JP6846311B2 - Solid preparation, tablet manufacturing method and coated tablet manufacturing method - Google Patents

Description

The present invention relates to a method for producing a solid preparation, a tablet, and a method for producing a coated tablet.

Among 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.

However, when loxoprofen (salt) and acetaminophen are used in combination, loxoprofen (salt) and acetaminophen are discolored due to the interaction between the two during storage of solid preparations such as compositions and tablets containing them. There was a problem.

As a technique for suppressing the interaction between loxoprofen (salt) and acetaminophen, for example, Patent Document 1 discloses a method in which a xanthine derivative coexists in a combination of loxoprofen (salt) and acetaminophen.
Patent Document 2 discloses a method of packaging and storing a solid preparation containing loxoprofen (salt) and acetaminophen in an airtightly preservable package.

International Publication No. 2012/157752 Japanese Unexamined Patent Publication No. 2015-227347

However, the methods described in Patent Documents 1 and 2 have not always had a sufficient effect of suppressing discoloration. In addition, in the method described in Patent Document 2, the container (packaging body) for storing the solid preparation is limited.

An object of the present invention is to provide a solid preparation containing loxoprofen (salt) and acetaminophen, which is resistant to discoloration, a method for producing a tablet, and a method for producing a coated tablet.

As a result of diligent studies, the present inventors have found that a solid preparation that is resistant to discoloration can be obtained by further using a specific additive in the combination of loxoprofen (salt) and acetaminophen, and complete the present invention. It came to.

That is, the present invention has the following aspects.
[1] A solid preparation containing the following components (A), (B) and (C).
(A) Ingredient: One or more selected from the group consisting of loxoprofen and salts thereof (B) Ingredient: Acetaminophen (C) Ingredient: Group consisting of ethyl cellulose, methyl cellulose, pregelatinized starch, partially pregelatinized starch and hydroxypropyl starch One or more selected from [2] The solid preparation according to [1], wherein the content of the component (A) is 3 to 85% by mass with respect to the total mass of the solid preparation.
[3] The solid preparation according to [1] or [2], wherein the content of the component (B) is 3 to 85% by mass with respect to the total mass of the solid preparation.
[4] The solid preparation according to any one of [1] to [3], wherein the content of the component (C) is 1 to 85% by mass with respect to the total mass of the solid preparation.
[5] The solid according to any one of [1] to [4], wherein the mass ratio represented by (C) component / ((A) component + (B) component) is 0.01 to 8. Formulation.
[6] The solid preparation according to any one of [1] to [5], wherein the mass ratio represented by the component (B) / component (A) is 0.25 to 15.
[7] The solid preparation according to any one of [1] to [6], which is a tablet.
[8] The solid preparation according to any one of [1] to [7], which has a coating layer on the surface.
[9] A method for producing a tablet, which comprises a step of tableting and molding a drug-containing powder containing the following components (A), (B) and (C) to obtain a tablet.
(A) Ingredient: One or more selected from the group consisting of loxoprofen and salts thereof (B) Ingredient: Acetaminophen (C) Ingredient: Group consisting of ethyl cellulose, methyl cellulose, pregelatinized starch, partially pregelatinized starch and hydroxypropyl starch One or more selected from [10] Powder A containing the following component (A) and powder B containing the following component (B) (however, at least one of powder A and powder B has the following (C). A method for producing a tablet, which comprises a step of filling a mortar with (containing an ingredient) and tableting to obtain a tablet.
(A) Ingredient: One or more selected from the group consisting of loxoprofen and salts thereof (B) Ingredient: Acetaminophen (C) Ingredient: Group consisting of ethyl cellulose, methyl cellulose, pregelatinized starch, partially pregelatinized starch and hydroxypropyl starch One or more selected from the above [11] A tablet is produced by the method for producing a tablet according to [9] or [10], the obtained tablet is used as an uncoated tablet, and a coating layer is provided on the surface of the uncoated tablet. How to make tablets.

According to the present invention, it is possible to provide a solid preparation containing loxoprofen (salt) and acetaminophen, which is resistant to discoloration, a method for producing a tablet, and a method for producing a coated tablet.

