Tablet and method for manufacturing tablet

Abstract

To provide a tablet that does not easily cause delayed disintegration over time and not require a particularly complicated manufacturing process while containing ibuprofen and ethenzamide, and to provide a method for manufacturing the same.SOLUTION: Provided is a tablet containing: component (A): ibuprofen; component (B): at least one selected from the group consisting of low-substituted hydroxypropyl cellulose, starch, crystalline cellulose, sodium carboxymethyl starch, carmellose, croscarmellose sodium, crospovidone, carmellose calcium, sodium starch glycolate, and partially pregelatinized starch; and component (C): ethenzamide, the volume average particle size of the (A) component being 5 to 20 μm.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to tablets and a method for manufacturing tablets.

Background Art

[0002] Ibuprofen is a propionic acid-based non-steroidal anti-inflammatory drug and is widely used not only as a medical drug but also as an active ingredient in antipyretic analgesics and general cold remedies for general use. On the other hand, ethenzamide is widely used as a salicylic acid-based non-steroidal anti-inflammatory drug in antipyretic analgesics and general cold remedies. When ibuprofen and ethenzamide coexist, it is known that a melting point drop occurs due to their interaction, and problems such as wetting, caking, generation of spots, color change, and clouding of the bottle occur in the preparation under high-temperature conditions.

[0003] In order to avoid the interaction of multiple components, it is common to avoid direct contact by separate granulation, multilayer tablets, etc., but it is difficult to sufficiently suppress the interaction by these means. Therefore, in Patent Document 1, a technique has been proposed in which ibuprofen and ethenzamide are blended in different granulated particles, and the granulated particles containing ibuprofen are coated with a film layer such as polyvinyl alcohol.

[0004] However, coating of the granulated particles tends to increase the cost because the manufacturing process becomes complicated. Therefore, in Patent Document 2, it has been proposed to add magnesium oxide or the like to ibuprofen and ethenzamide to suppress wetting of the preparation and suppress changes in the appearance of the preparation. The solid preparation obtained by the method of Patent Document 2 is said to be excellent in disintegration and elution of drug efficacy.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0006] However, as confirmed by the present inventor, although the initial disintegration property of the preparation obtained by the method of Patent Document 2 is improved to some extent, there is a problem of disintegration delay in which the disintegration time becomes longer over time. Therefore, an object of the present invention is to provide a tablet and a method for producing the same, which contain ibuprofen and ethenzamide, are less likely to cause disintegration delay over time, and do not particularly complicate the manufacturing process.

Means for Solving the Problems

[0007] As a result of intensive studies, the present inventor has found that by co-grinding ibuprofen with low-substituted hydroxypropyl cellulose (sometimes referred to as L-HPC (registered trademark)) or the like and blending this co-ground product with ethenzamide, it is possible to suppress the disintegration delay of the tablet over time. Generally, in order to suppress the interaction between multiple components, it is advantageous to increase the particle size so that the contact area between them is minimized. However, the present inventor has found that, unexpectedly, the disintegration delay can be suppressed by co-grinding ibuprofen until it has a sufficiently small particle size. The present invention is based on the above findings and has the following aspects.

[0008] <1> (A) component: ibuprofen and, (B) component: at least one selected from the group consisting of low-substituted hydroxypropyl cellulose, starch, crystalline cellulose, sodium carboxymethyl starch, carmellose, croscarmellose sodium, crospovidone, calcium carmellose, sodium starch glycolate, and partially pregelatinized starch, and (C) component: ethenzamide and, containing A tablet in which the volume-average particle diameter of the component (A) is 5 to 20 μm. <2> The tablet according to <1>, wherein the difference in disintegration time before and after storage at 50 °C for 6 weeks by the disintegration test method for tablets in the Eighteenth Revision of the Japanese Pharmacopoeia is less than 5 minutes. <3> The tablet according to <1> or <2>, comprising granulated particles (P) containing at least a part of the component (A) and the component (B). <4> The tablet according to <3>, further comprising granulated particles (Q) containing a part of the component (B) and the component (C) and not containing the component (A). <5> (D) component: The tablet according to any one of <1> to <4>, further containing an antacid. <6> A method for producing a tablet by tableting a powder mixture containing the following components (A) to (C) to obtain a tablet, Comprising a co-grinding step (X) of co-grinding at least a part of the component (A) and the component (B) to obtain a co-ground product having a volume-average particle diameter of 5 to 20 μm, The method for producing a tablet, wherein the powder mixture contains the co-ground product. (A) Ibuprofen, (B) At least one selected from the group consisting of low-substituted hydroxypropyl cellulose, starch, crystalline cellulose, sodium carboxymethyl starch, carmellose, croscarmellose sodium, crospovidone, calcium carmellose, sodium starch glycolate, and partially pregelatinized starch, (C) Etenzamide. <7> The method for producing a tablet according to <6>, wherein the co-grinding step (X) is performed using an impact mill. <8> Furthermore, comprising a granulation step (Y1) of granulating a granulation material (p) containing the co-ground product by any method selected from fluidized bed granulation, stirring granulation, and extrusion granulation to obtain granulated particles (P), The method for producing a tablet according to <6> or <7>, wherein the powder mixture contains the granulated particles (P). <9> Furthermore, a granulation step (Y2) is provided, in which a granulation material (q) containing a part of the component (B) and the component (C) and not containing the component (A) is granulated by any method selected from fluidized bed granulation, stirring granulation, and extrusion granulation to obtain granulated particles (Q). The method for producing a tablet according to <8>, wherein the powder mixture contains the granulated particles (P) and the granulated particles (Q). [Effect of the Invention]

[0009] According to the present invention, it is possible to provide a tablet that contains ibuprofen and ethenzamide, is less likely to cause a delay in disintegration over time, and does not have a particularly complicated manufacturing process, and a method for producing the same. [Embodiments for Carrying Out the Invention]

[0010] In this specification and the claims, "~" indicating a numerical range means that the numerical values described before and after it are included as the lower limit value and the upper limit value. The volume average particle diameter is a value measured by a laser diffraction / scattering particle size distribution measuring device (for example, "LS13320 type" manufactured by Beckman Coulter).

[0011] In this specification, unless otherwise specified, the content ratio of each component etc. with respect to the total mass of the tablet is the content ratio of each component etc. with respect to the total mass of the plain tablet, and the mass of the coating in the coated tablet is not considered. In the case of a plain tablet having a layer that does not contain any of the component (A) and the component (C), such as a laminated tablet or a nucleated tablet, it is the content ratio of each component etc. with respect to the total mass of the layer containing at least one of the component (A) and the component (C), and the mass of the layer that does not contain any of the component (A) and the component (C) is not considered.

[0012] [Tablet] The tablet of the present invention contains the component (A), the component (B), and the component (C), and the volume average particle diameter of the component (A) is 5 to 20 μm. The tablets of the present invention may further contain component (D) and component (E). Further, the tablets may further contain optional components other than component (A), component (B), component (C), component (D) and component (E). The tablets of the present invention preferably contain granulated particles (P) containing at least a part of component (A) and component (B). Further, in addition to the granulated particles (P), it is more preferable to contain granulated particles (Q) containing a part of component (B) and component (C) and not containing component (A).

[0013] <(A) component> (A) component is ibuprofen (2-(4-isobutylphenyl)propionic acid). By containing component (A), an antipyretic and analgesic effect can be obtained. (A) component preferably forms granulated particles (P) together with component (B). The granulated particles (P) may contain component (C), but it is preferably not contained in terms of making it less likely to cause a delay in disintegration over time. It is preferable that all of component (A) in the tablets constitutes the granulated particles (P).

