JP5793466B2 - tablet - Google Patents

Description

  The present invention relates to a tablet.

A poorly water-soluble drug has a slow dissolution rate in water as it is, and has a problem of poor dissolution from a tablet containing the drug. Therefore, various methods have been researched and developed to improve the dissolution property of poorly water-soluble drugs.
One of them is a method of refining a poorly water-soluble drug. By miniaturizing, the surface area is increased and the elution is improved. However, many poorly water-soluble drugs such as ibuprofen have strong secondary aggregation properties, and the desired effect may not be obtained due to aggregation during tablet production.
There is also a method of blending other ingredients with a poorly water-soluble drug in order to improve the dissolution property. For example, a method using an excipient such as low-substituted hydroxypropyl cellulose and a method using a water-soluble or water-swellable polymer compound as a binder have been proposed. For example, Patent Document 1 discloses that a poorly water-soluble drug is co-pulverized with an excipient, and wet-granulated while spraying an aqueous liquid containing a water-soluble or water-swellable polymer compound on the co-ground product. Granulated particles and tablets containing the same are disclosed. Patent Documents 2 to 3 propose a method of blending a basic salt with ibuprofen.

International Publication No. 2007/126063 JP-A-6-239738 JP 2008-534477 A

In the method described in Patent Document 1, by pulverizing a poorly water-soluble drug together with an excipient, the dissolution property of the poorly water-soluble drug from the resulting granulated particles is higher than when the poorly water-soluble drug is pulverized alone. improves. In addition, the presence of a water-soluble or water-swellable polymer compound (binder) on the surface of the granulated particles allows the granulated particles to adhere to each other when the pressure is applied during tableting, thereby improving the moldability. In terms of tablet disintegration, the presence of a water-soluble or water-swellable polymer compound in the granulated particles or between the granulated particles causes erosion of water when the tablet is taken. Grain particles are easily separated, and a fast disintegration effect is obtained.
In the method of blending a basic salt as in Patent Documents 2 to 3, drug dissolution is enhanced.
However, according to the study of the present inventors, in the case of a tablet containing a water-soluble polymer compound, the disintegration delay of the tablet occurs, and as a result, the effect of improving the dissolution property may be affected. It was sought after. The present inventor considers that the above-mentioned decay delay is caused by gelation when the binder comes into contact with moisture and inhibits separation and dispersion of particles.
This invention is made | formed in view of the said situation, Comprising: Disintegration delay by gelatinization of a water-soluble high molecular compound is suppressed, and it aims at providing the tablet excellent in quick disintegration.

As a result of intensive studies, the inventor of the present invention contains a drug and a water-soluble polymer compound in the same granulated particle, and also makes a neutral to acidic water-soluble salt exist around the granulated particle. The present inventors have found that the gelation of the water-soluble polymer compound when taking tablets and the disintegration delay due to this can be suppressed and the disintegration time can be shortened, and the present invention has been completed.
That is, the tablet of the present invention comprises (A) a drug and (B) a granulated particle containing a water-soluble polymer compound in which the amount of water required to dissolve 1 g at 20 ° C. is less than 100 mL ;
(C) a water-soluble salt in which the pH of a 1% by mass aqueous solution is 0.1 or more and less than 7.5;
Contain,
At least a part of the (A) contained in the granulated particles, ibuprofen, acetaminophen, Ru least 1 Tanedea selected from the group consisting of Allylisopropylacetylurea and dried aluminum hydroxide gel.

  ADVANTAGE OF THE INVENTION According to this invention, the disintegration delay by gelatinization of a water-soluble polymer compound is suppressed, and the tablet excellent in quick disintegration can be provided.

