Particles containing sodium azulene sulfonate, oral preparation, and method for producing sodium azulene sulfonate particles

Abstract

To provide sodium azulene sulfonate-containing particles, an oral formulation, and a method for producing sodium azulene sulfonate-containing particles, which exhibit excellent stability and high productivity. [Solution] A particle containing sodium azulene sulfonate, comprising (A) component: sodium azulene sulfonate, (B) component: antacid, and (C) component: binder, wherein component (A) exists in an amorphous state and substantially does not contain sugar alcohols.

Description

Technical Field

[0001] The present invention relates to sodium azulenesulfonate-containing particles, oral preparations, and a method for producing sodium azulenesulfonate-containing particles.

Background Art

[0002] Sodium azulenesulfonate can directly approach the repair of mucosal damage caused by various uncomfortable symptoms such as stomachache, heartburn, and a burning sensation, and is contained as an active ingredient in gastrointestinal drugs from the viewpoint of having a complex pharmacological action such as an anti-inflammatory effect and a granulation-promoting effect. However, sodium azulenesulfonate is known to be an unstable component that is gradually decomposed by light.

[0003] As a method for stabilizing sodium azulenesulfonate, for example, Patent Document 1 discloses a method in which a granulation solution containing sodium azulenesulfonate and a sugar alcohol is added to antacid particles and wet granulation is performed.

Prior Art Documents

Patent Documents

[0006] The present invention has the following aspects. [1] (A) Components: Sodium azulene sulfonate and (B) Ingredients: Antacids and (C) Components: Binder and, Includes, The above-mentioned component (A) exists in an amorphous state, Particles containing sodium azulene sulfonate, substantially free of sugar alcohols. [2] The sodium azulene sulfonate-containing particles according to [1], wherein component (B) is one or more selected from synthetic hydrotalcite, magnesium aluminosilicate, and magnesium aluminometasilicate. [3] The sodium azulene sulfonate-containing particles according to [1] or [2], wherein the (C) component is one or more selected from hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, and polyvinyl alcohol. [4] A sodium azulene sulfonate-containing particle according to any of [1] to [3] above, having an average particle diameter of 150 to 1000 μm. [5] A sodium azulene sulfonate-containing particle according to any one of [1] to [4], wherein A / B, which represents the mass ratio of the content of component (A) to the content of component (B), is 0.001 to 0.15. [6] Azulene sulfonate sodium-containing particle according to any one of [1] to [5], wherein the A / C ratio, which represents the mass ratio of the content of component (A) to the content of component (C), is 0.01 to 2. [7] An oral preparation comprising a sodium azulene sulfonate-containing particle as described in any of [1] to [6] above. [8] A method for producing sodium azulene sulfonate-containing particles according to any of the above [1] to [6], A method for producing sodium azulene sulfonate-containing particles, comprising adding a solution containing the above-mentioned components (A) and (C) to the above-mentioned component (B), and granulating by a wet granulation method. [Effects of the Invention]

[0007] According to the present invention, it is possible to provide sodium azulene sulfonate-containing particles, an oral formulation, and a method for producing sodium azulene sulfonate-containing particles that exhibit excellent stability and high productivity. [Modes for carrying out the invention]

[0008] The embodiments of the present invention will be described in detail below, but the present invention is not limited to the embodiments described below and can be implemented with various modifications within the scope of its gist. In this specification and in the claims, a numerical range represented by "~" means a numerical range that includes the numbers before and after "~" as the lower and upper limits, respectively. For example, A~B is synonymous with A or greater and B or less. The numerical ranges of content, various physical properties, and characteristic values ​​disclosed herein can be modified by arbitrarily combining their lower and upper limits to create new numerical ranges.

[0009] [Particles containing sodium azulene sulfonate] The sodium azulene sulfonate-containing particles according to the present invention contain the following components (A), (B), and (C). Particles containing sodium azulene sulfonate substantially do not contain component (D) listed below. In addition to components (A), (B), and (C), the sodium azulene sulfonate-containing particles may further contain components other than (A), (B), (C), and (D) as needed, as long as they do not impair the effects of the present invention (hereinafter also referred to as "optional components").

[0010] <(A) component> (A) The component is sodium azulene sulfonate. Sodium azulene sulfonate is a water-soluble and stable form of the active ingredient in chamomile, which has been used as a folk remedy to treat various inflammatory diseases. It possesses anti-inflammatory and wound-healing properties, and is included in over-the-counter gastrointestinal medications as a mucosal repair component because it directly addresses the repair of mucosal damage that causes various unpleasant symptoms such as stomach pain, indigestion, and burning sensations. Note that component (A) usually exists in a hydrated state. Therefore, component (A) is also called "sodium azulene sulfonate hydrate". Examples of sodium azulene sulfonate hydrates include sodium azulene sulfonate monohydrate and sodium azulene sulfonate half-hydrate. Sodium azulene sulfonate half-hydrate contains approximately 2% by mass of water in the active pharmaceutical ingredient powder. In the present invention, the content and proportion of component (A) are calculated on a 1 / 2 hydrate basis.

[0011] In particles containing sodium azulene sulfonate, component (A) exists in an amorphous state. The presence of component (A) in an amorphous state improves its stability. In the present invention, whether or not component (A) exists in an amorphous state is defined as follows: 10 mg of the sample (sodium azulene sulfonate-containing particles) is weighed, placed in an aluminum container, and differential scanning calorimeter is used to measure the differential scanning calorimeter while heating from 20°C to 120°C at a heating rate of 2°C / min. If an exothermic peak appears around 98°C, it indicates exothermic reaction due to the dissolution of component (A) in a crystalline state. Therefore, the smaller the exothermic peak around 98°C, that is, the smaller the peak area of ​​the exothermic peak around 98°C, the greater the proportion of component (A) in the sodium azulene sulfonate-containing particles that exists in an amorphous state. In this invention, when a similar differential scanning calorimetry is performed on a mixed powder obtained by mixing component (A) and component (B) (specifically, the mixed powder obtained in Comparative Example 1 described later), the peak area of ​​the exothermic peak appearing around 98°C is determined, and if the relative value of the peak area of ​​the sample to the peak area of ​​the mixed powder (relative peak area) is less than 40%, or if no exothermic peak appears (is not detected) around 98°C, it is determined that "component (A) exists in an amorphous state." A smaller relative peak area indicates a larger proportion of component (A) existing in an amorphous state. The relative peak area is preferably 25% or less, more preferably 20% or less, even more preferably 15% or less, even more preferably less than 10%, especially preferably 6% or less, particularly preferably 3% or less, and most preferably no exothermic peak appears around 98°C. Furthermore, "relative peak area less than 40%" means that the proportion of component (A) present in an amorphous state in the sodium azulene sulfonate-containing particles is 60% by mass or more of the total mass of all components (A). Furthermore, the relative peak area can be calculated using the following formula (1). Relative peak area (%) = (Peak area of ​​sample / Peak area of ​​mixed powder) × (Total amount of sample / Content of component (A) in the sample) × (6 / 106) × 100 ... (1)

