mass%, more preferably from 2 to 40 mass%, and still more preferably from 5 to 20 mass%, based on the total mass of the tablet And most preferably from 8.4% by mass to 14.3% by mass.

Since the particle group (B) is generally a hard particle in many cases, that is, the compression moldability is not good, hardness is hardly obtained when the particle group (B) is purified. In addition, 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 alkali substance, it has an unpleasant taste such as bitter taste and salty taste. Therefore, if the value is below the upper limit, it is easy to avoid such disadvantages.

In one aspect of the present invention, the blending amount of the particle group (B) in one tablet is determined so that the mass of all the tablets produced in one preparation It is expressed as a ratio of total mass.

The mass ratio (B / A ratio) of the particle group (B) represented by "particle group (B) / particle group (A)" to the particle group (A) is preferably 0.001 or more, more preferably 0.06 Or more, more preferably 0.15 or more. The mass ratio is preferably 8.5 or less, more preferably 1.2 or less, and still more preferably 0.65 or less.

That is, the mass ratio (B / A ratio) is preferably 0.001 or more and 8.5 or less, more preferably 0.06 or more and 1.2 or less, still more preferably 0.15 or more and 0.65 or less, still more preferably 0.221 or more and 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) in one tablet / the total mass of components constituting the particle group (A) The B / A ratio is preferably 0.001 or more and 8.5 or less, more preferably 0.06 or more and 1.2 or less, still more 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 determined by the ratio of the mass of all the particle groups (B) used in one production to the mass of all the particle groups (A) used in one production Lt; / RTI >

If the lower limit value is not less than the lower limit value, the dispersibility can be further improved. If the upper limit is not more than the above upper limit, the amount of the additive other than the drug is decreased, so that the dose per dose can be reduced, so that the dosage can be improved and the above disadvantage is easily avoided.

<Optional ingredients>

The tablet of the present invention may contain other raw materials such as a surfactant (C), a water-soluble excipient (D), a disintegrant (E), a binder, a lubricant (B) , A flavoring agent, a mating agent (sweetener, acidulant, etc.), and the like (also referred to as a pharmaceutically unacceptable carrier).

(Surfactant (C))

(C) (hereinafter also referred to as &quot; component (C) &quot;) in order to improve the wettability of the component (a1). (C) are mixed, it is possible to further improve the dispersibility of the water-insoluble drug which is an effect of the present invention.

As the component (C), an anionic surfactant, a cationic surfactant, a nonionic surfactant, and a positive surfactant are exemplified.

Examples of the anionic surfactant include N, N-dialkylammonium salts such as alkylsulfuric acid ester salts such as sodium laurylsulfate, alkyl ether sulfates, alkyl ether carboxylates, N-acyl sarcosinates, N-acylglutamates and N-acyl- Alkylpolyoxyethylene salts, alpha -olefin sulfonic acid salts, N-acyl-N-methyl tauric acid salts, alkylsulfosuccinic acid salts, alkyl phosphate salts, polyoxyethylene alkyl ether phosphate salts and the like.

Examples of the cationic surfactant include N-acylaminoethyldiethylamine salt, N-acylguanidine salt, alkyltrimethylammonium salt, dialkyldimethylammonium salt, alkylbenzyldimethylammonium salt and the like.

Examples of the nonionic surfactant include polyoxyethylene (2) alkyl ether, polyoxyethylene (9) alkyl ether, polyoxyethylene (21) alkyl ether, polyoxyethylene (25) alkyl ether, polyoxyethylene , Polyoxyethylene (10) alkylphenyl ether, polyoxyethylene (15) alkylphenyl ether, polyoxyethylene (10) polyoxypropylene (4) alkyl ether, polyoxyethylene (40) castor oil, polyoxyethylene ) Polyoxyethylene (80) castor oil, polyoxyethylene (40) hardened castor oil, polyoxyethylene (60) hardened castor oil, polyoxyethylene (80) hardened castor oil, polyoxyethylene glycerin fatty acid ester, Sorbitan fatty acid esters, polyoxyethylene (10) sorbitan fatty acid esters, polyoxyethylene (20) sorbitan fatty acid esters, polyoxyethylene (30) sorbit fatty acid esters, poly Sorbitol fatty acid esters, polyoxyethylene (10) sterols, polyoxyethylene (20) sterols, polyoxyethylene (30) sterols, hydrogenated sterols, polyethylene (40) sorbitol fatty acid esters, polyoxyethylene (2) fatty acid esters, polyethylene glycols (4) fatty acid esters, polyethylene glycols (10) fatty acid esters, polyethylene glycols (25) fatty acid esters, polyethylene glycol (40) fatty acid esters, polyoxyethylene Polyoxyethylene lanolin alcohol, polyoxyethylene (6) beeswax derivatives, polyoxyethylene (20) beeswax derivatives, polyoxyethylene (5) alkylamine, polyoxyethylene (10) alkylamine, polyoxyethylene (15) Alkyl amines, polyoxyethylene (5) fatty acid amides, polyoxyethylene (10) fatty acid amides, polyoxyethylene (15) fatty acid amides, alkyldiethanes Alkyl amines, alkyl amines, alkyl amines, alkyl amines, alkyl amines, alkyl amines, alkyl amines, alkyl amines, alkyl amines,