The tablet of the present invention has (A) a drug and (B) a granulated particle containing a water-soluble polymer compound (hereinafter referred to as granulated particle P) and (C) a 1% by mass aqueous solution having a pH of 0.1. And a water-soluble salt that is less than 7.5.
By containing the granulated particles P and the component (C) in the tablet, gelation of the component (B) due to moisture during taking is suppressed. By suppressing the gelation of the component (B), the granulated particles P in the tablet are easily separated from each other, and the disintegration time of the tablet is shortened (fast disintegration is improved). Moreover, since the effect of (B) component is fully exhibited, the granulated particle P itself will also be easily disintegrated and the elution property of (A) component will also improve.
The reason why the gelation of the component (B) is suppressed is not clear, but by incorporating the component (B) in the granulated particles and the presence of the component (C) on the outside thereof, the tablet can erode moisture. When received, it is considered that the component (C) is dissolved in the moisture before the moisture reaches the component (B), and an effect such as salting out is exhibited. Further, the component (B), for example, a water-soluble polymer having a hydroxyl group (—OH) such as hydroxypropyl cellulose and a water-soluble polymer having a carboxyl group (—COOH) such as polyacrylic acid are particularly alkaline. Tend to exert a strong thickening effect. Therefore, it is thought that the viscosity increase is suppressed because the water | moisture content of (B) component vicinity becomes acidic-neutral by (C) component.
On the other hand, when a water-soluble salt having a 1% by mass aqueous solution having a pH of 7.5 or higher is used instead of the component (C), the effect of suppressing the decay delay is not sufficiently obtained, and the rapid disintegration property is insufficient. It becomes. This is presumably because the component (B) exhibits a strong thickening effect because the water in the vicinity of the component (B) becomes alkaline due to the salt when the tablet is wetted with water.

The effects of the present invention as described above are particularly excellent when at least one of the following [1] to [3] is satisfied.
[1] The content of the component (C) is 0.2 to 10% by mass.
[2] The mass ratio (C / B) of the content of the component (C) to the content of the component (B) is 0.2 or more.
[3] The component (C) is at least one inorganic salt selected from sodium chloride, potassium chloride, potassium dihydrogen phosphate, and sodium dihydrogen phosphate.
Hereinafter, the tablet of the present invention will be described in more detail.

<Ingredients contained in tablets>
[(A) component: drug]
The drug of component (A) is not particularly limited, and can be appropriately selected from, for example, various known drugs as active ingredients that can be blended in tablets. Specific examples include acetaminophen, aspirin, ibuprofen, ethenamide, phenacetin, mefenamic acid, antipyrine, phenylbutazone, sulpyrine, diclofenate, ketoprofen, naproxen, epilysole, tiaramid hydrochloride, indomethacin, pentazocine, acetylcholine chloride, alimemazine tartrate , Cyproheptadine hydrochloride, diphedramine hydrochloride, chlorpheniramine maleate, codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, pentoxyberine citrate, theophylline, aminophylline, ephedrine hydrochloride, epinephrine hydrochloride, salbutamol sulfate, trichloride Metoquinol, Procaterol hydrochloride, Methylephedrine hydrochloride, Phenylpropanolamine hydrochloride, Guaif Nesine, tranexamic acid, caffeine anhydride, caffeine, salicylic acid, choline salicylate, sodium salicylate, allylisopropylacetylurea, aluminum hydroxide, magnesium aluminate silicate, synthetic hydrotalcite, magnesium oxide, magnesium hydroxide, magnesium carbonate, Examples thereof include magnesium silicate and sodium hydrogen carbonate.
As the component (A), one type may be used alone, or two or more types may be used in combination.

At least a part of the component (A) is blended with the granulated particles P.
The tablet of this invention may contain (A) component in parts other than the granulated particle P. FIG. For example, in addition to the granulated particles P, granulated particles containing the component (A) and not containing the component (B) may be contained. Moreover, you may contain a powdery (A) component as a granulated particle outer component.

In terms of the usefulness of the present invention, it is preferable that at least a part of the component (A) contained in the granulated particles P is a poorly water-soluble drug.
The poorly water-soluble drug refers to a drug that belongs to the Japanese pharmacopoeia that belongs to “not soluble” to “almost insoluble”. Specifically, if the amount of water required to dissolve 1 g at 20 ° C. is 100 mL or more, it can be said to be a poorly water-soluble drug.
Among poorly water-soluble drugs, aspirin, ibuprofen, ketoprofen, salicylic acid, sodium salicylate, allylisopropylacetylurea, aluminum hydroxide, magnesium aluminate silicate, synthetic hydrotalcite, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate At least one selected from is preferred.
The component (A) may further contain a drug other than the poorly water-soluble drug. The drug may be contained in the granulated particles P, or may be contained as a granulated particle other than the granulated particles P or as an ingredient outside the granulated particles.

