Tablet, granulated particles, method for producing granulated particles, and method for producing tablet

Abstract

To provide a tablet containing ibuprofen and having reduced abrasion.SOLUTION: A tablet comprises granulated particles containing (A) component: ibuprofen, (B) component: at least one selected from the group consisting of low-substituted hydroxypropyl cellulose, starch, and crystalline cellulose, and (C) component: antacid, wherein the volume average particle diameter of the (A) component and the (B) component ranges from 5 to 20 μm.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to tablets, granulated particles, a method for producing granulated particles, and a method for producing tablets.

Background Art

[0002] Since ibuprofen is a poorly soluble drug, attempts have been made to improve the elution property of ibuprofen from solid preparations containing ibuprofen. Patent Document 1 discloses a technique of wet granulating a co-ground product of ibuprofen and an excipient such as low-substituted hydroxypropyl cellulose using an aqueous solution of a water-soluble polymer.

[0003] On the other hand, ibuprofen is known to have gastric injury as a side effect. In order to suppress gastric injury caused by ibuprofen, an antacid may be formulated. Since ibuprofen, which is an acidic substance, and an antacid, which is a basic substance, are likely to cause a formulation change, attempts have been made to suppress the formulation change. Patent Document 2 discloses a technique of wet granulating a composition containing ibuprofen, an antacid, and a swelling agent such as low-substituted hydroxypropyl cellulose.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] However, ibuprofen is a waxy substance with weak binding properties between powders and is prone to elongation by friction. Therefore, tablets containing ibuprofen are likely to be worn due to the impact received by the tablets during transportation or manufacturing processes, and small depressions are likely to occur due to part of the tablet surface falling off. In addition, when manufacturing tablets by tableting raw materials containing ibuprofen, part of the raw materials is likely to adhere to the tableting machine. Particularly in the case of a rotary tableting machine, it is likely to adhere like streaks on the rotating disk. Such problems have not been solved even in the above-mentioned conventional technologies.

[0006] An object of the present invention is to provide a tablet containing ibuprofen and having wear resistance suppressed, as well as a granulated particle containing ibuprofen and having wear resistance suppressed and a method for manufacturing the tablet.

Means for Solving the Problems

[0007] As a result of intensive studies, the present inventor has found that by pre-cogrinding ibuprofen and a specific excipient until a specific volume average particle diameter is obtained, adding an antacid to this cogrind product, and performing wet granulation, surprisingly, the wear of the tablet is reduced, and further, the occurrence of small depressions due to part of the tablet surface falling off and the adhesion to the tableting machine during tableting are also suppressed. 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, and crystalline cellulose, and (C) component: an antacid, and containing granulated particles, a tablet, wherein the volume average particle diameter of the (A) component and the (B) component is 5 to 20 μm. <2> The tablet according to <1>, wherein the (C) component is at least one selected from the group consisting of magnesium oxide and dried aluminum hydroxide gel. <3> The tablet according to <1> or <2>, wherein the granulated particles further contain component (D): a water-soluble polymer. <4> The tablet according to <3>, wherein the component (D) is at least one selected from the group consisting of sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gum arabic, carboxyvinyl polymer, povidone, polyvinyl alcohol, and hydroxypropylcellulose polyacrylate. <5> The tablet according to any one of <1> to <4>, wherein the abrasion degree is less than 1% by mass when the abrasion degree test is performed under the conditions of a rotation speed of 30 rpm and 15 minutes, using the abrasion degree tester described in the 18th Revised Japanese Pharmacopoeia and using the number of the tablets that can be made as close as possible to a total amount of 30 g as a sample. <6> (A) component: ibuprofen, and (B) component: at least one selected from the group consisting of low-substituted hydroxypropylcellulose, starch, and crystalline cellulose, and (C) component: an antacid, and containing Granulated particles, wherein the volume average particle diameters of the component (A) and the component (B) are 5 to 20 μm. <7> The granulated particles according to <6>, wherein the component (C) is at least one selected from the group consisting of magnesium oxide and dried aluminum hydroxide gel. <8> The granulated particles according to <6> or <7>, further containing component (D): a water-soluble polymer. <9> The granulated particles according to <8>, wherein the component (D) is at least one selected from the group consisting of sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gum arabic, carboxyvinyl polymer, povidone, polyvinyl alcohol, and hydroxypropylcellulose polyacrylate. <10> A method for producing the granulated particles according to any one of <6> to <9>, A method for producing granulated particles, comprising pulverizing a first powder composition containing the component (A) and the component (B) so that the volume average particle diameter becomes 5 to 20 μm, and wet granulating a second powder composition containing the obtained pulverized product and the component (C). <11> A method for producing granulated particles according to any one of <6> to <9>, A method for producing granulated particles, comprising pulverizing a first powder composition containing the component (A), the component (B), and the component (C) so that the volume average particle diameter becomes 5 to 20 μm, and wet granulating a second powder composition containing the obtained pulverized product. <12> The method according to <10> or <11>, wherein the wet granulation method is a fluidized bed granulation method, a stirring granulation method, or an extrusion granulation method. <13> The method according to any one of <10> to <12>, wherein the first powder composition is pulverized by an impact pulverizer. <14> A method for producing tablets, comprising producing granulated particles by the production method according to any one of <10> to <13>, and tableting a third powder composition containing the obtained granulated particles. <15> The method according to <14>, wherein the third powder composition contains at least one selected from the group consisting of an excipient and a lubricant in addition to the granulated particles.

