JP6407085B2 - Tablet and production method thereof - Google Patents

Description

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

Among non-steroidal anti-inflammatory drugs (NSAIDs), loxoprofen sodium is widely used as a component of antipyretic analgesics because it has excellent anti-inflammatory, analgesic and antipyretic effects and has relatively few side effects.
However, tablets containing loxoprofen sodium generally have a slow disintegration, and there is a problem that an excellent analgesic effect is not rapidly developed.

As a means for enhancing the disintegration of a tablet containing loxoprofen sodium, for example, a method of increasing the water absorption of a tablet by combining a specific grade of hydroxypropyl cellulose and magnesium stearate with loxoprofen sodium is known ( (See Patent Documents 1 and 2).
In addition, a method of improving the disintegration time of a tablet delayed by co-blending loxoprofen sodium and tranexamic acid by further blending magnesium oxide (see, for example, Patent Document 3), loxoprofen sodium and tipepidine are co-blended There is also known a method for improving the disintegration time of the tablet delayed by further adding L-carbocysteine (for example, see Patent Document 4).

Japanese Patent Application Laid-Open No. 09-169641 JP 2000-178190 A JP 2014-162743 A JP 2014-1111565 A

However, the disintegration property of the tablets obtained by the methods described in Patent Documents 1 and 2 is not sufficiently fast.
Further, the disintegration property of the tablets obtained by the methods described in Patent Documents 3 and 4 has not been sufficient. The methods described in Patent Documents 3 and 4 are techniques that are not utilized when a drug that causes a change in composition is not co-blended, and even in such a case, excellent disintegration is required.
By the way, tablets are required to have excellent disintegration properties after taking, but are also required to have a strength that prevents chipping and cracking before taking such as during production and storage.

  The present invention has been made in view of the above circumstances, and an object thereof is to provide a tablet having excellent disintegration and high strength, and a method capable of easily producing a tablet having excellent disintegration and high strength.

The present invention has the following aspects.
[1] A tablet comprising a drug layer having both the following component (A), the following component (B) and the following component (C), wherein the water content of the drug layer is 5% by mass or more.
(A) component: At least 1 sort (s) chosen from the group which consists of loxoprofen and its salt.
Component (B): At least one selected from the group consisting of dry aluminum hydroxide gel, aluminum glycinate, magnesium carbonate, magnesium oxide, magnesium aluminate metasilicate, and synthetic hydrotalcite.
(C) Component: Coloring agent.
[2] The tablet according to [1], wherein the component (C) is at least one of ferric oxide and yellow ferric oxide.
[3] The tablet according to [1] or [2], wherein a mass ratio represented by 1000 × (C) component / (A) component is 0.15 to 3.5.
[4] The tablet according to any one of [1] to [3], wherein the mass ratio represented by (B) component / (A) component is 0.14 to 3.

[5] A method for producing a tablet according to any one of [1] to [4], wherein the drug layer is formed by tableting the powder constituting the drug layer. .
[6] The powder (A) component, the powder (B) component, and the powder (C) component are mixed to prepare a powder constituting the drug layer. [5] A method for producing a tablet according to [5].
[7] The powder constituting the drug layer contains a powder other than the component (A), the component (B) and the component (C) as the component (D), and the powder (C) Mixing the mixed powder of the component and part of the component (D), the component (A) of the powder, the component (B) of the powder and the remainder of the component (D), The method for producing a tablet according to [5] or [6], comprising a step of obtaining a powder constituting the drug layer.
[8] The powder constituting the drug layer includes a powder other than the component (A), the component (B), and the component (C) as the component (D). Mixing the mixed powder of the component and the component (D) with the component (A) of the powder and the component (B) of the powder to obtain a powder constituting the drug layer [5] or [6].
[9] The method for producing a tablet according to [7] or [8], wherein the component (D) is one or more selected from the group consisting of a binder, an excipient, and a disintegrant.
[10] The powder constituting the drug layer is prepared by adjusting the moisture content of at least one of the component (A) and the component (B) so that the moisture content of the drug layer is 5% by mass or more. The method for producing a tablet according to any one of [6] to [9], which is prepared.

The tablet of the present invention has excellent disintegration and high strength.
Moreover, according to the manufacturing method of the tablet of this invention, the tablet excellent in disintegration and high intensity | strength can be manufactured simply.

[tablet]
The tablet of the present invention comprises a drug layer. The tablet may have a single layer structure (single layer tablet) composed only of a drug layer, or a layered structure (layered tablet) composed of a drug layer and a layer other than the drug layer (arbitrary layer). May be.
The drug layer has the following component (A), component (B), and component (C).

<(A) component>
The component (A) is at least one selected from the group consisting of loxoprofen and a salt thereof.
(A) A component is an antipyretic analgesic component.
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 and a salt thereof may exist in a hydrate state. A preferred example of 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.
As the component (A), a loxoprofen salt is preferable, and loxoprofen sodium is more preferable.
(A) A component may be used individually by 1 type and may be used in combination of 2 or more type as appropriate.