  Although content of (A) component in a tablet is not specifically limited, 0.1-95 mass% is preferable and 1-90 mass% is more preferable.

[(B) component: water-soluble polymer compound]
The component (B) is a component that functions as a binder.
The water-soluble polymer compound refers to a polymer compound in which the amount of water required to dissolve 1 g at 20 ° C. is less than 100 mL. As the water-soluble polymer compound, those in which the amount of water required to dissolve 1 g at 20 ° C. is less than 25 mL are preferable.
Component (B) may be a natural polymer or a synthetic polymer, and these may be used in combination.
Examples of the natural polymer include starch, soluble starch, dextrin, α starch, sodium alginate, arabic gum, gelatin, tragacanth gum, locust bean gum, and casein.
Synthetic polymers include, for example, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxyalkyl cellulose such as hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium salt (Na-CMC), methyl cellulose (MC), carboxymethylated starch sodium Salt, hydroxyethylated starch, starch phosphate sodium salt, polyvinyl alcohol (PVA), polyvinyl methyl ether (PVM), polyacrylamide, sodium polyacrylate, water-soluble copolymer, partially saponified vinyl acetate and vinyl ether Polymers, polymers or copolymers of acrylic acid, methacrylic acid, maleic acid and esters or salts thereof, polyethylene glycol (PEG), polyester Ren'okishido, polyvinylpyrrolidone (PVP) and the like.
As the component (B), one type may be used alone, or two or more types may be used in combination.
Among the above, the component (B) is preferably at least one selected from hydroxyalkyl cellulose and polyvinyl alcohol from the viewpoint of granulation and operability when an aqueous solution is used, and is selected from hydroxypropyl cellulose and polyvinyl alcohol. At least one is more preferable, and hydroxypropyl cellulose is particularly preferable.
Hydroxypropyl cellulose preferably has a viscosity at 20 ° C. of a 2% by weight aqueous solution of 1 to 5000 mPa · s, more preferably 1 to 500 mPa · s, and particularly preferably 1 to 20 mPa · s. .
Polyvinyl alcohol preferably has a viscosity at 20 ° C. of a 4 mass% aqueous solution of 1 to 100 mPa · s, more preferably 3 to 50 mPa · s, and particularly preferably 20 to 50 mPa · s.
The viscosity of each aqueous solution can be measured with a rotational viscometer (for example, a Brookfield viscometer).

At least a part of the component (B) is blended with the granulated particles P.
The tablet of this invention may contain (B) component in parts other than the granulated particle P. FIG. For example, in addition to the granulated particles P, granulated particles containing the component (B) and not containing the component (A) may be contained. Moreover, you may contain powdery (B) component as a granulated particle outer component. However, considering the effect of the present invention, it is preferable that the component (B) is present only in the granulated particles.

[Component (C)]
Component (C) is a water-soluble salt in which the pH of a 1% by mass aqueous solution is 0.1 or more and less than 7.5. The pH is preferably 4.0 or more and less than 7.5. As described above, the gelation of the component (B) in the granulated particles P is performed by adding a water-soluble salt having a pH of 0.1 to less than 7.5 in addition to the granulated particles P. Is suppressed, and the delay of the disintegration time of the tablet due to the gelation can be prevented.
Here, the water-soluble salt refers to a salt belonging to “slightly soluble” to “extremely soluble” in the Japanese Pharmacopoeia. Specifically, it can be said to be a water-soluble salt if the amount of water required to dissolve 1 g at 20 ° C. is less than 30 mL.
The pH is a value at 20 ° C.

