JP2018030841A - Solid preparation, method for producing tablet and method for producing coated tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a solid preparation which suppress an unpleasant odor by a simple method, a method for producing a tablet and a method for producing a coated tablet in a solid preparation comprising loxoprofen (salt) and acetaminophen.SOLUTION: There is provided a solid preparation which comprises the following components (A), (B) and (C). There is provided a method for producing a tablet which comprises a step of tableting molding a drug-containing powder comprising the following components (A), (B) and (C) to obtain the tablet. There is provided a method for producing a coated tablet which comprises a step of producing the tablet by the method of producing the tablet, using the resulting tablet as an uncoated tablet and providing a coating layer on a surface of the tablet. (A) component: one or more selected from the group consisting of loxoprofen and its salt, (B) component: acetaminophen, and (C) component: at least one of low-substituted hydroxypropyl cellulose and crospovidone.SELECTED DRAWING: None

Description

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

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. It is widely used as a component of antipyretic analgesics because of its small amount. Over-the-counter drugs such as antipyretic analgesics and cold medicines are formulated with multiple active ingredients with the expectation of a wide range of pharmacological effects on various symptoms. Loxoprofen (salt) can be used in combination with various drugs. It is being considered.
For example, Patent Document 1 discloses an oral administration containing one or more drugs selected from caffeine, allylisopropylacetylurea, bromvalerylurea, acetaminophens and etenzaamide, and loxoprofen sodium dihydrate. A pharmaceutical composition for administration is disclosed.

Japanese Patent Laid-Open No. 11-139971

  However, when acetaminophen is combined with loxoprofen (salt), an unpleasant odor may be felt when taking it after storing a solid preparation such as a composition or a tablet containing them.

As a technique for suppressing unpleasant odor, a method of coating a solid preparation with a coating agent is generally used.
However, in the case of a method of coating a solid preparation using a coating agent, abrasion may occur during coating. If a tablet with high hardness is used in order to suppress abrasion, dissolution may be reduced. Furthermore, since the number of manufacturing processes increases, the manufacturing cost is high.
In the over-the-counter drug, the ingestion is an important factor, and a technique for suppressing an unpleasant odor that may be a factor that obstructs the administration by a simpler method is required.

  An object of the present invention is to provide a solid preparation containing loxoprofen (salt) and acetaminophen in which an unpleasant odor is suppressed by a simple method, a method for producing a tablet, and a method for producing a coated tablet. And

  As a result of intensive studies, the present inventors have further suppressed the unpleasant odor after storage by further using at least one of low-substituted hydroxypropylcellulose and crospovidone in the combination of loxoprofen (salt) and acetaminophen. The present inventors have found that a solid preparation can be obtained, and have completed the present invention.

That is, this invention has the following aspects.
[1] A solid preparation containing the following component (A), component (B) and component (C).
(A) Component: one or more selected from the group consisting of loxoprofen and salts thereof (B) Component: acetaminophen (C) Component: at least one of low-substituted hydroxypropylcellulose and crospovidone [2] above (A) The solid preparation according to [1], wherein the content of the component is 3 to 85 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 0.5 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 (B) component / (A) component is 0.25 to 15.
[7] The solid preparation according to any one of [1] to [6], further containing at least one of caffeine and anhydrous caffeine and allyl isopropyl acetyl urea.
[8] The solid preparation according to any one of [1] to [7], which is a tablet.
[9] The solid preparation according to any one of [1] to [8], which has a coating layer on the surface.
[10] A method for producing a tablet comprising a step of tableting a drug-containing powder comprising the following component (A), component (B) and component (C) to obtain a tablet.
(A) Component: one or more selected from the group consisting of loxoprofen and salts thereof (B) Component: Acetaminophen (C) Component: At least one of low-substituted hydroxypropylcellulose and crospovidone [11] (A) Filling the mortar with powder A containing the component and powder B containing the following component (B) (however, at least one of powder A and powder B contains the following component (C)), A method for producing a tablet, comprising a step of tableting to obtain a tablet.
(A) Component: one or more selected from the group consisting of loxoprofen and salts thereof (B) Component: acetaminophen (C) Component: at least one of low-substituted hydroxypropylcellulose and crospovidone [12] [10] or A method for producing a coated tablet, wherein the tablet is produced by the method for producing a tablet according to [11], the obtained tablet is used as a plain tablet, and a coating layer is provided on the surface of the plain tablet.