<(B) component>
The component (B) is at least one selected from the group consisting of dry aluminum hydroxide gel, aluminum glycinate, magnesium carbonate, magnesium oxide, magnesium aluminate metasilicate, and synthetic hydrotalcite.
The component (B) serves as an antacid.
Water such as bound water may be retained in the dry aluminum hydroxide gel, aluminum glycinate, magnesium carbonate, magnesium oxide, magnesium aluminate metasilicate, and synthetic hydrotalcite.
As the component (B), it is easy to obtain a tablet excellent in disintegration, and it is difficult for a delay in disintegration to occur even after storage of the tablet. Therefore, dry aluminum hydroxide gel, aluminum glycinate, magnesium aluminate metasilicate, Synthetic hydrotalcite is preferable, and dry aluminum hydroxide gel and aluminum glycinate are more preferable.
Examples of the dry aluminum hydroxide gel include dry aluminum hydroxide gel described in “16th revision Japanese Pharmacopoeia”.
(B) A component may be used individually by 1 type and may be used in combination of 2 or more type as appropriate.

<(C) component>
(C) A component is a coloring agent.
By using the component (C) and the component (B) in combination, the adhesion between the granules is lowered, and the disintegration property of the tablet is improved.

Examples of the component (C) include edible colorants, organic pigments and inorganic pigments other than edible colorants, and animal and plant extracts.
Examples of food coloring 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 Edible red 102 and the like.
Examples of organic pigments include copper chlorophyllin sodium, copper chlorophyll, and riboflavin.
Examples of inorganic pigments include iron sesquioxide, yellow iron sesquioxide, black iron oxide, talc, zinc oxide, titanium oxide, gold foil, and medicinal charcoal.
Examples of the animal and plant extracts include licorice extract, acacia tannin powder, turmeric extract, and green tea powder.
Among these, inorganic pigments are preferable from the viewpoint that wrinkle adhesion during tableting molding is further suppressed, and inorganic pigments mainly composed of iron such as iron sesquioxide, yellow iron sesquioxide, and black iron oxide are more preferable. Particularly preferred are iron dioxide and yellow ferric oxide.
(C) A component may be used individually by 1 type and may be used in combination of 2 or more type as appropriate.

<Tablet form>
The size of the tablet is not particularly limited, but the tablet diameter is preferably 6 to 13 mmφ, more preferably 7 to 10 mmφ, and even more preferably 7 to 9 mmφ from the viewpoint of ease of handling and swallowability.
The shape of the tablet is preferably a rounded R tablet or a two-stage R tablet, and the height of the cap part is preferably 1.0 to 2.0 mm from the viewpoint of ingestion. If the height of a cap part is in the said range, the disintegration property of a tablet will improve more and tablet strength will also increase.

The tablet includes a drug layer having both the component (A), the component (B), and the component (C). That is, the component (A), the component (B), and the component (C) are present in the same layer. In order for the component (A), the component (B), and the component (C) to be present in the same layer, the component (A), the component (B), and the component (C) are tableted together to form one layer. (Drug layer) may be formed.
Moreover, it is preferable that (A) component, (B) component, and (C) component do not exist in the same granule. Here, “not present in the same granule” means that the bulk powder of component (A), the bulk powder of component (B), and the bulk powder of component (C) are not granulated together.

The content of the component (A) in the drug layer is preferably 15 to 35% by mass and more preferably 20 to 30% by mass in 100% by mass of the total mass of the drug layer. If the content of the component (A) is 15% by mass or more, the number of tablets taken per dose can be reduced, and sufficient antipyretic and analgesic effects can be obtained. If the content is 35% by mass or less, the component (B) And since (C) component can fully be contained, sufficient antacid effect and the improvement effect of disintegration are acquired.
The content of the component (B) in the drug layer is preferably 4.5 to 50% by mass, more preferably 10 to 45% by mass, and even more preferably 28 to 40% by mass in 100% by mass of the total mass of the drug layer. If the content of the component (B) is 4.5% by mass or more, a sufficient antacid effect is obtained, and if the content is 50% by mass or less, the component (A) can be sufficiently contained. The number of tablets taken per hit can be reduced.
The content of the component (C) in the drug layer is preferably 0.001 to 0.2% by mass and more preferably 0.01 to 0.1% by mass in 100% by mass of the total mass of the drug layer. If the content of the component (C) is 0.001% by mass or more, sufficient disintegration improvement effect is obtained, and if the content is 0.2% by mass or less, the component (A) can be sufficiently contained. Therefore, the number of tablets taken per time can be reduced.
In addition, let mass of (A) component and (B) component be a pure equivalent amount (anhydrous equivalent amount).

Moreover, 45-85 mg is preferable and, as for content of (A) component in a tablet, 50-70 mg is more preferable.
The content of the component (B) in the tablet is preferably 20 to 170 mg, more preferably 40 to 130 mg.
The content of the component (C) in the tablet is preferably from 0.01 to 0.2 mg, more preferably from 0.03 to 0.1 mg.
The tablet mass per tablet is preferably 150 to 550 mg.
Moreover, let mass of (A) component and (B) component be the amount equivalent to a pure part (anhydrous equivalent amount).

The mass ratio represented by the component (B) / component (A) is preferably 0.14 to 3, more preferably 0.14 to 2.9, still more preferably 0.3 to 2.9, and 0 0.7 to 2.9 is particularly preferable, and 1.4 to 2.2 is most preferable. By setting the mass ratio within the above range, the disintegration property of the tablet is further improved.
In addition, let mass of (A) component and (B) component be a pure equivalent amount (anhydrous equivalent amount).

Further, the mass ratio represented by 1000 × (C) component / (A) component is preferably 0.15 to 3.5, more preferably 0.5 to 3.5, and 1.0 to 3.5. Further preferred. By setting the mass ratio within the above range, the disintegration property of the tablet is further improved. Moreover, the external appearance of a tablet also becomes favorable.
In addition, let mass of (A) component be a pure equivalent amount (anhydride equivalent amount).