[0012] The amount of component (A) in the sodium azulene sulfonate-containing particles is appropriately selected so as to be within the range of sodium azulene sulfonate commonly used in treatment, for example, as follows: The content of component (A) in the azulen sulfonic acid sodium-containing particles is preferably 0.1 to 6 mg, more preferably 0.3 to 4 mg, and even more preferably 0.5 to 3 mg as the dosage per administration. The content of component (A) in the azulen sulfonic acid sodium-containing particles is preferably 0.3 to 20 mg, more preferably 1 to 10 mg as the dosage per day. The content ratio of component (A) to the total mass of the azulen sulfonic acid sodium-containing particles is preferably 0.1 to 8% by mass, more preferably 0.2 to 5% by mass, and even more preferably 0.5 to 3% by mass. If the content of component (A) or the content ratio of component (A) is not less than the above lower limit value, pharmacological effects such as anti-inflammatory effects and granulation formation effects can be sufficiently exerted. If the content of component (A) or the content ratio of component (A) is not more than the above upper limit value, the stability of component (A) can be further enhanced, and physical properties excellent in moldability can be obtained.

[0013] <(Component B)> Component (B) is an antacid. In the present invention, the antacid refers to one having an antacid power of 200 mL or more determined by the antacid power test method defined in the Japanese Pharmacopoeia (18th edition). The antacid power determined by the antacid power test method defined in the Japanese Pharmacopoeia (18th edition) is indicated by the consumption amount (mL) of 0.1 mol / L hydrochloric acid per 1 g.

[0014] Examples of component (B) include magnesium aluminosilicate (antacid power: 250 mL), magnesium metasilicate aluminate (antacid power: 230 mL), magnesium aluminum hydroxide (antacid power: 300 mL), synthetic hydrotalcite (antacid power: 270 mL), dried aluminum hydroxide gel (antacid power: 320 mL), and the like. Among these, synthetic hydrotalcite, magnesium aluminosilicate, and magnesium metasilicate aluminate are preferable, and synthetic hydrotalcite is more preferable from the viewpoints of exhibiting an immediate and sustained gastric acid neutralization effect and having less discoloration of component (A) and the azulen sulfonic acid sodium-containing particles after storage. (B) Component may be used alone or in combination of two or more as appropriate.

[0015] (B) Component can be a commercially available antacid or particles obtained by granulating them using a known method. If component (B) is in particulate form, its average particle size is not particularly limited as long as it is within the range normally used for oral preparations, but for example, the average particle size of component (B) is preferably 10 to 500 μm, and more preferably 20 to 300 μm. Here, "(B) Average particle size" refers to the 50% particle size of the cumulative weight (weight-average particle size) obtained from the particle size distribution obtained by the sieving method (rotap method) described in the Japanese Pharmacopoeia (18th edition) "Method for determining particle size of powders".

[0016] The amount of component (B) in the sodium azulene sulfonate-containing particles is appropriately selected to be within the range normally used in treatment as an antacid. For example, the amount is preferably such that the antacid power derived from component (B) in the sodium azulene sulfonate-containing particles is 15 to 1000 mL, more preferably 50 to 1000 mL, and even more preferably 160 to 800 mL, as determined by the antacid power test method specified in the Japanese Pharmacopoeia (18th edition). One or more types of component (B) can be used in combination as long as the antacid power derived from component (B) falls within the above range. If the antacid power derived from component (B) falls within the above range, it has the gastric acid neutralizing power necessary to exert its effect as a gastrointestinal medicine. In addition, the stability of component (A) is further enhanced. Note that the antacid power derived from component (B) in the sodium azulene sulfonate-containing particles is the value based on the daily dose.

[0017] An example of a preferred range for the content of component (B) in sodium azulene sulfonate-containing particles is as follows: The content of component (B) in the azulene sulfonate sodium-containing particles is preferably 50 to 1000 mg per dose, more preferably 100 to 800 mg, and even more preferably 150 to 600 mg. The amount of component (B) in the azulene sulfonate sodium-containing particles is preferably 100 to 3000 mg per day, and more preferably 250 to 2000 mg. The content of component (B) relative to the total mass of azulene sulfonate sodium-containing particles is preferably 40 to 98% by mass, more preferably 50 to 97% by mass, and even more preferably 80 to 96% by mass. In particular, when component (B) is one or more selected from magnesium hydroxide, magnesium aluminosilicate, synthetic hydrotalcite, magnesium aluminometasilicate, and calcium carbonate, the content of component (B) is more preferably 3 to 90% by mass, and even more preferably 10 to 75% by mass. If the content or proportion of component (B) is above the lower limit, the acid-neutralizing power necessary for the gastrointestinal effect can be well maintained. In addition, the stability of component (A) is further enhanced. If the content or proportion of component (B) is below the upper limit, when sodium azulene sulfonate-containing particles are made into tablets, the tablets will not become too large, and the ease of administration will be improved. Note that the content and percentage of component (B) are calculated on an anhydrous basis.

[0018] Furthermore, the A / B ratio (hereinafter also referred to as the "A / B ratio"), which represents the mass ratio of the content of component (A) (mg) to the content of component (B) (mg), is preferably 0.001 to 0.15, more preferably 0.004 to 0.1, and even more preferably 0.004 to 0.08. If the A / B ratio is within the above range, the stability of component (A) is further improved. In particular, if the A / B ratio is below the above upper limit, the amount of component (B) added to component (A) will not be too large, and when the azulene sulfonate sodium-containing particles are made into tablets, the tablets will not become too large, improving ease of administration.

