Ibuprofen-containing solid preparation

Abstract

To provide a solid preparation having excellent dissolution of ibuprofen and a good color tone.SOLUTION: A solid preparation includes a granular product containing the following ingredients (a1), (a2), (a3), and (a4): (a1) ibuprofen or a salt thereof or a solvate thereof; (a2) magnesium oxide; (a3) sodium lauryl sulfate; and (a4) one or more disintegrating agents selected from the group consisting of low substituted hydroxypropylcellulose, sodium carboxymethyl starch, carmellose, carmellose calcium, crospovidone, and croscarmellose sodium.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for producing a solid preparation and tablets containing ibuprofen.

Background Art

[0002] Ibuprofen (chemical name: 2-(4-isobutylphenyl)propionic acid) is a widely known drug as one of the NSAIDs (Patent Document 1, etc.), but there is a problem that the dissolution property becomes low when it is made into tablets. On the other hand, when a poorly soluble drug such as ibuprofen is granulated together with a basic compound and a disintegrant, it is generally considered that when the granulated product disintegrates at the time of disintegration, the granulated product itself disintegrates and the basic compound disperses from the vicinity of the poorly soluble drug, so that the environment suitable for the dissolution of the poorly soluble drug is lost. Therefore, as tablets with improved dissolution properties of ibuprofen, a granulated product containing magnesium hydroxide and magnesium oxide as basic compounds in addition to ibuprofen and sodium lauryl sulfate is prepared without adding a disintegrant, and crospovidone and magnesium stearate are added to the obtained granulated product and tabletted. Tablets have been proposed (Patent Document 2).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0004] However, when the inventors examined, it was found that the ibuprofen-containing granulated product prepared without adding a disintegrant had a dark color tone, and it was difficult to produce tablets with a good color tone from this granulated product. Furthermore, it was found that when ibuprofen-containing granules prepared without a disintegrant were mixed with low-substituted hydroxypropyl cellulose and compressed into tablets, not only did they become darker in color, but their dissolution properties actually decreased. The object of the present invention is to provide a solid formulation that has excellent ibuprofen dissolution properties and a good color. [Means for solving the problem]

[0005] Therefore, after diligent research, the inventors discovered that a solid formulation containing granules containing ibuprofen, magnesium oxide, and sodium lauryl sulfate, along with one or more disintegrants selected from low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, carmellose, carmellose calcium, crospovidone, and croscarmellose sodium, surprisingly exhibits excellent ibuprofen dissolution and good color, thus completing the present invention.

[0006] In other words, the present invention is as follows: <1> ~ <9> This provides... <1> A solid preparation comprising granules containing the following components (a1), (a2), (a3), and (a4). (a1) Ibuprofen or its salts or solvates thereof (a2) Magnesium oxide (a3) Sodium lauryl sulfate (a4) One or more disintegrants selected from low-substituted hydroxypropylcellulose, carboxymethyl starch sodium, carmellose, carmellose calcium, crospovidone, and croscarmellose sodium. <2> The dosage form is granules, fine granules, powder, tablet, pill, capsule, or dry syrup. <1> The solid dosage form described above.

[0007] <3> A solid preparation comprising an additive layer and granules dispersed in the additive layer, wherein the granules contain the following components (a1), (a2), (a3), and (a4). (a1) Ibuprofen or its salts or solvates thereof (a2) Magnesium oxide (a3) Sodium lauryl sulfate (a4) One or more disintegrants selected from low-substituted hydroxypropylcellulose, carboxymethyl starch sodium, carmellose, carmellose calcium, crospovidone, and croscarmellose sodium. <4> The mass ratio of the additive layer (B) to the granules [(B) / (A)] is 0.001 to 1.5. <3> The solid dosage form described above. <5> The dosage form is a tablet. <3> or <4> The solid dosage form described above.

[0008] <6> Component (a4) is one or more disintegrants selected from low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, carmellose, and crospovidone. <1> ~ <5> A solid dosage form as described in any of the following. <7> The mass ratio of component (a3) ​​to component (a1) in the granules [(a3) / (a1)] is between 0.0001 and 0.5. <1> ~ <6> A solid dosage form as described in any of the following.

[0009] <8> A method for producing tablets, comprising a tableting step of mixing granules containing the following components (a1), (a2), (a3), and (a4) with an additive, and compressing the resulting mixture into tablets. (a1) Ibuprofen or its salts or solvates thereof (a2) Magnesium oxide (a3) Sodium lauryl sulfate (a4) One or more disintegrants selected from low-substituted hydroxypropylcellulose, carboxymethyl starch sodium, carmellose, carmellose calcium, crospovidone, and croscarmellose sodium. <9> Component (a4) is one or more disintegrants selected from low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, carmellose, and crospovidone. <8> The manufacturing method described above. [Effects of the Invention]

[0010] According to the production method of the present invention, tablets excellent in the elution property of ibuprofen and having a good color tone can be produced. The solid preparation of the present invention is excellent in the elution property of ibuprofen and has a good color tone.