Component (C) may be an inorganic salt or an organic salt.
Examples of the inorganic salt include chloride and dihydrogen phosphate, and alkali metal chloride and alkali metal dihydrogen phosphate are preferable. As the alkali metal, sodium or potassium is preferable. Specific examples of the chloride include sodium chloride and potassium chloride. Specific examples of the dihydrogen phosphate include potassium dihydrogen phosphate, sodium dihydrogen phosphate, ammonium dihydrogen phosphate, disodium dihydrogen pyrophosphate, and the like.
Examples of the organic salt include alkali metal salts (sodium salt, potassium salt) of acids such as citric acid, lactic acid, acetic acid, tartaric acid, succinic acid, malic acid, and fumaric acid.
These salts may be used alone or in combination of two or more.
Among these, at least one inorganic salt selected from alkali metal chlorides and alkali metal dihydrogen phosphates is preferable from the viewpoint of high solubility. Sodium chloride, potassium chloride, potassium dihydrogen phosphate, phosphoric acid At least one selected from sodium dihydrogen and the like is more preferable.
Furthermore, from the viewpoint of maintenance (rust prevention) of the production apparatus, the component (C) is particularly preferably an alkali metal dihydrogen phosphate. The alkali metal dihydrogen phosphate may be used alone or in combination of two or more.

In the tablet of the present invention, at least a part of the component (C) is blended separately from the granulated particles P.
The component (C) may be incorporated in a granulated particle different from the granulated particle P, or the powdered (C) component may be blended as it is as an external component of the granulated particle. In view of the effects of the present invention, it is preferable that at least a part of the composition is blended as an outside component of the granulated particles.
A part of the component (C) may be contained in the granulated particles P within a range not impairing the effects of the present invention.
When the powdered component (C) is blended as an external component of the granulated particles, the granulated particles to be blended with this are 850 μm in order to ensure mixing uniformity with the component (C) and to express stable physical properties. It is preferable to use one having a particle size that passes through a sieve.

  The content of the component (C) in the tablet is preferably 0.2 to 10% by mass, more preferably 0.5 to 5% by mass, and particularly preferably 1.0 to 2.5% by mass. When it is 0.2% by mass or more, a sufficient gelation suppressing effect can be obtained. This is presumably because the salting-out effect is sufficiently exhibited when the salt concentration in the aqueous solution generated by dissolving the component (C) in water at the time of taking is sufficiently high. On the other hand, when the content exceeds 10% by mass, the tablet performance may be deteriorated (swelling or hardness reduction) due to the presence of a large amount of the water-absorbing component (C).

  In the tablet, the mass ratio (C / B) of the content of the component (C) to the content of the component (B) is preferably 0.2 or more, more preferably 0.35 to 0.60. . When C / B is 0.2 or more, a sufficient gelation suppressing effect can be obtained. When C / B is 0.60 or less, since a sufficient amount of the component (B) is present in the tablet, the tablet moldability is good.

The tablet of this invention may contain other components other than said (A)-(C) component as needed in the range which does not inhibit the effect of this invention. The other components are not particularly limited, and components that are usually blended in tablets can be contained. Examples of such components include disintegrants, excipients other than disintegrants, surfactants, lubricants, fragrances, corrigents (sweeteners, acidulants, etc.), fluidizing agents, and the like.
Although the specific example of each component is illustrated below, it is not restricted to this.

Examples of the disintegrant include carmellose, carmellose calcium, carmellose sodium, carboxymethylcellulose calcium, and low-substituted hydroxypropylcellulose.
Examples of excipients other than the disintegrant include saccharides, corn starch, talc, crystalline cellulose (such as Avicel), light anhydrous silicic acid, calcium carbonate, L-cysteine, and the like. Examples of sugars include monosaccharides (such as xylose), disaccharides or more (such as sugar (granulated sugar), lactose, maltose, sucrose, trehalose, isomerized lactose, and other various oligosaccharides), sugar alcohols (palatinite, sorbitol). , Lactitol, erythritol, xylitol, maltitol, mannitol, etc.), starch syrup, isomerized sugar, reduced starch saccharified product (reduced starch degradation product) and the like.

The surfactant is not particularly limited, and nonionic surfactants, anionic surfactants, cationic surfactants, amphoteric surfactants and the like that are usually used in oral preparations and the like can be used. Among these, nonionic surfactants or anionic surfactants are preferable.
Nonionic surfactants include, for example, sugar alcohol fatty acid esters such as sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester; glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyethylene glycol fatty acid Polyhydric alcohol fatty acid ester such as ester; ether type activator such as polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene copolymer, polyoxyethylene alkylphenyl ether, polyoxyethylene hydrogenated castor oil; lauric acid diethanolamide And fatty acid alkanolamides.
Examples of the anionic surfactant include sodium lauryl sulfate, potassium N-glutamate, sodium N-glutamate and the like.
These surfactants can be used alone or in combination of two or more.
Among the above, sucrose fatty acid ester and sodium lauryl sulfate are particularly preferable.

