KR20190074197A - Tablet and method for manufacturing tablet - Google Patents

Abstract

The present invention relates to a tablet and a method for manufacturing the tablet having improved productivity and good appearance. The tablet contains components of: (A) ibuprofen; (B) acetaminophen; (C) dry aluminum hydroxide gel; (D) at least one selected from caffeine and anhydrous caffeine, wherein a mass ratio of the component (B)/component (A) is 0.75 to 2.0, the mass ratio of the component (C)/component (A) is 0.35 to 0.45, and the mass ratio of the component (D)/the component (A) is 0.10 to 0.35.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for preparing tablets and tablets,

The present invention relates to tablets and a process for producing tablets.

Among non-steroidal antiinflammatory agents, ibuprofen has been widely used as an effective ingredient of analgesic and antipyretic agents because of its excellent anti-inflammatory, analgesic and antipyretic action. In general medicine such as antipyretic medicine or cold medicine, a plurality of active ingredients are mixed in anticipation of a wide range of pharmacological effects against various symptoms, and it has been studied to use ibuprofen in combination with various medicines.

For example, Patent Document 1 proposes an antipyretic analgesic that uses ibuprofen, acetaminophen, antacid, and anhydrous caffeine in combination. In the antipyretic analgesic of Patent Document 1, the duration of action of the active ingredient is prolonged, and the synergistic antipyretic analgesic action is improved.

Japanese Patent Application Laid-Open No. 5-246845

However, as in Patent Document 1, tablets using ibuprofen, acetaminophen, antacid, and anhydrous caffeine tend to produce protrusions called burrs at the edges of the tablets at the time of manufacturing, It is the cause. In addition, the powder mixture to be the raw material of the tablet is placed on the top surface of the rotary table of the rotary tablet machine for tableting, and the friction between the half of the tablet machine and the parts installed on the tabletop It is stretched and attached by. This attachment increases the load on the apparatus when the half is rotated, resulting in non-conformity of stopping the tablet machine, and in addition, incompatibility of being peeled off from the (board surface) and mixing with the product.

Therefore, the object of the present invention is to provide a method for producing tablets and tablets having improved productivity and good appearance.

As a result of extensive study, the inventors of the present invention have found that a dry aluminum hydroxide gel is selected as an antacid agent which can obtain a high tablet hardness and is highly effective in inhibiting stomach trouble, The ratio was set to a specific range. As a result, it has been found that the size of the burr at the time of tablet production can be suppressed and the appearance can be improved. In addition, it is possible to suppress the adhesion of the powder mixture to the upper surface of the rotary shaft of the tablet machine, and it becomes unnecessary to stop the tableting process in the middle due to the cleaning of the tablet machine, and the productivity of the tablet can be improved.

That is, the present invention has the following aspects.

[1] A pharmaceutical composition comprising (A) component: ibuprofen, (B) component: acetaminophen, (C) component: dry aluminum hydroxide gel, and (D) component: caffeine and anhydrous caffeine, Wherein the mass ratio of the component (B) / the component (A) is 0.75 to 2.0, the mass ratio of the component (C) / the component (A) is 0.35 to 0.45, A), wherein the mass ratio is 0.10 to 0.35.

[2] The tablet according to [1], wherein the content of the component (A) relative to the total mass of the tablet is 5 to 45.5 mass%.

[3] The tablet according to [1] or [2], wherein the content of the component (B) relative to the total mass of the tablet is 3.75-58 mass%.

[4] The tablet according to any one of [1] to [3], wherein the content of the component (C) relative to the total mass of the tablet is 1.75 to 19.6 mass%.

[5] The tablet according to any one of [1] to [4], wherein the content of the component (D) relative to the total mass of the tablet is 0.5 to 14.3 mass%.

[6] The tablet according to any one of [1] to [5], wherein the mass ratio of the component (C) / component (B) is 0.18 to 0.6.

[7] The tablet according to any one of [1] to [6], wherein the mass ratio of the component (D) / component (C) is 0.22 to 1.0.

[8] The tablet according to any one of [1] to [7], further comprising an excipient, wherein the content of the disintegrant relative to the total mass of the tablet is 5 to 30 mass%.

[9] The tablet according to any one of [1] to [8], further comprising a binder, wherein the content of the binder relative to the total mass of the tablet is 0.5 to 10% by mass.

[10] A process for producing a tablet according to any one of [1] to [9], wherein the component (A): ibuprofen, the component (B): acetaminophen, the component (C) D) Component: Caffeine and anhydrous caffeine, wherein the mass ratio of component (B) / component (A) is 0.75 to 2.0, component (C) / component Wherein the powder mixture having a mass ratio of 0.35 to 0.45 and a mass ratio of the component (D) / component (A) of 0.10 to 0.35 is titulated with a rotary tablet machine.

According to the method for producing tablets and tablets of the present invention, the productivity of tablets can be improved and the appearance can be improved.

[refine]

The tablets of the present invention contain the components (A), (B), (C) and (D) shown below.

The tablet of the present invention has, for example, a mortar and a pestle,

And then tableting the powder mixture to be a raw material of the tablet by using a tableting machine having a rotating disk.

The shape of the tablets is not particularly limited, but is preferably a corner angle tablet, a circular tablet, a rounded R tablet or a two-stage R tablet.

