JP6433066B2 - Tablet and production method thereof - Google Patents

Description

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

Non-steroidal anti-inflammatory drugs (hereinafter referred to as “NSAIDs”) such as loxoprofen sodium and ibuprofen have strong adhesion, so when tablets containing NSAIDs are compressed, the powder adheres to the punches of the tablet press. Phenomenon (hereinafter referred to as “wrinkle adhesion”) is likely to occur.
Until now, a method of blending a large amount of lubricant such as magnesium stearate has been adopted as one method for preventing wrinkle adhesion.
However, when the amount of the lubricant is increased, the tablet strength is lowered, cracking and chipping are likely to occur during the production process and transportation, and disintegration and dissolution properties are liable to be lowered.

Other methods for preventing wrinkle adhesion include a method of granulating NSAIDs together with excipients such as corn starch and saccharides.
For example, Patent Document 1 includes a step of mixing loxoprofen sodium and corn starch to obtain a mixture, kneading the mixture with a cellulose-containing aqueous solution, granulating and drying to obtain granules, and A method is disclosed in which a tablet is obtained through a step of mixing the granule with light anhydrous silicic acid and a lubricant to obtain a composition for producing a compressed preparation, and then compressing and molding the composition for producing a compressed preparation. .

Patent Document 2 discloses a method of obtaining tablets by spraying a solution containing a cellulosic preparation raw material onto a granular material containing loxoprofen sodium and a saccharide, drying and tableting.
However, when the method of granulating loxoprofen sodium together with excipients such as corn starch and saccharides is adopted, the number of production steps increases, resulting in a decrease in production efficiency and an increase in cost.

  Furthermore, Patent Document 3 discloses a powder obtained by mixing a high-adhesive drug such as loxoprofen sodium with a water-absorbing additive such as magnesium aluminate metasilicate and low-substituted hydroxypropyl cellulose and pregelatinized starch in a predetermined amount. A method for producing a tablet is disclosed in which a tablet is mixed and supplied to a rotary tableting machine for tableting. According to this manufacturing method, the manufacturing process is simplified and a tablet with reduced tableting troubles can be obtained.

Japanese Patent Laid-Open No. 10-182448 JP 2000-16936 A JP 2006-143650 A

However, even the invention described in Patent Document 3 does not sufficiently suppress wrinkle adhesion that occurs when tableting powder containing NSAIDs, and further improvements are desired. In particular, when the blending ratio of the NSAIDs in the layer containing NSAIDs is 30% by mass or more, it is difficult to suppress wrinkle adhesion during tableting.
Then, this invention aims at the tablet with which the wrinkle adhesion at the time of tableting produced when manufacturing the tablet which has a layer which mix | blends 30 mass% or more of NSAIDs was suppressed.

As a result of intensive studies, the present inventors produce a tablet having a layer containing 30% by mass or more of NSAIDs by adding a coloring agent (B) to a drug layer containing 30% by mass or more of NSAIDs. The present inventors have found that the adhesion of wrinkles that occurs during tableting can be suppressed, and the present invention has been completed.
That is, the present invention has the following aspects [1] to [7].
[1] It has a drug layer containing a non-steroidal anti-inflammatory drug (A) and a colorant (B), and the blending ratio of the non-steroidal anti-inflammatory drug (A) in the drug layer is 30% by mass or more. Yes, tablet whose mass ratio represented by “10000 × (B) component / drug layer” is 0.01 or more and 3 or less.
[2] The tablet according to [1], wherein the component (A) is at least one selected from loxoprofen sodium, ibuprofen and aspirin.
[3] The tablet according to [1] or [2], which is a multilayer tablet having the drug layer and a layer containing an antacid and an inorganic salt other than the antacid.
[4] The method for producing a tablet according to [1] or [2], wherein a tableting machine having a mortar and a punch is used to fill the mortar with the powder constituting the drug layer and tablet the tablet.
[5] Using a tableting machine having a mortar and a punch, the powder constituting the drug layer is placed after the powder constituting the layer containing the antacid and an inorganic salt other than the antacid. The method for producing a tablet according to [3], wherein the mortar is filled and tableted.
[6] The powder constituting the drug layer contains powder (C) other than the components (A) to (B), and the (B) component and part of the (C) component of the powder [4] or [5], wherein the mixed powder is mixed with the component (A) and the remainder of the component (C) to obtain the powder constituting the drug layer. ] The manufacturing method of the tablet of description.
[7] The powder constituting the drug layer contains powder (C) other than the components (A) to (B), and the powder (B) and the component (C) are mixed. The method for producing a tablet according to [4] or [5], comprising a step of mixing the powder and the component (A) of the powder to obtain a powder constituting the drug layer.
[8] The method for producing a tablet according to [6] or [7], wherein the component (C) is at least one selected from a binder, an excipient, and a disintegrant.

  ADVANTAGE OF THE INVENTION According to this invention, the tablet with which the wrinkle adhesion at the time of tableting produced when manufacturing the tablet which has a layer which mix | blends 30 mass% or more of NSAIDs was suppressed can be provided.

