Tablet having high content of acotiamide or salt thereof

Abstract

The present invention addresses the problem of providing a tablet which contains acotiamide or a salt thereof at a high concentration and which has not only a good elution property but also good storage stability.　The present invention relates to a tablet characterized by comprising granules that contain (A) acotiamide or a salt thereof, (B) pregelatinized starch, and (C) a disintegrant selected from low-substituted hydroxypropyl cellulose and sodium starch glycolate wherein the content of the component (A) in an uncoated tablet is 65-91 mass%.

Description

Acotiamide or its salt high-concentration tablets

[0001] The present invention relates to a tablet with a high content of acotiamide or a salt thereof.

[0002] Acotiamide has the chemical name N-[2-[Bis(1-methylethyl)amino]ethyl]-2-[( 2-hydroxy-4,5-dimethoxybenzoyl)amino]thiazole-4-carboxamide, molecular formula C 21 H 30 Acotiamide is known to improve gastrointestinal motility disorders by significantly enhancing gastrointestinal motility (Patent Document 1), and its hydrochloride hydrate is commercially available as a therapeutic agent for functional dyspepsia.

[0003] Acofide (registered trademark) tablets 100 mg containing acotiamide hydrochloride hydrate are tablets with a total weight of 257 mg that contain, in addition to 100 mg of acotiamide hydrochloride hydrate, lactose hydrate, crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, light anhydrous silicic acid, magnesium stearate, hypromellose, titanium oxide, and carnauba wax. In the treatment of functional dyspepsia, 100 mg is taken three times a day before meals (Non-Patent Document 1).

[0004] As a technique for miniaturizing tablets containing acotiamide or a salt thereof, a technique for producing tablets with a high content of acotiamide hydrochloride has been reported, in which a water-insoluble first filler such as calcium sulfate is added to acotiamide hydrochloride hydrate, the mixture is wet granulated, and then the granules obtained by drying are added to a second filler such as pregelatinized starch and a disintegrant such as cross-linked carboxymethylcellulose or low-substituted hydroxypropylcellulose, and the mixture is compressed into tablets (Patent Document 2).

[0005] Generally, tablets with a high content of active ingredients are difficult to mold because the amount of additives that can be incorporated into the formulation is limited, making them prone to tableting problems such as sticking and capping. As a measure to improve tableting problems in preparations with a high taurine content, a technology has been reported in which the surface of finely ground taurine powder is coated with a water-soluble polymer and then compressed and molded (Patent Document 3).

[0006] International Publication No. 1996 / 36619 Chinese Patent Publication No. 105769784 Japanese Patent Laid-Open Publication No. 11-060476

[0007] Acofide 100mg Tablet Interview Form Res. Rep. Urol. 2015; 7: 81-83 Res. Rep. Urol. 2017; 9: 141-143 Int. J. Urol. 2019; 26(8): 848-849 Journal of the Japanese Society of Urinary Function. 2022; 33(1): 224

[0008] The tablets containing acotiamide or a salt thereof described in Patent Document 2 have a reduced total weight and are compact, but the compact size of the tablets increases the active ingredient content per tablet, resulting in problems such as reduced storage stability of the tablets. Therefore, an object of the present invention is to provide tablets that contain acotiamide or a salt thereof at a high concentration, have good dissolution properties and good storage stability, and can be continuously compressed.

[0009]

[0009] The present inventors have conducted extensive studies to solve the above-mentioned problems, and have found that by obtaining a granule containing (A) acotiamide or a salt thereof, (B) pregelatinized starch, and (C) a disintegrant selected from low-substituted hydroxypropyl cellulose and sodium starch glycolate, and compressing the granule, a tablet containing component (A) acotiamide or a salt thereof at a high concentration of 65% to 91% by mass can be obtained, and the tablet not only has good dissolution properties, but also does not decrease in dissolution properties even after storage under high humidity conditions, and can maintain tablet hardness, thereby completing the present invention. Furthermore, the inventors have found that by adjusting the moisture content of the granule and the tablet within an appropriate range, the distribution of the active ingredient in the obtained tablet is made more uniform, the obtained tablet has good dissolution properties, and the decrease in hardness after storage under high humidity conditions is suppressed.

[0010] That is, the present invention provides the following [1] to

[18] . [1] A tablet comprising a granule containing (A) acotiamide or a salt thereof, (B) pregelatinized starch, and (C) a disintegrant selected from low-substituted hydroxypropyl cellulose and sodium starch glycolate, wherein the uncoated tablet contains 65% by mass to 91% by mass of component (A). [2] The tablet according to [1], wherein the granule is a wet granule. [3] The tablet according to [1] or [2], wherein the content of component (B) in the uncoated tablet is 2% by mass to 10% by mass. [4] The tablet according to any of [1] to [3], wherein the content of component (C) in the uncoated tablet is 5% by mass to 20% by mass. [5] The tablet according to any of [1] to [4], wherein the total content of components (B) and (C) in the uncoated tablet is 8% by mass or more. [6] The tablet according to any one of [1] to [5], wherein the content of component (B) in the uncoated tablet is 2% by mass or more and 8% by mass or less. [7] The tablet according to any one of [1] to [6], wherein the content of component (C) in the uncoated tablet is 5% by mass or more and 15% by mass or less. [8] The tablet according to any one of [1] to [7], wherein the total content of component (B) and component (C) in the uncoated tablet is 8% by mass or more and 25% by mass or less. [9] The tablet according to any one of [1] to [8], wherein the content of component (B) in the uncoated tablet is 3% by mass or more and 8% by mass or less.

[10] The tablet according to any one of [1] to [9], wherein the total content of component (B) and component (C) in the uncoated tablet is 8% by mass or more and 22% by mass or less.

[11] A method for producing a tablet containing 65% to 91% by mass of component (A) in a uncoated tablet, the method comprising a step of compressing a wet granulation containing (A) acotiamide or a salt thereof, (B) pregelatinized starch, and (C) a disintegrant selected from low-substituted hydroxypropyl cellulose and sodium starch glycolate.

[12] A tablet containing a wet granulation product containing (D) a medicinal ingredient, (B) pregelatinized starch, and (C) a disintegrant selected from low-substituted hydroxypropyl cellulose and sodium starch glycolate, the moisture content of the dry powder of which is 4.0% to 11.0%.

[13] The tablet according to

[12] , wherein the moisture content of the dry powder of the wet granulation product is 4.0% to 9.0%.

[14] The tablet according to

[12] or

[13] , wherein the moisture content of the tablet is 4.0% to 13.0%.

[15] The tablet of

[12] or

[13] , wherein the tablet has a moisture content of 4.0% or more and 11.0% or less.

[16] The tablet of any of

[12] to

[15] , wherein (D) the active ingredient is acotiamide or a salt thereof.

[17] The tablet of any of

[12] to

[16] , wherein the moisture retention ratio of component (A) to component (B) in the tablet is 0.07 to 2.4.

[18] The tablet of any of

[12] to

[17] , wherein the moisture retention ratio of component (A) to component (B) in the tablet is 0.15 to 2.0.

[0011] The tablets containing acotiamide or a salt thereof of the present invention contain a high concentration of acotiamide or a salt thereof in the uncoated tablet (65% by mass or more but 91% by mass or less), yet exhibit good dissolution of acotiamide or a salt thereof, do not decrease in dissolution even after storage under high humidity conditions, and maintain tablet hardness. Therefore, the total weight per tablet can be reduced, and the tablets are useful as tablets with excellent administrability even when the single dose is increased. Furthermore, by adjusting the moisture content of the granules and tablets within an appropriate range, the distribution of the active ingredient in the resulting tablets is made more uniform, the dissolution of the resulting tablets is improved, and a decrease in hardness after storage under high humidity conditions is suppressed. Furthermore, although the tablets of the present invention have a high drug content, they are stable even in high-speed continuous tableting processes without tableting problems such as lamination or capping during tablet compression, thereby improving industrial production efficiency.