≪ Component (A) >

(A) is ibuprofen ((RS) -2- (p-isobutylphenyl) propionic acid). Ibuprofen is a compound classified as a non-steroidal anti-inflammatory analgesic (NSAIDs).

The middle diameter of the component (A) is preferably 0.1 to 80 占 퐉, more preferably 0.1 to 20 占 퐉. If the median diameter of the component (A) is not lower than the lower limit described above, handling of the powder mixture becomes easy. If the median diameter of the component (A) is lower than the upper limit, the elution property of the drug tends to be good.

In the present specification, the term " middle position diameter " refers to a particle diameter of a point which is 50% in a cumulative volume distribution curve in which the entire volume of a particle distribution obtained on a volume basis is 100% , That is, a volume-based cumulative 50% diameter.

The particle diameter means the volume average particle diameter, and can be measured by, for example, a laser diffraction / scattering particle distribution measuring apparatus (LS13320 type manufactured by Pekerman-Colter).

The content of the component (A) is preferably 5 to 45.5 mass%, more preferably 15 to 30 mass%, and still more preferably 20 to 25 mass%, based on the total mass of the tablet. When the content of the component (A) is at least the lower limit, the size of the burr of the purified product at the time of production and the adhesion of the powder mixture to the rotating disk can be suppressed, the size of the tablet can be reduced, and the dosage can be easily improved. When the content of the component (A) is less than the upper limit value, the size of the burr of the purified product at the time of production and the adhesion of the powder mixture to the rotating body are inhibited, and the collapsing property of the tablet tends to be good.

The content of the component (A) in the tablet of the tablet is preferably 50 to 200 mg, more preferably 76 to 90 mg, and most preferably 80 mg. If the content of the component (A) in the tablet of the tablet is more than the lower limit value described above, the heat-releasing and analgesic effect tends to be exerted. If the content of the component (A) in the tablet of the tablet is lower than the upper limit, the stimulation on the tablet after administration is liable to be reduced.

The component (A) may be granulated (granulated) by a conventional method with a physiologically active ingredient, a disintegrant, an excipient, and a binder described below before the tableting process. The content of the component (A) in the granulated product is preferably 10 to 90 mass%, more preferably 30 to 65 mass%, with respect to the mass of the granulated product. When the content of the component (A) in the granulated product is not less than the above-mentioned lower limit value, the size of the tablet can be made small and the dosage can be easily improved. If the content of the component (A) in the granulated product is less than the upper limit, the disintegration property of the tablet tends to be good.

≪ Component (B) >

(B) is acetaminophen (N- (4-hydroxyphenyl) acetamide). Acetaminophen is a component that is widely used as an antipyretic analgesic component.

The median diameter of the component (B) is preferably 0.1 to 200 占 퐉, more preferably 0.1 to 90 占 퐉. When the median diameter of the component (B) is not lower than the lower limit described above, handling of the powder mixture is facilitated. If the median diameter of the component (B) is lower than the upper limit, the elution property of the drug tends to be good.

The median diameter of the component (B) can be measured by the same method as the median diameter of the component (A).

The content of the component (B) is preferably from 3.75 to 58 mass%, more preferably from 12 to 39 mass%, and still more preferably from 20 to 25 mass%, based on the total mass of the tablets. When the content of the component (B) is at least the lower limit value, the size of the burr of the tablet at the time of production and the attachment of the powder mixture to the rotating disk can be suppressed, the size of the tablet can be reduced, and the dosage can be easily improved. If the content of the component (B) is less than the upper limit value, the hardness of the tablet becomes high, and the size of the burr of the tablet at the time of production and the adhesion of the powder mixture to the rotating body are liable to be inhibited.

The content of the component (B) in the tablet of the tablet is preferably 50 to 150 mg, more preferably 76 to 90 mg, and most preferably 80 mg. When the content of the component (B) in the tablet of the tablet 1 is not lower than the lower limit described above, the heat-releasing and analgesic effect tends to be exerted. If the content of the component (B) in the tablet of the tablet is lower than the above-mentioned upper limit value, the bitter taste (bitterness) upon taking is likely to be reduced.

The component (B) may be assembled by a routine method with a physiologically active ingredient, a disintegrant, an excipient, and a binder described below before the tableting process. The content of the component (B) in the granulated product is preferably 5 to 90 mass%, more preferably 15 to 40 mass%, with respect to the mass of the granulated product. If the content of the component (B) in the granulated product is not lower than the lower limit value described above, handling of the powder mixture becomes easy. If the content of the component (B) in the granulated product is less than the upper limit value, the elution property of the drug tends to be good.

The mass ratio of (B) / (A) in the tablet is 0.75 to 2.0, preferably 0.8 to 1.3, more preferably 0.9 to 1.1, and most preferably 1.0. When the mass ratio represented by (B) / (A) in the tablet is within the above-mentioned numerical range, the size of the burr of the purified product at the time of production and the adhesion of the powder mixture to the rotating body are liable to be suppressed.

≪ Component (C) >

Component (C) is a dry aluminum hydroxide gel. The dried aluminum hydroxide gel is a component used as an antacid. When dry aluminum hydroxide gel is used as the antacid, a high tablet hardness can be obtained and the gastric disorder-preventing effect can be obtained.

The median diameter of the component (C) is preferably 10 to 600 占 퐉. When the median diameter of the component (C) is within the above-mentioned numerical range, handling of the powder mixture becomes easy.

