JP7419057B2 - Tablets and coated tablets - Google Patents

Description

The present invention relates to tablets and coated tablets.

Ethenzamide is widely used as a salicylic acid-based nonsteroidal anti-inflammatory drug (NSAIDs) that is effective for antipyretic, analgesic, and the like. However, tablets containing ethenzamide have problems with disintegration and hardness (abrasion resistance).
To solve the above problem, an ethanol aqueous solution of polyvinylpyrrolidone was added to the particle cores of crystalline lactose, and ethenzamide, which had been improved in powder properties by adding and mixing silicic anhydride in advance, was powder-coated thereon, dried, and sized. A method is known in which granulated lactose, crystalline cellulose, crospovidone, and maltitol are mixed, and then magnesium stearate is mixed and tableted (Patent Document 1).

Japanese Patent Application Publication No. 2008-189634

Although ethenzamide is an NSAID that causes less gastric irritation than ibuprofen and the like, antacids may be added to it to further reduce gastric irritation. However, tablets containing ethenzamide and antacids tend to have reduced disintegration properties (delayed disintegration) over time.
Patent Document 1 does not consider the problem of delayed disintegration when ethenzamide and an antacid are combined. Furthermore, there are concerns that the method of Patent Document 1 may result in larger tablets and an increase in the number of tablets to be taken at one time.
A common method for improving tablet disintegration and disintegration delay is to increase the amount of disintegrant, but there are concerns that this method also increases the size of the tablet and the number of tablets to be taken at a time. Ru.

One aspect of the present invention aims to provide tablets and coated tablets that have hardness that does not easily cause abrasion and rapid disintegration, and in which the delay in disintegration caused by the combination of ethenzamide and antacids is suppressed.

As a result of extensive studies, the present inventors have surprisingly found that by incorporating loxoprofen, an NSAID, or its salt into tablets containing ethenzamide and antacids, they maintain hardness that prevents wear and tear and rapid disintegration. At the same time, they found that the delay in disintegration can be suppressed, and have completed the present invention.

The present invention has the following aspects.
[1] A tablet containing the following components (A), (B) and (C).
(A) Component: ethenzamide.
Component (B): An antacid containing one or more selected from aluminum atoms and magnesium atoms.
Component (C): at least one member selected from the group consisting of loxoprofen and pharmaceutically acceptable salts thereof.
[2] Component (B) is dry aluminum hydroxide gel, magnesium aluminate metasilicate, magnesium aluminate silicate, synthetic hydrotalcite, synthetic aluminum silicate, magnesium carbonate, dihydroxyaluminum aminoacetate, aluminum hydroxide, The tablet of [1] above, which is at least one selected from the group consisting of aluminum hydroxide/sodium hydrogen carbonate coprecipitate, aluminum hydroxide/magnesium hydrogen carbonate mixed dry product, magnesium oxide, and magnesium silicate.
[3] The tablet of [1] or [2] above, wherein the mass ratio represented by the component (C)/(component (A) + component (B)) is 0.01 to 1.5.
[4] The tablet according to any one of [1] to [3] above, wherein the mass ratio represented by the component (A)/component (B) is 0.1 to 15.
[5] The tablet according to any one of [1] to [4] above, wherein the mass ratio represented by the component (A)/component (C) is 0.2 to 25.
[6] A coated tablet comprising the tablet of any one of [1] to [5] above as a plain tablet, and having a coating layer on the surface of the plain tablet.
[7] The coated tablet of [6] above, wherein the coating layer contains an inorganic pigment.

According to one aspect of the present invention, it is possible to provide tablets and coated tablets that have hardness that does not easily cause abrasion and rapid disintegration, and in which the delay in disintegration caused by the combination of ethenzamide and antacids is suppressed.

〔tablet〕
The tablet according to one aspect of the present invention contains the following components (A), (B), and (C).

<(A) component>
Component (A) is ethenzamide.
Ethenzamide (2-ethoxybenzamide) is a salicylic acid-based nonsteroidal anti-inflammatory drug (NSAIDs) and is used as an antipyretic and analgesic ingredient.