<Tablets>
The tablet of the present invention has a drug layer containing NSAIDs (A) (hereinafter referred to as “component (A)”) and a colorant (B) (hereinafter referred to as “component (B)”). The blending ratio of the component (A) in the layer is 30% by mass or more.
The tablet may be a monolayer tablet or a multilayer tablet as long as it has the drug layer.
In tablets containing NSAIDs, the tablets are usually used in combination with an antacid from the viewpoint of suppressing gastrointestinal damage caused by NSAIDs. However, NSAIDs and antacids interfere with each other when they come into contact with each other in the preparation, causing problems such as a decrease in the content of NSAIDs or discoloration of the preparation over time. Therefore, when a tablet containing NSAIDs and an antacid is used, the tablet is often a multilayer tablet divided into a layer containing NSAIDs and a layer containing antacid. When a tablet containing NSAIDs and an antacid is made into a multilayer tablet, it is necessary to increase the blending ratio of the NSAIDs in the layer containing NSAIDs from the viewpoint of maintaining the content of NSAIDs per tablet. Therefore, when a tablet containing NSAIDs and an antacid is a multi-layered tablet, wrinkle adhesion is more likely to occur compared to a single-layer tablet. Therefore, the tablet of the present invention is preferably a multilayer tablet from the viewpoint of easily enjoying the effects of the present invention.
Moreover, it is preferable that the said tablet is a gastric disintegrating tablet which disintegrates in a stomach from the point which is easy to use as an antipyretic analgesic and a cold medicine, and the point which is easy to drink.

The size of the tablet is not particularly limited, but the tablet diameter is preferably 6 to 13 mm, more preferably 7 to 10 mm, and even more preferably 7 to 9 mm from the viewpoint of ease of tablet handling and swallowability. Moreover, 3.0-7.5 mm is preferable, as for the thickness of a multilayer tablet, 3.5-7.0 mm is more preferable, and 4.0-6.5 mm is further more preferable.
Further, the mass per tablet is preferably 150 to 550 mg.

[Drug layer]
The drug layer contains the component (A) and the component (B). Moreover, the blending ratio of the component (A) in the drug layer is 30% by mass or more.

((A) component)
The component (A) is NSAIDs.
NSAIDs are not particularly limited. NSAIDs include loxoprofen, ibuprofen, acetaminophen, acetylsalicylic acid (aspirin), naproxen, ketoprofen, indomethacin, bufexamac, diclofenac, alclofenac, fenclofenac, etodolac, flurbiprofen, ketoprofen, mefenamic, me Examples include clofenamic and piroxicam. Among these, loxoprofen, ibuprofen, acetaminophen, and aspirin are preferable because the effects of the present invention can be easily obtained.
These NSAIDs may be used alone or in combination of two or more.

The compounding ratio of the component (A) in the drug layer is 30% by mass or more. The blending ratio of the component (A) in the drug layer is preferably 32% by mass or more and 90% by mass or less, and more preferably 35% by mass or more and 80% by mass or less.
If the compounding ratio of the component (A) in the drug layer is equal to or higher than the lower limit value, the number of tablets to be taken per time can be reduced, while if it is equal to or lower than the upper limit value, the component (B) is added to the drug layer. It can be contained sufficiently, and wrinkle adhesion during tableting can be suppressed.

((B) component)
Examples of the colorant include food colorants, organic pigments and inorganic pigments other than food colorants, animal and plant extracts, and the like.
Food colorants include orange essence, caramel, carmine, β-carotene, edible blue No. 1, edible yellow No. 4, edible yellow No. 4 aluminum lake, edible yellow No. 5, edible red No. 2, edible red No. 3, 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 animal and plant extracts include licorice extract, Acacia tannin powder, turmeric extract, and green tea powder.
Among them, inorganic pigments are preferable from the viewpoint of suppressing soot adhesion, and inorganic pigments mainly composed of iron such as yellow iron sesquioxide, iron sesquioxide, and black iron oxide are more preferable. Is most preferred.
A coloring agent may be used individually by 1 type, and 2 or more types may be used in combination.

The blending ratio of the component (B) in the drug layer is not particularly limited. For example, the mass ratio represented by “10000 × (B) component / drug layer” is preferably 0.01 or more and 3 or less.
When the component (A) is loxoprofen, ibuprofen or a salt thereof, the lower limit of “10000 × (B) component / drug layer” is preferably 0.05 or more, more preferably 0.2 or more. Preferably, it is more preferably 0.4 or more, and most preferably 0.5 or more.
When the component (A) is aspirin, acetaminophen or a salt thereof, the lower limit of “10000 × (B) component / drug layer” is preferably 0.01 or more, and preferably 0.1 or more. Is more preferable and 0.2 or more is most preferable.
When the blending ratio of the component (B) in the drug layer is within the above range, an adhesion suppressing effect can be obtained, the color density of the drug layer becomes appropriate, and the tablet hardness is improved.

  The blending ratio of the component (B) to the component (A) in the drug layer is not particularly limited, but is, for example, 0.03 or more in a mass ratio represented by “10000 × (B) component / (A) component”. The following is preferable.