The numerical values in parentheses in the notation of the nonionic activator in the above example represent the average addition mole number of ethylene oxide (EO).

Of these, anionic surfactants are preferred.

Among the above anionic surfactants, sodium lauryl sulfate is preferable in order to produce good wettability by the drug.

When the component (C) is contained in the tablet, the dispersibility of the water-insoluble drug can be improved. The component (C) may be mixed with the particle group (A) to be purified to obtain tablets, or may be contained in the particles (A ') constituting the particle group (A).

When the component (C) is added to the particle group (A), the amount of the component (C) in the particle group (A) is preferably from 0.1 to 50 mass% with respect to the total mass of the particle group (A) Preferably 0.5 to 25% by mass. The amount of the component (C) in the tablet is preferably 0.005 to 45% by mass, and more preferably 0.025 to 22.5% by mass based on the total mass of the tablet.

In one aspect of the present invention, the blending amount of the component (C) in each particle of the plurality of particles (A ') constituting the particle group (A) is 0.1 to 50 By mass, more preferably 0.5 to 25% by mass.

When the amount is within the above range, good wettability can be generated by the water-insoluble drug, thereby further improving the dispersibility.

In another aspect of the present invention, the amount of the component (C) in each particle of the plurality of particles (A ') constituting the particle group (A) Of the total mass of the component (C) used in the production of all the particle groups (A).

In another aspect of the present invention, the amount of the component (C) in one tablet is preferably set such that the total mass of the components (C) used in the preparation of all the tablets .

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 preferably from 0.1 to 20 mass%.

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) Or may be blended so as to be coexistent with each particle of the particles (A ') and the outside thereof. When the component (C) is added to the outside of each particle of the particle (A '), the amount of the component (C) present on the outside of each particle of the particle (A') is from 0.1 to 20 % By mass is preferable.

When the amount is within the above range, good wettability can be generated by the water-insoluble drug, thereby further improving the dispersibility.

When the component (C) is added as a powder, the average particle diameter of (C) is preferably 1 to 300 mu m.

If the lower limit value is not less than the lower limit value, the powder has good fluidity and handling properties are improved. If the amount is within the upper limit value, the poorly water-soluble drug will produce good wettability and the dispersibility can be further improved.

The average particle diameter (volume average particle diameter) of the particle group (C) was measured by a laser diffraction / scattering particle size distribution analyzer &quot; LA-920 &quot; (Horiba Seisakusho Co., &Lt; / RTI &gt;

In one aspect of the present invention, when the component (C) is added as a powder, the average particle diameter of the particles of the component (C) means the average particle diameter before the tableting, The particle diameter of at least a part of each particle of the component C) is maintained even after tableting.

In another aspect of the present invention, the particles of component (C) have an interface between the other particles or components in the tablets of the present invention.

(Water-soluble excipient)

A water-soluble excipient (referred to as "component (D)" in the present specification) refers to a substance having a solubility in water at 20 ° C of 13 mg / mL or more. The water-soluble excipient preferably has a solubility in water at 20 DEG C of greater than 33 mg / mL, more preferably greater than 100 mg / mL. Examples thereof include saccharides such as lactose or its hydrate, sucrose and fructose, sugar alcohols such as mannitol, erythritol, xylitol and sorbitol, and inorganic substances such as anhydrous potassium dihydrogenphosphate, sodium chloride and potassium chloride. Among them, sugars and sugar alcohols are preferable, and lactose or its hydrate, erythritol, and mannitol are more preferable.

When the component (D) is included in the tablets of the present invention, the wettability of tablets can be improved and the dispersibility of the water-insoluble drug can be further improved.

The amount of the component (D) (excluding the component (a3) in the particle group (A)) in the tablet is preferably 5 to 70% by mass, and more preferably 10 to 65% by mass.

In one aspect of the present invention, the component (D) is compounded on the outside of each particle of the particle (A '). In this case, the blending amount of the component (D) present on the outside of each particle of the particle (A ') is preferably 5 to 70 mass%, more preferably 10 to 65 mass%, based on the total mass of one tablet.

