JP7634984B2 - tablet - Google Patents

Description

The present invention relates to tablets.

Compared with water-soluble drugs, poorly water-soluble drugs tend to aggregate in polar solutions, which means that their transition from the stomach to the intestines is delayed, and once they aggregate, they often become difficult to redissolve in solution. For this reason, oral tablets containing poorly water-soluble drugs are generally produced by wet granulating them with excipients such as water-soluble polymers to form granulated particles, which are then compressed into tablets. Among poorly water-soluble drugs, analgesic ingredients such as acetylsalicylic acid are required to be fast-acting as an analgesic, so it is important to increase the disintegration of the tablet in the body and quickly dissolve the drug.

As a conventional technique for improving the disintegration and dissolution properties of tablets containing poorly water-soluble drugs, for example, Patent Document 1 proposes a tablet containing low-substituted hydroxypropylcellulose. According to the invention of Patent Document 1, the dissolution rate of the tablet is improved.

Japanese Unexamined Patent Publication No. 63-83025

Low-substituted hydroxypropyl cellulose is a component that is widely used as a disintegrant. Although tablets containing low-substituted hydroxypropyl cellulose have excellent disintegration properties immediately after production (initial stage), the dissolution properties of poorly water-soluble drugs are not sufficient, and dissolution may be delayed over time. This poses the problem of a further decrease in dissolution rate over time (after storage).

Therefore, the present invention aims to provide a tablet that has excellent initial dissolution properties and suppresses the decrease in dissolution rate after storage.

The present invention has the following aspects.
[1] (A) component: one or more drugs selected from acetylsalicylic acid, ibuprofen, and allylisopropylacetylurea;
(B) component: methylcellulose,
(C) component: a disintegrant,
A tablet, wherein the component (C) is one or more disintegrants selected from the group consisting of cellulose or a pharma- ceutically acceptable derivative thereof, and starch or a pharma- ceutically acceptable derivative thereof.
[2] The tablet according to [1], wherein the component (C) is one or more disintegrants selected from carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and hydroxypropyl starch.
[3] The tablet according to [1] or [2], wherein the content of the component (B) in the tablet is 0.3 to 35% by mass.
[4] The tablet according to any one of [1] to [3], further comprising a component (D): one or more selected from partially pregelatinized starch and pregelatinized starch.
[5] The tablet according to any one of [1] to [4], further comprising one or more selected from the group consisting of light anhydrous silicic acid, hydrous silicon dioxide, and talc as a component (E).

The tablet of the present invention has excellent initial dissolution properties and can suppress the decrease in dissolution rate after storage.

FIG. 1 is a side view showing an example of a tablet (standard R tablet or sugar-coated R tablet) according to one embodiment of the present invention. FIG. 2 is a side view showing another example of a tablet (two-stage R tablet) according to one embodiment of the present invention. FIG. 2 is a side view showing another example of a tablet (a circular, square flat tablet) according to one embodiment of the present invention. A side view showing another example of a tablet (circular Sumimaru flat tablet) according to one embodiment of the present invention.

Tablets
The tablet of the present invention contains component (A), component (B) and component (C).
In this specification, a "tablet" may be an uncoated tablet (plain tablet) that has no coating such as a coating agent applied to the surface of the compressed tablet, or a coated tablet (sugar-coated tablet) in which a coating layer is formed on part or all of the uncoated tablet.

<Component (A)>
The component (A) is one or more drugs selected from acetylsalicylic acid, ibuprofen, and allylisopropylacetylurea, and is a poorly water-soluble drug. The tablet of the present embodiment exhibits an analgesic effect by containing the component (A).
In this specification, "poorly water-soluble" refers to a solubility in water at 20°C (hereinafter also simply referred to as "solubility") of less than 0.7 g/100 mL. The solubility of component (A) is preferably 0.5 g/100 mL or less. When the solubility of component (A) is less than the above upper limit or equal to or less than the above upper limit, the storage stability of the tablet can be improved.
The solubility is measured by a test according to the 17th edition of the Japanese Pharmacopoeia. Specifically, the drug component is placed in water at 20°C, vigorously shaken for 30 seconds every 5 minutes, and the mass of the drug component that dissolves within 30 minutes relative to the volume of water is measured.

Specific examples of the component (A) include acetylsalicylic acid (solubility: 0.46 g/100 mL), ibuprofen (solubility: 0.01 g/100 mL or less), and allylisopropylacetylurea (solubility: 0.01 g/100 mL or less). As the component (A), acetylsalicylic acid is preferred because it provides a high effect of the present invention.
The component (A) may be used alone or in combination of two or more types.