[0019] <(C) component> Component (C) is a binder. Examples of binders include hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, hydroxyethylcellulose, gum arabic, pregelatinized starch, carboxyvinyl polymer, agar, and honey. Among these, hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and hydroxyethylcellulose are preferred from the viewpoint of ease of adjusting the viscosity range during manufacturing and further reducing powder adhesion to the walls of the granulator; hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol are more preferred; and hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol are even more preferred. (C) Component may be used alone or in combination of two or more as appropriate.

[0020] The content of component (C) in the sodium azulene sulfonate-containing particles is appropriately selected to be within the range typically used as a binder, for example, as follows: The content of component (C) in the azulene sulfonate sodium-containing particles is preferably 0.3 to 30 mg per dose, more preferably 0.5 to 25 mg, and even more preferably 1 to 20 mg. The amount of component (C) in the azulene sulfonate sodium-containing particles is preferably 1 to 100 mg per day, and more preferably 5 to 50 mg. The content ratio of component (C) to the total mass of azulene sulfonate sodium-containing particles is preferably 0.5 to 40% by mass, more preferably 1 to 25% by mass, and even more preferably 2 to 20% by mass. If the content or proportion of component (C) is within the above range, the stability of component (A) will be further improved. In particular, if the content or proportion of component (C) is above the lower limit, the adhesion of powder to the walls of the granulator can be further reduced when producing sodium azulene sulfonate-containing particles, thereby increasing productivity. If the content or proportion of component (C) is below the upper limit, the variation in particle size of sodium azulene sulfonate-containing particles will be reduced.

[0021] Furthermore, the A / C ratio (hereinafter also referred to as the "A / C ratio"), which represents the mass ratio of the content of component (A) (mg) to the content of component (C) (mg), is preferably 0.01 to 2, more preferably 0.03 to 1, and even more preferably 0.05 to 0.8. If the A / C ratio is within the above range, the stability of component (A) is further improved. In addition, when manufacturing sodium azulene sulfonate-containing particles, the adhesion of powder to the walls of the granulator can be further reduced, and productivity is further increased. In particular, if the A / C ratio is below the above upper limit, the variation in particle size of sodium azulene sulfonate-containing particles is reduced.

[0022] Furthermore, the total percentage of components (A), (B), and (C) relative to the total mass of azulene sulfonate sodium-containing particles is preferably 50% by mass or more, more preferably 65% ​​by mass or more, even more preferably 75% by mass or more, and may also be 100% by mass, 95% by mass or less, or 90% by mass or less.

[0023] <(D) component> Component (D) is a sugar alcohol. Examples of sugar alcohols include mannitol, maltitol, erythritol, xylitol, sorbitol, palatinitol, and lactitol.

[0024] The particles containing sodium azulene sulfonate are substantially free of sugar alcohol, which is component (D). Therefore, when manufacturing the particles containing sodium azulene sulfonate, the adhesion of powder to the walls of the granulator can be reduced, thereby increasing productivity. In the present invention, "substantially absent" means that the content ratio of component (D) to the total mass of sodium azulene sulfonate-containing particles is 0.5% by mass or less. The content ratio of component (D) is preferably 0.1% by mass or less, more preferably 0.01% by mass or less, and even more preferably below the detection limit.

[0025] <Optional ingredients> Optional ingredients include, for example, active ingredients other than components (A) and (B) (hereinafter also referred to as "other active ingredients"), organic acids, excipients, disintegrants, bases, sweeteners, lubricants, preservatives, fragrances, flavorings, colorants, etc. The optional components may be used individually or in appropriate combinations of two or more.

[0026] Other active ingredients include, for example, mucosal repair components such as algioxa, sucralfate, copper chlorophyllin sodium, methylmethionine sulfonium chloride, teprenone, sulpiride, praunotol, gefarnate, cetraxate hydrochloride, and L-glutamine; gastric acid secretion inhibitors such as ranitidine or ranitidine hydrochloride, famotidine, cimetidine, roxatidine acetate hydrochloride, nizatidine, lafutidine, lansoprazole, rabeprazole, omeprazole, and vonoprazan; muscarinic receptor antagonists such as belladonna extract, atropine, and scopolamine; and stomachic herbal ingredients such as magnolia fluid extract, laurel fluid extract, turmeric fluid extract, ginseng fluid extract, Coptis japonica tincture, clove tincture, gentian tincture, and cinnamon tincture. Among these, mucosal repair components are preferred because they can directly address the repair of mucosal damage that causes various unpleasant symptoms such as pain, bloating, and burning. Other active ingredients may be used individually or in combination of two or more as appropriate.

[0027] Components (A), (B), and other active ingredients can be used in combination with organic acids. While there are no particular limitations on the organic acids used, alginic acid, citric acid, malic acid, ascorbic acid, glucuronic acid, aspartic acid, glutamic acid, adipic acid, gluconic acid, tartaric acid, succinic acid, lactic acid, acetic acid, butyric acid, maleic acid, and fumaric acid are preferred from the viewpoint of excellent flavor and dispersion stability. Among these, citric acid, malic acid, and lactic acid are more preferred. Organic acids may be used individually or in appropriate combinations of two or more types.

[0028] Examples of excipients include monosaccharides, oligosaccharides such as lactose, polysaccharides and other sugars, starches such as corn starch, crystalline cellulose, and potato starch, sodium bicarbonate, and sucrose. Examples of disintegrants include crospovidone, croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, and low-substituted hydroxypropyl cellulose. Examples of base materials include lower alcohols such as ethanol; and polyhydric alcohols such as polyethylene glycol (PEG), glycerin, and propylene glycol. Examples of sweeteners include sucrose, fructose, aspartame, sucralose, thaumatin, acesulfame potassium, sorbitol, stevia, refined white sugar, saccharin, and glycyrrhizin. Examples of lubricants include magnesium stearate, calcium stearate, sodium stearyl fumarate, sucrose fatty acid esters, light anhydrous silicic acid, hydrated silicon dioxide, and talc. Examples of preservatives include parabens such as alkylparabens, benzoic acid, and sodium benzoate. Examples of fragrances include well-known essential oils such as limonene, orange flavor, lychee flavor, lemon flavor, lime flavor, strawberry flavor, pineapple flavor, mint flavor, and grapefruit flavor. Examples of stimulants include menthol (l-isomer, dl-isomer). Examples of pigments include caramel, carmine, carotene solution, beta-carotene, copper chlorophyll, and copper chlorophyllin sodium. These excipients, disintegrants, sweeteners, lubricants, preservatives, fragrances, flavorings, and colorants may be used individually or in appropriate combinations of two or more. Furthermore, the total content of components (A) to (D) and any optional components in the sodium azulene sulfonate-containing particles shall not exceed 100% by mass.