Advantages of the Invention

[0009] According to the present invention, it is possible to provide a tablet containing ibuprofen and having suppressed wear, and a method for producing granulated particles and tablets capable of obtaining a tablet containing ibuprofen and having suppressed wear.

Embodiments for Carrying Out the Invention

[0010] 〔Tablets〕 The tablets of the present invention contain granulated particles (hereinafter also referred to as granulated particles (P)) containing the component (A), the component (B), and the component (C). The granulated particles (P) may further contain a component (D). The granulated particles (P) may further contain components other than the component (A), component (B), component (C), and component (D) (hereinafter also referred to as optional component (1)). The tablets of the present invention may further contain components other than the granulated particles (P) (hereinafter also referred to as optional component (2)).

[0011] <(Component A)> (A) The component is ibuprofen (2-(4-isobutylphenyl)propionic acid). By containing the component (A), an antipyretic and analgesic effect can be obtained.

[0012] The content ratio of the component (A) to the total mass of the granulated particles (P) is preferably 10 to 80% by mass, more preferably 30 to 45% by mass. If the content ratio of the component (A) is at least the above lower limit value, the elution property of the component (A) can be further enhanced. If the content ratio of the component (A) is at most the above upper limit value, the tablet can be made smaller, and wear of the tablet and indentation of the tablet surface due to particles falling off from the tablet surface (hereinafter also referred to as granule dropout indentation) can be more suppressed.

[0013] The content ratio of the component (A) to the total mass of the tablet is preferably 5 to 60% by mass, more preferably 20 to 40% by mass. If the content ratio of the component (A) is at least the above lower limit value, the elution property of the component (A) can be further enhanced. If the content ratio of the component (A) is at most the above upper limit value, the tablet can be made smaller, wear of the tablet and granule dropout indentation can be more suppressed, and adhesion of powder to the tablet press during tableting can be more suppressed.

[0014] The content of the component (A) in one tablet is preferably 40 to 400 mg, more preferably 65 to 100 mg. If the content of the component (A) is at least the above lower limit value, the elution property of the component (A) can be further enhanced. If the content of the component (A) is at most the above upper limit value, the tablet can be made smaller, wear of the tablet and granule dropout indentation can be more suppressed, and adhesion of powder to the tablet press during tableting can be more suppressed.

[0015] <(Component B)> Component (B) is at least one selected from the group consisting of low-substituted hydroxypropyl cellulose (hereinafter also referred to as L-HPC), starch, and crystalline cellulose. In the present invention, component (B) is pulverized (co-pulverized) together with component (A) in the production process of granulated particles. Component (A) has a high adhesiveness to the pulverizer and is difficult to pulverize alone. By co-existing component (B) during pulverization, the adhesion of component (A) to the pulverizer is suppressed, making it easier to pulverize and enabling the volume average particle diameter after pulverization to be reduced.

[0016] As component (B), L-HPC is preferable from the viewpoint of excellent adhesion suppression effect to the pulverizer during co-pulverization. In this specification, L-HPC is synonymous with "low-substituted hydroxypropyl cellulose" described in the Japanese Pharmacopoeia, Fourteenth Edition, and refers to low-substituted hydroxypropyl cellulose in which the hydroxy groups of cellulose are substituted with hydroxypropoxy groups (-OC 3 H 6 OH). Specifically, it refers to those having a substitution degree (content) of hydroxypropoxy groups of 5 to 16% by mass.

[0017] The content ratio of component (B) with respect to the total mass of the granulated particles (P) is preferably 5 to 50% by mass, more preferably 10 to 40% by mass. If the content ratio of component (B) is at least the above lower limit value, wear of the tablets, depression of granule dropout, and adhesion of the powder to the tableting machine during tableting are more suppressed. If the content ratio of component (B) is at most the above upper limit value, the tablets are more miniaturized.

[0018] The content ratio of component (B) with respect to the total mass of the tablets is preferably 5 to 45% by mass, more preferably 5 to 35% by mass. If the content ratio of component (B) is at least the above lower limit value, the handleability of the powder is more improved. Also, wear of the tablets, depression of granule dropout, and adhesion of the powder to the tableting machine during tableting are more suppressed. If the content ratio of component (B) is at most the above upper limit value, depression of granule dropout is more suppressed and the tablets are more miniaturized.

[0019] The content of component (B) in one tablet is preferably 10 to 200 mg, more preferably 30 to 100 mg. If the content of component (B) is at least the above lower limit, the handleability of the powder is further improved. Further, wear of the tablet, depression due to granule dropout, and adhesion of the powder to the tableting machine during tableting are more suppressed. If the content of component (B) is at most the above upper limit, depression due to granule dropout is more suppressed and the tablet is further miniaturized.

[0020] <Volume average particle diameter of component (A) and component (B)> In the granulated particles (P), the volume average particle diameter of component (A) and component (B) is 5 to 20 μm, preferably 5 to 15 μm. If the volume average particle diameter is at least the above lower limit, the fluidity of the powder is improved and the handling during the production of the granulated particles (P) is excellent. If the volume average particle diameter is at most the above upper limit, wear of the tablet, depression due to granule dropout, and adhesion of the powder to the tableting machine during tableting are suppressed. Further, the elution property of component (A) is improved. The volume average particle diameter is measured by a laser diffraction / scattering particle size distribution analyzer (for example, "LS13320 type" manufactured by Beckman Coulter).

