Granulated material and method for producing tablets containing the same

Abstract

To provide a method for producing a granulated material that suppresses sticking during tableting.SOLUTION: Provided is a method for producing a granulated material containing the following components (A) to (C): (A) a surfactant; (B) ibuprofen; (C) one or more selected from carmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, gum arabic, carboxyvinyl polymer, povidone, and polyvinyl alcohol, the method comprising: an aqueous dispersion preparation step (X) containing the following components (A) and (B) and substantially free of the following component (C); a grinding step (Y) in which the aqueous dispersion obtained in step (X) is ground using a high-pressure homogenizer; and a granulation step (Z) in which the ground material obtained in step (Y) is added with the following component (C) and granulated.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for producing a granulated product with suppressed sticking during tableting, and a method for producing a tablet using a composition containing the granulated product produced by the production method.

Background Art

[0002] Since ibuprofen is a poorly soluble drug, attempts have been made to improve its elution from formulations. As a method for enhancing elution by pulverizing ibuprofen, for example, a technique of granulating a co-ground product of ibuprofen and low-substituted hydroxypropyl cellulose with a water-soluble polymer is known (Patent Document 1). Further, as a method for preparing a dispersion of ibuprofen as fine particles, a method has been reported in which ibuprofen is added to water in which sodium lauryl sulfate is dissolved and wet pulverized with a bead mill to prepare a dispersion in which ibuprofen is fine particles with an average particle diameter of 0.7 μm (Patent Document 2). Another method for micronizing ibuprofen may be to use a high-pressure homogenizer. As a method for pulverizing a poorly soluble drug using a high-pressure homogenizer, for example, a production method has been reported in which a poorly soluble drug is suspended in a liquid containing no granulation-dissolving agent, subjected to high-pressure treatment with a high-pressure homogenizer, and then a granulation-dissolving agent is added to dissolve the agglomerated particles to obtain a dispersion in which the poorly soluble drug is pulverized into particles of nano-order size (Patent Document 3). However, a granulation-dissolving agent is required to disperse ibuprofen, which is difficult to disperse in water, in water. Therefore, a method has been proposed in which a dispersing agent composed of a water-soluble polymer such as methyl cellulose or hydroxypropyl methyl cellulose is added to water, and then a water dispersion containing a poorly soluble drug is prepared and treated with a high-pressure homogenizer to obtain a stable suspension (Patent Document 4).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

[0004] On the other hand, ibuprofen has a property that the binding force between powders is not strong and it is easy to stretch by friction. Therefore, when wet pulverization is performed using a high-pressure homogenizer to make it finer, since the surface area of ibuprofen increases, there is a problem that sticking easily occurs during tableting.

[0005] As a result of repeated studies, the inventors of the present invention co-pulverized a suspension in which a surfactant and ibuprofen were suspended with a high-pressure homogenizer in a wet pulverization step using a high-pressure homogenizer, and then dissolved a specific water-soluble polymer to obtain a granulated product. Surprisingly, it was found that sticking during tableting was suppressed, and the present invention was completed. MEANS FOR SOLVING THE PROBLEM

[0006] The present invention includes the following contents. [1] A step (X) of preparing an aqueous dispersion containing the following component (A) and the following component (B) and substantially not containing the following component (C), A pulverization step (Y) of pulverizing the aqueous dispersion obtained in the step (X) with a high-pressure homogenizer, A granulation step (Z) of adding the following component (C) to the pulverized product obtained in the step (Y) and granulating, A method for producing a granulated product containing the following components (A) to (C). (A) Surfactant (B) Ibuprofen One or more selected from sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, gum arabic, carboxyvinyl polymer, povidone, and polyvinyl alcohol. [2] The production method according to [1], wherein the component (A) is one or more selected from sodium lauryl sulfate, polyoxyl stearate, and polyoxyethylene polyoxypropylene glycol. [3] The production method according to [1] or [2], wherein in the step (X), the mass ratio of the component (A) to the component (B) is 0.005 to 0.5. [4] The production method according to any one of [1] to [3], wherein in the step (Y), the volume average particle diameter of the component (B) in the obtained aqueous dispersion is 3 μm to 20 μm. [5] The production method according to any one of [1] to [4], wherein the granulation method in the step (Z) is fluidized bed granulation, stirring granulation, or extrusion granulation. [6] A method for producing tablets, which comprises preparing a composition containing a granulated product obtained by the method according to any one of [1] to [5] and tableting the composition. [Advantages of the Invention]