  ADVANTAGE OF THE INVENTION According to this invention, in the solid formulation containing loxoprofen (salt) and acetaminophen, the solid formulation by which the unpleasant odor was suppressed by the simple method, the manufacturing method of a tablet, and the manufacturing method of a coated tablet can be provided.

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, for example, granules (powder, granules, enteric granules, etc.), tablets (plain tablets, dragees, coated tablets, enteric tablets, orally disintegrating tablets, chewable tablets, Effervescent tablets), capsules, pills, lozenges and the like. Among these, a tablet is preferable from the viewpoint that the effect of the present invention (odor suppression) 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 from the viewpoint of ease of handling and swallowability, the tablet diameter is preferably 5 to 14 mmφ, more preferably 6 to 13 mmφ, and 7 to 12 mmφ. Further preferred. The tablet mass per tablet is preferably 150 mg to 550 mg.
The shape of the tablet is not particularly limited, but Sumi square flat tablets, Sumi round flat tablets, rounded R tablets or two-stage R tablets are 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 layered structure (layer tablet). From the point that it is easier to enjoy the effects of the present invention, it has a layer having both the following components (A), (B) and (C) (that is, (A) component, (B) component and (C) It is preferred that 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 “drug layer”. When the solid preparation is a monolayer 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 (arbitrary layer) other than the drug layer.
In addition, when (A) component and (B) component exist in a separate layer, and these layers make the laminated tablet which these layers adjoin, the (C) component is in at least one layer. What is necessary is just to contain. That is, when the layer in which the component (A) is present is “A layer” and the layer in which the component (B) is present is “B layer”, the component (C) is contained in at least one of the A layer and the B layer. In this case, the effect of the present invention can be sufficiently obtained.

<(A) component>
(A) component is 1 or more types chosen from the group which consists of loxoprofen and its salt (loxoprofen (salt)).
Loxoprofen (salt) is an antipyretic analgesic ingredient listed in the Japanese Pharmacopoeia.

The loxoprofen salt 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 exist in a hydrated state. A preferred example of loxoprofen (salt) in the hydrated state is loxoprofen sodium dihydrate. In the case of loxoprofen sodium dihydrate, the moisture content of the bulk powder is about 12% by mass.
In addition, when the component (A) is a hydrate, the content of the component (A) described later, the dose per unit and the mass ratio with other components include the amount of water in the component (A). Shall be.

The component (A) is preferably a loxoprofen salt, more preferably loxoprofen sodium, and even more preferably loxoprofen sodium dihydrate.
(A) A component may be used individually by 1 type and may be used in combination of 2 or more type.

(A) As for content of a component, 3-85 mass% is preferable with respect to the total mass of a solid formulation, and 5-50 mass% is more preferable.
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 mass% is preferable and 5-55 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 A layer. Is preferable, and 10-65 mass% is more preferable.
As the content of the component (A) increases, an unpleasant odor after storage becomes more prominent, and therefore the effect of the present invention due to the addition of the component (C) is easily exhibited. In addition, a sufficient antipyretic analgesic effect is obtained. (A) If content of a component is below the said upper limit, adhesion to the manufacturing machine in a manufacturing process can be suppressed.
When the solid preparation is a monolayer 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.

  (A) The dosage per component is preferably 11 to 170 mg, more preferably 22 to 113 mg. If the dose per component (A) is equal to or higher than the above lower limit, a sufficient antipyretic effect can be obtained, and if it is equal to or lower than the upper limit, adhesion to the manufacturing machine in the manufacturing process can be suppressed.

