JP7188974B2 - Tablet manufacturing method and granulated particle group - Google Patents

Description

TECHNICAL FIELD The present invention relates to a tablet manufacturing method and a granulated particle group.

Tablets containing acetaminophen have good disintegration properties but are prone to friability.
As a method for improving the friability of tablets containing acetaminophen, a method has been proposed in which acetaminophen or the like is granulated using a water-soluble polymer such as polyvinyl alcohol, and the resulting granules are compressed into tablets. (Patent Document 1).

Japanese Unexamined Patent Application Publication No. 2017-210478

However, in the method of Patent Document 1, although abrasion is improved, tablet disintegration remarkably deteriorates.
SUMMARY OF THE INVENTION An object of the present invention is to provide a method for producing a tablet and a granulated particle group by which a tablet having good disintegration properties and reduced wear and tear can be obtained.

As a result of intensive studies, the present inventors have found that by granulating acetaminophen with loxoprofen or a salt thereof to form a granulated particle group having a total amount of 30% by mass or more, while maintaining disintegration properties. It was found that abrasion can be suppressed. In addition, we found that other drugs (ethenzamide, allylisopropylacetylurea, caffeine, anhydrous caffeine), which have the same problem of wear and tear as acetaminophen, can be controlled while maintaining disintegration properties by the same method. rice field.
The present invention is based on the above findings and has the following aspects.

[1] Powder containing granulated particles containing the following component (A) and the following component (B), wherein the total content of the component (A) and the component (B) is 30% by mass or more A method for producing a tablet, comprising a step of compressing.
Component (A): At least one selected from the group consisting of the following components (a1) and (a2) below.
(a1) Component: at least one selected from the group consisting of acetaminophen and ethenzamide.
(a2) component: at least one selected from the group consisting of allylisopropylacetylurea, caffeine and anhydrous caffeine.
(B) Component: At least one selected from the group consisting of loxoprofen and salts thereof.
[2] The tablet of [1], which has a step of obtaining the granulated particles by granulating at least the component (A) and the component (B) before the step of tableting the powder. manufacturing method.
[3] The method for producing a tablet according to [2] above, wherein the step of obtaining the granulated particle group is performed by a wet granulation method.
[4] Before the step of obtaining the granulated particles, at least the step of mixing the powdery component (A) and the powdery component (B) to obtain a powder mixture. ,
The method for producing a tablet according to [2] or [3] above, wherein the step of obtaining the granulated particle group is a step of granulating the powder mixture to obtain the granulated particle group.
[5] The method for producing a tablet according to [4] above, wherein the mixing time in the step of obtaining the powder mixture is 10 minutes or less.
[6] The method for producing a tablet according to any one of [1] to [5] above, wherein the granulated particle group has a water-soluble polymer content of 5% by mass or less.
[7] The method for producing a tablet according to any one of [1] to [6], wherein the mass ratio represented by component (A)/component (B) is 0.1 to 12.5.
[8] The method for producing a tablet according to any one of [1] to [7], wherein the granulated particles further contain the following component (C).
Component (C): at least one selected from the group consisting of insoluble starch derivatives and insoluble cellulose derivatives.
[9] The method for producing a tablet according to [8], wherein the mass ratio represented by component (C)/(component (A) + component (B)) is 0.01 to 3.
[10] A granulated particle group containing the following component (A) and the following component (B), wherein the total content of the component (A) and the component (B) is 30% by mass or more.
Component (A): At least one selected from the group consisting of the following components (a1) and (a2) below.
(a1) Component: at least one selected from the group consisting of acetaminophen and ethenzamide.
(a2) component: at least one selected from the group consisting of allylisopropylacetylurea, caffeine and anhydrous caffeine.
(B) Component: At least one selected from the group consisting of loxoprofen and salts thereof.
[11] The granulated particle group according to [10] above, wherein the content of the water-soluble polymer is 5% by mass or less.
[12] The granulated particle group according to [10] or [11], wherein the mass ratio represented by component (A)/component (B) is from 0.1 to 12.5.
[13] The granulated particle group according to any one of [10] to [12], further comprising the following component (C).
Component (C): at least one selected from the group consisting of insoluble starch derivatives and insoluble cellulose derivatives.
[14] The granulated particle group according to [13], wherein the mass ratio represented by component (C)/(component (A) + component (B)) is 0.01 to 3.

According to the method for producing a tablet of the present invention, a tablet having good disintegration properties and reduced wear and tear can be obtained.
According to the granulated particle group of the present invention, tablets having good disintegration properties and reduced wear and tear can be obtained.

FIG. 2 is a side view showing an example of a tablet (standard R tablet or sugar-coated R tablet). Fig. 10 is a side view showing another example of a tablet (two-stage R tablet); Fig. 10 is a side view showing another example of a tablet (round square flat tablet). FIG. 10 is a side view showing another example of a tablet (round round flat tablet).

≪Granulated particle group≫
The granulated particle group of the present invention (hereinafter also referred to as "particle group (X)") contains the component (A) and the component (B), and contains the total of the component (A) and the component (B). A group of granulated particles (hereinafter also referred to as "particles (x)") having an amount of 30% by mass or more.
Particles (x) preferably further contain component (C).
Particles (x) may further contain components other than components (A), (B), and (C), if necessary, within a range that does not impair the effects of the present invention.

<(A) Component>
Component (A) is at least one selected from the group consisting of components (a1) and (a2). Since the particles (x) contain the component (A), the disintegration of the tablet is excellent.
The component (a1) is at least one selected from the group consisting of acetaminophen and ethenzamide.
Acetaminophen (N-(4-hydroxyphenyl)acetamide) and ethenzamide are each antipyretic analgesic ingredients listed in the Japanese Pharmacopoeia. Acetaminophen is also called paracetamol.
Component (a2) is at least one selected from the group consisting of allylisopropylacetylurea, caffeine and anhydrous caffeine.
Allylisopropylacetylurea is a sedative-hypnotic ingredient. Caffeine and anhydrous caffeine are central stimulants.
(A) component may be used individually by 1 type, and may be used in combination of 2 or more types as appropriate.