[0021] <Component (C)> Component (C) is an antacid. When the granulated particles contain component (C), wear of the tablet and depression due to dropout of the granulated particles are less likely to occur. In this specification, an antacid refers to one having an antacid power of 50 mL or more determined by the antacid power test method defined in the 18th Japanese Pharmacopoeia. The antacid power determined by the antacid power test method defined in the 18th Japanese Pharmacopoeia is indicated by the consumption amount (mL) of 0.1 mol / L hydrochloric acid per 1 g.

[0022] The component (C) may be a known antacid, and examples thereof include compounds containing a divalent or trivalent metal (metal salts, metal oxides, metal hydroxides, etc.). Specific examples include dried aluminum hydroxide (acid-neutralizing power: 250 mL or more), dried aluminum hydroxide gel (acid-neutralizing power: 300 to 340 mL), magnesium oxide (acid-neutralizing power: 460 to 500 mL), magnesium carbonate (acid-neutralizing power: 200 to 240 mL), magnesium aluminometasilicate (acid-neutralizing power: 210 to 250 mL), aluminum glycinate (acid-neutralizing power: 170 mL or more), aluminum hydroxide (acid-neutralizing power: 250 mL or more), calcium carbonate (acid-neutralizing power: 180 to 220 mL), and the like. The component (C) may be used alone or in combination of two or more. As the component (C), at least one selected from magnesium oxide and dried aluminum hydroxide gel is preferable from the viewpoint of the adhesion of the powder to the tableting machine.

[0023] The volume average particle diameter of the component (C) is preferably 5 to 250 μm, more preferably 5 to 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 is improved and the uniformity of the components in the granulated particles is enhanced. When at least a part of the component (A), the component (B), and the component (C) are co-ground in the production process of the granulated particles, the volume average particle diameter of the co-ground component (A), component (B), and component (C) is preferably 5 to 20 μm, more preferably 5 to 15 μm.

[0024] The content ratio of the component (C) 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. If the content ratio of the component (C) is not less than the above lower limit value and not more than the above upper limit value, wear of the tablets and depression of the granules are more suppressed.

[0025] The content ratio of component (C) to the total mass of the tablets is preferably 5 to 40% by mass, more preferably 10 to 30% by mass. If the content ratio of component (C) is at least the above lower limit, wear of the tablets, pitting due to granule loss is more suppressed, and furthermore, gastric injury and intestinal injury caused by component (A) are more suppressed. If the content ratio of component (C) is at most the above upper limit, wear of the tablets, pitting due to granule loss is more suppressed.

[0026] The content of component (C) in one tablet is preferably 20 to 150 mg, more preferably 30 to 100 mg. If the content of component (C) is at least the above lower limit, wear of the tablets, pitting due to granule loss is more suppressed, and furthermore, gastric injury and intestinal injury caused by component (A) are more suppressed. If the content of component (C) is at most the above upper limit, wear of the tablets, pitting due to granule loss is more suppressed.

[0027] In the granulated particles (P), the mass ratio of component (C) to the total of component (A) and component (B) (hereinafter also referred to as C / (A + B)) is preferably 0.1 to 1.0, more preferably 0.37 to 0.6. If C / (A + B) is at least the above lower limit, wear of the tablets, pitting due to granule loss is more suppressed, and if it is at most the above upper limit, the hardness of the tablets is more improved.

[0028] The total content ratio of component (A), component (B), and component (C) to the total mass of the granulated particles (P) is preferably 25% by mass or more, more preferably 55% by mass or more. The total content ratio of component (A), component (B), and component (C) to the total mass of the granulated particles (P) may be 100% by mass, but when the granulated particles (P) contain at least one selected from component (D) and optional component (1), for example, it can be 90% by mass or less, further 65% by mass or less.

[0029] <(D) component> Component (D) is a water-soluble polymer. By the granulated particles containing component (D), wear of the tablets, pitting due to granule loss is more suppressed. In this specification, the water-soluble polymer refers to a polymer that requires less than 10 g of water to dissolve 1 g of the polymer at 20°C.

[0030] Examples of the component (D) include at least one selected from the group consisting of sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gum arabic, carboxyvinyl polymer, povidone, polyvinyl alcohol, and hydroxypropylcellulose polyacrylate.

[0031] The component (D) may be added in powder form or dissolved in water during the production of the granulated particles. The volume average particle diameter of the component (D) in powder form is preferably 5 to 200 μm. If the volume average particle diameter is not less than the above lower limit and not more than the above upper limit, the handleability will be better.

[0032] The content ratio of the component (D) to the total mass of the granulated particles is preferably 1 to 20% by mass, more preferably 3 to 15% by mass. If the content ratio of the component (D) is not less than the above lower limit, wear of the tablets and depression of granule dropout are more suppressed. If the content ratio of the component (D) is not more than the above upper limit, the disintegration property of the tablets is more improved.

[0033] The content ratio of the component (D) to the total mass of the tablets is preferably 1 to 15% by mass, more preferably 2 to 10% by mass. If the content ratio of the component (D) is not less than the above lower limit, wear of the tablets and depression of granule dropout are more suppressed. If the content ratio of the component (D) is not more than the above upper limit, the disintegration property of the tablets is more improved.

[0034] The content of the component (D) in one tablet is preferably 3 to 30 mg, more preferably 8 to 20 mg. If the content of the component (D) is not less than the above lower limit, wear of the tablets and depression of granule dropout are more suppressed. If the content of the component (D) is not more than the above upper limit, the disintegration property of the tablets is more improved.

[0035] <Optional Component (1)> Examples of the optional component (1) include bioactive components other than the component (A) and the component (C) (hereinafter also referred to as other bioactive components), and additives other than the component (B) and the component (D) (hereinafter also referred to as other additives).

