JP2012046454A - Tablet for internal use and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a tablet for internal use having high disintegrability and excellent storage stability, and a method for producing the same.SOLUTION: The tablet for internal use contains a granule obtained by providing a coating layer, that contains a disintegrator, on a surface of a core particle, that contains a drug, by a stirring granulating method, wherein the content of the disintegrator in the coating layer is 5-50 mass% based on the total mass of the granule.

Description

  The present invention relates to a tablet for internal use and a method for producing the tablet.

Drugs such as antipyretic analgesics, gastrointestinal drugs, sickness prevention, antitussive expectorants, etc. are required to be effective in a short time after taking (fast action). For example, in the case of tablets, It is important how quickly the drug is eluted.
In order to increase the dissolution rate of the drug from the tablet, it is first necessary to shorten the disintegration time of the tablet. Conventional methods used to shorten the disintegration time of tablets include a method of changing the hardness and size of the tablet, a method of blending a disintegrant, and the like. In addition, as a method of blending the disintegrant, the disintegrant is mixed with other components such as a drug and compressed as it is, the method of coating the surface of a granular drug with a disintegrant, and granulating the disintegrant together with the drug Then, there is a method of blending into tablets. For example, in Patent Document 1, a coated granulated product in which a core containing a water-soluble drug or a core composed of a granulated product containing a drug and a saccharide is coated with a disintegrant for a pharmaceutical preparation is manufactured by tableting. An intraoral rapidly disintegrating tablet is disclosed. Patent Document 2 discloses a tablet in which granules coated with a disintegrant are compression-molded, and an intraoral rapidly disintegrating tablet containing a disintegrant inside the granules.

International Publication No. 2004/064810 Pamphlet Japanese Patent Laid-Open No. 2007-153887

However, even the tablets described in Patent Documents 1 and 2 are not sufficiently disintegratable, and further improvement in disintegration is required.
It is conceivable to increase the amount of the disintegrant in order to enhance the disintegration property. However, disintegrants usually have water solubility or water swellability, and an increase in the amount thereof may lead to a decrease in the storage stability of the tablet. For example, the tablet may swell during storage.
This invention is made | formed in view of the said situation, Comprising: It aims at providing the tablet for internal use with high disintegration and favorable storage stability, and its manufacturing method.

As a result of intensive studies, the present inventors have obtained coated particles obtained by providing a coating layer by a stirring granulation method using a specific amount of disintegrant on the surface of particles (core particles) containing a drug. It was found that the disintegration property of the blended tablet was improved and the storage stability was good, and the present invention was completed.
The present invention for solving the above problems has the following aspects.
[1] A granulated product in which a coating layer containing a disintegrant is provided on the surface of core particles containing a drug by a stirring granulation method,
The tablet for internal use whose content of the said disintegrant in the said coating layer is 5-50 mass% with respect to the total mass of the said granulated material.
[2] The tablet for internal use according to [1], wherein the disintegrant is at least one selected from low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium, and carboxyvinyl polymer.
[3] The tablet for internal use according to [1] or [2], wherein the coating layer further contains a binder.
[4] The tablet for internal use according to any one of [1] to [3], wherein the drug is at least one selected from antipyretic analgesics, antacids, anti-inflammatory agents, and antitussive expectorants.
[5] A method for producing the tablet for internal use according to any one of [1] to [4],
After forming a granulated product by forming a coating layer containing a disintegrant on the surface of the core particle containing the drug by a stirring granulation method, the tableting ingredients containing the granulated product are tableted. A tablet for internal use, wherein the content of the disintegrant in the coating layer is 5 to 50% by mass with respect to the total mass of the granulated product. Method.

  ADVANTAGE OF THE INVENTION According to this invention, the tablet for internal use with high disintegration and favorable storage stability, and its manufacturing method can be provided.

  The tablet for internal use of the present invention (hereinafter sometimes simply referred to as a tablet) is a granulated product (hereinafter referred to as a granulated product) in which a coating layer containing a disintegrant is provided on the surface of core particles containing a drug by a stirring granulation method. , Sometimes referred to as coated particles (A)). When the coating layer containing the disintegrant is provided on the surface of the core particle by the agitation granulation method, the disintegrant is blended in a portion other than the coating layer (inside the core particle or a portion other than the coated particle) As compared with the case where the coating layer is provided by a granulation method (for example, fluidized bed granulation method) other than the stirring granulation method, the disintegration property of the obtained tablet is improved.

