Pharmaceutical composition and tablet

Abstract

Provided is a pharmaceutical composition which makes it possible for a tablet to hold the shape thereof for an extended period after being ingested. The composition contains a suppressed amount of a polyvinyl alcohol.　The present invention contains a polyvinyl alcohol-based resin (A), a polyhydric phenol compound (B), and amorphous silica (C). The content of the amorphous silica (C) is 0.1-20 parts by mass per 100 parts by mass of the polyvinyl alcohol-based resin. Also provided is a tablet which contains the pharmaceutical composition as a matrix composition (I). A medicinal component (II) is dispersed in the tablet, and the content ratio of the medicinal component (II) is 30-90 mass%.

Description

Pharmaceutical compositions and tablets

[0001] The present invention relates to a pharmaceutical composition and a tablet using the same, and more specifically to a pharmaceutical composition suitable as a matrix substrate for sustained-release tablets and a tablet containing the same.

[0002] Sustained-release tablets, which are controlled so that the active ingredient dissolves over a long period of time, have been the subject of active research and development in recent years because they can improve medication compliance by reducing the number of times a drug is taken and prevent side effects by reducing the fluctuation range of blood concentration.

[0003] Sustained-release tablets include membrane permeation-controlled tablets that control dissolution using a sustained-release coating layer; matrix diffusion-controlled tablets that use an insoluble base material as the main excipient; matrix tablets that use a hydrophilic polymer; and osmotic pressure-controlled tablets.

[0004] Among these, matrix-type tablets using hydrophilic polymers have been studied in recent years because of their superior manufacturing convenience, such as the ability to employ direct compression. In matrix-type sustained-release tablets, the hydrophilic polymer matrix base material swells when exposed to a physiological medium, forming a mesh-like gel matrix, thereby preventing the rapid release of the drug. The physiological medium that penetrates the tablet interior erodes the gel matrix over time, eventually causing the matrix to disintegrate and the tablet shape to be lost (tablet disintegration).

[0005] Polyvinyl alcohol (PVA) is a biodegradable hydrophilic polymer and is therefore a promising choice for the matrix substrate used in matrix-type sustained-release tablets. When polyvinyl alcohol is used as the matrix substrate, the time until the gel matrix disintegrates must be extended in order to extend the drug release time. On the other hand, a low content of polyvinyl alcohol, the matrix substrate, not only reduces gel strength and deteriorates sustained release, but also makes the tablet more susceptible to disintegration due to peristaltic movement in the digestive tract, leading to over-release of the drug. While it is possible to delay the drug release time by increasing the amount of polyvinyl alcohol to form a dense network structure, increasing the amount of polyvinyl alcohol results in an increase in tablet size. Due to the need to maintain tablet size within a specified range in relation to dosage, there are limitations on the amount of polyvinyl alcohol that can be contained per tablet.

[0006] As a way to increase the gel matrix strength so as to ensure the desired sustained release, Patent Document 1 (WO 2022 / 202138) proposes adding a polyphenol compound (tannic acid) to the matrix PVA. Patent Document 1 discloses that the use of tannic acid in combination can increase tablet hardness and suppress the drug dissolution rate 1 hour and 3 hours after administration.

[0007] Furthermore, Patent Document 2 (WO2023 / 027056) discloses that by using a combination of polyvinyl alcohol and crystalline cellulose as a matrix substrate and adjusting the average particle size and blend ratio of both components to fall within a specific range, it is possible to increase tablet hardness and exhibit sustained release properties.

[0008] WO2022 / 202138WO2023 / 027056

[0009] In the examples of Patent Document 1, the sustained-release tablets contain less than 50% by mass (approximately 47%) of the active ingredient. Furthermore, in a dissolution test using metformin hydrochloride as the drug, all of the active ingredient (100% by mass) was released after 10 hours.

[0010] Recently, sustained-release tablets have been required to retain their active ingredients even 10 hours after administration, so that they can be taken only once a day. To meet this requirement, it is necessary to further extend the retention time of the matrix while controlling the content of polyvinyl alcohol, which is the matrix substrate, within a predetermined range.

[0011] Patent Document 2 proposes a sustained-release tablet (active ingredient: metformin hydrochloride), and discloses that the sustained-release tablet produced in the examples contained less than 50% by mass (approximately 48%) of the active ingredient, and the dissolution rate was less than 100% even 10 hours after administration. However, nearly 50% was dissolved early in administration (1 hour after administration), and there is room for improvement as a sustained-release tablet that can maintain its efficacy for a long period of time.

[0012] The present invention has been made in consideration of the above circumstances, and its object is to provide a pharmaceutical composition that can provide sustained-release tablets containing 50% by mass or more of a medicinal ingredient in tablets using polyvinyl alcohol as a matrix substrate, or sustained-release tablets in which the medicinal ingredient remains even after a dissolution test, and tablets containing the same.

[0013] The present inventors have conducted various investigations into components that can increase gel strength while suppressing the content of polyvinyl alcohol resin, which is the matrix substrate, in order to provide a tablet that can contain 50% by mass or more of a medicinal ingredient and that has excellent sustained efficacy by continuing to release the medicinal ingredient even 10 hours after administration. As a result, they have found that by adding silica particles and a polyhydric phenol compound together, the tablet shape can be maintained in a swollen state even 10 hours after administration, and have completed the present invention.

[0014] That is, the pharmaceutical composition of the present invention has the following aspects: (1) A pharmaceutical composition comprising a polyvinyl alcohol-based resin (A), a polyhydric phenol compound (B), and amorphous silica (C), wherein the content of amorphous silica (C) is 0.1 to 20 parts by mass per 100 parts by mass of the polyvinyl alcohol-based resin (A). (2) The pharmaceutical composition of aspect (1), further comprising a medicinal ingredient (D), wherein the content of the medicinal ingredient in the pharmaceutical composition is 30% by mass or more and 90% by mass or less. (3) The pharmaceutical composition of aspect (1) or (2), wherein the content of polyvinyl alcohol-based resin (A) in the pharmaceutical composition is 5 to 35% by mass. (4) The pharmaceutical composition of any of aspects (1) to (3), wherein the polyhydric phenol compound (B) is 0.05 to 32 parts by mass per 100 parts by mass of the polyvinyl alcohol-based resin (A). (5) The pharmaceutical composition of aspect (1), wherein the specific surface area of ​​the amorphous silica (C), as measured by the BET method, is 50 to 1,000 m. ２ / g. (6) The pharmaceutical composition of any of Aspects (1) to (5), wherein the amorphous silica (C) is a chain aggregate of silica nanoparticles. (7) The pharmaceutical composition of any of Aspects (1) to (6), wherein the polyvinyl alcohol resin (A) has an average degree of polymerization of 500 to 3,000 and a degree of saponification of 78 to 96 mol %. (8) The pharmaceutical composition of any of Aspects (1) to (7), wherein the mass ratio (B / C) of the content of the polyhydric phenol compound (B) to the content of the amorphous silica (C) is 30 / 70 to 95 / 5.

