JP7012492B2 - Tablets and their manufacturing methods - Google Patents

Description

The present invention relates to tablets and methods for producing the same.

Among the non-steroidal anti-inflammatory drugs (NSAIDs), loxoprofen and its salts (hereinafter collectively referred to as "loxoprofen (salt)") have excellent anti-inflammatory, analgesic and antipyretic effects, and have relatively few side effects. Due to its small amount, it is widely used as an ingredient in anti-inflammatory analgesics. Over-the-counter drugs such as antipyretic analgesics and common treatments contain multiple active ingredients with the expectation of a wide range of pharmacological effects on various symptoms, and loxoprofen (salt) can also be used in combination with various drugs. It is being considered.
For example, Patent Document 1 contains, orally, one or more agents selected from caffeine, allylisopropylacetylurea, bromvalerylurea, acetaminophens and ethenzamide, and loxoprofen sodium dihydrate. Pharmaceutical compositions for administration are disclosed.

By the way, since loxoprofen (salt) and the like have strong adhesiveness, it adheres to manufacturing equipment, especially when powder containing loxoprofen (salt) adheres to the pestle of a tableting machine (hereinafter, "pestle only"). "Adhesion") etc. are likely to occur. The combination of loxoprofen (salt) with acetaminophen also causes the problem of pestle adhesion.
As a tablet in which pestle only is suppressed, for example, Patent Document 2 discloses a tablet containing loxoprofen (salt) and a specific amount of a colorant.

Japanese Unexamined Patent Publication No. 11-139971 JP-A-2015-193600

However, when a colorant is used in combination with loxoprofen (salt) and acetaminophen, an unpleasant odor may be felt when the tablets containing them are taken after storage. In particular, when tablets are stored under high temperature and high humidity, unpleasant odors are likely to occur even if they are packaged in a closed container.

As a technique for suppressing an unpleasant odor, a method of coating a tablet with a coating agent is common.
However, in the case of the method of coating the tablet with a coating agent, abrasion may occur during the coating. If a tablet having a high hardness is used to suppress wear, the elution property may decrease. Furthermore, the manufacturing cost is high because the number of manufacturing processes increases.
Ingestibility is an important factor in over-the-counter drugs, and there is a need for a technique for suppressing an unpleasant odor that may be a factor that hinders ingestion by a simpler method.

INDUSTRIAL APPLICABILITY The present invention is a tablet and a method for producing the same, in which the adhesion of a pestle at the time of tableting, which occurs when producing a tablet containing loxoprofen (salt) and acetaminophen, is suppressed, and the unpleasant odor is also suppressed by a simple method. The purpose is to provide.

As a result of diligent studies by the present inventors, in the combination of loxoprofen (salt), acetaminophen and a colorant, crystalline cellulose, starch or calcium hydrogen phosphate is further used to suppress the adhesion of the punch and under high temperature and high humidity. It has been found that a tablet in which an unpleasant odor is suppressed can be obtained even when stored in, and the present invention has been completed.

That is, the present invention has the following aspects.
[1] A tablet containing the following components (A), (B), (C) and (D).
(A) Component: One or more selected from the group consisting of loxoprofen and its salts (B) Component: Acetaminophen (C) Component: Colorant (D) Component: Group consisting of crystalline cellulose, starch and calcium hydrogen phosphate One or more selected from [2] The tablet according to [1], wherein the component (C) is one or more selected from the group consisting of iron sesquioxide, yellow iron sesquioxide, titanium oxide and zinc oxide.
[3] The tablet according to [1] or [2], wherein the mass ratio represented by 10000 × (C) component / ((A) component + (B) component) is 0.11 to 20.
[4] The tablet according to any one of [1] to [3], wherein the mass ratio represented by (D) component / ((A) component + (B) component) is 0.005 to 5. ..
[5] The tablet according to any one of [1] to [4], wherein the content of the component (A) is 3 to 85% by mass with respect to the total mass of the tablet.
[6] The tablet according to any one of [1] to [5], wherein the content of the component (B) is 3 to 85% by mass with respect to the total mass of the tablet.
[7] The tablet according to any one of [1] to [6], wherein the mass ratio represented by 10000 × (C) component / tablet is 0.01 to 3.
[8] The tablet according to any one of [1] to [7], wherein the content of the component (D) is 1 to 85% by mass with respect to the total mass of the tablet.
[9] The tablet according to any one of [1] to [8], wherein the mass ratio represented by the component (B) / component (A) is 0.25 to 15.
[10] The invention according to any one of [1] to [9], further containing one or more selected from the group consisting of caffeine, anhydrous caffeine, allylisopropylacetylurea and low-degree-of-substitution hydroxypropyl cellulose. tablet.
[11] A method for producing a tablet, comprising a step of tableting and molding a drug-containing powder containing the following components (A), (B), (C) and (D) to obtain a tablet.
(A) Component: One or more selected from the group consisting of loxoprofen and its salts (B) Component: Acetaminophen (C) Component: Colorant (D) Component: Group consisting of crystalline cellulose, starch and calcium hydrogen phosphate One or more selected from [12] Powder A containing the following component (A) and powder B containing the following component (B) (however, each of the following components (C) and (D) is a powder. A method for producing a tablet, which comprises a step of filling a mortar with (included in at least one of A and powder B) and tableting to obtain a tablet.
(A) Component: One or more selected from the group consisting of loxoprofen and its salt (B) Component: Acetaminophen (C) Component: Colorant (D) Component: Group consisting of crystalline cellulose, starch and calcium hydrogen phosphate One or more selected from

According to the present invention, a tablet containing loxoprofen (salt) and acetaminophen is suppressed from sticking to a pestle at the time of tableting, and an unpleasant odor is also suppressed by a simple method. A manufacturing method can be provided.