<Coated particle (A)>
[Core particles]
The drug contained in the core particle is not particularly limited, and can be appropriately selected according to the purpose from among drugs known as drugs conventionally blended in tablets for internal use. The present invention is particularly useful for drugs that require immediate action after administration. Examples of such drugs include antipyretic analgesics, antacids, antiphlogistics, antitussive expectorants, gastrointestinal drugs, diarrhea drugs, and the like. Can be mentioned. Among these, antipyretic analgesics, antacids, anti-inflammatory agents, and antitussive expectorants are preferred in terms of fast solubility.
Specific examples of antipyretic analgesics include ibuprofen, acetaminophen, loxoprofen sodium, etodolag, naproxen, ketoprofen, salicylic acid, etenzaamide and the like.
As the antacid, a compound containing a divalent or trivalent metal (metal salt, metal oxide, metal hydroxide, etc.) is generally used. Specific examples include, for example, dry aluminum hydroxide, dry Examples thereof include aluminum hydroxide gel, magnesium oxide, magnesium carbonate, magnesium aluminate metasilicate, aluminum glycinate, aluminum hydroxide and calcium carbonate. Among these, dry aluminum hydroxide gel, magnesium oxide, magnesium carbonate, and magnesium magnesium aluminometasilicate are preferable from the viewpoint of exhibiting a blending effect in a small amount.
Specific examples of the anti-inflammatory agent include indomethacin, felbinac, diclofenac sodium, azulene, glycol salicylate and the like.
Specific examples of antitussive expectorant include, for example, methylephedrine hydrochloride, protecarol hydrochloride, codeine phosphate, dextromethorphan hydrobromide, ephedrine hydrochloride, clobutinol hydrochloride, bromhexine hydrochloride, carbocystine, ethylcysteine hydrochloride, methylcysteine hydrochloride Etc.
Specific examples of gastrointestinal drugs include famotidine, cimetidine, ranitidine, sucralfate, and the like.
Specific examples of diarrheal drugs include berberine tannate and albumin tannate.
Any one of these drugs may be used alone, or two or more thereof may be used in combination.

For the drug, the bulk powder may be used as the core particle as it is, or the granulated product may be used as the core particle. The core particle is preferably a drug substance in terms of simplicity and granulation.
When the core particle is a granulated product, the granulated product may be composed only of a drug, and if necessary, contains other components other than the drug as long as the effects of the present invention are not impaired. Also good.
Examples of other components other than the drug that may be contained in the granulated product include components that are usually used as pharmaceutical carriers in the production of granulated particles. Agents, binders and the like.
Excipients include, for example, lactic acid, tartaric acid, phosphoric acid, malic acid, oxalic acid, calcium lactate, disodium hydrogen phosphate, sodium dihydrogen phosphate, citric acid, glacial acetic acid, corn starch, crystalline cellulose, mannitol, macrogol Potato starch, wheat starch, lactose, sucrose, fructose, light anhydrous silicic acid and the like.
Examples of the disintegrant include low-substituted hydroxypropyl cellulose (L-HPC), crospovidone, croscarmellose, croscarmellose sodium, carboxyvinyl polymer, carmellose calcium and the like.
Examples of the binder include hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, gelatin, polyvinyl pyrrolidone (povidone), polyvinyl alcohol and the like.
Each of these components may be used alone or in combination of two or more.
30-80 mass% is preferable with respect to the total mass of this granulated material, and, as for content of the drug in a granulated material, 50-80 mass% is more preferable. When the amount is not less than the lower limit of the range, the effect of the drug is sufficiently obtained, and when it is not more than the upper limit, the granulation property is good.

The average particle diameter of the core particles is preferably 10 μm or more and more preferably 50 μm or more from the viewpoint of easy granulation. The upper limit of the average particle diameter is not particularly limited, but is preferably 500 μm or less, more preferably 300 μm or less from the viewpoint of the solubility of the particles themselves.
Here, the “average particle diameter” in the present specification is a value obtained by powder particle size measurement by a laser diffraction method listed in the 15th revision Japanese Pharmacopoeia.