[0007] According to the method for producing a granulated product of the present invention, a granulated product containing micronized ibuprofen and having suppressed sticking during tableting can be obtained. By using a composition containing such a granulated product, tablets can be stably produced. [Embodiments for Carrying Out the Invention]

[0008] Hereinafter, the present invention will be described in detail. [Method for Producing Granulated Product] The method for producing a granulated product of the present invention has an aqueous dispersion preparation step (X), a pulverization step (Y), and a granulation step (Z).

[0009] [Aqueous Dispersion Preparation Step (X)] The aqueous dispersion preparation step (X) is a step of preparing an aqueous dispersion containing (A) a surfactant and (B) ibuprofen and substantially not containing any one or more selected from (C) sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gum arabic, carboxyvinyl polymer, povidone, and polyvinyl alcohol.

[0010] (A) component: Surfactant By containing the (A) component in the aqueous dispersion, the (B) component can be pulverized in the (Y) step. Further, the water dispersibility of the granulated product obtained by the method for producing a granulated product of the present invention can be improved, and sticking can be suppressed when producing a tablet containing the granulated product. Furthermore, in the tablet obtained by the method for producing a tablet of the present invention, the drug elution property of the (B) component can be improved.

[0011] Examples of the (A) component include sodium lauryl sulfate, polyoxyl stearate, or polyoxyethylene polyoxypropylene glycol. Among them, sodium lauryl sulfate is preferable in terms of being able to cause better wettability with the drug and being able to more effectively suppress sticking when producing a tablet containing the granulated product. These (A) components may be used alone or in combination of two or more.

[0012] The content of the (A) component in the aqueous dispersion is preferably 0.1 to 5% by mass, more preferably 0.3 to 1% by mass, based on the total mass of the aqueous dispersion. If the content of the (A) component is at least the above lower limit, sticking during tableting can be more effectively suppressed, and the elution property of the (B) component can be further improved. On the other hand, if the content of the (A) component is at most the above upper limit, the generation of foam during pulverization of the aqueous dispersion can be more effectively suppressed, and the pulverization efficiency can be further improved.

[0013] (B) component: Ibuprofen (B) Ibuprofen (chemical name: 2-(4-isobutylphenyl)propionic acid) is a poorly water-soluble drug and is widely known as a drug having an antipyretic and analgesic effect. By incorporating the (B) component into the granulated product by co-grinding and refining it with the (A) component according to the method for producing the granulated product of the present invention, sticking can be suppressed in the method for producing tablets of the present invention. The content of the (B) component is preferably 1 to 50% by mass, more preferably 10 to 40% by mass, based on the total mass of the aqueous dispersion. If the content of the (B) component is at least the above lower limit value, the amount of liquid sprayed during the granulation step (Z) described later decreases, and the spraying time can be further shortened. On the other hand, if the content of the (B) component is at most the above upper limit value, the dispersibility is further improved in the method for producing the granulated product of the present invention. Furthermore, sticking is more suppressed in the method for producing tablets of the present invention.

[0014] The mass ratio of (A) / (B) in the aqueous dispersion is preferably 0.005 to 0.5, more preferably 0.01 to 0.1. When the mass ratio of (A) / (B) is at least the above lower limit value, precipitation of the (B) component in the flow path of the high-pressure homogenizer is suppressed, and the grindability can be further improved. On the other hand, when the mass ratio of (A) / (B) is at most the above upper limit value, a granulated product in which sticking during tableting is more suppressed can be obtained in the granulation step (Z), and the disintegrability of the tablets obtained by the production method of the present invention can be further improved.