The median diameter of the component (C) can be measured by the same method as the median diameter of the component (A).

The content of the component (C) is preferably 1.75 to 19.6 mass%, more preferably 6 to 13.5 mass%, and even more preferably 8 to 11 mass% with respect to the total mass of the tablet. When the content of the component (C) is not lower than the lower limit described above, the size of the burr of the purified product at the time of production and the adhesion of the powder mixture to the rotating body can be suppressed, the size of the tablet can be reduced, and the dosage can be easily improved. When the content of the component (C) is not more than the upper limit, the size of the burr of the purified product at the time of production and the adhesion of the powder mixture to the rotating body are suppressed. When the content of the component (C) is not more than the upper limit, discoloration due to the interaction between the component (C) and the component (A) is likely to be suppressed.

The content of the component (C) in the tablet of the tablet is preferably 5 to 100 mg, more preferably 25 to 40 mg, and most preferably 35 mg. When the content of the component (C) in the tablet of the tablet is more than the lower limit value described above, the effect as the antacid agent tends to be exerted. When the content of the component (C) in the tablet 1 is less than the upper limit, discoloration due to the interaction between the component (C) and the component (A) is likely to be suppressed.

The component (C) may be assembled by a routine method with a physiologically active ingredient, a disintegrant, an excipient, and a binder described below before the tableting process. The content of the component (C) in the granulated product is preferably 10 to 90 mass%, more preferably 50 to 80 mass%, with respect to the mass of the granulated product. If the content of the component (C) in the granulated product is not lower than the lower limit value described above, handling of the powder mixture becomes easy. If the content of the component (C) in the granulated product is less than the upper limit value, the collapsibility of the granulated product tends to be good.

The mass ratio represented by (C) / (A) in the tablet is 0.35 to 0.45, preferably 0.40 to 0.45, and most preferably 0.44. When the mass ratio represented by (C) / (A) in the tablet is within the above-mentioned numerical range, the size of the burr of the purified product at the time of production and the adhesion of the powder mixture to the rotating body are liable to be suppressed.

The mass ratio of (C) / (B) in the tablet is preferably 0.18 to 0.6, more preferably 0.31 to 0.56, and further preferably 0.36 to 0.51. When the mass ratio represented by (C) / (B) in the tablet is within the above-mentioned numerical range, the size of the burr of the purified product at the time of production and the adhesion of the powder mixture to the rotating body are liable to be suppressed.

≪ Component (D) >

The component (D) is at least one selected from caffeine and anhydrous caffeine. Caffeine or anhydrous caffeine is a component that increases analgesic effects. As the component (D), anhydrous caffeine is preferable because the size of the burr of the purified product at the time of production and the attachment of the powder mixture to the rotating body are easily suppressed.

The median diameter of the component (D) is preferably 20 to 600 占 퐉, more preferably 150 to 400 占 퐉. If the median diameter of the component (D) is not lower than the lower limit described above, handling of the powder mixture becomes easy. If the median diameter of the component (D) is less than the upper limit, the collapsibility of the granule tends to be good.

The median diameter of the component (D) can be measured by the same method as the median diameter of the component (A).

The content of the component (D) is preferably 0.5 to 14.3 mass%, more preferably 3 to 10 mass%, and still more preferably 5 to 8 mass%, based on the total mass of the tablets. When the content of the component (D) is within the above-mentioned numerical range, the size of the burr of the purified product at the time of production and the attachment of the powder mixture to the rotating disk are liable to be suppressed.

The content of the component (D) in the tablet of the tablet is preferably 5 to 50 mg, more preferably 20 to 30 mg, and most preferably 25 mg. When the content of the component (D) in the tablet 1 is more than the above lower limit value, the effect of increasing the analgesic effect tends to be exerted. When the content of the component (D) in the tablet of the tablet 1 is less than the upper limit, the size of the tablet can be made small and the dosage can be easily improved.

The mass ratio of (D) / (A) in the tablet is 0.10 to 0.35, preferably 0.20 to 0.35, more preferably 0.25 to 0.35, and most preferably 0.31. When the mass ratio represented by (D) / (A) in the tablet is within the above-mentioned numerical range, the size of the burr of the purified product at the time of production and the adhesion of the powder mixture to the rotating body are liable to be suppressed.

The mass ratio of (D) / (C) in the tablet is preferably 0.22 to 1.0, more preferably 0.44 to 0.85, and further preferably 0.56 to 0.79. When the mass ratio represented by (D) / (C) in the tablet is within the above-mentioned numerical range, the size of the burr of the purified product at the time of production and the adhesion of the powder mixture to the rotating disk are liable to be suppressed.

<Optional ingredients>

(A), the component (B), the component (C) and the component (D) (hereinafter referred to as the component (A)) are contained within the range of not deteriorating the physical properties such as the effect of the present invention and the storage stability, (Component (D)) &quot;).

Examples of optional components include physiologically active ingredients other than the components (A) to (D), additives other than the components (C) and (D), and the like.