[0036] Examples of other bioactive components include the same ones as those of the other bioactive components in the optional component (2) described later. The other bioactive components may be used alone or in combination of two or more. The content ratio of the other bioactive components to the total mass of the granulated particles (P) is preferably 0 to 70% by mass, more preferably 0 to 40% by mass.

[0037] Examples of other additives include the same ones as those of the additives in the optional component (2) described later (excluding the component (B) and the component (D)). The other additives may be used alone or in combination of two or more. The content ratio of the other additives to the total mass of the granulated particles (P) is preferably 0 to 50% by mass, more preferably 0 to 20% by mass.

[0038] <Optional component (2)> Examples of the optional component (2) include bioactive components and additives. Examples of the physiologically active ingredient in the optional component (2) include component (A), component (C), and other physiologically active ingredients. Examples of the 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; anti-epileptic 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 nitrate, nifedipine, dipyridamole; antitussive agents 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, clomadinone 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 kind or a combination of two or more kinds. Further, these other physiologically active ingredients may be pharmaceutically acceptable salts (for example, sodium salts, hydrochlorides, sulfates, nitrates, etc.). In terms of further suppressing tablet wear and adhesion of powder to the tablet press during tableting, it is preferable that the optional component (2) does not contain component (A). In terms of further suppressing the indentation of granules from tablets, it is preferable that the optional component (2) does not contain the component (C).

[0039] Examples of the additives in the optional component (2) include excipients, lubricants, binders, disintegrants, fragrances, and flavoring agents (sweeteners, acidulants, etc.). Examples of the excipients include carmellose, calcium carmellose, sodium carmellose, croscarmellose sodium, calcium carboxymethylcellulose, L-HPC, crystalline cellulose (such as Avicel), corn starch, talc, lactose, powdered sugar, mannitol, light anhydrous silicic acid, calcium carbonate, and L-cysteine. Examples of the lubricants include magnesium stearate, calcium stearate, polyethylene glycol, talc, stearic acid, and sucrose fatty acid ester. Examples of the binders include starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, methylcellulose, carmellose, calcium carmellose, sodium carmellose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, and dextrin. Examples of the fragrances include menthol, limonene, and essential oils (such as peppermint oil, mint oil, lychee oil, orange oil, lemon oil, etc.). Examples of the sweeteners include sodium saccharin, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, and sucralose. Examples of the acidulants include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, and their salts. The additives may be used alone or in combination of two or more.

[0040] In terms of further suppressing the adhesion of powder to the tablet press during tableting, it is preferable that the optional component (2) 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, 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, more preferably 0.2 to 1% by mass.

[0041] The content ratio of the granulated particles (P) to the total mass of the tablets is preferably 10% by mass or more, more preferably 40% by mass or more. The content ratio of the granulated particles (P) to the total mass of the tablets may be 100% by mass, but when the tablets contain the optional component (2), for example, it can be 90% by mass or less, further 80% by mass or less.

[0042] <Method for producing granulated particles> The granulated particles (P) can be produced, for example, by the following production method (1) or production method (2). Production method (1): A method of pulverizing a first powder composition containing component (A) and component (B) so that the volume average particle diameter becomes 5 to 20 μm, and wet granulating a second powder composition containing the obtained pulverized product and component (C). Production method (2): A method of pulverizing a first powder composition containing component (A), component (B), and component (C) so that the volume average particle diameter becomes 5 to 20 μm, and wet granulating a second powder composition containing the obtained pulverized product. In production method (2), a part of component (C) may be contained in the second powder composition. The first powder composition may further contain at least one selected from component (D) and the optional component (1). The second powder composition may further contain the optional component (1). Also, as long as the volume average particle diameters of component (A) and component (B) are in the range of 5 to 20 μm, it may contain component (A), component (B), and component (C) (powder with a volume average particle diameter of 20 μm or more) without performing the pulverization treatment described later. Hereinafter, the step of pulverizing the first powder composition is also referred to as step X, and the step of wet granulating the second powder composition is also referred to as step Y.

[0043] (Step X: Pulverization) The first powder composition contains component (A) and component (B). By pulverizing the first powder composition, component (A) and component (B) are co-pulverized. Thereby, the adhesion of component (A) to the pulverizer during pulverization is suppressed, and the volume average particle diameter of the pulverized product can be made 20 μm or less.

[0044] In the first powder composition, the mass ratio of component (B) to component (A) (hereinafter also referred to as B / A) is preferably from 0.01 to 10, more preferably from 0.07 to 5, and still more preferably from 0.22 to 1.3. If B / A is at least the above lower limit value, the adhesion of component (A) to the pulverizer or the like is further suppressed, and the mixing efficiency and pulverizability are improved. If B / A is at most the above upper limit value, the tablets can be made smaller.

[0045] In production method (2), at least a part of component (C) is contained in the first powder composition. By adding and co-pulverizing component (C) as well, the uniformity of component (C) is further improved. The content of component (C) in the first powder composition can be appropriately set within a range not exceeding the content of component (C) in the granulated particles (P). The content of component (C) in the first powder composition is preferably 10 parts by mass or more, more preferably 20 parts by mass or more, based on 100 parts by mass in total of component (A) and component (B). If the content of component (C) is at least the above lower limit value, the effect of improving the uniformity of component (C) can be more easily obtained.

[0046] The total content of component (A), component (B) and component (C) in the first powder composition (when component (C) is not included, the total content of component (A) and component (B)) is preferably 30% by mass or more, more preferably 70% by mass or more, and may be 100% by mass, based on the total mass of the first powder composition.