[0015] In addition to the (A) component and the (B) component, other components (optional components for the aqueous dispersion) may be added to the aqueous dispersion as long as the effects of the present invention are not impaired. Examples of optional components for the aqueous dispersion include excipients, lubricants, binders, disintegrants, and the like. Specifically, examples of excipients include carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose (sometimes referred to as "L-HPC" (registered trademark)), crystalline cellulose (such as "Avicel" (registered trademark)), corn starch, talc, lactose, powdered sugar, mannitol, light anhydrous silicic acid, calcium carbonate, L-cysteine, and the like, as well as combinations of two or more of these. Examples of lubricants include magnesium stearate, calcium stearate, polyethylene glycol, talc, stearic acid, sucrose fatty acid ester, and the like, as well as combinations of two or more of these. Examples of binders include starch, pregelatinized starch, sucrose, gelatin, carmellose, carmellose calcium, pullulan, dextrin, and the like, as well as combinations of two or more of these. Examples of disintegrants include crospovidone, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmellose, carboxymethyl starch sodium, hydroxypropyl starch, partially pregelatinized starch, corn starch, and the like, as well as combinations of two or more of these.

[0016] In step (X), the aqueous dispersion can contain the above-mentioned optional components (optional components for the aqueous dispersion), but the content is preferably small. The above-mentioned optional components other than component (A) and component (B) are 5% by mass or less, preferably 1% by mass or less, and particularly preferably below the detection limit, based on 100% by mass of the total amount of the aqueous dispersion. If the content of the optional component is below the above upper limit value, sticking properties can be reduced in the granulation step (Z) described below.

[0017] In the (X) step, the aqueous dispersion substantially does not contain the component (C) described below. Here, "substantially does not contain" means that the content of the component (C) is 0 to 1 part by mass with respect to 100 parts by mass of the aqueous dispersion, more preferably below the detection limit, and even more preferably not formulated and contained in the aqueous dispersion. By doing so, sticking is more suppressed when producing tablets containing the granulated product.

[0018] (Adjustment of the aqueous dispersion) The method for adjusting the aqueous dispersion is not particularly limited. For example, it can be adjusted by sequentially adding the component (A), the component (B), and, if necessary, optional components to water in a container while stirring so as to have the above-described predetermined content ratio.

[0019] (Grinding step (Y)) The grinding step (Y) is a step of grinding the aqueous dispersion adjusted in the aqueous dispersion preparation step (X) with a high-pressure homogenizer. Thereby, a ground product of (B) ibuprofen is obtained. The high-pressure homogenizer used in the grinding step (Y) is not particularly limited, and it can be carried out using a Starburst (Sugino Machine Co., Ltd.), a Microfluidizer (Parex Co., Ltd.), a pressure-type homogenizer (SPX Flow Technology Japan Co., Ltd.), etc.

[0020] The treatment pressure during grinding with the high-pressure homogenizer is preferably 50 MPa to 160 MPa, more preferably 100 MPa to 160 MPa. When the treatment pressure is within the above pressure range, the treatment speed increases and the production efficiency can be further enhanced. On the other hand, if the treatment pressure is higher than the above pressure range, the temperature rises during grinding and the component (B) melts, so the particle size of the component (B) does not become smaller.

[0021] The volume average particle diameter of the pulverized product of the (B) component obtained by the pulverization step (Y) is preferably 3 to 20 μm, more preferably 3 to 10 μm. When the volume average particle diameter is at least the above lower limit value, sticking during production is further reduced. On the other hand, when the volume average particle diameter is at most the above upper limit value, the elution property is further improved and sticking during tablet production is further reduced. In the present invention, the particle diameter means the volume average particle diameter. The volume average particle diameter can be measured, for example, by a laser diffraction / scattering particle size distribution measuring device (for example, "LS13320 type" manufactured by Beckman Coulter).

[0022] <Granulation step (Z)> The granulation step is a step of adding the (C) component to the co-pulverized product of the (A) component and the (B) component obtained by the pulverization step (Y), dissolving it, and then performing wet granulation to obtain a granulated product.

[0023] (C) component: The (C) component is at least one selected from sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, gum arabic, carboxyvinyl polymer, povidone, and polyvinyl alcohol. From the viewpoint of further reducing sticking during tablet production, it is preferably at least one selected from methylcellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose, and more preferably hydroxypropyl cellulose.