Examples of the physiologically active ingredient other than the components (A) to (D) include aspirin (acetylsalicylic acid), naproxen, ketoprofen, indomethacin, buxic desert, diclofenac, alclofenac, etodolac, Non-steroidal anti-inflammatory agents such as propene, mefenamic, meclofenamic, and piroxycam; Hypnotics and sedatives such as Nitrazam, Triazolam, Phenobarbital, Amobarbital, and Allyl isopropylacetal; Antiepileptics such as phenytoin, primidone, clonazepam, carbamazepine and valproic acid; Minkilline hydrochloride, dimenhydrinate, and the like; Psychotropic solvents such as haloperidol, chlorodiaxanthide, diazepam, and diazepam; Antispasmodics such as atropine; Cardiac drugs such as digoxin; Arrhythmia agents such as pinoleilol and dysopyramide; Diuretics such as hydrochlorothiazide, spironolactone, triamterene, furosemide, and bumetanide; Antihypertensive agents such as prazosin hydrochloride; Vascular vasodilators such as isosorbide nitrate, nifedipine, dipyridamole and the like; Nasal decongestants such as nocapine, tallobuterol, and tranilast; Expectorants such as bromohexane hydrochloride; Erythromycin, irradiated mycine, chloramphenicol. Antibiotics such as rifampicin and griseofulvin; Antihistamines such as clemastine fumarate; Steroid agents such as dexamethasone, betamethasone, prednisolone, danazol, chlormadine acetate and the like; Vitamins such as vitamin A and folic acid (vitamin M class); Therapeutic agents for digestive system diseases such as famotidine, metoclopramide, omeprazole, treadtone, and sucralfate; Clopribrate, mercaptopurine, methotrexate, dihydroergartamine mesylate, aluminum hydroxide, synthetic hydrotalcite, magnesium oxide, magnesium hydroxide and the like.

These physiologically active ingredients may be used singly or in combination of two or more kinds.

When the tablet contains a physiologically active component other than the components (A) to (D), the content of the physiologically active component other than the components (A) to (D) is preferably 1 to 20 mass% , More preferably from 3 to 15 mass%, and still more preferably from 5 to 10 mass%. When the content of the physiologically active ingredients other than the components (A) to (D) is not lower than the lower limit value described above, the effect of the physiologically active ingredient tends to be exerted. If the content of the physiologically active components other than the components (A) to (D) is less than the upper limit value, discoloration due to the interaction between the physiologically active components tends to be suppressed.

Examples of additives other than the components (C) and (D) include disintegrators, excipients, binders, flavors, lubricants, sweeteners, and acidifiers.

Examples of the disintegrator include carmellose, carmellose calcium, carmellose sodium, carboxymethyl cellulose calcium, and low-substituted hydroxypropyl cellulose (L-HPC). Among them, low-substituted hydroxypropylcellulose is preferable from the standpoint of enhancing collapsibility of tablets. The disintegrant may be contained in the granulated product or may be added when preparing the powder mixture for tableting.

When the tablet contains a disintegrant, the content of the disintegrant is preferably from 2 to 20 mass%, more preferably from 8 to 14 mass%, based on the total mass of the tablet. If the content of the disintegrant is above the lower limit, the disintegration of the tablet tends to be good. When the content of the disintegrant is less than the upper limit, expansion of the tablets after storage is easily suppressed.

Examples of the excipient include saccharides, corn starch, talc, crystalline cellulose, hydrated silicon dioxide, light silicic anhydride, calcium carbonate, potassium dihydrogen phosphate, L-cysteine and the like. Specific examples of the saccharides include polysaccharides such as monosaccharides (such as xylose), polysaccharides with two or more saccharides (sugar (such as granule sugar), lactose, maltose, sucrose, 25 trehalose, isomerized lactose, (Reduced palmitate, sorbitol, lactitol, erythritol, xylitol, maltitol, mannitol), starch syrup, isomerized sugar, reduced starch glycolate (reduced starch hydrolyzate) and the like.

Among them, crystalline cellulose, hydrated silicon dioxide and potassium dihydrogen phosphate are preferable because the binding force of the tablet is high and the size of the burr of the tablet during production is suppressed.

When the tablet contains an excipient, the content of the excipient is preferably from 5 to 30 mass%, more preferably from 10 to 20 mass%, based on the total mass of the tablet. When the content of the excipient is not less than the lower limit, the binding force of the tablet is increased and the size of the burr of the tablet at the time of production is suppressed. When the content of the excipient is less than the upper limit value, the concentration of the drug is increased, whereby the size of the tablet can be reduced and the dosage can be easily improved.

As the binder, a water-soluble polymer is preferable. When the polymer bound to the components (A) to (D) is dissolved in water, the area in which the components (A) to (D) are in contact with gastric juice increases and the dissolution rate of the drug can be increased. Further, since the binding force of the tablets is increased, the size of the burr of the tablets at the time of production is suppressed.

In the present specification, the water-soluble polymer compound means a polymer compound having an amount of water less than 100 ml required for dissolving 1 g at 20 캜. As the water-soluble polymer compound, it is preferable that the amount of water required to dissolve 1 g at 20 DEG C is less than 25 mL.

The water-soluble polymer may be a natural polymer, a synthetic polymer, or a combination thereof.

Examples of natural polymers include starch, soluble starch, dextrin, pregelatinized starch, sodium alginate, gum arabic, gelatin, tragacanth gum, locust bean gum, casein and the like.