[0047] The pulverization of the first powder composition can be carried out using a known pulverizer. 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.

[0048] The pulverization conditions are set so that the volume average particle size of the pulverized product is 5 to 20 μm, preferably 5 to 15 μm. If the volume average particle size of the pulverized product is equal to or greater than the above lower limit value, the fluidity of the powder becomes good and handling is excellent. If the volume average particle size is equal to or less than the above upper limit value, wear of tablets, granule dropout dents, and adhesion of the powder to the tableting machine during tableting are suppressed. The pulverization conditions can be appropriately set according to the target volume average particle size and the crusher used. For example, in the case of a disk rotation type crusher, preferably, pulverization is performed under the condition of a peripheral speed of 1000 m / min or more, more preferably a peripheral speed of 1600 m / min to 2240 m / min, whereby a pulverized product having the above volume average particle size can be obtained.

[0049] (Step Y: Wet granulation) In step Y, the second powder composition is wet granulated to obtain granulated particles (P). When the component (D) is contained in the granulated particles (P), the component (D) may be contained as a powder in the second powder composition, or may be added when preparing an aqueous solution of the component (D) and performing wet granulation. In terms of further suppressing tablet wear and granule dropout dents, it is preferable to prepare and add an aqueous solution of the component (D). When preparing an aqueous solution of the component (D), from the viewpoint of handling properties during addition, the concentration of the component (D) in the aqueous solution is preferably 3 to 10% by mass.

[0050] 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, granulation is carried out while spraying an aqueous liquid such as an aqueous solution of component (D) using a stirring type fluidized bed granulation apparatus such as Multiplex (product name, manufactured by Pauleck Co., Ltd.) or Spiraflow (product name, manufactured by Freund Industry Co., Ltd.). In the stirring granulation method, for example, granulation is carried out using a stirring granulator such as a high-speed mixer (product name, manufactured by Fukae Powtec Co., Ltd.) or a high-speed stirring granulator (product name, manufactured by Dalton Co., Ltd.). In the extrusion granulation method, for example, granulation is carried out using an extrusion granulator such as Dome Gran (product name, manufactured by Dalton Co., Ltd.). The granulation conditions can be appropriately set according to the target volume average particle diameter and the granulation apparatus to be used.

[0051] The volume average particle diameter of the granulated particles (P) is preferably 50 to 1000 μm, more preferably 100 to 700 μm. If the volume average particle diameter of the granulated particles (P) is at least the above lower limit value, the fillability into the die during tableting becomes better, and if it is at most the above upper limit value, the mass variation of the tablets becomes better (the variation becomes smaller).

[0052] <Tablet form> The tablet may have a single-layer structure (single-layer tablet) or a laminated structure (laminated tablet). When the tablet is a single-layer tablet, the tablet is composed only of a layer containing the granulated particles (P) (hereinafter also referred to as the "drug layer"). When the tablet is a laminated tablet, the tablet may be composed of two or more drug layers, or may be composed of one or more drug layers and one or more layers other than the drug layers (hereinafter also referred to as the "optional layer").

[0053] The optional layer does not contain the granulated particles (P). That is, the optional layer consists of the optional component (2). The components contained in the optional layer and their contents can be appropriately selected in consideration of the dosage of the component per tablet, etc. In terms of suppressing tablet wear, granule dropout dents, and adhesion of powder to the tableting machine during tableting, it is preferable that the optional layer does not contain component (A).

[0054] Examples of the shape of the tablets include square flat tablets, round flat tablets, R tablets, etc. In terms of further reducing tablet wear and granule loss depressions, the shape of each of the top and bottom surfaces, that is, the shape of the tablet pressing surface, is preferably a flat surface or a curved surface, and a curved surface (R tablet) is more preferable. Examples of R tablets include single R tablets and two-stage R tablets. A single R tablet, also referred to as a normal R tablet or a standard R tablet, has a cylindrical portion and bulging portions that bulge from both end faces in the axial direction of the cylindrical portion. It is a biconvex tablet in which the radius of curvature R of the curve of the surface of the bulging portion is constant regardless of the position of the surface of the bulging portion. A two-stage R tablet has a cylindrical portion and bulging portions that bulge from both end faces in the axial direction of the cylindrical portion. It is a biconvex tablet in which the radius of curvature R1 of the rising portion from the periphery of the bulging portion is different from the radius of curvature R2 of the zenith, and R1 < R2. The radius of curvature of the curve of the surface of the bulging portion refers to the radius of the circle when the curve drawn by the surface of the bulging portion is regarded as a part of a circle in the cross section when cutting perpendicularly to the end face of the cylindrical portion so as to pass through the zenith of the bulging portion. In terms of further reducing tablet wear and granule loss depressions, the radius of curvature R of the single R tablet is preferably 8 to 15 mm, and more preferably 11 to 13 mm. The radius of curvature R1 of the two-stage R tablet is preferably 2 to 6 mm, more preferably 3 to 4 mm, and the radius of curvature R2 is preferably 8 to 13 mm, more preferably 9 to 11 mm.

[0055] In terms of further reducing tablet wear and granule loss depressions, the tablet diameter is preferably 7 mm to 12 mm, and more preferably 8.5 to 10 mm. The tablet mass per tablet is preferably 100 to 500 mg, and more preferably 250 to 400 mg.

[0056] <Tablet characteristics> The wear degree of the tablet is preferably less than 1% by mass, and more preferably less than 0.1% by mass. In this specification, the wear degree of the tablet is the value when a wear degree test is performed under the conditions of a rotation speed of 30 rpm and 15 minutes, using the tablets in a number such that the total amount can be as close as possible to 30 g as samples, with the wear degree tester described in the 18th revised Japanese Pharmacopoeia.