[0024] Specific examples of the wet granulation method include a fluidized bed granulation method, a stirring granulation method, and an extrusion granulation method. Among these, from the viewpoint of productivity, the fluidized bed granulation method capable of performing drying and granulation simultaneously is preferred. The production of the granulated product by the fluidized bed granulation method can be carried out, for example, using a stirring type fluidized granulation device (for example, the Flowcoater of Pauleck Co., Ltd. or the Spiraflow of Front Industry Co., Ltd.) to granulate while spraying the aqueous dispersion after pulverization. The production of the granulated product by the stirring granulation method can be carried out, for example, by using a stirring granulator (for example, the high-speed mixer FS-10 of Earth Technica Co., Ltd.), stirring and kneading while spraying or dropping the pulverized aqueous dispersion, and then granulating using an extrusion granulator (for example, the dome gran DG-LI of Dalton Co., Ltd.). The granulation conditions are not particularly limited, but it is preferably carried out at a temperature lower than the melting point of component (B): 65°C.

[0025] The volume average particle diameter of the granulated product is preferably 50 to 1000 μm, more preferably 100 to 700 μm. When the volume average particle diameter of the granulated product is below the above upper limit value, the mixing uniformity of the composition containing the granulated product described later can be improved. On the other hand, when the volume average particle diameter of the granulated product is above the above lower limit value, the handleability of the composition containing the granulated product can be improved.

[0026] The content of component (A) in the granulated product is preferably 0.2 to 5% by mass, more preferably 0.4 to 1.2% by mass, based on the total mass of the granulated product. When the content of component (A) in the granulated product is above the above lower limit value, the water dispersibility of the granulated product can be further improved, and the elution property of component (B) can be further improved. On the other hand, when the content of component (A) in the granulated product is below the above upper limit value, the disintegration property of the tablet can be further improved.

[0027] The content of component (B) in the granulated product is preferably 10 to 80% by mass, more preferably 30 to 45% by mass, based on the total mass of the granulated product. When the content of component (B) in the granulated product is above the above lower limit value, the tablet will be made smaller. On the other hand, when the content of component (B) in the granulated product is below the above upper limit value, sticking during granulation is more suppressed, and the disintegration property of the tablet obtained by the production method of the present invention can be further improved.

[0028] The content of component (C) in the granulated product is preferably 1 to 20% by mass, more preferably 2 to 10% by mass, based on the total mass of the granulated product. When the content of component (C) in the granulated product is at least the above lower limit value, sticking is more suppressed. On the other hand, when the content of component (C) in the granulated product is at most the above upper limit value, in addition to the viscosity of the binding liquid being lowered and the spraying rate during granulation being able to be increased more, the disintegrability of the tablets obtained by the production method of the present invention can be further improved.