[0012] 1 is a diagram showing the relationship between the sulfur element (acotiamide hydrochloride) composition ratio and color. 2 is a diagram showing the uniformity of acotiamide hydrochloride distribution in the tablets of Example 2, Example 4, Comparative Example 2, and Comparative Example 8. 3 is a diagram showing the uniformity of acotiamide hydrochloride distribution in the tablets of Comparative Examples 10 and 11.

[0013] The acotiamide or salt thereof-containing tablet of the present invention is a tablet having a high acotiamide or salt thereof content of 65% by mass or more and 91% by mass or less in the uncoated tablet. One aspect of the present invention is a tablet comprising a granule containing (A) acotiamide or a salt thereof, (B) pregelatinized starch, and (C) a disintegrant selected from low-substituted hydroxypropyl cellulose and sodium starch glycolate, and wherein the uncoated tablet contains 65% by mass or more and 91% by mass or less of component (A).

[0014] Acotiamide has the chemical name N-[2-[Bis(1-methylethyl)amino]ethyl]-2-[( 2-hydroxy-4,5-dimethoxybenzoyl)amino]thiazole-4-carboxamide, molecular formula C 21 H 30 It is NOS. Acotiamide is known to improve gastrointestinal motility disorders by significantly enhancing gastrointestinal motility (Patent Document 1), and its hydrochloride hydrate is commercially available as a therapeutic drug for functional dyspepsia. More specifically, the efficacy and effects of a therapeutic drug for functional dyspepsia containing acotiamide are postprandial fullness, upper abdominal bloating, and early satiety associated with functional dyspepsia, and the dosage and administration method for adults is to orally administer 100 mg of acotiamide hydrochloride hydrate three times a day before meals.

[0015] Acotiamide or a salt thereof has been reported to be effective against urinary disorders in studies using a rat model of underactive bladder and in pilot studies in patients with underactive bladder in combination with an α1-receptor blocker (Non-Patent Documents 2 to 5). Furthermore, when acotiamide or a salt thereof was administered at high doses significantly exceeding those used to improve gastrointestinal motility, its effects on detrusor contraction pressure, urinary flow rate, and urethral pressure were examined. It was found that, unlike existing cholinergic agonists, it increased bladder contraction pressure and maximum urination contraction pressure at doses higher than those used to treat functional dyspepsia, without affecting urethral pressure at these doses, making it useful as an agent for improving urinary disorders. When acotiamide or a salt thereof is used as an agent for improving urinary disorders, it is preferably administered orally at a dose of 200 mg to 300 mg per dose, or 600 mg to 900 mg per day, to adults (Patent Application No. 2023-040926).

[0016] Salts of acotiamide include acid addition salts, specifically acid addition salts with inorganic acids such as hydrochloride, sulfate, nitrate, phosphate, hydrobromide, and hydroiodide, and acid addition salts with organic acids such as acetate, oxalate, malonate, succinate, maleate, fumarate, lactate, malate, citrate, tartrate, methanesulfonate, and ethanesulfonate. Among these, acotiamide hydrochloride is more preferred. Also included are various solvates such as hydrates of acotiamide or its salts. Acotiamide hydrochloride hydrate is even more preferred. These acotiamides or salts thereof can be produced, for example, by the method described in Patent Document 1.

[0017] From the viewpoint of improving the ease of administration by miniaturizing the tablets and from the viewpoint of improving the ease of administration of high-dose tablets, such as orally administering 200 mg to 300 mg at a time, at a rate of 600 mg to 900 mg per day, the acotiamide or salt thereof is preferably contained in the uncoated tablet of the present invention in an amount of 65% by mass to 91% by mass, more preferably 65% ​​by mass to 88% by mass, and even more preferably 65% ​​by mass to 75% by mass. When acotiamide or a salt thereof is used as an agent for improving dysuria, the single dose is large, so this content is particularly preferred.

[0018] The tablet of the present invention contains a granule containing (A) acotiamide or a salt thereof, (B) pregelatinized starch, and (C) a disintegrant selected from low-substituted hydroxypropyl cellulose and sodium starch glycolate. That is, in the tablet of the present invention, it is preferable that the granule contains (A) acotiamide or a salt thereof, (B) pregelatinized starch, and (C) a disintegrant selected from low-substituted hydroxypropyl cellulose and sodium starch glycolate, from the viewpoints of not only good dissolution but also not decreasing dissolution even after storage under high humidity conditions and maintaining tablet hardness.

[0019] (B) Pregelatinized starch is starch derived from wheat, corn, potato, rice, tapioca, etc., which is heated with water under normal pressure or under pressure to pregelatinize (gelatinize) starch granules, and then dried. (B) Pregelatinized starch in the present invention includes "pregelatinized starch" and "partially pregelatinized starch" listed in the Pharmaceutical Additives Standards 2018, as well as pregelatinized starches that can generally be added to pharmaceuticals and foods. Commercially available pregelatinized starch products include PCS PC-10 (Asahi Kasei Corporation), SWELSTAR TM WB-1 (Asahi Kasei Corporation), SWELSTAR TM PD-1 (Asahi Kasei Corporation), SWELSTAR TM MX-1 (Asahi Kasei Corporation), Corn Alpha W (Sanwa Starch Industry Co., Ltd.), Waxy Alpha Y (Sanwa Starch Industry Co., Ltd.), Tapioca Alpha NTP (Sanwa Starch Industry Co., Ltd.), Lycatab TMC (Roquette Freres), Lycatab TM CLM (Roquette Freres), Lycatab TM CT (Roquette Freres), Lycatab TM PGS (Roquette Freres), Starch1500 TM (Colorcon), Starch1500 TM LM (Colorcon), Starch1500 TM G (Colorcon), Prejel PA5 PH (DFE Pharma), Nutrofeli TM ST200 (DFE Pharma), Nutrofeli TM Examples include ST300 (DFE Pharma). From the viewpoints of dissolution property and tablet stability, the content of pregelatinized starch in the uncoated tablet is preferably 2% by mass to 10% by mass, more preferably 2% by mass to 8% by mass, and even more preferably 3% by mass to 8% by mass.

[0020] (B) Pregelatinized starch is preferably pregelatinized starch having a cold water soluble content of 1.0% or more. Here, the cold water soluble content is defined as a value obtained by the following measurement method. <Method for measuring cold water soluble content (%)> Approximately 1 g of sample (W A0 99 g of purified water at 20±5°C was added to the mixture, and the mixture was stirred for 2 hours to disperse. 40 mL of the resulting dispersion was transferred to a 50 mL centrifuge tube and centrifuged (approximately 5000 G, 15 minutes). 20 mL of the supernatant was dried at 110°C until a constant mass was obtained, and the dry mass W of the cold water solubles was determined. A (g) was calculated. B0 ) was dried at 110°C until a constant mass was obtained. B The value calculated from these values ​​and the following formula was taken as the cold water soluble content (%).