The solid preparation of the present invention contains the following components (A), (B) and (C).
Examples of the dosage form of the solid preparation of the present invention include granules (powder, granules, enteric granules, etc.), tablets (bare tablets, sugar-coated tablets, coated tablets, enteric-coated tablets, orally disintegrating tablets, chewable tablets, etc.). Foaming tablets, etc.), capsules, pills, troches, etc. Among these, tablets are preferable from the viewpoint that the effect of the present invention (suppression of discoloration) can be more easily enjoyed.

When the solid preparation of the present invention is a tablet, 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 7 to 12 mmφ from the viewpoint of ease of handling and swallowability of the tablet. More preferred. 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.

When the solid preparation of the present invention is a tablet, the tablet may have a single-layer structure (single-layer tablet) or a laminated structure (laminated tablet). From the viewpoint that the effects of the present invention can be more easily enjoyed, it has a layer having both the components (A), (B) and (C) shown below (that is, the components (A), (B) and (C). ) The components are present in the same layer). Hereinafter, the layer having both the component (A), the component (B) and the component (C) is also referred to as a “drug layer”. When the solid preparation is a single layer tablet, the solid preparation is composed of a drug layer. When the solid preparation is a laminated tablet, the solid preparation is composed of a drug layer and a layer other than the drug layer (arbitrary layer).
When the solid preparation of the present invention 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, the component (C) is contained in at least one layer. It may be contained. 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 component (C) is contained in at least one of the A layer and the B layer. By doing so, the effect of the present invention can be sufficiently obtained.

<Ingredient (A)>
The component (A) is at least one 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 raw 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 solid preparation.
When the solid preparation is a laminated tablet and the component (A), the component (B) and the component (C) are present in the same layer, the content of the component (A) is 3 to 3 based on the total mass of the drug layer. 90% by mass is preferable, and 5 to 55% by mass is more preferable.
When the solid preparation 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. Is preferable, and 10 to 65% by mass is more preferable.
As the content of the component (A) increases, the discoloration of the solid preparation due to the interaction with the component (B) becomes more remarkable, so that the effect of the present invention due to the addition of the component (C) is likely to be exhibited. 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, adhesion to the manufacturing machine in the manufacturing process can be suppressed.
When the solid preparation 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 solid preparation.

The single dose of the component (A) is preferably 11 to 170 mg, more preferably 22 to 113 mg. If the dose of the component (A) per dose is at least the above lower limit value, the antipyretic analgesic effect can be sufficiently obtained, and if it is at least the above upper limit value, adhesion to the manufacturing machine in the manufacturing process can be 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 solid preparation.
When the solid preparation is a laminated tablet and the component (A), the component (B) and the component (C) are present in the same layer, the content of the component (B) is 5 to 5 with respect to the total mass of the drug layer. 90% by mass is preferable, and 20 to 85% by mass is more preferable.
When the solid preparation 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. Is preferable, and 20 to 85% by mass is more preferable.
As the content of the component (B) increases, the discoloration of the solid preparation due to the interaction with the component (A) becomes more remarkable, so that the effect of the present invention due to the addition of the component (C) is likely to be exhibited. 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 solid preparation is a tablet.
When the solid preparation 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 solid preparation.

The blending ratio of the component (A) and the component (B) in the solid preparation can be arbitrarily set, but in order to make it easier to obtain the effect of the present invention, it is represented by the component (B) / component (A). The mass 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, discoloration after storage can be suppressed more effectively, and adhesion to the manufacturing machine in the manufacturing process can be suppressed. On the other hand, if the B / A ratio is not more than the above upper limit value, the tablet hardness can be maintained satisfactorily when the solid preparation is a tablet.