Moreover, 0.2-3 are preferable, as for the mass ratio represented by 1000x (C) component / (B) component, 0.25-2.35 are more preferable, and 0.35-2 are more preferable. By setting the mass ratio within the above range, the disintegration property of the tablet is further improved. Moreover, the external appearance of a tablet also becomes favorable.
In addition, let the mass of (B) component be a pure equivalent amount (anhydride equivalent amount).

<Physical properties of tablets>
The water content of the drug layer is 5% by mass or more in 100% by mass of the drug layer, preferably 5 to 15% by mass, more preferably 6 to 12% by mass, and still more preferably 7 to 10% by mass. When the water content of the drug layer is 5% by mass or more, excellent tablet strength and tablet disintegration can be exhibited. Further, the water content is preferably 15% by mass or less from the viewpoint of tableting suitability.
When the tablet is a monolayer tablet, the water content of the drug layer is the water content of the tablet. That is, the moisture content of the tablet is 5% by mass or more in 100% by mass of the tablet, preferably 5 to 15% by mass, more preferably 6 to 12% by mass, and further preferably 7 to 10% by mass.
On the other hand, when the tablet is a laminated tablet, the water content of the arbitrary layer is not particularly limited as long as the water content of at least the drug layer is 5% by mass or less, and may be 5% by mass or less, or more than 5% by mass. However, it is preferable that the water content of the whole tablet is 5% by mass or more.

For the water content of the drug layer, the water content (mg) of each component is obtained from the water content (% by mass) and the content (mg) of each component constituting the drug layer, and the total of these is the content of each component. It can be calculated by dividing by the total (mg). Moreover, you may obtain | require the moisture content of a drug layer as follows.
When the tablet is a single layer tablet, first, the tablet is coarsely pulverized in a mortar. Next, the water content of the tablet is calculated from the loss on drying when the pulverized tablet is heated at 120 ° C. for 10 minutes with an electronic moisture meter, and this is used as the water content of the drug layer.
On the other hand, when the tablet is a laminated tablet, for example, the laminated tablet is cut at the interface between the drug layer and the arbitrary layer so that the drug layer does not include the optional layer, and only the drug layer is roughly pulverized with a mortar, The moisture content is calculated from the loss on drying when heated at 120 ° C. for 10 minutes with a moisture meter, and this is used as the moisture content of the drug layer. Moreover, what is necessary is just to measure the moisture content of the whole laminated tablet similarly to the case of a single layer tablet.

<Optional component>
The tablet may contain components (arbitrary components) other than the components (A), (B), and (C).
When the tablet is a monolayer tablet, the optional component may be contained in the drug layer, and when the tablet is a laminated tablet, it may be contained in the drug layer, or may be contained in the optional layer. It is preferable that it is contained in the drug layer from the viewpoint that it can be produced in the tableting process.

Examples of optional components include physiologically active components and additives.
As the physiologically active component, antipyretic analgesic components other than the component (A) (for example, piroxicam, meloxicam, ampiroxicam, celocoxib, rofecoxib, thiaramide, acetaminophen, etenzamide, sulpyrine, etc.), sedative hypnotic components (for example, allylisopropylacetyl) Urea, bromvalerylurea, etc.), antihistamine components (e.g., isothipenzil hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, dipheterol hydrochloride, triprolidine hydrochloride, tripelenamine hydrochloride, tonzylamine hydrochloride, phenetazine hydrochloride, methodirazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, Alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teocrate, mebhydroline napadisylate, Methazine methylene disalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate, chlorpheniramine maleate, dipheterol phosphate, etc.), central excitatory components (eg sodium benzoate caffeine, caffeine, anhydrous cafe ), Antitussive expectorant components (for example, 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), vitamin components (eg vitamin B1 and its derivatives and salts thereof) , Vitamin B2 and derivatives thereof, and salts thereof, vitamin C and derivatives thereof, and salts thereof, hesperidin and its derivatives and salts thereof, etc.) and the like. These physiologically active components may be used singly or in appropriate combination of two or more.

Additives include binders, excipients, disintegrants, lubricants, flavors, sweeteners, acidulants and the like. These additives may be used individually by 1 type, and may be used in combination of 2 or more types as appropriate.
Examples of the binder include starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, polyvinyl pyrrolidone, pullulan, and dextrin.
Examples of the excipient include crystalline cellulose, lactose hydrate, lactose granulated product, corn starch, powdered sugar, mannitol, L-cysteine and the like.
Examples of the disintegrant include low-substituted hydroxypropylcellulose, crospovidone, carmellose, croscarmellose sodium, and partially pregelatinized starch.
Examples of the lubricant include magnesium stearate, sodium stearyl fumarate, sucrose fatty acid ester, light anhydrous silicic acid and the like.
Examples of the fragrances include menthol, limonene, plant essential oil (for example, mint oil, mint oil, lychee oil, orange oil, lemon oil, etc.).
Examples of the sweetener include saccharin sodium, 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, glacial acetic acid, phosphoric acid and salts thereof.

  The content of the physiologically active ingredient or additive is not particularly limited as long as it does not impair the effects and storage stability of the present invention. However, among the additives described above, when the sour agent is used in combination with the component (A), the effect of the component (A) may be reduced. Therefore, it is preferable that a tablet does not contain a sour agent substantially. Here, “substantially free” means less than 0.1% by mass in 100% by mass of the tablet.