The content of the (A) component in the tablet is preferably 0.83 to 90% by mass, more preferably 1.7 to 85% by mass, and even more preferably 30 to 85% by mass. When the (A) component is acetylsalicylic acid, the content of the (A) component in the tablet is preferably 60 to 90% by mass, more preferably 65 to 85% by mass, and even more preferably 75 to 85% by mass. When the (A) component is ibuprofen, the content of the (A) component in the tablet is preferably 3.3 to 90% by mass, more preferably 6.7 to 85% by mass, and even more preferably 30 to 80% by mass. When the (A) component is allylisopropylacetylurea, the content of the (A) component in the tablet is preferably 0.83 to 90% by mass, and more preferably 1.7 to 85% by mass.
When the content of the (A) component is equal to or greater than the lower limit, the analgesic effect can be further enhanced. When the content of the (A) component is equal to or less than the upper limit, the tablet can be made smaller, the tablet can be more easily taken, the tablet can be easily disintegrated, and the dissolution can be further enhanced. In addition, when the content of the (A) component is equal to or less than the upper limit, the decrease in the dissolution rate after storage can be further suppressed. In this specification, the content in the tablet does not include the coating layer described below. When the tablet is a coated tablet, it means the content in the plain tablet.

The content of component (A) in one tablet is preferably 5 to 510 mg, more preferably 10 to 460 mg, and even more preferably 20 to 410 mg.
When the component (A) is acetylsalicylic acid, the content in one tablet is preferably 200 to 450 mg, more preferably 250 to 400 mg, and even more preferably 300 to 350 mg. When the component (A) is ibuprofen, the content in one tablet is preferably 20 to 350 mg, more preferably 40 to 300 mg, and even more preferably 60 to 200 mg. When the component (A) is allylisopropylacetylurea, the content in one tablet is preferably 5 to 180 mg, more preferably 10 to 180 mg, and even more preferably 20 to 180 mg.
The reason why the content of the component (A) in one tablet is preferably not less than the lower limit and not more than the upper limit is the same as the content ratio of the component (A) described above. In this specification, the content in one tablet does not include the coating layer described below. When the tablet is a coated tablet, it means the content in the plain tablet.

The median diameter of component (A) is preferably 5 to 1000 μm, more preferably 10 to 500 μm, and even more preferably 30 to 150 μm. When the median diameter of component (A) is equal to or greater than the above lower limit, the fluidity is good and the tablet is easily filled during tableting. In addition, when the median diameter of component (A) is equal to or greater than the above lower limit, the disintegration delay is suppressed, and the decrease in dissolution rate after storage can be further suppressed. When the median diameter of component (A) is equal to or less than the above upper limit, the tablet is easily disintegrated, and the dissolution property can be further improved.
In this specification, the "median diameter" means the volume average particle diameter, and is measured, for example, by a laser diffraction/scattering particle size distribution analyzer (such as "LS230" manufactured by Beckman Coulter, Inc.).

<Component (B)>
The component (B) is methylcellulose. The tablet of this embodiment contains the component (B), which increases the dissolution rate. In particular, the initial dissolution rate is increased. This is believed to be because the methyl group of the component (B) disrupts the crystallinity between cellulose molecules and interacts with the component (A).

The content of component (B) in the tablet is preferably 0.3 to 35% by mass, more preferably 0.5 to 30% by mass, and even more preferably 1 to 25% by mass.
When component (A) is acetylsalicylic acid, the content of component (B) in the tablet is preferably 0.3 to 8 mass%, more preferably 0.5 to 5.5 mass%, and even more preferably 1 to 4 mass%. When component (A) is ibuprofen or allylisopropylacetylurea, the content of component (B) in the tablet is preferably 0.9 to 16 mass%, more preferably 3 to 13 mass%, and even more preferably 6 to 10 mass%.
When the content of the (B) component is equal to or greater than the lower limit, the dissolution rate of the (A) component can be increased. In addition, when the content of the (B) component is equal to or greater than the lower limit, the disintegration delay is suppressed, and the decrease in the dissolution rate after storage can be suppressed. When the content of the (B) component is equal to or less than the upper limit, the dissolution rate of the (A) component can be increased, the tablet can be easily disintegrated, and the initial disintegration property of the tablet can be improved.

The content of component (B) in one tablet is preferably 1 to 130 mg, more preferably 2 to 90 mg, and even more preferably 3 to 60 mg.
When the (A) component is acetylsalicylic acid, the content of the (B) component in one tablet is preferably 1 to 30 mg, more preferably 2 to 20 mg, and even more preferably 3 to 10 mg. When the (A) component is ibuprofen, the content of the (B) component in one tablet is preferably 2 to 62 mg, more preferably 10 to 46 mg, and even more preferably 15 to 25 mg. When the (A) component is allylisopropylacetylurea, the content of the (B) component in one tablet is preferably 1.5 to 40 mg, more preferably 8 to 30 mg, and even more preferably 15 to 25 mg.
The reason why the content of component (B) in one tablet is preferably not less than the above lower limit and not more than the above upper limit is the same as the content ratio of component (B) described above.