The dose of component (A) per dose is preferably 30 to 1000 mg, more preferably 50 to 500 mg, even more preferably 70 to 300 mg. If the dose of component (A) per dose is at least the above lower limit, a sufficient antipyretic and analgesic effect can be obtained, and if it is below the above upper limit, the number of tablets to be taken per dose can be reduced.
The mass of component (A) per tablet is preferably 30 to 400 mg. If the mass of component (A) per tablet is greater than or equal to the above lower limit, the number of tablets per dose can be reduced, and if it is less than or equal to the above upper limit, good tablet hardness can be maintained, and the number of tablets per tablet can be reduced. Other active ingredients can be sufficiently incorporated therein.
The mass proportion of component (A) per tablet is preferably 5 to 70% by mass, more preferably 10 to 60% by mass, and even more preferably 13 to 40% by mass. If the mass ratio of component (A) is at least the above lower limit, the number of tablets per dose can be reduced, and if it is below the above upper limit, other active ingredients can be sufficiently blended into one tablet.

<(B) component>
Component (B) is an antacid containing one or more selected from aluminum atoms and magnesium atoms.
By using component (A) and component (B) together, gastric disorders caused by component (A) are alleviated. In addition, the physical properties of the tablet, such as disintegration and strength, immediately after production are improved. Furthermore, the fluidity of the powder containing component (A) is improved, and adhesion to manufacturing machines during the manufacturing process is suppressed.

Component (B) is not particularly limited as long as it is an antacid containing one or more selected from aluminum atoms and magnesium atoms, and examples include dry aluminum hydroxide gel, magnesium aluminate metasilicate, and aluminate silicate. Magnesium, synthetic hydrotalcite, synthetic aluminum silicate, magnesium carbonate, dihydroxyaluminum aminoacetate, aluminum hydroxide, aluminum hydroxide/sodium hydrogen carbonate coprecipitate, dried aluminum hydroxide/magnesium hydrogen carbonate mixture, magnesium oxide, silica Examples include magnesium oxide.
Ingredients (B) are dry aluminum hydroxide gel, magnesium aluminate metasilicate, magnesium aluminate silicate, synthetic hydrotalcite, magnesium carbonate, aluminum hydroxide, water Aluminum oxide/sodium bicarbonate coprecipitate and magnesium oxide are preferred, dried aluminum hydroxide gel, magnesium aluminate metasilicate, synthetic hydrotalcite, aluminum hydroxide, and magnesium oxide are more preferred, and dried aluminum hydroxide gel and metasilicate More preferred are magnesium aluminate, synthetic hydrotalcite, and magnesium oxide. Among these, dry aluminum hydroxide gel and magnesium aluminate metasilicate are preferred because they are highly effective in suppressing the odor of tablets after storage.
Examples of the dry aluminum hydroxide gel include the dry aluminum hydroxide gel listed in the "17th Edition Japanese Pharmacopoeia". Note that the dry aluminum hydroxide gel may retain water such as bound water, and the dose and mass ratio of component (B) described below include hydrated water.
Component (B) may be used alone or in an appropriate combination of two or more.

The dose of component (B) per dose is preferably 5 to 500 mg, more preferably 30 to 300 mg, even more preferably 50 to 200 mg. If the dose of component (B) is above the above lower limit, gastric disorders caused by component (A) can be sufficiently alleviated, and if it is below the above upper limit, other active ingredients can be sufficiently incorporated. .
The mass of component (B) per tablet is preferably 5 to 200 mg. If the mass of component (B) per tablet is greater than or equal to the above lower limit, it will be easier to ensure hardness that does not cause wear and tear, and if it is less than the above upper limit, it will be difficult to cause delayed disintegration, and other active ingredients Since the drug can be sufficiently blended, the amount per dose can be reduced.
The mass proportion of component (B) per tablet is preferably 1 to 70% by mass, more preferably 3 to 50% by mass, and even more preferably 5 to 40% by mass. If the mass ratio of component (B) is above the above lower limit, it will be easier to ensure hardness that does not cause wear and tear, and if it is below the above upper limit, it will be difficult to cause delayed disintegration, and other active ingredients will be sufficiently blended. This makes it possible to reduce the dose per dose.

<(C) component>
Component (C) is at least one member selected from the group consisting of loxoprofen and pharmaceutically acceptable salts thereof.
By using component (C) in combination with component (A) and component (B), the product has hardness that does not easily cause abrasion and rapid disintegration immediately after production, and the delay in disintegration is suppressed.