[Coating layer]
The coating layer of the coated particles (A) contains a disintegrant.
The disintegrant contained in the coating layer (hereinafter sometimes referred to as disintegrant A) is not particularly limited, and for example, low-substituted hydroxypropylcellulose (L-HPC), crospovidone, croscarmellose, croscarme Examples include sodium sodium, carboxyvinyl polymer, and carmellose calcium. Among these, at least one selected from L-HPC, crospovidone, croscarmellose sodium, and carboxyvinyl polymer is preferable because of its high swelling ability and excellent effects of the present invention. L-HPC, crospovidone, and cloth At least one selected from carmellose sodium is more preferable, and at least one selected from L-HPC and crospovidone is more preferable.
1 type or 2 types or more may be sufficient as the disintegrating agent A contained in a coating layer.
Content of the disintegrant A in a coating layer is 5-50 mass% with respect to the total mass of a coating particle (A), 10-45 mass% is preferable and 15-40 mass% is more preferable. When the content of the disintegrant A is less than the lower limit of the above range, the disintegration property is insufficient, and when the content exceeds the upper limit, the storage stability is deteriorated such that the tablet swells during storage.
Moreover, 1-20 mass% is preferable with respect to the total mass of a tablet, and, as for content of the disintegrant A contained in the tablet of this invention, 3-15 mass% is more preferable.

The coating layer preferably further contains a binder. Furthermore, by using a binder together, the surface of the core particle is more densely coated.
Examples of the binder include hydroxypropyl cellulose (HPC), methyl cellulose, ethyl cellulose, gelatin, polyvinyl pyrrolidone, polyvinyl alcohol and the like.
1 type or 2 types or more may be sufficient as the binder contained in a coating layer.
1-15 mass% is preferable with respect to the total mass of a coating particle (A), and, as for content of the binder contained in a coating layer, 2-10 mass% is more preferable. When the content of the binder is not less than the lower limit of the above range, the effect of blending the binder is sufficiently obtained, and when it is not more than the upper limit, the tableting moldability is improved.
The coating layer may contain components other than the disintegrant and the binder as long as the effects of the present invention are not impaired. Examples of the other components include bases, stabilizers, solubilizers, surfactants, disintegration aids and the like listed in the Pharmaceutical Additives Dictionary (2007).

The coating layer is provided on the surface of the core particle by a stirring granulation method. Thereby, the disintegration property of the obtained tablet improves. This is because the coated particles (A) obtained are harder than the case where a coating layer having the same composition is provided by other granulation methods such as fluidized bed granulation, and thus the coated particles ( It is considered that A) is hardly crushed and exists in the tablet while having a coating layer having a high swelling ability on the surface.
The coating layer can be formed, for example, by sequentially performing a coating process and a drying process according to the following procedure.
Coating step: Core particles are put into a stirring granulator (for example, Fukae Kogyo Co., Ltd., high speed mixer FS.GS.10J type), heated to a predetermined temperature while stirring, and then water is added. After further stirring, the disintegrant is added and stirred. Thereafter, if necessary, an aqueous solution of a binder is added and further stirred. After stirring for a predetermined time and stopping stirring, the obtained coated granulated product is discharged from the granulator.
Drying step: The coated granulated product obtained in the coating step is put into a preheated fluidized bed dryer to start the drying operation. Drying operation is performed for a predetermined time to obtain a granular dried product.

As a temperature condition (temperature condition at the time of stirring) at the time of a coating process, 50-90 degreeC is preferable from a viewpoint of raising the hardness of a granulated material, and 60-80 degreeC is more preferable. From the same viewpoint, the stirring time (the time from the start of addition of the disintegrant to the stop of stirring) is preferably 1 to 30 minutes, more preferably 3 to 20 minutes.
In order to further adjust the particle size distribution, the granulated product obtained by the above method may be subjected to a sizing operation.
Examples of the sizing operation include a pulverization process and a sieving process, and these are preferably combined. The pulverization treatment can be performed using a commercially available pulverizer, and the pulverizer is preferably a model having a classification screen and a rotating blade. Specifically, Fitzmill (product name, manufactured by Hosokawa Micron Corporation), New A speed mill (product name, manufactured by Okada Seiko Co., Ltd.), a comminator (product name, manufactured by Dalton Co., Ltd.), a feather mill (product name, manufactured by Hosokawa Micron Co., Ltd.), and the like. The sieving treatment can be carried out using a commercially available sieving device. Specifically, as the sieving device, a gyro shifter (product name, manufactured by Tokuju Kogakusho Co., Ltd.), a Rotex screener (product name, ) Seisin Corporation), Dalton Vibrating Sieve (product name, manufactured by Dalton).