[0014] The content ratio of component (A) to the total mass of the tablets is preferably 5 to 60% by mass, more preferably 10 to 40% by mass, and even more preferably 13 to 30% by mass. If the content ratio of component (A) is at least the above lower limit value, the change in the disintegration time over time is likely to be significant, so the effects of the present invention are more likely to be exhibited. If the content ratio of component (A) is at most the above upper limit value, wear of the tablets, pitting and dropping of granules are more suppressed, adhesion of powder to the tableting machine during tableting is more suppressed, and the tablets are more miniaturized.

[0015] The content of component (A) in one tablet is preferably 40 to 400 mg, more preferably 65 to 100 mg. If the content of component (A) is at least the above lower limit value, the elution property of component (A) can be further enhanced. If the content of component (A) is at most the above upper limit value, the tablets can be more miniaturized.

[0016] (A) component has a volume average particle diameter of 5 to 20 μm, preferably 5 to 15 μm. If the volume average particle diameter is at least the above lower limit value, the fluidity of the powder becomes good and it is excellent in handling during the production of the granulated particles (P). When the (A) component forms the granulated particles (P) together with the (B) component, if the volume average particle diameter is at most the above upper limit value, the delay of disintegration over time can be suppressed.

[0017] <(B) component> (B) component is at least one selected from the group consisting of low-substituted hydroxypropyl cellulose, starch, crystalline cellulose, sodium carboxymethyl starch, carmellose, croscarmellose sodium, crospovidone, calcium carmellose, sodium starch glycolate, and partially pregelatinized starch.

[0018] From the viewpoint of excellent effect of suppressing the delay of disintegration, preferably, at least one selected from the group consisting of low-substituted hydroxypropyl cellulose, starch, and crystalline cellulose is preferred, and particularly low-substituted hydroxypropyl cellulose is preferred. Note that low-substituted hydroxypropyl cellulose is synonymous with "low-substituted hydroxypropyl cellulose" described in the 18th revised Japanese Pharmacopoeia, and refers to low-substituted hydroxypropyl cellulose in which the hydroxy group of cellulose is substituted with a hydroxypropoxy group (-OC3H6OH). Specifically, it refers to those having a substitution degree (content) of the hydroxypropoxy group of 5 to 16% by mass.

[0019] (B) components all function as disintegrants. Further, by co-grinding with the (A) component, it is possible to suppress the adhesion of the (A) component to the grinder. Furthermore, the tablets of the present invention contain granulated particles (P) obtained by granulating a granulation material (p) containing a co-ground product of the (A) component and the (B) component, whereby the delay of disintegration over time is more suppressed.

[0020] Preferably, at least a part of the (B) component forms the granulated particles (P) together with the (A) component. Further, a part of the component (B) preferably forms granulated particles (Q) together with the component (C). Among the entire component (B), the component (B) forming the granulated particles (Q) is preferably the remainder of the component (B) forming the granulated particles (P). That is, the component (B) preferably consists of the component (B) forming the granulated particles (P) and the component (B) forming the granulated particles (Q). Also, a part of the component (B) that is not included in either of the granulated particles (P) and (Q) may be added before tableting.

[0021] The content ratio of the component (B) to the total mass of the tablets is preferably 1 to 45% by mass, more preferably 3 to 30% by mass, and even more preferably 5 to 15% by mass. If the content ratio of the component (B) is at least the above lower limit value, a decrease in the hardness of the tablets over time and a delay in disintegration can be more suppressed. Also, adhesion to the turntable during tableting is more suppressed. If the content ratio of the component (B) is at most the above upper limit value, the tablets can be made smaller, and the ease of administration can be enhanced. Also, the uniformity of the components is more improved.

[0022] The content of the component (B) in one tablet is preferably 10 to 100 mg, more preferably 15 to 75 mg, and even more preferably 20 to 70 mg. If the content of the component (B) is at least the above lower limit value, a decrease in the hardness of the tablets over time and a delay in disintegration can be more suppressed. Also, adhesion to the turntable during tableting is more suppressed. If the content of the component (B) is at most the above upper limit value, the tablets can be made smaller, and the ease of administration can be enhanced. Also, the uniformity of the components is more improved.

[0023] For those of the component (B) that form the granulated particles (P) together with the component (A), the volume average particle diameter is 5 to 20 μm, preferably 5 to 15 μm. If the volume average particle diameter is at least the above lower limit value, the fluidity of the powder becomes good, and handling during the production of the granulated particles (P) is excellent. Also, if the volume average particle diameter is at most the above upper limit value, a delay in disintegration over time can be suppressed.

[0024] (B) component other than forming the granulated particles (P) together with the (A) component has no particular limitation on the volume average particle diameter, but is preferably 5 to 250 μm, more preferably 10 to 100 μm. If the volume average particle diameter is equal to or greater than the above lower limit value, the handleability of the powder becomes better. Also, if the volume average particle diameter is equal to or less than the above upper limit value, the uniformity with other powders becomes better.

[0025] <(C) component> (C) component is ethenzamide (2-ethoxybenzamide). The (C) component is a salicylic acid-based non-steroidal anti-inflammatory drug (NSAIDs: Non-Steroidal Anti-Inflammatory Drugs), and by blending the (C) component, an antipyretic and analgesic effect can be obtained. Also, it alleviates gastric injury and intestinal injury caused by the (A) component.

[0026] (C) component may be blended with other raw materials as a powder before tableting, but from the point of more suppressing the delay in disintegration over time, it is preferable that it forms granulated particles together with a part of the (B) component. (C) component-containing granulated particles may form granulated particles (P) together with the (A) component and the (B) component, but from the point of more suppressing the delay in disintegration over time, it is preferable that it forms granulated particles (Q) containing a part of the (B) component but not containing the (A) component. It is preferable that all of the (C) component in the tablet constitutes the granulated particles (Q). By forming granulated particles (Q) not containing the (A) component, it becomes easier to avoid the interaction with the (A) component.

[0027] The content ratio of the (C) component to the total mass of the tablet is preferably 20 to 70% by mass, more preferably 25 to 57% by mass. If the content of the (C) component is equal to or greater than the above lower limit value, the change in the disintegration time over time tends to be significant, so the effects of the present invention are more likely to be exhibited. If the content of the (C) component is equal to or less than the above upper limit value, wear of the tablet, granule dropout and dents are more suppressed, and also, the adhesion of the powder to the tableting machine during tableting is more suppressed. Also, the tablet becomes smaller.

[0028] The content of component (C) in one tablet is preferably 10 to 500 mg, more preferably 25 to 300 mg, and even more preferably 50 to 250 mg. If the content of component (C) is at least the above lower limit, the gastric injury caused by component (A) can be more alleviated. In addition, since the change in the disintegration time over time is likely to be remarkable, the effects of the present invention are more likely to be exhibited. If the content of component (C) is at most the above upper limit, the tablet can be made smaller.

[0029] The volume-average particle diameter of component (C) is preferably 5 to 200 μm, more preferably 5 to 100 μm. If the volume-average particle diameter is at least the above lower limit, the fluidity of the powder becomes good, and it is excellent in handling during production. Also, if the volume-average particle diameter is at most the above upper limit, the delay in disintegration over time can be more suppressed.

[0030] <Mass ratio of component (A) and component (C)> The mass ratio (C) / (A) of component (C) to component (A) is preferably 0.5 to 5, more preferably 1.4 to 3.5. Since (C) / (A) is at least the preferred lower limit, the disintegrability immediately after production can be further enhanced. In addition, since the change in the disintegration time over time is likely to be remarkable, the effects of the present invention are more likely to be exhibited. Since (C) / (A) is at most the preferred upper limit, wear of the tablet, depression of granule loss, and adhesion of the powder to the tableting machine during tableting are more suppressed.