<(B) Component>
Component (B) is at least one selected from the group consisting of loxoprofen and salts thereof. The friability of the tablet is excellent because the particles (x) contain the component (B). Here, "excellent friability" means that the friability in the friability test is suppressed. Friability refers to both the friability measured after tablet manufacture (initial friability) and the friability measured after storage (post-storage friability). As the storage conditions for measuring the friability after storage, the conditions shown in Examples described later or equivalent conditions can be adopted. The friability is measured by the tablet friability test method listed in the 17th revision of the Japanese Pharmacopoeia, or a friability test performed under conditions equivalent thereto.
The salt of loxoprofen is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and the like.
As the component (B), a salt of loxoprofen is preferable, and loxoprofen sodium is more preferable.
The component (B) may exist in the form of a hydrate. Examples of hydrates include loxoprofen sodium dihydrate (corresponding to about 12% of the powder of the drug substance in terms of water content).

<(C) Component>
Component (C) is at least one selected from the group consisting of insoluble starch derivatives and insoluble cellulose derivatives. The component (C) is used to further enhance disintegration and friability.
Here, "insoluble" means that the solubility in water is "almost insoluble" in the general rules of the 17th revision of the Japanese Pharmacopoeia (the amount of solvent required to dissolve 1 g or 1 mL of solute is 10000 mL or more, 20 ± 5 ° C.). It means that there is
Examples of insoluble starch derivatives include corn starch, wheat starch, potato starch, pregelatinized starch, partially pregelatinized starch, and the like.
Examples of insoluble cellulose derivatives include crystalline cellulose, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, ethyl cellulose and the like.
As the component (C), corn starch, partially pregelatinized starch, crystalline cellulose, and low-substituted hydroxypropyl cellulose are preferable from the viewpoint of maintaining good disintegration and friability, and corn starch and low-substituted hydroxypropyl. Cellulose is more preferred.
(C) component may be used individually by 1 type, and may be used in combination of 2 or more types as appropriate.

<Other ingredients>
Other ingredients include those similar to the tablet optional ingredients described later.

<Content ratio of each component>
The total content of the components (A) and (B) in the particles (x) is 30% by mass or more, preferably 40% by mass or more, and 55% by mass with respect to the total mass of the particles (x). The above is more preferable, and 80% by mass or more is even more preferable. When the total content of components (A) and (B) is at least the above lower limit, the effect of suppressing tablet abrasion, especially after storage, is excellent.
The upper limit of the total content of components (A) and (B) is not particularly limited, and may be 100% by mass. Considering the preferred contents of each component (C) and other components, the total amount of all components can be appropriately set to 100% by mass.
In addition, in this invention, content of (B) component also includes the water|moisture content which couple|bonds with loxoprofen.

In the particles (x), the mass ratio represented by component (A)/component (B) (hereinafter also referred to as “(A)/(B)”) is preferably 0.1 to 12.5. When (A)/(B) is at least the lower limit of the above range, the disintegration property is more excellent, and when it is at most the upper limit of the above range, abrasion and variation in physical properties of the tablet can be further suppressed.
When component (A) is component (a1), (A)/(B) is more preferably 0.5 to 12.5, more preferably 1.0 to 10.0, and 4.0 to 6.0. 0 is particularly preferred.
When component (A) is component (a2), (A)/(B) is more preferably 0.1 to 5.0, still more preferably 0.5 to 3.0, and 0.75 to 1.0. 5 is particularly preferred.

When the particles (x) contain the (C) component, the mass ratio represented by (C) component/((A) component+(B) component) (hereinafter also referred to as “(C)/(A+B)”). ) is preferably 0.01 to 3, more preferably 0.01 to 0.42, even more preferably 0.02 to 0.3, and particularly preferably 0.07 to 0.2. When (C)/(A+B) is at least the lower limit of the above range, the disintegration and friability are more excellent. In addition, effects such as suppression of adhesion to equipment during tableting and improved appearance stability after storage can be obtained. When (C)/(A+B) is equal to or less than the upper limit of the above range, the total content of components (A) and (B) can be sufficiently increased.

The content of the water-soluble polymer in the particles (x) is preferably 5% by mass or less, more preferably 2% by mass or less, and 1% by mass or less, relative to the total mass of the particles (x). is more preferable, and 0% by mass is particularly preferable. That is, it is particularly preferred that the particles (x) do not contain a water-soluble polymer. The smaller the water-soluble polymer content, the better the disintegration.
In the present invention, "water-soluble" means that the solubility in water at 20°C is 1.3 g/100 mL or more.

The average particle size of the particle group (X) is preferably 30-1500 μm, more preferably 50-700 μm. If the average particle size is at least the lower limit of the range, adhesion to production equipment is suppressed, and if the average particle size is at most the upper limit of the range, uniformity of the powder is improved.
The average particle diameter of the particle group (X) is a value measured by a laser diffraction/scattering particle size distribution analyzer (for example, "LS13320" manufactured by Beckman Coulter).

The moisture content of the particle group (X) is preferably 0.1 to 4.0% by mass, more preferably 0.1 to 3.0% by mass, even more preferably 0.1 to 2.0% by mass. When the moisture content of the particle group (X) is at least the lower limit of the above range, tablet abrasion can be further suppressed. When the moisture content of the particle group (X) is equal to or lower than the upper limit of the above range, the particle group (X) has excellent flowability, good filling properties in a die before tableting, and small mass deviation of the tablet.
The moisture content of the particle group (X) is calculated from the loss on drying when the particle group (X) is heated at 120° C. for 10 minutes. That is, when the mass (g) before heating is W1 and the mass (g) after heating is W2, it is calculated by the following formula.
Moisture content (mass%) = (W1-W2) / W1 x 100

<Method for producing granulated particles>
Particle group (X) can be produced, for example, by a production method comprising a step of granulating at least component (A) and component (B) (granulation step).
The production method optionally includes a step of mixing the powdery component (A) and the powdery component (B) (powder mixing step) before the granulation step. good too. When the powder mixing step is provided, the powder mixture obtained in the powder mixing step is granulated in the granulation step.
Hereinafter, the manufacturing method of the aspect having a powder mixing step and a granulation step will be described in detail.