<Manufacturing method>
The tablet of the present invention can be obtained by tableting a powder constituting the drug layer (hereinafter referred to as “drug-containing powder”) to form the drug layer.
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 the component (A) of the powder, the component (B) of the powder, and the component (C) of the powder, or the component (A), (B) A granulated product containing the component and the component (C) may be used. Among these, a powder mixture is preferable because a tablet can be more easily produced.

  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. From the viewpoint of more easily producing tablets, it is preferable to use the raw powder as it is.
When the granulated product is used, a known granulation method can be adopted as the granulation method. Examples of the granulation method include a dry granulation method and a fluidized bed granulation method.

As a mixing method in the powder preparation step, the powder (A) component, the powder (B) component, the powder (C) component, and an optional component as required are mixed in a powder mixer. Examples include a method (collective mixing method) in which the powder is mixed and mixed to obtain a drug-containing powder.
Further, for example, as a mixing method in the powder preparation process, the powder (A) component, the powder (B) component, the powder (C) component, and optional components as necessary A method (sequential mixing method) of mixing them while sequentially charging them into a mixer can be mentioned.

When the drug mixed powder contains a powder other than the component (A), the component (B) and the component (C) (that is, an optional component of the powder; hereinafter referred to as “component (D)”), powder preparation As a mixing method in the process, a mixed powder (mixed powder i) of the powder (C) component and a part of the component (D), a powder (A) component, and a powder (B) component And the remainder of component (D) (division mixing method I), powder mixture (mixed powder ii) of component (C) and component (D) of powder, and powder (A) A method of mixing the component and the component (B) of the powder (division mixing method II) can be mentioned.
Above all, the mixing method in the powder preparation process is divided mixing method I, divided mixing, in order to enhance the dispersion state of the component (C) in the drug-containing powder and the tablet and to further increase the disintegration and strength of the tablet. Method II is preferred.

The component (D) contained in the mixed powder i and the mixed powder ii (hereinafter, the component (D) used in the mixed powder i and the mixed powder ii is particularly referred to as “double powder”) is described above. Among the physiologically active ingredients and additives, powders are exemplified. Among them, the powdered powder is preferably a binder, excipient, and disintegrant, and is selected from the group consisting of low-substituted hydroxypropylcellulose, carmellose, starches, lactose hydrate, lactose granule, crystalline cellulose, and mannitol. More preferably, at least one selected from the above. These powdered powders can further improve the dispersion state of the component (C) in the drug-containing powder and the tablet.
Here, the low-substituted hydroxypropyl cellulose means a low-substituted one among hydroxypropyl celluloses in which the hydroxy group of cellulose is substituted with a hydroxypropyl group. Specifically, the substitution degree (content) of the hydroxypropoxy group is 7 to 16% by mass.
Examples of starches include corn starch, pregelatinized starch, partially pregelatinized starch, potato starch, and rice starch.

As the powdered powder, low-substituted hydroxypropyl cellulose, carmellose, corn starch, partially pregelatinized starch, lactose hydrate, crystalline cellulose, and mannitol are preferable, and low-substituted hydroxypropyl cellulose, carmellose, corn starch, lactose hydrate And crystalline cellulose are more preferable, and low-substituted hydroxypropyl cellulose is particularly preferable.
A double powder may be used individually by 1 type, and may be used in combination of 2 or more types as appropriate.

The mixed powder i may be pre-mixed or newly prepared.
As a method for preparing the mixed powder i (concentration method), the powder component (C) and a part of the component (D) (concentration powder) are mixed with a high-speed stirrer, stone mill, mortar, etc. And a method of sieving a mixture of the component (C) and a part of the component (D) (double powder) with an arbitrary sieve. Especially, the method of mixing with a high-speed stirring apparatus and a stone mill grinder is preferable at the point which can mix more uniformly and can improve productivity.
In the mixed powder i, the blending ratio of the component (C) and the powdered powder is determined in consideration of the type of the powdered powder and the like, for example, the mass represented by 1000 × (B) component / powdered powder. The ratio is preferably 1-10. By setting the mass ratio within the above range, it is easy to make components other than the triturated powder into appropriate amounts while further improving the dispersion state of the component (C) in the drug-containing powder and the tablet.

The mixed powder ii may be pre-mixed or newly prepared.
As a preparation method (double powder method) of the mixed powder ii, the powder (C) component and all of the component (D) (double powder) are mixed with a high-speed stirring device, a stone mill, a mortar or the like. Method: A method of sieving a mixture of the component (C) and the component (D) (powdered powder) of the powder with an arbitrary sieve. Especially, the method of mixing with a high-speed stirring apparatus and a stone mill grinder is preferable at the point which can mix more uniformly and can improve productivity.
In the mixed powder ii, the mixing ratio of the component (C) and the powdered powder is the same as that of the mixed powder i.

  In the powder preparation process, which of the divided mixing method I and the divided mixing method II is adopted is appropriately determined according to the blending amounts of the component (C) and the component (D).

(Tablet process)
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.

(Moisture adjustment)
When manufacturing a tablet, the water content is adjusted so that the water content of the drug layer is 5% by mass or more.
The following methods (1) to (3) may be mentioned as methods for adjusting the water content.
(1) The drug-containing powder is prepared by adjusting the water content of at least one of the component (A) and the component (B) so that the water content of the drug layer is 5% by mass or more.
(2) Tableting is performed after adjusting the water content of the drug-containing powder so that the water content of the drug layer is 5% by mass or more.
(3) A drug layer having a water content of 5% by mass or more is formed and dried until the water content of the drug layer reaches a desired value (preferably 5 to 15% by mass).