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

<Ingredient (C)>
The component (C) is at least one selected from the group consisting of ethyl cellulose, methyl cellulose, pregelatinized starch, partially pregelatinized starch and hydroxypropyl starch.
As the component (C), ethyl cellulose, methyl cellulose, pregelatinized starch, and partially pregelatinized starch are preferable from the viewpoint that the effect of suppressing discoloration can be more easily obtained.
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 1 to 85% by mass, more preferably 2 to 80% by mass, still more preferably 4 to 60% by mass, based on the total mass of the solid preparation.
When the solid preparation is a laminated tablet and the component (A), the component (B) and the component (C) are present in the same layer, the content of the component (C) is 1 to 1 with respect to the total mass of the drug layer. 90% by mass is preferable, 2 to 80% by mass is more preferable, and 4 to 60% by mass is further preferable.
When the solid preparation 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 with respect to the total mass of the layer A. ~ 90% by mass is preferable, 2 to 80% by mass is more preferable, and 4 to 60% by mass is further preferable. The content of the component (C) in the B layer is preferably 0 to 90% by mass, more preferably 2 to 80% by mass, still more preferably 4 to 60% 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 are preferably 1 to 90% by mass, more preferably 2 to 80% by mass. %, More preferably 4 to 60% by mass.
When the content of the component (C) is at least the above lower limit value, discoloration of the solid preparation can be suppressed more effectively, and when it is at least the above upper limit value, the dose per dose can be suppressed.
When the solid preparation 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 solid preparation.

The total content of the component (A), the component (B) and the component (C) in the solid preparation is preferably 7 to 99.5% by mass, preferably 20 to 99.5% by mass, based on the total mass of the solid preparation. Is more preferable, and 40 to 99.5% by mass is further preferable.
Further, when the solid preparation is a laminated tablet and the component (A), the component (B) and the component (C) are present in the same layer, the contents of the component (A), the component (B) and the component (C) are contained. The total is preferably 7 to 99.5% by mass, more preferably 20 to 99.5% by mass, still more preferably 40 to 99.5% by mass, based on the total mass of the drug layer.
If the total content of the component (A), the component (B) and the component (C) is at least the above lower limit, a sufficient antipyretic analgesic effect can be obtained while suppressing discoloration of the solid preparation, and below the above upper limit. If there is, it can be a solid preparation having excellent ingestibility.

The total of the components (A) and (B) in the solid preparation and the blending ratio of the component (C) can be arbitrarily set, but in order to make the effect of the present invention more easily obtained, the component (C) / The mass ratio represented by (component (A) + component (B)) (hereinafter, also referred to as “C / (A + B) ratio”) is preferably 0.01 to 8. When the C / (A + B) ratio is at least the above lower limit value, discoloration of the solid preparation can be suppressed more effectively, and when it is at least the above upper limit value, a solid preparation having excellent ingestibility can be obtained.

The single dose of the component (C) is preferably 5 to 500 mg, more preferably 10 to 300 mg, still more preferably 20 to 200 mg. If the dose of the component (C) per dose is at least the above lower limit, discoloration due to the interaction between the component (A) and the component (B) can be more effectively suppressed, and if it is at least the above upper limit. The dose per dose can be reduced.
The total dose of the component (A), the component (B) and the component (C) is preferably 46 to 1170 mg, more preferably 82 to 713 mg, and even more preferably 180 to 470 mg. If the total dose of the components (A), (B) and (C) is at least the above lower limit, the antipyretic analgesic effect can be sufficiently obtained while suppressing discoloration, and below the above upper limit. If so, it can be a solid preparation having excellent ingestibility.

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

Examples of the physiologically active component include antipyretic analgesic components (pyroxicam, meloxicam, ampiroxicam, serocoxib, rofecoxib, thialamide, ethenzamide, sulpyrine, etc.) other than the components (A) and (B).
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, bromvalerylurea, etc.), antihistamine components (isotipendyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, diferrol hydrochloride, triprolysine hydrochloride, tryperenamine hydrochloride, etc. Tonsylamine hydrochloride, phenetazine hydrochloride, metodylazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonic acid, arimemazine tartrate, diphenhydramine tannate, diphenylpyraline theocrate, mebuhydroline napadisylate, mebuhydroline napadisylate, 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, Tipepidin 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, magnesium aluminometasilicate, magnesium aluminomerate, synthetic hydrotalcite, magnesium carbonate, magnesium oxide, magnesium silicate, sodium hydrogencarbonate, etc.) and the like.
One of these physiologically active ingredients may be used alone, or two or more thereof may be used in combination.