Mode for Carrying Out the Invention

[0011] <Solid Preparation> The solid preparation of the present invention includes a granulated product containing the above components (a1), (a2), (a3) and (a4). First, the components (a1) to (a4) contained in the granulated product will be described.

[0012] (Component (a1)) Examples of ibuprofen or its salt or their solvates include ibuprofen; alkali metal salts of ibuprofen such as sodium ibuprofen and potassium ibuprofen; hydrates and alcohol solvates thereof. Moreover, as ibuprofen or its salt or their solvates, a powdery form is preferable. The average particle size of the powder is preferably 5 to 75 μm, more preferably 15 to 60 μm. The average particle size of the powder can be measured by the laser diffraction method. Ibuprofen or its salt or their solvates can be produced by a known method, and commercially available products can also be used.

[0013] From the viewpoints of the elution property of ibuprofen and the productivity during tableting, the content of ibuprofen or its salt or their solvates in the granulated product is preferably 5 to 70% by mass, more preferably 15 to 55% by mass, still more preferably 25 to 50% by mass, and particularly preferably 30 to 45% by mass based on the total mass of the granulated product.

[0014] (Component (a2)) Magnesium oxide may be heavy magnesium oxide or light magnesium oxide. Further, the particle size, specific volume, etc. of magnesium oxide are not particularly limited, but the specific volume is preferably 1 to 12 mL / g, more preferably 2 to 10 mL / g. Magnesium oxide can be produced by known methods or commercially available products can also be used.

[0015] From the viewpoints of immediate effect, reduction of unpleasant taste, color tone, etc., the content of magnesium oxide in the granulated product is preferably 5 to 30% by mass, more preferably 7.5 to 27.5% by mass, still more preferably 12.5 to 25% by mass, and particularly preferably 15 to 25% by mass with respect to the total mass of the granulated product.

[0016] Also, from the viewpoints of immediate effect, reduction of unpleasant taste, color tone, etc., the content mass ratio [(a2) / (a1)] of component (a2) to component (a1) in the granulated product is preferably 0.3 to 0.7.

[0017] (Component (a3)) Sodium lauryl sulfate is an anionic surfactant represented by CH3(CH2) 11 OS(=O)2O - Na + By incorporating sodium lauryl sulfate into the granulated product, the elution property of ibuprofen is improved. Sodium lauryl sulfate can be produced by known methods or commercially available products can also be used.

[0018] From the viewpoints of the elution property, moldability, granulation property, etc. of ibuprofen, the content of sodium lauryl sulfate in the granulated product is preferably 0.005 to 12.5% by mass, more preferably 0.01 to 10% by mass, still more preferably 0.05 to 7.5% by mass, still more preferably 0.1 to 5% by mass, and particularly preferably 0.3 to 3% by mass with respect to the total mass of the granulated product. When the content of sodium lauryl sulfate in the granulated product is 0.1% by mass or more or 0.3% by mass or more and 10% by mass or less, 5% by mass or less or 3% by mass or less, the elution property of ibuprofen is particularly improved.

[0019] Furthermore, the mass ratio of component (a3) ​​to component (a1) in the granules [(a3) / (a1)] is preferably 0.0001 to 0.5, more preferably 0.0005 to 0.4, even more preferably 0.001 to 0.25, even more preferably 0.001 to 0.2, and particularly preferably 0.01 to 0.1, from the viewpoint of ibuprofen dissolution, moldability, and granulation properties. The dissolution of ibuprofen is particularly improved when the content mass ratio [(a3) / (a1)] is 0.01 or higher, and when it is 0.2 or lower or 0.1 or lower.

[0020] (ingredient (a4)) The solid dosage form of the present invention contains (a4) one or more disintegrants selected from low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, carmellose, carmellose calcium, crospovidone, and croscarmellose sodium in the granules. By including component (a4) in the granules, not only are the disintegration properties of the solid dosage form and the dissolution properties of ibuprofen improved, but the color of the solid dosage form is also improved. As described in Patent Document 2 (Japanese Patent Application Publication No. 2014-141518), it was generally thought that when a poorly soluble drug such as ibuprofen is granulated together with a basic compound and a disintegrant, the granules themselves disintegrate during disintegration, causing the basic compound to disperse from the vicinity of the poorly soluble drug, thus losing an environment suitable for the dissolution of the poorly soluble drug. However, in the present invention, the dissolution properties of ibuprofen were improved in the manner described above, quite unexpectedly.

[0021] In this specification, low-substituted hydroxypropyl cellulose refers to low-substituted hydroxypropyl cellulose as described in the 17th edition of the Japanese Pharmacopoeia. Specifically, it refers to hydroxypropyl cellulose in which 5.0 to 16.0% of hydroxypropoxy groups are quantified when dried. The content of said hydroxypropoxy groups is preferably 6 to 13% by mass, and particularly preferably 7 to 11% by mass. Low-substituted hydroxypropyl cellulose can be produced by known methods, and commercially available products can also be used. Examples of commercially available low-substituted hydroxypropyl cellulose include L-HPC(LH31), L-HPC(LH21), L-HPC(LH11), L-HPC(LH32), and L-HPC(NBD-020) manufactured by Shin-Etsu Chemical Co., Ltd.