In method (1), the water content of at least one of component (A) and component (B) is adjusted.
In the case where the raw material powder is used without granulating the component (A), shelf drying may be mentioned as a method for drying the raw material powder of the component (A). For example, a box-type ventilating dryer may have a drying temperature of 40 to 80. It is preferable to dry the raw powder of component (A) under the conditions of ° C and a drying time of 5 to 120 minutes.

When the raw powder of the component (A) is granulated, it may be dried while granulating, or may be dried after granulation.
When drying while granulating, fluidized bed granulation is suitable. For example, the amount of water is adjusted while fluidized bed granulation at an air supply temperature of less than 70 ° C. Furthermore, it is preferable to dry by supplying hot air at a supply air temperature of less than 70 ° C. for about 10 to 30 minutes even after the spraying of the binder is stopped.
When drying is performed after granulation, it is preferable to perform the above-described shelf drying after granulating the raw powder of component (A) by, for example, stirring granulation.

In the case where the component (B) is used as it is without being granulated, the method for drying the component (B) may be the above-described shelf drying.
When the raw powder of component (B) is granulated and used, it may be dried while granulating as in component (A), or may be dried after granulation.

In the method (1), the water content of the component (A) and the component (B) may be adjusted, or one of the water content may be adjusted. It is preferable to adjust the water content of the component (B) in terms of tablet disintegration, strength and tableting suitability.
(B) 5 mass% or more of the lower limit of the moisture content of a component is preferable, 7.5 mass% or more is more preferable, and 10 mass% or more is further more preferable. (B) 30 mass% or less of the upper limit of a component is preferable, 25 mass% or less is more preferable, and 20 mass% or less is further more preferable. (B) The intensity | strength of a tablet increases more by adjusting the moisture content of a component to 5 mass% or more.
The water content of the component (A) and the component (B) is calculated from the loss on drying when each component is heated with an electronic moisture meter at 120 ° C. for 10 minutes.

In the method (2), tableting is performed after adjusting the water content of the drug-containing powder so that the water content of the drug layer is 5% by mass or more.
Examples of the method for drying the drug-containing powder include the above-described shelf drying.
The water content of the drug-containing powder is not particularly limited as long as the water content of the drug layer is 5% by mass or more when tableted into tablets, but is preferably 5% by mass or more, preferably 5 to 15% by mass. Is more preferable, 6-12 mass% is further more preferable, and 7-10 mass% is especially preferable. When the water content of the drug-containing powder is within the above range, a drug layer having a water content of 5% by mass or more can be easily formed.
The water content of the drug-containing powder is calculated from the loss on drying when the mixture is heated at 120 ° C. for 10 minutes with an electronic moisture meter.

In the method (3), a drug layer having a water content of 5% by mass or more is formed and dried until the drug layer has a desired water content (preferably 5 to 15% by mass).
Examples of the tablet drying method include the above-described shelf drying.

  As a method for adjusting the moisture content of the tablet, the method (1) is preferable in that disintegration is further improved and a tablet having a higher strength can be efficiently obtained, and without granulating the bulk powder of the component (B). More preferably, the moisture content is adjusted by drying.

(Other processes)
The obtained tablets may be coated with a coating agent as necessary.
It is preferable to select and use a coating agent that does not impair the disintegration property of the tablet, and a water-soluble polymer compound and a plasticizer are suitable.
Examples of the water-soluble polymer compound include celluloses such as carmellose, hydroxypropylcellulose, hydroxypropylmethylcellulose, low-substituted hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, and ethylcellulose; gum arabic, carboxyvinyl polymer, povidone, crospovidone, Polyvinyl alcohol, polyacrylic acid, monosaccharides, disaccharides or higher polysaccharides (sugar (such as granulated sugar), lactose hydrate, maltose, xylose, isomerized lactose, etc.), sugar alcohols (paratinite, sorbitol, lactitol, erythritol, Xylitol, reduced starch saccharified product, maltitol, mannitol, etc.), starch syrup, isomerized sugar, oligosaccharide, sucrose, trehalose, reduced starch saccharified product (reduced starch degradation product), etc. It is below.
Examples of the plasticizer include those described in official documents such as Japanese Pharmacopoeia (Hirokawa Shoten) such as triethyl citrate and triacetin and Pharmaceutical Additives Standard (Pharmaceutical Daily News).
These water-soluble polymer compounds and plasticizers may be used alone or in appropriate combination of two or more.
The coating amount of the coating agent is appropriately set as long as the effect of the present invention is not impaired.

<Effect>
Since the tablet of the present invention contains the above-described component (A), component (B), and component (C) in the same layer, it is excellent in disintegration. In addition, since the water content of the drug layer is 5% by mass or more, the strength is high.
Moreover, according to the manufacturing method of the tablet mentioned above, it is excellent in disintegration and can manufacture a tablet with high intensity | strength simply.

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, component C trituration method, measurement / evaluation method used in each example and comparative example are as follows.