Examples of the synthetic polymer include hydroxyalkyl celluloses such as hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) and hydroxypropylmethyl cellulose, carboxymethyl cellulose sodium (Na-CMC), methyl cellulose ), Carboxymethylated starch sodium, hydroxyethylated starch, starch phosphate ester sodium, polyvinyl alcohol (PVA), polyvinyl methyl ether (PVM), polyacrylamide, sodium polyacrylate, water soluble copolymer, partially saponified vinyl acetate Vinyl ether copolymers, polymers or copolymers of acrylic acid, methacrylic acid, maleic acid and its esters or salts, polyethylene glycol (PEG), polyethylene oxide, polyvinylpyrrolidone (PVP) and the like.

Among the binders described above, at least one member selected from hydroxyalkyl cellulose and PVA is preferable and at least one member selected from HPC and PVA is more preferable, and HPC More preferable.

The viscosity of the 2 mass% aqueous solution of HPC at 20 캜 is preferably 1 to 5000 mPa · s, more preferably 1 to 500 mPa · s, further preferably 1 to 20 mPa · s. If the viscosity of the 2 mass% aqueous solution of HPC at 20 캜 is not lower than the lower limit described above, the assemblability is easily improved. When the viscosity of the 2 mass% aqueous solution of HPC at 20 캜 is lower than the upper limit value, it is excellent in operability.

When the tablet contains a binder, the content of the binder is preferably 0.5 to 10 mass%, more preferably 3 to 6 mass%, based on the total mass of the tablet. When the content of the binder is not less than the lower limit, the binding force of the tablet is increased, and the size of the burr of the tablet at the time of production is suppressed. When the content of the binder is less than the upper limit value, increase in viscosity at the time of dissolving the tablet is suppressed, and the collapsibility is likely to be improved.

Examples of the perfume include menthol, limonene, plant essential oil (peppermint oil, mint oil, lyche oil, orange oil, lemon oil, etc.) and the like.

Examples of the lubricant include magnesium stearate, sodium stearyl fumarate, sucrose fatty acid ester, light anhydrous silicic acid, hydrated silicon dioxide, talc, and the like.

Examples of the sweetening agent include saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, tau martin, sucralose, mannitol, erythritol and the like.

Examples of acidic agents include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, and salts thereof.

These additives may be used singly or in combination of two or more kinds.

When the tablet contains an optional component, the content of the optional ingredient is preferably from 10 to 60 mass%, more preferably from 20 to 50 mass%, and further preferably from 30 to 40 mass%, based on the total mass of the tablet . If the content of the optional ingredient is not less than the above lower limit value, it is easy to improve the tablet formability and collapse property. If the content of the arbitrary component is less than the upper limit value, it is likely to exert a heat-releasing and analgesic effect. The total amount of each component constituting the tablet does not exceed 100% by mass based on the mass of the tablet.

The refining mass of one tablet is preferably 100 to 600 mg, more preferably 200 to 500 mg, and still more preferably 300 to 400 mg. If the refining mass of one tablet is above the lower limit value, the consumption amount of the powder mixture at the upper portion of the mortar of the tablet machine is increased, and the attachment of the powder mixture to the slider can be suppressed. If the refining mass of one tablet is below the upper limit value, the contact area between the mortar and the powder mixture decreases, and the attachment of the powder mixture to the tips of the balls of the tablet machine is apt to be suppressed.

[Preparation of tablets]

The tablet of the present invention is obtained by mixing and kneading the component (A), the component (B), the component (C) and the component (D). Hereinafter, an example of a method for producing a tablet of the present invention will be described.

The method for producing a tablet of the present embodiment has a tableting step of tableting a powder mixture containing the components (A) to (D) to form tablets.

The powder mixture is obtained by mixing components (A) to (D). The method of mixing the components (A) to (D) is not particularly limited and conventionally known methods may be mentioned. As an apparatus to be used, for example, a Vore-Container mixer, a V-type mixer, a W-cone mixer and the like can be given.

Examples of the method for calibrating the powder mixture include a method of calibrating using a tablet machine having a mortar and a pore. As a tableting machine, a rotary tableting machine having a high production efficiency is preferable.

The rotary tablet machine has a rotating disk. The rotating speed of the rotating disk can be appropriately adjusted, preferably 10 to 100 rpm, and preferably 25 to 60 rpm. If the rotational speed of the rotating disk is not less than the lower limit, the production efficiency can be increased. When the rotational speed of the rotating disk is less than the upper limit value, the ejection of the powder mixture in the mortar at the time of compression is suppressed, so that the size of the burr of the tablet is liable to be suppressed. When the rotational speed of the rotating disk is less than the upper limit value, collision with the take-out damper is suppressed when the tablet is taken out from the tableting machine, and occurrence of nonconformity such as cracking of the tablet can be suppressed.

As the component (A), commercially available products can be used as they are, but they may be ground or granulated so as to have a desired median diameter before mixing.

As a method for pulverizing the component (A), for example, a method using a pulverizer such as pin mill may be mentioned. The higher the rotation speed of the crushing blade of the crusher, the smaller the median diameter of the component (A).

As a method for granulating the component (A), for example, a dry granulation method such as a dry compacting method; A wet granulation method such as a fluidized bed granulation method, an agitation granulation method, an extrusion granulation method, a rolling granulation method, and an aging / crushing granulation method. Further, the granulated product in which the component (A) is assembled may be pulverized again.