[0031] <Component (D)> Component (D) is an antacid. In this specification, an antacid refers to one having an antacid power of 50 mL or more as determined by the antacid power test method defined in the 18th Revised Japanese Pharmacopoeia. The antacid power determined by the antacid power test method defined in the 18th Revised Japanese Pharmacopoeia is represented by the consumption amount (mL) of 0.1 mol / L hydrochloric acid per 1 g. By containing component (D), the disintegrability immediately after production becomes good, and the change in the disintegration time over time can also be suppressed.

[0032] (D) component may be a known antacid, for example, compounds containing divalent or trivalent metals (metal salts, metal oxides, metal hydroxides, etc.). Specific examples include dried aluminum hydroxide (antacid power: 250 mL or more), dried aluminum hydroxide gel (antacid power: 300 - 340 mL), magnesium oxide (antacid power: 460 - 500 mL), magnesium carbonate (antacid power: 200 - 240 mL), magnesium aluminometasilicate (antacid power: 210 - 250 mL), aluminum glycinate (antacid power: 170 mL or more), aluminum hydroxide (antacid power: 250 mL or more), calcium carbonate (antacid power: 180 - 220 mL), magnesium aluminosilicate (antacid power: 250 - 290 mL or more), synthetic hydrotalcite (antacid power: 270 - 310 mL or more), sodium hydrogen carbonate (antacid power: 100 - 140 mL or more), etc. (D) component may be used alone or in combination of two or more. As the (D) component, at least one selected from dried aluminum hydroxide gel and magnesium aluminometasilicate is preferable from the viewpoint of the adhesion of the powder to the tablet press.

[0033] The volume average particle diameter of the (D) component is preferably 5 - 250 μm, more preferably 5 - 150 μm. If the volume average particle diameter is not less than the above lower limit value and not more than the above upper limit value, the handleability of the powder becomes good, and the uniformity of the components in the granulated particles is improved. There is no particular limitation on the blending method of the (D) component, and it may be granulated together with other components or added before tableting.

[0034] The content ratio of the (D) component to the total mass of the tablet is preferably 3 - 50% by mass, more preferably 5 - 30% by mass, and even more preferably 5 - 15% by mass. If the content ratio of the (D) component is not less than the above lower limit value, the disintegration property immediately after production becomes better, and the change in the disintegration time over time can be more suppressed. If the content ratio of the (D) component is not more than the above upper limit value, the tablet becomes smaller. Also, the abrasion degree is more reduced.

[0035] The content of component (D) in one tablet is preferably 10 to 150 mg, more preferably 20 to 100 mg. If the content of component (D) is at least the above lower limit value, the disintegrability immediately after production becomes better, and the change in the disintegration time over time can be more suppressed. If the content ratio of component (D) is at most the above upper limit value, the tablet becomes smaller in size. Also, the degree of wear is more reduced.

[0036] <Component (E)> Component (E) is a water-soluble polymer. In this specification, a water-soluble polymer refers to a polymer in which the amount of water required to dissolve 1 g of the polymer at 20°C is less than 10 g. By using component (E) when granulating the granulated particles (P), the present invention can reduce the contact area between component (A) and component (C), and further suppress the delay in disintegration. Also, by using component (E) when granulating the granulated particles (Q), it is possible to prevent the granulated particles (Q) from powdering, reduce the contact between component (A) and component (C), and further suppress the delay in disintegration. Moreover, the moldability when forming into a tablet can be further enhanced.

[0037] Examples of component (E) include at least one selected from the group consisting of sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gum arabic, carboxyvinyl polymer, povidone, and polyvinyl alcohol. The volume average particle diameter of component (E) in powder form is preferably 5 to 200 μm. If the volume average particle diameter is at least the above lower limit value and at most the above upper limit value, the handleability becomes better.

[0038] The content ratio of component (E) with respect to the total mass of the tablet is preferably 1 to 15% by mass, more preferably 2 to 7% by mass. If the content ratio of component (E) is at least the above lower limit value, wear of the tablet and depression of granule loss are more suppressed. If the content ratio of component (E) is at most the above upper limit value, the disintegrability of the tablet is more improved.

[0039] The content of component (E) in one tablet is preferably 3 to 30 mg, more preferably 7 to 25 mg. If the content of component (E) is at least the above lower limit value, wear of the tablet, granule loss, and indentation are more suppressed. If the content of component (E) is at most the above upper limit value, the disintegration property of the tablet is more improved.

[0040] <Optional component> As the optional component, for example, other physiologically active components other than component (A), component (C), and component (D), additives other than component (B), etc. may be contained.

[0041] Examples of other physiologically active ingredients include non-steroidal anti-inflammatory agents such as acetylsalicylic acid, loxoprofen, acetaminophen, naproxen, ketoprofen, indomethacin, bufexamac, diclofenac, alclofenac, etodolac, flurbiprofen, mefenamic acid, meclofenamic acid, piroxicam; central stimulants such as sodium benzoate caffeine, caffeine, anhydrous caffeine; hypnotics and sedatives such as nitrazepam, triazolam, phenobarbital, amobarbital, allylisopropylacetylurea, bromovalerylurea; antiepileptic agents such as phenytoin, primidone, clonazepam, carbamazepine, valproic acid; antiemetic agents such as meclizine hydrochloride, dimenhydrinate; psychotropic agents such as haloperidol, chlordiazepoxide, diazepam, sulpiride; antispasmodics such as atropine; cardiotonic agents such as digoxin; antiarrhythmic agents such as pindolol, disopyramide; diuretics such as hydrochlorothiazide, spironolactone, triamterene, furosemide, bumetanide; antihypertensive agents such as prazosin hydrochloride; coronary vasodilators such as isosorbide dinitrate, nifedipine, dipyridamole; antitussives such as noscapine, tulobuterol, tranilast; expectorants such as bromhexine hydrochloride; antibiotics such as erythromycin, josamycin, chloramphenicol, rifampicin, griseofulvin; antihistamines such as clemastine fumarate; steroid agents such as dexamethasone, betamethasone, prednisolone, danazol, chloramdinone acetate; vitamin agents such as vitamin A compounds, folic acid (vitamin M compounds); therapeutic agents for digestive system diseases such as famotidine, metoclopramide, omeprazole, trepitide, sucralfate; and clofibrate, mercaptopurine, methotrexate, dihydroergotamine mesylate. The physiologically active ingredient may be a single species or a combination of two or more species. Further, these other physiologically active ingredients may be pharmaceutically acceptable salts (for example, sodium salts, hydrochlorides, sulfates, nitrates, etc.).

[0042] Examples of additives include excipients, lubricants, binders, disintegrants other than component (B), fragrances, and flavoring agents (sweeteners, acidulants, etc.). Examples of excipients include, for example, sodium carboxymethylcellulose, corn starch, talc, lactose, powdered sugar, mannitol, light anhydrous silicic acid, calcium carbonate, and L-cysteine. Examples of lubricants include, for example, magnesium stearate, calcium stearate, polyethylene glycol, talc, stearic acid, and sucrose fatty acid ester. Examples of binders include, for example, starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, and dextrin. Examples of disintegrants other than component (B) include adipic acid, methylcellulose, povidone, calcium stearate, etc.

[0043] Examples of fragrances include, for example, menthol, limonene, and essential oils (such as perilla oil, mint oil, lychee oil, orange oil, lemon oil, etc.). Examples of sweeteners include, for example, sodium saccharin, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, and sucralose. Examples of acidulants include, for example, citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, and their salts. These additives may be used alone or in combination of two or more.

[0044] In terms of further suppressing the adhesion of the powder to the tableting machine during tableting, the optional component preferably contains at least one selected from the group consisting of excipients and lubricants, and more preferably contains excipients and lubricants. The content ratio of the excipient to the total mass of the tablets is preferably 10 to 60% by mass, and more preferably 20 to 40% by mass. The content ratio of the lubricant to the total mass of the tablets is preferably 0.1 to 3% by mass, and more preferably 0.2 to 1% by mass. The optional component may be contained in the granulated particles (P) or granulated particles (Q), or may be added before tableting.