[0021]

[0022] Component (C) is a disintegrant. Specifically, one or two selected from low-substituted hydroxypropyl cellulose and sodium starch glycolate are preferred. From the viewpoint of dissolution, the disintegrant used in the present invention preferably has a water retention capacity of 500% or more. Here, the water retention capacity is defined as the value obtained by the following measurement method. <Method for measuring water retention capacity> 15 mL of purified water at 20±5°C was added to approximately 1 g of sample (W0) placed in a 50 mL centrifuge tube, dispersed, and then shaken at 200 rpm for 10 minutes. Another 15 mL of purified water at 20±5°C was added, and the mixture was allowed to stand for 20 minutes, followed by centrifugation (approximately 2000 G, 10 minutes). The water retention capacity (%) was calculated using the following formula from the residue mass W (g) after removing the supernatant and the initial sample mass W0 (g).

[0023]

[0024] Low-substituted hydroxypropyl cellulose is a cellulose derivative in which a small amount of hydroxypropoxy groups are introduced into the glucose ring of cellulose. While the molar substitution of the hydroxypropoxy groups in general hydroxypropyl cellulose is 3, low-substituted hydroxypropyl cellulose preferably has a molar substitution of 0.2 to 0.4. Here, the molar substitution is the average number of hydroxyl groups substituted with hydroxypropoxy groups per glucose. Commercially available low-substituted hydroxypropyl celluloses include L-HPC TM (Shin-Etsu Chemical Co., Ltd.). Several varieties are commercially available, including L-HPC TM Examples of the varieties include LH-11, LH-21, LH-22, LH-B1, LH-31, LH-32, NBD-020, NBD-021, and NBD-022.

[0025] Sodium starch glycolate is a sodium salt of starch carboxymethyl ether or its cross-linked product. There are neutralization types A and B, and when the insoluble matter in an ethanol (99.5) / water mixture (8:2) is dried, it contains 2.8% to 4.2% and 2.0% to 3.4% sodium (Na: 22.99), respectively. Commercially available products of sodium starch glycolate include GLYCOLYS TM(Roquette Freres), Primojel TM (DFE Pharma), EXPLOTAB TM (JRS Pharma), EXPLOTAB TM CLV (JRS Pharma), EXPLOTAB TM PCF (JRS Pharma), EXPLOTAB TM LowpH (JRS Pharma) and the like.

[0026] The content of the disintegrant selected from low-substituted hydroxypropyl cellulose and sodium starch glycolate in the uncoated tablet is preferably 5% by mass or more and 20% by mass or less, and more preferably 5% by mass or more and 15% by mass or less, from the viewpoints of dissolution property and tablet stability.

[0027] The content by mass of (B) pregelatinized starch per 100 parts by mass of component (A) (acotiamide or a salt thereof) is preferably 2 to 15 parts by mass, more preferably 2 to 11 parts by mass, and even more preferably 3 to 11 parts by mass, from the viewpoints of dissolution property and tablet stability. The content by mass of (C) a disintegrant selected from low-substituted hydroxypropyl cellulose and sodium starch glycolate per 100 parts by mass of component (A) (acotiamide or a salt thereof) is preferably 5 to 30 parts by mass, more preferably 5 to 20 parts by mass. The total content of component (B) pregelatinized starch and (C) a disintegrant selected from low-substituted hydroxypropyl cellulose and sodium starch glycolate in the uncoated tablet is preferably 8% by mass or more, more preferably 8 to 25% by mass, and even more preferably 8 to 22% by mass, from the viewpoints of dissolution property and tablet stability. The mass ratio (C / B) of the content of the disintegrant selected from (C) low-substituted hydroxypropyl cellulose and sodium starch glycolate to the content of (B) pregelatinized starch is preferably 1 or more and 6 or less, more preferably 1 or more and 3 or less, from the viewpoints of dissolution property and tablet stability.

[0028] The average particle size D50 of the granules containing the components (A), (B) and (C) is preferably 90 μm or more and 700 μm or less, and more preferably 120 μm or more and 500 μm or less, from the viewpoints of dissolution property and tablet stability.

[0029] In addition to the components (A), (B), and (C), the granules may contain excipients commonly used in tablet production. Examples of such excipients include crystalline cellulose, lactose, powdered cellulose, mannitol, sucrose, corn starch, potato starch, and the like. Among these excipients, crystalline cellulose, lactose, and powdered cellulose are more preferred. The content of these excipients in the granules is preferably 25% by mass or less from the viewpoint of dissolution property and tablet stability, and more preferably 11% by mass or less, and even more preferably 8% by mass or less, from the viewpoint of tablet miniaturization.

[0030] Another aspect of the present invention is a method for producing tablets containing 65% by mass or more and 91% by mass or less of component (A) in a uncoated tablet, the method comprising the step of compressing a granule containing (A) acotiamide or a salt thereof, (B) pregelatinized starch, and (C) a disintegrant selected from low-substituted hydroxypropyl cellulose and sodium starch glycolate. Here, the granule is preferably a wet granule from the viewpoints of dissolution property, tablet stability, and manufacturability.

[0031] The granules can be produced by mixing the components (A), (B), and (C) and, if necessary, an excipient, and subjecting them to a conventional granulation method, preferably a wet granulation method. Examples of wet granulation methods include agitation granulation, fluidized bed granulation, and tumbling fluidized bed granulation. Specifically, the components (A), (B), and (C) and, if necessary, an excipient are mixed, water or a water / ethanol mixture is added, and the mixture is granulated in the granulator, followed by drying and sizing. Alternatively, the components (A), (C), and, if necessary, an excipient are mixed, water or a water / ethanol mixture containing a dispersion of (B) is added, and the mixture is granulated in the granulator, followed by drying and sizing. The amount of liquid added during granulation is preferably 25 to 60% by mass of the granulation charge in the case of agitation granulation, and preferably 25 to 100% by mass of the granulation charge in the case of fluidized bed granulation and tumbling fluidized bed granulation.

[0032] The tablets of the present invention can be obtained by adding lubricants, flow agents, excipients, etc. to the obtained granules as needed and compressing them. The excipients mentioned above can be used. Examples of lubricants that can be used include magnesium stearate, sodium stearyl fumarate, sodium lauryl sulfate, carnauba wax, and macrogols. Among these, magnesium stearate and sodium stearyl fumarate are more preferred. Examples of flow agents that can be used include light anhydrous silicic acid, heavy anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, and talc. Among these, light anhydrous silicic acid is more preferred. Since the uncoated tablet contains 65% to 91% by mass of component (A), it is desirable to add only small amounts of these lubricants, flow agents, excipients, etc. Furthermore, the tablets of the present invention may be uncoated tablets obtained in this manner, or the uncoated tablets may be film-coated.

[0033] The present inventors have also found that adjusting the moisture content of the granules and tablets to 4.0% or more and 11.0% or less increases the uniformity of the distribution of the active ingredient in the resulting tablets, improves the dissolution properties of the resulting tablets, and suppresses a decrease in hardness after storage under high humidity conditions. That is, another aspect of the present invention is a tablet containing granules in which the moisture content of the dried powder of wet granulation is 4.0% or more and 11.0% or less, and the granules contain (D) an active ingredient, (B) pregelatinized starch, and (C) a disintegrant selected from low-substituted hydroxypropyl cellulose and sodium starch glycolate.

[0034] Here, (D) the active ingredient is preferably (A) acotiamide or a salt thereof, but is not limited thereto. From the viewpoints of dissolution property and tablet stability, the moisture content of the dried powder of the wet granulation product is preferably 4.0% or more and 11.0% or less, and more preferably 4.0% or more and 9.0% or less. Here, methods for measuring the moisture content include loss on drying, Karl Fischer titration, and near-infrared analysis.