[Raw materials]
・ Loxoprofen sodium hydrate: Daiwa Pharmaceutical Co., Ltd. ・ Dry aluminum hydroxide gel: Kyowa Chemical Industry Co., Ltd. ・ Aluminum glycinate: Kyowa Chemical Industry Co., Ltd. ・ Synthetic hydrotalcite: Kyowa Chemical Industry Co., Ltd. Magnesium aluminate metasilicate: manufactured by Fuji Chemical Industry Co., Ltd. Magnesium oxide: manufactured by Tomita Pharmaceutical Co., Ltd., magnesium carbonate: manufactured by Tomita Pharmaceutical Co., Ltd., iron sesquioxide: manufactured by Kasei Kasei Co., Ltd. Product: Low substituted hydroxypropyl cellulose: Shin-Etsu Chemical Co., Ltd., product name: LH-31
-Corn starch: Matsutani Chemical Industry Co., Ltd.-Partially pregelatinized starch: Asahi Kasei Chemicals Co., Ltd.-Mannitol: Rocket Japan Co., Ltd.-Lactose hydrate: DSP Gokyo Food & Chemicals Co., Ltd.-Lactose granule: Product name: Lactose G, manufactured by Freund Sangyo Co., Ltd.
・ Carmellose: Nichirin Chemical Industries, Ltd. ・ Magnesium stearate: Taihei Chemical Industries, Ltd.

[Tabletting conditions]
-Tablet press: Rotary tablet press (manufactured by Kikusui Seisakusho Co., Ltd., “Libra 3L”)
-Board rotation speed: 20 rpm
-Usuki: diameter 8.5mm (2 steps R) x 12 stands, no stamping (cap height 0.1mm, R1 = 10, R2 = 3.4)
・ Main pressure: 10 kN (about 100 MPa, about 1000 kg / cm ² )

[Method for doubling component (C)]
<High speed stirring>
Component (C) and powdered powder are weighed to a predetermined ratio and a total of 200 g, put into a high-speed stirrer high-speed mixer 2L type (manufactured by Earth Technica Co., Ltd.), and stirred at high speed under the following conditions: Then, component (C) was dry-typed.
・ Agitator rotation speed: 300rpm
・ Chopper rotation speed: 2000rpm
・ Stirring time: 5 minutes

<Sieving>
(C) Ingredients and triturated powder are weighed to a predetermined ratio and a total of 200 g, put in a plastic bag, mixed by shaking about 20 times by hand, and then sieved using a sieve having an opening of 150 μm. The component (C) was dry-typed.

<Wet granulation>
Component (C) and powdered powder are weighed to a predetermined ratio and a total of 200 g, put into a high-speed stirrer high-speed mixer 2L type (manufactured by Earth Technica Co., Ltd.), and water is added dropwise at 4 g / min. While stirring at high speed for 5 minutes under the following conditions (amount of water dropped was 20 g in total), granules were obtained. The obtained granule was put into a fluidized bed granulator (Spiler flow type 5), dried at a supply air temperature of less than 70 ° C., and the component (C) was wet-dried.
・ Agitator rotation speed: 300rpm
・ Chopper rotation speed: 2000rpm
・ Stirring time: 5 minutes

[Measurement and evaluation method]
<Calculation of water content>
The water content (% by mass) of the drug layer is determined from the water content (% by mass) and the content (mg) of each component constituting the drug layer, and the total amount of each is determined for each component. It was calculated by dividing by the total content (mg) of the components.
The moisture content (% by mass) of each component was calculated from the loss on drying when heated at 120 ° C. for 10 minutes with an electronic moisture meter (manufactured by Shimadzu Corporation, “MOISTURE BALANCE MOC-120H”). Specifically, the mass before heating was a, and the mass after heating was b.
Water content (% by mass) = (ab) / a × 100

<Evaluation of disintegration>
(initial)
The disintegration time of the tablets in water was measured according to the disintegration test method for tablets listed in the Japanese Pharmacopoeia. The disintegration test was conducted on 6 tablets, and the average value of the measurement results was calculated and evaluated according to the following evaluation criteria. A shorter disintegration time means better disintegration. Pass 3 or more points.
6 points: The average value of the disintegration time is less than 1 minute.
5 points: The average value of the disintegration time is 1 minute or more and less than 1.5 minutes.
4 points: The average value of the disintegration time is 1.5 minutes or more and less than 2 minutes.
3 points: The average value of the disintegration time is 2 minutes or more and less than 3 minutes.
2 points: The average value of the disintegration time is 3 minutes or more and less than 5 minutes.
1 point: The average value of the disintegration time is 5 minutes or more or does not disintegrate even if 5 minutes or more have elapsed.

(After saving)
The tablets were packed in PTP (press-through package) and stored for 6 weeks under conditions of a temperature of 50 ° C. and a humidity of 75% RH.
About the tablet after a preservation | save, the disintegration test was done like the initial stage and disintegration was evaluated.

<Strength evaluation>
Twenty tablets were subjected to a friability tester (manufactured by Toyama Sangyo Co., Ltd.) and rotated at 25 rpm for 10 minutes. After the end of rotation, the tablet mass was measured to determine the friability. Specifically, the mass of 20 tablets before the test was set as c, and the mass of the 20 tablets after the test was set as d.
Friction degree (%) = (cd) / c × 100

Based on the obtained friability, the following evaluation criteria were used. A lower friability means higher tablet strength. Three or more points were accepted.
6 points: Wear rate is less than 0.1%.
5 points: Abrasion rate is 0.1% or more and less than 0.2%.
4 points: Abrasion rate is 0.2% or more and less than 0.3%.
3 points: Abrasion rate is 0.3% or more and less than 0.4%.
2 points: The degree of friability is 0.4% or more, but tablet breakage does not occur.
1 point: Tablet breakage occurred.