Examples of the additive include a binder, an excipient, a disintegrant, a fragrance, a lubricant, a sweetener, an acidulant, a colorant and the like.
Examples of the binder include starch, sucrose, gelatin, gum arabic powder, polyvinylpyrrolidone, pullulan, dextrin, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose and the like.
Examples of excipients include crystalline cellulose, lactose, lactose granules, cornstarch, powdered sugar, mannitol, L-cysteine and the like.
Examples of the disintegrant include crospovidone, croscarmellose sodium, carboxymethyl cellulose, sodium carboxymethyl cellulose and the like.
Examples of the fragrance include menthol, limonene, and vegetable essential oils (mint oil, mint oil, lychee oil, orange oil, lemon oil, etc.).
Examples of the lubricant include magnesium stearate, stearyl sodium fumarate, sucrose fatty acid ester, and light anhydrous silicic acid.
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.
Examples of the colorant include edible colorants, organic pigments and inorganic pigments other than edible colorants, animal and plant extracts, and the like. 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 sodium copper chlorophyll, copper chlorophyll, riboflavin and the like. Examples of the inorganic pigment include iron sesquioxide, yellow iron sesquioxide, black iron oxide, zinc oxide, titanium oxide, black iron oxide, brown iron oxide, zinc oxide, gold foil, and medicated charcoal. Examples of animal and plant extracts include licorice extract, cinnamon yak tannin powder, turmeric extract, green tea powder and the like. Among these, inorganic pigments are preferable because the solid preparation does not easily fade even after storage, the masking effect of discoloration is high, and the adhesion to the manufacturing machine can be reduced, and iron sesquioxide, yellow iron sesquioxide, and iron black oxide are preferable. Inorganic pigments containing iron as a main component, such as zinc oxide and titanium oxide, are preferable, iron sesquioxide, yellow iron sesquioxide, zinc oxide and titanium oxide are more preferable, and iron sesquioxide and yellow iron sesquioxide are even more preferable.
These additives may be used alone or in combination of two or more.

When the solid preparation is a laminated tablet and the component (A), the component (B) and the component (C) are present in the same layer, the optional component may be contained only in the arbitrary layer or the optional component. A part of the drug layer may be contained in the drug layer. Further, a part of the component (C) may be contained in an arbitrary layer.
When the solid preparation 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, or the A layer. And may be contained in a layer other than the B layer.

<Moisture content>
The water content in the solid preparation 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 solid preparation.
When the water content is within the above range, unpleasant odor and discoloration after storage can be suppressed more effectively.

The method for measuring the amount of water is an electronic moisture meter, which can be calculated from the weight loss by drying when the solid preparation 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 amount of water in the solid preparation can be adjusted by adding water or drying during the production of the solid preparation. When a hydrate such as loxoprofen sodium dihydrate is used as the component (A), the amount of water in the solid preparation includes the amount of water brought in by this hydrate.

<Coating layer>
The solid preparation of the present invention may have a coating layer on the surface. In particular, when the solid preparation is a tablet, the tablet having a coating layer on the surface is also referred to as "coated tablet". In a coated tablet, the portion excluding the coating layer is also referred to as a "bare tablet".
The coating layer is a layer formed of a constituent material containing a coating agent. As such a 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 methyl cellulose, hydroxypropyl methyl cellulose (hypromerose), carmellose, hydroxypropyl cellulose, and hydroxymethyl cellulose; gum arabic, carboxyvinyl polymer, povidone, polyvinyl alcohol, polyacrylic acid, monosaccharide, and the like. Polysaccharides of disaccharide or higher (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 sugar, oligosaccharide, sucrose, trehalose, reduced starch saccharified product (reduced starch decomposition product, etc.) and the like. In particular, hydroxypropyl methylcellulose (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.

