JP7824025B2 - Powder composition, solid oral preparation containing powder composition, and method for producing the same - Google Patents

Description

The present invention relates to a powder composition containing sucrose octasulfate aluminum salt.

Aluminum sucrose octasulfate (sucralfate) specifically adheres to ulcers in the stomach and forms a protective film (paste) that physically protects the ulcer. In recent years, attempts have been made to apply the properties of sucralfate to areas other than the stomach, such as esophagitis, esophageal ulcers, small intestine and large intestine ulcers, and stomatitis. For example, Japanese Patent Application Laid-Open No. 8-268895 (Patent Document 1) discloses a technology that enhances the adhesiveness of sucralfate to esophagitis, ulcers, small intestine and large intestine ulcers, stomatitis, etc., by combining sucralfate with an organic carboxylic acid having two or more carboxyl groups or one or more hydroxyl groups in the molecule. Furthermore, Japanese Patent Application Laid-Open No. 2016-145187 (Patent Document 2) discloses a technology that enhances the adhesiveness of sucralfate in a liquid formulation by adding a neutralizing thickener to a liquid composition containing sucralfate, an organic acid, and water, adjusting the pH to a specific range, and gelling the composition.

Regarding solid formulations, the applicant has proposed in JP 2018-52869 A (Patent Document 3) a powder composition in which sucralfate is treated with an organic acid, then dried, and the water content and the sum of the heats of fusion calculated from the endothermic peak area of the DSC curve measured with a differential scanning calorimeter are adjusted to appropriate ranges. This results in a powder composition that quickly gels upon contact with water again, thereby exhibiting excellent mucoadhesion. However, from the perspective of improving the performance of solid formulations, further improvements are desired in the tableting properties during tablet production, the disintegration properties of the resulting tablets, and the storage stability of sucralfate.

As such, liquid and gel-form pharmaceuticals that quickly exhibit good mucosal adhesion have been obtained, but there is a need for the development of new solid formulations that combine excellent disintegration upon contact with water after ingestion, good mucosal adhesion to the mucous membranes of organs with short transit times, such as the oral cavity and esophagus, and excellent storage stability.

Japanese Patent Application Publication No. 8-268895 Japanese Patent Application Laid-Open No. 2016-145187 Japanese Patent Application Laid-Open No. 2018-52869

The present invention has been made in consideration of the above circumstances, and aims to provide a powder composition containing sucrose octasulfate aluminum salt that produces a solid preparation that combines excellent disintegrability when in contact with water, good mucoadhesion to the mucous membranes of organs with short transit times, such as the oral cavity and esophagus, and excellent storage stability, as well as a method for producing the same.

The present inventors have discovered that a powder composition containing (A) sucrose octasulfate aluminum salt, (B) an organic acid, and (C) one or more selected from alkali metals, alkaline earth metals, and zinc, and a solid preparation containing the same, exhibit excellent disintegration properties when contacted with water, rapidly gel when contacted with water again, exhibit excellent mucosal adhesion, and also have excellent storage stability, leading to the completion of the present invention.

Accordingly, the present invention provides the following powder composition and method for producing the same.
1. (A) sucrose octasulfate aluminum salt,
A powder composition comprising (B) an organic acid and (C) one or more elements selected from alkali metals, alkaline earth metals, and zinc.
2. The powder composition according to 1, wherein component (C) is one or more elements selected from the group consisting of sodium, calcium, magnesium, and zinc.
3. The powder composition according to 1 or 2, wherein the molar equivalent ratio of component (A) to component (B), expressed as the (A)/(B) molar equivalent ratio, is 0.4 to 6.
4. The powder composition according to any one of 1 to 3, wherein component (B) is one or more acids selected from malic acid, lactic acid, citric acid, glucuronic acid, gluconic acid, maleic acid, fumaric acid, and tartaric acid.
5. The powder composition according to any one of 1 to 4, having a bulk density of 0.4 to 0.9 g/mL and a median diameter of 75 to 500 μm.
6. An oral solid preparation containing the powder composition according to any one of 1 to 5.
7. The solid oral preparation according to 6, which is a tablet having a disintegration time of 30 minutes or less.
8. (A) sucrose octasulfate aluminum salt,
A method for producing a powder composition, comprising: a mixing step of preparing a water and/or ethanol dispersion containing (B) an organic acid and (C) one or more elements selected from alkali metals, alkaline earth metals, and zinc; and a drying step of drying the dispersion.
9. The method for producing a powder composition according to 8, wherein component (C) is one or more selected from sodium, calcium, magnesium, and zinc.
10. (A) sucrose octasulfate aluminum salt,
(b1) A method for producing a powder composition, comprising: a mixing step of preparing a water and/or ethanol dispersion containing one or more selected from alkali metal salts of organic acids, alkaline earth metal salts of organic acids, and zinc salts of organic acids; and a drying step of drying the dispersion.
11. (A) sucrose octasulfate aluminum salt,
(B) an organic acid, and (c) one or more selected from carbonates, hydrogencarbonates, sulfates, hydrochlorides, oxides, and hydroxides of alkali metals, alkaline earth metals, or zinc;
Or a method for producing a powder composition, comprising a step of granulating by dry granulation a mixture containing (A) sucrose octasulfate aluminum salt and (b1) one or more selected from alkali metal salts of organic acids, alkaline earth metal salts of organic acids, and zinc salts of organic acids.

The present invention provides a powder composition that produces a solid formulation that combines excellent disintegration upon contact with water, good mucoadhesion to the mucous membranes of organs with short transit times, such as the oral cavity and esophagus, and excellent storage stability.

1 is an electron microscope photograph of a powder composition according to Example 2.

The present invention will be described in detail below.
The powder composition of the present invention contains (A) sucrose octasulfate aluminum salt, (B) an organic acid, and (C) one or more elements selected from alkali metals, alkaline earth metals, and zinc.