The tablet of the present invention contains the following components (A), (B), (C) and (D).
The size of the tablet is not particularly limited, but 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 from the viewpoint of ease of handling and swallowing. The tablet mass per tablet is preferably 150 mg to 550 mg.
The shape of the tablet is not particularly limited, but a Sumi square flat tablet, a Sumi round flat tablet, a rounded R tablet, or a two-stage R tablet is preferable.

Further, the tablet may have a single-layer structure (single-layer tablet) or a laminated structure (laminated tablet). From the viewpoint that the effect of the present invention can be more easily enjoyed, it has a layer having the components (A), (B), (C) and (D) shown below (that is, the component (A), (B). ), (C) and (D) are present in the same layer). Hereinafter, the layer having both the (A) component, the (B) component, the (C) component and the (D) component is also referred to as a “drug layer”. If the tablet is a single layer tablet, the tablet is composed of a drug layer. When the tablet is a laminated tablet, the tablet is composed of a drug layer and a layer other than the drug layer (arbitrary layer).

When the tablet is a laminated tablet in which the component (A) and the component (B) are present in separate layers and these layers are adjacent to each other, each of the component (C) and the component (D) is at least. It may be contained in one layer. That is, when the layer in which the component (A) is present is referred to as the "A layer" and the layer in which the component (B) is present is referred to as the "layer B", the components (C) and (D) are respectively the layer A and the layer (D). It suffices to contain it in at least one of the B layers, whereby the effect of the present invention can be sufficiently obtained. In particular, it is preferable that the component (C) is contained in at least the A layer from the viewpoint that the effect of the present invention can be easily obtained. In this case, the component (C) may also be contained in the layer B. Further, the component (D) may be contained only in the A layer, may be contained only in the B layer, or may be contained in both the A layer and the B layer.

Particularly preferred tablet forms are single-layer tablets composed of a drug layer; a layer A containing a component (A), a component (C) and a component (D), a component (B) and, if necessary, an antacid. Laminated tablets in which a B layer containing an agent is adjacent; a laminated tablet in which a drug layer and an arbitrary layer containing an antacid are adjacent to each other can be mentioned.

<Ingredient (A)>
The component (A) is one or more selected from the group consisting of loxoprofen and a salt thereof (loxoprofen (salt)).
Loxoprofen (salt) is an antipyretic analgesic ingredient listed in the Japanese Pharmacopoeia.

The salt of loxoprofen is not particularly limited as long as it is a pharmaceutically acceptable salt of loxoprofen, and examples thereof include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt.
Loxoprofen (salt) may be present in the form of a hydrate. Preferable examples of loxoprofen (salt) in the hydrated state include loxoprofen sodium dihydrate. In the case of loxoprofen sodium dihydrate, the water content of the bulk powder is about 12% by mass.
When the component (A) is a hydrate, the content of the component (A) described later, the dose per dose and the mass ratio with other components include the water content in the component (A). It shall be.

As the component (A), a salt of loxoprofen is preferable, loxoprofen sodium is more preferable, and loxoprofen sodium dihydrate is further preferable.
As the component (A), one type may be used alone, or two or more types may be used in combination.

The content of the component (A) is preferably 3 to 85% by mass, more preferably 5 to 50% by mass, based on the total mass of the tablet.
When the tablet is a laminated tablet and the component (A), the component (B), the component (C) and the component (D) are present in the same layer, the content of the component (A) is the total mass of the drug layer. On the other hand, 3 to 90% by mass is preferable, and 5 to 55% by mass is more preferable.
When the tablet is a laminated tablet and the component (A) and the component (B) are present in separate layers, the content of the component (A) is 3 to 90% by mass with respect to the total mass of the layer A. It is preferable, 10 to 65% by mass is more preferable.
As the content of the component (A) increases, the unpleasant odor after storage becomes more pronounced, so that the effect of the present invention can be easily exhibited by adding the component (D). In addition, a sufficient antipyretic and analgesic effect can be obtained. When the content of the component (A) is not more than the above upper limit value, the adhesion to the manufacturing machine in the manufacturing process can be further suppressed.
When the tablet is a single-layer tablet, the content of the component (A) with respect to the total mass of the drug layer is the same as the content of the component (A) with respect to the total mass of the tablet.

The single dose of the component (A) is preferably 11 to 170 mg, more preferably 22 to 113 mg. When the dose of the component (A) per dose is not less than the above lower limit value, the antipyretic analgesic effect can be sufficiently obtained, and when it is not more than the above upper limit value, the adhesion to the manufacturing machine in the manufacturing process can be further suppressed.

<Ingredient (B)>
The component (B) is acetaminophen.
Acetaminophen (N- (4-hydroxyphenyl) acetamide), also known as paracetamol, is an antipyretic analgesic ingredient listed in the Japanese Pharmacopoeia.