Further, the coating layer preferably contains a colorant from the viewpoint of manufacturability and moisture resistance. As the colorant, an inorganic pigment is preferable because it does not easily fade even after storage and can suppress the delay in disintegration over time. Among them, iron-based inorganic pigments such as iron sesquioxide, yellow sesquioxide, and black iron oxide, zinc oxide, and titanium oxide are preferable, and iron sesquioxide, yellow iron sesquioxide, zinc oxide, and titanium oxide are preferable. More preferred, iron sesquioxide, yellow iron sesquioxide, and titanium oxide are even more preferred.

When the solid preparation has a coating layer on the surface, the contents and water content of each of the above-mentioned components (A), (B) and (C) are the total mass of the solid preparation excluding the coating layer. It shall be the content with respect to. For example, when the solid preparation is a coated tablet, the contents and water content of each of the above-mentioned components (A), (B) and (C) are taken as the contents with respect to the total mass of the uncoated tablet.

<Manufacturing method>
The solid preparation of the present invention can be obtained, for example, by mixing the components (A), (B) and (C) with any component, if necessary.
Each component may be obtained by a known production method, or a commercially available product may be used.
Further, as each component, the raw powder may be used as it is, or may be granulated.

When the solid preparation is a tablet, it can be obtained, for example, by forming a drug layer by tableting the powder constituting the drug layer (hereinafter, referred to as “drug-containing powder”). In the tablet thus obtained, the component (A), the component (B) and the component (C) are present in the same tablet.
Examples of the method for producing a tablet include those having a step (tablet step) of obtaining a tablet by tableting and molding a drug-containing powder using a tableting machine having a mortar and a pestle.

The drug-containing powder may be any powder containing the component (A), the component (B) and the component (C), and may contain an arbitrary component if necessary.
The drug-containing powder may be, for example, a powder mixture of the (A) component of the powder, the (B) component of the powder, and the (C) component of the powder, or the (A) component and the (B) component. It may be a granule containing the component (C) and (C).

The drug-containing powder may be a premixed powder or a newly prepared powder. That is, the tablet manufacturing method 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, and the component (C) of the powder are mixed to obtain a drug-containing powder.
The mixing method in the powder preparation step is not particularly limited, and examples thereof include conventionally known powder mixing methods.

Each component used in the powder preparation step may be obtained by a known production method, or a commercially available one may be used. As each component, the raw 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.

In the case of producing a laminated lock in which the component (A) and the component (B) are present in separate layers, the powder constituting the layer A (hereinafter, also referred to as "powder A") is used instead of the drug-containing powder. ) 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 an arbitrary component if necessary. The powder B may be any powder containing the component (B), and may contain an arbitrary component if necessary. However, it is assumed that at least one of powder A and powder B contains the component (C).
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).

(Manufacturing method of coated lock)
The coated tablet can be produced by producing a tablet by the above-mentioned production method, using the obtained tablet as an uncoated tablet, and providing the above-mentioned coating layer on the surface of the uncoated tablet. As a method for preparing the coating agent and a method for providing the coating layer containing the coating agent on the surface of the uncoated tablet, conventionally known methods can be used. For example, first, a colorant is added to a dispersion of the coating agent in which the coating agent is dispersed in a solvent such as water, if necessary, to obtain a coating liquid. After that, the coating liquid is provided so as to cover the uncoated tablet by spraying or the like. Then, the component of the solvent of the coating liquid is dried to obtain a coated tablet.

<Effect>
According to the present invention, since the component (C) is further used in the combination of the component (A) and the component (B), discoloration of the solid preparation due to the interaction between the component (A) and the component (B) can be suppressed. .. Therefore, the solid preparation of the present invention is not easily discolored.
Further, since discoloration of the solid preparation of the present invention is suppressed by the action of the component (C), the container for storing the solid preparation is not limited.

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, storage conditions and evaluation methods used in each Example and Comparative Example are as follows.