[(A) Sucrose octasulfate aluminum salt]
(A) Aluminum sucrose octasulfate is a drug that binds to proteins in inflamed mucosal areas, covering and protecting the inflamed areas while repairing them. In the present invention, in addition to its effect on inflamed gastric areas, by forming it into an orally disintegrating tablet, it can also exert an excellent effect on inflamed esophageal areas, which are the cause of heartburn. Examples of aluminum sucrose octasulfate that can be used include sucralfate hydrate (JP) containing approximately 11 to 14% water by mass and undried aluminum sucrose octasulfate containing 50% or more water by mass. In the present invention, sucralfate hydrate (JP) is more preferably used, as it has an excellent stabilizing effect on sucrose octasulfate.

The content of component (A) in the powder composition is preferably 30 to 85% by mass, more preferably 40 to 80% by mass. The dosage of component (A) is preferably 100 to 2,000 mg per day, more preferably 500 to 1,500 mg. By keeping the content of component (A) at or below the upper limit of the above range, it becomes easier to balance the blend with the other components described below, while by keeping it at or above the lower limit, a good mucosal protective effect can be achieved. The content of component (A) in the powder composition can be quantified, for example, by the quantitative method (HPLC method) described in the Japanese Pharmacopoeia, 17th Edition, "Sucralfate Hydrate."

[(B) Organic acid]
The organic acid (B) is not particularly limited as long as it is water-soluble (i.e., easily soluble in water), and one type may be used alone or two or more types may be used in appropriate combination. In the present invention, an organic acid that is solid at room temperature and normal pressure is preferred, and in consideration of improving the stability of sucrose octasulfate, its adhesiveness to the mucosa, and the bulk density of the resulting powder composition, one or more types selected from malic acid, lactic acid, citric acid, glucuronic acid, gluconic acid, maleic acid, fumaric acid, and tartaric acid are preferred, with malic acid, lactic acid, citric acid, glucuronic acid, maleic acid, and tartaric acid being more preferred.

As component (B), the organic acids listed above may be used as they are. However, instead of combining them with component (c), described below, component (b1) may be used, which includes one or more selected from alkali metal salts, alkaline earth metal salts, and zinc salts of component (B). Considering the improved stability of sucrose octasulfate, its mucoadhesiveness, and the bulk density of the resulting powder composition, sodium salts, magnesium salts, calcium salts, and zinc salts of the organic acids listed above are preferred as component (b1), with calcium salts, magnesium salts, and zinc salts being more preferred. Specific examples of component (b1) include disodium malate, sodium malate, calcium lactate, disodium citrate, trisodium citrate, sodium tartrate, disodium tartrate, and zinc gluconate, with disodium malate, sodium malate, calcium lactate, disodium citrate, trisodium citrate, sodium tartrate, and disodium tartrate being preferred.

The content of component (B) in the powder composition is preferably 3 to 50% by mass, more preferably 5 to 40% by mass. Furthermore, the content is preferably 0.5 to 9 molar equivalents, more preferably 1 to 3 molar equivalents, per 500 mg of sucralfate hydrate (3.84 mmol equivalents in molar equivalents). By setting the content of component (B) at or below the upper limit of the above range, rapid disintegration of tablets and improved mucosal adhesion are facilitated. By setting the content at or above the lower limit, good stability of component (A) is facilitated and improved mucosal adhesion is achieved. The content of component (B) in the powder composition can be quantified, for example, by high-performance liquid chromatography (HPLC) or ultraviolet absorbance (UV). The amount of component (b1) used can be calculated based on the ratio of the organic acid to the alkali metal, alkaline earth metal, or zinc contained in component (b1). For example, when using disodium malate (molecular weight: 179), the proportion of malic acid (molecular weight: 134.09) contained in the disodium malate is 0.749, and the proportion of sodium (atomic weight: 22.99) is 0.257; therefore, based on these proportions, the amounts of component (B) and component (C) used can be set so that the contents fall within the ranges described above or below.

In the present invention, the term "molar equivalent" (unit: meq) refers to the ionic valence per mole of an ionic species. For example, citric acid (molecular weight: 192) has three carboxylic acid groups, so 192 g of citric acid is expressed as 1 mole = 3 molar equivalents (3 meq). The molar equivalent of 100 mg of citric acid is 100/192 x 3 = 1.56 millimolar equivalents (mmeq).

[(C) One or more selected from alkali metals, alkaline earth metals, and zinc]
Examples of alkali metals include lithium, sodium, potassium, etc., and examples of alkaline earth metals include magnesium, calcium, strontium, barium, etc. In the present invention, sodium, potassium, magnesium, calcium, and zinc are preferred, as they facilitate rapid disintegration of tablets, etc.

In the present invention, the component (C) can be one or more selected from (c) carbonates, hydrogencarbonates, sulfates, hydrochlorides, oxides, and hydroxides of alkali metals, alkaline earth metals, or zinc.
Specific examples of component (c) include sodium bicarbonate, sodium carbonate, sodium chloride, magnesium oxide, magnesium carbonate, magnesium sulfate, magnesium chloride, calcium carbonate, calcium hydroxide, calcium oxide, calcium chloride, zinc oxide, zinc sulfate, and zinc chloride, of which sodium bicarbonate, sodium carbonate, magnesium oxide, magnesium carbonate, calcium carbonate, calcium hydroxide, calcium oxide, and zinc sulfate are preferred, sodium bicarbonate, magnesium oxide, magnesium carbonate, calcium carbonate, calcium hydroxide, and calcium oxide are more preferred, and sodium bicarbonate, magnesium carbonate, and calcium carbonate are even more preferred.