When component (A) is loxoprofen sodium or a salt thereof, the lower limit of “10000 × (B) component / (A) component” is preferably 0.1 or more, more preferably 0.5 or more. Preferably, it is more preferably 1.0 or more, and most preferably 1.4 or more.
When the component (A) is ibuprofen or a salt thereof, the lower limit of “10000 × (B) component / (A) component” is preferably 0.1 or more, and more preferably 0.5 or more. 0.9 or more is most preferable.
When the component (A) is acetaminophen or a salt thereof, the lower limit of “10000 × (B) component / (A) component” is preferably 0.05 or more, and more preferably 0.2 or more. More preferably, it is 0.4 or more.
When the component (A) is aspirin or a salt thereof, the lower limit of “10000 × (B) component / (A) component” is preferably 0.03 or more, and more preferably 0.15 or more. 0.25 or more is most preferable.
When the blending ratio of the component (B) to the component (A) is within the above range, an adhesion suppressing effect is obtained, the color density of the drug layer becomes appropriate, and the tablet hardness is improved.

(Optional component)
In the drug layer, in addition to the component (A) and the component (B), optional components such as physiologically active components and additives may be blended within a range not impairing the effects of the present invention.

Bioactive ingredients:
Examples of the physiologically active component include antipyretic analgesic components other than the component (A) (for example, piroxicam, meloxicam, ampiroxicam, serocoxib, rofecoxib, thiaramide, acetaminophen, etenzamide, sulpyrine, etc.), sedative hypnotic components (for example, allyl Isopropylacetylurea, bromvalerylurea, etc.), antihistamine components (for example, isothipenzil hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, dipheterol hydrochloride, triprolidine hydrochloride, tripelenamine hydrochloride, tonsylamine hydrochloride, phenetazine hydrochloride, methodirazine hydrochloride, diphenhydramine salicylate, diphenyldisulfonic acid Carbinoxamine, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teocrate, mebhydro napadisylate , Promethazine methylene disalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate, chlorpheniramine maleate, dipheterol phosphate, etc.), central excitatory components (eg sodium benzoate caffeine, caffeine, anhydrous Caffeine etc.), antitussive expectorant ingredients (codeine phosphate, dextromethorphan hydrobromide, dimemorphan phosphate, tipepidine hibenzate, methoxyphenamine hydrochloride, trimethquinol hydrochloride, carbocysteine, acetyl Cysteine, ethylcysteine, dl-methylephedrine, bromhexine hydrochloride, serrapeptase, lysozyme chloride, ambroxol, theophylline, aminophylline, etc.), vitamin components (eg vitamin B1 and its derivatives and their S, vitamin B2 and derivatives thereof, and salts thereof, vitamin C and its derivatives and their salts, hesperidin and its derivatives and salts thereof, etc.) and the like.
These physiologically active components can be used singly or in appropriate combination of two or more.

Additive:
Examples of the additive include a binder, an excipient, a disintegrant, a lubricant, a fragrance, a sweetener, a sour agent, and a coating agent other than the component (B).
Examples of the binder include starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, polyvinyl pyrrolidone, pullulan, and dextrin.
Excipients include crystalline cellulose, lactose (hydrate), corn starch (corn starch), powdered sugar, mannitol, L-cysteine, etc. Among them, crystalline cellulose, lactose (hydrate), powdered sugar , Mannitol and L-cysteine are preferred.
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 acid and the like.

Examples of the fragrances include menthol, limonene, plant essential oil (mint oil, mint oil, lychee oil, orange oil, lemon oil, etc.) and the like.
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, and salts thereof.
Among these additives, crystalline cellulose, sucrose fatty acid ester, and low-substituted hydroxypropylcellulose are preferable from the viewpoint of better suppressing wrinkle adhesion during tableting.
These additives can be used singly or in appropriate combination of two or more.

The mixing ratio (mass%) of the optional component in the drug layer is not particularly limited as long as it does not impair the effects of the present invention and the properties such as the disintegration property and dissolution property of the tablet. Moreover, the blending ratio of the optional component in the drug layer is preferably less than 70% by mass, more preferably 60% by mass or less, further preferably 30% by mass or less, and particularly preferably 10% by mass or less.
In particular, when a lubricant is included in the drug layer, the blending ratio of the lubricant in the drug layer reduces tablet strength, cracks and chips during the manufacturing process and during transportation, and decreases disintegration and dissolution properties. From the point to suppress, 0.1-5 mass% is preferable, and 0.5-2 mass% is more preferable.

[Arbitrary layer]
When the tablet is a multilayer tablet, layers other than the drug layer (hereinafter referred to as “arbitrary layer”) are arbitrarily set. The arbitrary layer may be a single layer or two or more layers.
The components to be blended in the arbitrary layer are appropriately set, and examples thereof include the physiologically active component, the additive, the antacid, and inorganic salts other than the antacid.
Especially, it is preferable that an arbitrary layer contains an antacid from the point which suppresses the gastric acid secretion excessive by (A) component. Moreover, it is preferable that an arbitrary layer contains inorganic salt other than an antacid and this antacid from the point which suppresses soot adhesion more.