[0029] In addition to components (A), (B), and (C), other components (optional components in the granulated product) may be added to the granulated product as long as the effects of the present invention are not impaired. Examples of the optional components in the granulated product include physiologically active components other than component (A), excipients, disintegrants, lubricants, binders, fragrances, flavoring agents (sweeteners, acidulants, etc.), coloring agents, and the like. Examples of physiologically active ingredients other than component (A) 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; anti-emetic 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; antitussives such as noscapine, tulobuterol, tranilast; expectorants such as bromhexine hydrochloride; antibiotics such as erythromycin, josamycin, chloramphenicol, rifampicin, griseofulvin; antihistamines such as clemastine fumarate; steroid agents such as dexamethasone, betamethasone, prednisolone, danazol, chloramdinone acetate; vitamin agents such as vitamin A derivatives, folic acid (vitamin M derivatives); gastrointestinal disorder therapeutic agents such as famotidine, metoclopramide, omeprazole, trepitide, sucralfate; antacids such as dried aluminum hydroxide, dried aluminum hydroxide gel, magnesium oxide, magnesium carbonate, magnesium aluminometasilicate, aluminum glycinate, aluminum hydroxide, calcium carbonate; and clofibrate, mercaptopurine, methotrexate, dihydroergotamine mesylate may be mentioned. These physiologically active ingredients may be used alone or in combination of two or more. Further, these other physiologically active ingredients may be pharmaceutically acceptable salts (for example, sodium salt, hydrochloride, sulfate, nitrate, etc.). Examples of excipients include carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, crystalline cellulose (such as "Avicel" (registered trademark)), corn starch, talc, monosaccharides (such as xylose), disaccharides or higher polysaccharides (such as sugar (granulated sugar, etc.), lactose, powdered sugar, maltose, sucrose, trehalose, isomerized lactose, and various other oligosaccharides), sugar alcohols (such as palatinite, sorbitol, lactitol, erythritol, xylitol, maltitol, mannitol, etc.), starch syrup, isomerized sugars, reduced starch saccharides (reduced starch degradation products), light anhydrous silicic acid, calcium carbonate, calcium hydrogen phosphate anhydride, potassium dihydrogen phosphate, L-cysteine, sodium chloride, potassium chloride, etc. Examples of disintegrants include carmellose, carmellose calcium, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, etc. Examples of lubricants include magnesium stearate, calcium stearate, polyethylene glycol, talc, stearic acid, sucrose fatty acid ester, etc. Examples of binders include starch, pregelatinized starch, sucrose, gelatin, carmellose, carmellose calcium, pullulan, dextrin, etc. Examples of fragrances include menthol, limonene, essential oils (such as perilla oil, mint oil, lychee oil, orange oil, lemon oil, etc.). Examples of sweeteners include sodium saccharin, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose, etc. Examples of acidulants include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, or their salts, etc. Examples of colorants include inorganic pigments mainly composed of iron such as iron sesquioxide, yellow iron sesquioxide, iron black oxide, zinc oxide, and titanium oxide. The optional component in the granulated product, with the total amount of the granulated product being 100% by mass, is preferably 10 to 88.8% by mass, more preferably 43.8 to 67.6% by mass. When the content of the optional component in the granulated product is at least the above lower limit value, the elution property of component (B) is further improved when tableted. Also, if it is at most the above upper limit value, the tablet will be smaller. The optional component in the granulated product may be added after the dissolution of component (C), or may be added simultaneously with component (C), but from the viewpoint of being able to sufficiently dissolve component (C), it is preferably added after the dissolution of component (C). Further, an aqueous dispersion obtained by adding and dissolving component (C) can also be sprayed or dropped onto the optional component in the granulated product, and dried to obtain the granulated product. From the viewpoint of being able to shorten the granulation time and improve productivity, the latter addition and granulation method is more preferable.

[0030] <Adjustment of the composition containing the granulated product (mixing step)> The composition containing the granulated product can contain the granulated product containing components (A), (B), and (C) obtained by the above-described method for producing the granulated product, and an optional component for tablets. The optional component for tablets is not particularly limited, and usually, components that are formulated in tablets can be contained. Examples of the optional component for tablets include the components described as the optional component in the above-described granulated product, etc. The optional component for tablets may be used alone, or two or more kinds may be used in combination. Also, a commercially available premix product may be used. The content of the optional component for tablets is not particularly limited, but is preferably 0 to 80% by mass, more preferably 15 to 50% by mass, based on the total mass of the tablets.

[0031] (Mixing method) For mixing, general mixers such as a Borre container mixer, V-type mixer, ribbon mixer, etc. can be used. The mixing order is not particularly limited. For example, all components can be charged into the mixer and mixed, or each component can be sequentially charged into the mixer and mixed. The mixing time is not particularly limited, and is set to a time when each component can be dispersed approximately uniformly.