If the amount is less than the lower limit value, the dispersibility of the water-insoluble drug can be further improved. If the amount is less than the upper limit value, the amount of the additive other than the drug is decreased, so the dose per one time can be reduced and the dosage can be improved.

In one aspect of the present invention, the blending amount of the component (D) in one tablet is such that the mass of the component (D) used in the production of all the tablets .

(Disintegrating)

Examples of the disintegrant (hereinafter referred to as &quot; component (E) &quot;) include carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylcellulose calcium, Propylcellulose, partially pregelatinized starch, carboxymethylstarch sodium, and the like. Among them, low-substituted hydroxypropylcellulose and crospovidone are preferable.

When the component (E) is included in the tablet of the present invention, the disintegration property of the tablet is enhanced, and the dispersibility of the water-insoluble drug can be further improved.

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 still more preferably 2 to 6% by mass based on the total mass of the tablet.

Within this range, the collapsibility of the tablet can be further increased, and the dispersibility of the water-insoluble drug can be further improved.

In one aspect of the present invention, the blending amount of the component (E) in one tablet is not more than the mass of all the tablets produced in one preparation, the mass of the component (E) .

(Other optional components)

As the binder, crystalline cellulose, anhydrous calcium hydrogen phosphate, hydroxypropyl cellulose, and polyvinyl pyrrolidone 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 them, magnesium stearate is preferable.

As the fragrance, for example, menthol, limonene, vegetable essential oils (peppermint oil, mint oil, riche oil, orange oil, lemon oil, etc.) can be used.

As the sweetener, for example, saccharin sodium, aspartame, stevia, potassium glycyrrhizin acid, potassium acetosulfam, taumatin, sucralose and the like can be used.

As the acidifier, for example, citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, or a salt thereof can be used.

&Lt; Process for producing tablets of the present invention &

The method for producing a tablet of the present invention comprises a granulation process and a tabletting process.

<Assembly process>

The assembling process is a process of manufacturing the particle group (A).

As the granulation step of the present invention, a particle group containing the component (a1) may be obtained.

For example, a dispersion containing the component (a1) (optionally, an optional component is added) is prepared, and then a solution of ( The component (a3) can be assembled by spraying the dispersion.

If a commercially available product of the component (a1) having a desired average particle diameter is present as a dispersion containing the component (a1), a commercially available product of the component (a1) may be directly dispersed in a solution to prepare a dispersion. As the dispersion containing the component (a1), a dispersion in which a water-insoluble drug is dispersed may be milled with a bead mill to obtain a desired average particle diameter. When pulverizing the dispersion with a beads mill, ordinary beads can be used. For example, beads made of zirconia, polystyrene, polyurethane, glass, or stainless steel can be used, and beads having a diameter of 0.015 to 20 mm can be used.

The optional components may be added to the dispersion beforehand, or may be added as a spray solution at the time of assembly by spraying. Particularly, the component (C) is preferably sprayed as a spraying liquid at the time of granulation from the viewpoint of further increasing the dispersibility of the water-insoluble drug.

The average particle diameter of the component (a3) coated with the dispersion is preferably 5 to 500 mu m, more preferably 10 to 300 mu m. If the lower limit value is not less than the lower limit value, the fluidity of the powder becomes good, and the handling property at the time of production improves. If the upper limit is below the upper limit value, the dispersibility becomes better.

The spraying of the dispersion containing the component (a1) is preferably carried out until the content of the component (a1) in the particle group (A) becomes 5 to 90 mass% with respect to the total mass of the particle group (A) To 10% by mass to 80% by mass, and more preferably from 20% by mass to 70% by mass.

If the amount is above the lower limit value, the amount of the additive other than the drug is decreased, so that the dose per one dose can be reduced and the dosage is improved. If the upper limit is not exceeded, coarsening of the assembled particles can be reduced.

<Mixing Process>

The mixing step is a step of obtaining a mixed powder by mixing the particle group (A) produced in the above-mentioned assembling step, the particle group (B) and optional components such as the components (C) to (E)

The component (C) may be included in the particle group (A) in the above-mentioned assembling step, and the particle group (A), the particle group (B) ) Component. In either case, the dispersibility of the water-soluble drug is further improved.

A commonly used mixer can be used for mixing. Examples of the mixer include a Boley container mixer (manufactured by Kotobuki Kogyo Co., Ltd.), a V type mixer (manufactured by Dalton Co., Ltd.), and a ribbon mixer (manufactured by Dalton Co., Ltd.).

The whole components may be added to a mixing vessel and mixed. Alternatively, after mixing some of the components, the other components may be sequentially added and mixed.