[0015] The present invention also encompasses a tablet containing the pharmaceutical composition of any one of the above aspects (1) to (8) (aspect (9)). The tablet of the present invention has the following aspects. (10) A tablet having a medicinal ingredient (II) dispersed in a matrix composition (I), wherein the matrix composition (I) comprises a polyvinyl alcohol-based resin (A), a polyhydric phenol compound (B), and amorphous silica (C), and wherein the loss tangent tan δ [loss modulus E" / storage modulus E'] calculated by measuring the dynamic viscoelasticity of the remaining portion of the tablet after a dissolution test in accordance with Japanese Pharmacopoeia 6.10 is 10 or less. (11) The tablet of aspect 10, wherein the content of the medicinal ingredient (II) is 30% by mass or more and 90% by mass or less. (12) The tablet of aspect (10) or (11), wherein the content of the polyvinyl alcohol-based resin (A) is 5 to 35% by mass. (13) The tablet of aspect (10) or (11), wherein the specific surface area of ​​the amorphous silica (C) measured by the BET method is 50 to 1000 m ２ / g. (14) The tablet of any of aspects (10) to (13), wherein the amorphous silica (C) is a chain aggregate of silica nanoparticles. (15) The tablet of any of aspects (10) to (14), wherein the polyvinyl alcohol-based resin (A) has an average degree of polymerization of 500 to 3,000 and a degree of saponification of 78 to 96 mol%. (16) The tablet of any of aspects (10) to (15), wherein the mass ratio (B / C) of the content of the polyhydric phenol compound (B) to the content of the amorphous silica (C) is 30 / 70 to 95 / 5.

[0016] Tablets containing the pharmaceutical composition of the present invention have high gel strength, with a loss tangent tanδ of 10 or less as calculated by dynamic viscoelasticity measurement, even after a dissolution test. Therefore, they are useful as matrices for tablets, particularly sustained-release tablets. Tablets containing the pharmaceutical composition of the present invention as a matrix have a tablet size that is easy to take, contain a high content of a medicinal ingredient, and can sustainably release the medicinal ingredient over a long period of time.

[0017] 1 is a schematic diagram for explaining the dissolution of sustained-release tablets. FIG. 2 is a schematic diagram for explaining the method for measuring the shape retention employed in the examples.

[0018] <Pharmaceutical Composition> The pharmaceutical composition of the present invention contains a polyvinyl alcohol resin (A), a polyhydric phenol compound (B), and amorphous silica (C), with the content of amorphous silica (C) being 0.1 to 20 parts by mass per 100 parts by mass of the polyvinyl alcohol resin (A). Furthermore, the pharmaceutical composition may contain a medicinal ingredient (D) in an amount of 30% by mass or more and 90% by mass or less. Each component will be described below.

[0019] Polyvinyl alcohol (PVA)-based resin (A) The polyvinyl alcohol-based resin (A) is a resin mainly composed of vinyl alcohol structural units obtained by saponifying a vinyl ester-based resin obtained by polymerizing a vinyl ester-based monomer, and has vinyl alcohol structural units corresponding to the degree of saponification and vinyl ester structural units in the unsaponified portion.

[0020] The polyvinyl alcohol resin (A) is not limited to an unmodified PVA resin composed of vinyl alcohol units and vinyl ester units, but may be a modified PVA resin obtained by saponifying a vinyl ester resin obtained by polymerizing a monomer copolymerizable with a vinyl ester monomer (copolymerizable monomer), or a post-modified modified PVA resin, but an unmodified PVA resin is more preferred. In the case of a modified PVA resin, the degree of modification (the content of structural units other than vinyl alcohol units and vinyl ester units) is less than 10 mol%, preferably 5 mol% or less, and particularly preferably 1 mol% or less.

[0021] Examples of the vinyl ester monomer include vinyl formate, vinyl acetate, vinyl propionate, vinyl valerate, vinyl butyrate, vinyl isobutyrate, vinyl pivalate, vinyl caprate, vinyl laurate, vinyl stearate, vinyl benzoate, and vinyl versatate, with vinyl acetate being preferred for practical use.

[0022] Examples of the copolymerizable monomer include olefins such as ethylene, propylene, isobutylene, α-octene, α-dodecene, and α-octadecene; hydroxyl group-containing α-olefins such as 3-buten-1-ol, 4-penten-1-ol, 5-hexen-1-ol, and 3,4-dihydroxy-1-butene, and derivatives thereof such as acylated products; unsaturated acids such as acrylic acid, methacrylic acid, crotonic acid, maleic acid, maleic anhydride, itaconic acid, and undecylenic acid, salts thereof, monoesters, or dialkyl esters thereof; nitriles such as acrylonitrile and methacrylonitrile; diacetone acrylamide; Examples of copolymerizable monomers include amides such as acrylamide and methacrylamide, olefin sulfonic acids such as ethylene sulfonic acid, allyl sulfonic acid, and methallylsulfonic acid, or salts thereof, alkyl vinyl ethers, dimethylallyl vinyl ketone, N-vinylpyrrolidone, vinyl chloride, vinyl ethylene carbonate, 2,2-dialkyl-4-vinyl-1,3-dioxolane, and glycerin monoallyl ether, substituted vinyl acetates such as isopropenyl acetate and 1-methoxyvinyl acetate, vinylidene chloride, 1,4-diacetoxy-2-butene, 1,4-dihydroxy-2-butene, and vinylene carbonate. These copolymerizable monomers may be used alone or in combination. The copolymerizable monomer accounts for less than 10 mol %, preferably 5 mol % or less, and particularly preferably 1 mol % or less, based on the total amount of the polymer.