[0022] Furthermore, in this specification, carboxymethyl starch sodium refers to carboxymethyl starch sodium as described in the 17th edition of the Japanese Pharmacopoeia. Specifically, it refers to the sodium salt of carboxymethyl ether of starch or its crosslinked product, in which sodium is quantified at a concentration of 2.8-4.2% or 2.0-3.4% when the insoluble material in ethanol (99.5%) / water mixture (8:2) is dried. Carboxymethyl starch sodium can be manufactured by known methods, and commercially available products can also be used. Examples of commercially available carboxymethyl starch sodium include Primojel (manufactured by DMV), Exprotab (manufactured by Kimura Sangyo Co., Ltd.), and GLYCOLYS (manufactured by Rocket Japan Co., Ltd.).

[0023] Furthermore, "carmellose" refers to the carmellose described in the 17th edition of the Japanese Pharmacopoeia. Specifically, it refers to partially O-carboxymethylated cellulose. Carmellose can be manufactured by known methods, and commercially available products can also be used. Examples of commercially available carmellose include NS-300 (manufactured by Gotoku Pharmaceutical Co., Ltd.).

[0024] Furthermore, "carmellose calcium" refers to the carmellose calcium described in the 17th edition of the Japanese Pharmacopoeia. Specifically, it refers to the calcium salt of polyvalent carboxymethyl ether of cellulose. Carmellose calcium can be manufactured by known methods, and commercially available products can also be used. Examples of commercially available carmellose calcium include ECG-505 (manufactured by Gotoku Pharmaceutical Co., Ltd.).

[0025] Furthermore, crospovidone is a cross-linked polymer of 1-vinyl-2-pyrrolidone. Preferably, the crospovidone is one that, when dried, contains 11.0-12.8% nitrogen, as described in the 17th edition of the Japanese Pharmacopoeia. The average particle size (D50%) of crospovidone is typically 3-140 μm. Additionally, the crospovidone may be either type A or type B crospovidone as defined in the 17th edition of the Japanese Pharmacopoeia. Crospovidone can be manufactured by known methods, and commercially available products can also be used. Examples of commercially available crospovidone include Coridon CL, Coridon CL-F, Coridon CL-SF (all manufactured by BASF Japan), Polyplasdone (manufactured by ISP Japan), and Crospovidone (manufactured by DSP Gokyo Food & Chemical Co., Ltd.).

[0026] Furthermore, croscarmellose sodium refers to croscarmellose sodium as described in the 17th edition of the Japanese Pharmacopoeia. Specifically, it refers to the sodium salt of a polyvalent carboxymethyl ether crosslinked cellulose. Croscarmellose sodium can be manufactured by known methods, and commercially available products can also be used. Examples of commercially available croscarmellose sodium include Primellose-300 (manufactured by DMV), Ac-Di-Sol (manufactured by DuPont), and Kikkolate (manufactured by Asahi Kasei).

[0027] Among the components (a4), low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, carmellose, and crospovidone are preferred from the viewpoint of the disintegration properties of the solid dosage form, the dissolution properties of ibuprofen, and the color of the solid dosage form; low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and crospovidone are more preferred; low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch are even more preferred; and low-substituted hydroxypropyl cellulose is particularly preferred.

[0028] The content of component (a4) in the granules is preferably 3 to 55% by mass, more preferably 10 to 50% by mass, even more preferably 15 to 45% by mass, and particularly preferably 20 to 40% by mass, relative to the total mass of the granules, from the viewpoint of the disintegration properties of the solid dosage form, the dissolution properties of ibuprofen, and the color tone of the solid dosage form.

[0029] Furthermore, the mass ratio of component (a4) to component (a1) in the granules [(a4) / (a1)] is preferably 0.05 to 2, more preferably 0.1 to 1.5, even more preferably 0.3 to 1.2, and particularly preferably 0.6 to 1, from the viewpoint of the disintegration properties of the solid dosage form, the dissolution properties of ibuprofen, and the color tone of the solid dosage form. When the mass ratio of the content [(a4) / (a1)] is 0.3 or higher or 0.6 or higher, the dissolution of ibuprofen is particularly improved.

[0030] The granules may contain, in addition to the above components (a1) to (a4), drugs other than components (a1) and (a2). Drugs other than components (a1) and (a2) include one or more drugs selected from (a5) caffeines and (a6) hypnotics and sedatives, as well as drugs other than components (a1), (a2), (a5), and (a6) (hereinafter also referred to as "other drugs").

[0031] (ingredient (a5)) Examples of caffeine compounds include caffeine hydrate, anhydrous caffeine, and sodium benzoate caffeine. These may be used individually or in combination of two or more. The caffeine content in the granules is preferably 0 to 25% by mass, more preferably 0 to 20% by mass, even more preferably 0 to 17.5% by mass, and particularly preferably 0 to 15% by mass, relative to the total mass of the granules.