[0032] <Tabletting process> The tabletting process is a process of tabletting a composition containing granulated material. For tabletting, a commonly used tabletting machine can be used. Examples of tabletting machines include rotary tabletting machines such as Libra (Kikusui Seisakusho Co., Ltd.) and L-41 type (Hata Iron Works Co., Ltd.). In the tabletting process, when using a rotary tabletting machine, the number of revolutions of the turntable is preferably 10 to 90 rpm, more preferably 20 to 60 rpm. The tabletting pressure is preferably set so that the tablet hardness is 5.0 kgf to 10.0 kgf. As the shape of the punch, the tabletting surface is preferably smooth or a curved surface (R tablet), more preferably a curved surface (R tablet). In the case of an R tablet, it may be a single R tablet or a two-stage R tablet. The tablet diameter is preferably 7 mm to 12 mm, more preferably 8.5 to 10 mm. In the case of a single R tablet, the radius of curvature 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 on the edge side is preferably 2 to 6 mm, more preferably 3 to 4 mm. The radius of curvature r2 of the top and bottom surfaces is preferably 8 to 13 mm, more preferably 9 to 11 mm. By setting the tablet within the above-mentioned preferred range, sticking can be reduced.

[0033] The content of component (A) in the tablet is preferably 0.1 to 3.5% by mass, more preferably 0.3 to 0.7% by mass, based on the total mass of the tablet. When the content of component (A) in the tablet is at least the above lower limit value, sticking during tabletting is more suppressed, and the elution property of component (B) can be further improved. On the other hand, when the content of component (A) in the tablet is at most the above upper limit value, sticking during tabletting is more suppressed, and the disintegration property of the tablet can be further improved.

[0034] The content of component (B) in the tablet is preferably 5 to 60% by mass, more preferably 20 to 40% by mass, based on the total mass of the tablet. When the content of component (B) in the tablet is at least the above lower limit value, the tablet can be made smaller. On the other hand, when the content of component (B) in the tablet is at most the above upper limit value, sticking can be further reduced.

[0035] The content of component (C) in the tablet is 0.5 to 15% by mass, more preferably 2 to 6% by mass, based on the total mass of the tablet. When the content of component (C) in the tablet is at least the above lower limit value, sticking can be further suppressed. On the other hand, when the content of component (C) in the tablet is at most the above upper limit value, sticking is further suppressed and the disintegration property of the obtained tablet can be further improved.

[0036] <Coating step> After the tableting step, a step of providing a film containing a coating agent on the surface of the obtained uncoated tablet (coating step) may be performed. Thereby, a coated tablet can be obtained. The coating step can be carried out using a general coating apparatus. As the coating agent, it is preferable to select and use one that does not impair the disintegration property of the tablet. Among them, water-soluble polymer compounds and saccharides are preferable. As the water-soluble polymer compound, for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, gum arabic, carboxyvinyl polymer, povidone, polyethylene glycol, polyvinyl alcohol, etc. can be used. Examples of saccharides include monosaccharides, polysaccharides of disaccharides or more (sugar (granulated sugar, etc.), lactose, maltose, xylose, isomerized lactose, etc.), sugar alcohols (palatinit, 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 premix products such as "Opadry" (manufactured by Nippon Colorcon Co., Ltd.) may be used. The amount of the coating agent used is preferably 0.1 to 5% by mass based on 100% by mass of the total amount of the core tablets.

[0037] <Effect> According to the method for producing the granulated product of the present invention, in the pulverization step of ibuprofen, a water dispersion containing ibuprofen and a surfactant and substantially not containing a specific water-soluble polymer ((C) component) is prepared and pulverized, whereby sticking during tableting can be suppressed. According to the production method of the present invention, since the drug has good disintegrability and elution property, the size of the tablet per tablet can be reduced, and the burden during administration can be reduced.

Example

[0038] Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to the following description. The raw materials, measurement and evaluation methods used in each example and comparative example are as follows. The following descriptions of "JP-compliant product" and "product compliant with the specifications of pharmaceuticals outside the Japanese Pharmacopoeia" mean that the raw materials are compliant with the specifications of the 18th revised Japanese Pharmacopoeia and the specifications of pharmaceuticals outside the Japanese Pharmacopoeia (2002), respectively.

[0039] [Raw materials used] As the (A) component, the following compounds were used. · Sodium lauryl sulfate: "SLS-P" (manufactured by Nikko Chemicals Co., Ltd.), JP-compliant product · Polyoxyethylene (105) polyoxypropylene (5) glycol: "Kolliphor P188" (manufactured by BASF) · Polyoxyl 40 stearate "MYS-40MV" (manufactured by Nikko Chemicals Co., Ltd.), JP-compliant product

[0040] As the (B) component, the following compounds were used. · Ibuprofen: "Ibuprofen 25" (manufactured by BASF), JP-compliant product.