[0023] The modified PVA resin is preferably a copolymer with an unsaturated acid, its salt, monoester, or dialkyl ester, and in particular, a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0024] The polymerization of the vinyl ester monomer (and the copolymerizable monomer contained as needed) can be carried out by a conventionally known method (bulk polymerization, solution polymerization, suspension polymerization, dispersion polymerization, emulsion polymerization, etc.), and known polymerization catalysts and solvents can also be used during polymerization. Polymerization is usually carried out by solution polymerization using methanol as a solvent. Saponification of the obtained vinyl ester polymer can also be carried out by a conventionally known method. In industrial applications, the polymer is dissolved in alcohol and saponified in the presence of an alkali catalyst. Examples of alkali catalysts that can be used include hydroxides and alcoholates of alkali metals such as sodium hydroxide, potassium hydroxide, and sodium methylate.

[0025] The polyvinyl alcohol-based resin particles obtained by saponification are washed with a lower alcohol such as methanol and then dried using hot air or the like in a continuous or batchwise manner. The drying temperature is usually 50 to 150°C, particularly 60 to 130°C, and especially 70 to 110°C. If the drying temperature is too high, the PVA-based resin particles tend to deteriorate due to heat, while if the drying temperature is too low, drying tends to take a long time. The drying time is usually 1 to 48 hours, particularly 2 to 36 hours. If the drying time is too long, the PVA-based resin particles tend to deteriorate due to heat, while if the drying time is too short, drying tends to be insufficient or drying at a high temperature tends to be required. The solvent content in the dried PVA-based resin is usually 10% by mass or less, particularly 5% by mass or less, and especially 1% by mass or less is preferred.

[0026] The average saponification degree of the PVA-based resin (A) is 78 to 96 mol%, as specified for partially saponified polyvinyl alcohol in the Japanese Food Additives Standards (JPE), and preferably 85 to 89 mol%, which satisfies both the European Pharmacopoeia (EP) and the United States Pharmacopoeia (USP). Within this range of average saponification degree, water solubility is high, and after oral administration, hydrogen bonds are formed with the hydroxyl groups of the polyphenol compound and silica particles, easily forming a hydrogel for sustained release of the active ingredient. On the other hand, if the saponification degree is too low, the amount of hydroxyl groups contributing to gel formation decreases, and as a result, the gel-forming ability contributing to sustained release tends to decrease. In the present invention, the average saponification degree refers to the saponification degree measured by a method in accordance with JIS K 6726 (1994).

[0027] The average degree of polymerization of the PVA-based resin (A) is 500 or more, preferably 800 or more, 1000 or more, 1500 or more, or 2100 or more. The upper limit is preferably 3000 or less, more preferably 2600 or less. If the average degree of polymerization is too low, the gel-forming ability is insufficient, and the suppression of the release of the medicinal ingredient is insufficient. Polyvinyl alcohol-based resins with an average degree of polymerization of less than 800, which are commonly used as binders described below, are more likely to dissolve in water than form a gel after oral administration, and therefore the release of the medicinal ingredient cannot be sufficiently suppressed, and the desired sustained release cannot be achieved. On the other hand, if the average degree of polymerization is too high, the elasticity of the PVA-based resin particles increases, which may reduce compression moldability and tablet moldability. The average degree of polymerization in the present invention refers to the average degree of polymerization (number average degree of polymerization) measured by a method in accordance with JIS K 6726 (1994).

[0028] The viscosity of a 4% by weight aqueous solution of the PVA-based resin (A) at 20°C is preferably 6.0 mPa·s or more, more preferably 15.0 to 70.0 mPa·s, and even more preferably 20.0 to 60.0 mPa·s. If the viscosity of the 4% by weight aqueous solution is too high, the average degree of polymerization of the PVA-based resin is too high, which may increase the elasticity of the PVA-based resin, resulting in decreased compression moldability and tableting moldability. On the other hand, if the viscosity of the 4% by weight aqueous solution is too low, the average degree of polymerization of the PVA-based resin tends to decrease, resulting in decreased strength and density of the hydrogel formed upon contact with a physiological medium, making it difficult to achieve sustained-release tablets. In the present invention, the viscosity of the 4% by weight aqueous solution at 20°C is measured by a method in accordance with JIS K 6726 (1994).

[0029] The polyvinyl alcohol-based resin (A) may be used as a powder, which is an aggregate of particles, or may be dissolved in water to be granulated and mixed with other components as granules. From the viewpoint of tablet production and productivity, it is preferable to use it as a powder.

[0030] The average particle size of the PVA-based resin particles when used as a powder is 40 μm to 200 μm, preferably 45 to 100 μm, more preferably 45 to 80 μm, and even more preferably 45 to 70 μm. If the average particle size is too large, voids tend to form during tableting in a packed state, resulting in a low tablet hardness. The above average particle size is the median diameter based on the particle size distribution (volume basis) measured by laser diffraction.

[0031] The content of the polyvinyl alcohol-based resin (A) in the pharmaceutical composition is preferably 5 to 35% by mass. The content of the polyvinyl alcohol-based resin is limited to the above range, since the active ingredient contained in the tablet produced from the composition of the present invention is 30% by mass or more, preferably 40% by mass or more, and more preferably 50% by mass or more.

[0032] Polyhydric phenol compound (B) Examples of the polyhydric phenol compound (B) include catechol, resorcinol, hydroquinone, pyrogallol, oxyhydroquinone, phloroglucinol, tannic acid, etc. These can be used alone or in combination of two or more kinds, but tannic acid is particularly preferred.

[0033] Tannic acid can be extracted from various plant materials. For example, it can be extracted using water or ethanol from persimmon fruit, chestnut astringent skin, Chinese gallnut, gall nut, tara powder, tamarind seed coat (a legume), or mimosa bark. Preferably, tannic acid extracted from Chinese gallnut or gall nut, which are listed in the 18th revised Japanese Pharmacopoeia, can be used. Tannic acid may be either unrefined or refined, with refined products being more preferred.

[0034] Polyphenol compounds such as tannic acid have a high affinity for water, and when coexisting with a PVA-based resin, they can form hydrogen bonds with the hydroxyl groups of the PVA-based resin and with silanol groups (Si—OH) on the surface of silica particles (described later), contributing to the formation of a three-dimensional network structure. When a tablet containing the composition is produced, the formation of a gel having a three-dimensional network structure inhibits the dissolution of the active ingredient in the tablet, thereby achieving the desired sustained release.

[0035] The polyhydric phenol compound (tannic acid) having such a role is preferably contained in an amount of 0.05 to 32 parts by mass, more preferably 0.1 to 30 parts by mass, 1 to 25 parts by mass, or 5 to 15 parts by mass per 100 parts by mass of the PVA-based resin (A). When the composition is used as a matrix for a tablet, the polyhydric phenol compound can contribute to densifying the network structure of the gel matrix. On the other hand, while it is effective to increase the content of the polyhydric phenol compound while reducing the content of the polyvinyl alcohol-based resin, if the amount of tannic acid is too high, the tablet tends to become discolored.