The content of the component (B) is preferably 3 to 85% by mass, more preferably 20 to 80% by mass, based on the total mass of the tablet.
When the tablet is a laminated tablet and the component (A), the component (B), the component (C) and the component (D) are present in the same layer, the content of the component (B) is the total mass of the drug layer. On the other hand, 5 to 90% by mass is preferable, and 20 to 85% by mass is more preferable.
When the tablet is a laminated tablet and the component (A) and the component (B) are present in separate layers, the content of the component (B) is 5 to 90% by mass with respect to the total mass of the layer B. It is preferably 20 to 85% by mass, more preferably 20 to 85% by mass.
As the content of the component (B) increases, the unpleasant odor after storage becomes more pronounced, so that the effect of the present invention can be easily exhibited by adding the component (D). In addition, a sufficient antipyretic and analgesic effect can be obtained. When the content of the component (B) is not more than the above upper limit value, the tablet hardness can be maintained satisfactorily.
When the tablet is a single-layer tablet, the content of the component (B) with respect to the total mass of the drug layer is the same as the content of the component (B) with respect to the total mass of the tablet.

The blending ratio of the component (A) and the component (B) in the tablet can be arbitrarily set, but in order to make it easier to obtain the effect of the present invention, the mass represented by the component (B) / component (A) The ratio (hereinafter, also referred to as “B / A ratio”) is preferably 0.25 to 15, more preferably 1 to 10, and even more preferably 4.5 to 7. When the B / A ratio is at least the above lower limit value, the unpleasant odor after storage can be further suppressed, and the adhesion to the manufacturing machine in the tablet manufacturing process can be further suppressed. On the other hand, when the B / A ratio is not more than the above upper limit value, the tablet hardness can be maintained satisfactorily.

The single dose of the component (B) is preferably 30 to 500 mg, more preferably 50 to 300 mg. When the dose of the component (B) per dose is not less than the above lower limit value, the antipyretic analgesic effect can be sufficiently obtained, and when it is not more than the above upper limit value, the tablet hardness can be maintained satisfactorily.

<Ingredient (C)>
The component (C) is a colorant.
By using the component (C) in combination in the combination of the component (A) and the component (B), it is possible to suppress the adhesion of the pestle at the time of tableting that occurs when the tablet is manufactured.

Examples of the component (C) include food coloring agents, organic pigments and inorganic pigments other than food coloring agents, animal and plant extracts, and the like. The component (C) is illustrated below, but the component (C) is not limited to the one illustrated below.
Examples of edible colorants include orange essence, caramel, carmine, β-carotene, edible blue No. 1, edible yellow No. 4, edible yellow No. 4 aluminum lake, edible yellow No. 5, edible red No. 2, edible red No. 3, and so on. Edible red No. 102 and the like can be mentioned.
Examples of the organic pigment include copper chlorophyllin sodium, copper chlorophyll, riboflavin and the like.
Examples of the inorganic pigment include iron sesquioxide, yellow iron sesquioxide, black iron oxide, zinc oxide, titanium oxide, gold foil, and medicated charcoal.
Examples of animal and plant extracts include licorice extract, acene yak tannin powder, turmeric extract, green tea powder and the like.
Among these, inorganic pigments are preferable from the viewpoint of further suppressing the adhesion of the punch during tableting, and iron-based inorganic pigments such as iron sesquioxide, yellow iron sesquioxide, and black iron oxide, zinc oxide, and oxidation. Titanium is preferred, iron sesquioxide, yellow iron sesquioxide, titanium oxide and zinc oxide are more preferred, and iron sesquioxide and yellow iron sesquioxide are even more preferred.
As the component (C), one type may be used alone, or two or more types may be used in combination.

The content of the component (C) is preferably 0.001 to 0.2% by mass, more preferably 0.005 to 0.1% by mass, and 0.01 to 0.05% by mass with respect to the total mass of the tablet. Is even more preferable.
When the tablet is a laminated tablet and the component (A), the component (B), the component (C) and the component (D) are present in the same layer, the content of the component (C) is the total mass of the drug layer. On the other hand, 0.002 to 0.4% by mass is preferable, and 0.01 to 0.3% by mass is more preferable.
When the tablet is a laminated tablet and the component (A) and the component (B) are present in separate layers, the content of the component (C) in the layer A is 0 to 0 with respect to the total mass of the layer A. 0.3% by mass is preferable, and 0.01 to 0.2% by mass is more preferable. The content of the component (C) in the B layer is preferably 0 to 0.4% by mass, more preferably 0.01 to 0.3% by mass, based on the total mass of the B layer. However, the total content of the component (C) in the layer A and the total content of the component (C) in the layer B satisfy 0.001 to 0.2% by mass with respect to the total mass of the tablet. Is preferable.
If the content of the component (C) is at least the above lower limit value, the adhesion of the pestle at the time of tableting that occurs during tableting can be further suppressed, and if it is at least the above upper limit value, the components (C) are aggregated with each other. It becomes difficult and the appearance of the tablet can be maintained well.
When the tablet is a single-layer tablet, the content of the component (C) with respect to the total mass of the drug layer is the same as the content of the component (C) with respect to the total mass of the tablet.

The total of the components (A) and (B) in the tablet and the blending ratio with the component (C) can be arbitrarily set, but in order to make the effect of the present invention more easily obtained, 10000 × component (C). The mass ratio represented by / ((A) component + (B) component) (hereinafter, also referred to as “10000 × C / (A + B) ratio”) is preferably 0.11 to 20 and 0.25 to 15. Is more preferable. If the 10000 × C / (A + B) ratio is at least the above lower limit value, the adhesion of the pestle at the time of tableting that occurs during tablet production can be further suppressed, and if it is at least the above upper limit value, the (C) components are aggregated with each other. It is less likely to occur and the appearance of the tablet can be maintained well.