[0041] As the (C) component, the following compounds were used. · Hydroxypropyl cellulose: "HPC-SSL" (manufactured by Nippon Soda Co., Ltd.), conforming to Japanese Pharmacopoeia · Methyl cellulose: "SM-4" (manufactured by Shin-Etsu Chemical Co., Ltd.), conforming to Japanese Pharmacopoeia · Hydroxypropyl methyl cellulose: "TC-5" (manufactured by Shin-Etsu Chemical Co., Ltd.), conforming to Japanese Pharmacopoeia

[0042] As optional components, the following compounds were used. · Acetaminophen: "Acetaminophen (powder)" (manufactured by Spherix), conforming to Japanese Pharmacopoeia · L-HPC: Low-substituted hydroxypropyl cellulose, "LH-31" (manufactured by Shin-Etsu Chemical Co., Ltd.), conforming to Japanese Pharmacopoeia · Calcium hydrogen phosphate anhydrous: "GSH" (manufactured by Kyowa Chemical Industry Co., Ltd.), conforming to Japanese Pharmacopoeia · Caffeine anhydrous: "Caffeine anhydrous" (manufactured by Shiratori Pharmaceutical Co., Ltd.), conforming to Japanese Pharmacopoeia · Dried aluminum hydroxide gel: "S-100" (manufactured by Kyowa Chemical Industry Co., Ltd.), conforming to Japanese Pharmacopoeia · Potassium dihydrogen phosphate: "Japanese Pharmacopoeia External Pharmaceutical Standard Potassium Dihydrogen Phosphate" (manufactured by Taihei Chemical Industry Co., Ltd.), conforming to Japanese Pharmacopoeia External Pharmaceutical Standard · Crystalline cellulose: "Ceolus PH-302" (manufactured by Asahi Kasei Corporation), conforming to Japanese Pharmacopoeia · Magnesium stearate: "Magnesium stearate (light), vegetable" (manufactured by Taihei Chemical Industry Co., Ltd.), conforming to Japanese Pharmacopoeia

[0043] <Evaluation of sticking during tableting> Using a rotary tableting machine (Ribra 2, manufactured by Kikusui Seisakusho Co., Ltd.), the evaluation of sticking during tableting was carried out. At a turret rotation speed of 30 rpm of the rotary tableting machine, the sticking to the punch after 10 minutes, 20 minutes, and 30 minutes of tableting was visually confirmed and evaluated according to the following criteria. If sticking occurs 10 minutes after the start of tableting, it can be said that the occurrence of sticking is not suppressed. If sticking occurs 20 minutes after the start of tableting, it can be said that the occurrence of sticking is suppressed. If sticking occurs 30 minutes after the start of tableting, it can be said that the suppression of the occurrence of sticking is good. Even if 30 minutes have passed since the start of tableting and sticking has not occurred, it can be said that the occurrence of sticking is significantly suppressed. According to the evaluation criteria, it is shown as follows in Tables 1 to 3. Sticking occurs after 10 minutes... × Sticking occurs after 20 minutes... △ Sticking occurs after 30 minutes... 〇 There is no sticking after 30 minutes... ◎

[0044] (Examples 1 to 13, Comparative Examples 1 to 5)

[0045] Grinding: (X) process, (Y) process Water was put into a container with a stirrer and stirring was started so as to obtain the composition ratios shown in Tables 1 to 3. The (A) component of each example and comparative example was dissolved therein (except for Comparative Examples 1 and 2), and further the (B) component was added, and the aqueous dispersion was adjusted to a total of 5 kg. In Comparative Example 1, the (C) component was dissolved instead of the (A) component, and in Comparative Example 4, both the (A) and (C) components were dissolved. This aqueous dispersion was ground with a high-pressure homogenizer (Starburst LABO, manufactured by Sugino Machine Ltd.) under the conditions and for the number of times shown in the table. In Comparative Example 5, it was ground with a bead mill (UAM1, manufactured by Kotobuki Kogyo Co., Ltd., treatment time: 120 minutes) instead of a high-pressure homogenizer. In Comparative Example 2, since the (A) component could not be dispersed in water, it could not be ground even when treated under the conditions and rotation speed shown in the table, so the subsequent steps were not carried out.