The mass ratio represented by [mass of component (A)]/[mass of component (B)] (hereinafter also referred to as "(A)/(B) ratio") is preferably 0.03 to 500, more preferably 0.1 to 230, and even more preferably 0.3 to 130.
When the (A) component is acetylsalicylic acid, the (A)/(B) ratio is preferably from 7 to 450, more preferably from 13 to 200, and even more preferably from 30 to 100. When the (A) component is ibuprofen, the (A)/(B) ratio is preferably from 3 to 100, more preferably from 5 to 28, and even more preferably from 7 to 13. When the (A) component is allylisopropylacetylurea, the (A)/(B) ratio is preferably from 1 to 100, more preferably from 5 to 20, and even more preferably from 7 to 12.
When the (A)/(B) ratio is within the above range, the dissolution rate of the (A) component can be increased. In addition, when the (A)/(B) ratio is within the above range, the disintegration delay is suppressed, and the decrease in the dissolution rate after storage can be further suppressed.

The median diameter of component (B) is preferably 5 to 200 μm, more preferably 10 to 150 μm, and even more preferably 30 to 100 μm. When the median diameter of component (B) is equal to or greater than the lower limit, the fluidity is good and the tableting is easy during tableting. When the median diameter of component (B) is equal to or less than the upper limit, the initial dissolution property of component (A) can be further improved.
The median diameter of component (B) is determined in the same manner as for the median diameter of component (A).

<Component (C)>
The component (C) is a disintegrant. More specifically, the component (C) is one or more disintegrants selected from cellulose or a pharmaceutically acceptable derivative thereof, and starch or a pharmaceutically acceptable derivative thereof. The tablet of this embodiment contains the component (C), which further enhances the disintegration property of the tablet.

Examples of disintegrants selected from cellulose or its pharma- ceutically acceptable derivatives include carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, low-substituted hydroxypropylcellulose, etc. Note that component (B) (methylcellulose) is not included in component (C).
Examples of disintegrants selected from starch or pharma- ceutically acceptable derivatives thereof include sodium carboxymethyl starch, hydroxypropyl starch, etc. Note that component (D) (one or more selected from partially pregelatinized starch and pregelatinized starch) described below is not included in component (C).
As component (C), a disintegrant selected from cellulose or a pharma- ceutically acceptable derivative thereof is preferred because it is highly effective in improving the disintegrability of the tablet, and low-substituted hydroxypropyl cellulose is more preferred because it does not reduce the hardness of the tablet.
The component (C) may be used alone or in combination of two or more types.

The content of component (C) in the tablet is preferably 3 to 15% by mass, more preferably 4 to 12% by mass, and even more preferably 5 to 10% by mass. When the content of component (C) is equal to or greater than the above lower limit, the initial disintegration of the tablet can be improved, and the dissolution of component (A) can be improved. When the content of component (C) is equal to or less than the above upper limit, an increase in the thickness of the tablet after storage can be suppressed. In addition, when the content of component (C) is equal to or less than the above upper limit, the tablet can be made smaller, and ease of administration can be improved.

The content of component (C) in one tablet is preferably 10 to 50 mg, more preferably 15 to 45 mg, and even more preferably 16 to 40 mg. The reason why the content of component (C) in one tablet is equal to or greater than the above lower limit, and the reason why the content is preferably equal to or greater than the above lower limit, is the same as the content ratio of component (C) described above.

The mass ratio represented by [mass of component (A)]/[mass of component (C)] (hereinafter also referred to as "(A)/(C) ratio") is preferably 0.6 to 45, more preferably 1 to 25, and even more preferably 2 to 17. When the (A)/(C) ratio is within the above numerical range, the initial dissolution of component (A) can be further improved.

The median diameter of component (C) is preferably 1 to 500 μm, more preferably 10 to 300 μm, and even more preferably 30 to 150 μm. When the median diameter of component (C) is equal to or greater than the above lower limit, the fluidity is good and the tableting is easy. When the median diameter of component (C) is equal to or less than the above upper limit, the initial disintegration property of the tablet can be further improved.
The median diameter of component (C) is determined in the same manner as for the median diameter of component (A).

<Optional ingredients>
The tablet of this embodiment may contain other components (optional components) in addition to the components (A), (B) and (C).
Examples of the optional components include the components (D) and (E) described below, binders, excipients, lubricants, flavors, sweeteners, and acidulants.
These optional components may be used alone or in combination of two or more.