[0035] The moisture content of the tablet of the present invention is preferably 4.0% to 13.0%, more preferably 4.0% to 11.0%, from the viewpoints of dissolution property and tablet stability. Examples of methods for measuring the moisture content include loss on drying, Karl Fischer titration, and near-infrared analysis. Furthermore, from the viewpoints of dissolution property and tablet stability, the moisture retention ratio of component (A) to component (B) in the tablet is preferably 0.07 to 2.4, more preferably 0.15 to 2.0.

[0036] From the viewpoint of dissolution property and tablet stability, it is preferable that the distribution of the active ingredient (D) within the obtained tablet of the present invention is such that the ingredient (D) is not localized, i.e., the ingredient (D), the ingredient (B) pregelatinized starch, and the ingredient (C) disintegrant selected from low-substituted hydroxypropyl cellulose and sodium starch glycolate are uniformly distributed within the tablet. Methods for evaluating the distribution of ingredients within the tablet include elemental analysis of the tablet surface and / or tablet cross section by energy dispersive X-ray spectroscopy (EDS), Auger electron spectroscopy (AES), laser-induced breakdown spectroscopy (LIBS), X-ray photoelectron spectroscopy (XPS), or X-ray fluorescence analysis, and component mapping analysis of the tablet surface and / or tablet cross section by time-of-flight secondary ion mass spectroscopy (TOF-SIMS) or microscopic Raman spectroscopy. The preferred examples, contents, and content of the ingredient (D) of the tablet of this embodiment are the same as those of the above-mentioned tablet.

[0037] Although the tablet of the present invention has a high content of (A) acotiamide or a salt thereof, the dissolution of component (A) is good, and furthermore, the storage stability is such that the dissolution does not decrease even after storage under high humidity conditions, and the tablet hardness is also maintained. Therefore, it is possible to further reduce the size of tablets containing 100 mg of component (A), and even if the content of component (A) in a single tablet is high, the size can be reduced, thereby improving ease of administration.

[0038] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0039] (Raw Materials Used) The acotiamide hydrochloride hydrate used in the examples of the present invention was pulverized in a pulverizer at Zeria Pharmaceutical Co., Ltd. and had a water retention capacity (%) of 59. The (B) pregelatinized starch used in the examples is as shown in Table 1.

[0040]

[0041] The low-substituted hydroxypropyl cellulose used in the examples is as shown in Table 2.

[0042]

[0043] The sodium starch glycolates used in the examples are as shown in Table 3.

[0044]

[0045] (Granulation device) Agitation granulation device, fluidized bed granulation device or tumbling fluidized bed granulation device described in the table. (Tableting conditions) Tableting pressure described in the examples.

[0046] (Measurement of Moisture Content) Measurement was carried out under conditions of 80° C. for 20 minutes according to the loss on drying test method described in the Japanese Pharmacopoeia.

[0047] (Measurement of tablet hardness) Measurement was carried out using a hardness tester, PTB-502, manufactured by PHARMA TEST.

[0048] (Measurement of dissolution rate) A dissolution test was performed by the paddle method (test medium: water or second dissolution test medium, paddle rotation speed: 50 rpm) of the dissolution test method specified in the Japanese Pharmacopoeia, and the dissolution rate (%) was calculated 15 minutes after the start of the test.

[0049] (Storage Conditions of Tablets) The tablets were stored for 1 or 2 weeks under open conditions in a constant temperature and humidity testing room set at a temperature and humidity of 40°C and 75% RH.

[0050] (Evaluation of the uniformity of acotiamide hydrochloride hydrate within the tablet) Elemental analysis of the tablet surface was performed by laser-induced breakdown spectroscopy using a microscope equipped with a laser elemental analysis head. The measurement range was 720 μm × 450 μm in the central part of the top surface of the tablet, with a total of 400 measurement points spaced 30 μm apart. Elemental analysis was performed using oxygen, carbon, hydrogen, sulfur, and silicon as the detection elements, and the composition ratios of these elements were calculated. From the measurement results obtained, a mapping was created using the colors shown in Figure 1 according to the composition ratio of sulfur element.

[0051] (Evaluation) The initial hardness of the tablet was rated as ⊚ when it was 120 N or more, and x when it was less than 120 N. The dissolution rate of the active ingredient was rated as ⊚ when it was 85% or more at 15 minutes after the start of the dissolution test, and x when it was less than 85%. The hardness reduction rate after storage was rated as ⊚ when it was 30% or less, ◯ when it was more than 30% and less than 50%, and x when it was more than 50%. The dissolution rate after storage was rated as ⊚ when it was 85% or more, and x when it was less than 85%. The uniformity of acotiamide hydrochloride hydrate within the tablet was rated as ⊚ when, out of 400 measurement points, less than 5 points had a sulfur elemental composition ratio of 60% or more, ◯ when it was 5 points to less than 10 points had a sulfur elemental composition ratio of 60% or more, and x when it was 10 points or more had a sulfur elemental composition ratio of 60%.