<Tabletting process>

The tableting step is a step of tableting the mixed powder prepared in the mixing step.

The tablets of the present invention can be produced, for example, by tableting using a rotary tabletting machine such as Lipa (Kikusui Ishizakuso Co., Ltd.), L-41 (Hatatekkosho).

In one aspect of the present invention, the tableting step may be performed by compression molding 50 to 1,500 mg, more preferably 150 to 500 mg of the mixed powder prepared in the mixing step.

In another aspect of the present invention, the compression pressure in the compression molding is 400 to 1,800 kgf, more preferably 600 to 1,400 kgf.

<Coating Process>

The tablets to be produced may then be subjected to a coating treatment with a coating agent as necessary for the purpose of improving stability and the like.

As a device used for coating, a general one can be used. For example, a fan-type coating apparatus such as HiCoter (manufactured by Proton Sankyo) and Aquacoater (manufactured by Proton Sankyo) can be used.

The coating agent is preferably selected so as not to significantly impair the dispersibility of the water-miscible drug (a1) in the body, which is an effect of the present invention. Among these, hydrophilic polymer compounds and sugars are more preferably selected. Specifically, cellulose such as hydroxypropylcellulose, hydroxypropylmethylcellulose, low-substituted hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, and ethylcellulose; Hydrophilic polymer compounds such as arabic gum, carboxyvinyl polymer, polyvinylpyrrolidone, crospovidone, polyvinyl alcohol and polyacrylic acid, sugar (such as granule), lactose, maltose, xylose, lactose and its hydrate, starch syrup , Saccharides such as isomerized sugars, oligosaccharides, sucrose, trehalose and reduced starch hydrolyzate (reduced starch hydrolyzate), palatinit, sorbitol, lactitol, erythritol, xylitol, reduced starch sugar, maltitol, mannitol Sugar alcohol and the like. Further, commercially available premixes such as Opadry (manufactured by Nippon Kayaku Tokai Co., Ltd.) may be used if the dispersibility is not significantly impaired.

These coating agents may be used singly or in combination of two or more kinds.

The amount of the coating agent to be used is preferably about 0.1 to 20 parts by mass with respect to 100 parts by mass of the tablet.

According to the present invention, it is possible to provide tablets containing a poorly water-soluble drug exhibiting good dispersibility because it contains the particle group (A) and the particle group (B).

As the tablet of the present invention, for example, a tablet in which the component (a1) is ibuprofen and the component constituting the particle group (B) is sodium hydrocarbons can be exemplified.

The tablet of the present invention can be obtained, for example, in the case where the amount of the component (a1) in the tablet is 4 to 56 mass% based on the total mass of one tablet, and the amount of the component (a2) Wherein the amount of the component (a3) in the tablet is from 1.4 to 45 mass% based on the total mass of the tablet, and the amount of the component (C) in the tablet is from 1 to 4 mass% And tablets having a total mass of 0.025 to 22.5 mass% can be exemplified. The amount of the component (a1) in the tablet is 4 to 56% by mass with respect to the total mass of one tablet, and the amount of the component (a2) in the tablet is 0.075 to 4.5% , The amount of the component (a3) in the tablet is 1.4 to 45 mass% with respect to the total mass of the tablet, and the amount of the component (C) in the tablet is 0.025 to 22.5 mass% And the amount of the particle group (B) in the tablet is 5 to 20% by mass relative to the total mass of the tablet. However, the total amount of the above blending amounts does not exceed 100% by mass.

As the tablet of the present invention, for example, the mass ratio (B / A ratio) of the particle group (A) to the particle group (A) of the particle group (B) is 0.15 or more and 0.65 or less, / a3 ratio) is 0.03 or more and less than 0.12.

As the tablet of the present invention, for example, tablets having a dispersion ratio of the water-miscible drug after 10 minutes from adding the tablet to the above model solution is 60% or more, more preferably 80% or more.

As the tablets of the present invention, for example, tablets having a dispersion lowering value of 0 to 10%, more preferably 0 to 7% and 0 to 3% can be exemplified.

Example

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples. In the examples, &quot; part &quot; and &quot;% &quot;, unless otherwise specified, are solid contents excluding water and represent mass parts and mass%, respectively.

"material"

Main materials used in this embodiment are shown below.

Ibuprofen "ibuprofen 25" (BASF)

Hydroxypropylcellulose &quot; HPC-SSL &quot; (manufactured by Nippon Soda Co., Ltd.)

· Mannitol "Fairitol 50C" (manufactured by Rocket)

· Mannitol "Fairitol 200SD" (manufactured by Rocket)

Sodium bicarbonate &quot; sodium bicarbonate KF &quot; (manufactured by Asahi Glass Co., Ltd.)