[0029] <Particle size> The average particle size of the sodium azulene sulfonate-containing particles is preferably 150 to 1000 μm, more preferably 200 to 750 μm, and even more preferably 250 to 500 μm. If the average particle size of the sodium azulene sulfonate-containing particles is above the lower limit, component (A) is more likely to exist in an amorphous state within the sodium azulene sulfonate-containing particles, meaning that the proportion of component (A) existing in an amorphous state increases, and the stability of component (A) is further enhanced. If the average particle size of the sodium azulene sulfonate-containing particles is below the upper limit, heterogeneity during mixing with other additives and active pharmaceutical ingredients when manufacturing pharmaceutical formulations using sodium azulene sulfonate-containing particles is further reduced, and mixing uniformity can be maintained. Here, "average particle size of particles containing sodium azulene sulfonate" refers to the 50% particle size of the cumulative weight (weight-average particle size) obtained from the particle size distribution obtained by the sieving method (rotap method) described in the Japanese Pharmacopoeia (18th edition) "Method for determining particle size of powders".

[0030] <Manufacturing method> Particles containing sodium azulene sulfonate can be obtained, for example, by adding a solution containing components (A) and (C) (hereinafter also referred to as the "granulation solution") to component (B) and granulating it using a wet granulation method. In other words, the method for producing sodium azulene sulfonate-containing particles includes the granulation step described below. Furthermore, the method may further include a preparation step for preparing a granulation solution prior to the granulation step. Additionally, if necessary, the method may further include a drying step after the granulation step. Furthermore, when manufacturing particles containing sodium azulene sulfonate, sugar alcohols, which are substantially component (D), are not used.

[0031] (Preparation process) The preparation step is the step of preparing a granulated solution containing component (A) and component (C). The proportion of component (A) and component (C) in the granulation solution is preferably such that the A / C ratio is 0.01 to 2, and more preferably 0.05 to 1. Furthermore, the combined content of component (A) and component (C) in the granulation solution is preferably 0.5 to 20% by mass relative to the total mass of the granulation solution.

[0032] The granulation solution contains a solvent in addition to components (A) and (C). Examples of solvents include water; hydrophilic solvents such as ethanol; and mixed solvents of water and hydrophilic solvents. Among these, water or a mixed solvent of water and ethanol is preferred. The proportion of solvent in the granulation solution is preferably 87% by mass or more, more preferably 88% by mass or more, even more preferably 90% by mass or more, and preferably 99% by mass or less, when the total of component (A), component (C), and solvent is taken as 100% by mass. If the proportion of solvent is above the lower limit, the average particle size of the sodium azulene sulfonate-containing particles tends to increase. As a result, component (A) tends to exist in an amorphous state in the sodium azulene sulfonate-containing particles, that is, the proportion of component (A) existing in an amorphous state increases, and the stability of component (A) tends to increase. If the proportion of solvent is below the upper limit, an appropriate amount of granulation solution can be obtained, and the addition of the granulation solution to component (B) in the granulation process becomes easier.

[0033] The granulation solution may further contain, as optional, the aforementioned components in addition to components (A), (C), and the solvent. However, the granulated solution is substantially free of component (D). Specifically, the content of component (D) relative to the total mass of the granulated solution is preferably 0.5% by mass or less, more preferably 0.1% by mass or less, even more preferably 0.05% by mass or less, and particularly preferably below the detection limit.

[0034] (granulation process) The granulation process involves adding the above-mentioned granulation solution to component (B) and granulating it using a wet granulation method. Examples of wet granulation methods include rolling granulation, extrusion granulation, fluidized bed granulation, agitation granulation, and kneading granulation. Among these, agitation granulation is preferred, and agitation granulation, in which the granulation solution is added while stirring component (B) using a high-speed agitation granulator (e.g., a high-speed mixer), is more preferred. In another respect, fluidized bed granulation is preferred. In fluidized bed granulation, the granulation solution is added while the component (B) is fluidized with hot air using a fluidized bed granulator and dryer. Since the fluidized bed granulation method allows the granulation process and the drying process described later to be carried out in an integrated manner, sodium azulene sulfonate-containing particles can be produced efficiently. These granulation methods can be carried out using known granulation apparatus. The amounts of each component (A), (B), and (C) added are adjusted as appropriate so that the content ratio and mass ratio of each component in the sodium azulene sulfonate-containing particles are within the range described above.

[0035] The time and rate of adding the granulation solution to component (B) are not particularly limited, but for example, the preferred rate of addition is 20 to 100 mL / min per 1 kg of component (B), more preferably 25 to 70 mL / min, and even more preferably 30 to 40 mL / min. The slower the addition rate and the longer the addition time, the larger the average particle size of the sodium azulene sulfonate-containing particles tends to be. As a result, component (A) is more likely to exist in an amorphous state within the sodium azulene sulfonate-containing particles, meaning that the proportion of component (A) existing in an amorphous state increases, and the stability of component (A) tends to improve. On the other hand, if the addition time is too long, the average particle size of the sodium azulene sulfonate-containing particles becomes too large, which may result in a particle size unsuitable for mixing with other additives or active pharmaceutical ingredients or for tableting when manufacturing pharmaceutical preparations such as tablets using sodium azulene sulfonate-containing particles. In addition, productivity tends to decrease. If the addition time is below the above upper limit, productivity can be maintained at a good level. Note that "addition time" refers to the time from the start to the end of adding component (B) of the granulation solution.

[0036] (drying process) The drying process is the process of drying the granulated particles obtained in the granulation process. The drying method for granulated particles is not particularly limited, but examples include drying the granulated particles while they are flowing in a fluidized bed granulator and dryer, drying the granulated particles in a shelf dryer, drying the granulated particles in a dry oven, and freeze-drying the granulated particles. The drying temperature (supply air temperature) and drying time are not particularly limited, and the drying process should be carried out under conditions that result in a desired moisture content for the sodium azulene sulfonate-containing particles. For example, the drying temperature is preferably 40 to 90°C, and the drying time is preferably 15 minutes or more and 5 hours or less.