  Antacids include aminoacetic acid, dry aluminum hydroxide gel, aluminum glycinate, anhydrous calcium hydrogen phosphate, light anhydrous silicic acid, magnesium aluminate metasilicate, magnesium carbonate, magnesium oxide, synthetic hydrotalcite, synthetic silicic acid Aluminum, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / calcium carbonate / magnesium carbonate coprecipitation product, magnesium hydroxide / aluminum potassium sulfate co-precipitation product Precipitation products, sucralfate, magnesium silicate and the like can be mentioned. Among these, those containing aluminum are preferable.

Examples of inorganic salts other than the antacid include inorganic pigments such as hydrous silicon dioxide, talc, kaolin, zinc oxide, titanium oxide, yellow ferric oxide, ferric oxide. Among these, hydrous silicon dioxide and iron-based components (iron trioxide, black iron oxide, yellow iron trioxide) are preferable, and iron trioxide is more preferable.
The components included in the arbitrary layer can be used singly or in appropriate combination of two or more.

[coating]
The tablet of the present invention may be coated with a coating agent.
A coating agent that does not significantly impair disintegration and solubility is preferable. Specific examples include water-soluble polymer compounds and plasticizers.
Examples of water-soluble polymer compounds 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 (granulated sugar), etc.), lactose, maltose, xylose, isomerized lactose, etc., sugar alcohols (palatinite, sorbitol, lactitol, erythritol, xylitol, reduced starch) Saccharified product, maltitol, mannitol, etc.), starch syrup, isomerized saccharide, oligosaccharide, sucrose, trehalose, reduced starch saccharified product (reduced starch degradation product) and the like.
Examples of the plasticizer include those described in official documents such as Japanese Pharmacopoeia (Hirokawa Shoten) such as triethyl citrate and triacetin, and pharmaceutical additive standards (Pharmaceutical Daily Inc.).
The coating amount of the coating agent is appropriately set as long as the effects of the present invention and the characteristics such as disintegration and dissolution properties of the tablet are not impaired.

<Tablet production method>
The tablet is produced by a known tableting method. As a method for producing a tablet, for example, using a tableting machine having a mortar and a punch, a step of forming a tablet by compressing a powder constituting a drug layer (sometimes referred to as a drug-containing powder) (molding) Having a step).

The drug-containing powder may be a powder containing the components (A) to (B), 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 and the component (B) of the powder, or a granulated product containing the components (A) to (B). A powder mixture is preferable because a tablet can be more easily produced.

  The drug-containing powder may be premixed 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 drug-containing powder is obtained by mixing the components (A) to (B) of the 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.

  10-2000 micrometers is preferable and, as for the volume average particle diameter of each component which is powder, 100-1500 micrometers is more preferable.

As a mixing method in the powder preparation step, the components (A) to (B) of the powder and optional components as needed are collectively charged into a powder mixer and mixed to obtain a drug-containing powder. The method (batch mixing method) is mentioned.
Further, for example, as a mixing method in the powder preparation step, there may be mentioned a method in which the components (A) to (B) of the powder and optional components as necessary are sequentially added to the powder mixer while mixing them. (Sequential mixing method).

In the case where the drug-containing powder contains powder (C) other than the components (A) to (B) (that is, an optional component of the powder, hereinafter may be referred to as component (C)), in the powder preparation step As a mixing method, a mixed powder (mixed powder i) of the component (B) and a part of the component (C) is mixed with the remaining components (A) and (C) (divided mixing method). A mixed powder (mixed powder ii) of the components I) and (B) and the component (C) and the component (A) are mixed (divided mixing method II).
Among them, as the mixing method in the powder preparation step, the divided mixing method I or II is used in that the dispersion state of the component (B) in the drug-containing powder and the tablet can be increased, and wrinkle adhesion during tableting can be further suppressed. preferable.

  As the component (C) contained in the mixed powders i and ii (hereinafter, the component (C) used in the mixed powder i or ii may be referred to as a powdered powder), the above-mentioned physiologically active components and additives Of these, powders can be mentioned. Among these, as the powdered powder, a binder, an excipient, and a disintegrant are preferable, and one or more kinds selected from low-substituted hydroxypropylcellulose, carmellose, lactose hydrate, and corn starch are more preferable. These powdered powders can further improve the dispersion state of the component (B) in the drug-containing powder and the tablet.

The mixed powder i may be pre-mixed or newly prepared.
Examples of the method for preparing the mixed powder i include a method in which the component (B) and a part of the component (C) are mixed with a high-speed stirrer, a stone mill, a mortar, or the like. Moreover, for example, a method of sieving the component (B) of the powder with an arbitrary sieve and mixing the sieved (B) component with a part of the (C) component can be mentioned. Especially, the method of mixing with a high-speed stirring apparatus and a stone mill type 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 (B) and the triturating medium is determined in consideration of the type of the triturating powder and the like, for example, the mass represented by 1000 × (B) component / diluting powder. The ratio is preferably 1 to 10, more preferably 2 to 8, and still more preferably 3 to 6. If it is more than the said lower limit, the further improvement of the dispersion state of (B) component in a medicine containing powder and a tablet can be aimed at. If it is below the said upper limit, it will be easy to make components other than triturated powder into appropriate quantity.