[Example 1]
The dried aluminum hydroxide gel (component (B)) was dried and conditioned under conditions of a temperature of 40 ° C. and a humidity of 75% RH until the water content reached 15% by mass.
Iron sesquioxide and low-substituted hydroxypropyl cellulose in a ratio of 5 mg of low-substituted hydroxypropylcellulose ((D) component: triturated powder) to 0.05 mg of iron sesquioxide (component (C)) 200 g was weighed and ferric trioxide was triturated by high speed stirring.
Loxoprofen sodium hydrate (component (A)) 68.1 mg, conditioned dry aluminum hydroxide gel 120 mg, dry triturated iron sesquioxide, lactose granulated product (component (D)) 100 mg, stearin 2 mg of magnesium acid (component (D)) was mixed to obtain a drug mixed powder, which was tableted to obtain a tablet comprising a drug layer. The amount of iron trioxide that was dry-divided was such that the amount of iron trioxide in the drug layer was 0.05 mg and the amount of low-substituted hydroxypropylcellulose was 5 mg.
Table 1 shows the mass ratio of each component. In addition, the mass of (A) component and (B) component was made into the pure component conversion amount (anhydride conversion amount).

The resulting tablets were evaluated for disintegration and strength. These results are shown in Table 1.
Moreover, when the water content of the tablet (drug layer) was calculated, it was as shown below. The results are shown in Table 1.
The water content of the loxoprofen sodium hydrate as component (A) was 11.9% by mass. Accordingly, 8.1 mg of water is contained in 68.1 mg of loxoprofen sodium hydrate.
Since the moisture content of the dry aluminum hydroxide gel (B) is 15% by mass, the dry aluminum hydroxide gel 120 mg contains 18 mg of water.
The water content of the components other than the components (A) and (B) (the components (C) and (D)) was 1% by mass in total. Therefore, the total of 107.05 mg of component (C) and component (D) contains 1.07 mg of water.
The total amount of water contained in each component constituting the drug layer (that is, the amount of water in the drug layer) is 27.17 mg, and the total content of each component constituting the drug layer (ie, the mass of the tablet) Was 295.15 mg, so the water content in 100% by mass of the tablet (drug layer) was 9.2% by mass.

[Examples 2 to 6]
The component (B) of the type shown in Table 1 was dried and conditioned under conditions of a temperature of 40 ° C. and a humidity of 75% RH until the water content was 15% by mass.
A tablet was produced in the same manner as in Example 1 except that the conditioned component (B) was used in an amount shown in Table 1, and the water content of the tablet (drug layer) was calculated. Evaluated. These results are shown in Table 1.

[Example 7]
(C) Except having changed the kind of component into yellow ferric oxide, the tablet was manufactured like Example 1, the moisture content of the tablet (drug layer) was computed, and disintegration and intensity | strength were evaluated. These results are shown in Table 1.

[Comparative Example 1]
Loxoprofen sodium hydrate 68.1 mg, dried aluminum hydroxide gel 120 mg conditioned in the same manner as in Example 1, low-substituted hydroxypropylcellulose 5 mg, lactose granule 100 mg, and magnesium stearate 2 mg The mixture was mixed to obtain a drug mixed powder, and this was tableted to obtain a tablet comprising a drug layer. Table 2 shows the mass ratio of each component.
The water content of the tablet (drug layer) was calculated and evaluated for disintegration and strength. These results are shown in Table 2.

[Comparative Example 2]
A tablet was produced in the same manner as in Example 1 except that the conditioned dry aluminum hydroxide gel was not used, the water content of the tablet (drug layer) was calculated, and the disintegration and strength were evaluated. These results are shown in Table 2.

[Comparative Example 3]
A tablet was produced in the same manner as in Example 1 except that the dried aluminum hydroxide gel was dried until the moisture content was 2.2% by mass, and the moisture content of the tablet (drug layer) was calculated. The results are shown in Table 2.
In addition, although it tried to evaluate disintegration and intensity | strength, since it collapsed immediately when a tablet was picked, it was not able to evaluate.

As is apparent from Table 1, the tablets obtained in each Example were excellent in disintegration and high in strength.
On the other hand, the tablets obtained in Comparative Examples 1 and 2 were inferior in disintegration and low in strength.
Note that, as described above, the tablet obtained in Comparative Example 3 collapses as soon as it is picked by hand. Therefore, although the disintegration is excellent, the strength is low.

[Examples 8 to 13]
A tablet was produced in the same manner as in Example 1 except that the conditioned dry aluminum hydroxide gel was used so as to have an amount shown in Table 3, and the moisture content of the tablet (drug layer) was calculated. The strength was evaluated. These results are shown in Table 3.

[Examples 14 to 18]
A total of 200 g of ferric sesquioxide and low-substituted hydroxypropylcellulose are weighed at a ratio of 5 mg of low-substituted hydroxypropylcellulose to the amount of ferric sesquioxide shown in Table 4, and the ferric sesquioxide is dry-typed by high speed stirring Scattered.
A tablet was prepared in the same manner as in Example 1 except that dry triturated iron sesquioxide was used so that the amounts of iron sesquioxide and low-substituted hydroxypropylcellulose in the drug layer were as shown in Table 4. The water content of the tablet (drug layer) was calculated, and disintegration and strength were evaluated. These results are shown in Table 4.

  As is apparent from Tables 3 and 4, the tablets obtained in each Example were excellent in disintegration and high in strength.