[0057] The hardness of the tablets is preferably 3 to 12 kgf, more preferably 5 to 8 kgf. If the hardness is at least the above lower limit value, the wear degree and the depression due to granule loss are more suppressed, and if it is at most the above upper limit value, the disintegration property of the tablets is more improved.

[0058] <Tablet manufacturing method> The tablets of the present invention are obtained by tableting a third powder composition containing granulated particles (P).

[0059] The third powder composition typically further contains an optional component (2). As described above, the optional component (2) preferably contains at least one selected from the group consisting of an excipient and a lubricant. When the third powder composition contains the optional component (2), before the tableting step, there is a step of mixing the granulated particles (P) and the optional component (2). The mixing can be carried out by a known method. The optional component (2) may be granulated particles (Q). The granulated particles (Q) can be produced in the same manner as the granulated particles (P).

[0060] Tableting can be carried out using a known tableting machine. Examples of the tableting machine include rotary tableting machines such as Libra (manufactured by Kikusui Seisakusho) and L-41 type (manufactured by Hata Iron Works). The tableting conditions can be appropriately set according to the tableting machine used, taking into account the tablet hardness and the like. For example, in the case of a rotary tableting machine, the number of revolutions of the turntable is preferably 10 to 90 rpm, more preferably 20 to 60 rpm.

[0061] The shape of the punch of the tableting machine is preferably such that the tableting surface is smooth or a curved surface (R tablet), more preferably a curved surface (R tablet). In the case of a single R tablet, the radius of curvature R of the curved surface is preferably 8 to 15 mm, more preferably 11 to 13 mm. In the case of a two-stage R tablet, the radius of curvature R1 of the peripheral part is preferably 2 to 6 mm, more preferably 3 to 4 mm, and the radius of curvature R2 of the zenith top is preferably 8 to 13 mm, more preferably 9 to 11 mm. By setting it within the above preferable range, the wear and the depression due to granule loss of the tablets are more reduced. The mortar diameter of the tableting machine is preferably 7 mm to 12 mm, more preferably 8.5 to 10 mm. By setting it within the above suitable range, wear of the tablets and indentation due to granule loss are further reduced.

[0062] The obtained tablets may be used as uncoated tablets, and a coating film may be formed on the surface thereof to obtain coated tablets. The coating film contains a coating agent (such as a water-soluble polymer compound, saccharides, etc.). The coating 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, a colorant, an acidulant, and a sweetener. As the coating agent for the coated tablets, it is preferable to select one that does not significantly impair the physical properties (such as disintegration property, etc.) of the uncoated tablets. Among them, water-soluble polymer compounds and saccharides are preferable. Examples of the water-soluble polymer compounds include celluloses such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxymethylcellulose, methylcellulose, and ethylcellulose; gum arabic, carboxyvinyl polymer, povidone, polyethylene glycol, polyvinyl alcohol, polyacrylic acid, etc. Examples of the saccharides include monosaccharides, polysaccharides of disaccharides or more (such as granulated sugar, lactose, maltose, xylose, isomerized lactose, etc.), sugar alcohols (such as palatinite, sorbitol, lactitol, erythritol, xylitol, reduced starch saccharide, maltitol, mannitol, etc.), starch syrup, isomerized saccharides, oligosaccharides, sucrose, trehalose, reduced starch saccharide (reduced starch degradation product), etc. These may be used alone or in combination of two or more. Also, commercially available premixed products such as "Opadry" (manufactured by Nippon Karakon Co., Ltd.) may be used. The amount of the coating agent (coating amount) used in the coated tablets is appropriately set within a range that does not impair the effects of the present invention. For example, it is 0.1 to 5 parts by mass with respect to 100 parts by mass of the uncoated tablets.

[0063] The coating process can be carried out using a general coating apparatus. For example, pan-type coating apparatuses such as a high coater (manufactured by Freund Industry Co., Ltd.) and an Aqua coater (manufactured by Freund Industry Co., Ltd.) can be used. In the coating process, 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 sprayed or the like to coat the core tablets. Then, the solvent component of the coating solution is dried to obtain coated tablets.

[0064] According to the tablets of the present invention, since the granulated particles (P) are included, wear can be suppressed. Further, granule dropout dents and adhesion of powder to the tableting machine during tableting can also be suppressed. Note that most antacids are inorganic substances, and it was generally considered that when an antacid was blended into granulated particles, it would be difficult to be crushed during tableting and the binding force would be lowered (therefore, conventionally, it was not common to contain an antacid in the granulated particles blended into tablets as a means for reducing the wear degree). Further, when ibuprofen was micronized, it was generally considered that the surface area increased and the contact area with the tableting machine increased, so that the powder was likely to adhere to the tableting machine. It can be said that the suppression of tablet wear and adhesion of powder to the tableting machine during tableting by the granulated particles (P) containing the component (C) is an unexpected effect.

Examples

[0065] Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited by the following description.

[0066] 〔Raw materials used〕 <Component (A)> Ibuprofen: Product name "Ibuprofen 25", manufactured by BASF, conforming to the Japanese Pharmacopoeia. <Component (B)> L-HPC: Low-substituted hydroxypropyl cellulose, product name "LH-31", manufactured by Shin-Etsu Chemical Co., Ltd., conforming to the Japanese Pharmacopoeia. <Component (C)> Magnesium Oxide: Magnesium oxide, product name "Heavy Magnesium Oxide", manufactured by Kyowa Chemical Industry Co., Ltd., conforming to Japanese Pharmacopoeia. Dried Aluminum Hydroxide Gel: Dried aluminum hydroxide gel, product name "S-100", manufactured by Kyowa Chemical Industry Co., Ltd., conforming to Japanese Pharmacopoeia.