Pharmaceutically acceptable salts of loxoprofen include, for example, alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts.
Loxoprofen and its pharmaceutically acceptable salts may each exist in the form of a hydrate. An example of a hydrate is loxoprofen sodium dihydrate (corresponding to about 12% water content in the bulk drug powder). When loxoprofen and its pharmaceutically acceptable salt are hydrates, the dose and mass proportion of component (C) described below include hydrated water.
As component (C), an alkali metal salt of loxoprofen is preferable, and loxoprofen sodium is more preferable.
Component (C) may be used alone or in an appropriate combination of two or more.

The dose of component (C) per dose is preferably 11 to 170 mg, more preferably 20 to 113 mg, and even more preferably 27 to 70 mg. If the dose of component (C) per dose is equal to or higher than the above lower limit, enhancement of the antipyretic and analgesic effect can be expected, and if it is equal to or lower than the above upper limit, gastric injury caused by component (C) can be suppressed.
The mass of component (C) per tablet is preferably 10 to 100 mg. If the mass of component (C) per tablet is equal to or greater than the above lower limit, the effect of suppressing disintegration delay will be sufficiently obtained, and wear and tear will be less likely to occur. adhesion can be suppressed, and other active ingredients can be sufficiently incorporated.
The mass proportion of component (C) per tablet is preferably 1 to 70% by mass, more preferably 2 to 50% by mass, and even more preferably 2 to 20% by mass. If the mass ratio of component (C) is at least the above lower limit, the effect of suppressing disintegration delay will be sufficiently obtained, and wear and tear will be less likely to occur, and if it is below the above upper limit, adhesion to the manufacturing machine during the manufacturing process will be suppressed. In addition, since other active ingredients can be sufficiently incorporated, the amount per dose can be reduced.

<C/(A+B) ratio>
Mass ratio expressed as (C) component/((A) component + (B) component) (hereinafter also referred to as "C/(A+B) ratio"), that is, the sum of (A) component and (B) component The ratio of the mass of component (C) to the mass is preferably 0.01 to 1.5, more preferably 0.02 to 1, even more preferably 0.03 to 0.5, and 0.2 to 0.5. Particularly preferred, and most preferably 0.2 to 0.3. If the C/(A+B) ratio is at least the above lower limit, the effect of suppressing the delay in disintegration is more likely to be obtained and wear and tear is less likely to occur, and when it is at or below the above upper limit, the disintegration properties immediately after production are better, and Since other active ingredients can be sufficiently incorporated, the dosage per dose can be reduced.

<A/B ratio>
The mass ratio expressed by component (A)/component (B) (hereinafter also referred to as "A/B ratio"), that is, the ratio of the mass of component (A) to the mass of component (B) is 0.1 -15 is preferred, 0.15-10 is more preferred, 0.2-8 is even more preferred, 0.35-4.5 is particularly preferred, and 1-4.5 is most preferred. If the A/B ratio is at least the above lower limit, the effect of suppressing the delay in disintegration can be more easily obtained, and if it is at most the above upper limit, wear and tear will be less likely to occur, and the disintegration properties immediately after production will be better.

<A/C ratio>
The mass ratio expressed by component (A)/component (C) (hereinafter also referred to as "A/C ratio"), that is, the ratio of the mass of component (A) to the mass of component (C) is 0.2 -25 is preferred, 0.2-20 is more preferred, 0.4-10 is even more preferred, 0.5-7 is particularly preferred, and 1-4.5 is most preferred. When the A/C ratio is at least the above lower limit, adhesion to the manufacturing machine during the manufacturing process is suppressed, and when it is at most the above upper limit, the effect of suppressing the delay in disintegration after storage is more excellent.

<A+B>
The total mass of component (A) and component (B) per tablet (hereinafter also referred to as "A+B total mass") is not particularly limited as long as it is within a range that does not cause any problems in manufacturing, but 35 to 600 mg is acceptable. preferable. When component (C) is not included, when the total mass of A+B per tablet exceeds the above lower limit, there is a tendency for the occurrence of delayed disintegration to become noticeable. If the total mass of A+B per tablet is at least the above lower limit, the present invention is highly useful. If the total mass of A+B per tablet is below the above upper limit, the size of the tablet can be easily adjusted to suit ease of administration.
The ratio of the total mass of A + B per tablet (hereinafter also referred to as "A + B ratio") is preferably 6 to 97% by mass, more preferably 13 to 90% by mass, and even more preferably 18 to 80% by mass. If the A+B ratio is at least the above lower limit value, the usefulness of the present invention is high, and if it is below the above upper limit value, other active ingredients can be sufficiently blended, so that the dosage per dose can be reduced.