The median diameter of the granules containing the component (A) is preferably 50 to 500 mu m, more preferably 100 to 350 mu m, and even more preferably 150 to 250 mu m. If the median diameter of the granules containing the component (A) is not lower than the lower limit described above, the handling of the powder mixture tends to be facilitated. If the median diameter of the granules containing the component (A) is not more than the upper limit, adhesion of the powder mixture to the slider is liable to be suppressed.

The median diameter of the granules containing the component (A) can be measured by a laser diffraction / scattering particle distribution measuring apparatus (LS13320 type, manufactured by Pekuman-Coulter).

As the component (B), commercially available products can be used as they are, but they may be ground or agglomerated so as to have a desired median diameter before mixing.

As a method for pulverizing the component (B), for example, there can be mentioned a method using a pulverizer such as a comb and a pin mill. The higher the rotation speed of the crushing blade of the pulverizer, the smaller the median diameter of the component (B).

As a method for assembling the component (B), for example, a dry granulation method such as a dry compacting method; A fluidized bed granulation method, an agitation granulation method, an extrusion granulation method, a motorized granulation method, and a wet granulation method such as agar / crush granulation.

Further, the granulated product of the component (B) may be pulverized again.

The median diameter of the granules containing the component (B) is preferably 50 to 500 mu m, more preferably 100 to 350 mu m, and even more preferably 150 to 250 mu m. If the median diameter of the granule containing the component (B) is not lower than the lower limit described above, the handling of the powder mixture tends to be facilitated. If the median diameter of the granules containing the component (B) is not more than the upper limit, adhesion of the powder mixture to the rotating body is likely to be suppressed.

The median diameter of the granules containing the component (B) can be measured by the same method as the median diameter of the granules containing the component (A).

The component (A) and the component (B) may be respectively assembled or assembled as the same granules. From the viewpoint that the uniformity of the component (A) and the component (B) is improved and the size of the burr of the purified product at the time of production and the attachment of the component (A) The component (A) and the component (B) are preferably assembled as the same granules.

As the component (C), a commercially available product can be used as it is, and it is preferable to assemble it separately from the component (A). By separately assembling the component (C) and the component (A), discoloration due to interaction between the component (A) and the component (C) can be suppressed and the stability of the component (A) can be improved. As a method of assembling the component (C), the same method as the method of assembling the component (A) can be mentioned.

The median diameter of the granules containing the component (C) is preferably 100 to 600 占 퐉, more preferably 150 to 500 占 퐉, and even more preferably 200 to 400 占 퐉. If the median diameter of the granules containing the component (C) is not lower than the lower limit described above, the handling of the powder mixture tends to be facilitated. When the median diameter of the granules containing the component (C) is not more than the upper limit, it is easy to suppress the size of the burr of the tablet at the time of production. The median diameter of the granules containing the component (C) can be measured by the same method as the median diameter of the granules containing the component (A).

The component (D) may be assembled, not assembled, or a commercially available product may be used as it is. When the component (D) is to be assembled, the method of assembling the component (D) may be the same as the method of assembling the component (A). The component (D) may be incorporated together with the above-mentioned disintegrator, excipient and binder. As the disintegrant, low-substituted hydroxypropyl cellulose is preferable. As the excipient, mannitol is preferable. As the binder, HPC is preferable. By granulating the component (D), the granules at the time of tableting are favorably collapsed, and adhesion of the powder mixture to the ball of the tablet machine can be suppressed.

The obtained tablets may be subjected to a coating treatment with a coating agent as required.

As the coating agent, the above-mentioned binders, plasticizers, colorants and the like can be exemplified, and from the viewpoint of not remarkably damaging the collapsibility, the above-mentioned binders and plasticizers are preferable.

Examples of the binder include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, polyvinyl alcohol methacrylmethyl polymer, and the like.

Examples of the plasticizer include those listed in Japanese official pharmacopoeia such as triethyl citrate, triacetin, carnauba and soybean lecithin, and in official documents such as specifications for pharmaceutical additives.

Examples of the colorant include titanium oxide, talc, ferric oxide, and blue No. 1.

These coating agents may be used alone or in combination of two or more.

Further, a commercially available premix product in which these components are mixed may be used. For example, Opadora (registered trademark) manufactured by Nippon Karacon Co., Ltd. may be mentioned.

The coating treatment can be carried out by a known method.

Examples of the apparatus used in the coating process include a high coater, an aqua coater, a doria coater and the like.

According to the tablets of the present invention, since the dry aluminum hydroxide gel is selected as the antacid and the components (A) to (D) are blended in a specific ratio, the size of the burr at the time of tablet production can be suppressed, .

In addition, since the powder mixture can be prevented from adhering to the tablet machine during tablet production, there is no need to stop the tableting process during cleaning by cleaning the tablet machine. As a result, the productivity of tablets can be improved.

[Example]

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

The raw materials and evaluation methods used in this embodiment are as follows.

[Materials used]

&Lt; Component (A) >

Ibuprofen: trade name &quot; ibuprofen 25 &quot; (manufactured by Synthetic Pharmaceutical Co., Ltd.);

&Lt; Component (B) >

Acetaminophen: trade name &quot; Acetaminophen &quot; (manufactured by IWAKI PHARMACEUTICAL CO., LTD.);

&Lt; Component (C) >

Dry aluminum hydroxide gel: trade name &quot; dry aluminum hydroxide gel S100 &quot; (manufactured by Kyowa Chemical Co., Ltd.), and a median diameter of 60 占 퐉.