Sodium bicarbonate &quot; sodium bicarbonate KP &quot; (manufactured by Asahi Glass Co., Ltd.)

Potassium hydrogen carbonate "Potassium hydrogen carbonate" (manufactured by Wako Pure Chemical Industries, Ltd.)

Sodium carbonate &quot; sodium carbonate &quot; (manufactured by Wako Pure Chemical Industries, Ltd.)

Calcium carbonate Calcium carbonate (manufactured by Asahi Glass Co., Ltd.)

Sodium lauryl sulfate &quot; SLS &quot; (manufactured by Nikko Chemicals Co., Ltd.)

· Cross Povidone "Kollidon CL-SF" (BASF)

Magnesium stearate &quot; Magnesium stearate &quot; (manufactured by Taiheikagaku Sangyo Co., Ltd.)

Acetaminophen &quot; retinol &quot; (manufactured by Iwaki Seiyaku Co., Ltd.)

Allyl isopropyl acetyl urea &quot; Alipronal Congo &quot; (manufactured by Congo Kagaku Co., Ltd.)

Etodlac "Etodlac micronized" (manufactured by LONZA)

&Quot; Dispersibility evaluation test &quot;

And the dispersibility was evaluated using a paddle dissolution tester (Toyama Kyo Co., Ltd.).

Two tablets of purified water were added to 333 mL of the above model liquid (sodium chloride 6.8 mmol / L, hydrochloric acid 16.3 mmol / L, adjusted to pH 1.8) to such an extent that the stirring blades of the paddles were sufficiently blocked, .

A portion of the above model solution was added to the vial to contain the poorly soluble drug dispersed after 10 minutes and 30 minutes after addition of 2 tablets to the above model solution. The water-soluble drug, for example, ibuprofen, which is dispersed by adding acetonitrile and acetic acid to the above-mentioned model solution transferred into a vial bottle was dissolved. In addition, the dispersed water-insoluble drug means a drug which is not dissolved in the model solution but suspended and dispersed in the liquid, but the solution used for calculating the dispersion ratio also includes the drug dissolved in the model solution.

After dissolution, the solution was filtered with a 0.45 占 퐉 filter, and the amount of water-soluble drug was measured by high performance liquid chromatography. From the measurement results of this high performance liquid chromatography, the amount of the poorly soluble drug dispersed in the above model solution from the tablet was inversed.

The dispersion ratios of the drug at 10 minutes and 30 minutes after the addition of the tablet were calculated by calculating the ratio (%) of the mass of the poorly soluble drug dispersed from the tablets to the mass of the poorly soluble drug in the tablet .

In the present embodiment, the dispersion ratio is sufficiently high if it is 40% or more at 10 minutes after the addition of the tablet. If it is 60% or more, it is remarkably high. If it is 80% or more, it is remarkably high, and if it is 90% or more, it is very high.

Further, when the value (%) (hereinafter referred to as &quot; dispersion rate lowering value &quot;) calculated by "(dispersion rate of drug for 10 minutes after addition of tablet) - (dispersion rate of drug for 30 minutes after tablet addition) , And the stability of drug dispersibility is high. For example, when the dispersion lowering value is 10% or less, the stability of dispersibility is sufficiently high. When it is 7% or less, stability of dispersibility is remarkably high, and when it is 3% or less, stability of dispersibility is remarkably high.

(Examples 1 to 10 and Comparative Example 1)

&Quot; Preparation of ibuprofen-containing particles &quot;

In Examples 1 and 2, "ibuprofen 25" was used as it was as the particle group (A).

In this example, the average particle size of the dried particle group was measured by a laser diffraction / dispersion method using a laser diffraction / scattering particle size distribution measuring apparatus "LS230 type" (manufactured by Beckman Coulter).

As a result, the average particle diameter of the ibuprofen 25 was 25 m.

The particle groups (A) in Examples 3 to 10 and Comparative Example 1 were produced as follows.

680 mL of water was placed in a container equipped with a stirrer, and stirring was started. 14 g of hydroxypropyl cellulose (component (a2)) &quot; HPC-SSL &quot; was dissolved, and then 300 g of ibuprofen was added thereto and dispersed. This dispersion was treated with a bead mill "UAM015" (Kotobuki Kogyo Co., Ltd.) to obtain a dispersion of the ibuprofen particle group (component (a1)).

In this example, the average particle diameter of the group of particles in the dispersion was measured by a manual flow cell measurement method using a laser diffraction / scattering type particle size distribution measuring apparatus "LA-920" (manufactured by Horiba Seisakusho Co., Ltd.) .

As a result, the average particle diameter of the component (a1) in the dispersion was 0.5 mu m.