[0032] (component (a6)) Examples of hypnotic sedatives include allyl isopropylacetylurea and bromovalerylurea. These may be used individually or in combination. The content of the hypnotic sedative in the granules is preferably 0 to 20% by mass, more preferably 0 to 17.5% by mass, even more preferably 0 to 15% by mass, and particularly preferably 0 to 12.5% ​​by mass, based on the total mass of the granules.

[0033] Other drugs include, for example, anti-inflammatory agents other than component (a1), antacids other than component (a2), cough and expectorant drugs, antihistamines, antiallergic agents, anticholinergics, vitamins, muscle relaxants, and herbal medicines. One of these may be used alone, or two or more may be used in combination.

[0034] Other anti-inflammatory agents besides component (a1) include, for example, glycyrrhizic acid or its salts, tranexamic acid, glycyrrhetinic acid, sodium azulene sulfonate, aspirin, salicylamide, etc. One of these may be used alone, or two or more may be used in combination. The content of anti-inflammatory agents other than component (a1) in the granules is usually 0 to 30% by mass, preferably 0 to 10% by mass, and more preferably 0 to 0.1% by mass, relative to the total mass of the granules.

[0035] Examples of antacids other than component (a2) include sodium bicarbonate, precipitated calcium carbonate, calcium silicate, synthetic aluminum silicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, aluminum hydroxide gel, dried aluminum hydroxide gel, aluminum hydroxide-sodium bicarbonate coprecipitation product, aluminum hydroxide-magnesium carbonate mixed dried gel, aluminum hydroxide-magnesium carbonate-calcium carbonate coprecipitation product, magnesium hydroxide-potassium aluminum sulfate coprecipitation product, glycine, magnesium silicate, dihydroxyaluminum aminoacetate, and magnesium carbonate. One of these may be used alone, or two or more may be used in combination. The content of antacids other than component (a2) in the granules is preferably 0 to 5% by mass, more preferably 0 to 1% by mass, even more preferably 0 to 0.1% by mass, even more preferably 0 to 0.01% by mass, and particularly preferably 0% by mass, relative to the total mass of the granules.

[0036] Examples of cough suppressants and expectorants include ambroxol hydrochloride, L-ethylcysteine ​​hydrochloride, potassium guaiacolsulfonate, potassium cresolsulfonate, guaifenesin, bromhexine hydrochloride, L-carbocysteine, codeine phosphate hydrate, dihydrocodeine phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalein salt, dimemorphan phosphate, noscapine, noscapine hydrochloride hydrate, dl-methylephedrine hydrochloride, and dl-methylephedrine saccharin salt. One of these may be used alone, or two or more may be used in combination. The amount of cough suppressant and expectorant in the granules is usually 0 to 30% by mass, preferably 0 to 10% by mass, and particularly preferably 0 to 0.1% by mass, relative to the total mass of the granules.

[0037] Examples of antihistamines and antiallergic agents include mequitazine, azelastine hydrochloride, fexofenadine hydrochloride, epinastine hydrochloride, loratadine, cetirizine hydrochloride, olopatadine hydrochloride, alimazine tartrate, carbinoxamine maleate, clemastine fumarate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, and diphenhydramine hydrochloride. These may be used individually or in combination of two or more.

[0038] Examples of anticholinergic drugs include isopropamide iodide, belladonna extract, belladonna root, total belladonna alkaloids, scopolamine hydrobromide, butylscopolamine bromide, methylbenactydium bromide, timepidium bromide, and pirenzepine. These may be used individually or in combination of two or more.

[0039] Examples of vitamins include vitamin B1, vitamin B1 derivatives, vitamin B2, vitamin B2 derivatives, vitamin C, vitamin C derivatives, hesperidin, hesperidin derivatives, and salts thereof. One of these may be used alone, or two or more may be used in combination.

[0040] Examples of muscle relaxants include methocarbamol, chlorzoxazone, pridinol mesylate, chlorphenesin carbamate, eperisone hydrochloride, afloquarone, and tizanidine hydrochloride. These may be used individually or in combination of two or more.

[0041] Examples of crude drugs include Ziyu, Cinnamon bark, Licorice, Peony root, Peony root bark, Citrus peel, Ginger, Japanese pepper, Platycodon, Ephedra, Apricot kernel, Pinellia tuber, Plantago asiatica, Senega, Bupleurum root, Magnolia bark, etc. One of these may be used alone, or two or more may be used in combination.

[0042] The total content of other drugs in the granules is typically 0 to 50% by mass, preferably 0 to 10% by mass, more preferably 0 to 1% by mass, even more preferably 0 to 0.01% by mass, and particularly preferably 0% by mass, relative to the total mass of the granules.