(Powder mixing process)
In the powder mixing step, the powdery component (A) and the powdery component (B) are mixed to obtain a powdery mixture. At this time, the powdery component (A) and the powdery component (B) may be mixed with the powdery component (C) and other powdery components. Other powdery components include excipients, disintegrants, and the like, which will be described later.
The total amount of the powdery (A) component and the powdery (B) component with respect to the total mass of the powder mixture is the sum of the (A) component and the (B) component with respect to the total mass of the particles (x) is equivalent to the content of 30% by mass or more.

Each component to be mixed in the powder mixing step may be manufactured by a known manufacturing method or may be commercially available. Each component may be used as a raw powder, may be used after pulverizing the raw powder, or may be used after granulating the raw powder. When granulating the bulk powder, a known granulation method can be employed as the granulation method.

The mixing method is not particularly limited, and includes known powder mixing methods. For example, each powder can be mixed using a device (mixer) generally used for powder mixing.
Examples of mixers include fluid bed granulators, stirring granulators, Bohle container mixers, V-type mixers, W-cone mixers and ribbon mixers. Among these, fluidized bed granulators and agitating granulators are preferred from the viewpoints of efficient mixing of powdery component (A) and powdery component (B), operability, and productivity. is preferred.
The order of charging each powder into the mixer is not particularly limited as long as there is no problem in manufacturing.
Mixing conditions can be appropriately selected according to the mixer to be used. For example, when mixing is performed by a fluidized bed granulator, mixing can be performed at an air supply temperature of 60 to 100° C. and an air supply flow rate of 1.0 to 4.0 m ³ /min. When mixing is carried out with a stirring granulator, mixing can be carried out at a chopper rotation speed of 500 to 3000 rpm and an agitator rotation speed of 100 to 500 rpm.
The mixing time is preferably 10 minutes or less, more preferably 5 minutes or less, and even more preferably 3 minutes or less. If the mixing time is equal to or less than the above upper limit, the disintegration and friability of the tablet will be more excellent.
The mixing time is preferably longer than 0 seconds, more preferably 10 seconds or longer, and even more preferably 20 seconds or longer, in terms of powder uniformity.

(Granulation process)
In the granulation step of this aspect, the powder mixture obtained in the powder mixing step is granulated.
Granulation methods include dry granulation, wet granulation and the like. Wet granulation methods include fluid bed granulation, stirring granulation, tumbling granulation, and extrusion granulation.
As the granulation method, a wet granulation method is preferable from the viewpoint of manufacturability. Among these, the fluidized bed granulation method and the stirring granulation method are preferable from the viewpoints of efficient contact between the components (A) and (B), operability, and productivity.
Granulation conditions can be appropriately selected according to the granulation method. For example, when granulation is performed by a fluidized bed granulation method, granulation can be performed at an air supply temperature of 60 to 100° C. and an air supply air volume of 1.0 to 4.0 m ³ /min. When granulation is performed by the stirring granulation method, granulation can be performed at a chopper rotation speed of 500 to 3000 rpm and an agitator rotation speed of 100 to 500 rpm.

Granulation may be carried out while spraying a liquid that poses no problem in production. Such liquids include water, ethanol, and the like.
Generally, in wet granulation, granulation is performed while spraying a binder liquid in which a binder such as a water-soluble polymer or a water-insoluble acrylic acid polymer is dispersed or dissolved in water. Also in the granulation step of this embodiment, granulation may be performed while spraying the binding liquid. In this case, the particles (x) constituting the resulting particle group (X) contain the binder.
When the binder contains a water-soluble polymer, the particles (x) preferably have a low binder content in order to maintain good disintegration properties. Specifically, the amount of the binding liquid to be sprayed is preferably such that the content of the water-soluble polymer is 5% by mass or less with respect to the total mass of the particles (x). A more preferred content of the water-soluble polymer is as described above.

After granulation, if necessary, the obtained granules are dried for the purpose of adjusting the moisture content.
The drying method is not particularly limited, but shelf drying using a dryer such as a fluidized bed granulator or a box-type ventilation dryer is preferable.
Drying conditions can be appropriately selected according to the drying method. For example, when drying is performed using a fluidized bed granulator, drying can be performed at an air supply temperature of 60 to 100° C., a drying time of 10 to 90 minutes, and an air supply air volume of 1.0 to 4.0 m ³ /min. . When drying is performed using a box-type ventilation type dryer, drying can be performed at a drying temperature of 40 to 90° C. for a drying time of 15 to 130 minutes.

Although the production method having the powder mixing step and the granulation step has been described above, the production method of the particle group (X) is not limited to this production method.
For example, the particle group (X) may be produced by a production method that includes a granulation step and does not include a powder mixing step. In this case, in the granulation step, each component to be granulated (component (A), component (B), component (C), etc.) may be brought into contact in a solid state such as powder, or may be dissolved in a liquid medium. Alternatively, they may be contacted in a dispersed state.

When the granulation step is performed without the powder mixing step, the order of adding the components (A) and (B) to the granulator is not particularly limited as long as there is no problem in terms of production. For example, after the component (A) is added and granulated, the component (B) may be added to the granulator and granulated, and the order of adding the components (A) and (B) is reversed. can be In terms of making the particles (x) more uniform and avoiding complication of the process, it is preferable to granulate the components (A) and (B) by charging them into a granulator at the same time. .

≪Tablet≫
The tablet produced by the tablet production method of the present invention (hereinafter also referred to as "tablet (Y)") uses the particle group (X) and therefore contains a component derived from the particle group (X). .
The component derived from the particle group (X) includes at least component (A) and component (B), and optionally component (C) and other components. The (A) component may be only the (a1) component, only the (a2) component, or both the (a1) component and the (a2) component.
The tablet (Y) may optionally contain a component not derived from the particle group (X) (hereinafter also referred to as "tablet optional component") within a range that does not impair the effect of the present invention, tablet physical properties, and storage stability. It may contain further.