<Optional ingredients>
The tablet of this embodiment optionally contains components other than component (A), component (B), and component (C) (hereinafter also referred to as "optional component") within a range that does not impair the physical properties or storage stability of the tablet. You may do so.
Optional components include physiologically active components other than component (A), component (B), and component (C), additives, and the like.

Examples of physiologically active ingredients include antipyretic analgesic ingredients other than component (A) and component (C) (e.g. piroxicam, meloxicam, ampiroxicam, cerocoxib, rofecoxib, tialamide, acetaminophen, sulpirin, etc.), sedative-hypnotic ingredients (e.g. , allylisopropylacetylurea, bromovalerylurea, etc.), antihistamine components (e.g., isothipendyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, difeterol hydrochloride, triprolidine hydrochloride, tripelenamine hydrochloride, tonzylamine hydrochloride, phenethazine hydrochloride, methdilazine hydrochloride, diphenhydramine salicylate, diphenyl Carbinoxamine disulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline theoculate, mebhydroline napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, difeterol phosphate, etc. ), central stimulant ingredients (e.g. sodium benzoate caffeine, caffeine, anhydrous caffeine, etc.), antitussive expectorant ingredients (codeine phosphate, dextromethorphan hydrobromide, dimemorphan phosphate, tipepidine hibenzate) salt, methoxyphenamine hydrochloride, trimethoquinol hydrochloride, carbocysteine, acetylcysteine, ethylcysteine, dl-methylephedrine, bromhexine hydrochloride, serrapeptase, lysozyme chloride, ambroxol, theophylline, aminophylline), vitamin components (e.g. , vitamin B1 and its derivatives and their salts, vitamin B2 and its derivatives and their salts, vitamin C and its derivatives and their salts, hesperidin and its derivatives and their salts, etc.), herbal medicines (for example, valerian root, valerian root, Keihi, Botanpi, Sansho, Shokyo, Chinpi, etc.). These physiologically active ingredients can be used alone or in an appropriate combination of two or more.

When the tablet of this embodiment contains a crude drug, the mass proportion of the crude drug per tablet is preferably 50% by mass or less, more preferably 10% by mass or less. If the mass proportion of the crude drug is below the above upper limit, it can be expected that the effect of suppressing the delay in disintegration will be enhanced.
Preferably, the tablet of this embodiment does not contain any crude drug.

Examples of additives include binders, excipients, disintegrants, lubricants, fragrances, sweeteners, and acidulants.
Examples of the binder include starch (corn starch, wheat starch, potato starch, etc.), pregelatinized starch, crystalline cellulose, gelatin, gum arabic powder, polyvinylpyrrolidone, pullulan, dextrin, and the like.
Excipients include lactose, mannitol, erythritol, xylitol, lactitol, trehalose, maltitol, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch, sodium carboxymethyl starch, sodium hydrogen phosphate, calcium hydrogen phosphate, etc. .
Examples of the disintegrant include low-substituted hydroxypropylcellulose, carmellose, carmellose sodium, carmellose calcium, crospovidone, croscarmellose sodium, partially pregelatinized starch, and the like.
Examples of the lubricant include magnesium stearate, calcium stearate, sodium stearyl fumarate, sucrose fatty acid ester, light silicic anhydride, and talc.
Examples of fragrances include menthol, limonene, vegetable essential oils (mentha oil, mint oil, lychee oil, orange oil, lemon oil, etc.).
Examples of sweeteners include sodium saccharin, aspartame, stevia, sucralose, dipotassium glycyrrhizinate, potassium acesulfame, and the like.
Examples of the acidulant include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, or salts thereof.
These additives can be used alone or in an appropriate combination of two or more.

The tablet of this embodiment preferably contains a binder from the viewpoint of easily ensuring hardness that does not easily cause wear and tear.
The mass of the binder per tablet is preferably 0.1 to 300 mg, more preferably 1 to 100 mg. When the mass of the binder is at least the above lower limit, wear and tear is less likely to occur, and when it is at most the above upper limit, the disintegration properties are more excellent.
The mass proportion of the binder per tablet is preferably 0.1 to 50% by mass, more preferably 1 to 30% by mass. If the mass proportion of the binder is at least the above lower limit, wear and tear will be less likely to occur, and if it is below the above upper limit, the disintegration properties will be better.