[0037] The moisture content of the sodium azulene sulfonate-containing particles after the drying process is preferably 10% by mass or less, and more preferably 5% by mass or less, relative to the total mass of the sodium azulene sulfonate-containing particles. If the moisture content is below the above upper limit, the stability of component (A) is further improved. While a lower moisture content is preferable for sodium azulene sulfonate-containing particles, considering the moisture carried in from each component, the moisture content of sodium azulene sulfonate-containing particles is preferably 0.1% by mass or more, and more preferably 0.5% by mass or more, relative to the total mass of the sodium azulene sulfonate-containing particles. The moisture content of sodium azulene sulfonate-containing particles can be calculated from the loss on drying when the particles are heated at 120°C for 10 minutes using an electronic moisture meter (for example, the "MOISTURE BALANCE MOC-120H" product manufactured by Shimadzu Corporation).

[0038] Component (A), used in the production of sodium azulene sulfonate-containing particles, is a crystalline powder before dissolving in the solvent, but dissolves in the granulation solution to become a solution. When the granulation solution is added to component (B), component (A) adheres to the surface of component (B), or, if component (B) is a porous material such as synthetic hydrotalcite, magnesium aluminosilicate, or magnesium aluminometasilicate, component (A) penetrates into the interior of component (B), and component (A), dissolved in the solvent, is supported on component (B). When granulation and drying are performed in this state, the solvent evaporates, and component (A) is supported on component (B) in an amorphous state. It is thought that sodium azulene sulfonate-containing particles containing component (A) in an amorphous state, component (B), and component (C) are obtained. In other words, some or all of component (A) in the sodium azulene sulfonate-containing particles (specifically, 60% by mass or more of component (A)) is supported on component (B). The greater the proportion of component (A) that is supported on component (B), the greater the proportion of component (A) that exists in an amorphous state. The larger the average particle size of the sodium azulene sulfonate-containing particles, the greater the proportion of component (A) that is supported on component (B).

[0039] <Effects and Effects> As described above, the sodium azulene sulfonate-containing particles of the present invention have excellent stability because component (A) exists in an amorphous state. Moreover, the sodium azulene sulfonate-containing particles are substantially free of sugar alcohols. To obtain sodium azulene sulfonate-containing particles that are substantially free of sugar alcohols, the particles are manufactured without using sugar alcohols, which reduces the adhesion of powder to the walls of the granulator, thus enabling the production of sodium azulene sulfonate-containing particles with high productivity. Therefore, the sodium azulene sulfonate-containing particles of the present invention also have excellent productivity. Furthermore, the method for producing sodium azulene sulfonate-containing particles of the present invention allows for the productive production of sodium azulene sulfonate-containing particles with excellent stability.

[0040] Using the sodium azulene sulfonate-containing particles of the present invention, a gastrointestinal medicine that is highly effective against stomach pain and various unpleasant stomach symptoms can be obtained. The effects and efficacy of the sodium azulene sulfonate-containing particles of the present invention, and pharmaceutical preparations containing sodium azulene sulfonate-containing particles, include stomach pain, indigestion, stomach heaviness, abdominal bloating, stomach discomfort, dyspepsia, abdominal bloating due to dyspepsia, promotion of digestion, loss of appetite, overeating, excessive drinking, nausea (nausea from hangovers, stomach upset, vomiting, sickness), chest tightness, vomiting, heartburn, excessive stomach acid, and belching.

[0041] [Pharmaceutical preparations] The pharmaceutical formulation according to the present invention contains particles containing sodium azulene sulfonate. That is, the pharmaceutical formulation contains component (A), component (B), and component (C) described above. The pharmaceutical preparation may consist solely of the pharmaceutical preparation of the present invention, or it may be a combination of the pharmaceutical preparation of the present invention and other components (such as a carrier or coating). Examples of carriers include containers (such as capsules) that contain pharmaceutical preparations, and substrates (such as adhesive substrates) that hold layers of pharmaceutical preparations on their surfaces. Examples of coatings include film coating layers and sugar coating layers.

[0042] <Dosage form> The dosage form of a pharmaceutical preparation can be appropriately selected according to the method of administration. Examples of methods of administration for pharmaceutical preparations include oral administration (including preparations that can be applied orally) and parenteral administration (inhalation, vaginal administration, transdermal administration, etc.). The dosage form of the oral preparation is not particularly limited and can be used in the form of tablets (orally disintegrating tablets, chewable tablets, effervescent tablets, etc.), granules, fine granules, capsules, powders, lozenges, pills, gums, etc. Examples of tablets include uncoated tablets and coated tablets (film-coated tablets, sugar-coated tablets, etc.). Examples of capsules include soft capsules, etc. Capsules may also be microcapsules.

[0043] These dosage forms can be formulated by adding appropriate pharmaceutically acceptable liquid or solid organic acids, excipients, disintegrants, bases, sweeteners, lubricants, preservatives, fragrances, flavorings, colorants, and other auxiliary agents (pharmaceutical additives). To prepare oral solid dosage forms such as tablets, granules, fine granules, capsules, powders, lozenges, pills, and chewables, excipients such as sodium bicarbonate, starch, sucrose, and mannitol, and additives such as calcium stearate, magnesium stearate, and glycerin, can be added by conventional methods. Such preparations are preferred for oral administration and can effectively act on the stomach and duodenum. Furthermore, they can be formulated as enteric-coated preparations that disintegrate in the small intestine by applying an enteric coating such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol phthalate, styrene-maleic anhydride copolymer, or methacrylic acid-methyl methacrylate copolymer. Furthermore, the organic acids, excipients, disintegrants, bases, sweeteners, lubricants, preservatives, fragrances, flavorings, and colorants mentioned above may be those exemplified in the description of optional components contained in the sodium azulene sulfonate-containing particles.

[0044] Furthermore, sugar alcohols may be used as excipients during formulation. That is, a pharmaceutical preparation may be manufactured by mixing azulene sulfonate sodium-containing particles with sugar alcohols, etc. In this case, although the azulene sulfonate sodium-containing particles themselves do not substantially contain sugar alcohols, the pharmaceutical preparation contains sugar alcohols, etc., in addition to the azulene sulfonate sodium-containing particles. Examples of sugar alcohols include component (D), which was previously exemplified in the description of the sodium azulene sulfonate-containing particles.