The single dose of the component (C) is preferably 0.001 to 0.5 mg, more preferably 0.01 to 0.2 mg, and even more preferably 0.03 to 0.1 mg. If the dose of the component (C) per dose is at least the above lower limit, the sticking of the pestle at the time of tableting that occurs during tablet production can be further suppressed, and if it is at least the above upper limit, the components (C) are used with each other. Aggregation is less likely to occur, and the appearance of the tablet can be maintained well.

<(D) component>
The component (D) is one or more selected from the group consisting of crystalline cellulose, starch and calcium hydrogen phosphate.
Crystalline cellulose is obtained by partially depolymerizing α-cellulose obtained as pulp from a fibrous plant with an acid and purifying it (listed in the Japanese Pharmacopoeia).
The starch is not particularly limited, and examples thereof include corn starch, potato starch, wheat starch, rice starch, pregelatinized starch, and partially pregelatinized starch.
Calcium hydrogen phosphate may be present in the form of a hydrate. Preferable examples of calcium hydrogen phosphate in the hydrated state include calcium hydrogen phosphate dihydrate. In the case of calcium hydrogen phosphate dihydrate, the water content of the bulk powder is about 21% by mass. When a hydrate of calcium hydrogen phosphate is used as the component (D), the content of the component (D) described later, the dose per dose and the mass ratio with other components shall be the component (D). The amount of water inside is also included.
As the component (D), one type may be used alone, or two or more types may be used in combination.

Among the above, crystalline cellulose and corn starch are preferable as the component (D) in that the effect of suppressing the odor after storage is particularly easy to obtain.

The content of the component (D) is preferably 1 to 85% by mass, more preferably 1 to 60% by mass, still more preferably 3 to 50% by mass, based on the total mass of the tablet.
When the tablet is a laminated tablet and the component (A), the component (B), the component (C) and the component (D) are present in the same layer, the content of the component (D) is the total mass of the drug layer. On the other hand, 1 to 85% by mass is preferable, 1 to 60% by mass is more preferable, and 2 to 50% by mass is further preferable.
When the tablet is a laminated tablet and the component (A) and the component (B) are present in separate layers, the content of the component (D) in the layer A is 0 to 0 with respect to the total mass of the layer A. It is preferably 85% by mass, more preferably 1 to 60% by mass, still more preferably 2 to 50% by mass. The content of the component (D) in the B layer is preferably 0 to 85% by mass, more preferably 1 to 60% by mass, still more preferably 2 to 50% by mass, based on the total mass of the B layer. However, the total content of the component (D) in the layer A and the total content of the component (D) in the layer B are preferably 1 to 85% by mass, more preferably 1 to 60% by mass. %, More preferably 3 to 50% by mass.
When the content of the component (D) is not less than the above lower limit value, the unpleasant odor after storage can be suppressed more effectively, and when it is not more than the above upper limit value, other active ingredients can be sufficiently contained. It is possible to reduce the dose per dose.
When the tablet is a single-layer tablet, the content of the component (D) with respect to the total mass of the drug layer is the same as the content of the component (D) with respect to the total mass of the tablet.

The total content of the component (A), the component (B), the component (C) and the component (D) in the tablet is preferably 10 to 100% by mass, preferably 35 to 100% by mass, based on the total mass of the tablet. More preferred.
Further, when the tablet is a laminated tablet and the component (A), the component (B), the component (C) and the component (D) are present in the same layer, the component (A), the component (B), and the component (C) are present. The total content of the component and the component (D) is preferably 10 to 100% by mass, more preferably 40 to 100% by mass, based on the total mass of the drug layer.
If the total content of the component (A), the component (B), the component (C) and the component (D) is equal to or higher than the above lower limit, the antipyretic analgesic effect can be obtained while suppressing the adhesion of the pestle and the unpleasant odor after storage. If it is sufficiently obtained and is not more than the above upper limit, a tablet having excellent ingestability can be obtained.

The total of the components (A) and (B) in the tablet and the blending ratio of the component (D) can be arbitrarily set, but in order to make the effect of the present invention more easily obtained, the component (D) / ( The mass ratio (hereinafter, also referred to as “D / (A + B) ratio”) represented by (A) component + (B) component) is preferably 0.005 to 5, more preferably 0.01 to 2. If the D / (A + B) ratio is at least the above lower limit value, the unpleasant odor after storage can be suppressed more effectively, and if it is at least the above upper limit value, the tablet can be easily taken.

The single dose of the component (D) is preferably 1 to 500 mg, more preferably 5 to 300 mg, still more preferably 10 to 200 mg. If the dose of the component (D) per dose is at least the above lower limit value, the unpleasant odor after storage can be suppressed more effectively, and if it is at least the above upper limit value, other active ingredients are sufficiently contained. Therefore, the dose per dose can be suppressed.
The total dose of the component (A), the component (B), the component (C) and the component (D) is preferably 42 to 1170 mg, more preferably 82 to 713 mg. If the total dose of the component (A), the component (B), the component (C) and the component (D) is equal to or higher than the above lower limit, the sticking of the pestle and the unpleasant odor after storage are suppressed. A tablet having a sufficient antipyretic and analgesic effect and having an excellent ingestability can be obtained if it is at least the above upper limit.

<Arbitrary ingredient>
The tablet of the present invention contains a component (arbitrary component) other than the component (A), the component (B) and the component (C) as long as the physical properties such as the effect and storage stability of the present invention are not impaired. You may.
Examples of the optional component include a bioactive component other than the component (A) and the component (B), an additive other than the component (C) and the component (D), and the like.