[Examples 19 to 24]
The dried aluminum hydroxide gel was dried until the amount of water (mass%) reached the value shown in Table 5. When the water content was less than 15% by mass, drying was performed under conditions of a temperature of 40 ° C. and a humidity of 75% RH. When the water content was 15% by mass or more, humidification was performed under conditions of a temperature of 40 ° C. and a humidity of 90% RH. Moreover, the moisture content of (B) component was adjusted by adjustment of drying or humidification time. For example, in Example 21, it was dried for 240 minutes to obtain a dry aluminum hydroxide gel having a moisture content of 7.5% by mass.
A tablet was produced in the same manner as in Example 1 except that dry aluminum hydroxide gel adjusted to each moisture content was used, and the moisture content of the tablet (drug layer) was calculated to evaluate disintegration and strength. These results are shown in Table 5.

  As is apparent from Table 5, the tablets obtained in each Example were excellent in disintegration and high in strength.

[Example 25]
A total of 200 g of iron sesquioxide and low-substituted hydroxypropyl cellulose was weighed at a ratio of 0.05 mg of iron sesquioxide to 10 mg of low-substituted hydroxypropyl cellulose, and the iron sesquioxide was triturated by high speed stirring.
Loxoprofen sodium hydrate 68.1 mg, dry aluminum hydroxide gel 100 mg conditioned in the same manner as in Example 1, dry triturated iron sesquioxide, lactose granule 100 mg, and magnesium stearate 2 mg The mixture was mixed to obtain a drug mixed powder, and this was tableted to obtain a tablet comprising a drug layer. The amount of iron trioxide that was dry-divided was such that the amount of iron trioxide in the drug layer was 0.05 mg and the amount of low-substituted hydroxypropylcellulose was 10 mg. Table 6 shows the mass ratio of each component.
The water content of the tablet (drug layer) was calculated and evaluated for disintegration and strength. These results are shown in Table 6.

[Examples 26 to 30]
A tablet was produced in the same manner as in Example 25 except that the ferric trioxide was dry-dried using the powdered powder of the type shown in Table 6, and the water content of the tablet (drug layer) was calculated. The strength was evaluated. These results are shown in Table 6.

[Examples 31 and 32]
The water content of the tablet (drug layer) was calculated in the same manner as in Example 25 except that ferric sesquioxide was triturated by the method shown in Table 6, and disintegration and strength were evaluated. These results are shown in Table 6.

  As is clear from Table 6, the tablets obtained in each Example were excellent in disintegration and high in strength. Among them, the tablets obtained in Examples 25 to 30 in which the component (C) was dry-typed by high-speed stirring were obtained in Examples 31 and 32 in which the component (C) was triturated by sieving or wet granulation. The disintegration was superior to that of tablets.

Claims (10)

And the following component (A), and the following component (B), comprising a drug layer having both following component (C) state, and are water content of the drug layer is 5 mass% or more,
In the total mass of the drug layer of 100% by mass, the content of the component (A) in the drug layer is 15 to 35% by mass, and the content of the component (B) in the drug layer is 4.5 to 50% by mass, The content of the component (C) in the drug layer is 0.0033 to 0.1% by mass,
The mass ratio represented by (B) component / (A) component is 0.14-3,
1000 × (C) component / (A) weight ratio expressed by component Ru der 0.15 to 3.5, the tablets.
(A) component: At least 1 sort (s) chosen from the group which consists of loxoprofen and its salt.
Component (B): At least one selected from the group consisting of dry aluminum hydroxide gel, aluminum glycinate, magnesium carbonate, magnesium oxide, magnesium aluminate metasilicate, and synthetic hydrotalcite.
Component (C): At least one selected from the group consisting of iron sesquioxide, yellow iron sesquioxide and black iron oxide .   The tablet according to claim 1, wherein the component (C) is at least one of ferric oxide and yellow ferric oxide. The tablet of Claim 1 or 2 whose mass ratio represented by 1000x (C) component / (B) component is 0.2-3 . The component (D) includes powders other than the component (A), the component (B), and the component (C), and the component (D) is selected from the group consisting of a binder, an excipient, and a disintegrant. The tablet as described in any one of Claims 1-3 which is 1 or more types . It is a manufacturing method of the tablet according to any one of claims 1 to 3 ,
A method for producing a tablet, wherein the drug layer is formed by tableting the powder constituting the drug layer.   The powder (A) of the powder, the component (B) of the powder, and the component (C) of the powder are mixed to prepare a powder constituting the drug layer. The manufacturing method of the tablet of description. The powder constituting the drug layer includes a powder other than the component (A), the component (B) and the component (C) as the component (D),
A powder mixture of the component (C) of the powder and a part of the component (D), the component (A) of the powder, the component (B) of the powder, and the remainder of the component (D) The method for producing a tablet according to claim 5 or 6, further comprising a step of obtaining a powder constituting the drug layer by mixing. The powder constituting the drug layer includes a powder other than the component (A), the component (B) and the component (C) as the component (D),
The mixed powder of the component (C) and the component (D) of the powder, the component (A) of the powder and the component (B) of the powder are mixed to form the drug layer. The manufacturing method of the tablet of Claim 5 or 6 which has the process of obtaining powder.   The method for producing a tablet according to claim 7 or 8, wherein the component (D) is one or more selected from the group consisting of a binder, an excipient, and a disintegrant.   Adjusting the water content of at least one of the component (A) and the component (B) so that the water content of the drug layer is 5% by mass or more, and preparing a powder constituting the drug layer, The manufacturing method of the tablet as described in any one of Claims 6-9.