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

(B) 3-85 mass% is preferable with respect to the total mass of a solid formulation, and, as for content of a component, 20-80 mass% is more preferable.
When the solid preparation is a laminated tablet and the components (A), (B) and (C) are present in the same layer, the content of the component (B) is 5 to 5% of the total mass of the drug layer. 90 mass% is preferable and 20-85 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 B layer. Is preferable, and 20-85 mass% is more preferable.
As the content of the component (B) increases, an unpleasant odor after storage becomes more prominent, and therefore the effect of the present invention due to the addition of the component (C) is easily exhibited. In addition, a sufficient antipyretic analgesic effect is obtained.
If content of (B) component is below the said upper limit, when a solid formulation is a tablet, tablet hardness can be maintained favorable.
When the solid preparation is a monolayer 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 effects of the present invention, it is represented by (B) component / (A) component. 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. If B / A ratio is more than the said lower limit, while being able to suppress the unpleasant smell after a storage more effectively, adhesion to the manufacturing machine in a manufacturing process can be suppressed. On the other hand, if the B / A ratio is less than or equal to the above upper limit, when the solid preparation is a tablet, the tablet hardness can be favorably maintained.

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

<(C) component>
Component (C) is at least one of low-substituted hydroxypropylcellulose and crospovidone.
Low-substituted hydroxypropylcellulose is synonymous with “low-substituted hydroxypropylcellulose” described in the Japanese Pharmacopoeia (No. 17), and the hydroxy group of cellulose is substituted with a hydroxypropyl group (—OC ₃ H ₆ OH). Of the hydroxypropylcellulose produced, it refers to those with low substitution. Specifically, the substitution degree (content) of the hydroxypropoxy group is 5 to 16% by mass.
Crospovidone is synonymous with “crospovidone” described in Japanese Pharmacopoeia (17th revision), and is a cross-linked polymer of 1-vinyl-2-pyrrolidone.
(C) A component should just contain the said component, and a granulated material and a coprecipitate may be sufficient as it.

(C) 0.5-85 mass% is preferable with respect to the total mass of a solid formulation, as for content of a component, 1-60 mass% is more preferable, and 1-50 mass% is further more preferable.
When the solid preparation is a laminated tablet and the components (A), (B) and (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. 85 mass% is preferable, 1-60 mass% is more preferable, and 1-50 mass% is further 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 (C) in the layer A is 0 with respect to the total mass of the layer A. -85 mass% is preferable, 1-60 mass% is more preferable, 1-50 mass% is further more preferable. Moreover, 0-85 mass% is preferable with respect to the total mass of B layer, as for content of (C) component in B layer, 1-60 mass% is more preferable, and 1-50 mass% is more preferable. However, it is preferable that the total content of the component (C) in the layer A and the total content of the component (C) in the layer B is 0.5 to 85% by mass, and more preferably 1 to It is 60 mass%, More preferably, it is 1-50 mass%.
If content of (C) component is more than the said lower limit, the unpleasant smell after a preservation | save can be suppressed more effectively, and if it is below the said upper limit, the dosage per time can be suppressed.
When the solid preparation is a monolayer 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.

6.5-90 mass% is preferable with respect to the total mass of a solid formulation, and, as for the sum total of content of (A) component, (B) component, and (C) component in a solid formulation, 26-90 mass% is more Preferably, 40 to 90% by mass is more preferable.
Further, when the solid preparation is a laminated tablet and the components (A), (B) and (C) are present in the same layer, the contents of the components (A), (B) and (C) Is preferably from 10 to 99 mass%, more preferably from 26 to 95 mass%, still more preferably from 40 to 95 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 not less than the above lower limit value, an antipyretic analgesic effect can be sufficiently obtained while suppressing an unpleasant odor after storage, and the above upper limit value. If it is the following, it can be set as the solid formulation excellent in ingestibility.

  Although the blending ratio of the sum of the component (A) and the component (B) in the solid preparation and the component (C) can be arbitrarily set, the component (C) / The mass ratio (hereinafter also referred to as “C / (A + B) ratio”) represented by ((A) component + (B) component) is preferably 0.01 to 8, and 0.012 to 1.5. More preferred. If the C / (A + B) ratio is not less than the above lower limit value, an unpleasant odor after storage can be more effectively suppressed, and if it is not more than the above upper limit value, a solid preparation excellent in dosage can be obtained.