[0045] From the viewpoint of usability, oral formulations are preferred for pharmaceutical preparations, and from the viewpoint of the stability of component (A), solid formulations such as tablets, granules, fine granules, capsules, powders, powders, lozenges, pills, and gums are more preferred, tablets, granules, fine granules, capsules, powders, and pills are even more preferred, and from the viewpoint of superior ease of administration, including taste, tablets, granules, fine granules, capsules, and powders are particularly preferred. Furthermore, oral preparations of pharmaceutical products are also specifically called "oral preparations." Among oral preparations, solid preparations are also called "oral solid preparations."

[0046] <Content> The content of component (A) in the pharmaceutical preparation is preferably 0.001 to 3% by mass, and more preferably 0.001 to 1.5% by mass, relative to the total mass of the pharmaceutical preparation. If the content of component (A) is above the lower limit, it can fully exert pharmacological effects such as anti-inflammatory effects and granulation-forming effects. If the content of component (A) is below the upper limit, the stability of component (A) is further enhanced, and it can be made to have excellent moldability.

[0047] The content of component (B) in the pharmaceutical preparation is preferably 2 to 95% by mass relative to the total mass of the pharmaceutical preparation. In particular, when component (B) is one or more selected from magnesium hydroxide, synthetic hydrotalcite, magnesium aluminosilicate, magnesium aluminometasilicate, and calcium carbonate, the content of component (B) is more preferably 3 to 90% by mass, and even more preferably 10 to 75% by mass. If the content of component (B) is above the lower limit above, the gastric acid neutralizing power necessary for the manifestation of the effect as a gastrointestinal drug can be well maintained. In addition, the stability of component (A) is further enhanced. If the content of component (B) is below the upper limit above, if the pharmaceutical preparation is in tablet form, the tablets will not become too large, and the ease of administration will be improved.

[0048] The content of component (C) in the pharmaceutical preparation is preferably 0.1 to 12% by mass, and more preferably 0.5 to 8% by mass, relative to the total mass of the pharmaceutical preparation. If the content of component (C) is within the above range, the stability of component (A) is further improved.

[0049] <Moisture content> The water content of the pharmaceutical preparation is preferably 15% by mass or less, and more preferably 13% by mass or less, relative to the total mass of the pharmaceutical preparation. If the water content is below the above upper limit, the stability of component (A) in the pharmaceutical preparation is further improved. While a lower water content in a pharmaceutical preparation is preferable, considering the water content from each component, the water content of the pharmaceutical preparation should be, for example, 0.1% by mass or more, and preferably 0.5% by mass or more, relative to the total mass of the pharmaceutical preparation. The moisture content of pharmaceutical preparations can be measured using the same method as for sodium azulene sulfonate-containing particles. If the pharmaceutical preparation is in the form of tablets, the tablets should be crushed and the moisture content measured.

[0050] <Dosage> The pharmaceutical preparation can be taken orally, and the dosage can be appropriately selected depending on the dosage form, the patient's sex, body type, constitution, and age, but it is generally preferable to take it 1 to 4 times a day. Furthermore, the amount of sodium azulene sulfonate-containing particles in the pharmaceutical preparation is preferably 0.1 to 200 mg per kg of body weight per dose, and more preferably 0.5 to 100 mg.

[0051] <Manufacturing method> The method for manufacturing the pharmaceutical preparation is not particularly limited and can be manufactured by known manufacturing methods. For example, an oral preparation can be obtained by formulating the sodium azulene sulfonate-containing particles of the present invention and, if necessary, the above-mentioned pharmaceutical additives to form a desired dosage form. When the pharmaceutical preparation is in tablet form, tablets can be manufactured by compressing particles containing sodium azulene sulfonate, or a mixture of sodium azulene sulfonate particles and an auxiliary agent, using a tablet press, and applying a coating as necessary. [Examples]

[0052] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following description. Unless otherwise specified, the amounts of components used in each example are calculated on a pure content basis.

[0053] "Raw materials used" The following compounds were used as raw materials. The terms "JP," "JP Standards," and "USP" below indicate that the raw materials conform to the 18th edition of the Japanese Pharmacopoeia, the 2002 Japanese Pharmacopoeia Standards for Non-Pharmacopoeial Drugs, and the United States Pharmacopeia, respectively. • Sodium azulene sulfonate: Manufactured by Alps Pharmaceutical Co., Ltd., product name "Sodium Azulene Sulfonate (Water-soluble Azulene)", hydrate, compliant with non-pharmacopoeia regulations. Synthetic hydrotalcite: Manufactured by Kyowa Chemical Industry Co., Ltd., product name "Alkamac SH", antacid power: 285 mL, compliant with pharmacopoeia standards. Magnesium aluminosilicate: Manufactured by Fuji Chemical Industry Co., Ltd., product name "Neusilin A (AS)", antacid power: 278 mL, conforms to the Japanese Pharmacopoeia. Magnesium aluminometasilicate: Manufactured by Fuji Chemical Industry Co., Ltd., product name "Neusilin NFL2N", antacid: 230 mL, compliant with the Japanese Pharmacopoeia. • Hydroxypropylcellulose: Manufactured by Nisso Shoji Co., Ltd., product name "HPC-L". • Hydroxypropyl methylcellulose: Manufactured by Shin-Etsu Chemical Co., Ltd., product name "Metholose 60SH-50", compliant with the Japanese Pharmacopoeia. • Polyvinylpyrrolidone: Manufactured by ISP Technologies, product name "POLYPLASDONE XL", USP compliant. • Polyvinyl alcohol: Manufactured by Mitsubishi Chemical Corporation, product name "Gosenol EG-50P", conforms to the Japanese Pharmacopoeia. • Sucralfate hydrate: Manufactured by Fuji Chemical Industry Co., Ltd., product name "Sucralfate hydrate", compliant with the Japanese Pharmacopoeia. • D-Mannitol: Manufactured by Mitsubishi Corporation Life Sciences Co., Ltd., product name "Mannit P", compliant with the Japanese Pharmacopoeia.

