Acetaminophen-containing solid dosage form

Abstract

To provide a novel oral solid preparation that basically comprises only acetaminophen as the active ingredient, the oral solid preparation capable of reducing bitterness of acetaminophen by simple operation and also being relatively compact in a size.SOLUTION: One example of the present invention can be an oral solid preparation that comprises a dry mixture comprising granules comprising acetaminophen and a calcium salt (excluding calcium lactate) and / or a sodium salt.SELECTED DRAWING: None

Description

【Technical Field】 【0001】 The present invention belongs to the technical field of pharmaceutical preparations containing organic active ingredients. The present invention relates to a pharmaceutical solid preparation containing acetaminophen as an active ingredient, and to the solid preparation in which the bitterness of acetaminophen is suppressed. 【Background Art】 【0002】 Acetaminophen is one of the well-known excellent antipyretic and analgesic drugs. Generally, it is provided in the form of oral solid preparations, particularly tablets. As a commercially available product provided as a tablet, for example, Tylenol (registered trademark) is known. Since acetaminophen has bitterness, in the case of preparations that disintegrate in the mouth and are taken, such as orally disintegrating tablets and chewable tablets, which have recently attracted attention as dosage forms that improve the patient's quality of life (QOL), there is room for consideration from the viewpoint of taking compliance. 【0003】 Examples of methods for suppressing the bitterness of drugs, that is, bitterness masking methods, include, for example, adding a sweetening agent or flavoring agent to offset its sweetness, a matrix method in which a solution in which a gastric-soluble polymer, a water-insoluble polymer, or wax is suspended or dissolved is sprayed onto the drug and dried to disperse the drug in the polymer carrier, or a coating method in which drug particles are coated with a polymer coating agent. 【0004】 Patent Document 1 discloses an invention for reducing the bitterness of acetaminophen by combining it with aspartame and a substance that exhibits a sour taste. Patent Document 2 discloses an invention for reducing the bitterness of a drug by combining it with magnesium aluminum silicate. Patent Document 3 discloses an invention for reducing the bitterness of a drug by coating drug particles such as acetaminophen with a certain water-insoluble polymer. Patent Document 4 discloses an invention for reducing the bitterness of a drug by simultaneously spray-drying a drug with organic calcium acid, porous inorganic material, etc. Patent Document 5 discloses an invention for reducing the bitterness of acetaminophen by combining granulated particles containing sugar alcohol and starch with acetaminophen-containing coated particles. Patent Document 6 discloses an invention for reducing the bitterness of acetaminophen by combining it with amino acids such as glutamic acid and sucralose. Patent Document 7 discloses an invention for reducing the bitterness of a drug by wet granulation of the drug with low-substituted hydroxypropyl cellulose. Patent Document 8 discloses an invention for reducing the bitterness of acetaminophen and other drugs by shielding them with ethylcellulose and synthetic hydrotalcite. Patent Document 9 discloses an invention for reducing the bitterness of a drug by incorporating calcium lactate into the drug. [Prior art documents] [Patent Documents] 【0005】 [Patent Document 1] Japanese Patent Publication No. 2001-294524 [Patent Document 2] Japanese Patent Publication No. 2008-260717 [Patent Document 3] Japanese Patent Publication No. 2011-093882 [Patent Document 4] Japanese Patent Publication No. 2012-056909 [Patent Document 5] Japanese Patent Publication No. 2013-136537 [Patent Document 6] Japanese Patent Publication No. 2014-133728 [Patent Document 7] Patent No. 4210615 [Patent Document 8] Patent No. 4716063 [Patent Document 9] Patent No. 5097488 [Overview of the Initiative] [Problems that the invention aims to solve] 【0006】 As mentioned above, various techniques have been proposed to reduce the bitterness of bitter-tasting drugs such as acetaminophen. However, each has its advantages and disadvantages, and none of them are sufficient to reduce the bitterness of acetaminophen with simple operation while simultaneously miniaturizing tablets. The present invention primarily aims to provide a novel oral solid dosage form that basically contains only acetaminophen as an active ingredient, can reduce the bitterness of acetaminophen through simple handling, and is also relatively small in size. [Means for solving the problem] 【0007】 As a result of diligent research, the inventors of the present invention have found that the above problems can be solved by forming a solid formulation from a dry mixture containing granules containing acetaminophen and a relatively small amount of calcium salt or sodium salt, and have completed the present invention. 【0008】 Examples of the present invention include the following: 【0009】 [1] An oral solid preparation comprising granules containing acetaminophen and a dry mixture containing calcium salts (excluding calcium lactate) and / or sodium salts. [2] The oral solid preparation according to [1] above, comprising a binder, a bulking agent, a sweetener, and / or a fluidizing agent in granules containing acetaminophen. [3] The oral solid preparation according to [1] or [2] above, further comprising an excipient, a disintegrant, a lubricant, a sweetener and / or a flavoring agent in the dry mixture. [4] An oral solid preparation according to any one of the above [1] to [3], wherein the calcium salt is an organic acid calcium and the sodium salt is an organic acid sodium. [5] The oral solid preparation according to [4] above, wherein the calcium organic acid is calcium gluconate or calcium citrate, and the sodium organic acid is sodium tartrate, sodium fumarate, or sodium benzoate. [6] An oral solid preparation according to any one of the above [2] to [5], wherein the sweetener is saccharin sodium, sucralose, aspartame, or acesulfame potassium. [7] An oral solid preparation according to any one of the above items [1] to [6], wherein the average particle size of the granules containing acetaminophen is in the range of 1 to 200 μm. [8] An oral solid preparation according to any one of the above items [1] to [7], wherein the dosage form is a tablet or an orally disintegrating tablet. [9] An oral solid dosage form as described in [8] above, having a weight in the range of 30 to 700 mg. 【0010】