The dose per component (C) is preferably 5 to 500 mg, more preferably 5 to 300 mg, and even more preferably 10 to 200 mg. (C) If the dose per component is greater than or equal to the above lower limit, the unpleasant odor after storage can be more effectively suppressed, and if it is less than or equal to the above upper limit, the dose per dose is suppressed. Can do.
Moreover, 46-1170 mg is preferable, and, as for the dose per time, the sum total of (A) component, (B) component, and (C) component, 82-713 mg is more preferable, 140-370 mg is further more preferable. If the total dose of component (A), component (B) and component (C) is equal to or more than the above lower limit, sufficient antipyretic analgesic effect can be obtained while suppressing unpleasant odor after storage. If it is below the said upper limit, it can be set as the solid formulation excellent in ingestibility.

<Optional component>
The solid preparation of the present invention contains components (arbitrary components) other than the component (A), the component (B) and the component (C) as long as the physical properties such as the effects and storage stability of the present invention are not impaired. May be.
Examples of the optional component include physiologically active components other than the components (A) and (B) and additives other than the component (C).

Examples of the physiologically active component include antipyretic analgesic components other than the component (A) and the component (B) (piroxicam, meloxicam, ampiroxicam, celocoxib, rofecoxib, thiaramide, etenzamid, sulpyrine, etc.)
In addition, physiologically active components other than antipyretic analgesic components can be blended. Examples of physiologically active components other than antipyretic analgesic components include sedative hypnotic components (such as allylisopropylacetylurea and bromvalerylurea), antihistamine components (isotipendyl hydrochloride, diphenylpyramine hydrochloride, diphenhydramine hydrochloride, dipheterol hydrochloride, triprolidine hydrochloride, tripelenamine hydrochloride, Tonsilamine hydrochloride, phenetazine hydrochloride, methodirazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teocrate, promethazine methylene disalicylate, carbinoxamine maleic acid dichlormamine hydrochloride , D-chlorpheniramine maleate, dipheterol phosphate, etc.), central excitation (Sodium benzoate caffeine, caffeine, anhydrous caffeine, etc.), antitussive expectorant components (codeine phosphate, dextromethorphan hydrobromide, dimemorphan phosphate, tipepidine hibenzate, methoxyphenamine hydrochloride) , Trimethquinol hydrochloride, carbocysteine, acetylcysteine, ethylcysteine, dl-methylephedrine, bromhexine hydrochloride, serrapeptase, lysozyme chloride, ambroxol, theophylline, aminophylline, etc.), vitamin components (vitamin B1 and derivatives thereof and the like) Salts, vitamin B2 and derivatives thereof and salts thereof, vitamin C and derivatives thereof and salts thereof, hesperidin and derivatives thereof and salts thereof), antacids (dried aluminum hydroxide gel, Magnesium silicate aluminate, magnesium aluminosilicate, synthetic hydrotalcite, magnesium carbonate, magnesium oxide, magnesium silicate, sodium hydrogen carbonate, etc.) and the like.
These physiologically active ingredients may be used alone or in combination of two or more. In particular, an unpleasant odor after storage can be further suppressed by using at least one of caffeine and anhydrous caffeine in combination with allylisopropylacetylurea.