Examples of the bioactive component include antipyretic and analgesic components other than the component (A) and the component (B) (pyroxicam, meloxicam, ampiroxicam, serocoxib, rofecoxib, thialamide, ethenzamide, metamizole, etc.).
In addition, physiologically active ingredients other than antipyretic and analgesic ingredients can also be blended. Physiologically active components other than the antipyretic and analgesic components include, for example, sedative and hypnotic components (allylisopropylacetylurea, bromvaleryluurea, etc.), antihistamine components (isotipendyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, dipheterol hydrochloride, triprolysine hydrochloride, triperenamine hydrochloride, etc. Tonsylamine hydrochloride, phenetazine hydrochloride, metodilazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonic acid, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline theocrate, mebuhydroline napadisylate, promethazine methylene disalicylate, carbinolamine maleate , D-Chlorpheniramine maleate, diferrol phosphate, etc.), Central excitatory components (sodium benzoate caffeine, caffeine, anhydrous caffeine, etc.), antitussive sputum components (codein phosphate, dextrometholphan hydrobromide) , Dimemorphan phosphate, Tipepidine hibenzate, methoxyphenamine hydrochloride, Trimethoquinol hydrochloride, Carbocysteine, Acetylcysteine, Ethylcysteine, dl-methylephedrine, Bromhexin hydrochloride, Serapeptase, Resoteam chloride, Ambroki Sole, theophylline, aminophyllin, etc.), vitamin components (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. ), Antioxidants (dry aluminum hydroxide gel, aluminum glycinate, magnesium aluminometasilicate, magnesium aluminometate, synthetic hydrotalcite, aluminum hydroxide gel, synthetic aluminum silicate, magnesium carbonate, magnesium oxide, kei Magnesium acid salt, sodium hydrogen carbonate, etc.) and the like.
These physiologically active ingredients may be used alone or in combination of two or more. In particular, if the tablet further contains one or more selected from the group consisting of caffeine, anhydrous caffeine and allylisopropylacetylurea, the unpleasant odor after storage can be further suppressed, and a tablet with higher storage stability can be obtained. .. In particular, it is preferable to use caffeine and anhydrous caffeine in combination with allylisopropylacetylurea in terms of obtaining an effect.

Examples of the additive include a binder, an excipient, a disintegrant, a fragrance, a lubricant, a sweetener, an acidulant and the like.
Examples of the binder include sucrose, hydroxypropyl cellulose, gelatin, gum arabic powder, polyvinylpyrrolidone, pullulan, dextrin, cyclodextrin, hypromellose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol polyethylene glycol. And so on.
Excipients include, for example, lactose, lactose granules, mannitol, corn starch, L-cysteine, methyl ethyl cellulose, xylitol, erythritol, trehalose, maltitol, lactitol, sorbitol, maltitol, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl. Examples include starch, sodium carboxymethyl starch, sodium hydrogen phosphate and the like.
Examples of the disintegrant include low-degree-of-substitution hydroxypropyl cellulose, crospovidone, carmellose, carmellose sodium, carmellose calcium, hydroxypropyl starch, croscarmellose sodium, carboxymethyl cellulose, sodium carboxymethyl cellulose and the like.
Examples of the fragrance include menthol, limonene, and vegetable essential oils (mentha oil, mint oil, lychee oil, orange oil, lemon oil, etc.).
Examples of the lubricant include magnesium stearate, sodium stearyl fumarate, sucrose fatty acid ester, light anhydrous silicic acid, talc and the like.
Examples of the sweetener include sodium saccharin, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose and the like.
Examples of the acidulant include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid and salts thereof.
These additives may be used alone or in combination of two or more. In particular, if the tablet further contains hydroxypropyl cellulose having a low degree of substitution, the unpleasant odor after storage can be further suppressed, and a tablet with higher storage stability can be obtained.

When the tablet is a laminated tablet and the component (A), the component (B), the component (C) and the component (D) are present in the same layer, the optional component may be contained only in the arbitrary layer. However, a part of the optional component may be contained in the drug layer. Further, a part of the component (C) and the component (D) may be contained in the arbitrary layer.
When the tablet is a laminated tablet and the component (A) and the component (B) are present in separate layers, the optional component may be contained in at least one of the A layer and the B layer, and the A layer and the A layer and the optional component may be contained in at least one of the A layer and the B layer. It may be contained in a layer other than the B layer.

<Moisture content>
The water content in the tablet is preferably 1 to 15% by mass, more preferably 1.5 to 13% by mass, and even more preferably 1.5 to 7% by mass with respect to the total mass of the tablet.
When the water content in the tablet is at least the above lower limit value, the tablet hardness immediately after production can be maintained satisfactorily. On the other hand, when the water content in the tablet is not more than the above upper limit value, the unpleasant odor after storage can be suppressed more effectively. In addition, the fluidity of the powder constituting the tablet is improved, the filling property of the powder into the mortar before tableting is improved, and the mass deviation of the tablet is reduced.

The method for measuring the water content is an electronic moisture meter, which can be calculated from the dry weight loss when the crushed tablet is heated at 120 ° C. for 10 minutes. As the electronic moisture meter, for example, "MOISTURE BALANCE MOC-120H" manufactured by Shimadzu Corporation can be used.
The water content in the tablet can be adjusted by adding water or drying during the manufacture of the tablet. When a hydrate such as loxoprofen sodium dihydrate is used as the component (A), the water content in the tablet includes the water content brought in by this hydrate.