Examples of the lubricant include magnesium stearate, calcium stearate, polyethylene glycol, talc, sodium stearyl fumarate, stearic acid and the like.
Examples of the fragrances include menthol, limonene, plant essential oil (mint oil, mint oil, lychee oil, orange oil, lemon oil, etc.).
Examples of the sweetener include saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, and sucralose.
These can be used individually by 1 type or in combination of 2 or more types.

<Granulated particles P>
The tablet of this invention contains the granulated particle P containing the said (A) component and (B) component.
The content of the component (A) in the granulated particles P is preferably 40 to 95% by mass, more preferably 60 to 90% by mass, and particularly preferably 70 to 80% by mass. If it is 40 mass% or more, aggregation of the granulated particles P hardly occurs. If it exceeds 95% by mass, the content of the component (B) decreases and the bonding strength decreases, so that granulation becomes difficult.
2-15 mass% is preferable, as for content of (B) component in the granulated particle P, 3-8 mass% is more preferable, and 4-6 mass% is especially preferable. If it is 2 mass% or more, sufficient bonding strength can be obtained and granulation is easy. Moreover, it is excellent also in the elution improvement effect of (A) component. When the content is 15% by mass or less, the granulated particles P hardly aggregate.
The total amount of the component (A) and the component (B) in the granulated particles P is preferably 10% by mass or more, more preferably 30% by mass or more, and particularly preferably 50% by mass or more. The upper limit of the total amount is not particularly limited, and may be 100% by mass.

The granulated particle P may contain components other than the component (A) and the component (B) as necessary, as long as the effects of the present invention are not impaired.
Examples of the component that may be contained in addition to the component (A) and the component (B) include a component (C), a disintegrant, an excipient other than the disintegrant, and a surfactant.
Examples of the disintegrant, the excipient other than the disintegrant, and the surfactant are the same as those exemplified as the other components other than the components (A) to (C).

Among these, the inclusion of a surfactant is preferable because wettability is improved and the elution of the component (A) is further improved.
When the granulated particle P contains a surfactant, the content of the surfactant in the granulated particle P is preferably 1 to 5% by mass, and more preferably 1 to 2% by mass. If it is 1 mass% or more, the compounding effect will be sufficiently obtained. If it exceeds 5% by mass, the contents of the component (A) and the component (B) will decrease.

There is no restriction | limiting in particular in the manufacturing method of the granulated particle P, It can manufacture by a well-known granulation method. As the granulation method, either a dry granulation method or a wet granulation method can be used.
Granulation by the dry granulation method can be performed, for example, by a dry compression method. Specifically, after mixing the component (A), the component (B) and other optional components, the mixture is compressed and granulated. A method is mentioned.
Granulation by the wet granulation method can be carried out, for example, by a method of granulating while adding an aqueous liquid containing the component (B) to the powdery component (A). At this time, you may add another arbitrary component to (A) component and aqueous liquid as needed. For example, a disintegrant may be added to the powdery component (A), and an excipient may be dissolved in the aqueous liquid.
Specific examples of the wet granulation method include a fluidized bed granulation method, a stirring granulation method, an extrusion granulation method, a rolling granulation method, and a kneading / crushing granulation.
Among these, the wet granulation method is preferable, and the fluidized bed granulation method or the stirring granulation method is particularly preferable.
Production of granulated particles by the fluidized bed granulation method uses, for example, a stirring type fluidized granulator (for example, a multiplex manufactured by POWREC Co., Ltd. or a spira flow manufactured by Freund Sangyo Co., Ltd. or a flow coater). Then, it can be carried out by granulating while spraying the aqueous liquid.
Production of granulated particles by the stirring granulation method, for example, using a stirring granulator (for example, a high speed mixer manufactured by Fukae Pautech Co., Ltd. or a high speed stirring granulator manufactured by Dalton Co., Ltd.) After stirring and kneading while spraying or dripping the aqueous liquid, it can be carried out by granulating using an extrusion granulator (for example, Dome Gran manufactured by Dalton Co., Ltd.).
The granulation conditions are not particularly limited, but it is preferable to carry out at a temperature lower than the melting point of (A). For example, when the component (A) is ibuprofen, granulation is preferably performed at a temperature lower than 65 ° C.
After granulation, the granulated product obtained may be subjected to a granulation treatment (pulverization, sieving, etc.) for adjusting the average particle size and particle size distribution.