14 g of sodium laurylsulfate (SLS) corresponding to the component (C) was dissolved in the dispersion of the above ibuprofen particle group.

Then, powdered mannitol "Fairitol 50C" (component (a3)) having an average particle diameter of 50 μm was added to a fluidized bed granulator "MP-01" (Powlex Co., Ltd.) . The dispersion was prepared by dissolving the powder in which the SLS was dissolved (granulation step).

The dispersion was sprayed until the content of ibuprofen in the granulation reached 60% by mass, and the granules were dried until the exhaust temperature reached 35 캜 to obtain a particle group corresponding to the particle group (A) of the present invention.

The average particle diameter of the obtained particle group (A) was 200 占 퐉. The measurement of the average particle diameter was carried out in the same manner as the measurement of the average particle diameter of the above-mentioned dried particle group.

In Examples 1 to 10 and Comparative Example 1, sodium bicarbonate KF having an average particle diameter of 120 占 퐉 was used as the particle group (B). The measurement of the average particle diameter was carried out in the same manner as the measurement of the average particle diameter of the above-mentioned dried particle group.

&Quot; Preparation of mixed powder &quot;

(A), a particle group (A), and a particle group (B) were added to a mixer ("Bolle Container Mixer LM20" manufactured by Kotobuki Kogyo KK, container "MC20", manufactured by Kotobuki Kogyo Co., (B) and optional components were added. The total amount of powder added was about 2 kg. "Fairitol 200SD", "Kollidon CL-SF" and "magnesium stearate" were used for mannitol, crospovidone and magnesium stearate, respectively. After the addition, mixing was carried out at a rotation speed of 21 rpm for 20 minutes to obtain a mixed powder (mixing step).

&Quot; Preparation of Tablets &quot;

The tablets having a tablet hardness of 6 to 7 kgf were prepared from the powder mixture using a rotary tabletting machine &quot; Correct 12HUK &quot; (manufactured by Kikusui Isayasakusho Co., Ltd.) to obtain tablets having a diameter of about 10 mm Tableting process).

The compounding amounts and the refining weights of the respective components of the tablets of Examples 1 to 10 and Comparative Example 1 were adjusted as shown in Table 1. The content ratio (%) of each component shown in parentheses in Table 1 means% by 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 containing no sodium hydrogencarbonate had a dispersion ratio of ibuprofen of 28% for 10 minutes after addition of the tablet. On the other hand, the tablets of Examples 1 to 10 containing sodium hydrogencarbonate showed a high dispersion ratio of 62% or more.

(Examples 11 to 13)

Examples 11 to 13 were replaced with sodium hydrogencarbonate in Example 6, and potassium hydrogencarbonate (average particle diameter 130 탆), sodium carbonate (average particle diameter 100 탆), or calcium carbonate (average particle diameter 110 mu m) was used instead of the above-mentioned solution. The measurement of the average particle diameter was carried out in the same manner as the measurement of the average particle diameter of the above-mentioned dried particle group.

Table 2 shows the results of the 10 minute dispersibility evaluation test using the tablets of Example 6 and Examples 11 to 13. The content ratio (%) of each component shown in parentheses in Table 2 means% by mass.

As shown in Table 2, in all of the tablets of Example 6 and Examples 11 to 13 containing potassium hydrogen carbonate, sodium carbonate or calcium carbonate, the dispersion rate of ibuprofen for 10 minutes after the addition of the tablet was 69% Respectively.

It was also found that the purification rate using the bicarbonate was higher than that of the carbonate.

(Examples 14 to 19)

Tablets were obtained in the same manner as in Example 6 except that the average particle diameter of ibuprofen shown in Table 3 was used for Examples 14 to 19.

Table 3 shows the results of the dispersibility test for 10 minutes and 30 minutes after the addition of the tablets using the tablets of Example 6 and Examples 14 to 19.

As shown in Table 3, the tablets of Example 6 and Examples 14 to 19, in which ibuprofen particles and hydrogencarbonate particles were contained in tablets, showed that the dispersion ratio of ibuprofen for 10 minutes after addition of the tablet was 83% or more, 1 (28%), respectively.

Particularly, it was also found that in Example 6 and Examples 14 to 18 in which the particle diameter of ibuprofen is less than 10 占 퐉, the lowering of the dispersion rate is 10% or less and the stability of dispersibility is high.

(Examples 20 to 24)

Tablets were obtained in the same manner as in Example 6 except that the average particle diameters of sodium hydrogencarbonate shown in Table 4 were used for Examples 20 to 24.

In Example 20, sodium hydrogencarbonate "sodium bicarbonate KP" having an average particle diameter of 40 μm was used. The measurement of the average particle diameter was carried out in the same manner as the measurement of the average particle diameter of the above-mentioned dried particle group.