The tablet of this embodiment preferably contains a lubricant in terms of hardness, disintegration, and manufacturability.
The mass of the lubricant per tablet is preferably 0.1 to 20 mg, more preferably 1 to 10 mg. If the mass of the lubricant is greater than or equal to the above lower limit, the manufacturability will be better, and if it is less than or equal to the above upper limit, the hardness and disintegrability will be better.
The mass proportion of the lubricant per tablet is preferably 0.01 to 5% by mass, more preferably 0.1 to 3% by mass. If the mass proportion of the lubricant is at least the above lower limit, the manufacturability will be better, and if it is less than the above upper limit, the hardness and disintegrability will be better.

<Tablet form>
The size of the tablet is not particularly limited, but from the viewpoint of ease of handling and swallowing of the tablet, the diameter of the tablet is preferably 5 to 14 mmφ, more preferably 6 to 13 mmφ, and even more preferably 7 to 12 mmφ.
The appropriate mass of each tablet is about 150 mg to 750 mg.
The shape of the tablet is not particularly limited, but preferably a square square tablet, a round flat tablet, a rounded R tablet, or a two-stage R tablet.

The tablet may be a single-layer tablet, or may be a laminated tablet by adding any other layer.
When the tablet is a single-layer tablet, the tablet is composed of a tablet containing the above-mentioned component (A), component (B), and component (C).
When the tablet is a layered tablet, the above-mentioned components (A), (B) and (C) may be contained in the same layer or in different layers. For example, a laminated tablet may be composed of a drug layer containing component (A), component (B), and component (C), and a layer (optional layer) other than the drug layer. Further, it may be composed of a drug layer containing the component (B) and the component (C), and a drug layer containing the component (A), and a drug layer containing the component (A) and the component (C), and a drug layer containing the component (A). ) may be composed of a drug layer containing the component (A) and the component (C), and a drug layer containing the component (B) and the component (C). , each form may further have an optional layer. In this embodiment, it is preferable to have a drug layer containing the above-described components (A), (B), and (C), since the effect of component (C) can be effectively obtained.
Note that the optional layer may contain one or more of component (A), component (B), and component (C), or may contain none of them. The presence or absence and content of these components in the arbitrary layer can be appropriately selected in consideration of the dosage of these components per tablet, etc. Further, the above-mentioned optional components may be contained only in the drug layer, only in the arbitrary layer, or in both the drug layer and the arbitrary layer. If the tablet is a single-layer tablet, the optional ingredients are included in the drug layer.

The amount of water in the tablet is preferably 1 to 10% by mass based on the total mass of the tablet. When the moisture content is at least the above lower limit, the moldability during compression is less likely to deteriorate over time, and when it is at most the above upper limit, the effect of suppressing disintegration delay is more excellent.
The amount of water in the tablet can be calculated from the loss on drying when the crushed tablet is heated at 120° C. for 10 minutes using an electronic moisture meter (for example, MOISTURE BALANCE MOC-120H manufactured by Shimadzu Corporation).
Note that when a hydrate such as loxoprofen sodium dihydrate is used as component (C), the water in the tablet also includes water brought in from this hydrate.

<Tablet manufacturing method>
The tablet of this embodiment is obtained by compressing the powder (hereinafter referred to as "drug-containing powder") constituting the tablet. An embodiment of the tablet manufacturing method of this aspect will be described below.
The method for manufacturing a tablet of this embodiment includes a step of compressing a drug-containing powder into a tablet using a tableting machine having a mortar and a punch (tableting step).

The drug-containing powder may be any powder containing component (A), component (B), and component (C), and may contain arbitrary components as necessary.
The drug-containing powder may be, for example, a powder mixture of component (A), component (B), and component (C), or component (A), component (B). It may also be a granulated product containing the component and component (C).
The drug-containing powder may be premixed or freshly prepared. That is, the method for manufacturing a tablet of the present embodiment may include a step of preparing a drug-containing powder by mixing each component of the powder (powder preparation step).