[0045] <Granulated particles (P)> The granulated particles (P) contain at least a part of the (A) component and the (B) component. The granulated particles (P) may contain the (C) component, but it is preferably not contained. The granulated particles (P) preferably further contain the (E) component and may contain other optional components.

[0046] When the granulated particles (P) do not contain the (C) component, 20 to 80% by mass of the (A) component with respect to the total mass of the granulated particles (P) is preferable, 30 to 75% by mass is more preferable, and 50 to 75% by mass is even more preferable. When the granulated particles (P) contain the (C) component, the content ratio of the (A) component with respect to the total mass of the granulated particles (P) is preferably 10 to 60% by mass, and more preferably 15 to 40% by mass.

[0047] When the content ratio of the (A) component in the granulated particles (P) is equal to or higher than the above lower limit value, the change in the disintegration time over time is likely to be remarkable, and thus the effects of the present invention are more likely to be exhibited. When the content ratio of the (A) component in the granulated particles (P) is equal to or lower than the above upper limit value, wear of the tablet and indentation on the tablet surface due to particles falling off from the tablet surface (hereinafter also referred to as granule dropout indentation) are more suppressed. Also, the tablet is miniaturized more.

[0048] When the granulated particles (P) do not contain the (C) component, the content ratio of the (B) component with respect to the total mass of the granulated particles (P) is preferably 10 to 50% by mass, more preferably 15 to 40% by mass, and even more preferably 20 to 30% by mass. When the granulated particles (P) contain the (C) component, the content ratio of the (B) component with respect to the total mass of the granulated particles (P) is preferably 3 to 40% by mass, more preferably 5 to 30% by mass, and even more preferably 5 to 15% by mass.

[0049] When the content ratio of the (B) component in the granulated particles (P) is equal to or higher than the above lower limit value, the delay in disintegration over time can be more suppressed. If the content ratio of component (B) in the granulated particles (P) is at or below the above upper limit value, the tablets can be made smaller in size, and the ease of taking can be further improved. Also, the uniformity of the components is further enhanced.

[0050] When the granulated particles (P) contain component (C), the content ratio of component (C) with respect to the total mass of the granulated particles (P) is preferably 30 to 80% by mass, more preferably 45 to 70% by mass. If the content ratio of component (C) in the granulated particles (P) is at or above the above lower limit value, the change in the disintegration time over time is likely to be significant, so the effects of the present invention are likely to be exhibited. If the content ratio of component (C) in the granulated particles (P) is at or below the above upper limit value, wear of the tablets and indentation due to granule loss are more suppressed. Also, the tablets are made smaller in size.

[0051] The content ratio of component (E) with respect to the total mass of the granulated particles (P) is preferably 1 to 20% by mass, more preferably 3 to 10% by mass. If the content ratio of component (E) in the granulated particles (P) is at or above the above lower limit value, wear of the tablets and indentation due to granule loss are more suppressed. If the content ratio of component (E) in the granulated particles (P) is at or below the above upper limit value, the disintegrability of the tablets is further improved.

[0052] The volume average particle diameter of the granulated particles (P) is preferably 50 to 1000 μm, more preferably 100 to 500 μm, and even more preferably 100 to 300 μm. If the volume average particle diameter of the granulated particles (P) is at or above the above lower limit value, the filling property into the die during tableting becomes better, and if it is at or below the above upper limit value, the mass variation of the tablets becomes better (the variation becomes smaller).

[0053] When the granulated particles (P) do not contain component (C), the content ratio of the granulated particles (P) with respect to the total mass of the tablets is preferably 10 to 60% by mass, more preferably 20 to 40% by mass. When the granulated particles (P) contain component (C), the content ratio of the granulated particles (P) with respect to the total mass of the tablets is preferably 50 to 95% by mass, more preferably 70 to 90% by mass. If the content ratio of the granulated particles (P) is at least the above lower limit value, abrasion of the tablets and depression due to granule loss are more suppressed. If the content ratio of the granulated particles (P) is at most the above upper limit value, the disintegration property of the tablets is more improved.

[0054] When the granulated particles (P) do not contain the component (C), the content of the granulated particles (P) in one tablet is preferably 60 to 300 mg, and more preferably 80 to 200 mg. When the granulated particles (P) contain the component (C), the content of the granulated particles (P) in one tablet is preferably 100 to 700 mg, and more preferably 250 to 450 mg. If the content of the granulated particles (P) is at least the above lower limit value, abrasion of the tablets and depression due to granule loss are more suppressed. If the content of the granulated particles (P) is at most the above upper limit value, the disintegration property of the tablets is more improved.

[0055] <Granulated particles (Q)> The granulated particles (Q) contain a part of the component (B) and the component (C), and do not contain the component (A). The granulated particles (Q) preferably further contain the component (E), and may contain other optional components.

[0056] The content ratio of the component (C) with respect to the total mass of the granulated particles (Q) is preferably 40 to 94% by mass, more preferably 60 to 90% by mass, and still more preferably 65 to 85% by mass. If the content ratio of the component (C) in the granulated particles (Q) is at least the above lower limit value, the change in the disintegration time over time is likely to be remarkable, and thus the effects of the present invention are more likely to be exhibited. If the content ratio of the component (C) in the granulated particles (Q) is at most the above upper limit value, abrasion of the tablets and depression due to granule loss are more suppressed. Also, the tablets are more miniaturized.

[0057] The content ratio of the component (B) with respect to the total mass of the granulated particles (Q) is preferably 5 to 50% by mass, more preferably 7 to 35% by mass, and still more preferably 10 to 25% by mass. If the content ratio of the component (B) in the granulated particles (Q) is at least the above lower limit value, a decrease in the hardness of the tablets over time and a delay in disintegration can be more suppressed. If the content ratio of component (B) in the granulated particles (Q) is at or below the above upper limit value, the tablets can be made smaller and the swallowability can be further improved. Also, the uniformity of component (C) is further enhanced.

[0058] The content ratio of component (E) with respect to the total mass of the granulated particles (Q) is preferably 1 to 20% by mass, more preferably 3 to 10% by mass. If the content ratio of component (E) is at or above the above lower limit value, wear of the tablets and indentation due to granule loss are further suppressed. If the content ratio of component (E) is at or below the above upper limit value, the disintegrability of the tablets is further improved.

[0059] The volume average particle diameter of the granulated particles (Q) is preferably 50 to 1000 μm, more preferably 100 to 500 μm, and even more preferably 100 to 350 μm. If the volume average particle diameter of the granulated particles (Q) is at or above the above lower limit value, the filling property into the die during tableting becomes better, and if it is at or below the above upper limit value, the mass variation of the tablets becomes better (the variation becomes smaller).

[0060] The content ratio of the granulated particles (Q) with respect to the total mass of the tablets is preferably 20 to 80% by mass, more preferably 30 to 65% by mass. If the content ratio of the granulated particles (Q) with respect to the total mass of the tablets is at or above the preferable lower limit value, wear of the tablets and indentation due to granule loss are further suppressed. If it is at or below the preferable upper limit value, the disintegrability of the tablets is further improved.

[0061] The content of the granulated particles (Q) in one tablet is preferably 60 to 400 mg, more preferably 80 to 300 mg. If the content of the granulated particles (Q) is at or above the above lower limit value, wear of the tablets and indentation due to granule loss are further suppressed. If the content of the granulated particles (Q) is at or below the above upper limit value, the disintegrability of the tablets is further improved.