(Component (D))
The component (D) is one or more selected from partially pregelatinized starch and pregelatinized starch. The tablet of this embodiment contains the component (D), which suppresses the delay in disintegration and further suppresses the decrease in dissolution rate after storage. The reason why the component (D) suppresses the decrease in dissolution rate after storage is thought to be because moisture is absorbed into the pregelatinized starch chains, preventing aggregation of the component (A).
The component (D) may be used alone or in combination of two or more types.

The content of component (D) in the tablet is preferably 3 to 15% by mass, more preferably 5 to 13% by mass, and even more preferably 8 to 11% by mass. When the content of component (D) is equal to or greater than the lower limit, the effect of suppressing disintegration delay can be further enhanced, and the decrease in dissolution rate after storage can be further suppressed. When the content of component (D) is equal to or less than the upper limit, the tablet can be made smaller, and ease of administration can be further improved.

The content of component (D) in one tablet is preferably 12 to 70 mg, more preferably 20 to 60 mg, and even more preferably 35 to 45 mg. The reason why the content of component (D) in one tablet is preferably equal to or more than the above lower limit and equal to or less than the above upper limit is the same as the content ratio of component (D) described above.

The median diameter of component (D) is preferably 1 to 200 μm, more preferably 10 to 100 μm, and even more preferably 30 to 80 μm. When the median diameter of component (D) is equal to or greater than the above lower limit, the fluidity is good and the tableting is easy during tableting. When the median diameter of component (D) is equal to or less than the above upper limit, the disintegration delay is suppressed, and the decrease in the dissolution rate after storage can be further suppressed.
The median diameter of component (D) is determined in the same manner as for the median diameter of component (A).

(Component (E))
The (E) component is one or more selected from light anhydrous silicic acid, hydrous silicon dioxide, and talc. The tablet of this embodiment contains the (E) component, which suppresses disintegration delay and further suppresses the decrease in dissolution rate after storage. The reason why the (E) component suppresses the decrease in dissolution rate after storage is thought to be that the (E) component is unlikely to interact with the (A) component and has a lubricating effect, thereby reducing the binding force between the (A) components.
The component (E) may be used alone or in combination of two or more types.

The content of component (E) in the tablet is preferably 0.01 to 2% by mass, more preferably 0.05 to 1.5% by mass, and even more preferably 0.1 to 1% by mass. When the content of component (E) is equal to or greater than the above lower limit, the effect of suppressing disintegration delay can be further enhanced. In addition, when the content of component (E) is equal to or greater than the above lower limit, the decrease in dissolution rate after storage can be further suppressed. When the content of component (E) is equal to or less than the above upper limit, the moldability of the tablet can be improved and the hardness of the tablet can be ensured.

The content of component (E) in one tablet is preferably 0.04 to 10 mg, more preferably 0.2 to 7.5 mg, and even more preferably 0.5 to 5 mg. The reason why the content of component (E) in one tablet is preferably equal to or more than the above lower limit and equal to or less than the above upper limit is the same as the content ratio of component (E) described above.

The median diameter of component (E) is preferably 0.1 to 100 μm, more preferably 1 to 50 μm, and even more preferably 2 to 20 μm. When the median diameter of component (E) is equal to or greater than the above lower limit, the fluidity is good and the tableting is easy during tableting. When the median diameter of component (E) is equal to or less than the above upper limit, the disintegration delay is suppressed, and the decrease in the dissolution rate after storage can be further suppressed.
The median diameter of component (E) can be determined in the same manner as for the median diameter of component (A).

(Binder)
Examples of the binder include polyvinylpyrrolidone, polyethylene glycol, etc. The above-mentioned component (D) is not included in the binder.

(Excipients)
Examples of the excipient include saccharides such as crystalline cellulose, corn starch, potato starch, lactose or its hydrate, sucrose, fructose, etc., sugar alcohols such as mannitol, erythritol, xylitol, sorbitol, etc., and inorganic salts such as anhydrous potassium dihydrogen phosphate, anhydrous calcium hydrogen phosphate, sodium chloride, potassium chloride, etc. The above-mentioned components (C), (D), and (E) are not included in the excipient.

(lubricant)
Examples of lubricants include magnesium stearate, calcium stearate, sodium stearyl fumarate, etc. The above-mentioned component (E) is not included in the lubricants.
As the lubricant, sodium stearyl fumarate is preferred because it helps maintain the stability of component (A).

(Fragrance)
Examples of the fragrance include menthol, limonene, peppermint oil, mint oil, lychee oil, orange oil, lemon oil, and other plant essential oils.