The content of component (C) in the powder composition is preferably 2 to 15% by mass, more preferably 4 to 10% by mass. Furthermore, the content of component (c) in the powder composition is preferably 5 to 40% by mass, more preferably 10 to 30% by mass. When the content of component (C) is below the upper limit of the above range, mucoadhesion and disintegrability are improved. When the content of component (C) is above the lower limit of the above range, a highly porous powder composition is easily produced, and disintegrability is improved. The content of component (C) in the powder composition can be quantified, for example, by elemental analysis or titration.

The amount of component (c) used can be calculated based on the proportion of alkali metal, alkaline earth metal, or zinc contained in component (c). For example, when using calcium carbonate (molecular weight: 100.087), the proportion of calcium (atomic weight: 40.078) contained in calcium carbonate is 0.400, so the amount of component (C) used can be set based on this proportion so that the content of component (C) falls within the above range.

Furthermore, when component (b1) is used as component (B), if the content of component (C) in the powder composition is within the desired range, it is not necessary to add component (c) from the standpoint of achieving the effects of the present invention. However, it is optional to add component (c) for the purpose of fine-tuning the blending ratio of each component. Furthermore, component (B) and component (b1) may be used in combination for the purpose of fine-tuning the blending ratio of component (B) and component (C).

[water]
From the viewpoint of obtaining a particulate product, the water content in the powder composition is preferably 15% by mass or less, more preferably 13% by mass or less, and even more preferably 10% by mass or less. On the other hand, the lower limit is not particularly limited as long as a particulate product is obtained, but is preferably 0.1% by mass or more, more preferably 1% by mass or more, even more preferably 3% by mass or more, and even more preferably 5% by mass or more in the powder composition.

In the present invention, the water content (moisture content) in the powder composition is a value (%) calculated by the following formula: The moisture content can be measured using a commercially available moisture meter (for example, "MOC63u" manufactured by Shimadzu Corporation).
Moisture content (%) = (amount of moisture lost at 105°C for 2 hours) / (mass of powder composition) x 100

[(A)/(B) mass ratio]
The mass ratio of component (A) to component (B), expressed as the (A)/(B) mass ratio, is preferably 0.5 to 10, more preferably 1 to 5. When DL-lactic acid is used as component (B), the mass ratio is preferably 2 to 10, more preferably 2 to 5. By setting the mass ratio to the upper limit or less of the above range, the stability and mucoadhesion of component (A) are improved. By setting the mass ratio to the lower limit or more of the above range, the stability of component (A) is improved and rapid disintegration of tablets and the like is facilitated.

[(A)/(B) molar equivalent (meq) ratio]
The molar equivalent (meq) ratio of component (A) to component (B), expressed as the (A)/(B) molar equivalent (meq) ratio, is preferably 0.4 to 6, more preferably 0.6 to 5, and even more preferably 1 to 3. By setting the meq ratio to the upper limit of the above range or less, the stability and mucoadhesiveness of component (A) are improved. By setting the meq ratio to the lower limit of the above range or more, the stability of component (A) is improved and rapid disintegration of tablets and the like is more easily achieved.

[(A)/(C) mass ratio]
The mass ratio of component (A) to component (C), represented by (A)/(C), is preferably 2 to 20, more preferably 6 to 16. By setting the mass ratio at or below the upper limit of the above range, it becomes easier to obtain a powder composition with high porosity, and it becomes easier to obtain tablets and other particles with rapid disintegration properties. In addition, the bulk density of the powder composition increases. By setting the mass ratio at or above the lower limit of the above range, tablets and granules do not become too large.

[Optional ingredients]
The powder composition of the present invention may contain optional ingredients as appropriate within the range that does not impair the effects of the present invention. Examples of optional ingredients include other active ingredients, polyols, excipients, binders, disintegrants, sweeteners, lubricants, preservatives, flavors, flavorings, and colorings.

Other active ingredients may include gastric acid secretion inhibitors such as ranitidine, ranitidine hydrochloride, famotidine, cimetidine, roxatidine acetate hydrochloride, nizatidine, lafutidine, lansoprazole, rabeprazole, omeprazole, and Scopolia extract; muscarinic receptor antagonists such as pirenzepine, atropine, and scopolamine; defense factor promoters such as aldioxa, azulene, L-glutamine, and rebamipide, as well as digestive enzymes such as lipase and diastase; anti-inflammatory drugs such as azulene sodium sulfonate; lactic acid bacteria such as bifidobacteria and Lactobacillus gasseri; intestinal probiotics such as butyric acid bacteria; and stomachic herbal ingredients such as magnolia bark fluid extract, atractylodes rhizome fluid extract, turmeric fluid extract, licorice extract, ginseng fluid extract, copper tincture, clove tincture, gentian tincture, and cinnamon tincture. Among these, in the present invention, gastric acid secretion inhibitors, stomachic herbal ingredients, and intestinal-regulating probiotics are preferred from the perspective of being used in digestive organ medicines containing (A) sucrose octasulfate aluminum salt and alleviating various symptoms in the digestive organs.

Polyols that can be blended include sugar alcohols such as mannitol, erythritol, xylitol, sorbitol, palatinite, and lactitol, as well as monosaccharides, oligosaccharides, and polysaccharides, as well as polyhydric alcohols such as PEG, glycerin, and propylene glycol. Lower alcohols such as ethanol can also be blended. The inclusion of such polyols not only improves the moldability and disintegration properties of the tablet, but also masks unpleasant tastes.

Examples of excipients include lactose, corn starch, crystalline cellulose, potato starch, etc. Examples of binders include hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, hydroxyethylcellulose, gum arabic, pregelatinized starch, carboxyvinyl polymer, agar, honey, etc. Examples of disintegrants include crospovidone, croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropylcellulose, etc.
In the present invention, among these ingredients, lactose, corn starch, crystalline cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, hydroxyethylcellulose, gum arabic, carboxyvinyl polymer, crospovidone, croscarmellose sodium, carmellose calcium, carboxymethylstarch sodium, and low-substituted hydroxypropylcellulose are preferred from the viewpoint of further improving the moldability and disintegrability of tablets.