The average particle diameter of the coated particles (A) is preferably 50 to 1000 μm, more preferably 100 to 800 μm, considering tableting moldability and the like.
The coated particles (A) contained in the tablet of the present invention may be one type or two or more types. For example, a plurality of coated particles (A) containing different drugs may be mixed and used.
In the tablet of the present invention, the content of the coated particles (A) is preferably 10 to 30% by mass and more preferably 15 to 25% by mass with respect to the total mass of the tablet. When it is at least the lower limit of the range, the effect of improving disintegration is sufficiently obtained, and when it is at most the upper limit, the storage stability is improved.

<Optional component>
The tablet of the present invention may contain components other than the coated particles (A) as long as the effects of the present invention are not impaired. Examples of the other components include drug-containing granulated products that are not applicable to the coated particles (A) (hereinafter sometimes referred to as drug-containing particles (B)), pharmaceutical carriers, and the like.
Examples of the drug in the drug-containing particle (B) include the same drugs as those described as the drug contained in the core particle in the description of the coated particle (A). In addition, sedative hypnotics (for example, allylisopropylacetylurea, bromvalerylurea, etc.), antihistamine components (for example, isothipentyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, dipheterol hydrochloride, triprolidine hydrochloride, tripelenamine hydrochloride, tonsilamine hydrochloride, hydrochloric acid hydrochloride Phenetadine, methodirazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teuroate, mebhydroline napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, dl-maleic acid chlorpheniramine maleate Chlorpheniramine acid, dipheterol phosphate, etc.), central stimulants (eg, benzoic acid) Thorium caffeine, caffeine, anhydrous caffeine, etc.), vitamin preparations (eg vitamin B1 and derivatives thereof and salts thereof, vitamin B2 and derivatives thereof and salts thereof, vitamin C and derivatives thereof and salts thereof, hesperidin and And derivatives thereof and salts thereof).
The drug contained in the drug-containing particles (B) may be the same as or different from the drug contained in the core particles of the coated particles (A).
As the drug-containing particles (B), a raw powder or a granulated product may be used. However, the granulated product used as an optional component does not correspond to the coated particles (A), that is, does not have a coating layer containing a disintegrant provided by a stirring granulation method.
The drug-containing particles (B) contained in the tablet of the present invention may be one type or two or more types.

As the pharmaceutical carrier, those usually used as a pharmaceutical carrier for the production of tablets can be used, and specific examples include excipients, disintegrants, binders, lubricants and the like.
Examples of the excipient, the disintegrant, and the binder are the same as the excipient, the disintegrant, and the binder mentioned in the description of the core particle as the preparation carrier that the granulated product may contain. It is done.
Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.
Each of these components may be used alone or in combination of two or more. Of these, disintegrants and lubricants are preferred.
Moreover, 2-20 mass% is preferable with respect to the total mass of a tablet, and, as for the total amount of all the disintegrating agents contained in a tablet, 5-15 mass% is more preferable. When it is at least the lower limit of the range, the disintegration is improved, and when it is at most the upper limit, the storage stability is improved.
0.1-2 mass% is preferable with respect to the total mass of a tablet, and, as for content of a lubricant in the tablet of this invention, 0.2-1 mass% is more preferable. When it is at least the lower limit of the range, the lubrication effect is improved, and when it is at most the upper limit, the tablet hardness is improved.