[0052] Example 1 Acotiamide hydrochloride hydrate (75.0% by mass), pregelatinized starch A (5.0% by mass), lactose hydrate (6.0% by mass), microcrystalline cellulose (2.0% by mass), and low-substituted hydroxypropyl cellulose A (10.0% by mass) were mixed, and 33.5% by mass of water based on the granulation components was added and stirred to granulate. The granules were then dried at 80°C and sized using a sieve sizer with a screen diameter of 1.905 mm. Light anhydrous silicic acid (1.0% by mass) and magnesium stearate (1.0% by mass) were added to the resulting granules, and the mixture was compressed to a diameter of 10.5 mm at a tableting pressure of 10.7 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0053] Example 2 Acotiamide hydrochloride hydrate (75.0% by mass), crystalline cellulose (8.0% by mass), and low-substituted hydroxypropyl cellulose A (10.0% by mass) were mixed, and a binder solution prepared by dispersing pregelatinized starch B (5.0% by mass) in water (57.4% by mass relative to the granulation components) was added, followed by stirring and granulation. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Light anhydrous silicic acid (0.5% by mass) and magnesium stearate (1.5% by mass) were added to the resulting granules, and the mixture was then compressed to a diameter of 10.5 mm at a tableting pressure of 15.1 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0054] Example 3 Acotiamide hydrochloride hydrate (75.0% by mass), crystalline cellulose (8.0% by mass), and low-substituted hydroxypropyl cellulose A (10.0% by mass) were mixed, and the mixture was granulated in a fluidized bed granulator while adding a binding liquid prepared by dispersing pregelatinized starch B (5.0% by mass) in water (31.3% by mass relative to the granulation components). The mixture was dried and sieved through a sieve with an opening of 850 μm. The resulting granules were mixed with light anhydrous silicic acid (1.0% by mass) and magnesium stearate (1.0% by mass), and then compressed to a diameter of 10.5 mm at a tableting pressure of 11.2 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0055] Example 4 Acotiamide hydrochloride hydrate (75.4% by mass), microcrystalline cellulose (8.0% by mass), and low-substituted hydroxypropyl cellulose A (10.1% by mass) were mixed, and the mixture was granulated in a tumbling fluidized bed granulator while adding a binding liquid prepared by dispersing pregelatinized starch B (5.0% by mass) in water (45.9% by mass relative to the granulation components). The mixture was dried and sieved through a sieve with an opening of 850 μm. The resulting granules were mixed with magnesium stearate (1.5% by mass), and then compressed to a diameter of 10.5 mm at tableting pressures of 11.0 kN and 15.0 kN to produce 398 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0056] Example 5 Acotiamide hydrochloride hydrate (66.7% by mass), pregelatinized starch A (5.0% by mass), lactose hydrate (4.3% by mass), microcrystalline cellulose (2.0% by mass), and low-substituted hydroxypropyl cellulose A (20.0% by mass) were mixed, and 49.0% by mass of water was added based on the granulation components, followed by stirring and granulation. The granules were then dried at 80°C and sized using a sieve sizer with a screen diameter of 1.905 mm. Light anhydrous silicic acid (1.0% by mass) and magnesium stearate (1.0% by mass) were added to the resulting granules, and the mixture was compressed to a diameter of 11 mm at a tableting pressure of 10.9 kN to produce 450 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0057] Example 6 Acotiamide hydrochloride hydrate (75.0% by mass), crystalline cellulose (11.0% by mass), and low-substituted hydroxypropyl cellulose A (10.0% by mass) were mixed, and a binder solution prepared by dispersing pregelatinized starch B (2.0% by mass) in water (44.6% by mass relative to the granulation components) was added, followed by stirring and granulation. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Light anhydrous silicic acid (1.0% by mass) and magnesium stearate (1.0% by mass) were added to the resulting granules, and the mixture was then compressed to a diameter of 10.5 mm at a tableting pressure of 11.0 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0058] Example 7 Acotiamide hydrochloride hydrate (75.0% by mass), crystalline cellulose (2.0% by mass), powdered cellulose (3.5% by mass), and low-substituted hydroxypropyl cellulose A (10.0% by mass) were mixed, and the mixture was granulated in a tumbling fluidized bed granulator while adding a binding liquid prepared by dispersing pregelatinized starch B (7.5% by mass) in water (45.8% by mass relative to the granulation components). After drying, the mixture was sieved through a sieve with an opening of 850 μm. The resulting granules were mixed with light anhydrous silicic acid (1.0% by mass) and magnesium stearate (1.0% by mass), and then compressed to a diameter of 10.5 mm at a tableting pressure of 10.0 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0059] Example 8 Acotiamide hydrochloride hydrate (75.0% by mass), crystalline cellulose (3.0% by mass), and low-substituted hydroxypropyl cellulose A (10.0% by mass) were mixed, and a binder solution prepared by dispersing pregelatinized starch B (10.0% by mass) in water (44.6% by mass relative to the granulation components) was added, followed by stirring and granulation. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Light anhydrous silicic acid (1.0% by mass) and magnesium stearate (1.0% by mass) were added to the resulting granules, and the mixture was then compressed to a diameter of 10.5 mm at a tableting pressure of 11.0 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0060] Example 9 Acotiamide hydrochloride hydrate (75.0% by mass), crystalline cellulose (8.0% by mass), and low-substituted hydroxypropyl cellulose A (10.0% by mass) were mixed, and a binder solution prepared by dispersing pregelatinized starch C (5.0% by mass) in water (44.6% by mass relative to the granulation components) was added, followed by stirring and granulation. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Light anhydrous silicic acid (0.5% by mass) and magnesium stearate (1.5% by mass) were added to the resulting granules, and the mixture was then compressed to a diameter of 10.5 mm at a tableting pressure of 11.0 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0061] Example 10 Acotiamide hydrochloride hydrate (75.0% by mass), crystalline cellulose (8.0% by mass), and low-substituted hydroxypropyl cellulose A (10.0% by mass) were mixed, and a binder solution prepared by dispersing pregelatinized starch D (5.0% by mass) in water (44.6% by mass relative to the granulation components) was added, followed by stirring and granulation. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Light anhydrous silicic acid (0.5% by mass) and magnesium stearate (1.5% by mass) were added to the resulting granules, and the mixture was compressed to a diameter of 10.5 mm at a tableting pressure of 15.0 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0062] Example 11 Acotiamide hydrochloride hydrate (75.0% by mass), crystalline cellulose (8.0% by mass), and low-substituted hydroxypropyl cellulose C (10.0% by mass) were mixed, and a binder solution prepared by dispersing pregelatinized starch B (5.0% by mass) in water (44.6% by mass relative to the granulation components) was added, followed by stirring and granulation. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Light anhydrous silicic acid (0.5% by mass) and magnesium stearate (1.5% by mass) were added to the resulting granules, and the mixture was compressed to a diameter of 10.5 mm at a tableting pressure of 15.1 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0063] Example 12 Acotiamide hydrochloride hydrate (75.0% by mass), crystalline cellulose (8.0% by mass), and low-substituted hydroxypropyl cellulose D (10.0% by mass) were mixed, and a binder solution prepared by dispersing pregelatinized starch B (5.0% by mass) in water (44.6% by mass relative to the granulation components) was added, followed by stirring and granulation. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Light anhydrous silicic acid (0.5% by mass) and magnesium stearate (1.5% by mass) were added to the resulting granules, and the mixture was compressed to a diameter of 10.5 mm at a tableting pressure of 15.1 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0064] Example 13 Acotiamide hydrochloride hydrate (75.0% by mass), crystalline cellulose (8.0% by mass), and low-substituted hydroxypropyl cellulose E (10.0% by mass) were mixed, and a binder solution prepared by dispersing pregelatinized starch B (5.0% by mass) in water (44.6% by mass relative to the granulation components) was added, followed by stirring and granulation. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Light anhydrous silicic acid (0.5% by mass) and magnesium stearate (1.5% by mass) were added to the resulting granules, and the mixture was then compressed to a diameter of 10.5 mm at a tableting pressure of 15.0 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0065] Example 14 Acotiamide hydrochloride hydrate (75.0% by mass), microcrystalline cellulose (8.0% by mass), and sodium starch glycolate (10.0% by mass) with a water retention capacity of 1625% were mixed, and a binding liquid prepared by dispersing pregelatinized starch B (5.0% by mass) in water (57.4% by mass relative to the granulation components) was added and stirred to granulate. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Light anhydrous silicic acid (0.5% by mass) and magnesium stearate (1.5% by mass) were added to the resulting granules, mixed, and then compressed to a diameter of 10.5 mm at a tableting pressure of 15.1 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0066] Example 15 Acotiamide hydrochloride hydrate (85.7% by mass), crystalline cellulose (4.1% by mass), and low-substituted hydroxypropyl cellulose A (5.1% by mass) were mixed, and a binder solution prepared by dispersing pregelatinized starch B (3.0% by mass) in water (36.4% by mass relative to the granulation components) was added, followed by stirring and granulation. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Light anhydrous silicic acid (1.0% by mass) and magnesium stearate (1.0% by mass) were added to the resulting granules, and the mixture was then compressed to a diameter of 10.5 mm at a tableting pressure of 15.0 kN to produce 350 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0067] Example 16: Acotiamide hydrochloride hydrate (90.9% by mass) and low-substituted hydroxypropyl cellulose A (5.2% by mass) were mixed, and a binder solution prepared by dispersing pregelatinized starch B (2.9% by mass) in water (38.3% by mass relative to the granulation components) was added, followed by stirring and granulation. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Magnesium stearate (1.0% by mass) was added to the resulting granules, and the mixture was compressed to a diameter of 10.5 mm at a tableting pressure of 15.0 kN to produce 330 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0068] Example 17 Acotiamide hydrochloride hydrate (75.0% by mass), crystalline cellulose (13.0% by mass), and sodium starch glycolate B (5.0% by mass) were mixed and stirred and granulated while adding a binding solution prepared by dispersing pregelatinized starch B (5.0% by mass) in water (44.6% by mass relative to the granulation components). The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. The resulting granules were mixed with light anhydrous silicic acid (0.5% by mass) and magnesium stearate (1.5% by mass), and then compressed to a diameter of 10.5 mm at a tableting pressure of 15.0 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0069] Example 18 Acotiamide hydrochloride hydrate (66.7% by mass), crystalline cellulose (6.3% by mass), and sodium starch glycolate A (20.0% by mass) were mixed and stirred and granulated while adding a binding solution prepared by dispersing pregelatinized starch B (5.0% by mass) in water (61.2% by mass relative to the granulation components). The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Light anhydrous silicic acid (1.0% by mass) and magnesium stearate (1.0% by mass) were added to the resulting granules, and the mixture was compressed to a diameter of 10.5 mm at a tableting pressure of 7.2 kN to produce 450 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0070] Example 19 Acotiamide hydrochloride hydrate (75.0% by mass), crystalline cellulose (8.0% by mass), and low-substituted hydroxypropyl cellulose A (10.0% by mass) were mixed, and the mixture was granulated in a fluidized bed granulator while adding a binding liquid prepared by dispersing pregelatinized starch B (5.0% by mass) in water (96.9% by mass relative to the granulation components). The mixture was dried and then sized using a sieve sizer with a screen diameter of 1.4 mm. The resulting granules were mixed with light anhydrous silicic acid (0.5% by mass) and magnesium stearate (1.5% by mass), and then compressed into tablets with a major axis of 13.0 mm and a minor axis of 6.9 mm using a high-speed rotary tablet press at a tableting pressure of 9.4 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0071] Example 20 Acotiamide hydrochloride hydrate (75.0% by weight), crystalline cellulose (8.0% by weight), and low-substituted hydroxypropyl cellulose A (10.0% by weight) were mixed, and a binder solution prepared by dispersing pregelatinized starch B (5.0% by weight) in water (45.9% by weight relative to the granulation components) was added. The mixture was granulated in a tumbling fluidized bed granulator, dried, and then sieved through an 850 μm mesh sieve. The particle size D50 of the granulated product was 278.7 μm, and the moisture content at the end of drying was 6.91%. The resulting granulated product was mixed with light anhydrous silicic acid (0.5% by weight) and magnesium stearate (1.5% by weight), and then compressed into tablets with a diameter of 10.5 mm at a tableting pressure of 9.6 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate. A coating solution consisting of hypromellose, titanium oxide, and purified water was sprayed onto the tablets to produce film-coated tablets. The initial hardness and dissolution rate % of this tablet were 241.8 N and 88.2%, respectively. The hardness reduction rate and dissolution rate of this tablet after 6 months of storage were 12.7% and 88.7%, respectively.