Sweetening agents include sucrose, fructose, aspartame, sucralose, thaumatin, acesulfame potassium, sorbitol, stevia, refined white sugar, saccharin, glycyrrhizin, etc. Lubricants include magnesium stearate, sodium stearyl fumarate, and sucrose fatty acid esters. Preservatives include parabens such as alkylparabens, benzoic acid, and sodium benzoate. Flavoring agents include known essential oils such as limonene, orange flavor, lychee flavor, lemon flavor, lime flavor, strawberry flavor, pineapple flavor, mint flavor, and grapefruit flavor. Flavoring agents include menthol, etc. Coloring agents include caramel, carmine, carotene liquid, beta-carotene, copper chlorophyll, and copper chlorophyllin sodium.

[Powder composition]
The powder composition of the present invention is a granulated particle containing component (A), component (B), and component (C), and the particle size of the powder composition is preferably 75 to 500 μm, and more preferably 100 to 300 μm. When the particle size is equal to or greater than the lower limit of the above range, content uniformity during compression is improved when tablets or granules are produced. The improved powder flowability improves manufacturability (handling ability). Furthermore, when the particle size is equal to or less than the upper limit of the above range, good mixing uniformity with multiple components is achieved when tablets or granules are produced, and content uniformity during tableting is particularly improved.
The particle size is the volume-based median diameter (D50) measured by a laser diffraction/scattering particle size distribution measurement method, for example, using an LS13 320 manufactured by Beckman Coulter, Inc., under measurement conditions of a dry powder module and volume-based mode.

The bulk density of the powder composition is preferably 0.4 to 0.9 g/mL, more preferably 0.4 to 0.85 g/mL. When the bulk density is at or above the lower limit of the above range, the relative volume of the particles becomes smaller, contributing to the miniaturization of the formulation. This is expected to improve medication compliance. When the bulk density is at or below the upper limit of the above range, the porosity of the powder composition improves, resulting in good tablet formability and disintegration properties. In the present invention, the bulk density is a value measured in accordance with the Japanese Pharmacopoeia, General Test Methods, Powder Property Measurement Methods, Bulk Density Test Method.

The powder composition of the present invention is preferably a porous (having voids) particle. The porosity of the powder composition can be confirmed by observation under normal measurement conditions using a scanning electron microscope (SEM) or the like. For example, it can be confirmed by directly observing the powder composition (particles) at a magnification of 100 to 50,000 times using a scanning electron microscope ProX Premium II (manufactured by Phenom World). The porosity of the present invention refers to a state in which voids are observed within the powder composition (particles) when the powder composition is observed using the above measurement. It is believed that the reason a powder composition with porosity or a low bulk density is produced in the present invention is that water present in the gaps between water-insoluble components (particles) in the aqueous dispersion evaporates during the drying process, creating voids.

[Method for producing powder composition]
A first method for producing the powder composition of the present invention includes a mixing step of preparing a water and/or ethanol dispersion containing (A) sucrose octasulfate aluminum salt, (B) an organic acid, and (C) one or more elements selected from alkali metals, alkaline earth metals, and zinc, and a drying step of drying the dispersion.

In the mixing step, components (A) to (C), optional components, and water and/or ethanol are mixed to prepare a water and/or ethanol dispersion. The blending ratios of components (A) to (C) and optional components should be determined based on the blending ratios in the powder composition after drying. For reasons of solubility and dispersibility, it is preferable to add components (A) to (C) in water and/or ethanol first, followed by sequential blending of components (C) and (A). Furthermore, the amount of water and/or ethanol in the water and/or ethanol dispersion (or the total amount, if used in combination) is preferably 0.1 to 100 times, more preferably 0.2 to 50 times, and even more preferably 0.2 to 40 times the total mass (dry weight) of the above components. By adjusting the amount of water and/or ethanol within the above ranges, component (B) disperses and dissolves, allowing it to be uniformly distributed throughout the powder composition. Furthermore, in the water and/or ethanol dispersion, the mixing ratio (mass ratio) of water to ethanol can be any and is not particularly limited, but is usually selected appropriately from the range of 100/0 to 0/100.

In the above mixing step, no special stirring or mixing is required; known stirring and mixing methods can be used. Examples of stirring devices include stirrers, propeller stirrers, homogenizers, homomixers, and emulsifiers. While standard mixing conditions can be used, the temperature during mixing is preferably 5 to 60°C, and more preferably 5 to 50°C.

In the drying step, the water and/or ethanol dispersion obtained in the mixing step is dried using a predetermined drying method to obtain the powder composition of the present invention. Any drying method commonly used in pharmaceutical formulation technology can be used as long as it can sufficiently dry the water and/or ethanol dispersion and obtain a powder composition that satisfies the requirements of the present invention. Drying methods that can be suitably used in the present invention include, for example, airflow drying methods such as spray dryers, micron dryers, and flow dryers; freeze drying; fluidized bed drying using a fluidized bed granulator such as a flow coater; and thermal drying using a box dryer. Considering the ease of obtaining a powder composition, airflow drying, fluidized bed drying, and thermal drying are more preferred, with airflow drying, fluidized bed drying, and thermal drying being even more preferred, and spray drying being even more preferred.

When performing the spray drying method, a known spray dryer (for example, "Spray Dryer L-8 Type" manufactured by Okawara Kakoki Co., Ltd.) can be used. The drying conditions are not particularly limited, but when drying is performed using the above-mentioned "Spray Dryer L-8 Type" manufactured by Okawara Kakoki Co., Ltd., the following conditions can be used, for example.
The temperature of the intake air is preferably 150 to 230°C, more preferably 170 to 210°C.
The exhaust temperature is preferably 50 to 90°C, more preferably 55 to 85°C, and even more preferably 60 to 80°C.
The cyclone differential pressure is preferably 0.2 to 0.8 kPa, more preferably 0.3 to 0.7 kPa, and even more preferably 0.4 to 0.6 kPa.
The liquid feeding rate is preferably 5 to 50 g/min, more preferably 10 to 40 g/min, and even more preferably 25 to 35 g/min.