The tablet of the present invention can be produced by preparing the coated particles (A) and then tableting the tableting ingredients containing the coated particles (A).
The procedure for preparing the coated particles (A) is as described above.
The tableting component may be composed only of the coated particles (A), or may be a mixture in which the coated particles (A) and other optional components are mixed.
Mixing and tableting can be carried out according to conventional methods. For example, tableting is performed by a rotary tableting machine such as a known tableting machine such as LIBRA (product name, manufactured by Kikusui Seisakusho Co., Ltd.), HP-AP-MS type (product name, manufactured by Hata Plant). It can be carried out using a lock molding machine or the like.
The size of the tablet is not particularly limited and can be appropriately determined in consideration of the compounding amount and dose of the drug, but the tablet diameter is preferably 5 to 14 mmφ, and more preferably 7 to 12 mmφ.
The tablet of the present invention may be a single layer tablet composed of a single layer, or may be a multilayer tablet in which a plurality of layers are laminated.

The tablet of the present invention contains the coated particles (A), so that when the disintegrant is blended in a portion other than the coating layer (inside the core particles or other than the coating particles), or when the coating layer is stirred. Compared with the case where it is provided by a granulation method other than the granulation method (for example, fluidized bed granulation method), the disintegration property of the obtained tablet is improved.
By improving the disintegration property of the tablet, the dissolution rate of the drug contained in the tablet is improved, and the quickness of the drug effect is improved.
The present invention is particularly useful when blending a plurality of drugs that cause blending changes. That is, a plurality of active ingredients are generally blended with pharmaceutical products. For example, in the case of a tablet for internal use in which an antipyretic analgesic agent such as ibuprofen is blended as a main ingredient, an antacid is blended for the purpose of reducing side effects such as stomach irritation caused by the antipyretic analgesic. On the other hand, when an acidic component such as ibuprofen and a basic component such as an antacid are blended, it is known that problems such as discoloration occur due to blending changes. Therefore, at least one of these components is contained in the coated particles (A), and the other is contained in another particle (other coated particles (A) or drug-containing particles (B)), so that the coating layer allows them to be contained. The contact of components is suppressed, and the mixing change is suppressed.
In the tablet of the present invention, the core particle of the coated particle (A) is an antacid or a granulated product thereof, and further contains at least an antipyretic analgesic or a granulated product thereof as the drug-containing particle (B). Is particularly preferred.

The present invention will be described more specifically with reference to examples. However, the present invention is not limited to these.
The raw materials used in the following examples are as follows.
<Raw materials>
Ibuprofen: manufactured by Shiratori Pharmaceutical Co., Ltd.
Acetaminophen: Iwaki Pharmaceutical Co., Ltd., Japanese Pharmacopoeia compatible product.
Anhydrous caffeine: manufactured by Shiratori Pharmaceutical Co., Ltd.
Dry aluminum hydroxide gel: manufactured by Kyowa Chemical Industry Co., Ltd., S-100, Japanese Pharmacopoeia compatible product, average particle size 50 μm.
Magnesium oxide: manufactured by Kyowa Chemical Industry Co., Ltd., Japanese Pharmacopoeia compatible product, average particle size 50 μm.
Magnesium carbonate: manufactured by Kyowa Chemical Industry Co., Ltd., Japanese Pharmacopoeia compatible product, average particle size 50 μm.
Magnesium aluminate metasilicate: manufactured by Fuji Chemical Industry Co., Ltd., Japanese Pharmacopoeia compatible product, average particle size 50 μm.
L-HPC (LH-21): Low-substituted hydroxypropyl cellulose, manufactured by Shin-Etsu Chemical Co., Ltd., LH-21, Japanese Pharmacopoeia compatible product.
L-HPC (LH-31): Low-substituted hydroxypropyl cellulose, manufactured by Shin-Etsu Chemical Co., Ltd., LH-31, Japanese Pharmacopoeia compatible product.
HPC-SSL: Hydroxypropylcellulose, Nippon Soda Co., Ltd., Japanese Pharmacopoeia compatible product.
D-mannitol: Rocket Japan Co., Ltd., Japanese Pharmacopoeia compatible product.
Magnesium stearate: Taihei Chemical Industry Co., Ltd., plant-based, Japanese Pharmacopoeia compatible product.
Crospovidone: manufactured by BASF, conforming to the Japanese Pharmacopoeia.
Croscarmellose sodium: manufactured by Nichirin Chemical Industry Co., Ltd.
Carboxyvinyl polymer: Nikko Chemicals, Japan Pharmacopoeia compatible product.