[0036] The polyhydric phenol compound (B) such as tannic acid is in the form of a powder at room temperature, and therefore may be used as such, or may be used as granulated polyhydric phenol granules obtained by spraying a solution of the polyhydric phenol onto the powder and granulating it by spray drying.

[0037] The particle size of tannic acid used as a powder is usually 5 to 100 μm, preferably 10 to 50 μm, as measured by laser diffraction.

[0038] Amorphous Silica (C) Amorphous silica (C) is amorphous silica particles having silanol groups on the surface.

[0039] The type and production method of amorphous silica that can be used in the present invention are not particularly limited, and either wet silica (precipitated silica, gel method silica) or dry silica (combustion method, arc method) may be used.

[0040] Fumed silica is amorphous silica (silicon dioxide) produced by reacting silicon tetrachloride with oxygen in a high-temperature flame. A typical example is fumed silica, and commercially available products include the Aerosil (trademark) series.

[0041] Wet silica is broadly classified into precipitated silica and gel-process silica. Precipitated silica is obtained by neutralizing an alkaline aqueous solution of sodium silicate or the like, and filtering, washing with water, and drying the precipitated amorphous silica. Gel-process silica is obtained by carrying out a neutralization reaction between sodium silicate and sulfuric acid in an acidic pH range, thereby causing aggregation while suppressing the growth of primary particles. Commercially available precipitated silica products include Nipsil, Ultrasil, Carplex, Mizukasil, and Tokusil, while commercially available gel-process silica (silica gel) products include Silysia, Syloid, and Nipgel.

[0042] In both wet silica and dry silica, primary particles (silica nanoparticles) with particle sizes of several nanometers to several hundred nanometers aggregate to form aggregates (secondary particles), and further exist as aggregates of aggregates formed by the aggregation of secondary particles. The specific surface area of ​​silica particles measured by the BET method is 50 to 1000 m. ２ / g is preferred, and 75 to 800m ２ / g is more preferable, and 100 to 500m ２ / g is more preferable, and 120 to 450m ２ / g is particularly preferred, and 150 to 400 m２ / g is preferred.

[0043] The shape, aggregation state (pore volume, pore diameter, etc.), and cohesive strength of primary particles of amorphous silica (C) aggregates vary depending on the type of silica, production method, production conditions, etc. Generally, dry silica aggregates are formed by chain-like, beaded, or irregularly shaped aggregates of spherically linked silica primary particles, and tend to have weaker cohesive strength than wet silica. On the other hand, wet silica tends to have a stronger cohesive strength of silica primary particles, forming spherical aggregates. For this reason, wet silica aggregates are often porous particles, such as silica gel, in which pores represent the internal surface area. From the viewpoint of shape retention, chain-like aggregates of silica nanoparticles are more suitable. Generally, the specific surface area of ​​chain-like aggregates tends to be smaller than that of spherical aggregates of porous particles (e.g., silica gel). For this reason, compared to wet silica, dry silica aggregates tend to have larger pores as aggregates, while wet silica tends to have a larger specific surface area.

[0044] The surfaces of the silica particles described above contain silanol groups (Si-OH). Therefore, in physiological media, they form hydrogen bonds with the hydroxyl groups of the PVA-based resin and polyphenolic compound (tannic acid), contributing to the densification and strength of the gel matrix. This extends the duration of the drug, prolongs the duration of the tablet form, and improves the sustained-release properties of pharmaceutical tablets. The functions of polyphenolic compounds and silica are similar in that they form hydrogen bonds with the OH groups in the PVA molecules to form a three-dimensional network structure hydrogel. However, gels obtained by combining PVA with tannic acid and silica are expected to have a higher crosslink density than gels obtained by combining PVA with a polyphenolic compound or PVA with silica alone. The combination of polyphenolic compounds and silica forms denser hydrogen bonds, which is thought to enhance the durability of the network structure of the matrix formed by the PVA-based resin. On the other hand, if the pore size of the silica particles (aggregates) becomes too small, it is thought that it becomes difficult to form hydrogen bonds with the PVA-based resin, which has a relatively large molecule. In other words, it is thought that silica in the form of chain-like aggregates, in which the cohesive force of primary particles is weak, is more likely to form hydrogen bonds with other components, such as polyhydric phenol compounds and PVA-based resins, and is more likely to contribute to increasing the degree of crosslinking and stabilizing the hydrogel.

[0045] Silica particles can also act as a fluidizing agent, and the coexistence of silica particles in the dry tableting process has the effect of reducing the porosity and pore size of the tablet, which means that tablets with good compressibility and high hardness can be easily obtained.

[0046] In the preparation process, amorphous silica (C) is usually supplied in the form of powder (silica primary particles or aggregates or agglomerates of primary particles). Such powder is a powder having a particle size at 50% cumulative value in the particle size distribution (D ５０, median diameter) is 0.1 μm or more, 0.5 μm or more, 1 μm or more, 5 μm or more, and 500 μm or less, 200 μm or less, 100 μm or less, 50 μm or less. In the compression molding method, silica powder having such particle sizes is mixed with other components and compression molded to obtain tablets. In the case of silica in the form of aggregates or agglomerates with a weak cohesion, it is believed that they are crushed during the mixing operation, and a powder mixture (pharmaceutical composition) of amorphous silica (C) dispersed in the other components (PVA-based resin (A), polyhydric phenol compound (B)) can be obtained. In addition, the average particle size D ５０ is obtained as a value at 50% of the integrated value in the particle size distribution (volume basis) measured by a laser diffraction particle size distribution analyzer.

[0047] In addition, there are also hydrophobic silica particles in which silica particles are hydrophobized by surface treatment, in which compounds such as organosilicon compounds and silicone oils are chemically immobilized on the surface of fumed silica particles, utilizing the reactivity of silanol groups (Si—OH) present on the silica surface. As the amorphous silica (C) used in the present invention, either hydrophobic silica or hydrophilic silica can be used as long as the specific surface area and particle size described above are satisfied. However, the use of hydrophilic silica is preferred. This is because hydrophilic silica particles have many hydroxyl groups (OH) on their surfaces, which can form hydrogen bonds with the hydroxyl groups of polyvinyl alcohol molecules and polyhydric phenol compounds, contributing to the formation of a dense hydrogel.