When drying is performed using a tray dryer, a known box dryer (for example, a BOX TYPE DRYER manufactured by Hyuga Manufacturing Co., Ltd.) can be used. The drying conditions are not particularly limited, but the following conditions can be used, for example.
Drying temperature: 80°C ± 5°C, drying time: as needed (until moisture content reaches target range)

A second method for producing the powder composition of the present invention includes a mixing step of preparing a water and/or ethanol dispersion containing (A) sucrose octasulfate aluminum salt and (b1) one or more selected from alkali metal salts of organic acids, alkaline earth metal salts of organic acids, and zinc salts of organic acids, and a drying step of drying the dispersion. The preferred mixing step and drying step in this embodiment are the same as those in the first embodiment.

A third method for producing the powder composition of the present invention includes the steps of:
(A) sucrose octasulfate aluminum salt,
(B) an organic acid, and (c) one or more selected from carbonates, hydrogencarbonates, sulfates, hydrochlorides, oxides, and hydroxides of alkali metals, alkaline earth metals, or zinc;
Alternatively, a method may be mentioned in which a mixture containing (A) sucrose octasulfate aluminum salt and (b1) one or more selected from alkali metal salts of organic acids, alkaline earth metal salts of organic acids, and zinc salts of organic acids is granulated by a dry granulation method. Furthermore, the above-mentioned raw materials may be pulverized, if necessary, during mixing.
For mixing and granulation, known devices can be used, such as a vertical granulator (manufactured by Powrex Corporation) or a high-speed mixer (manufactured by Earth Technica Corporation).

When using a vertical granulator, the following manufacturing method can be used, for example: Predetermined amounts of each component are added to the vertical granulator and stirred. The order of addition is not particularly limited. The stirring conditions are also not particularly limited, but preferred are agitator rotation conditions: 50-500 rpm, chopper rotation conditions: 500-3,000 rpm, stirring temperature: room temperature to 60°C (adjusted using a heat-retaining jacket, etc.), and stirring time: 5-30 minutes. To improve mixing efficiency, water-soluble components such as water or glycerin may be added as long as a drying process is not required.

The powder composition of the present invention is not limited to the above-mentioned first to third manufacturing methods and can also be obtained using well-known pharmaceutical manufacturing methods. However, from the perspective of practicality as pharmaceutical manufacturing equipment, it is preferable to manufacture it using the above-mentioned first to third manufacturing methods.

The powder composition of the present invention can be used for solid preparations in general, and as a dosage form, the powder composition may be used directly as granules or powders, or by appropriately blending the optional ingredients described above within a range that does not impair the effects of the present invention, it can be made into tablets (including chewable tablets and orally disintegrating tablets), hard capsules, granules, or powders. In the present invention, tablets, granules, and hard capsules are particularly preferred. For delivery to the stomach or intestinal mucosa, enteric-coated hard capsules are preferred.

[tablet]
Tablets using the powder composition of the present invention can be obtained by blending the obtained powder composition with appropriate optional ingredients such as excipients, and tableting under normal conditions using a known tablet press. Examples of tablet presses include rotary tablet presses (for example, "12HUK type" manufactured by Kikusui Seisakusho Co., Ltd.). When using a rotary tablet press, the rotation speed of the tablet press is preferably 5 to 60 rpm, more preferably 10 to 50 rpm. There are no particular restrictions on the tableting pressure, but considering the disintegration properties of the tablets, a pressure of about 500 to 2,000 kgf is preferred. The tablets of the present invention are
These include orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets and dissolving tablets.
The disintegration time of tablets using the powder composition of the present invention is preferably less than 30 minutes, more preferably 20 minutes or less, even more preferably 15 minutes or less, and even more preferably 10 minutes or less. The disintegration time mentioned above means the disintegration time measured when the tablet is placed in a water bath at 37°C in accordance with the disintegration test method of the General Test Method of the Seventeenth Japanese Pharmacopoeia.

[Hard capsule]
The powder composition of the present invention is enclosed in a shell made of an edible base such as gelatin, pullulan, or cellulose. The capsule itself can be prepared by a conventional method (such as a dipping method). The contents can be filled using a method commonly used for powder filling, such as an auger, die press, or funnel method.

When the powder composition of the present invention is formulated as a capsule, the mass ratio of the powder composition to the coating is preferably powder composition/coating = 0.1 to 5. When formulated as a hard capsule, the coating is dissolved by chewing or licking in the oral cavity, exposing the contents (powder composition) in the mouth, causing them to remain on the oral mucosa, or the exposed contents are swallowed and passed through the esophageal mucosa, allowing them to act directly on the esophageal mucosa. By keeping the single dose small (at most 10 g, preferably about 0.5 to 4 g, more preferably about 1 to 3 g), as in the present invention, most of the powder remains in the esophagus, especially immediately after swallowing, and does not immediately flow into the stomach. As a result, a high therapeutic effect can be expected.

Dosage forms to which the powder composition of the present invention is applied can contain optional ingredients as appropriate, as long as the effects of the present invention are not impaired. Optional ingredients include antacids, other active ingredients, polyols, excipients, binders, disintegrants, sweeteners, lubricants, preservatives, flavors, flavorings, and colorings.