The mixed powder ii may be pre-mixed or newly prepared.
Examples of the method for preparing the mixed powder ii include a method in which the components (B) and (C) are all mixed with a high-speed stirring device, a stone mill, a mortar, or the like. Further, for example, there is a method in which the (B) component of the powder is sieved with an arbitrary sieve and the sieved (B) component and all of the (C) component are mixed. Especially, the method of mixing with a high-speed stirring apparatus and a stone mill type 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 (B) and the triturating medium is the same as that of the mixed powder i.

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

Examples of the tableting machine used in the molding step include a rotary tableting machine (manufactured by Kikusui Seisakusho: LIBRA2).
Tableting conditions such as tableting pressure and rotation speed of the rotating disk are set as appropriate. For example, the tableting pressure is appropriately set so that the tablet hardness is 5 to 500N.

  When the tablet is a multi-layer tablet, the drug-containing powder may be initially filled in the die, or may be filled after the powder constituting any layer (arbitrary layer) other than the drug layer. . From the viewpoint of further suppressing wrinkle adhesion, the drug-containing powder is preferably filled into the mortar after the powder constituting the arbitrary layer.

<Effect>
ADVANTAGE OF THE INVENTION According to this invention, the tablet with which the wrinkle adhesion at the time of tableting produced when manufacturing the tablet which has a layer which mix | blends 30 mass% or more of NSAIDs was suppressed can be provided.
In addition, since the drug layer can be appropriately colored, it is excellent in tablet discrimination.
Furthermore, since the tablet of the present invention can suppress wrinkle adhesion without using a large amount of lubricant, the tablet strength is high, cracking and chipping hardly occur during transportation, and high quality.
Moreover, according to the manufacturing method of this invention, since it is not necessary to perform manufacturing processes, such as granulation and spraying, manufacturing time and running cost are suppressed. Moreover, since a tableting trouble is suppressed, useless manufacturing costs can be suppressed.
In addition, by adopting the split mixing method, it is possible to further suppress the adhesion of wrinkles.

Hereinafter, the present invention will be described in more detail using examples, but the present invention is not limited to the examples.
<Raw material>
The raw materials used in this example are summarized below.
[(A) component]
LOX-Na · 2H ₂ O: Loxoprofen sodium dihydrate (manufactured by Daiwa Pharmaceutical Co., Ltd.)
IBP: ibuprofen (BASF)
ASP: Aspirin (Novasil)
APAP: Acetaminophen (Iwaki Pharmaceutical Co., Ltd.)
[Component (B)]
(B) -1: Iron sesquioxide (manufactured by Hatake Kasei Co., Ltd.)
(B) -2: Yellow iron sesquioxide (manufactured by Hatake Kasei Co., Ltd.)
(B) -3: Talc (manufactured by Saneigen FFI Co., Ltd.)
(B) -4: Zinc oxide (manufactured by Sakai Chemical Industry Co., Ltd.)
(B) -5: Titanium oxide (manufactured by Sakai Chemical Industry Co., Ltd.)
[Double powder]
Low-substituted hydroxypropyl cellulose (L-HPC) (LH-31 (product name), manufactured by Shin-Etsu Chemical Co., Ltd.)
Carmellose (manufactured by Gotoku Pharmaceutical Co., Ltd.)
Crystalline cellulose (PH-302 (product name), manufactured by Asahi Kasei Chemical Co., Ltd.)
Lactose hydrate (DFE Pharma)
Corn starch (Matsuya Chemical Co., Ltd.)
[Optional ingredients]
Lactose granules (Freund Sangyo Co., Ltd.)
Magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.)
Magnesium oxide (made by Tomita Pharmaceutical Co., Ltd.)
Dry aluminum hydroxide gel (SN grade, manufactured by Kyowa Chemical Industry Co., Ltd.)

<Evaluation>
[Wrinkle adhesion test]
Evaluation of wrinkle adhesion in tableting of each Example and each Comparative Example described later was performed according to the following criteria. Three or more points were accepted.
6: Even if tableting is continued for 2 hours, no wrinkle adhesion occurs.
5: Continuous tableting for 1 hour 30 minutes or more and less than 2 hours causes wrinkle adhesion.
4: Continuous tableting for 1 hour or more and less than 1 hour and 30 minutes causes wrinkle adhesion.
3: Continuous tableting for 30 minutes or more and less than 1 hour causes wrinkle adhesion.
2: Wrinkle adhesion occurs with tableting for 20 minutes or more and less than 30 minutes.
1: Tableting in less than 20 minutes causes wrinkle adhesion.

[Internal friction angle of drug-containing powder]
The internal friction angle of the drug-containing powder was measured using a powder layer shear force measuring device (NS-500, manufactured by Nano Seeds). 1.2 g of the drug-containing powder of each example was placed in a φ15 mm cell, and the internal friction angle (°) with respect to the hard chrome plated surface was measured. It can be judged that the smaller the internal friction angle, the smaller the adhesion to the hard chrome plating.
Note that the mortar and pestle used in the following examples are those subjected to hard chrome plating. That is, it can be determined that the smaller the internal friction angle (°) in this evaluation is, the smaller the adhesion to the mortar or pestle is.