[0048] The mass ratio (B) / (C) of the content of the polyhydric phenol compound (B) to the content of the amorphous silica (C) is 30 / 70 to 95 / 5, preferably 40 / 60 to 92 / 8, more preferably 50 / 50 to 90 / 10.

[0049] In order for a matrix substrate mainly composed of a PVA-based resin to swell easily and dissolve and disappear appropriately, it is necessary to prevent the content of silica particles from becoming too high.From this viewpoint, the content of silica (C) is 0.1 parts by mass or more, preferably 1 part by mass or more, more preferably 1.5 parts by mass or more, and even more preferably 2 parts by mass or more, relative to 100 parts by mass of the polyvinyl alcohol-based resin (A).Furthermore, it is 20 parts by mass or less, preferably 10 parts by mass or less, and more preferably 8 parts by mass or less.

[0050] Active Ingredient (API) (D) The pharmaceutical composition of the present invention may further contain an active ingredient (D). Examples of the medicinal ingredient (D) include antipyretic analgesic and anti-inflammatory drugs, tonics, health supplements, psychotropic drugs, antidepressants, antianxiety drugs, hypnotics and sedatives, antispasmodics, drugs acting on the central nervous system, cerebral metabolism improvers, cerebral circulation improvers, antiepileptic drugs, sympathomimetics, gastrointestinal drugs, antacids, antiulcer drugs, antitussive and expectorant drugs, antiemetic drugs, respiratory stimulants, bronchodilators, allergy drugs, antihistamines, dental and oral drugs, cardiac stimulants, antiarrhythmic drugs, diuretics, antihypertensive drugs, vasoconstrictors, coronary vasodilators, peripheral vasodilators, anticoagulants, antihyperlipidemic drugs, choleretic drugs, antibiotics, chemotherapeutic drugs, drugs for diabetes, drugs for osteoporosis, antirheumatic drugs, skeletal muscle relaxants, antispasmodics, hormone drugs, alkaloid narcotics, sulfa drugs, drugs for gout, and anti-cancer drugs.

[0051] Suitable active ingredients include those that require sustained release (e.g., orally administered active ingredients that are required to be sustained-release because they are readily water-soluble) and active ingredients that are generally recognized to have poor compressibility. Specifically, metformin hydrochloride is suitable.

[0052] The content of the medicinal ingredient (D) in the pharmaceutical composition is preferably 30% by mass or more and 90% by mass or less, more preferably 80% by mass or less, and even more preferably 75% by mass or less. Tablets containing the pharmaceutical composition of the present invention maintain their tablet shape for a long time, so they can contain the medicinal ingredient at such a high content. Furthermore, the medicinal ingredient contained in tablets produced from the composition of the present invention is preferably 30% by mass or more, preferably 40% by mass or more, more preferably 50% by mass or more.

[0053] Other Components (E) The pharmaceutical composition of the present invention may contain various additives within the range that does not impair the effects of the present invention (20% by mass or less, preferably 10% by mass or less of the composition).

[0054] Binder (E1) Binder (E1) is added to provide binding between particles during dry or wet granulation, direct compression, and tablet production by a wet process.

[0055] Examples of binders that can be used include dextrin, gum arabic, gelatin, hydroxypropyl starch, methyl cellulose, hydroxypropyl cellulose, hypromellose, pullulan, starch paste, polyvinyl alcohol resins, etc. The amount of binder varies depending on the type of compound used, but is usually 0.1 to 10 parts by mass, preferably 0.2 to 5 parts by mass, and more preferably 0.5 to 3 parts by mass per 100 parts by mass of the granulation composition.

[0056] The polyvinyl alcohol resin used as a binder (PVA resin for binder) is distinguished from the polyvinyl alcohol resin (A) contained as the matrix substrate at least in terms of average degree of polymerization. That is, the number-average degree of polymerization of the polyvinyl alcohol resin used as a binder is usually from 100 to less than 800, and preferably from 200 to less than 500.

[0057] The PVA-based resin for the binder may have an average saponification degree of 70 to 99 mol %, but it is usually 78 to 96 mol %, preferably 85 to 89 mol %, similar to the PVA-based resin (A) for the matrix substrate.

[0058] As the polyvinyl alcohol-based resin for binder, a saponified copolymer (modified polyvinyl alcohol-based resin) with a copolymerizable monomer, as explained above in connection with the polyvinyl alcohol-based resin (A), can be used. The PVA-based resin for binder is usually preferably used in the form of an aqueous solution obtained by dissolving it in water.

[0059] When a PVA-based binder resin is contained, the tablet contains two or more polyvinyl alcohol-based resins with different average degrees of polymerization. When two or more polyvinyl alcohol-based resins with different average degrees of polymerization are contained, the average degree of polymerization of the polyvinyl alcohol-based resins contained in the tablet is the sum of the values ​​obtained by multiplying each average degree of polymerization by the proportion of each polyvinyl alcohol-based resin.

[0060] For example, in the case of a tablet containing two PVA-based resins, namely, a PVA-based resin (A) corresponding to a matrix substrate and a PVA-based resin for a binder, the degree of saponification SDm and degree of polymerization Pm of the PVA-based resin for the matrix substrate (A), the degree of saponification SDb and degree of polymerization Pb of the PVA-based resin for the binder, the proportion M of the PVA-based resin for the matrix substrate in the total PVA-based resins, and the proportion B of the PVA-based resin for the binder can be calculated using the following formula, where M+B=1.

[0061] Average degree of saponification = SDm x M + SDb x B Average degree of polymerization = Pm x M + Pb x B

[0062] Typically, the content of the PVA-based resin binder is at most about 5% by mass (usually 3% by mass or less, preferably 2.5% by mass or less) of the total PVA-based resin. Therefore, even if a PVA-based resin binder with an average degree of polymerization of less than 800 is contained in the tablet, the average degree of polymerization measured for the PVA-based resin contained in the tablet will be 500 or more.

[0063] Lubricant (E2) Lubricants are added to improve fluidity, impart lubricity during compression in a die and tablet release, and prevent tablets from adhering to the punch surface and die wall. In particular, when tableting by direct compression, they are useful for reducing friction between the powder and the punch and die during tableting. Examples of such lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.