[10] A method for producing an oral solid dosage form, comprising the following steps 1 to 3: 1. A step of granulating acetaminophen to prepare a granule containing acetaminophen, 2. A step of preparing a dry mixture by dry mixing the granules containing acetaminophen, calcium salts (excluding calcium lactate) and / or sodium salts, and additives. 3. A process of forming the dry mixture into an oral solid dosage form.

[11] A method for producing an oral solid dosage form according to

[10] above, comprising a binder, a bulking agent, a sweetener, and / or a fluidizing agent in granules containing acetaminophen.

[12] A method for producing an oral solid dosage form according to

[10] or

[11] above, wherein the additive is an excipient, a disintegrant, a lubricant, a sweetener and / or a flavoring agent.

[13] The method for producing an oral solid preparation according to any one of

[10] to

[12] above, wherein the calcium salt is calcium organic acid and the sodium salt is sodium organic acid.

[14] The method for producing an oral solid preparation according to

[13] above, wherein the calcium organic acid is calcium gluconate or calcium citrate, and the sodium organic acid is sodium tartrate, sodium fumarate, or sodium benzoate.

[15] The method for producing an oral solid preparation according to any one of

[11] to

[14] above, wherein the sweetening agent is sodium saccharin, sucralose, aspartame, or acesulfame potassium.

[16] The method for producing an oral solid preparation according to any one of

[10] to

[15] above, wherein the average particle diameter of the granulated product containing acetaminophen is in the range of 1 to 200 μm.

[17] The method for producing an oral solid preparation according to any one of

[10] to

[16] above, wherein the shaping is tableting, and the oral solid preparation is a tablet or an orally disintegrating tablet.