Examples of the additive include a binder, an excipient, a disintegrant, a fragrance, a lubricant, a sweetener, a sour agent, and a colorant.
Examples of the binder include starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, polyvinylpyrrolidone, pullulan, dextrin, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose and the like.
Examples of the excipient include crystalline cellulose, lactose, lactose granulated product, corn starch, powdered sugar, mannitol, L-cysteine and the like.
Examples of the disintegrant include croscarmellose sodium, carboxymethyl cellulose, carboxymethyl cellulose sodium, partially pregelatinized starch and the like.
Examples of the fragrances include menthol, limonene, plant essential oils (mint 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 and the like.
Examples of the sweetening agent include saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, and sucralose.
Examples of the sour agent include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, and salts thereof.
Examples of the colorant include food colorants, organic pigments and inorganic pigments other than food colorants, and animal and plant extracts. Examples of food coloring agents include orange essence, caramel, carmine, β-carotene, food blue No. 1, food yellow No. 4, food yellow No. 4 aluminum lake, food yellow No. 5, food red No. 2, food red No. 3, Food red 102 is listed. Examples of the organic pigment include copper chlorophyllin sodium, copper chlorophyll, and riboflavin. Examples of inorganic pigments include iron sesquioxide, yellow iron sesquioxide, black iron oxide, zinc oxide, titanium oxide, black iron oxide, brown iron oxide, zinc oxide, gold foil, and medicinal charcoal. Examples of animal and plant extracts include licorice extract, acacia tannin powder, turmeric extract, and green tea powder. Among these, inorganic pigments are preferred from the standpoint that solid preparations are less likely to fade after storage and can reduce adherence to manufacturing machines, and iron such as iron sesquioxide, yellow iron sesquioxide, and black iron oxide are the main components. Inorganic pigments, 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 still more preferable.
These additives may be used individually by 1 type, and may be used in combination of 2 or more type.

In addition, 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 optional layer, or the optional component May be contained in the drug layer. Moreover, a part of (C) component may be contained also in the arbitrary layers.
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. And may be contained in a layer other than the B layer.

<Moisture content>
1-15 mass% is preferable with respect to the total mass of a solid formulation, as for the moisture content in a solid formulation, 1.5-13 mass% is more preferable, and 1.5-7 mass% is more preferable.
If the amount of water is within the above range, an unpleasant odor after storage can be more effectively suppressed.

The method for measuring the amount of water is an electronic moisture meter, which can be calculated from the loss on 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 addition or drying at the time of 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 the 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, a tablet having a coating layer on the surface is also referred to as a “coated tablet”. In the coated tablet, the part excluding the coating layer is also referred to as “plain tablet”.
The coating layer is a layer formed from a constituent material containing a coating agent. As such a coating agent, it is preferable to select one that does not significantly impair disintegration, and among them, a water-soluble polymer compound and a plasticizer are preferable.
Examples of the water-soluble polymer compound include celluloses such as methylcellulose, hydroxypropylmethylcellulose (hypromellose), carmellose, hydroxypropylcellulose, hydroxymethylcellulose; gum arabic, carboxyvinyl polymer, povidone, polyvinyl alcohol, polyacrylic acid, monosaccharide, Disaccharides or more (sugar (granulated sugar, etc.), lactose, maltose, xylose, isomerized lactose, etc.), sugar alcohol (palatinite, sorbitol, lactitol, erythritol, xylitol, reduced starch saccharified product, maltitol, mannitol, etc.) , Starch syrup, oligosaccharide, sucrose, trehalose, reduced starch saccharified product (reduced starch degradation product 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 official documents such as Japanese Pharmacopoeia (Hirokawa Shoten) such as triethyl citrate, triacetin, and carnauba wax, and pharmaceutical additive standards (Pharmaceutical Daily Inc.).
These coating agents may be used individually by 1 type, and may be used in combination of 2 or more type.

  Moreover, it is preferable that a coating layer contains a coloring agent from a viewpoint of manufacturability or moisture resistance. As the colorant, an inorganic pigment is preferable because it is difficult to fade after storage and can suppress the decay delay with time. Among them, inorganic pigments mainly composed of iron such as iron sesquioxide, yellow iron sesquioxide, 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 are iron sesquioxide, yellow iron sesquioxide, and titanium oxide.

  In addition, when a solid formulation has a coating layer on the surface, each content and water content of the above-mentioned (A) component, (B) component, and (C) component are the total mass of the solid formulation of the part except a coating layer. Content. For example, when the solid preparation is a coated tablet, the above-mentioned contents (A), (B) and (C) and the water content of the above-mentioned components are the contents relative 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 component (A), the component (B) and the component (C), and optional components as necessary.
Each component may be obtained by a known production method or may be a commercially available product. In addition, as for 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 a 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 a drug-containing powder using a tableting machine having a mortar and a punch.