<Examples 1-9 and Comparative Examples 1-4>
In Examples 1 to 9 and Comparative Examples 1 to 4, tableting was performed as follows, and wrinkle adhesion was evaluated.
However, Example 3 is a reference example.
(A) component, (B) component, and arbitrary components are powder-mixed by a batch mixing method so that the content of each component per tablet is the mass (mg) shown in Table 1, and the drug layer is formed. A constituent powder (drug-containing powder) was obtained.
Using a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd .: LIBRA3L), the obtained drug-containing powder was tableted to produce a monolayer tablet.
The following tools were used as the mortar. Tableting was performed under the conditions of the tableting pressure and the rotation speed of the rotating disk shown below. The evaluation results of Examples 1 to 9 and Comparative Examples 1 to 4 are shown in the same table. In addition, since Examples 1-9 and Comparative Examples 1-4 are single layer tablets, the tablets themselves are drug layers.
[Musume]
LOX-Na · 2H ₂ O or IBP combination tablet: diameter 8.0 mm (2 steps R) × 12 ASP or APAP combination tablet: diameter 10.0 mm (2 steps R) × 12 [tablet pressure]
10kN
[Rotating speed of rotating plate]
Single layer tablet: 40rpm

As shown in Table 1, in Examples 1 to 9, wrinkle adhesion did not occur within 30 minutes from the start of tableting. In particular, when ferric oxide and yellow ferric oxide were blended as the component (B), wrinkle adhesion did not occur even after tableting for 2 hours from the start of tableting.
On the other hand, in Comparative Examples 1 to 4 that did not contain the component (B) in the tablet, wrinkle adhesion occurred in less than 30 minutes from the start of tableting.
In addition, any tablet of Examples 1-9 and Comparative Examples 1-4 was excellent in distinguishability.

<Examples 10 to 18 and Comparative Examples 5 to 8>
Each component of the drug layer was powder-mixed by a batch mixing method so that each component had a mass (mg) per tablet shown in Table 2 below to obtain a drug-containing powder. In addition, each component of the arbitrary layer was powder-mixed by a batch mixing method so that each component had a mass (mg) per tablet shown in Table 2 below to obtain a powder constituting the arbitrary layer. .
The powder constituting the arbitrary layer and the drug-containing powder were filled in this order in a mortar and tableted to obtain a two-layer tablet.
Tableting was performed under the same conditions as in Examples 1 to 9 and Comparative Examples 1 to 4 except that the tableting was performed at the rotational speed of the following rotating disk. The evaluation results of wrinkle adhesion in Examples 10 to 18 and Comparative Examples 5 to 8 are shown in the same table.
However, Example 12 is a reference example.
[Rotating speed of rotating plate]
2 layer tablet containing LOX-Na · 2H ₂ O: 15 rpm
Double-layer tablet with IBP: 20 rpm
2 layer tablet with ASP or APAP: 30rpm

<Example 19>
In Example 19, a bilayer tablet was obtained in the same manner as in Example 10 except that the drug-containing powder and the powder constituting the arbitrary layer were filled in this order in the die. The evaluation results of wrinkle adhesion in Example 19 are shown in the same table.

As shown in Table 2, Examples 10 to 19 were less than 30 minutes from the start of tableting, and no wrinkle adhesion occurred. In particular, when ferric oxide and yellow ferric oxide were blended as the component (B), wrinkle adhesion did not occur even after tableting for 2 hours from the start of tableting.
Further, when Example 10 and Example 19 having the same composition and blending ratio were compared, the powders constituting the optional layer and the drug-containing powder were filled in the order of tableting at the time of tableting. In Example 10, wrinkle adhesion was less likely to occur as compared with Example 19 in which the drug-containing powder and the powder constituting the arbitrary layer were filled in this order.
On the other hand, in Comparative Examples 5 to 8 in which (A) the drug layer does not contain the component (B), wrinkle adhesion occurred in less than 30 minutes from the start of tableting.
In addition, any tablet of Examples 10-19 and Comparative Examples 5-8 was excellent in distinguishability.

<Examples 20 to 36>
In Examples 20 to 36, Examples 1 to 9 and Comparative Examples 1 to 4 were obtained except that the drug-containing powder was obtained so that each component had a mass (mg) per tablet shown in Table 3 below. In the same manner, tablets were obtained. The evaluation results of wrinkle adhesion in Examples 20 to 36 are shown in the same table. Since Examples 20 to 36 are single layer tablets, the tablets themselves are drug layers.
However, Examples 20-21, 25-26, 29-31, 33-35 are reference examples.