[0062] <Form of the tablets> The tablets may be plain tablets or coated tablets (such as film-coated tablets, sugar-coated tablets, etc.). The coated tablet has a core tablet and a film coating the surface of the core tablet. The film contains a coating agent (such as a water-soluble polymer compound, saccharides, etc.). The film may further contain at least one selected from the group consisting of a plasticizer (such as triethyl citrate, triacetin, cetyl alcohol, etc.), a colorant, an acidulant, and a sweetener.

[0063] As the coating agent for the coated tablet, it is preferable to select one that does not significantly impair the physical properties (such as disintegration property, etc.) of the core tablet. Specifically, the above-mentioned coating agents can be mentioned. The coating agent may be used alone or in combination of two or more.

[0064] The amount of the coating agent used (coating amount) in the coated tablet is appropriately set within a range that does not impair the effects of the present invention. For example, the amount of the coating agent used is preferably 0.1 to 5 parts by mass, more preferably 0.5 to 2 parts by mass, based on 100 parts by mass of the core tablet. If the amount of the coating agent used is equal to or more than the above lower limit value, the swallowability can be maintained well, and if it is equal to or less than the above upper limit value, the disintegration property can be maintained well.

[0065] The form of the core tablet in the tablet is not particularly limited, and examples include a single-layer tablet (single-layer structure), a multilayer tablet (multilayer structure), a nucleus-containing tablet, etc. When the core tablet is a multilayer tablet, for example, it can be a two-layer tablet or a three-layer tablet. Since the effects of the invention can be obtained remarkably, it is preferable that the core tablet contains components (A) to (C) in the same layer, and it is preferable that it is a single-layer tablet from the viewpoint of manufacturability.

[0066] The single-layer tablet contains component (A) and component (C) which are likely to cause problems due to interaction in the same layer. However, since the volume-average particle diameter of component (A) is 5 to 20 μm, the delay in disintegration is suppressed. In particular, by including granulated particles (P) containing component (A) and component (B), the delay in disintegration is more suppressed. Especially, when the granulated particles (P) contain a co-ground product of component (A) and component (B) and the volume-average particle diameter thereof is 5 to 20 μm, the delay in disintegration is more suppressed. In addition, by including granulated particles (Q) that contain component (B) and component (C) and do not contain component (A) in addition to the granulated particles (P), the delay in disintegration is further suppressed.

[0067] Examples of the two-layer tablet include a two-layer tablet composed of a first layer containing components (A) to (C) and a second layer containing optional components. In this case, the first layer preferably contains granulated particles (P) containing a co-ground product of component (A) and component (B), and more preferably further contains granulated particles (Q) that contain component (B) and component (C) and do not contain component (A), similar to the above single-layer tablet. In this case, the second layer preferably does not contain component (A) and component (C). The second layer can contain any components other than component (A) and component (C).

[0068] Alternatively, it may be a two-layer tablet composed of a first layer containing component (A) but not containing component (C) and a second layer containing component (C) but not containing component (A). In this case, the first layer preferably contains granulated particles (P) containing a co-ground product of component (A) and component (B). In addition, the second layer preferably contains granulated particles (Q) that contain component (B) and component (C) and do not contain component (A).

[0069] Examples of the three-layer tablet include a three-layer tablet composed of a first layer containing components (A) to (C), a second layer containing optional components, and a third layer. In this case, the first layer preferably contains granulated particles (P) containing a co-ground product of component (A) and component (B), and more preferably further contains granulated particles (Q) that contain component (B) and component (C) and do not contain component (A), similar to the above single-layer tablet. In addition, one or both of the second layer and the third layer, which are in contact with the first layer, preferably do not contain component (A) and component (C). The second layer can contain any components other than component (A) and component (C).

[0070] Further, the first layer may be a layer containing the component (A) but not containing the component (C), and one or both of the second layer and the third layer may be a layer containing the component (C) but not containing the component (A). When one or both of the second layer and the third layer, which is a layer containing the component (C) but not containing the component (A), are in contact with the first layer, the effects of the present invention can be remarkably obtained.

[0071] In this case, the first layer preferably contains granulated particles (P) containing a co-ground product of the component (A) and the component (B). Also, one or both of the second layer and the third layer, which is a layer containing the component (C) but not containing the component (A), preferably contains granulated particles (Q) containing the component (B) and the component (C) and not containing the component (A).

[0072] Examples of the multi-core tablet include a multi-core tablet in which one of the inner core and the outer layer contains the components (A) to (C) in the same layer and the other contains optional components. In this case, the former preferably contains granulated particles (P) containing a co-ground product of the component (A) and the component (B), similar to the above single-layer tablet, and more preferably further contains granulated particles (Q) containing the component (B) and the component (C) and not containing the component (A). Also, the latter preferably does not contain the component (A) and the component (C). The latter can contain any components other than the component (A) and the component (C).

[0073] Examples of the multi-core tablet also include a multi-core tablet in which one of the inner core and the outer layer contains the component (A) but not the component (C), and the other contains the component (C) but not the component (A). In this case, the former preferably contains granulated particles (P) containing a co-ground product of the component (A) and the component (B). Also, the latter preferably contains granulated particles (Q) containing the component (B) and the component (C) and not containing the component (A).

[0074] The dimensions of the tablets are not particularly limited. From the viewpoints of ease of handling and swallowability of the tablets, the diameter of the tablets is preferably 7 to 12 mmφ, more preferably 8.5 to 10 mmφ. In the case of oval tablets or caplet tablets (oblong tablets), the major axis is preferably 9 to 18 mm, more preferably 10 to 14 mm. Also, the minor axis is preferably 5 to 12 mm, more preferably 6 to 9 mm. Also, the tablet mass per tablet is preferably 100 to 600 mg, more preferably 250 to 550 mg.

[0075] The hardness of the tablets is not particularly limited. From the viewpoint of more suppressing the decrease in hardness and swelling of the tablets over time, 7 kgf or more is preferable, 9 kgf or more is more preferable, and 10 kgf or more is even more preferable. As the upper limit of the hardness of the tablets, 20 kgf or less is preferable from the viewpoint of disintegration property.

[0076] The disintegration time immediately after production by the tablet disintegration test method of the 18th revised Japanese Pharmacopoeia is preferably less than 30 minutes, more preferably less than 10 minutes, and even more preferably less than 5 minutes. The disintegration time after storage at 50°C for 6 weeks by the tablet disintegration test method of the 18th revised Japanese Pharmacopoeia is preferably less than 30 minutes, more preferably less than 10 minutes, and even more preferably less than 5 minutes. The difference in the disintegration time before and after storage at 50°C for 6 weeks by the tablet disintegration test method of the 18th revised Japanese Pharmacopoeia is preferably less than 5 minutes, more preferably less than 2 minutes.

[0077] [Tablet manufacturing method] The method for manufacturing the tablets of the present invention is a method for manufacturing tablets by tableting a powder mixture containing components (A) to (C), and includes a co-grinding step (X) of co-grinding at least a part of component (A) and component (B) to obtain a co-ground product having a volume average particle diameter of 5 to 20 μm.

[0078] The method for manufacturing the tablets of the present invention preferably includes a granulation step (Y1) of granulating a granulation material (p) containing the co-ground product to obtain granulated particles (P). In this case, the powder mixture to be tableted contains the granulated particles (P). Furthermore, it is more preferable to include a granulation step (Y2) of granulating a granulation material (q) containing a part of the component (B) and the component (C) and not containing the component (A) to obtain granulated particles (Q). In this case, the powder mixture to be tabletted includes the granulated particles (Q) in addition to the granulated particles (P).

[0079] <Co-grinding step (X)> The co-grinding step (X) is a step of co-grinding at least a part of the component (A) and the component (B) to obtain a co-ground product. By co-grinding the component (A) together with the component (B), adhesion to the grinder is suppressed, and the volume average particle diameter of the ground product can be made 20 μm or less.