Optional tablet ingredients include physiologically active ingredients, additives and the like.
Examples of physiologically active ingredients include antipyretic analgesic ingredients (e.g., piroxicam, meloxicam, ampiroxicam, serocoxib, rofecoxib, tiaramide, sulpyrine, etc.), sedative-hypnotic ingredients (e.g., bromvaleryl urea, etc.), antihistamine ingredients (e.g., isothipendyl hydrochloride, diphenyl hydrochloride, etc.). Pyralin, diphenhydramine hydrochloride, diferol hydrochloride, triprolidine hydrochloride, tripelennamine hydrochloride, tonjilamine hydrochloride, phenetazine hydrochloride, methdilazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, arimemazine tartrate, diphenhydramine tannate, diphenylpyraline theocrate, mebhydroline napadisulfate, promethazine methylene Disalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, diferol phosphate, etc.), central stimulant ingredients (e.g., sodium caffeine benzoate, etc.), antitussive expectorant ingredients (e.g., Codeine Phosphate, Dextromethorphan Hydrobromide, Dimemorphan Phosphate, Tipepidine Hibenzate, Methoxyphenamine Hydrochloride, Trimetoquinol Hydrochloride, Carbocysteine, Acetylcysteine, Ethylcysteine, dl-Methylephedrine , bromhexine hydrochloride, serrapeptase, lysozyme chloride, ambroxol, theophylline, aminophylline), vitamin components (e.g., vitamin B1 and its derivatives and their salts, vitamin B2 and its derivatives and their salts, vitamin C and its derivatives and salts thereof, hesperidin and its derivatives and salts thereof), antacids (e.g., dried aluminum hydroxide gel, magnesium aluminometasilicate, magnesium aluminosilicate, synthetic hydrotalcite, magnesium carbonate, magnesium oxide, magnesium silicate, sodium hydrogen carbonate) and the like. These physiologically active ingredients can be used singly or in appropriate combination of two or more.
Among these physiologically active ingredients, dry aluminum hydroxide gel, which has good disintegration and friability, can suppress changes in odor after storage, and can provide a formulation with higher storage stability, At least one selected from the group consisting of magnesium aluminometasilicate, synthetic hydrotalcite and magnesium oxide is preferred.

Examples of additives include binders, excipients, disintegrants, flavors, lubricants, sweeteners, acidulants and the like.
Examples of binders include crystalline cellulose, gelatin, gum arabic powder, polyvinylpyrrolidone, pullulan, hypromellose, methylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyethylene glycol and the like. Examples of excipients include lactose, mannitol, erythritol, xylitol, lactitol, trehalose, maltitol, maize starch, wheat starch, potato starch, dextrin, cyclodextrin, carboxymethylcellulose, carboxymethylcellulose calcium, L-cysteine, phosphoric acid. sodium hydrogen, calcium hydrogen phosphate, and the like; Examples of disintegrants include low-substituted hydroxypropyl cellulose, partially pregelatinized starch, carmellose, carmellose sodium, croscarmellose sodium, crospovidone, and the like. Examples of lubricants include magnesium stearate, sodium stearyl fumarate, sucrose fatty acid esters, light anhydrous silicic acid, and the like. Examples of fragrances include menthol, limonene, and plant essential oils (mint oil, mint oil, lychee oil, orange oil, lemon oil, etc.). Examples of sweeteners include saccharin, saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, and the like. Examples of acidulants include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, and salts thereof.

The content of component (a1) in tablet (Y) is not particularly limited as long as it is within a range that causes no problem in manufacturing.
The content of component (a1) per tablet (Y) is preferably 30 to 500 mg, more preferably 50 to 300 mg, even more preferably 100 to 230 mg.
The ratio of component (a1) to the total mass of tablet (Y) is preferably 10-95% by mass, more preferably 35-85% by mass, and even more preferably 40-55% by mass.
When the content of the component (a1) is at least the lower limit of the above range, the disintegration property and the appearance stability after storage are more excellent. If the content of the component (a1) is equal to or less than the upper limit of the above range, the friability is more excellent. Also, from the viewpoint of the tablet size, the ease of administration is improved.

The content of component (a2) in tablet (Y) is not particularly limited as long as it is within a range that causes no problem in manufacturing.
The content of component (a2) per tablet (Y) is preferably 10 to 300 mg, more preferably 20 to 200 mg, even more preferably 30 to 150 mg.
The ratio of component (a2) to the total weight of tablet (Y) is preferably 5 to 75% by mass, more preferably 10 to 55% by mass, even more preferably 15 to 40% by mass.
If the content of component (a2) is at least the lower limit of the above range, the disintegration property and the appearance stability after storage are more excellent. If the content of the component (a2) is equal to or less than the upper limit of the above range, the friability is more excellent. Also, from the viewpoint of the tablet size, the ease of administration is improved.

The content of component (B) in tablet (Y) is not particularly limited as long as it is within a range that causes no problem in manufacturing.
The content of component (B) per tablet (Y) is preferably 5-170 mg, more preferably 10-113 mg, and even more preferably 20-85 mg in terms of loxoprofen sodium dihydrate.
The ratio of component (B) to the total mass of tablet (Y) is preferably 5 to 90% by mass, more preferably 5 to 60% by mass, even more preferably 8 to 30% by mass.
If the content of component (B) is at least the lower limit of the above range, the friability will be more excellent. If the content of component (B) is at most the upper limit of the above range, the appearance stability after storage is more excellent.

The content of component (C) in tablet (Y) is not particularly limited as long as it is within a range that causes no problem in manufacturing.
The content of component (C) per tablet (Y) is preferably 1 to 200 mg, more preferably 3 to 100 mg, even more preferably 10 to 60 mg.
The ratio of component (C) to the total mass of tablet (Y) is preferably 0.5 to 30% by mass, more preferably 1 to 20% by mass, even more preferably 2 to 15% by mass.
If the content of component (C) is at least the lower limit of the above range, the disintegration and friability will be more excellent. Furthermore, adhesion to manufacturing equipment and change in appearance after storage can be suppressed. If the content of the component (C) is equal to or less than the upper limit of the above range, the friability after storage is more excellent.