In the powder preparation step, component (A) of the powder, component (B) of the powder, component (C) of the powder, and optional components of the powder are mixed to form a drug-containing powder. Get a body.
The mixing method in the powder preparation step is not particularly limited, and conventionally known powder mixing methods can be used.
Each component used in the powder preparation step may be obtained by a known manufacturing method, or may be commercially available. Each component may be used as a raw powder or in a granulated form (granulated product). Two or more types of granules may be used in combination. The granules may contain at least one selected from component (A), component (B), and component (C), and may further contain an optional component. From the viewpoint of excellent manufacturability and the effect of suppressing the delay in disintegration after storage, component (C) is preferably contained in the same granule as at least one of component (A) and component (B), and component (A) It is more preferable that the granules are contained in the same granulate.
Known granulation methods can be used to granulate the granules, such as wet granulation, dry granulation, or melt granulation. Therefore, a wet granulation method is preferred, and among the wet granulation methods, stirring granulation or fluidized bed granulation is particularly preferred.

Examples of the tableting machine used in the tableting process include a rotary tabletting machine (Libra 3L, manufactured by Kikusui Seisakusho Co., Ltd.).
Tableting conditions such as tableting pressure and rotating speed of the rotary disk are appropriately set.
In addition, when the tablet is a laminated tablet, the drug-containing powder may be filled into the mortar first, or may be filled after the components constituting the arbitrary layers.

[Coated tablets]
The coated tablet according to one aspect of the present invention uses the above-mentioned tablet as an uncoated tablet, and has a coating layer on the surface of the uncoated tablet. That is, it has a plain tablet that is a tablet containing component (A), component (B), and component (C), and a coating layer provided on the surface of this plain tablet.

<Coating layer>
The coating layer is a layer formed from a constituent material containing a coating agent.
By having a coating layer on the surface of the uncoated tablet, moisture absorption of the uncoated tablet is suppressed, and the effect of suppressing disintegration delay is improved.

As the coating agent, it is preferable to select one that does not significantly impair the disintegrability, such as film forming agents and plasticizers.
Examples of film-forming agents include celluloses such as carmellose, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), hydroxymethylcellulose, and methylcellulose; gum arabic, carboxyvinyl polymer, povidone, polyvinyl alcohol, polyacrylic acid, monosaccharides, and disaccharides. The above polysaccharides (sugar (granulated sugar, etc.), lactose, maltose, xylose, isomerized lactose, etc.), sugar alcohols (palatinit, sorbitol, lactitol, erythritol, xylitol, reduced starch saccharide, maltitol, mannitol, etc.), starch syrup , isomerized sugars, oligosaccharides, sucrose, trehalose, reduced starch saccharides (reduced starch decomposition products, etc.), and the like. In particular, hydroxypropyl methylcellulose and polyvinyl alcohol are preferred from the viewpoint of excellent manufacturability and moisture resistance.
Examples of plasticizers include triethyl citrate, triacetin, carnauba wax, glycerin, macrogol, propylene glycol, and polysorbate, which are listed in the Japanese Pharmacopoeia (Hirokawa Shoten) and Pharmaceutical Excipient Standards (Yakuji Nippo Co., Ltd.). These include those listed.
One type of coating agent may be used alone, or two or more types may be used in combination.

Preferably, the coating layer contains an inorganic pigment. If the coating layer contains an inorganic pigment, the effect of suppressing the delay in disintegration will be more excellent.
Inorganic pigments are not particularly limited as long as they do not cause manufacturing problems, but examples include titanium oxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, brown iron oxide, zinc oxide, light anhydrous silicic acid, and hydrated silicon dioxide. etc. Among these, titanium oxide, iron sesquioxide, yellow iron sesquioxide, zinc oxide, and light anhydrous silicic acid are preferable, and titanium oxide and iron sesquioxide are particularly preferable, since they have a high effect of suppressing the delay in disintegration.
Inorganic pigments may be used alone or in combination of two or more.

When the coating layer contains an inorganic pigment, the content of the inorganic pigment is not particularly limited as long as it does not cause any problems in production, but it is preferably 0.01 to 5% by mass, and 0.05% by mass based on the total mass of the coating layer. It is more preferably 1% by mass, and particularly preferably 0.1% by mass to 0.7% by mass. If the content of the inorganic pigment is at least the above lower limit, it will be easier to obtain the effect of suppressing the delay in disintegration by the inorganic pigment, and if it is below the above upper limit, the moldability of the coating layer will be good.

The mass ratio of the coating layer to the mass of the uncoated tablet is preferably 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, and even more preferably 1 to 3% by mass. If the mass ratio of the coating layer is at least the above lower limit, the disintegration delay suppressing effect will be better, and if it is below the above upper limit, the disintegration properties immediately after production will be better.