The average particle diameter of the granulated particles P is preferably in the range of 50 to 600 μm, and more preferably in the range of 100 to 300 μm. If it is 50 μm or more, tableting troubles are unlikely to occur. When it is 600 μm or less, the tablet strength is good.
Here, the average particle size means a sieve with an aperture of 1000 μm, 850 μm, 500 μm, 355 μm, 250 μm, 150 μm, 75 μm, 45 μm and an inner diameter of 75 mm. “Measurement method” Based on the second method, the particle diameter is 50% of the cumulative mass when measured by measurement.

  The lower limit of the content of the granulated particles P in the tablet is preferably 1% by mass or more, more preferably 5% by mass or more, and particularly preferably 10% by mass or more. The upper limit is preferably 99% by mass or less, more preferably 95% by mass or less, and particularly preferably 90% by mass or less. Within this range, the effect of the present application is particularly good.

<Other granulated particles>
The tablet of the present invention may contain granulated particles other than the granulated particles P (hereinafter, granulated particles Q).
Examples of the granulated particles Q include granulated particles that do not contain the component (A) (excipient particles, disintegrant particles, etc.) and granulated particles that do not contain the component (B).

<Tablets>
The tablet of the present invention contains the granulated particles P and the component (C).
Examples of the tablet form include the following (1) to (4).
(1) A tablet having a single-layer structure composed of granulated particles P and a layer (X) containing the component (C).
(2) A tablet having a multilayer structure including granulated particles P and a layer (X) containing the component (C).
(3) A tablet having a multilayer structure comprising a layer (Y) containing granulated particles P and not containing component (C) and a layer (Z) containing components (C) and not containing granulated particles P.
(4) A film-coated tablet in which the surface of any one of the above (1) to (3) is coated with a coating agent containing a film base.

  The tablet of (2) has a different composition (type (A) and / or type (B) of the granulated particles P, content and type (C) of the component) as the layer (X). It may contain a plurality of layers, and may further contain a layer that does not contain either one or both of the granulated particles P and the component (C) in addition to the layer (X).

Examples of the film base used in the tablet of (4) include methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetal diethyl amino acetate, carboxymethyl cellulose, polyvinyl alcohol, Examples thereof include polyvinyl pyrrolidone, dextrin, pullulan, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, sucrose, mannitol, gelatin and the like. These 1 type (s) or 2 or more types can be mixed and used. Of these, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol and the like are more preferably used.
The ratio of the film substrate in the film layer formed on the surface of the tablet by coating with the coating agent is not particularly limited, but is preferably 40% by mass or more.

These tablets can be produced by conventional methods.
For example, the tablet of (1) is prepared by mixing the granulated particles P, the component (C) and optional components as necessary to prepare a tableting powder, and then compressing the tableting powder. Can be manufactured.