[0064] Others (E3) In addition to the above additives, other excipients (crystalline cellulose, sugar alcohols (e.g., mannitol, erythritol, xylitol, sorbitol, maltitol), sugars (e.g., glucose, fructose, lactose, sucrose, trehalose, maltose, oligosaccharides), calcium phosphates, starches, sodium phosphates, gelatin, etc.); disintegrants (carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, cellulose or its derivatives, starch or its derivatives, etc.); pH adjusters (citric acid and its salts, phosphoric acid and its salts, carbonic acid and its salts, tartaric acid and its salts, fumaric acid and its salts, acetic acid and its salts, amino acids and their salts, succinic acid and its salts, It may also contain: fluidizing agents (such as titanium oxide, stearic acid, corn gel, and heavy anhydrous silicic acid); surfactants (such as phospholipids, glycerin fatty acid esters, polyoxyethylene fatty acid esters, sorbitan fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ethers, sucrose fatty acid esters, sodium lauryl sulfate, polysorbates, sodium hydrogen phosphates, and potassium hydrogen phosphates); coloring agents (such as iron sesquioxide, yellow iron sesquioxide, food yellow no. 5, food yellow no. 4, aluminum chelate, titanium oxide, and talc); and sweeteners (such as saccharin, aspartame, acesulfame potassium, thaumatin, and sucralose).

[0065] <Tablet and manufacturing method thereof> The tablet of the present invention is a tablet containing the pharmaceutical composition of the above invention. The tablet of the present invention is a tablet in which an active ingredient (II) is dispersed in a matrix composition (I), and the matrix composition (I) contains a polyvinyl alcohol-based resin (A), a polyhydric phenol compound (B), and amorphous silica (C).

[0066] Tablets are usually produced by blending various ingredients and molding them directly or after granulation. Forming methods include compression (compressed tablets) and drying or cooling a wet mass (moist tablets). While either method is acceptable, the preferred method is dry compression molding, which produces fewer voids and makes it easier to obtain hard tablets.

[0067] In the case of compression molding, the matrix composition (I) is a mixed powder obtained by homogeneously mixing powders of a PVA-based resin (A), a polyhydric phenol compound (B), and amorphous silica (C). In this case, the amorphous silica (C) has an average particle size (D ５０ The silica powder has a particle size (median diameter) of 0.1 μm or more, 0.5 μm or more, 1 μm or more, or 5 μm or more, and 500 μm or less, 200 μm or less, 100 μm or less, or 50 μm or less. The fluidizing effect of the silica powder can reduce the interparticle gaps in the matrix composition.

[0068] Examples of the compression tableting method include direct powder compression (direct compression), semi-dry granule compression, granule compression, or an appropriate combination thereof, and any of these methods may be used.

[0069] It is preferable that the medicinal ingredient (II) is tableted so that it is homogeneously dispersed in the PVA-based resin (A), and it is also preferable that the medicinal ingredient is granulated in advance, and the granulated product (granules) of the medicinal ingredient is mixed with a powder of the matrix composition (I) and tableted. A mixture of the matrix composition (I) and the medicinal ingredient (II) may be used as a granulation composition and then granulated. Note that other additives may be added to and mixed with the granulation composition as necessary, or the granulation composition may be mixed with other additives and then subjected to tableting.

[0070] Granulation methods include a wet method in which a binder solution is added to powder and granulated as is, or a wet mass that has been kneaded and then granulated; a dry method in which the powder is compressed and molded in a dry state, then crushed and granulated; and a spray granulation method in which the powder is slurried with a large amount of water and then spray-dried to granulate.The solvent used in the binder solution is appropriately selected depending on the type of compound used as the binder.When a PVA-based resin is used as the binder, water can be used as the solvent.

[0071] Examples of granulators that can be used include dry granulators (high pressure is applied to powder to form agglomerates in a dry state, which are then crushed to form powder particles with an appropriate particle size), basket extrusion granulators, agitation granulators (raw material powders are mixed with agitating blades for several minutes, and then a binder solution is added dropwise to perform agitation granulation), centrifugal tumbling granulators, fluidized bed granulators (powder raw materials are fluidized and mixed with air, and a binder solution is sprayed onto the powder raw materials from a nozzle in a convective or countercurrent manner, causing the spray droplets to agglomerate the powder raw materials, which are then dried to promote particle growth), and spray dryers (spray drying granulators). Among these, a granulation method using a fluidized bed granulator is preferred from the viewpoints of both easily obtaining granules with excellent compression moldability and productivity.

[0072] For tableting, rotary tablet presses, single-punch tablet presses, etc., commonly used in the pharmaceutical field can be used. The compression pressure (tabletting pressure) in compression molding is preferably about 1 kN or more, more preferably about 2 kN or more, and tablets can be made at about 4 kN or more, 10 kN or more, or 20 kN or more. The upper limit is preferably about 60 kN or less, more preferably about 50 kN or less. As described above, the raw material powder of the present invention has excellent compression moldability and requires little voids as a powder mixture, so that even when tableted at the above compression pressure, tablets without chips or the like can be produced.

[0073] The tablet may have any shape, such as an ellipsoid, a cylinder, a doughnut, a sphere, etc. If necessary, the obtained tablet may be further coated with a film to form a coated tablet.

[0074] The tablet of the present invention is a tablet containing the matrix composition (I), the active ingredient (II), and other ingredients (III) as necessary, and is produced by, for example, the method described above, preferably by tableting. The other ingredients (III) can be the other ingredients (E) listed for the pharmaceutical composition of the present invention.

[0075] The volume of the tablet is 1000 mm from the viewpoint of ease of oral administration. ３ Preferably less than 800 mm ３ Less than 750 mm is more preferable. ３ The following is even more preferred:

[0076] Tablets produced as described above generally have a hardness of 50 to 200 N, although this varies depending on the form and size of the tablet. Tablets with such high hardness are generally difficult to chew, and after ingestion, the tablet swells upon contact with a physiological medium, forming a gel matrix with a dense cross-linked structure, making them suitable as sustained-release tablets.

[0077] When a dissolution test is performed on a tablet, the tablet immersed in a solution corresponding to a physiological medium (Fig. 1(a)) swells and gels (see Fig. 1(b)), and the gel matrix dissolves and disappears, causing the tablet shape to disintegrate (Fig. 1(c)).

[0078] When the matrix composition (I) comes into contact with a physiological medium such as intestinal fluid, the polyvinyl alcohol-based resin (A) forms a three-dimensional network structure through hydrogen bonding with compounds having many hydroxyl groups, such as polyphenol compounds and silica particles, resulting in gelation. The hydrogel formed through hydrogen bonding with the polyphenol compounds and silica is stronger and more durable than hydrogels formed with the PVA-based resin alone, for reasons that are unclear. This is thought to extend the release time of the medicinal ingredient encapsulated within the matrix, resulting in excellent sustained-release properties. The higher the degree of polymerization of the PVA-based resin, the more complex the entanglement structure with the tannic acid and silica particles, which is thought to enhance the sustained-release properties of such a three-dimensional network structure. Therefore, tablets containing the pharmaceutical composition of the present invention can form a highly sustained gel after administration and release the medicinal ingredient over a long period of time, making them excellent sustained-release tablets.