(sweetener)
Examples of sweeteners include sodium saccharin, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose, etc. The sugars and sugar alcohols of the above-mentioned excipients are not included in the sweeteners.

(Acidulant)
Examples of the acidulant include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, and salts thereof.

When the tablet of this embodiment contains an optional ingredient, the content of the optional ingredient in the tablet is preferably 0.1 to 15 mass %.
When the tablet of this embodiment contains an optional ingredient, the content of the optional ingredient in one tablet is preferably 0.5 to 75 mg.

<Tablet shape>
The shape of the tablet is not particularly limited in terms of the effects of the present invention, but from the viewpoint of ease of handling and swallowing, a shape having a cylindrical portion and a bulging portion bulging above and below the cylindrical portion is preferable. Examples of tablets having a cylindrical portion and a bulging portion include R tablets (standard R tablets, sugar-coated R tablets, etc.), two-stage R tablets, Sumi square flat tablets, Sumi round flat tablets, etc. The bulging portions of these tablets may be asymmetrical from top to bottom, but are preferably symmetrical from top to bottom.
Below, the shapes of standard R tablets or sugar-coated R tablets, two-tiered R tablets, circular corner square flat tablets, and circular corner round flat tablets will be explained in detail using drawings.

As shown in FIG. 1, a 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, and is a biconvex tablet in which the radius of curvature R of the curved surface of each of the first bulging portion 12 and the second bulging portion 22 is constant regardless of the position on the bulging portion surface.
The first bulge 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 bulge 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, "radius of curvature of the curve on the surface of the first bulge portion 12" refers to the radius of the circle when the curve on the surface of the first bulge portion 12 is considered to be part of a circle in a cross section cut perpendicular to the end face of the cylindrical portion 8 so as to pass through the zenith 12A.
The "radius of curvature of the curve on the surface of the second bulge portion 22" refers to the radius of the circle when the curve on the surface of the second bulge portion 22 is considered to be part of a circle in a cross section cut perpendicular to the end face of the cylindrical portion 8 so as to pass through the zenith 22A.
The zenith 12A of the first bulging portion 12 is the highest point with respect to one end face, and 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. From the viewpoint of tablet strength, it is preferable that the R of the first bulging portion 12 and the R of the second bulging portion 22 are the same.

As shown in Figure 2, the two-stage R tablet 200 has a cylindrical portion 8, a first bulging portion 12, and a second bulging portion 22, and the radius of curvature R1 of the rising portion from the periphery of each of the first bulging portion 12 and the second bulging portion 22 is different from the radius of curvature R2 of the zenith 12A, and is a biconvex tablet such that R1 < R2.
R1 of the first bulging portion 12 and R1 of the second bulging portion 22 may be the same or different. From the viewpoint of tablet strength, R1 of the first bulging portion 12 and R1 of the second bulging portion 22 are preferably the same.
R2 of the first bulging portion 12 and R2 of the second bulging portion 22 may be the same or different. From the viewpoint of tablet strength, R2 of the first bulging portion 12 and R2 of the second bulging portion 22 are preferably the same.

As shown in FIG. 3 , the round Sumi 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 bulge 12 rises linearly from near the periphery of one end face of the cylindrical portion 8 toward the center of said one end face at a predetermined rise angle θ, and any region including the zenith 12A becomes flat.
The second bulge 22 rises linearly at a predetermined rise angle θ from near the periphery of the other end face of the cylindrical portion 8 toward the center of the other end face, and any area including the zenith 22A becomes flat.
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. From the viewpoint of tablet strength, it is preferable that the rising angle θ of the first bulging portion 12 and the rising angle θ of the second bulging portion 22 are the same.

As shown in FIG. 4 , the circular Sumimaru flat tablet 400 is a biconvex tablet having a cylindrical portion 8 , a first bulge portion 12 , and a second bulge portion 22 .
The first bulge 12 rises from near the periphery of one end face of the cylindrical portion 8 toward the center of said one end face at a predetermined R, and any region including the zenith 12A becomes flat.
The second bulge 22 rises from near the periphery of the other end face of the cylindrical portion 8 toward the center of the other end face at a predetermined R, and any area including the zenith 22A becomes flat.
The R of the first bulging portion 12 and the R of the second bulging portion 22 may be the same or different. From the viewpoint of tablet strength, it is preferable that the R of the first bulging portion 12 and the R of the second bulging portion 22 are the same.

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

From the viewpoint of ease of administration, the size of the tablet is preferably within the following range.
・Standard R tablet...R = 4.0 to 24.0 mm, land width W = 0.05 to 0.1 mm.
- Sugar-coated R tablets...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.
- Circular Sumi round flat tablet...R = 0.7 to 5.0 mm, width of land part W = 0.05 to 0.1 mm.
- Circular corner flat tablet... rise angle θ = 25 to 35°, land width W = 0.05 to 0.1 mm.