[0072] Example 21 Acotiamide hydrochloride hydrate (66.7% by mass), crystalline cellulose (6.3% by mass), low-substituted hydroxypropyl cellulose A (15.0% by mass), and sodium starch glycolate A (5.0% by mass) were mixed and stirred and granulated while adding a binding solution prepared by dispersing pregelatinized starch B (5.0% by mass) in water (51.0% by mass relative to the granulation components). The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. The resulting granules were mixed with light anhydrous silicic acid (1.0% by mass) and magnesium stearate (1.0% by mass), and then compressed to a diameter of 10.5 mm at a tableting pressure of 6.6 kN to produce 450 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0073] Example 22 Acotiamide hydrochloride hydrate (75.0% by mass), microcrystalline cellulose (12.0% by mass), and low-substituted hydroxypropyl cellulose A (10.0% by mass) were mixed and stirred and granulated while adding a binding solution prepared by dispersing pregelatinized starch B (1.0% by mass) in water (44.6% by mass relative to the granulation components). The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Light anhydrous silicic acid (1.0% by mass) and magnesium stearate (1.0% by mass) were added to the resulting granules, mixed, and then compressed to a diameter of 10.5 mm at a tableting pressure of 6.7 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0074] Example 23 Acotiamide hydrochloride hydrate (66.7% by mass), microcrystalline cellulose (6.3% by mass), low-substituted hydroxypropyl cellulose A (17.0% by mass), and pregelatinized starch E (8.0% by mass) were mixed and stirred and granulated while adding 34.0% by mass of water based on the granulation components. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. The resulting granules were mixed with light anhydrous silicic acid (1.0% by mass) and magnesium stearate (1.0% by mass), and then compressed to a diameter of 10.5 mm at a tableting pressure of 6.7 kN to produce 450 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0075] Example 24 Acotiamide hydrochloride hydrate (75.0% by mass), microcrystalline cellulose (8.0% by mass), and low-substituted hydroxypropyl cellulose A (10.0% by mass) were mixed and tumbling fluidized bed granulated while adding a binding liquid prepared by dispersing pregelatinized starch B (5.0% by mass) in water (96.9% by mass relative to the granulation components). The granules were then dried at 80°C and sized using a sieve sizer with a screen diameter of 1.905 mm. Light anhydrous silicic acid (1.0% by mass) and magnesium stearate (1.0% by mass) were added to the resulting granules, mixed, and then compressed to a diameter of 10.5 mm at a tableting pressure of 10.9 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0076] Comparative Example 1 Acotiamide hydrochloride hydrate (75.0% by mass) and crystalline cellulose (23.0% by mass) were mixed, and 28.7% by mass of water based on the granulation components was added and stirred to granulate. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Light anhydrous silicic acid (1.0% by mass) and magnesium stearate (1.0% by mass) were added to the resulting granules, and the mixture was then compressed to a diameter of 10.5 mm at a tableting pressure of 15.0 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0077] Comparative Example 2 Acotiamide hydrochloride hydrate (75.0% by mass) and microcrystalline cellulose (18.0% by mass) were mixed, and a binding liquid prepared by dispersing pregelatinized starch B (5.0% by mass) in water (28.7% by mass relative to the granulation components) was added, followed by stirring and granulation. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Light anhydrous silicic acid (1.0% by mass) and magnesium stearate (1.0% by mass) were added to the resulting granules, and the mixture was then compressed to a diameter of 10.5 mm at a tableting pressure of 11.0 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0078] Comparative Example 3 Acotiamide hydrochloride hydrate (75.0% by mass), microcrystalline cellulose (8.0% by mass), and crospovidone (10.0% by mass) with a water retention capacity of 670% were mixed, and the mixture was granulated in a tumbling fluidized bed granulator while adding a binding liquid prepared by dispersing pregelatinized starch B (5.0% by mass) in water (45.9% by mass relative to the granulation components). The mixture was dried and sieved through a sieve with an opening of 850 μm. The resulting granules were mixed with light anhydrous silicic acid (1.0% by mass) and magnesium stearate (1.0% by mass), and then compressed to a diameter of 10.5 mm at a tableting pressure of 10.6 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0079] Comparative Example 4 Acotiamide hydrochloride hydrate (75.0% by mass), crystalline cellulose (8.0% by mass), and carmellose (10.0% by mass) with a water retention capacity of 215% were mixed, and a binder solution prepared by dispersing pregelatinized starch B (5.0% by mass) in water (31.9% by mass relative to the granulation components) was added, followed by stirring and granulation. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Light anhydrous silicic acid (0.5% by mass) and magnesium stearate (1.5% by mass) were added to the resulting granules, mixed, and then compressed to a diameter of 10.5 mm at a tableting pressure of 15.0 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0080] Comparative Example 5 Acotiamide hydrochloride hydrate (75.0% by mass), crystalline cellulose (13.0% by mass), and low-substituted hydroxypropyl cellulose A (10.0% by mass) were mixed, and 47.8% by mass of water was added relative to the granulation components, followed by stirring and granulation. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. The resulting granules were mixed with light anhydrous silicic acid (0.5% by mass) and magnesium stearate (1.5% by mass), and then compressed to a diameter of 10.5 mm at a tableting pressure of 11.0 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0081] Comparative Example 6 Acotiamide hydrochloride hydrate (66.7% by mass), hypromellose (5.0% by mass), lactose hydrate (4.3% by mass), microcrystalline cellulose (2.0% by mass), and low-substituted hydroxypropyl cellulose A (20.0% by mass) were mixed, and 34.0% by mass of water was added relative to the granulation components, followed by stirring and granulation. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. The resulting granules were mixed with light anhydrous silicic acid (1.0% by mass) and magnesium stearate (1.0% by mass), and then compressed to a diameter of 11.5 mm at a tableting pressure of 11.8 kN to produce 450 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0082] Comparative Example 7 Acotiamide hydrochloride hydrate (66.7% by mass), hydroxypropyl cellulose (5.0% by mass), lactose hydrate (4.3% by mass), crystalline cellulose (2.0% by mass), and low-substituted hydroxypropyl cellulose A (20.0% by mass) were mixed, and 34.0% by mass of water was added relative to the granulation components, followed by stirring and granulation. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. The resulting granules were mixed with light anhydrous silicic acid (1.0% by mass) and magnesium stearate (1.0% by mass), and then compressed to a diameter of 11.5 mm at a tableting pressure of 10.6 kN to produce 450 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0083] Comparative Example 8 Acotiamide hydrochloride hydrate (75.0% by mass), crystalline cellulose (13.0% by mass), and low-substituted hydroxypropyl cellulose A (10.0% by mass) were mixed, and 47.8% by mass of water was added relative to the granulation components, followed by stirring and granulation. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. The resulting granules were mixed with light anhydrous silicic acid (1.0% by mass) and magnesium stearate (1.0% by mass), and then compressed to a diameter of 10.5 mm at a tableting pressure of 11.0 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0084] Comparative Example 9: Acotiamide hydrochloride hydrate (75.0% by mass) was mixed with a binder solution prepared by dispersing pregelatinized starch B (10.0% by mass) in 25% ethanol (29.4% by mass relative to the granulation components) and granulated with stirring. The granules were then dried at 50°C and sieved through a sieve with an opening of 850 μm. The resulting granules were mixed with microcrystalline cellulose (8.5% by mass), crospovidone (5.0% by mass) with a water retention capacity of 312%, and magnesium stearate (1.5% by mass), and then compressed to a diameter of 10.5 mm at a tableting pressure of 14.8 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0085] Comparative Example 10: A binding liquid prepared by dispersing pregelatinized starch B (4.3% by mass) in water (20.3% by mass relative to the granulation components) was added to acotiamide hydrochloride hydrate (84.9% by mass), followed by stirring and granulation. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Low-substituted hydroxypropyl cellulose A (8.7% by mass) and magnesium stearate (2.0% by mass) were added to the resulting granules, mixed, and then compressed to a diameter of 10.5 mm at a tableting pressure of 15.0 kN to produce 345 mg tablets containing 293 mg of acotiamide hydrochloride hydrate.