[0054] "Measurement and Evaluation" <Measurement of particle size> The average particle size of particles containing sodium azulene sulfonate was determined by measuring the weight-based particle size distribution in accordance with the sieving method (rotap method) described in the Japanese Pharmacopoeia (18th edition) "Method for Measuring the Particle Size of Powders," and the particle size corresponding to 50% of the cumulative distribution (median diameter) was defined as the average particle size (weight-average particle size) of particles containing sodium azulene sulfonate.

[0055] <Analysis of Amorphization> 10 mg of the sample (sodium azulene sulfonate-containing particles, etc.) was weighed and placed in an aluminum container. Differential scanning calorimeter (NETZSCH, product name "DSC3500Sirius") was used to measure the differential scanning calorimeter while the temperature was increased from 20°C to 120°C at a heating rate of 2°C / min. If an exothermic peak appeared around 98°C, the peak area was calculated. Separately, the same differential scanning calorimetry was performed on the mixed powder obtained in Comparative Example 1, and the peak area of ​​the exothermic peak around 98°C was determined. The relative peak area of ​​the sample to the peak area of ​​the mixed powder obtained in Comparative Example 1 (relative peak area) was calculated using the following formula (1), and it was determined whether or not sodium azulene sulfonate was present in an amorphous state in the sodium azulene sulfonate-containing particles based on the evaluation criteria shown below. A △ or ○ indicates that sodium azulene sulfonate is present in an amorphous state. Relative peak area (%) = (Peak area of ​​sample / Peak area of ​​mixed powder) × (Total amount of sample / Content of component (A) in the sample) × (6 / 106) × 100 ... (1)

[0056] (Evaluation Criteria) ○: The relative peak area is less than 10% (i.e., the proportion of sodium azulene sulfonate present in an amorphous state is 90% or more by mass of the total mass of all sodium azulene sulfonate). △: Relative peak area is 10% or more and less than 40% (i.e., the proportion of sodium azulene sulfonate present in an amorphous state is 60% or more and less than 90% by mass of the total mass of all sodium azulene sulfonate). ×: Relative peak area is 40% or more (i.e., the proportion of sodium azulene sulfonate present in an amorphous state is less than 60% by mass of the total mass of all sodium azulene sulfonate).

[0057] <Evaluation of adhesion to walls> The adhesion of powder to the walls of the granulator used for granulation was visually observed and evaluated according to the following evaluation criteria. If the granulation process was not performed, "-" was recorded in the results. (Evaluation Criteria) ○: No powder adhesion to the granulator wall was observed. △: Powder can be observed adhering to the wall surface of the granulator, but the adhesion thickness is less than 3 mm, or less than 50% of the wall surface is covered with powder. ×: Powder can be observed adhering to the wall surface of the granulator, and the adhesion thickness is 3 mm or more, or 50% or more of the wall surface is covered with powder.

[0058] <Stability Evaluation> 20 g of sodium azulene sulfonate-containing particles were placed in a glass vial, sealed, and stored at 50°C for 4 weeks. The sodium azulene sulfonate content in sodium azulene sulfonate-containing particles before and after the storage test was measured by HPLC under the following conditions. For the measurement, a sample was used which sodium azulene sulfonate was dissolved in the mobile phase to a concentration of 1.0 μg / mL. (Measurement conditions) • Measuring device: Manufactured by Shimadzu Corporation, product name "Integrated HPLC Prominence-i". ·Separation column: Manufactured by Shinwa Kako Co., Ltd., product name "STR ODS-II (5.0μm, 150mm x 4.0mm)". Mobile phase: Water / acetonitrile / triethylamine = 200 / 100 / 0.21 (volume ratio), pH = 7.5. • Mobile phase flow rate: Adjust so that the retention time of sodium azulene sulfonate is approximately 5 minutes. • Sample injection volume: 10 μL. ·Measurement temperature: 25℃.

[0059] The amount of sodium azulene sulfonate in the sodium azulene sulfonate-containing particles before the storage test was defined as the "initial content," and the amount of sodium azulene sulfonate in the sodium azulene sulfonate-containing particles after the storage test was defined as the "relative to the initial content." The relative to the initial content was calculated using the following formula (2). A higher relative to the initial content indicates superior stability of sodium azulene sulfonate. Relative to initial content (%) = (Content of sodium azulene sulfonate in sodium azulene sulfonate-containing particles after storage test / initial content) × 100 ... (2)

[0060] <Overall Rating> Based on the evaluation results of wall adhesion and stability, a comprehensive evaluation was conducted using the following evaluation criteria. (Evaluation Criteria) ◎: The initial content is 90% or more, and the evaluation result for wall adhesion is "○". ○: The initial content is 90% or more, and the evaluation result for wall adhesion is "△". △: The initial content is 90% or more, and the evaluation result for wall adhesion is "×". ×: The initial content is less than 90%.

[0061] "Example 1" A granulation solution was prepared by dissolving sodium azulene sulfonate as component (A) and hydroxypropyl cellulose as component (C) in water. The amount of water in the granulation solution was set so that when the total amount of components (A), (C), and water is 100% by mass, the amount of water is 85% by mass. The percentage of water is shown in Table 1. According to the mixing ratios shown in Table 1, a high-speed stirring granulator (high-speed mixer) was used to wet-mix granulation by adding the granulation solution at an addition rate of 30 mL / min per 1 kg of component (B) while stirring synthetic hydrotalcite as component (B), thereby obtaining granulated particles. The obtained granulated particles were dried in a shelf-type dryer at 70°C for 3 hours to obtain approximately 20 g of azulene sulfonic acid-containing particles. The obtained azulene sulfonic acid-containing particles were subjected to various measurements and evaluations. The results are shown in Tables 1 and 3. The amounts (mg) of each ingredient shown in the table represent the daily dosage.

[0062] Examples 2-4 The granulated solution was prepared in the same manner as in Example 1, except that the proportion of water when the total of component (A), component (C), and water is set to 100% by mass was changed to the value shown in Table 1. Azulene sulfonic acid-containing particles were produced in the same manner as in Example 1, except that the obtained granulation solution was used, and various measurements and evaluations were performed. The results are shown in Table 1.