As shown in Examples 20 to 24 of Table 3, when LOX-Na · 2H ₂ O is added to the drug layer, if the 10000 × (B) component / drug layer is 0.06 or more, 30 starts from the start of tableting. In less than a minute, no soot deposition occurred. In particular, when the 10000 × (B) component / drug layer was 0.59 or more, wrinkle adhesion did not occur even after tableting for 2 hours from the start of tableting.
As shown in Examples 25 to 28 in the same table, when IBP is blended in the drug layer, if 10000 × (B) component / drug layer is 0.06 or more, wrinkle adheres in less than 1 hour from the start of tableting. Did not occur. In particular, when the 10000 × (B) component / drug layer was 0.4 or more, wrinkle adhesion did not occur even after tableting for 2 hours from the start of tableting.
As shown in Examples 29 to 32 of the same table, when ASP is added to the drug layer, if 10000 × (B) component / drug layer is 0.02 or more, wrinkle adheres in less than 1 hour from the start of tableting. Did not occur. In particular, when the 10000 × (B) component / drug layer was 0.21 or more, wrinkle adhesion did not occur even after tableting for 2 hours from the start of tableting.
As shown in Examples 33 to 36 of the same table, when APAP is added to the drug layer, if 10000 × (B) component / drug layer is 0.04 or more, wrinkle adheres in less than 1 hour from the start of tableting. Did not occur. In particular, when the 10000 × (B) component / drug layer was 0.28 or more, wrinkle adhesion did not occur even after tableting for 2 hours from the start of tableting.
In addition, any tablet of Examples 20 to 36 was excellent in distinguishability.

<Examples 37 to 53>
In Examples 37 to 53, Example 10 was obtained except that the drug-containing powder and the powder constituting the optional layer were obtained so that each component had a mass (mg) per tablet shown in Table 4 below. To 18 and Comparative Examples 5 to 8 were used to obtain tablets. The evaluation results of wrinkle adhesion in Examples 37 to 53 are shown in the same table.
However, Examples 37 to 38, 42 to 43, 46 to 48, and 50 to 52 are reference examples.

As shown in Examples 37 to 41 of Table 4, when LOX-Na · 2H ₂ O is added to the drug layer, if the 10000 × (B) component / drug layer is 0.06 or more, 30 starts from the start of tableting. In less than a minute, no soot deposition occurred. In particular, when the 10000 × (B) component / drug layer was 0.59 or more, wrinkle adhesion did not occur even after tableting for 2 hours from the start of tableting.
As shown in Examples 42 to 45 of the same table, when IBP is added to the drug layer, if 10000 × (B) component / drug layer is 0.06 or more, wrinkle adheres in less than 1 hour from the start of tableting. Did not occur. In particular, when the 10000 × (B) component / drug layer was 0.4 or more, wrinkle adhesion did not occur even after tableting for 2 hours from the start of tableting.
As shown in Examples 46 to 49 of the same table, when ASP is added to the drug layer, if 10000 × (B) component / drug layer is 0.02 or more, wrinkle adheres within 1 hour from the start of tableting. Did not occur. In particular, when the 10000 × (B) component / drug layer was 0.21 or more, wrinkle adhesion did not occur even after tableting for 2 hours from the start of tableting.
As shown in Examples 50 to 53 of the same table, when APAP is added to the drug layer, if 10000 × (B) component / drug layer is 0.04 or more, wrinkle adheres in less than 1 hour from the start of tableting. Did not occur. In particular, when the 10000 × (B) component / drug layer was 0.28 or more, wrinkle adhesion did not occur even after tableting for 2 hours from the start of tableting.
In addition, any tablet of Examples 37-53 was excellent in distinguishability.

<Example 54>
(A) component, (B) component, and arbitrary components were put into the polyethylene bag so that it might become the mass (mg) per tablet shown in the following Table 5. The polyethylene bag was shaken and the contents were mixed with powder to obtain a drug-containing powder (collective mixing method). The component (B) is sieved with a sieve having an opening of 250 μm. In addition, the components of the arbitrary layer were powder-mixed by a batch mixing method so as to obtain the mass (mg) per tablet shown in Table 5 below to obtain a powder constituting the arbitrary layer.
Using the obtained drug-containing powder and the powder constituting the optional layer, tablets were obtained in the same manner as in Examples 10-18. The evaluation result of wrinkle adhesion in Example 54 and the internal friction angle of the drug-containing powder are shown in the table.

<Examples 55-61>
A high speed mixer 2L type (Co., Ltd.) was prepared by mixing (B) component and a part of (C) component (described as powdered powder in the table) so that the mass per tablet shown in Table 5 (mg) was obtained. Made in advance by Earth Technica). The charged component (B) and powdered powder were mixed under the following mixing conditions to obtain a mixed powder.
The obtained mixed powder and the remainder of the component (C) (optional component in the table) were put in a polyethylene bag. The polyethylene bag was shaken and the contents were mixed with powder to obtain a drug-containing powder.
A tablet was obtained in the same manner as in Example 54 except that the obtained drug-containing powder was used. The evaluation results of wrinkle adhesion in Examples 55 to 61 and the internal friction angle of the drug-containing powder are shown in the table. In the table, the preparation method of the mixed powder of this example was described as “high-speed stirring”.
However, Example 61 is a reference example.
[Mixing conditions]
Agitator rotation speed: 400rpm
Chopper rotation speed: 2000rpm
Stirring time: 5 minutes

<Comparative Example 9>
Using a high speed mixer 2L, the powdered powder was stirred under the following stirring conditions (stirring treatment).
The component (A), the powdered powder subjected to the stirring treatment, and the optional component were put in a polyethylene bag so as to have a mass (mg) per tablet shown in Table 5. The polyethylene bag was shaken and the contents were mixed with powder to obtain a drug-containing powder.
A tablet was obtained in the same manner as in Example 54 except that the obtained drug-containing powder was used.
[Stirring conditions]
Agitator rotation speed: 400rpm
Chopper rotation speed: 2000rpm
Stirring time: 5 minutes

<Example 62>
In the same manner as in Example 55 except that instead of the high speed mixer 2L, a mortar was used and the mixed powder was obtained by grinding the component (B) and the triturated powder for 5 minutes so as to grind them, Got. The evaluation result of wrinkle adhesion in Example 62 and the internal friction angle of the drug-containing powder are shown in the table. In the table, the method for preparing the mixed powder of this example was described as “mortar”.