The drug-containing powder may be a powder containing the component (A), the component (B), and the component (C), and may contain an optional component as necessary.
The drug-containing powder may be, for example, a powder mixture of (A) component of powder, (B) component of powder, and (C) component of powder, or (A) component and (B) component. And a granulated product containing the component (C).

  The drug-containing powder may be pre-mixed or newly prepared. That is, the tablet manufacturing method may include a step of preparing a drug-containing powder by mixing each component of the powder (powder preparation step).

In the powder preparation step, 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.
It does not specifically limit as a mixing method in a powder preparation process, A conventionally well-known powder mixing method is mentioned.

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

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

In the case of producing a laminated tablet in which the component (A) and the component (B) are present in separate layers, the powder constituting the A layer (hereinafter also referred to as “powder A”) instead of the drug-containing powder. And a powder constituting the B layer (hereinafter also referred to as “powder B”) are filled into a mortar and compressed.
The powder A may be filled in the die first, or may be filled after the powder B.

The powder A may be a powder containing the component (A), and may contain an optional component as necessary. The powder B should just be the powder containing (B) component, and may contain arbitrary components as needed. However, it is assumed that component (C) is contained in at least one of powder A and powder B.
The powder A may be a powder mixture with the component (A) of the powder or other powder components, or may be a granulated product containing the component (A). The powder B may be a powder mixture with the component (B) of the powder or other powder components, or may be a granulated product containing the component (B).

(Method for producing coated tablets)
The coated tablet can be produced by producing a tablet by the production method described above, using the obtained tablet as an uncoated tablet, and providing the coating layer described above on the surface of the uncoated tablet. As a method for preparing a coating agent and a method for providing a coating layer containing a coating agent on the surface of an uncoated tablet, a conventionally known method can be used. For example, first, if necessary, a colorant is added to a dispersion of a coating agent in which the coating agent is dispersed in a solvent such as water to obtain a coating solution. Thereafter, the coating liquid is provided so as to cover the uncoated tablets by spraying or the like. Thereafter, the solvent component of the coating solution 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), an unpleasant odor after storage can be suppressed.
The solid preparation of the present invention may be coated with a coating agent (coating treatment), but even if it is not subjected to a coating treatment, an unpleasant odor after storage can be suppressed by the combined use of the component (C).
Thus, according to the present invention, in a solid preparation containing the component (A) and the component (B), a solid preparation with an unpleasant odor suppressed by a simple method can be provided.
In particular, the solid preparation is a granular tablet, the tablet in which the component (A) and the component (B) are present in the same layer, or the case in which the component (A) and the component (B) are present in separate layers. However, in the case of a laminated tablet in which each layer is adjacent, the component (A) and the component (B) are likely to come into contact with each other, so that an unpleasant odor is likely to be produced, but the present invention can suppress an unpleasant odor after storage. .

EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated in detail, this invention is not limited by the following description.
The raw materials, tableting conditions, storage conditions, and evaluation methods used in each example and comparative example are as follows.

[Raw materials]
As the component (A) or its substitute (component (A ′)), the following compounds were used.
・ Loxoprofen sodium dihydrate: Daiwa Pharmaceutical Co., Ltd., “Japanese Pharmacopoeia Loxoprofen Sodium Hydrate”
・ Ibuprofen: “Ibuprofen” manufactured by BASF

As the component (B), the following compounds were used.
・ Acetaminophen: Iwaki Pharmaceutical Co., Ltd., “Piretinol”

As the component (C) or its substitute (component (C ′)), the following compounds were used.
・ Low-substituted hydroxypropyl cellulose: “L-HPC LH-31” (registered trademark) manufactured by Shin-Etsu Chemical Co., Ltd.
・ Crospovidone: manufactured by BASF, "Kollidon CL-SF" (registered trademark)
-Crystalline cellulose: “CEOLUS UF-702” (registered trademark), manufactured by Asahi Kasei Chemicals Corporation
・ Hydroxypropyl cellulose: Nippon Soda Co., Ltd., “NISSO HPC SSL”
・ Carboxymethylcellulose sodium: Daicel Finechem Co., Ltd. “CMC Daicel”
・ Corn starch: Matsutani Chemical Industry Co., Ltd., “Popular Matsutani Corn Starch”