&Lt; Component (D) >

Anhydrous caffeine: Product name "anhydrous caffeine 0.2 / 0.5" (manufactured by Synthetic Pharmaceutical Co., Ltd.), 200 μm in the middle.

<Optional ingredients>

Low-substituted hydroxypropyl cellulose (L-HPC): trade name "LH-21" (manufactured by Shin-Etsu Chemical Co., Ltd.).

Low-substituted hydroxypropylcellulose (L-HPC): trade name "LH-31" (manufactured by Shin-Etsu Chemical Co., Ltd.).

Mannitol: Trade name "Feraritol 0C" (manufactured by Rocket).

Hydroxypropyl cellulose (HPC): trade name "HPC-SSL" (manufactured by Nippon Soda Co., Ltd.).

Lactic acid: "DL heritage 90%" (manufactured by Showa Chemical Industry Co., Ltd.).

Crystalline cellulose: trade name: SEORAS UF-702 (manufactured by Asahi Chemical Industry Co., Ltd.).

Function 2 Silicon oxide: trade name &quot; ADORODA-102 &quot; (manufactured by PROD INDUSTRIAL CO., LTD.).

Potassium dihydrogenphosphate: trade name "potassium dihydrogenphosphate" (manufactured by Taihei Chemical Industry Co., Ltd.).

Magnesium stearate: trade name "Magnesium stearate" (manufactured by Taihei Chemical Industry Co., Ltd.). Coating agent: "Opadori (registered trademark) AMB WHITE" (manufactured by Nippon Caracon Joint Association).

[Assessment Methods]

&Lt; Evaluation of Size of Burr &

The shape of the blank mortar was φ 9.0 mm, and the two-step R 2 (r 1 = 10.5 mm, r 2 = 3.6 mm) was used.

The two-stage RJ is the radius of curvature R of the curve of the surface of the spherical portion that swells up and down of the tablet body portion (columnar portion), and the curvature radius R of the central portion (r1) and the curvature radius r2 of the rising portion from the periphery have different radii of curvature, and r1 > r2.

Here, the &quot; radius of curvature of the curved surface of the spherical joint portion &quot; refers to the radius of curvature of the spherical surface of the spherical surface, The radius of the circle when the surface draws the curved line as a part of the circle. In a rotary tablet press ("Ribura 3L", manufactured by Kikusui Seisakusho Co., Ltd.), tablets were continuously produced by pressing a powder mixture at 45 rpm using twelve openings. Three minutes after the start of the tableting, tablets were taken for 3 minutes. Twenty tablets were arbitrarily taken out of the tablets collected, and the major diameter of each of the tablets was measured and the average value was determined. The size of burr was evaluated based on the following evaluation criteria. "◎ ◎", "◎", and "○".

«Evaluation Criteria»

◎ O: less than 0.5 mm.

?: 0.5 mm or more and less than 1.0 mm.

?: 1.0 mm or more and less than 1.5 mm.

X: at least 1.5 mm.

&Lt; Evaluation of adherence to the rotation shaft &

A ball, such as an evaluation of the size of the burr, was tableted for 15 minutes continuously using a rotary tabletting machine. Thereafter, the long diameter and the short diameter of arbitrary 20 places among the attachments on the top surface of the rotor were measured, and the product of the long diameter and the short diameter was regarded as the fixed area (fixed area). And the average value of the areas of adhesion of three attachments having a large area of fixation was obtained. The adhesion of the powder mixture to the rotor was evaluated based on the following evaluation criteria. "◎ ◎", "◎", and "○".

«Evaluation Criteria»

◎ O: No attachment.

◎: The average value of the bonded area is less than 25 mm 2 (except for no attachment).

○: The average value of the bonded area is 25 mm 2 or more and less than 50 mm 2.

X: Average value of the bonded area is 50 mm2 or more.

[Examples 1-8, Comparative Examples 1-6]

&Lt; Assembly of component (A) and component (B)

(A) component (ibuprofen) and a disintegrant (low-substituted hydroxypropyl cellulose) were mixed to obtain a mixed powder. Separately, hydroxypropylcellulose and D-mannitol were dissolved in ion-exchange water to prepare a spray solution. The above powder mixture and the component (B) (acetaminophen) were wet-assembled (supplied) in the fluidized bed granulator (Spiraire Pro SFC-5, (A) component and (B) component were mixed to obtain a mixture containing the components (A) and (B), and the resulting dried product was sieved (using an eye size of 850 μm) To obtain a granule having a median diameter of 195 mu m.

&Lt; Assembly of Component (C) >

After setting the jacket of the high-speed mixer (FS25, manufactured by Fukae Kogyo Co., Ltd.) to 80 DEG C, the agitator rotation speed was set to 300 rpm and the chopper rotation speed was set to 1500 rpm. (C) component (dry aluminum hydroxide gel) and low-substituted hydroxypropyl cellulose were put into a can of a high-speed mixer, and a mixture of hydroxypropyl cellulose and lactic acid was added while stirring and preliminary mixing. After completion of the addition, agitation was continued for 8 minutes to advance the granulation, followed by aging for 20 minutes after completion, and drying in a fluidized bed to obtain granules having a median diameter of 350 μm.