The binder content per tablet (Y) is preferably 0 to 30% by mass.
The content of excipients per tablet (Y) is preferably 0 to 40% by mass.
The content of the disintegrant per tablet (Y) is preferably 0 to 20% by mass.
The content of flavor per tablet (Y) is preferably 0 to 5% by mass.
The lubricant content per tablet (Y) is preferably 0 to 5% by mass.
The sweetening agent content per tablet (Y) is preferably 0 to 5% by mass.
The content of acidulant per tablet (Y) is preferably 0 to 5% by mass.

The type of tablet (Y) is not particularly limited, and examples thereof include uncoated tablets, sugar-coated tablets, coated tablets, enteric-coated tablets, orally disintegrating tablets, chewable tablets, and effervescent tablets.
The tablet (Y) may have a single-layer structure (single-layer tablet), a laminated structure (laminated tablet), or a dry-coated tablet. When tablet (Y) is a laminated tablet, at least one layer may be a layer using particle group (X).

The size of the tablet (Y) is not particularly limited, but from the viewpoint of ease of handling and swallowability of the tablet, the tablet diameter φ is preferably 5 to 14 mm, more preferably 6 to 13 mm, and even more preferably 7 to 12 mm.
It is appropriate that the mass of one tablet (Y) is about 150 mg to 550 mg.

The shape of the tablet (Y) is not particularly limited in terms of the effect of the present invention, but from the viewpoint of ease of handling and swallowing of the tablet, a shape having a cylindrical portion and a bulging portion that bulges vertically from the cylindrical portion is preferred. preferable. Examples of tablets having a shape having a cylindrical portion and a bulging portion include R tablets (standard R tablets, sugar-coated R tablets, etc.), two-step R tablets, Sumi square flat tablets, Sumi round flat tablets, and the like. Although the bulging portion of these tablets may be vertically asymmetrical, it is preferably vertically symmetrical.
The shapes of the standard R tablet, the sugar-coated R tablet, the two-tiered R tablet, the round sumi square flat tablet, and the round sumi round flat tablet will be described in detail below with reference to the drawings.

As shown in FIG. 1, the standard R tablet or sugar-coated R tablet 100 has a cylindrical portion 8, a first bulging portion 12, and a second bulging portion 22. The first bulging portion 12 , and second bulges 22 are biconvex tablets in which the radius of curvature R of the surface curve is constant regardless of the position of the bulge surface.
The first bulging portion 12 bulges from the vicinity of the periphery of one end face of the cylindrical portion 8 toward the center of the one end face. The second bulging portion 22 bulges from the vicinity of the periphery of the other end face of the cylindrical portion 8 toward the center of the other end face.
Here, the "curvature radius of the surface curve of the first bulging portion 12" means that the first bulging portion 12 is in a cross section taken in a direction perpendicular to the end surface of the cylindrical portion 8 so as to pass through the zenith 12A. It is the radius of a circle when the curve drawn by the surface of the bulging portion 12 is regarded as a part of the circle.
The “curvature radius of the surface curve of the second bulging portion 22” refers to the second bulging portion in a cross section taken in a direction perpendicular to the end surface of the cylindrical portion 8 so as to pass through the zenith 22A. It is the radius of the circle when the curve drawn by the surface of 22 is regarded as a part of the circle.
The zenith 12A of the first bulging portion 12 is the highest point with respect to one end face. The zenith 22A of the second bulging portion 22 is the lowest point with respect to the other end face.
The R of the first bulging portion 12 and the R of the second bulging portion 22 may be the same or different, and are preferably the same from the viewpoint of tablet strength.

As shown in FIG. 2, the two-stage R lock 200 has a columnar portion 8, a first bulging portion 12, and a second bulging portion 22. The first bulging portion 12, the second The curvature radius R1 of the rising portion from the peripheral edge of each bulging portion 22 and the curvature radius R2 of the zenith 12A are different, and R1<R2.
The R1 of the first bulging portion 12 and the R1 of the second bulging portion 22 may be the same or different, and are preferably the same from the viewpoint of tablet strength.
The R2 of the first bulging portion 12 and the R2 of the second bulging portion 22 may be the same or different, and are preferably the same from the viewpoint of tablet strength.

As shown in FIG. 3 , the round square flat tablet 300 is a biconvex tablet having a cylindrical portion 8 , a first bulging portion 12 and a second bulging portion 22 .
The first bulging portion 12 rises linearly at a predetermined rising angle θ from the vicinity of the peripheral edge of one end face of the cylindrical portion 8 toward the center of the one end face, and any region including the zenith 12A is flat. becomes.
The second bulging portion 22 rises linearly at a predetermined rising angle θ toward the center of the other end face from the vicinity of the peripheral edge of the other end face of the cylindrical portion 8, and any region including the zenith 22A is flat. becomes.
The rising angle θ of the first bulging portion 12 and the rising angle θ of the second bulging portion 22 may be the same or different, and should be the same from the viewpoint of tablet strength. is preferred.

As shown in FIG. 4 , the round round flat tablet 400 is a biconvex tablet having a cylindrical portion 8 , a first bulging portion 12 and a second bulging portion 22 .
The first bulging portion 12 rises from the vicinity of the peripheral edge of one end face of the cylindrical portion 8 toward the center of the one end face with a predetermined R, and any region including the zenith 12A is flat.
The second bulging portion 22 rises from the vicinity of the peripheral edge of the other end face of the cylindrical portion 8 toward the center of the other end face with a predetermined R, and any region including the zenith 22A is flat.
The R of the first bulging portion 12 and the R of the second bulging portion 22 may be the same or different, and are preferably the same from the viewpoint of tablet strength.

As shown in FIGS. 1 to 4, the standard R tablet or sugar-coated R tablet 100, the two-stage R tablet 200, the round corner flat tablet 300, and the round round flat tablet 400 each have a It has a horizontal surface (land portion 14 ) that is annular in plan view, and has a horizontal surface (land portion 24 ) that is annular in plan view on the outer periphery of the second swelling portion 22 .
The width of the land portion 14 is W. The "width of the land portion 14" is the distance from the peripheral edge of the first bulging portion 12 to the peripheral edge of the end face.
The width of the land portion 24 may be the same as W, or may be different. The width of the land portion 24 is preferably the same as W from the viewpoint of tablet strength.