[Ingredients used]
The following compounds were used as the component (A).
・ Loxoprofen sodium dihydrate: manufactured by Daiwa Yakuhin Kogyo Co., Ltd., "Loxoprofen sodium hydrate from the Japanese Pharmacopoeia"

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) or a substitute thereof (component (C')).
-Ethyl cellulose: "ETHOCEL STD" (registered trademark) manufactured by Dow Chemical Japan Co., Ltd.
-Methyl cellulose: "Metro's SM-4000" (registered trademark) manufactured by Shin-Etsu Chemical Co., Ltd.
-Pregelatinized starch: "SWELSTAR WB-1" (registered trademark) manufactured by Asahi Kasei Chemicals Co., Ltd.
-Partially pregelatinized starch: "PCS PC-10" (registered trademark) manufactured by Asahi Kasei Chemicals Co., Ltd.
-Hydroxypropyl starch: "HPS-101" manufactured by Freund Sangyo Co., Ltd.
・ Corn starch: "Matsutani Corn Starch" manufactured by Matsutani Chemical Industry Co., Ltd.
-Sodium carboxymethyl starch: "PRIMOJEL" (registered trademark) manufactured by DFE Pharma.

The following compounds were used as optional components.
-Magnesium stearate: "Magnesium stearate" manufactured by Taihei Kagaku Sangyo Co., Ltd.
-Crystalline cellulose: "CEOLUS UF-702" (registered trademark) manufactured by Asahi Kasei Chemicals Co., Ltd.

The following compounds were used as the material for forming the coating layer.
-Coating agent: "Opadry (using hydroxypropyl methylcellulose as a polymer)" (trademark) manufactured by Nippon Caracon LLC
・ Iron sesquioxide: "Iron sesquioxide" manufactured by Ami Kasei Co., Ltd.

[Locking conditions]
-Locking machine: Rotary type locking machine (Kikusui Seisakusho Co., Ltd., "Libra 3L")
・ Board rotation speed: 20 rpm
-Usuki (Examples 1 to 9, 11 to 26): Diameter 8.5 mm (2-stage R) x 12 stands, no engraving (cap height 0.1 mm, R1 = 3.4, R2 = 10)
-Usuki (Example 10) Diameter 9.5 mm (2-stage R) x 12 stands, no engraving (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 )

[Preservation conditions]
The powder mixture was placed in a glass bottle (4K standard bottle) and stored under 50 ° C. and 75% RH conditions with a lid on it.
Tablets or coated tablets are placed in the pocket of a preformed resin sheet (manufactured by Taisei Kako Co., Ltd., "TAS-230", polypropylene-cyclic polyolefin-polypropylene laminate) and wrapped in PTP (press-through package) with aluminum foil. , Stored under 50 ° C. and 75% RH conditions.

[Evaluation methods]
<Discoloration evaluation>
For the powder mixture, tablets or coated tablets before storage and 4 weeks after the start of storage ^{, measure the b * value using a color difference meter (manufactured by Konica Minolta Co., Ltd.), and measure the b *} value after storage from the b * value before storage. by subtracting the b ^* values, obtains a difference between b ^* values before and after storage ([Delta] b ^*), was evaluated by the following evaluation criteria. Pass 4 points or more.
7: Δb ^* is less than 5.00.
6: Δb ^* is 5.00 or more and less than 6.50.
5: Δb ^* is 6.50 or more and less than 8.00.
4: Δb ^* is 8.00 or more and less than 9.50.
3: Δb ^* is 9.50 or more and less than 11.00.
2: Δb ^* is 11.00 or more and less than 15.00.
1: Δb ^* is 15.00 or more.

[Examples 1 to 26]
The component (A), the component (B), and the component (C) were put into a mixing container and mixed so as to have the composition shown in Tables 1 to 3, to obtain a powder mixture.
The powder mixture obtained in Examples 1 to 20 was evaluated for discoloration. The results are shown in Tables 1 and 2.

Separately, after the components (A), (B), (C) and arbitrary components are added and mixed in a mixing container so that the composition per tablet has the compounding composition shown in Tables 1 to 3. , Tablet molding was performed under the above-mentioned tableting conditions to obtain a tablet (single layer tablet) composed of a drug layer. However, a usuki having a diameter of 8.5 mm was used for Examples 1 to 9 and 11 to 26, and a usuki having a diameter of 9.5 mm was used for Example 10.
The tablets obtained in Examples 1 to 20 were evaluated for discoloration. The results are shown in Tables 1 and 2.