<Method for manufacturing coated tablets>
The coated tablet of this embodiment can be manufactured by manufacturing a tablet by the above-described tablet manufacturing method, making the obtained tablet into a plain tablet, and providing the above-mentioned coating layer on the surface of the plain tablet.
A conventionally known method can be used to provide a coating layer on the surface of the uncoated tablet. For example, first, a coating agent is dispersed in a medium such as water to obtain a coating liquid that is a dispersion of the coating agent. At this time, the inorganic pigment is dispersed in the medium together with the coating agent, if necessary. Thereafter, the coating liquid is applied to cover the uncoated tablet by spraying or the like. Thereafter, the medium of coating liquid is dried. Thereby, a coating layer is formed and a coated tablet is obtained.

EXAMPLES Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited to the following description.

[Raw materials used]
The following compounds were used as component (A).
・Ethenzamide: Manufactured by Iwaki Pharmaceutical Co., Ltd., "Ethenzamide" Japanese Pharmacopoeia Standards.

As component (B), the following compounds were used.
- Dry aluminum hydroxide gel: "Dried aluminum hydroxide gel SN" manufactured by Kyowa Chemical Industry Co., Ltd.
- Magnesium metasilicate aluminate (Mg metasilicate aluminate): "Neusilin" (registered trademark) manufactured by Fuji Chemical Industry Co., Ltd.
-Synthetic hydrotalcite: "Alcamac SN" (registered trademark) manufactured by Kyowa Chemical Industry Co., Ltd.
・Magnesium oxide: "Magnesium oxide" manufactured by Tomita Pharmaceutical Co., Ltd.

As component (C), the following compounds were used.
・Loxoprofen sodium dihydrate: Manufactured by Daiwa Pharmaceutical Co., Ltd., Japanese Pharmacopoeia standards.

The following compounds were used as optional components.
- Low-substituted hydroxypropyl cellulose: "LH-31" manufactured by Shin-Etsu Chemical Co., Ltd.
・Corn starch: "Koppo Matsutani Corn Starch" manufactured by Matsutani Chemical Industry Co., Ltd.
- Crystalline cellulose: "UF-702" manufactured by Asahi Kasei Corporation.

The following compounds were used as materials for forming the coating layer.
・Coating agent: “Opadry (uses hydroxypropyl methylcellulose as polymer)” (trademark) manufactured by Nippon Colorcon LLC.
・Titanium oxide: "Titanium oxide" manufactured by Sakai Chemical Industry Co., Ltd.
・Iron sesquioxide: "Iron sesquioxide" manufactured by Hijimi Kasei Co., Ltd.

[Evaluation method]
<Evaluation of tablet strength>
For tablets manufactured by adjusting the main pressure so that the tablet hardness is 70N, the friability (mass percentage of the reduced mass relative to the initial mass) was determined according to the tablet friability test method listed in the 17th revised Japanese Pharmacopoeia. was determined and evaluated using the following criteria. A score of 2 points or more was considered a pass. Note that, according to the Japanese Pharmacopoeia, the degree of friability is desirably 1.0% or less.
(Evaluation criteria)
4: Friability is 0.1% or less.
3: Friability is more than 0.1% and less than 0.5%.
2: Friability of more than 0.5% to less than 1.0%.
1: Friability exceeds 1.0%.

<Evaluation of disintegration immediately after production>
For tablets manufactured by adjusting the main pressure so that the tablet hardness is 70N, the disintegration time of 6 tablets was determined using water as the disintegration test liquid according to the tablet disintegration test method listed in the 17th revised Japanese Pharmacopoeia. (minutes and seconds) and calculated the average value. The obtained average value was converted into minutes, and the value rounded to the first decimal place was defined as the "disintegration time immediately after production." For example, when the average value is 0.5 minutes or more and less than 1.5 minutes (30 seconds or more and less than 1 minute 30 seconds), the immediate disintegration time is 1 minute. Note that if it is less than 0.5 minutes, it is considered 0 minutes.

<Evaluation of disintegration after storage>
The manufactured tablets are placed in each pocket of a resin sheet (TAS-230, manufactured by Taisei Kako) that has been pre-molded with multiple pockets for accommodating tablets, aluminum foil is pasted on the pocket opening side of the resin sheet, and PTP ( A press-through package) was obtained. This PTP was stored at 50° C. and 75% RH for 8 weeks. Thereafter, the tablets were taken out from the PTP, and the disintegration times (minutes and seconds) of the six tablets were measured in the same manner as above, and the average value was determined. The obtained average value was converted into minutes, and the value rounded to the first decimal place was defined as the "post-storage disintegration time."