[0043] Furthermore, the granules may contain pharmaceutical additives other than components (a3) ​​to (a4). Examples of pharmaceutical additives other than components (a3) ​​to (a4) include surfactants other than component (a3), such as sucrose fatty acid esters and polyoxyethylene polyoxypropylene glycol; disintegrants other than component (a4), such as alginic acid, bentonite, and partially pregelatinized starch; excipients such as corn starch, crystalline cellulose, lactose, lactose monohydrate, sucrose, glucose, mannitol, sorbitol, and xylitol; and binders such as gelatin, sodium alginate, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and carmellose sodium. One of these may be used alone, or two or more may be used in combination. Furthermore, solubilizers, buffers, preservatives, etc., may be used as needed.

[0044] The total content of pharmaceutical additives other than components (a3) ​​to (a4) in the granules is usually 0 to 40% by mass, preferably 0 to 30% by mass, more preferably 0 to 25% by mass, even more preferably 0 to 0.01% by mass, and particularly preferably 0% by mass, relative to the total mass of the granules.

[0045] The granulated material is preferably in the form of granules. The average particle size of the granulated material is usually 100 to 1000 μm, preferably 150 to 710 μm. This average particle size can be measured by sieving.

[0046] The solid dosage form of the present invention can be granules, fine granules, powders, tablets, pills, capsules, or dry syrups, but granules, tablets, and capsules are preferred, and tablets are particularly preferred. The solid dosage form of the present invention exhibits excellent ibuprofen dissolution even when the dosage form is a tablet. Furthermore, examples of the above-mentioned tablets include uncoated tablets, film-coated tablets, sugar-coated tablets, orally disintegrating tablets, and chewable tablets. From the viewpoint of tablet disintegration, ibuprofen dissolution, and ease of administration, uncoated tablets, film-coated tablets, and orally disintegrating tablets are preferred. In addition, even when the dosage form is an uncoated tablet or an orally disintegrating tablet, the solid dosage form of the present invention has a good color. In addition, even when the solid dosage form is an uncoated type, it has a good color.

[0047] Furthermore, the solid formulation of the present invention may consist of the above-mentioned granules or may contain the above-mentioned granules and components other than the granules (additive layer or film coating layer). However, from the viewpoint of the disintegration properties of the solid formulation, the dissolution properties of ibuprofen, and the color tone of the solid formulation, a solid formulation comprising an additive layer and granules dispersed in the additive layer, wherein the granules contain components (a1) to (a4) (hereinafter, this solid formulation will also be referred to as "solid formulation (α)") is preferred, and a tablet comprising an additive layer and granules dispersed in the additive layer, wherein the granules contain components (a1) to (a4), is particularly preferred. Furthermore, it is sufficient that at least a portion of the granules contained in the solid dosage form (α) are dispersed in the additive layer, and as long as at least a portion of the granules are dispersed in the additive layer, multiple granules in the additive layer may be in contact with each other.

[0048] The solid formulation (α) includes an additive layer in addition to the granules described above. The additive layer is preferably in solid form. As for the additive layer, it is preferable to include (b1) a lubricant from the viewpoint of tablet compressibility and filling properties.

[0049] (Component (b1)) Examples of lubricants include talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, and glycerin fatty acid esters. These may be used individually or in combination of two or more.

[0050] The content of component (b1) in the additive layer is preferably 0.5 to 100% by mass, more preferably 0.75 to 95% by mass, even more preferably 1 to 90% by mass, and particularly preferably 2 to 85% by mass, relative to the total mass of the additive layer, from the viewpoint of tablet compressibility and filling properties.

[0051] As for the additive layer, from the viewpoint of ibuprofen dissolution, disintegration, and fluidity, it is preferable to include, in addition to the above component (b1), one or more selected from (b2) disintegrants and (b3) excipients.

[0052] (component (b2)) Examples of disintegrants include crospovidone, carmellose calcium, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, and croscarmellose sodium. These may be used individually or in combination of two or more. Examples of crospovidone, carmellose calcium, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, and croscarmellose sodium are those listed as component (a4). Among these, crospovidone, carboxymethyl starch sodium, and croscarmellose sodium are preferred from the viewpoint of the disintegration properties of the solid dosage form and the dissolution properties of ibuprofen, with crospovidone being more preferred.

[0053] The content of component (b2) in the additive layer is preferably 0 to 50% by mass, more preferably 0 to 40% by mass, even more preferably 0 to 35% by mass, and particularly preferably 0 to 30% by mass, relative to the total mass of the additive layer, from the viewpoint of the disintegration properties of the solid dosage form, the dissolution properties of ibuprofen, moldability, and manufacturability during tableting.

[0054] Furthermore, the mass ratio of component (b2) in the additive layer to component (a1) in the granules [(b2) / (a1)] is preferably 0 to 0.8, more preferably 0.05 to 0.6, even more preferably 0.075 to 0.4, and particularly preferably 0.1 to 0.2, from the viewpoint of the disintegration properties of the solid dosage form and the dissolution properties of ibuprofen.