From the viewpoint of ease of administration, the tablet size is preferably within the following range.
・Standard R lock: R = 4.0 to 24.0 mm, land width W = 0.05 to 0.1 mm.
· Sugar-coated R tablet: R = 2.0 to 18.5 mm, land width W = 0.01 to 0.1 mm.
・Two-stage R lock: R1 = 1.2 to 8.0 mm, R2 = 4.5 to 21.5 mm, land width W = 0.05 to 0.1 mm.
・Round round flat tablet: R = 0.7 to 5.0 mm, land width W = 0.05 to 0.1 mm.
・Circular square flat tablet: rise angle θ=25 to 35°, land width W=0.05 to 0.1 mm.

The tablet (Y) may, for example, have no land portion and the tablet peripheral edge portion and the bulging rising portion may be in contact with each other. When the shape of the tablet (Y) is a round square flat tablet or round round flat tablet, any region including the zenith of the first bulging portion or any region including the zenith of the second bulging portion Either one may not be flat. The shape of the tablet (Y) may not be circular in plan view, but may be elliptical in plan view, square in plan view, or a combination of circular and square in plan view.
The tablet (Y) may or may not have an imprint.

The shape of the tablet (Y) is not limited to the above examples, but in terms of easily obtaining the effects of the present invention, an R tablet, a two-tiered R tablet, a round round flat tablet, or a round round flat tablet with round corners may be used. R-tablets, two-tiered R-tablets, and round round flat tablets are more preferred, and R-tablets and two-tiered R-tablets are even more preferred.

The tablet (Y) preferably has a moisture content of 1 to 8%. If the moisture content of tablet (Y) is at least the lower limit of the above range, disintegration will be more excellent. If the moisture content of the tablet (Y) is equal to or less than the upper limit of the above range, the appearance stability after storage is good.
The moisture content of tablet (Y) is calculated from the loss on drying when the pulverized material of tablet (Y) is heated at 120° C. for 10 minutes. The method for calculating the moisture content is the same as the method for calculating the moisture content of the particle group (X).
The moisture content of the tablet (Y) can be appropriately adjusted by adjusting the moisture content of the powder to be compressed during the production of the tablet (Y), the blending of optional ingredients containing moisture, the drying conditions during the production process, and the like.

≪Tablet manufacturing method≫
The tablet manufacturing method of the present invention has a step of tableting powder containing the particle group (X) (tabletting step).
Particle group (X) may be produced before the tableting step. The method for producing the particle group (X) is as described above.

(powder)
The powder to be tableted in the tableting step (hereinafter also referred to as “powder for tableting”) contains the particle group (X). The particle group (X) contained in the powder for tableting may be of one type or two or more types. The powder for tableting may further contain powder other than the particle group (X).
The powder for tableting is a powder of multiple types (a powder containing two or more types of particle groups (X), a powder containing one or more types of particle groups (X) and one or more types of other powders, etc. ) (hereinafter also referred to as “mixed powder”), the step of mixing a plurality of types of powder containing the particle group (X) before the tableting step (powder preparation step for tableting )I do. In the powder preparation step for tableting, each powder can be mixed in the same manner as in the powder mixing step described above.
Other powders include powders of the tablet optional ingredients described above. As the powder of the optional tablet ingredient, bulk powder may be used as it is, or granulated powder may be used. When using a granulated product, a known granulation method can be employed as the granulation method.
The content of the particle group (X) in the powder for tableting can be appropriately selected according to the desired content of the components (A) and (B) in the tablet (Y) to be produced.

(Tabletting process)
The tableting method is not particularly limited, and includes known tableting methods. For example, there is a method of compressing the powder for tableting using a tableting machine having a die and a punch.
The tableting machine includes, for example, a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.: Libra 3L).
The tableting conditions such as the tableting pressure and the rotation speed of the rotating disk are appropriately set.
When the tablet (Y) is a laminated tablet, the powder for tableting may be filled in the die first, or may be filled after the ingredients constituting the arbitrary layers.

After the tableting process, if necessary, the tablets obtained in the tableting process may be coated with a coating agent.
As the coating agent, it is preferable to select one that does not significantly impair the disintegration property, and among these, water-soluble polymer compounds and plasticizers are preferable.
Examples of water-soluble polymer compounds include cellulose compounds such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose and methylcellulose, gum arabic, carboxyvinyl polymer, povidone, polyvinyl alcohol and polyacrylic acid.
Examples of plasticizers include those listed in the Japanese Pharmacopoeia (Hirokawa Shoten), such as triethyl citrate and triacetin, and official specifications such as Pharmaceutical Excipients Standards (Yakuji Nippo Co., Ltd.).
These coating agents may be used individually by 1 type, and may be used in combination of 2 or more type.
A coating process can be performed by a well-known method.

In the method for producing a tablet of the present invention as described above, a powder containing the particle group (X) is compressed to produce a tablet, so that a tablet having good disintegration properties and suppressed abrasion is obtained. can get.

The tablet obtained by the tablet manufacturing method of the present invention can satisfy the following formulas (1) and (2).
_t2w < _t2w+4w (1)
_t2w < _t0 (2)
Here, in _t2w , the tablets were filled (sealed with aluminum foil) into a press-through package having a moisture permeability of 0.13 to 0.16 mg per pocket (40°C, 90% RH, 24 hours). , and t2w+4w indicates the disintegration time (seconds) of the tablet when stored at 50°C and 75% RH for 2 weeks, and t _{2w + 4w} indicates the disintegration time (second) of the tablet when the tablet is stored for an additional 4 weeks. , t ₀ indicates the disintegration time (in seconds) of the tablets before storage. The moisture permeability is a value obtained by measuring according to JIS Z 0208 moisture permeability test method for moisture-proof packaging materials.

Satisfying the above formulas (1) and (2) indicates that the disintegration time is shorter than before storage at about 2 weeks after the start of storage under the above conditions, and then the disintegration time is longer. . Tablets exhibiting such behavior have good disintegration properties and are resistant to friability.
_t2w is preferably 5 seconds or more and less than 840 seconds (14 minutes).
The ratio of t ₀ to t _2w is preferably 105 to 500% (t ₀ is 10 seconds or more and less than 900 seconds (15 minutes)).
The ratio of t _{2w +4w} to t 2w is preferably 105 to 1000% (t _2w+4w is 10 seconds or more and less than 1800 seconds (30 minutes)).
The disintegration time is a value obtained by measuring the disintegration time of 6 tablets (disintegration test liquid is water) and averaging them according to the tablet disintegration test method listed in the 17th revision of the Japanese Pharmacopoeia. .