<Evaluation of decay delay>
_The difference ( _{T 2} -T ₁ ) was calculated. The value was defined as the decay delay and evaluated based on the following criteria. A score of 2 points or more was considered a pass. In addition, in tablets that do not cause disintegration delay, the above-mentioned difference may be less than 0 minutes due to measurement variations or rounding, and in that case, the score was set as 5.
(Evaluation criteria)
5: Disintegration delay is less than 10 minutes.
4: Disintegration delay is 10 minutes or more and less than 20 minutes.
3: Disintegration delay is 20 minutes or more and less than 30 minutes.
2: Disintegration delay is 30 minutes or more and less than 40 minutes.
1: Collapse delay is 40 minutes or more.

[Examples 1 to 16, Comparative Examples 1 to 4]
Component (A), component (B), component (C) and optional ingredients shown in Table 1, 2 or 4 are mixed so that the content of each component per tablet is the value shown in Table 1, 2 or 4. were weighed and mixed to prepare a drug-containing powder. The obtained drug-containing powder was compressed under the tableting conditions shown below to obtain a tablet (single-layer tablet). The evaluation results of the obtained tablets are shown in Tables 1, 2, and 4.

(Tableting conditions)
Tablet press: Rotary tablet press Libra 3L (manufactured by Kikusui Seisakusho).
Plate rotation speed: 20 rpm.
Mortar: φ8.5mm (2 steps R) x 12 pieces, no markings (cap height 0.1mm, R1 = 3.4, R2 = 10).
Preload: 2kN (about 20MPa, about 200kg/cm ² ).
Main pressure: Adjusted for each tablet (adjusted so that the tablet hardness was 70N).

[Examples 17 to 23]
Tablets were manufactured in the same manner as in Example 1, and the tablets were made into uncoated tablets.
The materials shown in the column of coating layer shown in Table 3 were weighed out so that the content of each material per tablet became the value shown in Table 3, and water was added to prepare a coating liquid. The solid content concentration of the coating liquid was 15% by mass. The obtained coating liquid was coated using an Aqua Coater Model 48 (manufactured by Freund Sangyo Co., Ltd.) under conditions of an air supply temperature of 60°C, a supply air flow rate of 2.3 m ³ /min, and an exhaust temperature of 42 ± 2°C. Sprayed onto tablets. Thereafter, the tablets were dried for 20 minutes at a supply air temperature of 60° C. and a supply air flow rate of 2.3 m ³ /min to obtain coated tablets in which a coating layer was provided on the surface of the plain tablet. Table 3 shows the evaluation results of the obtained coated tablets.

The tablet of Comparative Example 1 containing component (A) but not containing components (B) and (C) had high friability and poor disintegration immediately after production.
Tablets of Comparative Examples 2 to 4 containing component (A) and component (B) but not containing component (C) experienced significant disintegration delay during storage.
In contrast, the tablets or coated tablets of Examples 1 to 23 containing component (A), component (B), and component (C) in the same layer had low friability and good disintegration immediately after production. Ta. In addition, the delay in disintegration due to storage was suppressed.

The tablets and coated tablets of the present invention have hardness that prevents wear and tear and rapid disintegration. Furthermore, the delay in disintegration caused by the combination of ethenzamide and antacids is suppressed.

Claims (5)

Contains the following (A) component, (B) component and (C) component,
The mass ratio represented by the component (C)/(component (A) + component (B)) is 0.08 to 0.30,
The mass ratio represented by the component (A)/component (B) is 0.35 to 15,
A tablet, wherein the ratio of the total mass of the component (A) and the component (B) per tablet is 39.22 to 80% by mass .
(A) Component: ethenzamide.
(B) Component: Dry aluminum hydroxide gel .
Component (C): at least one member selected from the group consisting of loxoprofen and pharmaceutically acceptable salts thereof. The tablet according to claim 1 , wherein the mass ratio represented by the component (A)/component (C) is 0.2 to 25. Furthermore, it contains a binder,
The tablet according to claim 1 or 2, wherein the mass proportion of the binder per tablet is 0.1 to 50% by mass. A coated tablet comprising the tablet according to any one of claims 1 to 3 as an uncoated tablet, and having a coating layer on the surface of the uncoated tablet. The coated tablet according to claim 4 , wherein the coating layer contains an inorganic pigment.