The present invention will be described more specifically with reference to examples. However, the present invention is not limited to these.
% Indicates “% by mass” unless otherwise specified. The pH is a value at 20 ° C.
The raw materials used in the following examples are shown below.
[(A) component]
Ibuprofen: manufactured by BASF.
Acetaminophen: manufactured by Iwaki Pharmaceutical Co., Ltd.
Allyl isopropyl acetyl urea: “Alipronal” manufactured by Kongo Chemical Co., Ltd.
Dry aluminum hydroxide gel: Kyowa Chemical Industry Co., Ltd.
Anhydrous caffeine: manufactured by Shiratori Pharmaceutical Co., Ltd.
[Component (B)]
HPC-SSL: Hydroxypropyl cellulose (SSL), manufactured by Shin-Etsu Chemical Co., Ltd.
HPC-L: Hydroxypropyl cellulose (L), manufactured by Shin-Etsu Chemical Co., Ltd.
PVA: Polyvinyl alcohol, manufactured by Merck & Co., Inc.
[Component (C)]
Potassium dihydrogen phosphate: manufactured by Taihei Chemical Industry Co., Ltd. (pH of 1 mass% aqueous solution = 4.4-4.9).
Sodium dihydrogen phosphate: manufactured by Taihei Chemical Industry Co., Ltd. (pH of 1% by mass aqueous solution = 4.3-4.9).
Sodium chloride: manufactured by Tomita Pharmaceutical Co., Ltd. (pH of 1 mass% aqueous solution = 7).
Potassium chloride: manufactured by Takasugi Pharmaceutical Co., Ltd. (pH of 7% by weight aqueous solution = 7)
[Other ingredients]
LHPC: Low substituted hydroxypropyl cellulose, LH-21, manufactured by Shin-Etsu Chemical Co., Ltd.
D-mannitol: ROQUETE Japan, “PEARLITOL”.
Lactic acid: DSP & Gokyo Food Chemical Co., “DL-lactic acid”.
Crystalline cellulose: Asahi Kasei Corporation, “Crystalline cellulose UF-702”.
Crospovidone (CL): BASF Corporation, “Coridon CL”.
Crospovidone (CL-SF): BASF Corporation, “Collidon CL-SF”.
Hydrous silicon dioxide: Freund Sangyo Co., Ltd., “Ad Solider 102”.
Magnesium stearate: Taihei Chemical Industry, “magnesium stearate”.
Opadry 81W48956: manufactured by Nippon Colorcon Co., Ltd. (components in 100 g are polyvinyl alcohol 46.0 g, talc 31.4 g, titanium oxide 12.6 g, soybean lecithin 10.0 g).
Sucrose fatty acid ester: Mitsubishi Chemical Foods, Inc., J-1816.
Sodium lauryl sulfate: Nikko Chemicals, SLS.

<Examples 1-16, Comparative Examples 1-10>
Tablets having the compositions shown in Tables 1 to 5 containing granulated particles P1, granulated particles P2, and extragranular components were produced by the following procedure. The composition shown in Tables 1-5 shows the compounding quantity (mg) of each component in 1 tablet.

[1. Production of granulated particles P1]
Component (A) and a disintegrant (LHPC) were mixed to obtain a mixed powder.
Separately, a component (B) and an excipient (D-mannitol) were dissolved in ion-exchanged water to prepare a spray solution.
In a fluidized bed granulator (Spiraflow SFC-5, manufactured by Freund Sangyo Co., Ltd.), wet granulation (supplying temperature 56 ° C., supplying air) while spraying the spray liquid onto the mixed powder (spraying speed 70 g / min). The amount was 2.7 m ³ / min) and further dried, and the resulting dried product was sieved (use of an opening of 850 μm) to obtain granulated particles P1.

[2. Production of granulated particles P2]
After setting the jacket of the high-speed mixer (FS25, manufactured by Fukae Kogyo Co., Ltd.) to 80 ° C, the agitator rotation speed is set to 300 rpm, the chopper rotation speed is set to 1500 rpm, and a predetermined amount of drying is carried out in the mixer body. Aluminum hydroxide gel and LHPC were added, and after preliminary mixing, a mixed solution of HPC-SSL aqueous solution and lactic acid was added with stirring. After completion of the addition, stirring was continued for 8 minutes to allow granulation to proceed, and after completion, aging was performed for 20 minutes to obtain granulated particles P2.

[3. Production of tablets]
The granulated particles P1, the granulated particles P2, and the extragranular component were mixed to obtain a first powder.
3000 g of the first powder is mixed for 20 minutes with a mixer (Bore container mixer 20L, manufactured by Kotobuki Industries Co., Ltd.), and then a predetermined amount of lubricant (magnesium stearate) is added as the second powder for 5 minutes. The powder for tableting was obtained by mixing.
The tableting powder was tableted using a rotary tableting machine (LIBRA2, manufactured by Kikusui Seisakusho) to obtain a tablet with a diameter of 9.2 mm.

[4. Production of film-coated tablets]
In Example 4 and Comparative Example 2, the tablets (plain tablets) obtained as described above were further coated by the following procedure to obtain film-coated tablets.
A coating solution in which 180 g of Opadry 81W48956 is dissolved and suspended in 820 g of purified water is applied to the uncoated tablet with a coating machine (High Coater HCT-30N, manufactured by Freund Sangyo Co., Ltd.) in a solid content equivalent to the uncoated tablet weight. A film-coated tablet was obtained by coating 2%.