Sodium bicarbonate used in Examples 21 to 24 was produced by the following method.

1 kg of sodium hydrogencarbonate KF having an average particle diameter of 120 mu m was added to a stirring granulator (High Speed Mixer FS-10 (manufactured by Fukae Powtech Co., Ltd.). 50 g of water was added, , And the chopper was rotated at 1,500 rpm and assembled. The powder in the container was recovered and dried in a constant temperature layer. The dried powder was sieved and classified according to the particle diameter to obtain sodium bicarbonate having an average particle diameter shown in Table 4. The measurement of the average particle diameter was carried out in the same manner as the measurement of the average particle diameter of the above-mentioned dried particle group.

Table 4 shows the results of the dispersibility test at 10 minutes and 30 minutes after the addition of the tablets, using the tablets of Example 6 and Examples 20 to 24.

In the tablets of Example 6, Example 20, and Example 21 in which sodium hydrogen carbonate had an average particle diameter of 300 탆 or less, the dispersion ratio of ibuprofen for 10 minutes after the addition of the tablet was 92% or more, that of Example 22 for 500 탆 was 85% Example 23 having 720 占 퐉 had 72% and Example 24 having 960 占 퐉 had 58%. In any of the examples, the dispersibility of ibuprofen was higher than that of Comparative Example 1 (28%) which did not contain sodium hydrogencarbonate.

(Examples 25 to 28)

For Examples 25 to 28, tablets were prepared in the same manner as in Example 6 except that the amount of powder to be injected was adjusted so that the composition shown in Table 5 was obtained. The particle diameters of the component (a1) after the bead milling in Examples 25 to 28 were measured in the same manner as in Example 6, and the results are all 0.5 탆. The average particle diameter of the particle group (A) was 210 占 퐉 for Example 25, 220 占 퐉 for Example 26, 215 占 퐉 for Example 27, and 209 占 퐉 for Example 28. The measurement of the average particle diameter was carried out in the same manner as the measurement of the average particle diameter of the dried particles.

Table 5 shows the results of the dispersibility test for 10 minutes and 30 minutes after the addition of the tablets using the tablets of Example 6 and Examples 25 to 28. [

In the tablets of Example 6, Example 27, and Example 28 in which the amount of the component (a2) in the particle group (A2) was 1.5 to 5 mass%, the dispersion ratio of ibuprofen after 10 minutes was 92% or more. In the tablets of Example 26 in which the amount of the component (a2) in the particle group (A) was 0.8 to 10% by mass, the dispersion ratio of ibuprofen after 10 minutes from the addition of the tablet was 84% or more. In the tablets of Example 25 in which the blending amount of the component (a2) in the particle group (A) was 0.2 to 30% by mass, the dispersion ratio of ibuprofen after 10 minutes from the addition of the tablet was as high as 76%.

(Examples 29 to 33)

For Examples 29 to 33, the amount of the added powder was adjusted so that the composition shown in Table 6 was obtained, and tablets were produced in the same manner as in Example 6. The particle diameters of the components (a1) after the bead milling in Examples 29 to 33 were measured in the same manner as in Example 6, and the results were all 0.5 탆. The average particle diameter of the particle group (A) was 211 占 퐉 for Example 29, 212 占 퐉 for Example 30, 215 占 퐉 for Example 31, 205 占 퐉 for Example 32, and 201 占 퐉 for Example 33. The measurement of the average particle diameter was carried out in the same manner as the measurement of the average particle diameter of the dried particles.

Table 6 shows the results of the dispersibility test for 10 minutes and 30 minutes after the addition of the tablets using the tablets of Examples 29 to 33.

In the tablets of Examples 31, 32 and 33 in which the amount of the component (a3) in the particle group (A3) was 30 to 50 mass%, the dispersion ratio of ibuprofen after 10 minutes from the addition of the tablet was 92% or more. In the tablet of Example 30 in which the amount of the component (a3) in the particle group (A) was 20 to 70% by mass, the dispersion ratio of ibuprofen after 10 minutes from the addition of the tablet was 82%. In the tablets of Example 29 in which the blending amount of the component (a2) in the particle group (A) was 10 to 90% by mass, the dispersion ratio of ibuprofen for 10 minutes after the addition of the tablet was 72% or more. In any of the embodiments, the value of the high dispersion ratio was shown.

In the tablets of Examples 30 to 33 in which the blending ratio of the component (a2) to the component (a3) was 0.03 or more and less than 0.12, the dispersion ratio of ibuprofen after 10 minutes from the addition of the tablet was 82% or more. 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 dispersion ratio of ibuprofen after 10 minutes from the addition of the tablet was 72% or more.