The following compounds were used as optional components.
・ Anhydrous caffeine: manufactured by Shiratori Pharmaceutical Co., Ltd., “anhydrous caffeine 0.2 / 0.5”
・ Allyl isopropyl acetyl urea: manufactured by Kongo Chemical Co., Ltd., “Aripronal Congo”
・ Lactose granules: “Fructose G”, manufactured by Freund Sangyo Co., Ltd.
Magnesium stearate: Taihei Chemical Industry Co., Ltd., “Magnesium stearate”

As the material for forming the coating layer, the following compounds were used.
・ Coating agent: “Opadry (using hydroxypropylmethylcellulose as a polymer)” (trademark), manufactured by Nippon Colorcon LLC
・ Iron sesquioxide: Made by Kasei Kasei Co., Ltd. “Iron sesquioxide”

[Tabletting conditions]
-Tablet press: Rotary tablet press (manufactured by Kikusui Seisakusho Co., Ltd., “Libra 3L”)
-Board rotation speed: 20 rpm
-Usuki (Examples 1-5, 7-8, 10-18, 20-25): Diameter 9.0 mm (2 steps R) x 12 stands, no marking (cap height 0.1 mm, R1 = 3.4) , R2 = 10)
-Usuki (Examples 6, 9, 19, 26): 9.5 mm in diameter (2 steps R) x 12 stand, no stamping (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 )

[Storage conditions]
The powder mixture was placed in a glass bottle (4K standard bottle) and stored under conditions of 50 ° C. and 75% RH with the lid on.
The tablet or coated tablet is put in a pocket of a pre-molded resin sheet (Tasaka Chemical Co., Ltd., “TAS-230”, polypropylene-cyclic polyolefin-polypropylene laminate) and packaged with aluminum foil in a PTP (press-through package) package. And stored under conditions of 50 ° C. and 75% RH.

[Evaluation method]
<Odor evaluation: quantitative evaluation>
About the powder mixture before storage and 2 months after the start of storage, or tablets or coated tablets, the odor intensity is measured using an odor sensor (“Fragrance Sensor SF-105” manufactured by Mutual Yakuko Co., Ltd.) By subtracting the odor intensity before storage from the odor intensity after storage, the amount of change in odor intensity before and after storage was determined and evaluated according to the following evaluation criteria. A score of 5 or more is accepted.
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: Change amount is 115 Hz or more.

<Odor evaluation: sensory evaluation>
For the powder mixture or tablet 2 months after the start of storage, sensory evaluation was conducted by five adult males, and the following evaluation criteria were evaluated to determine the average value of the five persons. A score of 4 or more is accepted.
6: I do not feel the smell.
5: Almost no smell is felt.
4: Although a slight odor is felt, there is no problem in taking it.
3: A slightly unpleasant odor is felt.
2: An unpleasant odor is felt.
1: It has changed to a very unpleasant odor and can be taken.

[Examples 1 to 26]
(A) component, (B) component, (C) component, and arbitrary component (1) are thrown into and mixed in the mixing container so as to have the composition shown in Tables 1 to 3, and a powder mixture is obtained. It was.
Odor evaluation was performed about the powder mixture obtained in Examples 1-19. The results are shown in Tables 1 and 2.

Separately, (A) component, (B) component, (C) component, arbitrary component (1), and arbitrary component (2) so that the composition per tablet may become the compounding composition shown in Tables 1-3 in the mixing container. ) Were mixed and then tableted under the above tableting conditions to obtain a tablet (single-layer tablet) comprising a drug layer. However, a mortar with a diameter of 9.0 mm was used for Examples 1 to 5, 7 to 8, 10 to 18, and 20 to 25, and a mortar with a diameter of 9.5 mm was used for Examples 6, 9, 19, and 26. .
Odor evaluation was performed about the tablet obtained in Examples 1-19. The results are shown in Tables 1 and 2.