The following evaluation was performed about the obtained tablet. The results are shown in Tables 1-5.
[Measurement of tablet hardness]
Using an apparatus for measuring physical properties of tablets (manufactured by Japan Machinery Co., Ltd.), the inflection point of stress was measured by applying pressure from the side of the tablet, and tablet hardness was measured. The measurement was repeated 10 times, and the average value was taken as the hardness.
[Measurement of decay time]
A disintegration test was performed according to the method of the JP disintegration test, and the disintegration time (seconds) was measured. The disintegration test solution used ion-exchanged water, and the water bath temperature was 37 ° C. The average value of 6 measurements was calculated.

As shown in the following results, the tablets of Examples 1 to 16 all had a disintegration time of 45 seconds or less and were excellent in rapid disintegration. Moreover, it had sufficient hardness as a tablet.
On the other hand, the tablets of Comparative Examples 1 to 9 containing no component (C), the granulated particles P1 containing potassium dihydrogen phosphate as the component (C), and the comparative example containing no component (C) as an extragranular component In each of the 10 tablets, the disintegration time was significantly longer than in Examples 1 to 16, and a disintegration delay occurred.

<Examples 17-18, Comparative Examples 11-12>
When the granulated particles P1 were produced, tablets were produced in the same procedure as in Example 10, except that a surfactant (sucrose fatty acid ester, Na lauryl sulfate) was further added to the spray liquid.
About the obtained tablet and the tablet obtained in Example 10, the dissolution test was done in the following procedures.
[Dissolution test]
It carried out according to the method of the JP dissolution test. Using the first dissolution test solution (pH = 1.2), the dissolution rate (%) of ibuprofen at 5 minutes was calculated. The average value of 3 times of measurement was taken as the measurement value of elution rate.

Table 6 shows the composition of each tablet and the results of the dissolution test.
As shown in the results, the tablets of Examples 17 and 18 have the same composition except that Comparative Examples 11 and 12 having the same composition except that the component (C) is not included, and no surfactant is blended. Compared with the tablet of Example 10, the dissolution property was improved.

About Example 10, 17, and 18, manufacture suitability was evaluated by the presence or absence of the rust of the apparatus used for manufacture. The case where there was no rust was judged as ○, and the case where there was rust was judged as ×. The results are shown in Table 6.
As shown in the results, Examples 10, 17 and 18 were all excellent in terms of apparatus maintenance because no rust was generated in the apparatus used for production.
In addition, the other examples (Examples 1-6, 9, 11, 14-16) using dihydrogen phosphate as a water-soluble salt also had good production suitability.

Claims (9)

Granulated particles containing (A) a drug and (B) a water- soluble polymer compound wherein the amount of water required to dissolve 1 g at 20 ° C. is less than 100 mL ;
(C) a water-soluble salt in which the pH of a 1% by mass aqueous solution is 0.1 or more and less than 7.5;
Contain,
At least partially, ibuprofen, acetaminophen, at least Tanedea Ru tablets selected from the group consisting of Allylisopropylacetylurea and dried aluminum hydroxide gel of the (A) contained in the granulated particles. The tablet according to claim 1, wherein (B) is at least one selected from the group consisting of hydroxyalkyl cellulose and polyvinyl alcohol. The tablet according to claim 1 or 2, wherein the total amount of (A) and (B) in the granulated particles is 10% by mass or more. The tablet according to any one of claims 1 to 3, wherein a content of the (A) in the granulated particles is 40 to 95 mass%. The tablet according to any one of claims 1 to 4, wherein a content of the (B) in the granulated particles is 2 to 15% by mass. The tablet according to any one of claims 1 to 5, wherein the content of (C) is 0.2 to 10% by mass. The tablet according to any one of claims 1 to 6, wherein a mass ratio (C / B) of the content of (C) to the content of (B) is 0.2 or more. The tablet according to any one of claims 1 to 7 , wherein (C) is at least one inorganic salt selected from an alkali metal chloride and an alkali metal dihydrogen phosphate. The tablet according to any one of claims 1 to 8 , wherein (C) is an alkali metal dihydrogen phosphate.