[0055] Furthermore, the mass ratio of component (b2) in the additive layer to component (a4) in the granules [(b2) / (a4)] is preferably 0 to 0.8, more preferably 0.05 to 0.6, even more preferably 0.075 to 0.4, and particularly preferably 0.1 to 0.3, from the viewpoint of the disintegration properties of the solid dosage form and the dissolution properties of ibuprofen.

[0056] (Component (b3)) Examples of excipients include corn starch, crystalline cellulose, lactose, lactose monohydrate, sucrose, glucose, mannitol, sorbitol, and xylitol. One of these may be used alone, or two or more may be used in combination. Among these, crystalline cellulose, corn starch, and mannitol are preferred.

[0057] The content of component (b3) in the additive layer is preferably 0 to 95% by mass, more preferably 5 to 95% by mass, even more preferably 10 to 95% by mass, and particularly preferably 15 to 95% by mass, relative to the total mass of the additive layer, from the viewpoint of the disintegrability and moldability of the solid formulation.

[0058] The additive layer may further contain (b4) a fluidizing agent in addition to the above components (b1) to (b3). (component (b4)) Examples of fluidizing agents include light anhydrous silicic acid and hydrated silicon dioxide. One of these may be used alone, or two or more may be used in combination. The content of component (b4) in the additive layer is preferably 0 to 15% by mass, more preferably 0 to 10% by mass, even more preferably 0 to 7.5% by mass, and particularly preferably 0 to 5% by mass, relative to the total mass of the additive layer.

[0059] Furthermore, the additive layer may contain pharmaceutical additives other than components (b1) to (b4). Examples of pharmaceutical additives other than components (b1) to (b4) include surfactants such as sodium lauryl sulfate, sucrose fatty acid esters, and polyoxyethylene polyoxypropylene glycol. One of these may be used alone, or two or more may be used in combination. Furthermore, solubilizers, buffers, preservatives, fragrances, colorants, highly sensitive sweeteners, flavoring agents, etc., may be used as needed.

[0060] The total content of pharmaceutical additives other than components (b1) to (b4) in the additive layer is usually 0 to 30% by mass, preferably 0 to 10% by mass, more preferably 0 to 1% by mass, even more preferably 0 to 0.01% by mass, and particularly preferably 0% by mass, relative to the total mass of the additive layer.

[0061] Furthermore, the total content of the above-mentioned granules and additive layer is preferably 80-100% by mass, more preferably 90-100% by mass, even more preferably 95-100% by mass, and particularly preferably 99.9-100% by mass, relative to the total mass of the solid formulation (α). It is preferable that the solid formulation of the present invention does not contain phosphates such as disodium hydrogen phosphate or clay minerals such as smectite.

[0062] The mass ratio of the additive layer (B) to the granules (A) in the solid dosage form (α) [(B) / (A)] is preferably 0.001 to 1.5, more preferably 0.005 to 1, even more preferably 0.0075 to 0.5, even more preferably 0.01 to 0.5, and particularly preferably 0.1 to 0.3, from the viewpoint of the disintegration properties of the solid dosage form, the dissolution properties of ibuprofen, the color tone of the solid dosage form, and moldability.

[0063] Furthermore, as a solid dosage form (α), it is preferable that the additive layer is the outermost layer. Even in such cases, the solid dosage form of the present invention has good color, and it is possible to achieve both good ibuprofen dissolution and good color. Furthermore, the solid dosage form of the present invention is preferably for oral use.

[0064] The dosage of the solid dosage form of the present invention is preferably such that 100 to 2400 mg of component (a1) can be taken per day in free ibuprofen equivalent, more preferably 120 to 1200 mg per day, and particularly preferably 390 to 1200 mg per day. Furthermore, the dosage of component (a1) is preferably such that 60 to 800 mg can be taken per dose in free ibuprofen equivalent, more preferably 60 to 400 mg per dose, even more preferably 70 to 400 mg per dose, and particularly preferably 130 to 400 mg per dose.

[0065] Furthermore, the solid dosage form of the present invention exhibits excellent ibuprofen dissolution properties and good color. Therefore, the solid dosage form of the present invention can fully exert the anti-inflammatory and analgesic effects of ibuprofen and is extremely useful as an antipyretic analgesic, a cold medicine, a psychotropic drug, and the like.

[0066] <Method of manufacturing tablets> The solid dosage form of the present invention can be manufactured by combining conventional methods as appropriate, but when manufacturing a dosage form in tablet form, it may be manufactured by a method that includes a tableting step of mixing granules containing the above components (a1), (a2), (a3), and (a4) with an additive and compressing the resulting mixture into tablets.

[0067] The above granules can be obtained by a granulation process in which a composition (hereinafter also referred to as composition X) containing components (a1) to (a4) and, if necessary, other components (components (a5) to (a6), etc.) is granulated in accordance with a known granulation method described in the General Provisions for Preparations of the Seventeenth Edition of the Japanese Pharmacopoeia, etc. The order in which components (a1) to (a4) are added to composition X does not matter.