(Examples 34 and 35)

Tablets were prepared in the same manner as in Example 6, except that the compositions of Examples 34 and 35 were adjusted so as to have the composition shown in Table 7, and the powdery amount was adjusted and other components of the poorly soluble drug (a1) were used. As the water-miscible drug (a1) component, etorolac in Example 34 and allyl isopropyl acetyl urea in Example 35 were used. The particle diameter of the component (a1) after the bead milling in Examples 34 and 35 was measured in the same manner as in Example 6, and the result was 0.5 탆. The average particle diameter of the particle group (A) was 211 占 퐉 for Example 34 and 225 占 퐉 for Example 35. The measurement of the average particle diameter was carried out in the same manner as the measurement of the average particle diameter of the dried particles.

Table 7 shows the results of the dispersibility test for 10 minutes and 30 minutes after the addition of the tablet, which was carried out using the tablets of Examples 34 and 35. [

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

(summary)

From these results, it can be understood that when a particle group containing a particle group of a water-insoluble drug and a particle group of a carbonate particle or a particle group of a hydrogencarbonate are included in the purification, a preparation having a good dispersibility of the water-insoluble drug can be obtained have.

When the average particle diameter of the particle group of the water-insoluble drug contained in the particle group (A) is less than 10 mu m, the dispersibility of the water-insoluble drug and the stability of the dispersibility of the water-insoluble drug become particularly good.

(Industrial availability)

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a tablet containing a poorly soluble drug showing good dispersibility. Therefore, the present invention can be suitably used for &quot; tablet &quot; and is very important in industry.

Claims (11)

(A) comprising a particle group of a water-soluble drug, and
A tablet comprising at least one particle group (B) selected from the group of particles of sodium carbonate, the group of particles of sodium hydrogencarbonate and the group of particles of potassium hydrogencarbonate,
Wherein said poorly soluble drug is a non-steroidal anti-inflammatory drug,
Wherein the particle group (a1) of the water-insoluble drug contained in the particle group (A) has an average particle diameter of not less than 0.01 탆 and less than 10 탆,
Wherein the average particle diameter of the particle group (B) is 10 占 퐉 or more and 800 占 퐉 or less,
Wherein the mass ratio of the particle group (B) to the particle group (A) is 0.0229 or more and 0.917 or less,
Wherein the blending amount of the particle group (B) contained in the tablet is 5 to 20 mass% with respect to the total mass of one tablet. The method according to claim 1,
Wherein said nonsteroidal anti-inflammatory agent is selected from the group consisting of ibuprofen, aspirin, naproxen, ketoprofen, indomethacin, buxpen desert, diclofenac, alclofenac, etodolac, flurebiprofen, mefenamic, meclofenamic, &Lt; / RTI &gt; or more. The method according to claim 1,
Wherein the blending amount of the particle group (A) is 5 to 90% by mass with respect to the total mass of one tablet. 3. The method according to claim 1 or 2,
Wherein the blending amount of the water-insoluble drug contained in the particle group (A) is 5 to 90 mass% with respect to the total mass of the particle group (A). delete delete 3. The method according to claim 1 or 2,
The particle group (A) is a particle comprising a water-soluble binder (a2), a water-soluble compound particle group (a3) and a surfactant (C), wherein the compounding amount of the component (a2) (A3) is 0.5 to 81% by mass with respect to the total mass of the tablet, and the amount of the component (C) in the tablet is in the range of 0.01 to 27% by mass relative to the total mass of the tablet , And the total amount of the components is not more than 100% by mass. 8. The method of claim 7,
Wherein the mass ratio of the component (a2) to the component (a3) is from 0.0001 to less than 0.33. 8. The method of claim 7,
The particle group (A) is characterized in that a particle group (a1) of the water-insoluble drug and the surfactant (C) are attached to the surface of the water-soluble compound particle group (a3) As tablets. 3. The method according to claim 1 or 2,
Wherein the dispersion ratio of the water-miscible drug after 10 minutes from the above model solution is 80% or more. 8. The method of claim 7,
Wherein the component (a2) is at least one selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, methylcellulose, hypromelose, hydroxyethylcellulose, and hydroxypropylcellulose,
Wherein the component (a3) is at least one selected from mannitol, lactose or a hydrate thereof, sucrose, fructose, erythritol, xylitol, sorbitol, potassium dihydrogenphosphate, sodium chloride, potassium chloride, acetaminophen, anhydrous caffeine or a hydrate thereof ,
Wherein the component (C) is at least one selected from anionic surfactants, cationic surfactants, nonionic surfactants, and amphoteric surfactants.