For example, the tablet may not have a land portion, and the tablet periphery and the bulging rising portion may be in contact with each other. When the shape of the tablet is a circular Sumi square flat tablet or a circular Sumi round flat tablet, any one of the areas including the zenith of the first bulging portion and any area including the zenith of the second bulging portion may not be flat. The shape of the tablet does not have to be circular in plan view, and may be an ellipse in plan view, a square in plan view, or a shape that is a combination of a circular shape and a square shape in plan view.
The tablets may or may not be imprinted.

The shape of the tablets is not limited to the above examples, but in terms of the ease with which the effects of the present invention can be obtained, R tablets, two-tiered R tablets, round black flat tablets, or round black square flat tablets are preferred, R tablets, two-tiered R tablets, or round black flat tablets are more preferred, and R tablets or two-tiered R tablets are even more preferred.

The moisture content of the tablet is preferably 0.1 to 5% by mass. When the moisture content of the tablet is equal to or higher than the lower limit, the disintegration property is more excellent. When the moisture content of the tablet is equal to or lower than the upper limit, the appearance stability after storage is good.
The moisture content of a tablet can be calculated, for example, from the loss on drying when the tablet is heated at 120° C. for 10 minutes.

<Tablet manufacturing method>
The tablet of the present invention can be produced by a conventional method. For example, the tablet can be produced by mixing the components (A), (B), and (C), and, if necessary, optional components (mixing step), compressing the resulting mixture using a tablet press (tabletting step), and, if necessary, applying a coating (coating step).
Alternatively, each component may be granulated (granulation step) and then compressed into tablets to produce tablets. Each step will be described below.

(Mixing process)
The mixing step is a step of mixing the component (A), the component (B), the component (C), and, if necessary, any optional components.
In the mixing step, a general mixer can be used, such as a Bohle Container Mixer (manufactured by Hiroshima Metal & Machinery Co., Ltd.), a V-type mixer (manufactured by Dalton Co., Ltd.), or a ribbon mixer (manufactured by Dalton Co., Ltd.).

(Granulation process)
The granulation step is a step of granulating a mixture obtained by mixing component (A), component (B), component (C), and optional components as required, to obtain a granulated product.
The tablet manufacturing method of this embodiment may or may not include a granulation step.
Examples of the granulation method include dry granulation and wet granulation. Examples of the dry granulation method include roller compression granulation. Examples of the wet granulation method include fluidized bed granulation, stirring granulation, rolling granulation, and extrusion granulation.
As a granulation method, a dry granulation method is preferred because it is easy to maintain the stability of component (A).

In the granulation step, a general granulation device can be used, such as a dry granulator, a fluidized bed granulator, or an agitation granulator.
An example of a dry granulator is a roller compactor (manufactured by Freund Turbo Corp.). An example of a fluidized bed granulator is a Flowcoater (manufactured by Freund Corporation). An example of an agitation granulator is a Vertical Granulator (manufactured by Powrex Corp.).

(Tableting process)
The tableting step is a step of tableting the mixture or granules using a tablet press.
The tableting method is not particularly limited, and may be any known tableting method, such as a method of tableting the mixture using a tableting machine having a mortar and a pestle.
Examples of the tablet press include rotary tablet presses (Libra (manufactured by Kikusui Seisakusho Co., Ltd.), L-41 type (manufactured by Hata Iron Works Co., Ltd.), etc.).
Tableting conditions such as tableting pressure are not particularly limited and are appropriately determined taking into consideration the hardness required for the tablets, etc.

(Coating process)
The coating step is a step of providing a coating layer on the surface of the uncoated tablet obtained in the tabletting step. By providing a coating layer on the surface of the uncoated tablet, moisture absorption of the uncoated tablet is suppressed, and the effect of suppressing delayed disintegration is improved.
The coating layer can be formed by a conventional method. For example, a coating liquid in which a coating agent is dispersed in a solvent such as water is sprayed onto the surface of the plain tablet to coat it. The solvent component of the coating liquid is then dried to obtain a tablet on which a coating layer is formed.

In the coating step, a known coating device can be used.
Examples of the coating device include HiCoater (manufactured by Freund Corporation) and AquaCoater (manufactured by Freund Corporation).