[0080] There is no particular limitation on the volume average particle diameter of the component (A) before grinding in the grinding step, but it is preferably 5 to 100 μm, more preferably 15 to 100 μm. Also, there is no particular limitation on the volume average particle diameter of the component (B) before grinding in the grinding step, but it is preferably 5 to 250 μm, more preferably 10 to 100 μm.

[0081] The ratio of the component (B) to the component (A) in the grinding step (hereinafter also referred to as B / A) is preferably 0.01 to 10, more preferably 0.07 to 5, and even more preferably 0.2 to 1.3. If B / A is equal to or greater than the above lower limit value, adhesion of the component (A) to the grinder or the like is further suppressed, and the mixing efficiency and grindability are further improved. If B / A is equal to or less than the above upper limit value, the tablets are further miniaturized. In addition, the component (C) may be added to the components (A) and (B) and co-ground. It is preferable to co-grind without adding the component (C). When co-grinding with the addition of the component (C), the uniformity of the powder mixture containing the components (A) to (C) is further improved.

[0082] The co-grinding step (X) can be carried out using a known grinder. As a crusher, an impact crusher is preferred in terms of excellent productivity. An impact crusher is a crusher that mainly pulverizes solid raw materials by impact force. Among impact crushers, a disk rotation type crusher is preferred, a hammer mill or a pin mill is more preferred, and a pin mill is particularly preferred in that it can make the particle size smaller.

[0083] The crushing conditions are set so that the volume average particle size of the crushed product is 5 to 20 μm, preferably 5 to 15 μm. If the volume average particle size of the crushed product is equal to or greater than the above lower limit value, the fluidity of the powder becomes good and it is excellent in handling. If the volume average particle size is equal to or less than the above upper limit value, the delay in tablet disintegration is suppressed. In addition, wear of the tablet, depression of granule dropout, and adhesion of the powder to the tablet press during tableting are suppressed. When using a pin mill, the rotational speed of the pin disk preferably has a peripheral speed of 1000 m / min or more, and more preferably a peripheral speed of 1600 m / min to 2240 m / min. The larger the rotational speed, the smaller the particle size after crushing can be.

[0084] <Granulation step (Y1)> The granulation step (Y1) is a step of granulating a granulation material (p) containing the co-ground product obtained in the co-grinding step to obtain granulated particles (P). The granulation material (p) preferably contains the (E) component in addition to the co-ground product obtained in the co-grinding step, and may contain other optional components. The granulation material (p) may contain the (C) component in addition to the co-ground product, but it is preferable not to contain it.

[0085] When the granulation material (p) contains the (E) component, the (E) component may be added as a powder to the co-ground product, or may be added when preparing an aqueous solution of the (E) component for wet granulation. In terms of further suppressing tablet wear and granule dropout depression, it is preferable to prepare and add an aqueous solution of the (E) component. When preparing an aqueous solution of the (E) component, from the viewpoint of handling property at the time of addition, the concentration of the (E) component in the aqueous solution is preferably 3 to 10% by mass.

[0086] When the granulation material (p) does not contain the component (C), the proportion of the co-ground material in the granulation material (p) is preferably 80 to 99% by mass, more preferably 80 to 97% by mass, and even more preferably 90 to 95% by mass. When the granulation material (p) contains a co-ground material that does not contain the component (C) and the component (C), the proportion of the co-ground material in the granulation material (p) is preferably 15 to 60% by mass, more preferably 20 to 50% by mass, and even more preferably 25 to 40% by mass.

[0087] The granulation method in the granulation step (Y1) is preferably wet granulation. Examples of the wet granulation method include a fluidized bed granulation method, a stirring granulation method, an extrusion granulation method, etc. Granulation by these granulation methods can be carried out using a known granulation apparatus. In the fluidized bed granulation method, for example, a stirring type fluidized bed granulation apparatus such as Multiplex (registered trademark, manufactured by Paulekk Co., Ltd.) or Spiraflow (registered trademark, manufactured by Freund Industry Co., Ltd.) is used to granulate while spraying an aqueous liquid such as an aqueous solution of the component (D).

[0088] In the stirring granulation method, for example, a stirring granulator such as a high-speed mixer (manufactured by Fukae Powtec Co., Ltd.) or a high-speed stirring granulator (manufactured by Dalton Co., Ltd.) is used to granulate. In the extrusion granulation method, for example, an extrusion granulator such as Dome Gran (manufactured by Dalton Co., Ltd.) is used to granulate. The granulation conditions can be appropriately set according to the target volume average particle diameter and the granulation apparatus to be used.

[0089] <Granulation step (Y2)> The granulation step (Y2) is a step of granulating a granulation material (q) that contains a part of the component (B) and the component (C) and does not contain the component (A) to obtain granulated particles (Q). The granulation material (q) preferably contains the component (E) in addition to a part of the component (B) and the component (C), and may contain other optional components.

[0090] When the granulation material (q) contains the component (E), the component (E) may be added as a powder to a part of the component (B) and the component (C), or may be added when preparing an aqueous solution of the component (E) for wet granulation. From the viewpoint of further suppressing tablet wear and granule dropout depressions, it is preferable to prepare an aqueous solution of the component (E) and add it. When preparing an aqueous solution of the component (E), from the viewpoint of handling properties during addition, the concentration of the component (E) in the aqueous solution is preferably 3 to 10% by mass.

[0091] The granulation method in the granulation step (Y2) is preferably wet granulation. Examples of the wet granulation method include a fluidized bed granulation method, a stirring granulation method, an extrusion granulation method, and the like. Granulation by these granulation methods can be carried out using a known granulation apparatus in the same manner as in the granulation step (Y1). The granulation conditions can be appropriately set according to the target volume average particle diameter and the granulation apparatus to be used.

[0092] <Tableting step> The powder mixture to be tabletted is obtained by mixing the granulated particles (P), preferably the granulated particles (Q), and, if necessary, other optional components (components added before tableting). The mixing can be carried out using a known mixer. For example, a Borre container mixer (manufactured by Hiroshima Metal & Machinery Co., Ltd.), a V-type mixer (manufactured by Dalton Co., Ltd.), a ribbon mixer (manufactured by Dalton Co., Ltd.), and the like can be mentioned.

[0093] By tabletting the above powder mixture, a tablet core is obtained. Tableting can be carried out using a known tableting machine. Examples of the tableting machine include rotary tableting machines such as a Libra (manufactured by Kikusui Seisakusho Co., Ltd.) and an L-41 type (manufactured by Hatake Iron Works Co., Ltd.). The tableting conditions can be appropriately set according to the tableting machine to be used, taking into account the tablet hardness and the like.

[0094] For example, in the case of a rotary tableting machine, the rotational speed of the turntable is preferably 10 to 90 rpm, more preferably 20 to 60 rpm. When the rotational speed of the turntable is equal to or higher than the above lower limit value, the production efficiency can be increased. When the rotational speed of the turntable is equal to or lower than the above upper limit value, the filling amount of the powder into the mortar becomes stable. The pre-pressure is preferably 10 kN or less, more preferably 0.1 - 8 kN. By setting the pre-pressure within the above range, capping can be suppressed. The main pressure is preferably 3 - 20 kN, more preferably 4 - 14 kN. By setting the main pressure to be equal to or higher than the lower limit value, sufficient hardness can be obtained, and by setting it to be equal to or lower than the upper limit value, the disintegration property of the tablets is improved.