[18] The method for producing an oral solid preparation according to

[17] above, wherein the weight of the tablet or the orally disintegrating tablet is in the range of 30 to 700 mg. 【Advantages of the Invention】 【0011】 According to the present invention, it is possible to obtain a relatively small tablet in which the bitterness of acetaminophen is reduced by a simple operation. 【Modes for Carrying Out the Invention】 【0012】 Hereinafter, the present invention will be described in detail. 1 Oral Solid Preparation According to the Present Invention The oral solid preparation according to the present invention (hereinafter referred to as "the preparation of the present invention") is characterized by comprising a granulated product containing acetaminophen and a dry mixture containing a calcium salt (excluding calcium lactate) and / or a sodium salt. The acetaminophen content in the formulation of the present invention is not particularly limited, but is suitable in the range of 70 to 85% by mass per unit formulation, preferably in the range of 75 to 82% by mass, and particularly preferably 80% by mass. 【0013】 1.1 Granules containing acetaminophen The granules containing acetaminophen may contain an appropriate amount of binder. Such binders are not particularly limited as long as they can be used as binders from a pharmaceutical technology standpoint, but specific examples include hydroxypropyl cellulose, hypromellose (hydroxypropyl methylcellulose, HPMC), microcrystalline cellulose, dextrin, gelatin, pregelatinized starch, acacia gum, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and polyacrylates. Among these, those with high water solubility are preferred, and specifically, polyvinyl alcohol and its partially saponified products are preferred. 【0014】 The above-mentioned binders can be used individually or in combination of any two or more. The amount of the binder used varies depending on the binder used, but a range of 0.5 to 5 parts by mass is appropriate, preferably 0.7 to 3 parts by mass, and more preferably 1 to 2 parts by mass per 100 parts by mass of acetaminophen. 【0015】 The granules containing acetaminophen may, in addition to the binder mentioned above, contain appropriate amounts of bulking agents, sweeteners, and / or fluidizing agents as needed. Examples of fillers that can be used in the preparation of the granules include lactose (lactose monohydrate), starch (e.g., corn starch, potato starch, rice starch, wheat starch), crystalline cellulose, mannitol (D-isomer, α-type, β-type, δ-type), dextrin, sorbitol, erythritol, calcium hydrogen phosphate, sucrose, talc (naturally occurring magnesium silicate), kaolin, and precipitated calcium carbonate. Among these, lactose (lactose monohydrate), crystalline cellulose, and D-mannitol are preferred. 【0016】 The above-mentioned bulking agents can be used individually or in combination of any two or more. The amount of bulking agent to be used will vary depending on the bulking agent used, but a range of 0 to 5 parts by mass per 100 parts by mass of acetaminophen is appropriate, and it may also be in the range of 0.1 to 3 parts by mass or 0.5 to 2 parts by mass. 【0017】 Examples of sweeteners that can be used in the preparation of the granules include aspartame, stevia, sodium saccharin (including hydrate), dipotassium glycyrrhizinate, thaumatin, sucralose, and acesulfame potassium. Of these, sodium saccharin and sucralose are preferred. 【0018】 The above sweeteners can be used individually or in combination of any two or more. The amount of sweetener used will vary depending on the sweetener used, but a range of 0 to 5 parts by mass per 100 parts by mass of acetaminophen is appropriate, and it may also be in the range of 0.1 to 3 parts by mass or 0.5 to 2 parts by mass. 【0019】 The fluidizing agent that can be used in the preparation of the granules is not particularly limited as long as it can be used as a fluidizing agent from a pharmaceutical technology standpoint. Specifically, examples of such fluidizing agents include light anhydrous silicic acid, hydrated silicon dioxide, talc, synthetic aluminum silicate, titanium dioxide, heavy anhydrous silicic acid, magnesium aluminum hydroxide, tricalcium phosphate, magnesium aluminometasilicate, and calcium silicate. Among these, light anhydrous silicic acid and hydrated silicon dioxide are preferred. 【0020】 Among the fluidizing agents, those with a specific surface area of ​​10 to 500 m² 2 Preferably, it is within the range of / g. More preferably, the specific surface area is 100 to 450 m². 2 It is within the range of / g, and particularly preferably has a specific surface area of ​​200 to 400 m². 2It is within the range of / g. The specific surface area may be specified by the supplier of the fluidizing agent, or it can be measured by, for example, the so-called gas adsorption method using nitrogen gas. 【0021】 The above-mentioned fluidizing agent can be used in combination of one or any two or more types. The amount of fluidizing agent to be used varies depending on the amount of fluidizing agent and acetaminophen used, but a range of 0.1 to 3 parts by mass is appropriate, preferably 0.3 to 2 parts by mass, and more preferably 0.5 to 1 part by mass per 100 parts by mass of acetaminophen. 【0022】 The granules containing acetaminophen that constitute the formulation of the present invention may be coated with the above-mentioned fluidizing agent within the range of the above-mentioned amount used. When the formulation of the present invention is in tablet form, it is generally manufactured by tableting, but by coating the granules with a fluidizing agent, tableting problems that may occur during tableting can be suppressed. Therefore, methods that may lead to larger tablets, such as making the particles of the granules coarser, coating them with polymers, or increasing the amount of additives, become unnecessary, thus contributing to the miniaturization of the formulation (tablet) of the present invention. 