[0063] Example 5 A granulated solution was prepared in the same manner as in Example 1. Azulene sulfonic acid-containing particles were produced in the same manner as in Example 1, except that the obtained granulation solution was used and the mixing ratio of component (B) was changed to the values ​​shown in Table 1. Various measurements and evaluations were then performed. The results are shown in Table 1.

[0064] "Example 6" (C) The granulated solution was prepared in the same manner as in Example 1, except that the mixing ratio of component (C) was changed to the values ​​shown in Table 1. Azulene sulfonic acid-containing particles were produced in the same manner as in Example 1, except that the obtained granulation solution was used, and various measurements and evaluations were performed. The results are shown in Table 1.

[0065] Examples 7-11 A granulated solution was prepared in the same manner as in Example 1, except that component (B) or component (C) was changed to one of the compounds shown in Table 2. Azulene sulfonic acid-containing particles were produced in the same manner as in Example 1, except that the obtained granulation solution was used and component (B) was changed to the compound shown in Table 2. Various measurements and evaluations were then performed. The results are shown in Table 2.

[0066] Examples 12-15 The granulated solution was prepared in the same manner as in Example 1, except that the mixing ratio of component (B) or component (C) was changed to the values ​​shown in Table 3. Azulene sulfonic acid-containing particles were produced in the same manner as in Example 1, except that the obtained granulation solution was used and the mixing ratio of component (B) was changed to the values ​​shown in Table 3. Various measurements and evaluations were then performed. The results are shown in Table 3.

[0067] "Comparative Examples 1 and 2" A mixed powder was obtained by mixing component (A) and component (B) according to the formulation shown in Table 4. The obtained mixed powder was subjected to various measurements and evaluations. The results are shown in Table 4.

[0068] "Comparative Example 3" A granulated solution was prepared in the same manner as in Example 1. Azulene sulfonic acid-containing particles were produced in the same manner as in Example 1, except that the obtained granulation solution was used and sucralfate hydrate was used in place of component (B) in the proportions shown in Table 4. Various measurements and evaluations were then performed. The results are shown in Table 4.

[0069] "Comparative Example 4" The granulated solution was prepared in the same manner as in Example 1, except that D-mannitol was used as component (D) instead of component (C). Azulene sulfonic acid-containing particles were produced in the same manner as in Example 1, except that the obtained granulation solution was used, and various measurements and evaluations were performed. The results are shown in Table 4.

[0070] "Comparative Examples 5 and 6" A granulated solution was prepared in the same manner as in Example 1, except that components (C) and (D) were used in combination, and their mixing ratios were changed to the values ​​shown in Table 4. Azulene sulfonic acid-containing particles were produced in the same manner as in Example 1, except that the obtained granulation solution was used and the mixing ratio of component (B) was changed to the values ​​shown in Table 4. Various measurements and evaluations were then performed. The results are shown in Table 4.

[0071] "Comparative Example 7" The granulated solution was prepared in the same manner as in Example 1, except that the proportion of water when the total of component (A), component (C), and water is set to 100% by mass was changed to the value shown in Table 4. Azulene sulfonic acid-containing particles were produced in the same manner as in Example 1, except that the obtained granulation solution was used, and various measurements and evaluations were performed. The results are shown in Table 4.

[0072] [Table 1]

[0073] [Table 2]

[0074] [Table 3]

[0075] [Table 4]

[0076] In Tables 1-4, the "A / B ratio" is the mass ratio of the content of component (A) (mg) to the content of component (B) (mg). The "A / sucralfate ratio" is the mass ratio of the content of component (A) (mg) to the content of sucralfate hydrate (mg). The "A / C ratio" is the mass ratio of the content of component (A) (mg) to the content of component (C) (mg). The "water ratio" refers to the amount of water used in preparing the granulation solution, specifically the ratio (mass%) of water when the total of component (A), component (C), and water is considered to be 100% by mass. The relative peak area [%] is an indicator of the proportion of sodium azulene sulfonate present in a crystalline state relative to the total mass of all sodium azulene sulfonate contained in the sodium azulene sulfonate-containing particles. A higher relative peak area [%] value means a higher proportion of sodium azulene sulfonate present in a crystalline state. In other words, a lower relative peak area [%] value means a higher proportion of sodium azulene sulfonate present in an amorphous state. In Example 1, no exothermic peak appeared around 98°C, so it is indicated as "-". Please note that ingredients whose amounts are not listed in the table are not included.

[0077] As shown in the results above, the azulene sulfonic acid-containing particles obtained in each example exhibited excellent stability of sodium azulene sulfonate. Furthermore, in each example, powder adhesion to the granulator walls was suppressed, allowing for the productive manufacture of azulene sulfonic acid-containing particles. In contrast, the azulene sulfonic acid-containing particles obtained in each comparative example exhibited inferior stability compared to sodium azulene sulfonate. In particular, in comparative examples 4-6, where sugar alcohols were used to produce the azulene sulfonic acid-containing particles, the powder tended to adhere to the walls of the granulator, resulting in poor productivity.

Claims

1. (A) Ingredients: Sodium azulene sulfonate and (B) Ingredients: Antacids and (C) Components: Binder and Includes, The above-mentioned component (A) exists in an amorphous state, Particles containing sodium azulene sulfonate, substantially free of sugar alcohols.

2. The sodium azulene sulfonate-containing particles according to claim 1, wherein the (B) component is one or more selected from synthetic hydrotalcite, magnesium aluminosilicate, and magnesium aluminometasilicate.

3. The sodium azulene sulfonate-containing particles according to claim 1, wherein the (C) component is one or more selected from hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, and polyvinyl alcohol.

4. Particles containing sodium azulene sulfonate according to claim 1, wherein the average particle size is 150 to 1000 μm.

5. The sodium azulene sulfonate-containing particles according to claim 1, wherein A / B, which represents the mass ratio of the content of component (A) to the content of component (B), is 0.001 to 0.

15.

6. The sodium azulene sulfonate-containing particles according to claim 1, wherein A / C, which represents the mass ratio of the content of component (A) to the content of component (C), is 0.01 to 2.

7. An oral preparation comprising a sodium azulene sulfonate-containing particle as described in any one of claims 1 to 6.

8. A method for producing sodium azulene sulfonate-containing particles according to any one of claims 1 to 6, A method for producing sodium azulene sulfonate-containing particles, comprising adding a solution containing component (A) and component (C) to component (B) and granulating by a wet granulation method.

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