Antacids include sodium bicarbonate, dried aluminum hydroxide gel, magnesium aluminosilicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium alumina hydroxide, aluminum hydroxide gel, magnesium hydroxide, magnesium oxide, co-precipitation product of aluminum hydroxide and sodium bicarbonate, mixed dried gel of aluminum hydroxide and magnesium carbonate, co-precipitation product of aluminum hydroxide, magnesium carbonate and calcium carbonate, magnesium aluminometasilicate, bismuth dimagnesium aluminosilicate, co-precipitation product of magnesium hydroxide and aluminum potassium sulfate, calcium hydrogen phosphate, calcium carbonate, borey, aminoacetic acid, etc. Among these, in the present invention, from the viewpoint of being used in digestive organ medications containing (A) sucrose octasulfate aluminum salt and alleviating symptoms such as stomach pain, heavy stomach feeling, and heartburn caused by gastric acid hypersecretion, sodium bicarbonate, dried aluminum hydroxide gel, magnesium aluminosilicate, synthetic hydrotalcite, magnesium hydroxide, magnesium oxide, magnesium aluminometasilicate, bismuth dimagnesium aluminosilicate, calcium hydrogen phosphate, calcium carbonate, and aminoacetic acid are preferred, with magnesium aluminometasilicate, synthetic hydrotalcite, and magnesium aluminosilicate being more preferred. These can be used alone or in appropriate combinations of two or more.

The amount of antacid contained is not particularly limited, but from the standpoint of antacid effect, a single dose of 100 to 1,500 mg is preferred, with 200 to 1,000 mg being more preferred. Furthermore, the amount of antacid contained per 500 mg of component (A) is preferably 100 to 1,500 mg, with 200 to 1,000 mg being more preferred.

Specific examples of other active ingredients, polyols, excipients, binders, disintegrants, sweeteners, lubricants, preservatives, flavorings, taste enhancers, and colorants include the same as those listed above as examples of optional ingredients that can be incorporated into the powder composition.

The dimensions of tablets using the powder composition of the present invention are not particularly limited in terms of the effects of the present invention, but from the standpoint of ease of handling and swallowing of the tablets, the diameter φ of the tablets is preferably 6 to 14 mm.
The shape of the tablet is not particularly limited in terms of the effects of the present invention, but from the viewpoint of ease of handling and swallowing of the tablet, a shape having a cylindrical portion and bulging portions bulging above and below the cylindrical portion is preferred. Examples of tablets having the above-mentioned cylindrical portion and bulging portions include R tablets (standard R tablets, sugar-coated R tablets, etc.), two-tiered R tablets, Sumi square flat tablets, Sumi round flat tablets, etc. The bulging portions of these tablets may be asymmetrical from top to bottom, but are preferably symmetrical from top to bottom.

The method of administration of an oral solid preparation containing the powder composition of the present invention is not particularly limited, but a daily dose of 100 to 3,000 mg of sucralfate hydrate (dry matter equivalent) is preferred, and a single dose of 200 to 1,000 mg of sucralfate hydrate (dry matter equivalent) is preferred. The effects and efficacy of an oral solid preparation containing the powder composition of the present invention include stomach pain, heartburn, hyperacidity, belching, heavy stomach feeling, stomach bloating, stomach discomfort, chest tightness, overdrinking, nausea (retching, hangover/bad hangover nausea, stomach nausea, retching, nausea), and vomiting. Because of its excellent mucosal adhesion to the oral and esophageal mucosa, it is suitable for stomach pain, heartburn, heavy stomach feeling, and stomach nausea.

The present invention will be explained in detail below using examples and comparative examples, but the present invention is not limited to the following examples. In the following examples, "%" in the composition indicates % by mass unless otherwise specified.

The main raw materials used in the following examples are listed below. Unless otherwise specified, the amount of each component in the table is the pure amount.
Sucralfate: Fuji Chemical Industry Co., Ltd., "Sucralfate hydrate", molecular weight 2,086 (dry matter equivalent)
Malic acid: manufactured by Kanto Chemical Co., Ltd., trade name "Malic acid", a divalent organic acid. Lactic acid: manufactured by Showa Kako Co., Ltd., trade name "DL-lactic acid (90%)", a monovalent organic acid, molecular weight 90.08.
Citric acid: Kanto Chemical Co., Inc., trade name "Citric Acid", trivalent organic acid, molecular weight 192.12 Glucuronic acid: Alfa Aeser, trade name "D-Glucuronic Acid", monovalent organic acid, molecular weight 194.14
Maleic acid: Fujifilm Wako Pure Chemical Industries, Ltd., trade name "Maleic acid", divalent organic acid, molecular weight 116.1
Tartaric acid: Fujifilm Wako Pure Chemical Industries, Ltd., trade name "Tartaric acid", divalent organic acid, molecular weight 150.1
Phosphoric acid: Fujifilm Wako Pure Chemical Industries, Ltd., trade name "Phosphoric acid", molecular weight 97.99
Calcium carbonate: FUJIFILM Wako Pure Chemical Industries, Ltd., trade name "Calcium Carbonate", molecular weight 100.08 ( atomic weight of Ca 40.078 , valence 2)
Sodium hydrogen carbonate: AGC Co., Ltd., trade name "Sodium bicarbonate", molecular weight 84 ( atomic weight of Na 22.99 , valence 1)
Magnesium carbonate: FUJIFILM Wako Pure Chemical Industries, Ltd., trade name "Magnesium Carbonate", molecular weight 84.4 (Mg atomic weight 24.3 :1, valence 2)
Disodium malate: FUJIFILM Wako Pure Chemical Industries, Ltd., trade name "disodium malate hydrate", molecular weight 179 ( atomic weight of Na 22.99 , valence 2)
Calcium lactate: FUJIFILM Wako Pure Chemical Industries, Ltd., trade name "DL-calcium lactate pentahydrate", molecular weight 218 (Ca atomic weight 40.08 , valence 2)
Trisodium citrate: FUJIFILM Wako Pure Chemical Industries, Ltd., trade name "Trisodium Citrate", molecular weight 258 ( atomic weight of Na 22.99 , valence 3)
Sodium tartrate: FUJIFILM Wako Pure Chemical Industries, Ltd., trade name "Sodium tartrate dihydrate", molecular weight 194 (Na atomic weight 22.99 , valence 2)
Crystalline cellulose: Asahi Kasei Corporation, trade name "Ceolas UF-F702"
D-mannitol: Rocket Japan Co., Ltd., trade name "PEARITOL 50c"
Magnesium stearate: Taihei Chemical Industry Co., Ltd., product name "Vegetable Magnesium Stearate"