<Example 1>
[Production of coated particles (A)]
1225 g of dry aluminum hydroxide gel was added to an agitation granulator (Fukae Kogyo Co., Ltd., high speed mixer FS.GS.10J type) in which warm water of 80 ° C. was passed in advance (water flow continued until the contents were discharged). I put it in. After the addition, stirring was started under conditions of an agitator of 300 rpm and a chopper of 1500 rpm, and after stirring for 5 minutes, 450 g of purified water was added at a flow rate of 450 g / min. The mixture was further stirred for 2 minutes to obtain core particles (average particle size 100 μm). To this, 350 g of L-HPC (LH-21) was added and stirred for 3 minutes. Thereafter, 1750 g of a binding solution (HPC-SSL: water = 80: 1920 (mass ratio) aqueous solution) was added at a flow rate of 500 g / min. Stirring operation was continued for a total of 8 minutes including the addition time, and stirring was stopped, and then the stirred granulated product (temperature 75 ° C.) was discharged from the granulator. The obtained agglomerated granule is preheated at an intake air temperature of 80 ° C. and introduced into Spiraflow SFC-5 type (manufactured by Freund Sangyo Co., Ltd.) having an exhaust temperature of 60 ° C. The drying operation was started under conditions of an air volume of 2.6 m ³ / min and a rotor rotational speed of 200 rpm. The drying operation was continued for 90 minutes to obtain a granular dried product. The granular dried product was sieved using a sieve having an opening of 850 μm, and the particles that did not pass through the sieve were pulverized (Fiore F-0, manufactured by Tokuju Kogyo Co., Ltd. (screen φ1.2 mm, frequency 20 Hz). )) And pulverized. The obtained pulverized product was mixed with particles that passed through a sieve having an opening of 850 μm to obtain coated particles (A) containing an antacid.

[Production of drug-containing particles (B)]
After mixing 2145 g of ibuprofen and 858 g of L-HPC (LH-31) in a polyethylene bag, the mixture was put into a fine pulverizer Coroplex (manufactured by POWREC Co., Ltd., 160Z type), and pulverized under the condition of 12000 rpm. did. 1365 g of the obtained pulverized product and 975 g of acetaminophen were introduced into a preheated Spiraflow SFC-5 type (manufactured by Freund Sangyo Co., Ltd.), the intake air temperature was 55 ° C., the exhaust air flow was 2.7 m ³ / min, Flowing was started under conditions of a rotor rotation speed of 200 rpm. After confirming that the exhaust temperature was 43 ° C. or higher, a binding liquid (HPC-SSL: D-mannitol: purified water = 390: 312: 6110 (mass ratio) aqueous solution) was added to a two-fluid nozzle ATF type (hole diameter φ1). Spraying at a liquid speed of 100 mL / min. 15 minutes after the start of spraying, the liquid speed was changed to 60 mL / min, and a total of 2620 g was sprayed. After spraying was completed, the intake air temperature was changed to 65 ° C., and the drying operation was started with the same exhaust air volume as described above. When the exhaust temperature reached 43 ° C., the drying operation was finished to obtain a granulated product. The obtained granulated product was sieved in whole using a sieve having an opening of 850 μm (sieving while sieving the sieved product with a spatula) to obtain drug (antipyretic analgesic) -containing particles (B).

[Mixing process]
Each component was measured with a total amount of 3500 g so that the composition shown in Table 1 was obtained. Among these, components other than magnesium stearate were charged into a blender (manufactured by Kotobuki Industries Co., Ltd., Boule Container Mixer 20L LM-20 type). After mixing for 40 minutes at 20 rpm, magnesium stearate was added and mixed for 3 minutes at 20 rpm.

[Tabletting process]
Using the rotary tableting machine (LIBRA2 manufactured by Kikusui Seisakusho Co., Ltd.) equipped with a 8.5 mm (2 stage R) punch and mortar, the mixture obtained in the mixing step was rotated at 20 rpm. Tablets were obtained by tableting under the conditions of a stirring feed shoe rotational speed of 60 rpm, a preload of 2 kN, and a main pressure of 6 kN.