Examples of coating agents include celluloses such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydroxymethyl cellulose; hydrophilic polymers such as gum arabic, carboxyvinyl polymer, polyvinylpyrrolidone, and polyacrylic acid; sugars such as maltose, xylose, starch syrup, isomerized sugars, oligosaccharides, sucrose, trehalose, and reduced starch saccharification products (reduced starch hydrolyzates); and sugar alcohols such as palatinit, lactitol, and maltitol. The above-mentioned components (B), (C), and (D), binders, excipients, and sweeteners may also be used as coating agents. Commercially available premix products such as Opadry (manufactured by Nippon Colorcon LLC) may also be used as coating agents.

When the tablet has a coating layer, the mass ratio of the coating layer to the mass of the plain tablet is preferably 0.1 to 10 mass%, more preferably 0.5 to 5 mass%, and even more preferably 1 to 3 mass%. When the mass ratio of the coating layer is equal to or greater than the above lower limit, the effect of suppressing disintegration delay is superior. When the mass ratio of the coating layer is equal to or less than the above upper limit, the initial disintegrability can be further improved.

As described above, the tablet of this embodiment exhibits antipyretic and analgesic effects by containing component (A).
The tablet of the present embodiment contains component (A), component (B), and component (C), and thus has excellent initial dissolution properties.
In addition, the tablet of this embodiment contains the component (A), the component (B), and the component (C), and thus can suppress a decrease in dissolution rate after storage.

The present invention will be described in detail below with reference to examples, but the present invention is not limited to the following description.
The raw materials used in this example are as follows:

[Ingredients used]
<Component (A)>
Acetylsalicylic acid: product name "Rhodine 3220", manufactured by Rhodia, median diameter 45 μm.
Aspirin starch mixture: product name "Rhodine 2312", manufactured by Rhodia, a granule of acetylsalicylic acid and corn starch in a mass ratio of 9:1.
Ibuprofen: product name "Ibuprofen 25", manufactured by BASF, median diameter 25 μm.
Allylisopropylacetylurea: product name "Alipronal (registered trademark)", manufactured by Kongo Chemical Co., Ltd., median diameter 40 μm.

<Component (B)>
Methylcellulose: product name "Metolose (registered trademark) SM-4", manufactured by Shin-Etsu Chemical Co., Ltd., median diameter 80 μm.
<Component (B') (Comparative Component for Component (B)>>
Ethyl cellulose: product name "Ethocel (registered trademark)", manufactured by Japan Colorcon LLC, median diameter 20 μm.

<Component (C)>
Low-substituted hydroxypropyl cellulose: product name “L-HPC (registered trademark) LH-B1”, manufactured by Shin-Etsu Chemical Co., Ltd., median diameter 80 μm.
Carmellose: Carboxymethylcellulose, product name "NS-300 (registered trademark)", manufactured by Gotoku Pharmaceutical Co., Ltd., median diameter 60 μm.
Croscarmellose sodium: product name "Kiccolate (registered trademark)", manufactured by Asahi Kasei Corporation, median diameter 80 μm.

<Optional ingredients>
(Component (D))
Partially pregelatinized starch: product name “PCS (registered trademark) PC-10”, manufactured by Asahi Kasei Corporation, median diameter 80 μm.
Pregelatinized starch: product name "SWELSTAR (registered trademark)", manufactured by Asahi Kasei Corporation, median diameter 80 μm.

(Component (E))
Light anhydrous silicic acid: product name "Silisia (registered trademark) 350", manufactured by Fuji Silysia Chemical Ltd., median diameter 2 μm.
Talc: product name "Crown Talc (registered trademark)", manufactured by Matsumura Sangyo Co., Ltd., median diameter 15 μm.
(lubricant)
Sodium stearyl fumarate: product name "PRUV (registered trademark)", manufactured by JRS Pharma.
(Excipients)
Corn starch: Product name: "Pharmacopoeia Matsutani Corn Starch", manufactured by Matsutani Chemical Industry Co., Ltd.

[Example 1]
<Tablet manufacturing>
Components (A) to (C) and optional components were placed in a resin bag in the ratios shown in Table 1 so that the total weight was 5 kg, and the mixture was mixed by shaking well (mixing step). The mixed powder (mixture) was compressed into tablets using a rotary tablet press (LIBRA2, manufactured by Kikusui Seisakusho Co., Ltd.) equipped with a mortar and pestle having a diameter of 9 mm (two-stage R) (compression step) to obtain tablets (plain tablets). The compression pressure was adjusted so that the hardness was 6 kgf (58.8 N) using a tablet hardness tester (manufactured by Yamato Scientific Co., Ltd.).
The obtained tablets were packed in a PTP (press-through pack), and the package was stored under conditions of 50° C. and 75% RH for 4 weeks.
The disintegration time (seconds) and the dissolution rate (%) of component (A) were measured for each tablet just before the start of storage (initial) and for each tablet after storage (aged). The results are shown in Table 1.
In Table 1, "-" indicates that the component is not included.