The sucralfate hydrate contains approximately 12% water. Therefore, in the following table, the content of (A) sucralfate is shown as a solids content value excluding water. In the examples and comparative examples shown in the following table, 500 g of sucralfate (solids content) is used, which means that 570 g of sucralfate hydrate (water content: 70 g) was blended.
In the compositions of the aqueous dispersions in the following Examples and Comparative Examples, the moisture contained in sucralfate hydrate was considered to be included in water.

[Examples 1 to 15, Comparative Examples 1 to 4]
(1) Powder compositions were prepared according to the following procedures using the compositions shown in Tables 1 to 3.
(1-1) Preparation of aqueous dispersion (mixing step)
(B) Organic acid was dissolved in water (purified water). Component (c) was then added and the mixture was stirred for 2 hours using a propeller stirrer (Three-One motor, 100-500 rpm). Next, component (A), sucralfate hydrate, was added and the mixture was stirred for 2 hours to obtain an aqueous dispersion.

(1-2-1) Drying of aqueous dispersion (drying step: Examples 1 to 3, 10, 13, and 14)
The aqueous dispersion obtained in (1-1) was dried using a spray dryer to obtain a powder composition. The apparatus and drying conditions used are as follows:
Equipment: "Spray Dryer L-8" manufactured by Okawara Kakoki Co., Ltd.
Intake air temperature: 190°C,
Exhaust temperature: 60-80°C
Cyclone differential pressure: 0.5 kPa
Liquid delivery speed: 32 g/min
Disc rotation speed: 10Hz
(1-2-2) Drying of aqueous dispersion (drying step: Examples 4 to 9, 11, 12, and 15)
The aqueous dispersion obtained in (1-1) was spread on a metal tray (450 mm x 450 mm) and dried at the temperature and for the time specified below.
Box type dryer: (BOX TYPE DRYER, manufactured by Hyuga Seisakusho Co., Ltd., etc.)
Drying temperature: 80℃±5℃
Drying time: 6 to 12 hours (until the moisture content reaches the target range)

[Examples 16 to 19, 21]
(2) Powder compositions were prepared according to the formulations in Table 4 below, using the following procedure.
(2-1) Preparation of aqueous dispersion (mixing step)
As component (b1), an alkali metal salt of an organic acid or an alkaline earth metal salt of an organic acid was dispersed and dissolved in water (purified water). With continued propeller stirring (Three-One motor, 100 to 500 rpm), sucralfate hydrate as component (A) was added, and the mixture was stirred for 2 hours to obtain an aqueous dispersion.

(2-2) Drying of aqueous dispersion (drying step)
In the same manner as in (1-2-1) and (1-2-1) above, the aqueous dispersion obtained in (2-1) was dried under the conditions shown below to obtain a powder composition.
In Example 19, a powder composition was obtained by drying using a spray dryer under the same conditions as in (1-2-1).
In Examples 16 to 18 and 21, the powder compositions were dried using a tray dryer under the same conditions as in (1-2-2) to obtain powder compositions.

(3) Tablet Production The powder compositions produced in (1-1) and (1-2) and (2-1) and (2-2) above were mixed with the following ingredients to prepare powders for tableting, which were then compressed using a rotary tableting machine to produce test tablets. The powders for tableting and tableting conditions were as follows:
[Powder for tabletting]
Powder composition: appropriate amount (adjusted to be equivalent to 500 mg of sucralfate [dry matter basis])
Crystalline cellulose: 300 mg
D-mannitol: 150 mg
Magnesium stearate: 45 mg
[Tableting conditions]
Equipment: Kikusui Seisakusho rotary tablet press (12HUK type)
Tableting pressure: 900 kgf, adjusted to give the above amount for 3 tablets.
Mortar and pestle: φ9.5mm (single R)

(4) Evaluation The powder compositions and tablets obtained above were evaluated as follows. The results are shown in Tables 1 to 4.

[Water content of powder composition]
The moisture content of the obtained powder composition was determined using a moisture meter "MOC63u" manufactured by Shimadzu Corporation.

[Bulk density of powder composition]
Measurements were made in accordance with the test method for "loose bulk density" in the Japanese Pharmacopoeia, General Test Methods, Powder Property Measurement Methods, Bulk Density.

[Particle size of powder composition]
The median diameter (D50) was measured using a laser diffraction/scattering particle size distribution analyzer "LS13 320" manufactured by Beckman Coulter, Inc. The measurement conditions were as follows:
Measurement conditions: Dry powder module

[Observation of the Appearance of the Powder Composition Using an Electron Microscope]
The appearance of the powder composition was observed using a scanning electron microscope (SEM) using the following equipment.
Apparatus: "ProX Premium II" manufactured by Phenom World
Magnification: 100 to 30,000 times (manually adjustable)
The powder composition obtained in Example 2 was observed and found to have porosity. The electron microscope photograph taken is shown in FIG.