<Example 2>
Tablets were obtained in the same manner as in Example 1 except that crospovidone was used instead of L-HPC (LH-21) in [Production of coated particles (A)] (average particle diameter of core particles 100 μm) .

<Example 3>
Tablets were obtained in the same manner as in Example 1 except that croscarmellose sodium was used instead of L-HPC (LH-21) in [Production of coated particles (A)] (average particle diameter of core particles) 100 μm).

<Example 4>
Tablets were obtained in the same manner as in Example 1 except that carboxyvinyl polymer was used instead of L-HPC (LH-21) in [Production of coated particles (A)] (average particle size of core particles 100 μm) ).

<Example 5>
Tablets were obtained in the same manner as in Example 1 except that magnesium oxide was used in place of the dry aluminum hydroxide gel in [Production of coated particles (A)] (average particle diameter of core particles 150 μm).

<Example 6>
Tablets were obtained in the same manner as in Example 1 except that magnesium carbonate was used instead of the dry aluminum hydroxide gel in [Production of coated particles (A)] (average particle diameter of core particles 200 μm).

<Example 7>
A tablet was obtained in the same manner as in Example 1 except that magnesium metasilicate was used instead of the dry aluminum hydroxide gel in [Production of coated particles (A)] (average particle diameter of core particles 300 μm).

<Example 8>
In [Production of coated particles (A)], the amount of dry aluminum hydroxide gel added was changed from 1225 g to 1750 g, the amount of L-HPC (LH-21) added was changed from 350 g to 1750 g, and [ Tablets were obtained in the same manner as in Example 1 except that the mixing ratio of each component in the mixing step] was changed to the composition shown in Table 1 (average particle diameter of core particles: 450 μm).

<Example 9>
In [Production of coated particles (A)], the amount of L-HPC (LH-21) added was changed from 350 g to 140 g, and the mixing ratio of each component in [Mixing step] is shown in Table 2. A tablet was obtained in the same manner as in Example 1 except that the composition was changed so as to have a composition (core particle average particle size 100 μm).

<Example 10>
In [Production of coated particles], the amount of L-HPC (LH-21) added was changed from 350 g to 700 g, and the mixing ratio of each component in [Mixing step] was changed to the composition shown in Table 2. A tablet was obtained in the same manner as in Example 1 except that the average particle size was 100 μm.

<Example 11>
In [Production of coated particles (A)], the amount of L-HPC (LH-21) added was changed from 350 g to 1050 g, and the mixing ratio of each component in the [Mixing step] is shown in Table 2. A tablet was obtained in the same manner as in Example 1 except that the composition was changed so as to have a composition (core particle average particle size 100 μm).

<Example 12>
In [Production of coated particles (A)], the amount of dry aluminum hydroxide gel added was changed from 1225 g to 875 g, and the mixing ratio of each component in [Mixing step] was changed to the composition shown in Table 2. A tablet was obtained in the same manner as in Example 1, except that the average particle size of the core particles was 80 μm.

<Example 13>
In [Production of coated particles (A)], the amount of dry aluminum hydroxide gel added was changed from 1225 g to 2450 g, and the mixing ratio of each component in [Mixing step] was changed to the composition shown in Table 2. A tablet was obtained in the same manner as in Example 1, except that the average particle size of the core particles was 400 μm.

<Comparative Example 1>
In [Production of coated particles (A)], the amount of L-HPC (LH-21) added was changed from 350 g to 35 g, and the mixing ratio of each component in the [Mixing step] is shown in Table 2. A tablet was obtained in the same manner as in Example 1 except that the composition was changed so that the composition was changed.

<Comparative example 2>
In [Production of coated particles (A)], the amount of L-HPC (LH-21) added was changed from 350 g to 2100 g, and the mixing ratio of each component in [Mixing step] is shown in Table 2. A tablet was obtained in the same manner as in Example 1 except that the composition was changed so that the composition was changed.