[0086] Comparative Example 11 Acotiamide hydrochloride hydrate (75.6% by mass) and hydroxypropyl cellulose (2.7% by mass) were mixed, and 6.8% by mass of water based on the granulation components was added and stirred to granulate. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. The resulting granules were mixed with pregelatinized starch D (8.0% by mass), crystalline cellulose (9.3% by mass), corn starch (2.7% by mass), light anhydrous silicic acid (1.3% by mass), and magnesium stearate (0.5% by mass), and then compressed to a diameter of 10.5 mm at a tableting pressure of 11.0 kN to produce 377 mg tablets containing 285 mg of acotiamide hydrochloride hydrate.

[0087] Comparative Example 12 Acotiamide hydrochloride hydrate (76.4% by mass), pregelatinized starch B (13.4% by mass), methylcellulose (2.3% by mass), low-substituted hydroxypropyl cellulose B (6.9% by mass), and magnesium stearate (0.9% by mass) were mixed together and an attempt was made to produce a 432 mg tablet containing 330 mg of acotiamide hydrochloride hydrate and having a diameter of 10.5 mm, but the fluidity of the tableting powder was poor and production was not possible.

[0088] Comparative Example 13 Acotiamide hydrochloride hydrate (58.0% by mass) and calcium sulfate (18.0% by mass) were mixed, and 20.6% by mass of 40% ethanol based on the granulation components was added and stirred to granulate. The granules were then dried at 45°C and sieved through a sieve with an opening of 850 μm. The resulting granules were mixed with pregelatinized starch B (15.0% by mass), low-substituted hydroxypropyl cellulose A (8.8% by mass), and magnesium stearate (0.2% by mass), and then compressed to a diameter of 10.5 mm at a tableting pressure of 15.0 kN to produce 344.7 mg tablets containing 200 mg of acotiamide hydrochloride hydrate.

[0089] Comparative Example 14 Acotiamide hydrochloride hydrate (75.0% by mass) and calcium sulfate (10.0% by mass) were mixed, and 19.6% by mass of 40% ethanol based on the granulation components was added and stirred to granulate. The granules were then dried at 45°C and sieved through a sieve with an opening of 850 μm. The resulting granules were mixed with pregelatinized starch B (5.7% by mass), low-substituted hydroxypropyl cellulose A (8.8% by mass), and magnesium stearate (0.5% by mass), and then compressed to a diameter of 10.5 mm at a tableting pressure of 15.0 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0090] Comparative Example 15 Acotiamide hydrochloride hydrate (75.6% by mass) and hydroxypropyl cellulose (2.7% by mass) were mixed, and 16.9% by mass of water based on the granulation components was added and stirred to granulate. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. The resulting granules were mixed with pregelatinized starch D (8.0% by mass), crystalline cellulose (9.3% by mass), corn starch (2.7% by mass), light anhydrous silicic acid (1.3% by mass), and magnesium stearate (0.5% by mass), and then compressed to a diameter of 10.5 mm at a tableting pressure of 11.0 kN to produce 400 mg tablets containing 302 mg of acotiamide hydrochloride hydrate.

[0091] Comparative Example 16: A binding liquid prepared by dispersing pregelatinized starch B (4.3% by mass) in water (28.4% by mass relative to the granulation components) was added to acotiamide hydrochloride hydrate (84.9% by mass), followed by stirring and granulation. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Low-substituted hydroxypropyl cellulose A (8.7% by mass) and magnesium stearate (2.0% by mass) were added to the resulting granules, mixed, and then compressed to a diameter of 10.5 mm at a tableting pressure of 14.6 kN to produce 400 mg tablets containing 340 mg of acotiamide hydrochloride hydrate.

[0092] Comparative Example 17 Acotiamide hydrochloride hydrate (75.0% by mass), crystalline cellulose (13.0% by mass), and sodium starch glycolate A (10.0% by mass) were mixed, and 44.6% by mass of water based on the granulation components was added and stirred to granulate. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Light anhydrous silicic acid (0.5% by mass) and magnesium stearate (1.5% by mass) were added to the resulting granules, and the mixture was then compressed to a diameter of 10.5 mm at a tableting pressure of 10.4 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0093] Comparative Example 18 Acotiamide hydrochloride hydrate (75.0% by mass), hypromellose (5.0% by mass), microcrystalline cellulose (8.0% by mass), and sodium starch glycolate A (10.0% by mass) were mixed, and 44.6% by mass of water based on the granulation components was added and stirred to granulate. The granules were then dried at 80°C and sieved through a sieve with an opening of 850 μm. Light anhydrous silicic acid (0.5% by mass) and magnesium stearate (1.5% by mass) were added to the resulting granules, and the mixture was compressed to a diameter of 10.5 mm at a tableting pressure of 14.6 kN to produce 400 mg tablets containing 300 mg of acotiamide hydrochloride hydrate.