<Manufacturing method>
The tablet of the present invention can be obtained, for example, by forming a drug layer by tableting and molding a powder constituting the drug layer (hereinafter, referred to as “drug-containing powder”). In the tablet thus obtained, the component (A), the component (B), the component (C) and the component (D) are present in the same tablet. Each component may be obtained by a known production method, or a commercially available product may be used. Further, as each component, the bulk powder may be used as it is, or it may be granulated.
Examples of the method for producing a tablet include those having a step (tablet step) of tableting and molding a drug-containing powder using a tableting machine having a mortar and a pestle to obtain a tablet.

The drug-containing powder may be any powder containing the component (A), the component (B), the component (C) and the component (D), and may contain any component as needed.
The drug-containing powder may be, for example, a powder mixture of the (A) component of the powder, the (B) component of the powder, the (C) component of the powder, and the (D) component of the powder. It may be a granule containing the component (A), the component (B), the component (C) and the component (D).

The drug-containing powder may be a premixed powder or a newly prepared powder. That is, the method for producing a tablet may include a step (powder preparation step) of mixing each component of the powder to prepare a drug-containing powder.

In the powder preparation step, the component (A) of the powder, the component (B) of the powder, the component (C) of the powder, and the component (D) of the powder are mixed to obtain a drug-containing powder. obtain.
The mixing method in the powder preparation step is not particularly limited, and examples thereof include conventionally known powder mixing methods.

As each component used in the powder preparation step, one obtained by a known production method may be used, or a commercially available one may be used. As each component, the bulk powder may be used as it is, or it may be granulated.
When a granulated product is used, a known granulation method can be adopted as the granulation method.

Examples of the locking machine used in the locking process include a rotary type locking machine (manufactured by Kikusui Seisakusho Co., Ltd., “Libra 3L”).
Locking conditions such as locking pressure and rotation speed of the turntable are appropriately set.
When the tablet is a laminated tablet, the drug-containing powder may be filled in the mortar first or after the components constituting the arbitrary layer.

When a laminated tablet in which the component (A) and the component (B) are present in separate layers is produced, instead of the drug-containing powder, the powder constituting the layer A (hereinafter, also referred to as "powder A"). ) And the powder constituting the B layer (hereinafter, also referred to as “powder B”) may be filled in a mortar and locked.
The powder A may be filled in the mortar first or after the powder B.

The powder A may be any powder containing the component (A), and may contain any component as needed. The powder B may be any powder containing the component (B), and may contain an arbitrary component if necessary. However, it is assumed that each of the component (C) and the component (D) is contained in at least one of the powder A and the powder B. In particular, it is preferable that the component (C) is contained in at least the powder A from the viewpoint that the effect of the present invention can be easily obtained.
The powder A may be a powder mixture with the component (A) of the powder or another component of the powder, or may be a granule containing the component (A). The powder B may be a powder mixture with the component (B) of the powder or another component of the powder, or may be a granule containing the component (B).

The obtained tablets may be coated with a coating agent, if necessary.
As the coating agent, it is preferable to select one that does not significantly impair the disintegration property, and among them, a water-soluble polymer compound or a plasticizer is preferable.
Examples of the water-soluble polymer compound include celluloses such as carmellose, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromerose), hydroxymethylcellulose, and methylcellulose; Polysaccharides of disaccharide or more (sugar (granule sugar, etc.), lactose, malt sugar, xylose, isomerized lactose, etc.), sugar alcohols (palatinit, sorbitol, lactitol, erythritol, xylitol, reduced starch saccharified product, martitol, mannitol, etc.) , Water candy, isomerized saccharides, oligosaccharides, sucrose, trehalose, reduced starch saccharified products (reduced starch decomposition products, etc.) and the like. In particular, hydroxypropylmethylcellulose (hypromellose) and polyvinyl alcohol are preferable from the viewpoint of excellent manufacturability and moisture resistance.
Examples of the plasticizer include those described in the Japanese Pharmacopoeia (Hirokawa Shoten) such as triethyl citrate, triacetin, and carnauba wax, and official documents such as the Pharmaceutical Additives Standard (Yakuji Nippo Co., Ltd.).
These coating agents may be used alone or in combination of two or more.

<Action effect>
According to the present invention, since the component (C) is used in combination in the combination of the component (A) and the component (B), the adhesion of the pestle at the time of tableting, which occurs during the production of tablets, can be suppressed. Moreover, since the component (D) is further used in these combinations, an unpleasant odor can be suppressed even when stored under high temperature and high humidity.
As described above, according to the present invention, the adhesion of the pestle at the time of tableting, which occurs when a tablet containing the component (A) and the component (B) is produced, is suppressed, and an unpleasant odor is suppressed by a simple method. Can provide tablets.

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to the following description.
The raw materials, tableting conditions and evaluation methods used in each Example and Comparative Example are as follows.
Examples 1 to 18 , 24, and 25 are reference examples.

[Raw materials used]
The following compounds were used as the component (A) or a substitute thereof (component (A')).
・ Loxoprofen sodium dihydrate: manufactured by Daiwa Yakuhin Kogyo Co., Ltd., "Loxoprofen sodium hydrate from the Japanese Pharmacopoeia"
-Ibuprofen: "Ibuprofen" manufactured by BASF

The following compounds were used as the component (B).
・ Acetaminophen: "Piretinol" manufactured by Iwaki Pharmaceutical Co., Ltd.