[0067] <(D) Component> HPC: Hydroxypropyl cellulose, product name "HPC-SSL", manufactured by Nippon Soda Co., Ltd., conforming to Japanese Pharmacopoeia. <Optional Component> Acetaminophen: Product name "Acetaminophen (powder form)", manufactured by Sphernex Co., Ltd., conforming to Japanese Pharmacopoeia. Crystalline Cellulose: Product name "Ceolus PH-302", manufactured by Asahi Kasei Corporation, conforming to Japanese Pharmacopoeia. Magnesium Stearate: Magnesium stearate, vegetable origin, light quality, manufactured by Taihei Chemical Industry Co., Ltd., conforming to Japanese Pharmacopoeia.

[0068] [Examples 1 - 8, Comparative Examples 1 - 6] (Tablet Manufacturing) Tablets of Examples 1 - 8 and Comparative Examples 1 - 6 were manufactured according to the procedure shown below.

[0069] <Grinding Process> The raw materials shown in the "Grinding" column of Tables 1 - 4 were mixed at the blending ratios shown in each table to obtain a total of 3 kg of the first powder composition, and then ground using a pin mill (Coloplex 160Z, manufactured by Pauleck Co., Ltd.) under the conditions described in each table. Note that the pin mill is a continuous grinder, and the input powder is instantaneously ground and immediately discharged outside the apparatus. Therefore, the grinding time cannot be described. The blank spaces in Tables 1 - 4 indicate that the raw material is not blended.

[0070] The particle sizes of the obtained ground products are shown in Tables 1 - 4. The particle size indicates the volume - average particle size. Note that the volume - average particle sizes of ibuprofen and L - HPC in Comparative Example 6 where no pre - grinding or co - grinding was performed were as follows. Particle size of ibuprofen: 28 μm. Particle size of L-HPC: 35 μm. The volume-average particle size was measured by a laser diffraction / scattering particle size distribution analyzer (LS13320 type, manufactured by Beckman Coulter, Inc.) with a sample amount of approximately 0.5 g by dry measurement.

[0071] <Granulation process> Granulation was carried out by the granulation methods shown in Tables 1 to 4 to obtain granulated particles. The details of each granulation method are shown below. The particle sizes of the obtained granulated particles are shown in Tables 1 to 4.

[0072] Fluidized bed granulation: The pulverized product obtained in the pulverization process and the materials other than HPC among the raw materials shown in the "Addition during granulation" column of Tables 1 to 4 were mixed at the blending ratios shown in each table to a total of 3.5 kg to obtain a second powder composition. Using a fluidized bed granulator (FLO-5, manufactured by Freund Industry Co., Ltd.), a 5% by mass aqueous HPC solution was sprayed at 50 g / min while the blending ratio of HPC in the granulated particles was the value shown in Tables 1 to 4, and granulation was carried out at an intake air volume of 2.5 m 3 / min and an intake air temperature of 55°C. After spraying was completed, drying was carried out until the exhaust temperature reached 40°C.

[0073] Stirring granulation: The pulverized product obtained in the pulverization process and the raw materials shown in the "Addition during granulation" column of Tables 1 to 4 were put into a stirring granulator (High Speed Mixer FS-10, manufactured by Earth Technica Co., Ltd.) at the blending ratios shown in each table to a total of 3.5 kg (second powder composition). While stirring at an agitator rotation speed of 300 rpm and a chopper rotation speed of 1000 rpm, 0.5 kg of purified water was dropped and stirred for 20 minutes (heating or cooling was 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 and an intake air temperature of 55°C until the exhaust temperature reached 40°C.

[0074] Extrusion granulation: The ground material obtained in the grinding process and the raw materials shown in the "Additives during Granulation" columns in Tables 1 to 4 were put into a stirring granulator (High Speed Mixer FS-10, Earth Technica Co., Ltd.) so that the total amount was 3.5 kg according to the blending ratios shown in each table (the second powder composition). While stirring at an agitator rotation speed of 300 rpm and a chopper rotation speed of 1000 rpm, 0.5 kg of purified water was dropped and stirred for 20 minutes. The obtained powder was processed using an extrusion granulator (Dome Gran DG-LI, manufactured by Dalton Co., Ltd.) with a dome die mesh diameter of 1.0 mm. The obtained wet powder was dried in a fluidized bed granulator (FLO-5, manufactured by Freund Industries Co., Ltd.) until the exhaust temperature reached 40°C with an intake air volume of 2.5 m 3 / min and an intake air temperature of 55°C. In this granulation method, there are a stirring process using a stirring granulator and a drying process using a fluidized bed granulator before and after granulation using an extrusion granulator. However, when the powder passes through the mesh in the extrusion granulator, a stronger force is applied than in stirring granulation, and granulation is performed in a state close to kneading. Therefore, it can be called extrusion granulation.

[0075] <Tabletting Process> The granulated particles obtained in the granulation process and the raw materials shown in the "Additives before Tabletting" columns in Tables 1 to 4 were mixed to obtain a third powder composition according to the blending ratios shown in each table, and tabletted using a rotary tabletting machine (Libra 2, manufactured by Kikusui Seisakusho Co., Ltd.) with a mortar: φ9.0 mm, pestle: two-stage R tablet (curvature radius R1 = 3.6 mm, curvature radius R2 = 10.5 mm), and a rotating disk rotation speed of 30 rpm. The tabletting pressure was adjusted so that the average of the tablet hardness of 10 tablets was 6.0 to 8.0 kgf.