【0023】 The size (particle diameter) of the granules containing acetaminophen is not particularly limited, but an average particle diameter within the range of 1 to 200 μm is appropriate, preferably within the range of 5 to 130 μm, and more preferably within the range of 10 to 120 μm. A particle diameter of 100 μm or less is particularly preferred. If the particle diameter is greater than 200 μm, the hardness may not be maintained. Here, "average particle diameter" refers to the volume-average particle diameter, which is the particle diameter at which the cumulative distribution from smallest to largest accounts for 50% when measured by laser diffraction scattering (D 50 This refers to the median diameter. 【0024】 1.2 Calcium salts and sodium salts The formulation of the present invention includes, as one of the additives dry-mixed with granules containing acetaminophen, a calcium salt (excluding calcium lactate) and / or a sodium salt. The calcium and sodium salts are not particularly limited as long as they can be used as additives from a pharmaceutical technology standpoint. They may be calcium or sodium salts of inorganic acids or calcium or sodium salts of organic acids. 【0025】 Specific examples of calcium salts that can be used in the present invention include calcium carbonate, calcium chloride, calcium hydroxide, calcium dihydrogen phosphate, calcium gluconate, calcium glycerophosphate, calcium citrate, calcium acetate, calcium benzoate, calcium formate, calcium fumarate, calcium butyrate, calcium isobutyrate, calcium malate, and calcium propionate. Among these, organic calcium acids are preferred, and calcium gluconate is more preferred. Specific examples of sodium salts that can be used in the present invention include sodium chloride, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate, sodium citrate, sodium benzoate, sodium tartrate, and sodium fumarate. Among these, organic sodium acids are preferred, and sodium tartrate is more preferred. 【0026】 The calcium salt and sodium salt described above can be used individually or in combination of any two or more. The amount of calcium salt and sodium salt used will vary depending on the specific calcium salt and sodium salt used, but a range of 0.1% to 8% by mass relative to acetaminophen is appropriate, with 0.5% to less than 5% by mass being preferred, and 0.7% to less than 3% by mass being more preferred. 【0027】 1.3 Additives In addition to the calcium salt and sodium salt mentioned above, the formulation of the present invention may include, as additives dry-mixed with granules containing acetaminophen, pharmaceutically acceptable substances such as excipients, disintegrants, lubricants, flavoring agents, colorants, acidulants, and sweeteners. 【0028】 Examples of such excipients include lactose (lactose monohydrate), starch (e.g., corn starch, potato starch, rice starch, wheat starch), crystalline cellulose, mannitol (D-isomer, α-type, β-type, δ-type), dextrin, sorbitol, erythritol, calcium hydrogen phosphate, sucrose, talc (naturally occurring magnesium silicate), kaolin, and precipitated calcium carbonate. Among these, lactose (lactose monohydrate), crystalline cellulose, and D-mannitol are preferred. The above excipients may be used individually or in combination of any two or more. The content of the excipients varies depending on the amount of excipients, other additives, and acetaminophen used, but is suitable in the range of 1 to 40% by mass per unit formulation, preferably in the range of 5 to 30% by mass, and more preferably in the range of 7 to 20% by mass. 【0029】 Examples of such disintegrants include croscarmellose sodium, crospovidone, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, low-substituted hydroxypropylcellulose, and starch glycolate sodium. Among these, crospovidone is preferred. 【0030】 The above-mentioned disintegrants may be used individually or in combination of two or more. The content of the disintegrants varies depending on the amount of disintegrants, other additives, and acetaminophen used, but a range of 1 to 25% by mass per unit formulation is appropriate, preferably 2 to 15% by mass, and more preferably 3 to 10% by mass. 【0031】 Examples of the lubricant include magnesium stearate, calcium stearate, talc, stearic acid, sodium stearyl fumarate, sucrose fatty acid ester, and paraffin. Of these, magnesium stearate is preferred. 【0032】 The above lubricants can be used individually or in combination of any two or more. The amount of lubricant used varies depending on the amount of lubricant, other additives, and acetaminophen, but a range of 0.1 to 10% by mass per unit formulation is appropriate, preferably 0.5 to 5% by mass, and more preferably 0.7 to 2% by mass. 【0033】 Examples of the flavoring agent include l-menthol, peppermint oil, eucalyptus oil, cinnamon oil, fennel oil, clove oil, orange oil, lemon oil, and rose oil. Of these, l-menthol is preferred. 【0034】 The above-mentioned flavoring agents can be used individually or in combination of any two or more. The amount of flavoring agent used will vary depending on the flavoring agent, other additives, and the amount of acetaminophen used, but a range of 0.01 to 1% by mass per unit formulation is appropriate, preferably 0.02 to 0.5% by mass, and more preferably 0.03 to 0.2% by mass. 【0035】 Examples of such coloring agents include tar dyes, iron oxide, iron red, iron yellow, titanium dioxide, inorganic dyes, Red No. 3, Red No. 20, Yellow No. 6, Blue No. 2, Green No. 5, Orange No. 5, Red No. 8, and caramel, which can be used in pharmaceuticals, etc., as specified by Ministry of Health, Labour and Welfare ordinances. 