The following compounds were used as the component (C).
・ Iron sesquioxide: "Iron sesquioxide" manufactured by Ryomi Kasei Co., Ltd.
-Yellow iron sesquioxide: "Yellow tricarbonate" manufactured by Ami Kasei Co., Ltd.
-Titanium oxide: "Titanium oxide" manufactured by Sakai Chemical Industry Co., Ltd.
-Zinc oxide: "Zinc oxide" manufactured by Sakai Chemical Industry Co., Ltd.

The following compounds were used as the component (D) or a substitute thereof (component (D')).
-Crystalline cellulose: "CEOLUS UF-702" (registered trademark) manufactured by Asahi Kasei Chemicals Co., Ltd.
・ Corn starch: "Matsutani Corn Starch" manufactured by Matsutani Chemical Industry Co., Ltd.
-Calcium hydrogen phosphate: "Japanese Pharmacopoeia anhydrous calcium hydrogen phosphate GSH" manufactured by Kyowa Chemical Industry Co., Ltd.
-Hydroxypropyl cellulose: "NISSO HPC SSL" manufactured by Nippon Soda Co., Ltd.

The following compounds were used as optional components.
-Anhydrous caffeine: "Anhydrous caffeine 0.2 / 0.5" manufactured by Shiratori Pharmaceutical Co., Ltd.
・ Allyl isopropyl acetyl urea: "Alipronal Congo" manufactured by Kongo Chemical Co., Ltd.
-Low degree of substitution hydroxypropyl cellulose: "L-HPC LH-31" (registered trademark) manufactured by Shin-Etsu Chemical Co., Ltd.
・ Lactose granulated product: "Lactose G" manufactured by Freund Sangyo Co., Ltd.
-Magnesium stearate: "Magnesium stearate" manufactured by Taihei Kagaku Sangyo Co., Ltd.

[Locking conditions]
・ Locking machine: Rotary type locking machine (Kikusui Seisakusho Co., Ltd., "Libra 3L")
・ Board rotation speed: 15 rpm
-Usuki (Examples 1 to 23, Comparative Examples 1 to 3, Reference Example A): Diameter 9.0 mm (2-stage R) x 12 stands, no marking (cap height 0.1 mm, R1 = 3.6, R2) = 10.5)
Usuki (Examples 24 and 25): Diameter 9.5 mm (2-stage R) x 12 stands, no marking (cap height 0.1 mm, R1 = 3.8, R2 = 10)
-Preload: 2 kN (about 20 MPa, about 200 kg / cm ² )
・ Main pressure: 10 kN (about 100 MPa, about 1000 kg / cm ² )

[Evaluation methods]
<Pestle Only Test>
In each Example and Comparative Example, the adhesion of the pestle when continuously locking was visually confirmed and evaluated according to the following evaluation criteria. Two or more points were passed.
5 points: Pestle only does not occur even after continuous tableting for 2 hours.
4 points: Continuous tableting for 1 hour 30 minutes or more and less than 2 hours causes pestle only.
3 points: Continuous tableting for 1 hour or more and less than 1 hour and 30 minutes causes pestle only.
2 points: Continuous tableting for 30 minutes or more and less than 1 hour causes pestle only.
1 point: Pestle only occurs when the tablet is pressed for less than 30 minutes.

<Smell evaluation: Quantitative evaluation>
The obtained tablets were placed in a glass bottle (4K standard bottle) and stored in a sealed state under 50 ° C. and 75% RH conditions for 6 weeks.
For tablets before and after storage, the odor intensity was measured using an odor sensor (“Fragance Sensor SF-105” manufactured by Mutual Yakuko Co., Ltd.), and the odor intensity after storage was determined from the odor intensity before storage. Was subtracted to determine the amount of change in odor intensity before and after storage, which was evaluated according to the following evaluation criteria. Pass 5 points or more.
7: The amount of change is less than 41 Hz.
6: The amount of change is 41 Hz or more and less than 55 Hz.
5: The amount of change is 55 Hz or more and less than 70 Hz.
4: The amount of change is 70 Hz or more and less than 85 Hz.
3: The amount of change is 85 Hz or more and less than 100 Hz.
2: The amount of change is 100 Hz or more and less than 115 Hz.
1: The amount of change is 115 Hz or more.

<Smell evaluation: Sensory evaluation>
The tablets were stored in the same manner as in the quantitative evaluation.
The tablets after storage were subjected to sensory evaluation by 5 adult males, evaluated according to the following evaluation criteria, and the average value of the 5 adults was calculated. Pass 4 points or more.
6: I don't feel the smell.
5: I hardly feel the smell.
4: A slight odor is felt, but there is no problem in taking it.
3: A slightly unpleasant odor is felt.
2: I feel an unpleasant odor.
1: The odor has changed to an extremely unpleasant odor, and it is difficult to take it.

[Examples 1 to 23]
The component (A), the component (B), the component (C), the component (D), and the optional component are added to the mixing container so that the composition per tablet has the composition shown in Tables 1 to 3. After mixing, tableting was performed under the above-mentioned tableting conditions to obtain a tablet (single-layer tablet) composed of a drug layer.
The adhesion of the pestle at the time of tableting was evaluated, and the odor of the obtained tablets was evaluated. The results are shown in Tables 1 to 3.