In this way, by using the particle group (X), a tablet having good disintegration properties and suppressed abrasion can be obtained, so the particle group (X) is useful for tablets.
However, the application of the particle group (X) is not limited to this. For example, the particle group (X) can be used for granules, capsules, powders, effervescent granules and the like.

[EXAMPLES] Hereafter, although an Example is shown and this invention is demonstrated in detail, this invention is not limited by the following description. Examples 1 to 22 and 32 to 34 are reference examples.

<Raw materials used>
Acetaminophen: Iwaki Pharmaceutical Co., Ltd., "pyretinol" Japanese Pharmacopoeia Standards.
Ethenzamide: Made by Iwaki Pharmaceutical Co., Ltd., "Ethenzamide" Japanese Pharmacopoeia Standards.
Allyl isopropyl acetyl urea: "Aripronal Congo" manufactured by Kongo Chemical Co., Ltd.
Anhydrous caffeine: "Anhydrous caffeine 0.2/0.5" manufactured by Shiratori Pharmaceutical Co., Ltd.
Loxoprofen sodium dihydrate: Daiwa Pharmaceutical Co., Ltd., Japanese Pharmacopoeia Standards.
Corn starch: "Pharmacopoeia Matsutani Corn Starch" manufactured by Matsutani Chemical Industry Co., Ltd.
Partially pregelatinized starch: "PCS" manufactured by Asahi Kasei Corporation.
Low-substituted hydroxypropyl cellulose: “L-HPC LH-31” (registered trademark) manufactured by Shin-Etsu Chemical Co., Ltd.
Crystalline cellulose: "UF-702" manufactured by Asahi Kasei Corporation.
Crospovidone: "Kollidon (registered trademark) CL-SF" manufactured by BASF.
Granulated lactose: "Lactose G" manufactured by Freund Corporation.
Magnesium stearate: "Magnesium stearate" manufactured by Taihei Kagaku Sangyo Co., Ltd.
Polyvinyl alcohol: "Gosenol EG04" manufactured by Nippon Synthetic Chemical Industry Co., Ltd.

<Tabletting conditions>
Tableting machine: Rotary type tableting machine Libra 3L (manufactured by Kikusui Seisakusho).
Disk rotation speed: 20 rpm.
Usus and pestle: φ8.0mm (2 steps R) x 12 posts, no engraving (cap height 0.1mm, R1 = 3.2, R2 = 9.5) or φ9.0mm (2 steps R) x 12 posts, No marking (cap height 0.1 mm, R1=3.6, R2=10.5).
Preload: 1 kN (about 10 MPa, about 100 kg/cm ² ).
Main pressure: 11 kN (about 110 MPa, about 1100 kg/cm ² ).

<Method for measuring moisture content>
The moisture content was calculated from the loss on drying when about 5 g of a sample was heated at 120° C. for 10 minutes using an electronic moisture meter (MOISTURE BALANCE MOC-120H, manufactured by Shimadzu Corporation).
In measuring the moisture content of the granulated particle group, the granulated particle group was directly used as a sample. In measuring the moisture content of the tablets, the tablets were crushed using a mortar, and the obtained crushed product was used as a sample.

<Evaluation method>
(Evaluation of collapsibility)
The disintegration time of 6 tablets was measured according to the tablet disintegration test method described in the Japanese Pharmacopoeia 17th Edition (disintegration test liquid is water), and the average value was calculated. The disintegrability was evaluated from the obtained average values based on the following evaluation criteria. A score of 3 or more is considered passing.
"Evaluation criteria"
5: The average disintegration time is less than 5 minutes.
4: The average disintegration time is 5 minutes or more and less than 10 minutes.
3: The average disintegration time is 10 minutes or more and less than 15 minutes.
2: The average disintegration time is 15 minutes or more and less than 20 minutes.
1: The average disintegration time is 20 minutes or more.

(Friability evaluation 1 (initial friability evaluation))
The friability of the obtained tablets was repeatedly measured three times according to the tablet friability test described in the Japanese Pharmacopoeia 17th Edition, and the average value was determined. The friability was evaluated based on the following evaluation criteria from the obtained average values. A score of 2 or more is acceptable.
"Evaluation criteria"
4: The average value of friability is 0.3% or less.
3: The average value of friability is more than 0.3% and 0.6% or less.
2: The average value of friability is more than 0.6% and 1.0% or less.
1: The average value of friability exceeds 1.0%.

(Evaluation of friability 2 (evaluation of friability after storage))
The obtained tablets are accommodated in the pockets of a resin sheet ("TAS-230" manufactured by Taisei Kako Co., Ltd.) in which pockets for accommodating tablets are formed in advance, and aluminum foil is laminated on one side of the resin sheet to create a pocket. The opening of the part was sealed to obtain a press-through package. This press-through package was stored at 50° C. and 75% RH for 4 weeks. After that, the tablets were taken out from the press-through package, and the friability of the tablets was evaluated in the same manner as in the friability evaluation 1 above, to determine the average value of the friability. A score of 2 or more is acceptable.