<Comparative Example 3>
Tablets were obtained in the same manner as in Example 1 except that the granulation of the coated particles was performed by the fluidized bed granulation method in [Production of coated particles].
Specifically, granulation by the fluidized bed granulation method was performed according to the following procedure.
1225 g of dried aluminum hydroxide gel was put into a preheated Spiraflow SFC-5 type (manufactured by Freund Sangyo Co., Ltd.), and the intake air temperature was 55 ° C., the exhaust air volume was 2.7 m ³ / min, and the rotor rotation speed was 200 rpm. Flow started at the conditions. After confirming that the exhaust temperature was 43 ° C. or higher, 450 g of water was sprayed at a liquid speed of 100 g / min using a two-fluid nozzle ATF type (hole diameter φ1.8 mm). Thereafter, 350 g of L-HPC (LH-21) was added, and 1750 g of a binding solution (HPC-SSL: water = 80: 1920 (mass ratio) aqueous solution) was sprayed at a flow rate of 100 g / min. After spraying was completed, the intake air temperature was changed to 65 ° C., and the drying operation was started with the same exhaust air volume as described above. When the exhaust temperature reached 43 ° C., the drying operation was finished to obtain a granulated product. The obtained granulated product was sieved in whole using a sieve having an opening of 850 μm (sieving while smashing the sieved product with a spatula) to obtain coated particles (A) containing an antacid.

<Evaluation method>
The following evaluation was performed about the obtained tablet. The results and formulation composition are shown in Tables 1-2. In Tables 1 and 2, the numerical value of the pharmaceutical composition indicates the blending amount (mg) per tablet.

[Disintegration]
The disintegration time (minutes) of 6 tablets was measured according to the disintegration test method prescribed in the 15th revision Japanese Pharmacopoeia, and the average value was determined. From the disintegration time, the disintegration property of each tablet was evaluated according to the following criteria.
(Evaluation criteria for disintegration)
A: Less than 1.2 minutes.
○: 1.2 minutes or more and less than 1.5 minutes.
X: 1.5 minutes or more.

[Storage stability (swelling of tablets)]
The obtained tablet was stored as an uncoated tablet in an environment of 50 ° C. and 75% RH for 4 days. The expansion rate (%) was calculated from the thickness (mm) of the tablet before and after storage by the following formula, and the storage stability of each tablet was evaluated from the expansion rate according to the following criteria.
Expansion rate = tablet thickness after storage / tablet thickness before storage × 100
(Evaluation criteria for storage stability)
A: 105% or less.
○: More than 105% and 110% or less.
X: Over 110%.

[Comprehensive judgment]
From the evaluation results (◎, ○, ×) of the disintegration property and the storage stability, comprehensive judgment was performed according to the following criteria.
A: Both disintegration and storage stability are A.
○: One of disintegration and storage stability is ○, and the other is 他方 or ○.
X: At least one of disintegration and storage stability is x.

As shown in these results, the tablets of Examples 1 to 13 were good in disintegration and storage stability, and the results of Examples 1 to 7, 10, and 12 were particularly excellent.
On the other hand, Comparative Example 1 in which the amount of the disintegrant A blended in the coating layer of the coated particle (A) was small was poor in disintegration, and the amount of the disintegrant A blended in the coating layer of the coated particle (A) was large. In Example 2, the storage stability was poor. Moreover, although the comparative example 3 which provided the coating layer by the fluidized-bed granulation method had the same formulation composition as Example 1, disintegration was bad.

Claims (5)

Contains a granulated product in which a coating layer containing a disintegrant is provided on the surface of core particles containing a drug by a stirring granulation method,
The tablet for internal use whose content of the said disintegrant in the said coating layer is 5-50 mass% with respect to the total mass of the said granulated material.   The tablet for internal use according to claim 1, wherein the disintegrant is at least one selected from low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium, and carboxyvinyl polymer.   The tablet for internal use according to claim 1 or 2, wherein the coating layer further contains a binder.   The tablet for internal use as described in any one of Claims 1-3 whose said drug is at least 1 sort (s) chosen from an antipyretic analgesic, an antacid, an anti-inflammatory agent, and an antitussive expectorant. A method for producing the tablet for internal use according to any one of claims 1 to 4,
After forming a granulated product by forming a coating layer containing a disintegrant on the surface of the core particle containing the drug by a stirring granulation method, the tableting ingredients containing the granulated product are tableted. A tablet for internal use, wherein the content of the disintegrant in the coating layer is 5 to 50% by mass with respect to the total mass of the granulated product. Method.