[Comparative Examples 1 to 3]
The component (A), the component (B), the component (C), the component (D) or the component (D') are added to the mixing container so that the composition per tablet has the composition shown in Table 4. After mixing, the tablet was compacted under the above-mentioned tableting conditions to obtain a tablet (single-layer tablet) composed of a drug layer.
The adhesion of the pestle at the time of tableting was evaluated, and the odor of the obtained tablets was evaluated. The results are shown in Table 4.

[Reference Example A]
The component (A'), the component (B), and the component (C) are put into a mixing container and mixed so that the composition per tablet has the composition shown in Table 4, and then the tableting conditions are met. The tablet was molded into a tablet to obtain a tablet (single-layer tablet) composed of a drug layer.
The adhesion of the pestle at the time of tableting was evaluated, and the odor of the obtained tablets was evaluated. The results are shown in Table 4.

[Examples 24 and 25]
The component (A), the component (B), the component (C), the component (D), and the optional component were added and mixed in a mixing container so that the composition per tablet had the composition shown in Table 5. Then, it was tablet-molded under the above-mentioned tableting conditions to obtain a tablet (single-layer tablet) composed of a drug layer.
The adhesion of the pestle at the time of tableting was evaluated, and the odor of the obtained tablets was evaluated. The results are shown in Table 5.

In the table, "10000 x C / tablet ratio" is a mass ratio represented by 10000 x (C) component / tablet. The "B / A ratio" is a mass ratio represented by the component (B) / component (A). The "B / A'ratio" is a mass ratio represented by the component (B) / component (A'). The “10000 × C / (A + B) ratio” is a mass ratio represented by 10000 × (C) component / ((A) component + (B) component). The "10000 x C / (A'+ B) ratio" is a mass ratio represented by 10000 x (C) component / ((A') component + (B) component). The "D / (A + B) ratio" is a mass ratio represented by (D) component / ((A) component + (B) component). The "D'/ (A + B) ratio" is a mass ratio represented by the (D') component / ((A) component + (B) component). The "D / (A'+ B) ratio" is a mass ratio represented by (D) component / ((A') component + (B) component). "(A) + (B)" is the ratio of the total content of the component (A) and the component (B) in the tablet. "(A') + (B)" is the ratio of the total content of the component (A') and the component (B) in the tablet. "(A) + (B) + (C) + (D)" is the ratio of the total content of the component (A), the component (B), the component (C) and the component (D) in the tablet. "(A') + (B) + (C) + (D)" is the ratio of the total content of the (A') component, (B) component, (C) component and (D) component in the tablet. be. "(A) + (B) + (C) + (D')" is the ratio of the total content of the (A) component, (B) component, (C) component and (D') component in the tablet. be.

From the results of Tables 1 to 3 and 5, in each example, the pestle only did not occur in less than 1 hour and 30 minutes from the start of tableting. Above all, when iron sesquioxide or yellow iron sesquioxide was used as the component (C), pestle only did not occur even after tableting for 2 hours from the start of tableting.
In addition, the tablets obtained in each example had an unpleasant odor after storage suppressed.

On the other hand, from the results in Table 4, in the case of Comparative Example 1 in which the component (C) was not used, no unpleasant odor was felt after storage, but continuous tableting for 30 minutes or more and less than 1 hour from the start of tableting was performed. Pestle adhesion occurred.
The tablet of Comparative Example 2 containing no component (D) and the tablet of Comparative Example 3 containing hydroxypropyl cellulose instead of the component (D) had an unpleasant odor when stored.
In the case of the combination of ibuprofen as the component (A'), the component (B) and the component (C), no unpleasant odor after storage was felt even if the component (D) was not blended (reference example). A).
As is clear from these results, the unpleasant odor after storage is generated when the component (C) is added in the combination of the component (A) and the component (B).
As described above, according to the present invention, the unpleasant odor of the tablet after storage could be suppressed by a simple method of adding the component (D) to the component (A), the component (B) and the component (C). ..

Claims (5)

It contains the following components (A), (B), (C) and (D),
The content of the following component (B) is 48.27 to 85% by mass and the content of the following component (D) is 8.14 % by mass or more with respect to the total mass of the tablet .
A tablet having a mass ratio of component (B) / component (A) of 4 to 15 .
(A) Component: One or more selected from the group consisting of loxoprofen and its salt (B) Component: Acetaminophen (C) Component: Colorant (D) Component: Group consisting of crystalline cellulose, starch and calcium hydrogen phosphate One or more selected from The tablet according to claim 1, wherein the component (C) is at least one selected from the group consisting of iron sesquioxide, yellow iron sesquioxide, titanium oxide and zinc oxide. The tablet according to claim 1 or 2, wherein the mass ratio represented by 10000 × (C) component / ((A) component + (B) component) is 0.11 to 20. The tablet according to any one of claims 1 to 3, wherein the mass ratio represented by (D) component / ((A) component + (B) component) is 0.12 to 0.48. It has a step of tableting and molding a drug-containing powder containing the following components (A), (B), (C) and (D) to obtain a tablet.
The content of the following component (B) is 48.27 to 85% by mass and the content of the following component (D) is 8.14 % by mass or more with respect to the total mass of the tablet .
A method for producing a tablet, wherein the mass ratio represented by the component (B) / the component (A) is 4 to 15 .
(A) Component: One or more selected from the group consisting of loxoprofen and its salt (B) Component: Acetaminophen (C) Component: Colorant (D) Component: Group consisting of crystalline cellulose, starch and calcium hydrogen phosphate One or more selected from