【0036】 Examples of such acidulants include citric acid, tartaric acid, malic acid, ascorbic acid, fumaric acid, succinic acid, gluconic acid, and lactic acid. The above-mentioned acidulants may be used individually or in combination of any two or more. An appropriate amount of these acidulants may be included. 【0037】 Examples of sweeteners include aspartame, stevia, sodium saccharin (including hydrate), dipotassium glycyrrhizinate, thaumatin, sucralose, and acesulfame potassium. Of these, sodium saccharin and sucralose are preferred. 【0038】 The above sweeteners can be used individually or in combination of any two or more. The amount of sweetener used will vary depending on the amount of sweetener, other additives, and acetaminophen used, but a range of 0.1 to 5 parts by mass per unit formulation is appropriate, preferably 0.2 to 3 parts by mass, and more preferably 0.5 to 2 parts by mass. 【0039】 1.4 Others Examples of the unit form of the formulation of the present invention include tablets, granules, fine granules, and powders. Among these, tablets are preferred. Examples of such tablets include ordinary tablets, multilayer tablets, orally disintegrating tablets, dispersible tablets, sublingual tablets, lozenges, and chewable tablets. When the formulation of the present invention is an orally disintegrating tablet, it can disintegrate in the oral cavity of a healthy person within about 1 minute, preferably within 30 seconds. 【0040】 When the formulation of the present invention is in tablet form, its planar shape is not particularly limited, such as round, oval, polygonal, or rhombus. Similarly, there are no particular restrictions on thickness, tablet diameter, or corner radius (R, flat). However, its weight is typically within the range of 30 to 700 mg, preferably within the range of 180 to 650 mg. Its hardness is not particularly limited as long as it can withstand distribution and storage, but for example, a range of 30 to 200 N is appropriate, and 35 to 150 N is preferred. 【0041】 2. Method for producing the formulation of the present invention The formulation of the present invention can be manufactured by conventional methods, depending on the dosage form used. For example, the formulation of the present invention can be manufactured by a method comprising the following steps 1 to 3. Hereinafter, this manufacturing method will be referred to as the manufacturing method of the present invention. In the manufacturing method of the present invention, terms including components, the amount of each component used, and the content of each component are the same as described above. 【0042】 1. A step of granulating acetaminophen to prepare a granule containing acetaminophen, 2. A step of preparing a dry mixture by dry mixing the granules containing acetaminophen, calcium salts (excluding calcium lactate) and / or sodium salts, and additives. 3. A process of forming the dry mixture into an oral solid dosage form. 【0043】 The preparation of granules containing acetaminophen in step 1 can be carried out by conventional methods. Examples of granulation methods include wet granulation and dry granulation, and either method may be used. In the case of wet granulation, a solution containing acetaminophen can be prepared by dropping or spraying a solution containing water or a suitable pharmaceutically acceptable binder (as defined above), and optionally a suitable bulking agent, sweetener, and / or fluidizing agent (each as defined above), onto acetaminophen powder to wet it, and then drying and removing the moisture. Examples of wet granulation methods include agitation granulation, fluidized bed granulation, tumbling fluidized bed granulation, tumbling bed granulation, centrifugal tumbling granulation, spray drying granulation, and kneading granulation. 【0044】 Furthermore, in step 1, the granules containing acetaminophen can be coated with a fluidizing agent. Specifically, for example, when using a fluidized bed granulation method, the granules can be coated with a fluidizing agent by spraying a coating agent, which is a mixture of water, a fluidizing agent, and optionally the aforementioned sweetener, into the fluidized bed granulator to wet them, and then drying and removing the moisture. When the formulation of the present invention is in the form of tablets, they are generally compressed into tablets in the later step 3, but by coating the granules with a fluidizing agent, it is possible to suppress tableting problems that may occur during the tableting process. Therefore, it becomes unnecessary to use methods that could lead to larger tablets, such as making the particles of the granules coarser, coating them with polymers, or increasing the amount of additives, and thus it is possible to manufacture smaller forms of the formulation of the present invention (tablets). 【0045】 In step 1, the granules containing acetaminophen are mixed in step 2 by a conventional dry method with a predetermined amount of calcium salt and / or sodium salt, as well as appropriate additives, to prepare a dry mixture. This dry mixture is then molded by a conventional method according to the desired oral solid dosage form to produce the formulation of the present invention. 【0046】 If the formulation of the present invention is a tablet, such a tablet can be manufactured by preparing a dry mixture by conventionally mixing a predetermined amount of calcium salt and / or sodium salt, as well as additives such as excipients and disintegrants, with granules containing acetaminophen prepared in step 1 according to the manufacturing method of the present invention, and then compressing (compressing) the dry mixture using a suitable tablet press. 【0047】 In the manufacturing method of the present invention, further steps such as granulation, mixing, drying, and coating may be included as needed. These steps can be carried out by conventional methods. [Examples] 【0048】 The present invention will be described below with reference to examples, comparative examples, and test examples, but the present invention is not limited in any way by these examples. 