[Comparative Example 1]
Tablets (plain tablets) were obtained in the same manner as in Example 1, except that aspirin-starch mixture (a granule containing 330 mg of acetylsalicylic acid and 36.7 mg of corn starch) and sodium stearyl fumarate were mixed in the ratio shown in Table 1. The disintegration time (seconds) and dissolution rate (%) of component (A) of the obtained tablets were measured in the same manner as in Example 1. The results are shown in Table 1.

<Measurement of disintegration time>
For the tablets obtained in each example, the disintegration times of six tablets were measured in accordance with the tablet disintegration test method described in the 17th Edition of the Japanese Pharmacopoeia (disintegration test liquid was water) and the average value was calculated.

<Measurement of dissolution rate>
For the tablets obtained in each example, 900 mL of dissolution test first fluid (pH 1.2) (hereinafter also referred to as "test fluid") was used in accordance with the dissolution test method described in the 17th revised Japanese Pharmacopoeia, and the test fluid was collected 5 minutes after the start of the test at 50 rpm using the paddle method, and the amount of dissolution of component (A) was measured by high performance liquid chromatography. The dissolution rate (%) of component (A) was calculated according to the following formula.
Dissolution rate of component (A) (%)=[dissolution amount of component (A) (mg)]/[content of component (A) per tablet (mg)]×100
The dissolution rate (%) was calculated by measuring the dissolution rate (%) of component (A) of six tablets and averaging the results.

[Examples 2 to 24, Comparative Examples 2 to 5]
Tablets (plain tablets) were obtained in the same manner as in Example 1, except that the components shown in Tables 1 to 8 were mixed in the ratios shown in Tables 1 to 8. The disintegration time (seconds) and dissolution rate (%) of component (A) were measured for the obtained tablets in the same manner as in Example 1. The dissolution rate (%) of component (A) was measured by collecting the test liquid 5 minutes after the start of the test for Examples 1 to 14 and Comparative Examples 1 to 4, and collecting the test liquid 15 minutes after the start of the test for Examples 15 to 24 and Comparative Example 5. The results are shown in Tables 1 to 8. In Tables 1 to 8, "-" in the evaluation column indicates that the disintegration time was not measured.
However, Examples 4, 6, 7, and 15 to 24 are reference examples.

As shown in Tables 1 to 8, in Examples 1 to 24 in which the present invention was applied, the initial dissolution rate was high and the decrease in dissolution rate over time was suppressed. As shown in Comparative Example 5 described later, for ibuprofen and allylisopropylacetylurea, which have extremely low solubility in water of 0.01 g/100 mL or less, the dissolution rate of component (A) was extremely low in the absence of component (B), but the application of the present invention improved the dissolution rate of component (A) (Examples 15 to 24).
In contrast, Comparative Example 1, which did not contain components (B) and (C), had an initial dissolution rate of 15% and a dissolution rate after aging of 4%. Comparative Example 2, which did not contain component (B), had an initial dissolution rate of 21% and a dissolution rate after aging of 3%. Comparative Example 3, which did not contain component (C), had an initial dissolution rate of 5% and a dissolution rate after aging of 3%. Comparative Example 4, which used component (B') instead of component (B), had an initial dissolution rate of 18% and a dissolution rate after aging of 4%. Comparative Example 5, which did not contain component (B), had an initial dissolution rate of 5%.

These results demonstrate that the present invention provides excellent initial dissolution properties and prevents a decrease in dissolution rate after storage.

8 Cylinder portion 12 First bulge portion 12A, 22A Zenith 14, 24 Land portion 22 Second bulge portion 100 Standard R tablet or sugar-coated R tablet 200 Two-stage R tablet 300 Circular corner flat tablet 400 Circular corner flat tablet R, R1, R2 Radius of curvature θ Angle W Width of land portion

Claims (5)

(A) component: acetylsalicylic acid ,
(B) component: methylcellulose,
(C) component: a disintegrant,
a mass ratio represented by [mass of component (A)]/[mass of component (B)] is 30 to 100;
A tablet, wherein the component (C) is one or more disintegrants selected from carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and hydroxypropyl starch . The tablet according to claim 1, wherein the component (C) is one or more disintegrants selected from the group consisting of carmellose, croscarmellose sodium and low-substituted hydroxypropyl cellulose. The tablet according to claim 1 or 2, wherein the content of component (B) in the tablet is 0.3 to 35% by mass. The tablet according to any one of claims 1 to 3, further comprising component (D): one or more selected from partially pregelatinized starch and pregelatinized starch. The tablet according to any one of claims 1 to 4, further comprising component (E): one or more selected from light anhydrous silicic acid, hydrous silicon dioxide, and talc.

Images