[0079] Specifically, a dissolution test is conducted based on 6.10 of the Japanese Pharmacopoeia, 18th Edition, and the loss tangent tanδ (loss modulus E" / storage modulus E') of the tablets remaining after the dissolution test, calculated by dynamic viscoelasticity measurement, is 10 or less, preferably 8 or less, more preferably 5 or less, even more preferably 2 or less, and particularly preferably 1 or less.

[0080] The dissolution medium and dissolution time used in the dissolution test are determined by the Pharmacopoeia depending on the type of drug used. The tablet of the present invention is characterized in that, regardless of the dissolution medium and dissolution time determined depending on the type of drug contained, the tablet remaining after the dissolution test uses a matrix composition whose loss tangent tan δ (loss modulus E" / storage modulus E') calculated by dynamic viscoelasticity measurement is within the above-mentioned range.

[0081] The tablet of the present invention makes it possible to adjust the release rate, release time, and release site of the active ingredient from the tablet in accordance with the 18th revised Japanese Pharmacopoeia, for the purpose of reducing the number of administrations or reducing side effects.

[0082] Since the gastric residence time of a tablet is typically 2 to 3 hours, in order to maintain a desirable blood drug concentration, it is desirable for the dissolution concentration to be low 1 hour after administration and for the drug to be released over 3 to 10 hours. Even for tablets with a high content of active ingredient of 50% by mass or more, the dissolution rate of the tablet of the present invention is suppressed to approximately 20 to 40% at the beginning of administration (1 hour after the start of the dissolution test), but 85% or more is dissolved by approximately 10 hours after administration (10 hours after the start of the dissolution test). The specific release characteristics that must be satisfied vary depending on the type of drug. For example, when the drug used is metformin hydrochloride, Ranks A and B of the following rankings of extended-release characteristics can be satisfied. Ranks A and B satisfy the release characteristics specified in USP 41 "Metformin Hydrochloride Extended-Release Tablets," making them suitable for extended-release tablets.

[0083] Rank A: Dissolution rate of medicinal ingredients 1 hour after the start of the test: 20% to 40%; Dissolution rate of medicinal ingredients 3 hours after the start of the test: 45% to 65%; Dissolution rate of medicinal ingredients 10 hours after the start of the test: 85% or more; Rank B: Dissolution rate of medicinal ingredients 1 hour after the start of the test: 20% to 42%; Dissolution rate of medicinal ingredients 3 hours after the start of the test: 45% to 69%; Dissolution rate of medicinal ingredients 10 hours after the start of the test: 85% or more; Rank C: Dissolution rate of medicinal ingredients 1 hour after the start of the test is more than 42%, or more than 69% after 3 hours

[0084] The present invention will be further explained below with reference to examples and comparative examples, but the present invention is not limited to the following examples.

[0085] [Measurement and Evaluation Methods] (1) Tablet Hardness (N) The tablet hardness after tableting was measured using a tablet hardness tester (PC-30 manufactured by Okada Seiko Co., Ltd.).

[0086] (2) Dissolution Test The dissolution test was carried out in accordance with the 18th Edition of the Japanese Pharmacopoeia, Section 6.10. One liter of the second dissolution test fluid (compliant with the Japanese Pharmacopoeia, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) heated and degassed at 45°C for 2 hours was weighed into a measuring cylinder and placed in a thermostatic water bath dissolution tester (NTR-6600 manufactured by Toyama Sangyo Co., Ltd.). After confirming that the test fluid had stabilized at 37°C, one tablet was added to start the dissolution test, and the dissolution rates were measured 1 hour, 3 hours, and 10 hours after the start of the dissolution test.

[0087] The dissolution rate was calculated according to the method described in "Methoformin Hydrochloride Extended-Release Tablets" of the USP (The United States Pharmacopeia). Specifically, the amount of metformin hydrochloride in the dissolution solution obtained in the dissolution test was measured and calculated using a UV detector. Specifically, the amount of metformin hydrochloride was calculated based on the ratio of the peak values ​​attributable to metformin hydrochloride in the standard solution and the dissolution test solution. Assuming that the amount of metformin hydrochloride contained in one tablet was 500 mg, the dissolution rate (%) was calculated from the amount of metformin hydrochloride contained in the dissolution solution. When the calculated amount of metformin hydrochloride was 500 mg, the dissolution rate was 100%.

[0088] (3) Dynamic Viscoelasticity Measurement The remaining tablets (remaining portions of the tablets) were taken out 10 hours after the dissolution test (2) was conducted, and the loss tangent tanδ (= loss modulus E″ / storage modulus E′) was measured using a dynamic viscoelasticity measuring device (Rheogel-E4000 manufactured by UBM Co., Ltd.) under the following test conditions.

[0089] (Test conditions) Measurement frequency: 0.05 Hz Measurement strain: 5% Chuck distance: Adjusted according to sample size Deformation measurement mode: Compression Measurement temperature: 22°C

[0090] (4) Tablet Shape Retention The ratio of the gel thickness of the remaining tablet (remaining part of the tablet) 10 hours after the dissolution test (2) to the tablet thickness after molding (see Figure 2(a)) was calculated as shape retention %. Shape retention was evaluated based on the shape retention. The gel thickness was measured using the distance between the chucks of a dynamic viscoelasticity measuring device (Rheogel-E4000, manufactured by UBM Co., Ltd.) (see Figure 2(b)). Shape retention (%) = gel thickness / tablet thickness × 100

[0091] ◯: Shape retention rate of 60% or more △: Shape retention rate of 40% or more but less than 60% ×: Shape retention rate of less than 40%

[0092] (5) Particle size of raw material powder The median diameter (D) of the powder was determined based on the particle size distribution (volume basis) measured using a laser diffraction particle size distribution analyzer (Mastersizer 3000 manufactured by Malvern Panalytical Ltd). ５０ ) was measured.

[0093] <Compounds used in the production of tablets> Matrix composition (I) PVA (A) for matrix substrate: Unmodified polyvinyl alcohol (average saponification degree 88 mol%, average polymerization degree 2500) manufactured by Mitsubishi Chemical Corporation

[0094] Polyphenol compound (B): Tannic acid (purified alcohol product, median diameter: 33.8 μm) manufactured by Kishida Chemical Co., Ltd.