【0049】 [Example 1] According to the formulation shown in Table 1, acetaminophen was granulated using a fluidized bed granulation method with polyvinyl alcohol, D-mannitol, sodium saccharin hydrate, and light anhydrous silicic acid. The average particle size of the granules was 87 μm. The acetaminophen granules and the powders of the other components were mixed according to the formulation shown in Table 1, and the mixture was compressed into tablets using a rotary tablet press (HT-EX6SS-U, manufactured by Hata Iron Works Co., Ltd.) to produce the desired tablets. The tablets had a diameter of 9 mm, a height of 3.6 mm, a hardness of approximately 92 N, and an in-oral disintegration time of less than 30 seconds. 【0050】 [Table 1] 【0051】 [Comparative Example 1] Tablets identical to those in Example 1 were manufactured in the same manner as in Example 1, except that they did not contain calcium gluconate, according to the formulation shown in Table 1. These tablets had a diameter of 9 mm, a height of 3.6 mm, a hardness of approximately 82 N, and an in-oral disintegration time of less than 30 seconds. 【0052】 [Test Example 1] Evaluation of bitterness suppression effect A sensory evaluation was conducted by three testers. The tablets were disintegrated in the mouth (for approximately 30 seconds), spat out, and the bitterness perceived during the first half of disintegration (initial taste) and the bitterness perceived during the second half (aftertaste) were evaluated and scored using the Visual Analog Scale (VAS) method (0 to 100 points). A lower score indicates stronger bitterness, while a higher score indicates weaker bitterness. The results are shown in Table 2. 【0053】 [Table 2] 【0054】 As shown in Table 2, Example 1, which contained calcium gluconate, scored 15 to 20 points higher than Comparative Example 1, which did not contain calcium gluconate, clearly demonstrating that calcium gluconate has the effect of suppressing the bitterness of acetaminophen. 【0055】 [Examples 2-7, Comparative Example 2] According to the formulations shown in Table 3, acetaminophen was granulated using a fluid bed granulation method with polyvinyl alcohol and D-mannitol added. The average particle size of the granules was 66 μm (Comparative Example 2, Examples 2-4) to 95 μm (Examples 5-7). The acetaminophen granules were mixed with powders of other components according to the formulations in Table 3, and powders of calcium gluconate hydrate or sodium tartrate dihydrate in the proportions shown in Table 4. The mixture was then compressed into tablets using a rotary tablet press (HT-EX6SS-U, manufactured by Hata Iron Works Co., Ltd.) to produce the desired tablets. The tablets had a diameter of 9 mm, a height of 3.6-3.7 mm, a hardness of approximately 81-98 N, and an in-oral disintegration time of less than 30 seconds. 【0056】 [Table 3] 【0057】 [Table 4] 【0058】 [Test Example 2] Evaluation of bitterness suppression effect The evaluation was conducted by five testers using the same evaluation method as in Example 1. The results are shown in Table 5. 【0059】 [Table 5] 【0060】 As shown in Table 5, in Examples 2 to 7, which contained 0.5% to 5.0% (diluted externally) of calcium gluconate or sodium tartrate, the scores for both initial taste and aftertaste were more than 10 points higher compared to Comparative Example 2, which did not contain either. This clearly demonstrates that both calcium gluconate (calcium salt) and sodium tartrate (sodium salt) have the effect of suppressing the bitterness of acetaminophen, even in small amounts. 【0061】 [Example 8] Tablets (the formulation of the present invention) were manufactured in which granules containing acetaminophen were coated with light anhydrous silicic acid, using a formulation almost identical to that of Example 1. First, acetaminophen was granulated in a wet granulator (FD-MP-01, manufactured by Powrec Co., Ltd.) by spraying an aqueous solution of polyvinyl alcohol (partially saponified) onto it and drying it to obtain acetaminophen granules (average particle size: approximately 100 μm). These granules were then coated by spraying an aqueous suspension of saccharin sodium hydrate and light anhydrous silicic acid to prepare coated granules containing acetaminophen. These coated granules were mixed with crystalline cellulose, D-mannitol, crospovidone, sucralose, magnesium stearate, l-menthol, and a flavoring agent. This mixture was then compressed into tablets using a rotary tablet press (HT-EX6SS-U, manufactured by Hata Iron Works Co., Ltd.) to produce the desired tablets (Example 8). The tablets had a diameter of 9 mm, a height of 3.7 mm, a hardness of approximately 85 N, and a disintegration time in the oral cavity of approximately 30 seconds or less. The bitterness suppression effect was equivalent to that of Example 1. 【0062】 [Test Example 3] Evaluation of tablet compression disorders For Example 8, the discharge pressure and trimming pressure from the tablet dies were measured using a compression characteristics evaluation device (GTP-2, Gamlen Instruments). The discharge pressure and trimming pressure were 1.36 MPa and 1.99 MPa, respectively, indicating improved tableting problems compared to acetaminophen without light anhydrous silicic acid coating. This coating suppresses tableting problems without resorting to methods that lead to larger tablets, such as increasing the amount of additives, making it suitable for manufacturing smaller forms of the present invention's formulation (tablets). [Industrial applicability] 【0063】 The present invention suppresses the bitter taste of acetaminophen with calcium salts and / or sodium salts, and since these salts are effective even in small amounts, the present invention allows for a relatively small formulation. Therefore, it is useful in the pharmaceutical industry.