[0068] Composition X can be prepared, for example, by mixing components (a1) to (a4) and other components as needed, or by mixing components (a1) to (a4) and other components as needed, and then kneading the resulting mixture with a solvent such as water or aqueous alcohol. Examples of aqueous alcohols include a mixture of ethanol and / or isopropanol with water. Mixing and kneading are preferably carried out at 20 to 1200 rpm for 0.5 to 10 minutes, respectively.

[0069] Granulation in the granulation process may be carried out by a wet granulation method or a dry granulation method. Specifically, examples include extrusion granulation, rolling granulation, agitation granulation, fluidized bed granulation, spray drying granulation, and crushing granulation. Among these, extrusion granulation and agitation granulation are preferred.

[0070] Furthermore, the above-mentioned additive is preferably in solid form, and more preferably in powder form. The additive may also contain pharmaceutical additives. The pharmaceutical additive is the same as that which may be contained in the additive layer described above, and is preferably an additive containing at least component (b1), and more preferably an additive containing at least components (b1) to (b3). The tableting process should be carried out according to standard procedures using a rotary tablet press, single-shot tablet press, etc. The tableting pressure is usually 3 to 15 kN. In addition, prior to adding the additive, the granules may be dried and / or sized as needed. [Examples]

[0071] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. Examples 2, 3, and 5-7 are for reference only.

[0072] [Examples 1-7 and Comparative Examples 1-6: Uncoated Tablets] (Manufacturing method) Each component was weighed according to the granular formulations shown in Table 1 and placed in a high-speed stirring granulator (VG-10 model, manufactured by Powrec Co., Ltd.) and mixed for 3 minutes. Subsequently, an appropriate amount of purified water was added to the resulting granular formulation mixture and kneaded in the high-speed stirring granulator (VG-10 model, manufactured by Powrec Co., Ltd.) for 3 minutes. The kneaded mixture was extruded and granulated in an extruder (Twindome Gran TDG-80A, manufactured by Dalton Co., Ltd.) to obtain wet granules A. Subsequently, it was dried in a fluidized bed dryer (FLO-2, manufactured by Freund Industrial Co., Ltd.) to obtain dried granules B. Further sizing was performed in a sizing machine (Cormil QC-U10, manufactured by Powrec Co., Ltd.) to obtain sizing granules C. The obtained granules C were mixed with the additives shown in Table 1, and then compressed using a rotary tablet press (VIRG0512 model, manufactured by Kikusui Seisakusho Co., Ltd.) at a compression pressure of 4.5 kN to obtain the uncoated tablets (1000 mg per 4 tablets (daily dose)) of Examples 1-7 and Comparative Examples 1-6.

[0073] (Measurement method and evaluation method) (1) Ibuprofen elution The MacIlvaine buffer solution was diluted with purified water to obtain 900 mL of a solution with a pH of 4.0. One tablet of the core tablet of Example 1 was added to this solution, and the mixture was stirred at 50 rpm at 37°C. After 15 minutes had elapsed since the start of stirring, the elution rate of ibuprofen from the core tablet of Example 1 was measured. The elution rate of ibuprofen was measured by high performance liquid chromatography (HPLC) method and calculated from the elution amount of ibuprofen according to the following formula (α). Ibuprofen elution rate (mass %) = {(ibuprofen elution amount (mg)) / (initial ibuprofen content (mg))} × 100 ··· (α) <HPLC measurement conditions> Column: A stainless steel tube with an inner diameter of 3.0 mm and a length of 5 cm filled with 3 μm octadecylsilylated silica gel for liquid chromatography Detector: Ultraviolet absorption photometer (measurement wavelength: 210 nm) Mobile phase: Diluted phosphoric acid (1→1000) / acetonitrile mixture Also, for the core tablets of Examples 2 to 7 and Comparative Examples 1 to 6, the elution rate of ibuprofen was measured in the same manner. The results are shown in Table 1. It can be said that the higher the elution rate after 15 minutes, the better the elution property of ibuprofen.

[0074] (2) Color tone For each granule (sized granule C) and core tablet immediately after production, the surface color tone was visually confirmed and evaluated according to the following criteria. The results are shown in Table 1. (Evaluation criteria for granule color tone) -: No discoloration from white to grayish white +: A little discoloration from white to grayish white ++: Discoloration from white to grayish white (Evaluation criteria for tablet color tone) -: No black spots +: A few black spots ++: Many black spots

[0075]

Table 1

[0076] The symbols in Table 1 indicate the following: *1: Ibuprofen 25% manufactured by BASF *2: Heavy-duty type manufactured by Kyowa Chemical Industry Co., Ltd. *3: BASF Corifor SLS Fine *4: L-HPC (LH31) manufactured by Shin-Etsu Chemical Co., Ltd. *5: BASF Coridon CL-F (Crospovidone Type A) *6: Primojel manufactured by DFE Pharma *7: NS-300 manufactured by Gotoku Pharmaceutical Co., Ltd. *8: Pharmatose 200M manufactured by DFE Pharma. *9: VIVAPUR105 manufactured by JRS Pharma Co., Ltd. *10: Micro Ace P-3 manufactured by Nippon Talc Co., Ltd. *11: Magnesium stearate (plant-derived) manufactured by Taihei Chemical Co., Ltd.