&Lt; Preparation of powder mixture >

The above granules, the components other than the above component (D) and magnesium stearate were mixed for 20 minutes in a mixer (Borrel Container Mixer 20L, manufactured by Kotobuki Kogyo Co., Ltd.) so as to obtain the mixing ratios shown in Tables 1, 2, 5 and 6 . Subsequently, magnesium stearate was added and mixed for 5 minutes to obtain a powder mixture. The total mass of the powder mixture in each example was 3000 g each.

&Lt; Tablet of powder mixture >

Tablets were obtained by tabletting each example of the powder mixture under the conditions described in the above-mentioned &quot; evaluation of the size of burr &quot; and &quot; evaluation of adhesion to the slider. &Quot; The evaluation results are shown in Tables 1, 2, 5, and 6.

[Example 9]

&Lt; Assembly of component (A) >

(A) component (ibuprofen) and a disintegrant (low-substituted hydroxypropyl cellulose) were mixed to obtain a mixed powder. Separately, hydroxypropylcellulose and D-mannitol were dissolved in ion-exchange water to prepare a spray solution. The mixed powder was subjected to wet-type granulation (feeding temperature: 56 ° C, supply amount: 2.7 m 3 / min) while spraying the spray liquid (spray rate: 70 g / min) in a fluidized bed granulator (Spirror SFC- Minute), and further dried. The obtained dried product was subjected to a body bag (using an eye size of 850 mu m) to obtain a granule of component (A) having a median diameter of 180 mu m.

&Lt; Assembly of component (B) >

Hydroxypropylcellulose was dissolved in ion-exchange water to prepare a spray solution. (At an air supply temperature of 56 占 폚 while spraying the spray liquid at a spraying rate of 70 g / min in a fluidized bed granulator (SFC-5, manufactured by Prod Industries, Ltd.) And a drying amount of 2.7 m 3 / min.). The resulting dried product was passed through a body bar (using an eye size of 850 μm) to obtain a granulation product of component (B) having a median diameter of 198 μm.

<Preparation of powder mixture, tableting>

The granulation of the component (C), preparation of the powder mixture, and tableting were carried out in the same manner as in Example 1. The powder mixture was prepared so as to have a blending ratio shown in Table 3.

The obtained powder mixture was tableted under the conditions described in &quot; Evaluation of Size of Burr &quot; and &quot; Evaluation of Adhesion to Rotor Panels &quot;. The evaluation results are shown in Table 3.

[Example 10]

&Lt; Coating of Tablets >

The coating solution was dispersed in ion-exchanged water (82 parts by mass of ion-exchanged water relative to 18 parts by mass of Opadori) to prepare a coating solution. The tablets obtained in Example 1 were coated while spraying the coating liquid (liquid velocity: 1.3 g / min, air flow rate: 0.50 m 3 / min.) In a film coater (HiCotter FZ-LABO20, The mass of the coating material per one tablet was 4.2 mg), and the film-coated tablet was frozen. The results of evaluation of "evaluation of size of burr" and "evaluation of adhesion to the slider" when tablets were obtained by tableting a powder mixture were the same as those of Example 1. The evaluation results are shown in Table 4.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

As shown in Tables 1 to 4, in Examples 1 to 10 in which the present invention was applied, the productivity of the tablets was improved with the size of the burrs and the adherence to the rotating sheet both being "⊚", "⊚" And the appearance can be improved. On the other hand, as shown in Tables 5 and 6, the ratio of Comparative Examples 1 to 2 and (C) / (A) outside the range of application of the present invention to the ratio of (B) / (A) 4, and Comparative Examples 5 to 6 in which the ratio (D) / (A) was outside the range of application of the present invention was "×" in both the size of the burr and the adhesion to the rotating disk.

From these results, it was found that according to the present invention, the productivity of tablets can be improved and the appearance can be improved.

Claims (6)

(A) ingredient: ibuprofen, (B) ingredient: acetaminophen, (C) ingredient: dry aluminum hydroxide gel, (D) ingredient: one selected from caffeine and anhydrous caffeine,
Wherein the mass ratio of the component (B) / component (A) is from 0.75 to 2.0,
Wherein the mass ratio of the component (C) / component (A) is from 0.35 to 0.45,
Wherein the mass ratio of the component (D) / component (A) is 0.10 to 0.35. The method according to claim 1,
Wherein the content of the component (A) relative to the total mass of the tablet is 5 to 45.5 mass%. 3. The method according to claim 1 or 2,
Wherein the content of the component (B) relative to the total mass of the tablet is 3.75-58 mass%. 4. The method according to any one of claims 1 to 3,
Wherein the content of the component (C) relative to the total mass of the tablet is 1.75 to 19.6 mass%. 5. The method according to any one of claims 1 to 4,
Wherein the content of the component (D) relative to the total mass of the tablet is 0.5 to 14.3 mass%. A process for producing a tablet according to any one of claims 1 to 5,
(A) component: ibuprofen, component (B): acetaminophen, component (C): dry aluminum hydroxide gel, and component (D): caffeine and anhydrous caffeine,
Wherein the mass ratio of the component (B) / component (A) is from 0.75 to 2.0,
Wherein the mass ratio of the component (C) / component (A) is from 0.35 to 0.45,
Wherein the powder mixture having the mass ratio of the component (D) / component (A) of 0.10 to 0.35 is tableted with a rotary tablet machine.