[0095] The shape of the punch of the tableting machine is preferably such that the tableting surface is smooth or curved (R tablet), more preferably curved (R tablet). In the case of a single R tablet, the radius of curvature r of the curved surface is preferably 8 - 15 mm, more preferably 11 - 13 mm. In the case of a two-stage R tablet, the radius of curvature r1 of the peripheral part is preferably 2 - 6 mm, more preferably 3 - 4 mm, and the radius of curvature r2 of the zenith top is preferably 8 - 13 mm, more preferably 9 - 11 mm. By setting it within the above preferred range, wear of the tablets and indentation of granules are further reduced. The diameter of the mortar and the diameter of the punch of the tableting machine are preferably 7 mm - 12 mm, more preferably 8.5 - 10 mm. By setting it within the above preferred range, wear of the tablets and indentation of granules are further reduced.

[0096] <Coating process> After the tableting process, a step of providing a film containing a coating agent on the surface of the obtained plain tablets (coating process) may be performed. Thereby, coated tablets can be obtained. The coating process can be carried out using a general coating device. For example, pan-type coating devices such as a high coater (manufactured by Freund Industry Co., Ltd.) and an Aqua Coater (registered trademark, manufactured by Freund Industry Co., Ltd.) can be used.

[0097] In the coating step, for example, first, a coating agent is dispersed in a solvent such as water, and a colorant or the like is added as necessary to obtain a coating solution. Then, the coating solution is used to coat the core tablets by spraying or the like. Thereafter, the solvent component of the coating solution is dried to obtain coated tablets. The coating agent used in the coating step and the amount of the coating agent used are as described above.

[0098] According to the method for producing tablets of the present invention, since it includes a co-grinding step (X) of co-grinding at least a part of the component (A) and the component (B) to obtain a co-ground product having a volume average particle diameter of 5 to 20 μm, adhesion of the component (A) to the grinder is suppressed, and the volume average particle diameter of the ground product can be made 20 μm or less. Thereby, tablets that are less likely to cause delayed disintegration over time can be produced by a manufacturing process that is not particularly complicated.

Examples

[0099] Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to the following description. The raw materials and evaluation methods used in each example are as follows. In addition, the description of "JP Pharmacopoeia compliant product" below means that the raw material conforms to the specifications of the 18th revised Japanese Pharmacopoeia.

[0100] 〔Raw materials used〕 <(Component A)> Ibuprofen: Product name "Ibuprofen 25", manufactured by BASF, JP Pharmacopoeia compliant product, volume average particle diameter: 28 μm. <(Component B)> L-HPC: Low-substituted hydroxypropyl cellulose, product name "LH-31", manufactured by Shin-Etsu Chemical Co., Ltd., JP Pharmacopoeia compliant product, volume average particle diameter: 35 μm.

[0101] <(Component C)> Ethenzamide: Manufactured by Iwaki Pharmaceutical Co., Ltd., volume average particle diameter: 24 μm.

[0102] <(Component D)> Magnesium Oxide: Magnesium oxide, product name "Heavy Magnesium Oxide", manufactured by Kyowa Chemical Industry Co., Ltd., conforming to Japanese Pharmacopoeia, volume average particle diameter: 10 μm. Mg Aluminometasilicate: Magnesium aluminometasilicate, product name "Neusilin NFL2N", manufactured by Fuji Chemical Industry Co., Ltd., conforming to Japanese Pharmacopoeia, volume average particle diameter: 12 μm. Dried Aluminum Hydroxide Gel: Dried aluminum hydroxide gel, product name "S-100", manufactured by Kyowa Chemical Industry Co., Ltd., conforming to Japanese Pharmacopoeia, volume average particle diameter: 11 μm.

[0103] <(E) Component> HPC: Hydroxypropylcellulose, product name "HPC-SSL", manufactured by Nippon Soda Co., Ltd., conforming to Japanese Pharmacopoeia.

[0104] <Optional Component> Acetaminophen: Product name "Acetaminophen (powder)", manufactured by Sphernex Co., conforming to Japanese Pharmacopoeia. Crystalline Cellulose: Product name "Ceolus PH-302", manufactured by Asahi Kasei Co., Ltd., conforming to Japanese Pharmacopoeia. HPC: Hydroxypropylcellulose, product name "HPC-SSL", manufactured by Nippon Soda Co., Ltd., conforming to Japanese Pharmacopoeia. Mg Stearate: Magnesium stearate, vegetable origin, light quality, manufactured by Taihei Chemical Industry Co., Ltd., conforming to Japanese Pharmacopoeia.

[0105] 〔Examples, Comparative Examples, Reference Examples〕 Regarding the formulations of each example, refer to Tables 1 to 7 for explanation. Tables 1 to 7 show the content per tablet of the raw materials used in each example, the blending ratio in the tablets, and the blending ratio in the pulverized products or granulated particles, respectively. Note that the blending ratio of the granulated particles described in the column of granulated particles (P) is the blending ratio in granulated particles (P), and the blending ratio of the granulated particles described in the column of granulated particles (Q) is the blending ratio in granulated particles (Q). Also, the blank spaces in Tables 1 to 7 indicate that the raw material is not blended.

[0106] <Pulverization Process> For each of the examples and Comparative Example 4, the raw materials described in the pulverized product columns of Tables 1 to 5 and 7 were mixed so that the total amount was 3 kg at the blending ratios shown in each table, and pulverized using a pin mill (Coloplex 160Z, manufactured by Paulex Co., Ltd.) under the conditions described in each table. Also, for Comparative Examples 2 and 3 and the reference example, 3 kg of the raw materials described in the pulverized product columns of Tables 6 and 7 were pulverized using a pin mill (Coloplex 160Z, manufactured by Paulex Co., Ltd.) under the conditions described in each table.

[0107] Note that the pin mill is a continuous pulverizer, and the input powder is instantaneously pulverized and immediately discharged outside the apparatus. Therefore, the pulverization time cannot be described. The particle diameters of the obtained pulverized products are shown in Tables 1 to 7. The particle diameter indicates the volume average particle diameter. The volume average particle diameter was measured by dry measurement using a laser diffraction / scattering particle size distribution analyzer ("LS13320 type" manufactured by Beckman Coulter, Inc.) with a sample amount of approximately 0.5 g. For Comparative Example 2, the (A) component adhered to the pulverizer and could not be pulverized.

[0108] <Granulation step (Y1)> Except for Example 1 and Comparative Examples 1 and 2, a granulation material (p) composed of the pulverized product obtained in the pulverization step and the raw materials shown in the "Addition at granulation" columns of Tables 1 to 7 was granulated by the granulation methods shown in Tables 1 to 7 to obtain granulated particles (P). The details of each granulation method are as follows.

[0109] Fluidized bed granulation: In Examples 2 to 10, 12 to 14, Comparative Example 3, 4, and the reference example, the pulverized product obtained in the pulverization step and the materials excluding HPC among the raw materials shown in the "Addition at granulation" columns of Tables 1 to 7 were mixed so that the total amount was 3 kg at the blending ratios shown in each table to obtain a powder composition.

[0110] Next, while spraying a 5 mass% aqueous HPC solution onto the powder composition obtained in each example at a rate of 50 g / min using a fluidized bed granulator (FLO-5, manufactured by Freund Industries Co., Ltd.) so that the blending ratio of HPC in the granulation material (p) becomes the value shown in each table, with an intake air volume of 2.5 m 3Granulation was carried out at 55 °C of the intake air temperature and / min. After the spraying was completed, it was dried until the exhaust gas temperature reached 40 °C to obtain granulated particles (P).

[0111] Stirring granulation: Regarding Example 11, 3 kg of the pulverized product obtained in the pulverization step and the raw material (HPC) shown in the column of "Added during granulation" in Table 4 were mixed so as to have the blending ratio shown in Table 4 to obtain a powder composition. Regarding Comparative Example 5, the raw materials (including HPC) shown in the column of "Added during granulation" in Table 7 were mixed so as to have the blending ratio shown in Table 7, and the materials excluding HPC totaled 3 kg to obtain a powder composition.