[0077] [Formulation Examples 1-2: Granules] Each component, weighed according to the granular formulations listed in Table 2, was placed in a high-speed stirring granulator (VG-25 model, manufactured by Powrec Co., Ltd.) and mixed for 3 minutes. Subsequently, purified water was added and kneaded in the high-speed stirring granulator (VG-25 model, manufactured by Powrec Co., Ltd.) for 3 minutes. The kneaded mixture was extruded and granulated using an extruder (TDG-80 model, manufactured by Dalton Co., Ltd.). Furthermore, the obtained extruded granulated granules were placed in a fluidized bed dryer (FLO-5 model, manufactured by Freund Industrial Co., Ltd.) and dried, and then sized using a granulator (Cormil QC-U10) to obtain the granular formulations of Formulation Example 1 and Formulation Example 2.

[0078] [Table 2]

[0079] [Formulation Example 3: Hard Capsules] 910 g of the granules obtained in Formulation Example 1 were mixed with 2.8 g of magnesium stearate using a V-type mixer (TCV-5, manufactured by Tokuju Kogyo Co., Ltd.) to obtain 912.8 g of the mixed powder. This was filled into gelatin capsules to obtain the hard capsule formulation of Formulation Example 3 (capsule contents amounting to 326 mg, corresponding to 100 mg of ibuprofen).

[0080] [Formulation Example 4: Film-coated tablets] To 1560 g of the granules obtained in Formulation Example 1, 297.6 g of crystalline cellulose, 38.4 g of crospovidone, 9.6 g of light anhydrous silicic acid, and 14.4 g of magnesium stearate were added, and the mixture was combined in a V-type mixer (TCV-10, manufactured by Tokuju Kogyo Co., Ltd.) to obtain 1920 g of compressed tablet powder. Next, the tablets were compressed using a rotary tablet press (VIRG0512, manufactured by Kikusui Seisakusho Co., Ltd.) to produce uncoated tablets with a diameter of 9.5 mm and a tablet mass of 400 mg (ibuprofen content 100 mg). Next, 120 g of hypromellose and 20 g of macrogol 6000 were dissolved in purified water, and then 10 g of talc and 10 g of titanium dioxide were dispersed to prepare 2000 g of a film coating solution with a solid content of 8%. Then, 500 g of uncoated tablets were placed in a coating machine (HC-LABO type, manufactured by Freund Industrial Co., Ltd.), and the prepared film coating solution was sprayed to coat the tablets, obtaining the film-coated tablets of Formulation Example 4 (tablet mass 412 mg, white).

[0081] [Example of formulation 5: Orally disintegrating tablet] To 2064 g of the granules obtained in Formulation Example 2, 425.6 g of crystalline cellulose, 400 g of corn starch, 28.8 g of acesulfame potassium, 28.8 g of aspartame, 14.4 g of light anhydrous silicic acid, and 14.4 g of magnesium stearate were added and mixed in a V-type mixer (TCV-10, manufactured by Tokuju Kogyo Co., Ltd.) to obtain 2976 g of compressed tablet powder. Next, tablets were compressed using a rotary tablet press (VIRG0512, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain orally disintegrating tablets with a diameter of 12 mm and a tablet mass of 620 mg (ibuprofen content of 150 mg).

Claims

1. A tablet comprising an additive layer and granules dispersed in the additive layer, wherein the granules contain the following components (a1), (a2), (a3), and (a4), the mass ratio of component (a3) ​​to component (a1) in the granules [(a3) / (a1)] is 0.01 to 0.1, and the mass ratio of component (a4) to component (a1) in the granules [(a4) / (a1)] is 0.6 to 1. (a1) Ibuprofen or its salt or solvate thereof: 25 to 55% by mass of the total mass of the granules (a2) Magnesium oxide: 12.5 to 25% by mass relative to the total mass of the granules (a3) Sodium lauryl sulfate (a4) Low-substituted hydroxypropyl cellulose: 15 to 55% by mass relative to the total mass of the granules

2. The tablet according to claim 1, wherein the mass ratio of the additive layer (B) to the granules [(B) / (A)] is 0.001 to 1.

5.

3. A method for producing tablets, comprising a tableting step of mixing granules containing the following components (a1), (a2), (a3), and (a4), wherein the mass ratio of component (a3) ​​to component (a1) in the granules [(a3) / (a1)] is 0.01 to 0.1, and the mass ratio of component (a4) to component (a1) in the granules [(a4) / (a1)] is 0.6 to 1 with an additive, and compressing the resulting mixture into tablets. (a1) Ibuprofen or its salt or solvate thereof: 25 to 55% by mass of the total mass of the granules (a2) Magnesium oxide: 12.5 to 25% by mass relative to the total mass of the granules (a3) Sodium lauryl sulfate (a4) Low-substituted hydroxypropyl cellulose: 15 to 55% by mass relative to the total mass of the granules

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