<Example 63>
Implemented except that instead of the high-speed mixer 2L type, a mixed powder was obtained by mixing the component (B) and the powdered powder under the following mixing conditions using a stone mill crusher (manufactured by West Co., Ltd.). In the same manner as in Example 55, tablets were obtained. The evaluation results of wrinkle adhesion in Example 63 and the internal friction angle of the drug-containing powder are shown in the table. In the table, the preparation method of the mixed powder of this example was described as “stone mill pulverization”.
[Mixing conditions]
Clearance: 120μm
Chopper rotation speed: 2000rpm
Stirring time: 5 minutes

<Example 64>
The component (B) was sieved with a sieve having an opening of 250 μm. The sieved component (B) and triturated powder were charged into a polyethylene bag. The polyethylene bag was shaken and the contents were mixed with powder to obtain a mixed powder of component (B) and triturated powder. A tablet was obtained in the same manner as in Example 55 except that the obtained mixed powder was used. The evaluation results of wrinkle adhesion and the internal friction angle of the drug-containing powder in Example 64 are shown in the table. In the table, the preparation method of the mixed powder of this example was described as “bag mixing”.

As shown in Table 5, Examples 54 to 64 to which the present invention was applied did not cause wrinkle adhesion within 1 hour from the start of tableting. In addition, in Examples 54 to 64, the internal friction angle of the drug-containing powder was 14.91 ° or less.
In the comparison of Examples 54, 55, and 62 to 64, Examples (55) and (62) were obtained by mixing the component (B) and the powdered powder, and then mixing the component (A) and the optional component to obtain a drug-containing powder. In -64, the internal friction angle of the drug-containing powder was smaller than that in Example 54.
In Comparative Example 9 containing no component (B), wrinkle adhesion occurred in less than 30 minutes from the start of tableting. In Comparative Example 9, the internal friction angle of the drug-containing powder was 18.67 °.

Claims (9)

Having a drug layer containing a non-steroidal anti-inflammatory drug (A) and an inorganic pigment (B);
The non-steroidal anti-inflammatory drug (A) is at least one selected from loxoprofen, ibuprofen and salts thereof,
The blending ratio of the non-steroidal anti-inflammatory drug (A) in the drug layer is 30% by mass or more,
The tablet whose mass ratio represented by "10000x (B) component / drug layer" is 0.4 or more and 3 or less. Having a drug layer containing a non-steroidal anti-inflammatory drug (A) and an inorganic pigment (B);
The non-steroidal anti-inflammatory drug (A) is at least one selected from acetylsalicylic acid and salts thereof,
The blending ratio of the non-steroidal anti-inflammatory drug (A) in the drug layer is 30% by mass or more,
The tablet whose mass ratio represented by "10000x (B) component / drug layer" is 0.7 or more and 3 or less. Having a drug layer containing a non-steroidal anti-inflammatory drug (A) and an inorganic pigment (B);
  The non-steroidal anti-inflammatory drug (A) is at least one selected from acetaminophen and a salt thereof,
The blending ratio of the non-steroidal anti-inflammatory drug (A) in the drug layer is 30% by mass or more,
The tablet whose mass ratio represented by "10000x (B) component / drug layer" is 0.6 or more and 3 or less. The non-steroidal anti-inflammatory drug (A) is one or more selected from loxoprofen and a salt thereof, and a mass ratio represented by “10000 × (B) component / (A) component” is 1.4 or more. The tablet according to claim 1, which is 8 or less. The tablet according to any one of claims 1 to 4 , which is a multilayer tablet having the drug layer and a layer containing an antacid and an inorganic salt other than the antacid. The tablet manufacturing method according to any one of claims 1 to 4 , wherein a tableting machine having a mortar and a punch is used to fill the mortar with the powder constituting the drug layer and tablet the tablet. Using a tableting machine having a mortar and a pestle, the powder constituting the drug layer is used after the mortar after the powder constituting the layer containing the antacid and the inorganic salt other than the antacid. The tablet production method according to claim 5 , wherein the tablet is packed into tablets. The powder constituting the drug layer includes powder (C) other than the components (A) to (B),
The drug layer obtained by mixing a powder mixture of the component (B) and a part of the component (C) of the powder and the component (A) and the remainder of the component (C) of the powder. The manufacturing method of the tablet of Claim 6 or 7 which has the process of obtaining the powder which comprises. The powder constituting the drug layer includes powder (C) other than the components (A) to (B),
Mixing a powder mixture of the component (B) and the component (C) of the powder and the component (A) of the powder to obtain a powder constituting the drug layer, The manufacturing method of the tablet of Claim 6 or 7 .