[0112] Next, the powder compositions obtained in each of Example 11 and Comparative Example 5 were put into a stirring granulator (High Speed Mixer FS-10, manufactured by Earth Technica Co., Ltd.). While stirring at an agitator rotation speed of 300 rpm and a chopper rotation speed of 1000 rpm, 0.4 kg of purified water was dropped and stirred for 20 minutes to obtain a wet powder. Heating and cooling were not performed during stirring. The obtained wet powder was dried in a fluidized bed granulator (FLO-5, manufactured by Freund Industry Co., Ltd.) at an intake air volume of 2.5 m 3 / min until the exhaust gas temperature reached 40 °C at an intake air temperature of 55 °C to obtain granulated particles (P).

[0113] <Granulation step (Y2)> In Examples 6 to 8, 11, 13, 14 and Comparative Example 5, a granulation material (q) composed of the raw materials shown in the column of "Granulated particles (Q)" in Tables 3, 4, 5, and 7 was granulated by stirring granulation to obtain granulated particles (Q). The specific granulation method is as follows.

[0114] Stirring granulation: 2 kg of the raw materials shown in the column of "Granulated particles (Q)" in each example were put into a stirring granulator (High Speed Mixer FS-10, manufactured by Earth Technica Co., Ltd.). While stirring at an agitator rotation speed of 300 rpm and a chopper rotation speed of 1000 rpm, 0.3 kg of purified water was dropped and stirred for 20 minutes to obtain a wet powder. Heating and cooling were not performed during stirring. The obtained wet powder was dried in a fluidized bed granulator (FLO-5, manufactured by Freund Industry Co., Ltd.) at an intake air volume of 2.5 m3 / min, and dried until the exhaust temperature reached 40°C at an intake air temperature of 55°C to obtain granulated particles (Q).

[0115] <Tabletting Process> The granulated particles (P), granulated particles (Q) obtained in the granulation process, and the raw materials shown in the "Addition Before Tabletting" columns of Tables 1 to 7 were mixed so as to have the blending ratios shown in each table to obtain a powder mixture. In Example 1, instead of the granulated particles (P), a pulverized product was used. Also, for Examples and Comparative Examples in which the granulated particles (P) were not produced, a powder mixture was obtained without using the granulated particles (P). Also, for Examples and Comparative Examples in which the granulated particles (Q) were not produced, a powder mixture was obtained without using the granulated particles (Q).

[0116] The obtained powder mixture was tabletted using a rotary tableting machine (Libra 2, manufactured by Kikusui Seisakusho Co., Ltd.) at a rotational speed of the turntable of 30 rpm, and two-stage R tablets of each example were obtained with the punch diameters, the curvature radius r1 of the punch, and the curvature radius r2 of the punch shown in Tables 1 to 7. The tableting pressure was adjusted so that the average of the tablet hardness of 10 tablets was 6.0 to 8.0 kgf.

[0117] 〔Evaluation Method〕 The following evaluations were performed on the obtained tablets. The results are shown in Tables 1 to 7.

[0118] <Disintegratability> Regarding the manufactured tablets, according to the tablet disintegration test method described in the 18th Revised Japanese Pharmacopoeia, water was used as the disintegration test liquid, and the disintegration times (minutes and seconds) of 6 tablets were measured, and the average value obtained was taken as the "disintegration time" "immediately after manufacture" and evaluated according to the following criteria.

[0119] Also, the manufactured tablets were placed in each pocket of a resin sheet (manufactured by Daisheng Chemical Industry, "TAS-230") in which a plurality of pockets for accommodating the tablets had been previously formed, and an aluminum foil was bonded to the pocket opening side of the resin sheet to obtain a PTP (press-through package). This PTP was stored at 50°C and 75% RH for 6 weeks. Then, the tablets were taken out from the PTP, and the disintegration times (minutes and seconds) of 6 tablets were measured in the same manner as above, and the average value obtained was taken as the "disintegration time" "after storage" and evaluated according to the following criteria.

[0120] (Reference) 5: Disintegration delay is less than 1 minute. 4: Disintegration delay is 1 minute or more and less than 3 minutes. 3: Disintegration delay is 3 minutes or more and less than 5 minutes. 2: Disintegration delay is 5 minutes or more and less than 10 minutes. 1: Disintegration delay is 10 minutes or more.

[0121]

Table 1

[0122]

Table 2

[0123]

Table 3

[0124]

Table 4

[0125]

Table 5

[0126]

Table 6

[0127]

Table 7

[0128] As shown in Tables 1 to 5, the tablets of Examples 1 to 14 had good disintegrability both immediately after production and after storage, and the disintegration delay over time was suppressed. On the other hand, as shown in Table 6, in Comparative Example 1 where all components were mixed as raw powders and tableted, the disintegration delay over time was significant. Also, in Comparative Example 2 where an attempt was made to grind only the (A) component, grinding was not possible, and the usefulness of the production method of the present invention was confirmed.

[0129] Moreover, in Comparative Examples 3 and 5 where the (A) component was not ground, and in Comparative Example 4 where the (A) component was ground but not to a sufficiently small particle size, the disintegration delay over time was significant. In addition, in a reference example where acetaminophen was used instead of ethenzamide as the (C) component, no disintegration delay occurred despite the use of the (A) component without grinding. From this, it was confirmed that the disintegration delay is a specific problem that occurs when the (A) component and the (C) component coexist.

Claims

1. Component (A): Ibuprofen, and Component (B): At least one selected from the group consisting of low-substituted hydroxypropyl cellulose, starch, crystalline cellulose, sodium carboxymethyl starch, carmellose, croscarmellose sodium, crospovidone, calcium carmellose, sodium starch glycolate, and partially pregelatinized starch, and Component (C): Etenzamide, and contains A tablet in which the volume-average particle diameter of the component (A) is 5 to 20 μm.

2. The tablet according to claim 1, wherein the difference in disintegration time before and after storage at 50 ° C for 6 weeks by the disintegration test method for tablets in the eighteenth revised Japanese Pharmacopoeia is less than 5 minutes.

3. The tablet according to claim 1, comprising granulated particles (P) containing at least a part of the component (A) and the component (B).

4. The tablet according to claim 3, further comprising granulated particles (Q) containing a part of the component (B) and the component (C) and not containing the component (A).

5. The tablet according to any one of claims 1 to 4, further comprising (D) component: an antacid.

6. A method for producing a tablet, comprising tableting a powder mixture containing the following components (A) to (C) to obtain a tablet, Comprising a co-grinding step (X) of co-grinding at least a part of the component (A) and the component (B) to obtain a co-ground product having a volume-average particle diameter of 5 to 20 μm, The method for producing a tablet, wherein the powder mixture contains the co-ground product. (A) Ibuprofen, (B) At least one selected from the group consisting of low-substituted hydroxypropyl cellulose, starch, crystalline cellulose, sodium carboxymethyl starch, carmellose, croscarmellose sodium, crospovidone, calcium carmellose, sodium starch glycolate, and partially pregelatinized starch, (C) Etizolam.

7. The method for producing a tablet according to claim 6, wherein the co-grinding step (X) is performed using an impact grinder.

8. Further, a granulation step (Y1) is provided, in which a granulation material (p) containing the co-ground material is granulated by any method selected from fluidized bed granulation, stirring granulation, and extrusion granulation to obtain granulated particles (P). The method for producing a tablet according to claim 6, wherein the powder mixture contains the granulated particles (P).

9. Further, a granulation step (Y2) is provided, in which a granulation material (q) containing a part of the component (B) and the component (C) and not containing the component (A) is granulated by any method selected from fluidized bed granulation, stirring granulation, and extrusion granulation to obtain granulated particles (Q). The method for producing a tablet according to claim 8, wherein the powder mixture contains the granulated particles (P) and the granulated particles (Q).

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