In Examples 21 to 26, the obtained tablets were used as uncoated tablets, and a coating layer was provided on the surface of the uncoated tablets as follows.
That is, a dispersion liquid in which the coating agent was dispersed in water so that the concentration was 20% by mass was used as the coating liquid. Using Aquacoater 48 type (manufactured by Freund Sangyo Co., Ltd.), the amount of coating agent per tablet under the conditions of ^{air supply temperature 60 ° C, air supply air volume 2.3 m 3 / min, and exhaust temperature 42 ± 2 ° C.} The coating liquid was sprayed onto the uncoated tablets so that the (coating amount) had the values shown in Table 3. Then, it was dried at a supply air temperature of 60 ° C. and a supply air volume of 2.3 m ³ / min for 20 minutes to obtain a coated lock having a coating layer on the surface of the uncoated lock.
In Examples 24 to 26, a coating liquid further containing iron sesquioxide was used as the colorant so that the amount of the colorant (coating amount) per tablet would be the value shown in Table 3.
The coated tablets obtained in Examples 21 to 26 were evaluated for discoloration. The results are shown in Table 3.

[Comparative Examples 1 to 3]
The component (A), the component (B), and the component (C') were put into a mixing container and mixed so as to have the composition shown in Table 4 to obtain a powder mixture.
The obtained powder mixture was evaluated for discoloration. The results are shown in Table 4.

[Reference example A]
The component (A) was evaluated for discoloration in the same manner as the powder mixture. The results are shown in Table 4.

[Reference example B]
The component (B) was evaluated for discoloration in the same manner as the powder mixture. The results are shown in Table 4.

In the table, "B / A ratio" is a mass ratio represented by the component (B) / component (A). The "C / (A + B) ratio" is a mass ratio represented by (C) component / ((A) component + (B) component). The "C'/ (A + B) ratio" is a mass ratio represented by the (C') component / ((A) component + (B) component). "(A) + (B) + (C)" is the ratio of the total content of the component (A), the component (B) and the component (C) in the tablet (uncoated tablet).

From the results shown in Tables 1 to 3, the powder mixture obtained in each example and the tablet or coated tablet were hardly discolored even when stored.
On the other hand, from the results in Table 4, the powder mixture obtained in each Comparative Example was easily discolored.
Further, in the case of the component (A) alone and the component (B) alone, it was difficult to discolor even if stored (Reference Examples A and B). As is clear from these results, discoloration after storage occurs when the component (A) and the component (B) are combined.
As described above, according to the present invention, discoloration of the solid preparation could be suppressed by a simple method of adding the component (C) to the component (A) and the component (B).

Claims (7)

A solid preparation containing the following components (A), (B) and (C).
(A) Ingredient: One or more selected from the group consisting of loxoprofen and salts thereof (B) Ingredient: Acetaminophen (C) Ingredient: Group consisting of ethyl cellulose, methyl cellulose, pregelatinized starch, partially pregelatinized starch and hydroxypropyl starch One or more selected from The solid preparation according to claim 1, wherein the content of the component (C) is 1 to 85% by mass with respect to the total mass of the solid preparation. The solid preparation according to claim 1 or 2, wherein the mass ratio represented by (C) component / ((A) component + (B) component) is 0.01 to 8. The solid preparation according to any one of claims 1 to 3, which is a tablet. The solid preparation according to any one of claims 1 to 4, which has a coating layer on the surface. A method for producing a tablet, which comprises a step of tableting and molding a drug-containing powder containing the following components (A), (B) and (C) to obtain a tablet.
(A) Ingredient: One or more selected from the group consisting of loxoprofen and salts thereof (B) Ingredient: Acetaminophen (C) Ingredient: Group consisting of ethyl cellulose, methyl cellulose, pregelatinized starch, partially pregelatinized starch and hydroxypropyl starch One or more selected from A method for producing a coated tablet, wherein the tablet is produced by the method for producing a tablet according to claim 6, the obtained tablet is used as an uncoated tablet, and a coating layer is provided on the surface of the uncoated tablet.