Claims

[Claim 1] An oral solid dosage form characterized by comprising granules containing acetaminophen, and a dry mixture containing calcium gluconate and / or sodium tartrate in an amount of 0.5% by mass or more and less than 5% by mass relative to acetaminophen. [Claim 2] The oral solid dosage form according to claim 1, comprising acetaminophen in an amount of 70 to 85% by mass. [Claim 3] An oral solid preparation according to claim 1 or 2, comprising a binder, a bulking agent, a sweetener, and / or a fluidizing agent in granules containing acetaminophen. [Claim 4] An oral solid preparation according to any one of claims 1 to 3, further comprising an excipient, a disintegrant, a lubricant, a sweetener and / or a flavoring agent in the dry mixture. [Claim 5] The oral solid preparation according to claim 3 or 4, wherein the sweetener is sodium saccharin, sucralose, aspartame, or acesulfame potassium. [Claim 6] An oral solid preparation according to any one of claims 1 to 5, wherein the average particle size of the granules containing acetaminophen is in the range of 1 to 200 μm. [Claim 7] An oral solid preparation according to any one of claims 1 to 6, wherein the dosage form is a tablet or an orally disintegrating tablet. [Claim 8] The oral solid dosage form according to claim 7, wherein the weight is in the range of 30 to 700 mg. [Claim 9] A method for producing an oral solid dosage form, characterized by comprising the following steps 1 to 3:

1. A step of granulating acetaminophen to prepare a granule containing acetaminophen, 2. A step of preparing a dry mixture by dry mixing granules containing acetaminophen, calcium gluconate and / or sodium tartrate, and additives, wherein the amount of calcium gluconate and / or sodium tartrate is within the range of 0.5% by mass or more and less than 5% by mass relative to acetaminophen.

3. A process of forming the dry mixture into an oral solid dosage form.

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