[0076] (Evaluation) The obtained tablets were evaluated as follows. The results are shown in Tables 1 to 4.

[0077] <Wear Degree Test> Using a wear degree tester described in the 18th revised Japanese Pharmacopoeia, a number of tablets (around 90 tablets) with a total amount as close as possible to 30 g were used as samples, and a wear degree test was performed under the conditions of a rotation speed of 30 rpm for 15 minutes. The mass reduction rate from before the test was determined, and that value was taken as the wear degree. The frequency (ratio) of wear is preferably less than 1%, more preferably less than 0.1%. It is particularly preferable that no wear is observed.

[0078] <Tablet ratio of granule loss> After the above wear test, the tablets were visually observed, and the number of tablets (granule loss tablets) with depressions of 0.5 mm or more in diameter on the tablet surface was counted. The ratio of the number of granule loss tablets to the total number of tablets used in the test (granule loss tablet ratio) was calculated. The granule loss tablet ratio is preferably less than 4%, more preferably less than 1.5%, and particularly preferably 0%, that is, no granule loss tablets are observed.

[0079] <Adhesion to the turntable during tableting> After continuous tableting for 20 minutes under the above conditions using a rotary tableting machine, the adhesion of the raw material to the turntable surface was confirmed, and the length of the longest adhered part was measured. For adhesion to the turntable during tableting, it is preferable that there is no adhesion with a length of 20 mm or more, more preferably no adhesion with a length of 10 mm or more, and particularly preferably no adhesion is observed. In addition, in tableting with a rotary tableting machine, the adhesion length is more problematic than the number of adhesion points. When the adhesion becomes long, it accumulates on the turntable and the thickness also increases, so the friction between the turntable and the parts on the turntable increases.

[0080]

Table 1

[0081]

Table 2

[0082]

Table 3

[0083]

Table 4

[0084] As shown in the above results, in Examples 1 to 8, wear of the tablets and dropping of granules were suppressed. Also, adhesion of the raw material powder to the turret during tableting was suppressed. On the other hand, in Comparative Example 1 where the volume average particle diameter of the pulverized product exceeded 20 μm, there was a lot of wear of the tablets and dropping of granules, and the adhesion of the raw material powder to the turret during tableting was long. In Comparative Example 2 where the component (A) was pulverized alone, the component (A) adhered to the pulverizer, and it was not possible to produce the pulverized product, granulated particles, or tablets. In Comparative Example 3 where the component (B) was pulverized alone and the component (A) etc. were added during granulation after pulverization, there was a lot of wear of the tablets and dropping of granules, and the adhesion of the raw material powder to the turret during tableting was long. In Comparative Examples 4 and 5 where the granulated particles did not contain the component (C), there was a lot of wear of the tablets. Particularly in Comparative Example 5 where the component (C) was contained outside the granulated particles, there was also a lot of dropping of granules. In Comparative Example 6 where the components (A) and (B) were not co-pulverized and their volume average particle diameter exceeded 20 μm, there was a lot of wear of the tablets and dropping of granules, and the adhesion of the raw material powder to the turret during tableting was long.

Claims

1. Component (A): Ibuprofen and, Component (B): At least one selected from the group consisting of low-substituted hydroxypropyl cellulose, starch, and crystalline cellulose, Component (C): An antacid, comprising granulated particles, A tablet, wherein the volume average particle diameter of the component (A) and the component (B) is 5 to 20 μm.

2. The tablet according to claim 1, wherein the component (C) is at least one selected from the group consisting of magnesium oxide and dried aluminum hydroxide gel.

3. The tablet according to claim 1 or 2, wherein the granulated particles further comprise component (D): a water-soluble polymer.

4. Using a wear tester described in the eighteenth revised Japanese Pharmacopoeia, with the number of the tablets being as close as possible to a total amount of 30 g as a sample, when a wear test is performed under the conditions of a rotation speed of 30 rpm for 15 minutes, the wear degree is less than 1% by mass. The tablet according to claim 1 or 2.

5. Component (A): Ibuprofen and, Component (B): At least one selected from the group consisting of low-substituted hydroxypropyl cellulose, starch, and crystalline cellulose, Component (C): An antacid, comprising, Granulated particles, wherein the volume average particle diameter of the component (A) and the component (B) is 5 to 20 μm.

6. The granulated particles according to claim 5, wherein the component (C) is at least one selected from the group consisting of magnesium oxide and dried aluminum hydroxide gel.

7. A method for producing the granulated particles according to claim 5, comprising pulverizing a first powder composition containing the component (A) and the component (B) so that the volume average particle diameter becomes 5 to 20 μm, and wet granulating a second powder composition containing the obtained pulverized product and the component (C). A method for producing granulated particles.

8. A method for producing the granulated particles according to claim 5, comprising pulverizing a first powder composition containing the component (A), the component (B), and the component (C) so that the volume average particle diameter becomes 5 to 20 μm, and wet granulating a second powder composition containing the obtained pulverized product. A method for producing granulated particles.

9. The production method according to claim 7 or 8, wherein the first powder composition is co-pulverized with an impact pulverizer.

10. A method for producing a tablet, comprising producing granulated particles by the production method according to claim 7 or 8, and tableting a third powder composition containing the obtained granulated particles.

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