[Mucoadhesiveness]
A predetermined amount of mucin solution (equivalent to 75 mg of porcine stomach-derived mucin, manufactured by Wako Pure Chemical Industries, Ltd.) was added to a powder composition (equivalent to 500 mg of sucralfate [dry matter basis]), and the viscosity η _M+F was measured using an E-type viscometer-type rheometer (AR2000, manufactured by TA Instruments, measurement shear rate = 0.1 to 10 s ^-1 ). Separately, the viscosity η _F of the powder composition dispersion and the viscosity η _M of the mucin solution itself were measured, and the mucin interactivity Δη was calculated using the following formula:
Δη=η _M+F / (η _M +η _F )
The mucoadhesion is preferably 1.5 or more, more preferably 3 or more, and even more preferably 5 or more. There is no particular upper limit to the Δη value, but it is preferably 20 or less from the viewpoint of ease of administration.
The method of evaluating mucoadhesion based on the Δη value of interaction with mucin is a commonly used method, as shown in the paper "Carbohydrate Polymers 71 (2008) 170-179," for example.

[Tablet disintegration]
The evaluation was conducted in accordance with the Japanese Pharmacopoeia, General Test Methods, Disintegration Test Method, Immediate-Release Preparations. The tablet was placed in a test liquid (purified water) at 37°C, and the tablet was shaken 29 to 32 times back and forth per minute to measure the disintegration time (no auxiliary disc was used). In the present invention, a disintegration time of less than 30 minutes was considered acceptable.

[Storage stability of tablets]
The tablets were stored in sealed bottles and the sucrose octasulfate content was evaluated before and after storage in a 50°C thermostatic chamber for one week. The test was conducted in accordance with the quantitative determination method (HPLC method) of the 17th Japanese Pharmacopoeia "Sucralfate Hydrate." Storage stability is preferably 85% or more of the initial content, and more preferably 90% or more.

[Identification of the result]
The contents of components (A) to (C) and water in the powder composition of the present invention can be quantitatively analyzed by a general physicochemical test method as follows.

(A) Aluminum sucrose octasulfate (A) Aluminum sucrose octasulfate has a structure in which one molecule of sucrose octasulfate (molecular weight: 982.8) is bonded to eight molecules of aluminum hydroxide ( _Al2 (OH) ₅ ) (molecular weight: 139) (see the Japanese Pharmacopoeia commentary manual "Sucralfate Hydrate"). 1 mole of (A) Aluminum sucrose octasulfate contains 1 mole of (a1) sucrose octasulfate and 16 moles of (a2) aluminum.
Therefore, the content (mol) of the (A) sucrose octasulfate aluminum salt component can be calculated by calculating the content (mol) in the powder composition from the measured content (mg) of (a1) sucrose octasulfate. Typically, 16 mol of (a2) aluminum (molecular weight: 26.98) can be confirmed per 1 mol of (a1) sucrose octasulfate, with the mass ratio of the two being approximately 982.8:431.7 = 2.28:1. Furthermore, the content of the (A) component can be determined more accurately by quantifying both (a1) and (a2).
The above components (a1) and (a2) can be quantified by the following methods.
(a1) Sucrose octasulfate HPLC, RI method (see Japanese Pharmacopoeia)
(a2) Aluminum: Titration method, elemental analysis method (see Japanese Pharmacopoeia)

(B) Organic acids are determined by HPLC and UV methods.

(C) Inorganic compounds (alkali metals, alkaline earth metals, and zinc)
Quantitative determination is performed using titration, elemental analysis, etc.

- Moisture: Quantify using a moisture meter such as Kett.

Claims (7)

(A) sucrose octasulfate aluminum salt,
(B) one or more organic acids selected from malic acid, lactic acid, citric acid, glucuronic acid, gluconic acid, maleic acid, fumaric acid, and tartaric acid , and (C) one or more selected from sodium, calcium, and magnesium;
the molar equivalent ratio of the component (A) to the component (B), expressed as the (A)/(B) molar equivalent ratio, is 0.73 to 6;
the mass ratio of the component (A) to the component (C) represented by (A)/(C) is 6 to 16;
The component (C) contains one or more selected from the group consisting of sodium bicarbonate, magnesium oxide, magnesium carbonate, calcium carbonate, calcium hydroxide, and calcium oxide,
A powder composition having a content of component (C) of 4.3 to 15 mass% in the powder composition. The powder composition according to claim 1, further comprising, as component (C), one or more carbonates selected from (c) magnesium carbonate and calcium carbonate. 3. The powder composition according to claim 1, having a bulk density of 0.4 to 0.9 g/mL and a median diameter of 75 to 500 μm. A solid oral preparation containing the powder composition according to any one of claims 1 to 3 . 5. The solid preparation for oral administration according to claim 4 , which is a tablet having a disintegration time of 30 minutes or less. (A) sucrose octasulfate aluminum salt,
(B) one or more organic acids selected from malic acid, lactic acid, citric acid, glucuronic acid, gluconic acid, maleic acid, fumaric acid, and tartaric acid , and (C) one or more selected from calcium and magnesium,
A method for producing a powder composition, comprising: a mixing step of preparing a dispersion in water and/or ethanol, in which the molar equivalent ratio of component (A) to component (B), expressed as an (A)/(B) molar equivalent ratio, is 0.73 to 6; and a drying step of drying the dispersion,
The component (C) contains one or more selected from (c) magnesium carbonate and calcium carbonate,
A method for producing a powder composition, wherein the content of component (C) in the powder composition is 4.3 to 15 mass%. (A) sucrose octasulfate aluminum salt,
(b1) containing one or more selected from disodium malate, calcium lactate, trisodium citrate, and sodium tartrate ;
A method for producing a powder composition, comprising: a mixing step of preparing a dispersion in water and/or ethanol, in which the molar equivalent ratio of component (A) to component ( b1 ), expressed as an (A)/( b1) molar equivalent ratio, is 0.73 to 6; and a drying step of drying the dispersion,
A method for producing a powder composition, wherein the powder composition contains 4.3 to 15 mass % of component (b1) (C) one or more selected from sodium and calcium.