[0094] The results for the obtained granules are shown in Tables 4 to 7. Tables 4 to 5 show the results for tablets stored for two weeks under open conditions in a constant temperature and humidity test room set at a temperature and humidity of 40°C / 75% RH. Tables 6 to 7 show the evaluation results for tablets stored for one week under the same conditions. Table 8 shows the ratio of the water retention capacity of acotiamide hydrochloride hydrate to pregelatinized starch in the tablets obtained in Examples 1 to 24. Tables were granulated on a 130 kg scale and compressed in a high-speed rotary tablet press at turntable rotation speeds of 30 rpm, 40 rpm, and 50 rpm. Table 9 shows the results of an appearance inspection of the obtained tablets, as well as the tableting pressure deviation (%) and mass variation coefficient (%).

[0095]

[0096]

[0097]

[0098]

[0099] The water retention ratio was calculated by (water retention capacity of pregelatinized starch / 100×mass (%) of pregelatinized starch in the formulation) / (water retention capacity of acotiamide or a salt thereof / 100×mass (%) of acotiamide or a salt thereof in the formulation).

[0100]

[0101]

[0102] The results of Comparative Example 12 show that when a high content of acotiamide hydrochloride hydrate is contained, it is difficult from the viewpoint of manufacturability to compress and mold tablets without carrying out a granulation step.

[0103] The results of Comparative Examples 1 and 2 show that poor dissolution is a problem when the granules do not contain (C) low-substituted hydroxypropyl cellulose or sodium starch glycolate. The results of Comparative Example 5 show that a decrease in hardness after storage under high humidity conditions is a problem when the granules do not contain component (B) pregelatinized starch. The results of Comparative Examples 9 and 10 show that a decrease in hardness after storage under high humidity conditions is a problem when a disintegrant is added to a granule containing component (A) acotiamide hydrochloride and component (B). In contrast, the results of Examples 1 to 16 show that when a granule containing component (A), component (B), and component (C) is contained, dissolution is good and the decrease in hardness after storage under high humidity conditions is suppressed, thereby achieving the effects of the present invention.

[0104] The results of Example 1, Comparative Example 6, Comparative Example 7, Comparative Example 13, and Comparative Example 14 confirmed that component (B) pregelatinized starch is suitable as a binder to be added to the granules from the viewpoint of tablet dissolution. The results of Example 2, Example 9, and Example 10 confirmed that the effects of the present invention can be achieved even when component (B) has a different value for cold water soluble content.

[0105] The results of Examples 2, 14, and Comparative Examples 3 and 4 confirmed that, from the viewpoints of dissolution property and tablet stability, component (C) low-substituted hydroxypropyl cellulose or sodium starch glycolate is suitable as a disintegrant to be added to the granules. The results of Examples 2 and 11 to 14 confirmed that the effects of the present invention can be achieved if the water retention capacity of the disintegrant is 500% or more.

[0106] The results of Example 16 confirmed that the effects of the present invention could be obtained even when the acotiamide hydrochloride hydrate content was 90.9%.

[0107] The results of Examples 2, 6, 7, 8 and 15 confirmed that as the content of component (B) pregelatinized starch decreases or increases, the hardness tends to decrease more after storage under high humidity conditions, and that there is an optimal range of the content of component (B) for tablet stability.

[0108] The results of Examples 2, 5, 14, and 15 confirmed that as the content of component (C) low-substituted hydroxypropyl cellulose or sodium starch glycolate decreased or increased, the decrease in hardness after storage under high humidity conditions tended to increase, and that there was an optimal range of the content of component (C) for tablet stability.

[0109] The results of Examples 2, 5, 6, 14, and 15 confirmed that as the total content of component (B) pregelatinized starch and component (C) low-substituted hydroxypropyl cellulose or sodium starch glycolate increases, the decrease in tablet hardness after storage under high humidity conditions tends to increase, and that there is an optimal range for dissolution property and tablet stability.

[0110] The evaluation results of the uniformity of acotiamide hydrochloride hydrate within the tablets are shown in Figures 2 and 3. From the results in Figures 2 and 3, Comparative Examples 2, 8, 11, and 12 had many scattered points where the sulfur elemental ratio was 60% or more. This indicates that acotiamide hydrochloride hydrate containing sulfur element is localized within the tablets. In contrast, Examples 2 and 4 had almost no points where the sulfur elemental ratio was 60% or more, indicating that acotiamide hydrochloride hydrate is uniformly present within the tablets.

Claims

1. A tablet comprising a granule containing (A) acotiamide or a salt thereof, (B) pregelatinized starch, and (C) a disintegrant selected from low-substituted hydroxypropyl cellulose and sodium starch glycolate, wherein the uncoated tablet contains 65% by mass or more and 91% by mass or less of component (A).

2. The tablet according to claim 1, wherein the granules are wet granules.

3. A tablet according to claim 1 or 2, wherein the content of component (B) in the uncoated tablet is 2% by mass or more and 10% by mass or less.

4. A tablet according to any one of claims 1 to 3, wherein the content of component (C) in the uncoated tablet is 5% by mass or more and 20% by mass or less.

5. A tablet according to any one of claims 1 to 4, wherein the total content of component (B) and component (C) in the uncoated tablet is 8% by mass or more.

6. A tablet according to any one of claims 1 to 5, wherein the content of component (B) in the uncoated tablet is 2% by mass or more and 8% by mass or less.

7. A tablet according to any one of claims 1 to 6, wherein the content of component (C) in the uncoated tablet is 5% by mass or more and 15% by mass or less.

8. A tablet according to any one of claims 1 to 7, wherein the total content of component (B) and component (C) in the uncoated tablet is 8% by mass or more and 25% by mass or less.

9. A tablet according to any one of claims 1 to 8, wherein the content of component (B) in the uncoated tablet is 3% by mass or more and 8% by mass or less.

10. A tablet according to any one of claims 1 to 9, wherein the total content of component (B) and component (C) in the uncoated tablet is 8% by mass or more and 22% by mass or less.

11. A method for producing a tablet containing 65% by mass or more and 91% by mass or less of component (A) in the uncoated tablet, the method comprising the step of compressing a wet granulation containing (A) acotiamide or a salt thereof, (B) pregelatinized starch, and (C) a disintegrant selected from low-substituted hydroxypropyl cellulose and sodium starch glycolate.

12. A tablet containing a wet granulated product containing (D) a medicinal ingredient, (B) pregelatinized starch, and (C) a disintegrant selected from low-substituted hydroxypropyl cellulose and sodium starch glycolate, the moisture content of the dry powder of which is 4.0% or more and 11.0% or less.

13. The tablet according to claim 12, wherein the moisture content of the dried powder of the wet granulation product is 4.0% or more and 9.0% or less.

14. The tablet according to claim 12 or 13, wherein the moisture content of the tablet is 4.0% or more and 13.0% or less.

15. The tablet according to any one of claims 12 to 14, wherein the moisture content of the tablet is 4.0% or more and 11.0% or less.

16. A tablet according to any one of claims 12 to 15, wherein (D) the active ingredient is acotiamide or a salt thereof.

17. The tablet according to any one of claims 12 to 16, wherein the moisture retention ratio of component (A) to component (B) in the tablet is 0.07 or more and 2.4 or less.

18. The tablet according to any one of claims 12 to 17, wherein the moisture retention ratio of component (A) to component (B) in the tablet is 0.15 or more and 2.0 or less.

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