<Examples 1, 3, 5, 7, 9 and 11 to 34, Production Examples 1 to 6, Comparative Examples 1 to 4>
According to the blending ratio of the granulated particle groups shown in Tables 1 to 7, the powder used for granulation was collected, and the powder with a total mass of 3 kg was processed into a fluid bed granulator (manufactured by Freund Sangyo Co., Ltd., product name: FLO). -5), and mixed at an air supply temperature of 80°C, an air supply air volume of 2.0 m ³ /min, and a mixing time shown in Tables 1 to 7.
Subsequently, while spraying the liquid into the fluidized bed granulator, fluidized bed granulation was carried out at an air supply temperature of 80° C. and an air supply air volume of 2.0 m ³ /min. In Examples 1, 3, 5, 7, 9 and 11-34, Production Examples 1-6 and Comparative Examples 1, 3 and 4, water was sprayed as the liquid. The total spray amount of water was 1200 g with respect to the total mass of powder (3 kg). For Comparative Example 2, a binding liquid (5 mass % polyvinyl alcohol aqueous solution) was sprayed as a liquid. The total spray amount of the binding liquid was such that the mass of the polyvinyl alcohol in terms of solid content would be the mixing ratio shown in Table 7.
Subsequently, in the same fluidized bed granulator, the granules are dried under the conditions of an air supply temperature of 80° C. and an air supply air volume of 2.0 m ³ /min until the exhaust temperature reaches 50° C. to obtain a granulated particle group. Obtained.
After that, the obtained granulated particles were mixed with the tablet optional ingredients shown in Tables 1 to 5, and the obtained mixed powder was tableted under the tableting conditions described above to obtain tablets. For Examples 1, 3, 5, 7, 9 and 11 to 34 and Comparative Examples 3 and 4, a mortar and pestle with a diameter of 9.0 mm was used, and for Production Examples 1 to 6 and Comparative Examples 1 and 2, a mortar and pestle with a diameter of 8.0 mm was used. It was used.

<Examples 2, 4, 6, 8, 10>
The powder used for granulation was collected according to the blending ratio of the granulated particle group shown in Table 1, and the powder with a total mass of 3 kg was mixed with a stirring granulator (manufactured by Earth Technica Co., Ltd., product name: High Speed Mixer FS-). 10), 700 g of water was added dropwise, and stirring and granulation was performed at a chopper rotation speed of 1500 rpm and an agitator rotation speed of 300 rpm. The obtained granules are put into a fluidized bed granulator, and the granules are dried under the conditions of an air supply temperature of 80°C and an air supply air volume of 2.0 m ³ /min until the exhaust temperature reaches 50°C, Granulated particles were obtained.
Thereafter, the obtained granulated particles were mixed with the optional tablet ingredients listed in Table 1, and the obtained mixed powder was tableted using a 9.0 mm diameter mortar and pestle under the tableting conditions described above. , got the pills.

The tablets of Examples 1-34 and Comparative Examples 1-4 were evaluated for disintegration and friability. The results are shown in Tables 1-5 and 7.

In Tables 1 to 7, the amount (mg) of component (A), component (B), component (C), optional component, and tablet optional component indicates the amount in one tablet. A blank indicates that the corresponding component was not blended. "%" is mass %.

The tablets of Examples 1-34 had good disintegration properties. Both the initial friability and the friability after storage were 2 points or more (1.0% or less).
The tablet of Comparative Example 1, in which component (B) was not used, had both initial friability and post-storage friability of 1 point (more than 1.0%).
The tablet of Comparative Example 2, in which a binder (polyvinyl alcohol) was used instead of the component (B), had poor disintegration properties.
The tablet of Comparative Example 3, in which the component (B) was not blended in the granulated particles but blended as an optional tablet component, had both an initial friability and a friability after storage of 1 point (more than 1.0%). rice field.
The tablet of Comparative Example 4, in which the total content of the components (A) and (B) in the granulated particles is less than 30% by mass, has a friability of 1 point (more than 1.0%) after storage. there were.

100 standard R tablet or sugar-coated R tablet 200 double R tablet 300 round sumi square flat tablet 400 round sumi round flat tablet

Claims (12)

The following (A) component, the following (B) component, and the following (C) component are included, and the total content of the (A) component and the (B) component is 30% by mass or more, and the (C) ) component / (the (A) component + the (B) component) mass ratio is 0.01 ~ 0.42 powder containing granulated particles having a step of tableting tablet, manufacturing method.
(A) component : at least one selected from the group consisting of acetaminophen and ethenzamide .
(B) Component: At least one selected from the group consisting of loxoprofen and salts thereof.
(C) component: corn starch, wheat starch, potato starch, pregelatinized starch, partially pregelatinized starch, crystalline cellulose, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium and ethyl cellulose At least one selected from the group consisting of 2. The step of obtaining the granulated particles by granulating at least the component (A), the component (B) and the component (C) before the step of tableting the powder. Method for producing the tablet according to. 3. The method for producing a tablet according to claim 2, wherein the step of obtaining the granulated particle group is performed by a wet granulation method. Before the step of obtaining the granulated particle group, at least the powdery component (A), the powdery component (B), and the powdery component (C) are mixed to form a powder. obtaining a mixture;
The method for producing a tablet according to claim 2 or 3, wherein the step of obtaining the granulated particle group is a step of granulating the powder mixture to obtain the granulated particle group. 5. The method for producing a tablet according to claim 4, wherein the mixing time in the step of obtaining the powder mixture is 10 minutes or less. The method for producing a tablet according to any one of claims 1 to 5, wherein the granulated particle group has a water-soluble polymer content of 5% by mass or less. The method for producing a tablet according to any one of claims 1 to 6, wherein the mass ratio represented by component (A)/component (B) is 0.1 to 12.5. The method for producing a tablet according to any one of claims 1 to 7, wherein the component (C) is at least one selected from the group consisting of corn starch and low-substituted hydroxypropylcellulose. The following (A) component, the following (B) component, and the following (C) component are included, and the total content of the (A) component and the (B) component is 30% by mass or more, and the (C) ) component/(component (A) + component (B)) is a granulated particle group having a mass ratio of 0.01 to 0.42 .
(A) component : at least one selected from the group consisting of acetaminophen and ethenzamide .
(B) Component: At least one selected from the group consisting of loxoprofen and salts thereof.
(C) component: corn starch, wheat starch, potato starch, pregelatinized starch, partially pregelatinized starch, crystalline cellulose, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium and ethyl cellulose At least one selected from the group consisting of The granulated particle group according to claim 9 , wherein the content of the water-soluble polymer is 5% by mass or less. The granulated particle group according to claim 9 or 10 , wherein the mass ratio represented by component (A)/component (B) is 0.1 to 12.5. The granulated particle group according to any one of claims 9 to 11, wherein the component (C) is at least one selected from the group consisting of corn starch and low-substituted hydroxypropylcellulose.

Images