About Examples 20-26, the obtained tablet was used as the uncoated tablet and the coating layer was provided on the surface of the uncoated tablet as follows.
That is, a dispersion liquid in which a coating agent was dispersed in water so as to have a concentration of 20% by mass was used as a coating liquid. Using Aqua Coater 48 (Freund Sangyo Co., Ltd.), the amount of coating agent per tablet under the conditions of an air supply temperature of 60 ° C., an air supply air volume of 2.3 m ³ / min, and an exhaust temperature of 42 ± 2 ° C. The coating solution was sprayed onto the uncoated tablets so that (coating amount) was a value shown in Table 3. Thereafter, drying was performed at an air supply temperature of 60 ° C. and an air supply air volume of 2.3 m ³ / min for 20 minutes to obtain a coated tablet having a coating layer provided on the surface of the uncoated tablet.
In Examples 23 to 26, a coating liquid further blended with iron sesquioxide as a colorant was used so that the amount of colorant (coating amount) per tablet was a value shown in Table 3.
The coated tablets obtained in Examples 20 to 26 were evaluated for odor. The results are shown in Table 3.

[Comparative Examples 1-5]
(A) component, (B) component, and (C ') component were thrown into the mixing container and mixed so as to have the blending composition shown in Table 4 to obtain a powder mixture.
The obtained powder mixture was evaluated for odor. The results are shown in Table 4.

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

[Reference Example B]
For the component (B), the odor was evaluated in the same manner as the powder mixture. The results are shown in Table 4.

[Reference Example C]
Into the mixing container, the components (A ′) and (B) were added and mixed so as to have the blending composition shown in Table 4 to obtain a powder mixture.
The obtained powder mixture was evaluated for odor. The results are shown in Table 4.

  In the table, “B / A ratio” is a mass ratio represented by (B) component / (A) component. The “B / A ′ ratio” is a mass ratio represented by (B) component / (A ′) component. “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 (C ′) component / ((A) component + (B) component). The “C ′ / (A ′ + B) ratio” is a mass ratio represented by (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 (plain tablet).

From the results shown in Tables 1 to 3, the powder mixture obtained in each example, and the tablet or coated tablet were those in which an unpleasant odor after storage was suppressed.
On the other hand, from the results of Table 4, when the powder mixture obtained in each comparative example was stored, an unpleasant odor was felt.
In the case of component (A) alone, component (B) alone, or a combination of ibuprofen and component (B), an unpleasant odor was not felt even when stored (Reference Examples AC). As is apparent from these results, an unpleasant odor after storage is generated when the component (A) and the component (B) are combined.
Thus, according to the present invention, the unpleasant odor of the solid preparation after storage can 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 component (A), component (B) and component (C).
(A) Component: one or more selected from the group consisting of loxoprofen and salts thereof (B) Component: acetaminophen (C) Component: at least one of low-substituted hydroxypropylcellulose and crospovidone   The solid formulation according to claim 1, wherein the content of the component (C) is 0.5 to 85% by mass with respect to the total mass of the solid formulation.   The solid formulation of Claim 1 or 2 whose mass ratio represented by (C) component / ((A) component + (B) component) is 0.01-8.   The solid preparation according to any one of claims 1 to 3, which is a tablet.   The solid formulation as described in any one of Claims 1-4 which has a coating layer on the surface. The manufacturing method of a tablet which has the process of tablet-molding the medicine containing powder containing the following (A) component, (B) component, and (C) component, and obtaining a tablet.
(A) Component: one or more selected from the group consisting of loxoprofen and salts thereof (B) Component: acetaminophen (C) Component: at least one of low-substituted hydroxypropylcellulose and crospovidone   The manufacturing method of a coated tablet which manufactures a tablet with the manufacturing method of the tablet of Claim 6, uses the obtained tablet as an uncoated tablet, and provides a coating layer on the surface of the uncoated tablet.