[0046] Granulation: (Z) process Component (C) was added to the aqueous dispersion (ground product) so as to obtain the composition ratios shown in Tables 1 to 3, and the mixture was stirred for 1 hour to dissolve it. (In Comparative Example 1, component (A) was added instead of component (C). In Comparative Examples 3 and 4, component (C) was not added.). Then, the components to be added during granulation (acetaminophen, L-HPC, calcium hydrogen phosphate anhydrous) were mixed to a total of 1.5 kg so as to obtain the composition ratios shown in Tables 1 to 3, and the mixture was put into a fluidized bed granulator (manufactured by Freund Industry Co., Ltd., "Flow Coater FLO-5"), and then the above-mentioned mixed solution was sprayed, 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 completion of spraying, drying was carried out until the exhaust temperature reached 43°C. The particle diameter of the granulated product was 150 μm to 200 μm.

[0047] Tabletting: The above granulated product and the components to be added during tabletting (caffeine anhydrous, dried aluminum hydroxide gel, potassium dihydrogen phosphate, crystalline cellulose, magnesium stearate) were put into a plastic bag and mixed by hand so as to obtain the composition ratios shown in Tables 1 to 3, and tabletting was carried out at a turret rotation speed of 30 rpm using a rotary tableting machine (Ribra 2, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets. The tabletting pressure was adjusted so that the average tablet hardness of 10 sampled tablets was 6.0 to 8.0 kgf. The diameter of the die was φ9.0 mm. As the punch, a two-stage R punch for tablets (r1 = 3.6 mm, r2 = 10.5 mm) was used. During tabletting, an evaluation test was conducted on the presence or absence of sticking and the time of occurrence. The results of the evaluation test are shown in Tables 1 to 3.

[0048]

Table 1

[0049]

Table 2

[0050]

Table 3

[0051] From the results in Tables 1 and 2, the compositions containing the granulated products obtained in each example had suppressed sticking during tableting. On the other hand, from the results in Table 3, the compositions containing the granulated products obtained in each comparative example were inferior in suppressing sticking during tableting. From Comparative Example 1, when the (A) surfactant was added after pulverization instead of before pulverization and (C) hydroxypropyl cellulose was added before pulverization, sticking was not suppressed. Also, from Comparative Example 4, when the (A) surfactant and (C) hydroxypropyl cellulose were simultaneously added before pulverization, sticking was not suppressed. From Comparative Example 3, when (C) hydroxypropyl cellulose was not blended, sticking was not suppressed.

Claims

1. an aqueous dispersion preparation step (X) comprising the following component (A) and the following component (B), and substantially not including the following component (C); a grinding step (Y) of grinding the aqueous dispersion obtained in the step (X) using a high-pressure homogenizer; and a granulation step (Z) of adding the following component (C) to the pulverized product obtained by the step (Y) and granulating the mixture. A method for producing a granulated product comprising the following components (A) to (C): (A) Surfactant (B) Ibuprofen (C) One or more selected from sodium carmellose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, gum arabic, carboxyvinyl polymer, povidone, and polyvinyl alcohol.

2. 2. The method according to claim 1, wherein the component (A) is at least one selected from the group consisting of sodium lauryl sulfate, polyoxyl stearate, and polyoxyethylene polyoxypropylene glycol.

3. The method according to claim 1 or 2, wherein in step (X), a mass ratio of component (A) to component (B) is 0.005 to 0.

5.

4. The method according to claim 1 or 2, wherein in step (Y), the volume average particle size of the component (B) in the resulting aqueous dispersion is 3 μm to 20 μm.

5. The method according to claim 1 or 2, wherein the granulation method in step (Z) is fluidized bed granulation, stirring granulation, or extrusion granulation.

6. A method for producing tablets, comprising preparing a composition containing a granulated product obtained by the method according to claim 1 or 2, and compressing the composition into tablets.

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