[0095] Amorphous silica (C) Silica 1: "AEROSIL 200" manufactured by Nippon Aerosil Co., Ltd. Chain aggregates of spherical silica particles (hydrophilic), specific surface area: 200 m ２ / g Silica powder with a median diameter of 14.2 μm Silica 2: "AEROSIL 300" manufactured by Nippon Aerosil Co., Ltd. Chain aggregates of spherical silica particles with a specific surface area of ​​300 m ２ / g Silica powder with a median diameter of 12.8 μm Silica 3: "AEROSIL 50" manufactured by Nippon Aerosil Co., Ltd. Chain aggregates of spherical silica particles with a specific surface area of ​​50 m ２ / g Silica powder with a median diameter of 11.4 μm Silica 4: Fuji Silysia Chemical Industry Co., Ltd. "SYLOSPHOBIC 200" Gel-method silica particles (surface hydrophobic treatment), specific surface area: 220 m ２ / g Silica powder with a median diameter of 2.9 μm

[0096] Medicinal ingredient (II): Metformin hydrochloride

[0097] Others (III) PVA for binder: Polyvinyl alcohol (average saponification degree 88 mol%, average polymerization degree 300) manufactured by Mitsubishi Chemical Corporation. Crystalline cellulose: "PH102" manufactured by Asahi Kasei Chemicals Corporation. Magnesium stearate: Magnesium stearate as listed in the Japanese Pharmacopoeia by NOF Corporation.

[0098] [Tablet Production] Tablets No. 1 to 7: A PVA-based resin aqueous solution prepared from 3.8 g of PVA-based resin binder and 15.1 g of purified water and 296 g of metformin hydrochloride were placed in a stirring mixer granulator (FM-VG-01, manufactured by Powrex Corporation) and wet granulated for 1 minute. The granules were dried using a tumbling fluidized bed granulator (FD-MP-01, manufactured by Powrex Corporation) to obtain metformin hydrochloride granules (median diameter 170 μm, moisture content 0.4%).

[0099] 63.3 g of the obtained metformin hydrochloride granules, 34.1 g of a PVA-based resin for a matrix substrate, 3.4 g of tannic acid, and the silica powder shown in Table 1 were placed in a plastic bag and mixed by vigorously shaking for 5 minutes. 1.0 g of magnesium stearate was then added and gently mixed, and the mixture was compressed at 35 kN using a rotary tablet press (HT-EX12SS-U, manufactured by Hata Iron Works Co., Ltd.) to obtain round tablets (diameter 14.2 mm, tablet thickness 5.9 mm, metformin hydrochloride content 500 mg) shown in Figure 2(a).

[0100] Tablet No. 8: Tablets were produced in the same manner as No. 1, except that no silica powder was added. The results of the obtained sustained-release tablets based on the above-mentioned measurement and evaluation methods are shown in Table 1.

[0101] Tablet No. 9: Microcrystalline cellulose was used instead of silica particles, and tablets were produced in the same manner as in No. 1. The results of the obtained sustained-release tablets based on the above-mentioned measurement and evaluation methods are shown in Table 1.

[0102]

[0103] Tablets No. 1 to No. 7 are tablets containing silica. Compared with tablets No. 8 and No. 9, which do not contain silica, they had higher tablet hardness and shape retention, and tended to suppress drug dissolution in the early stages of administration (1 hour and 3 hours). Tablets No. 1 to No. 7 satisfied the sustained-release property ranks A and B described above, while Nos. 8 and 9 achieved the sustained-release property rank C described above.

[0104] When the same type of silica was contained, the shape retention improved as the content of silica particles increased (for example, for Silica 1, the shape retention increased in the order of No. 1, 2, and 3, and for Silica 2, the shape retention increased in the order of No. 4 and 5). Since tan δ decreased as the silica content increased, it is thought that silica can increase the crosslink density of the hydrogel, allowing it to maintain its solid state.

[0105] Comparing Nos. 1, 4, and 6, all had the same silica content and the same mixing ratio with tannic acid, but the larger the specific surface area, the smaller the tan δ tended to be. This is thought to be because the larger the specific surface area of ​​chain silica, the more hydrogen bonds it can form with other components (PVA for matrix substrate, tannic acid), increasing the crosslink density of the gel.

[0106] Comparing Nos. 2, 5, and 7, No. 7 had lower hardness, a larger volume, and reduced shape retention. Furthermore, even though No. 2 and No. 7 had similar silica contents and specific surface areas, No. 7 exhibited significantly lower shape retention. It is believed that the hydrophobic treatment of the silica particle surfaces in No. 7 prevented sufficient hydrogen bonding with other components, reducing the effect of increasing the crosslink density of the gel.

[0107] Tablets containing the pharmaceutical composition of the present invention have sufficient hardness so as to be difficult to chew, and can maintain their tablet shape for a long time after administration, allowing for sustained release of a high content of medicinal ingredients for a long period of time. Therefore, by using the pharmaceutical composition of the present invention as a raw material, tablets that are suitable as sustained-release tablets and have high compliance with administration can be provided.

Claims

1. A pharmaceutical composition comprising a polyvinyl alcohol-based resin (A), a polyhydric phenol compound (B), and amorphous silica (C), wherein the content of the amorphous silica (C) is 0.1 to 20 parts by mass per 100 parts by mass of the polyvinyl alcohol-based resin (A).

2. The pharmaceutical composition according to claim 1, further comprising an active ingredient (D), the content of which is from 30% by mass to 90% by mass in the pharmaceutical composition.

3. The pharmaceutical composition according to claim 1 or 2, wherein the content of the polyvinyl alcohol resin (A) in the pharmaceutical composition is 5 to 35% by mass.

4. A pharmaceutical composition according to any one of claims 1 to 3, comprising 0.05 to 32 parts by mass of the polyhydric phenol compound (B) per 100 parts by mass of the polyvinyl alcohol resin (A).

5. The specific surface area of ​​the amorphous silica (C) measured by the BET method is 50 to 1000 m ２ The pharmaceutical composition according to any one of claims 1 to 4, wherein the amount of the pharmaceutical composition is 100 mg / g.

6. A pharmaceutical composition according to any one of claims 1 to 5, wherein the amorphous silica (C) is a chain-like aggregate of silica nanoparticles.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the polyvinyl alcohol resin (A) has an average degree of polymerization of 500 to 3,000 and a degree of saponification of 78 to 96 mol %.

8. A pharmaceutical composition described in any one of claims 1 to 7, wherein the mass ratio (B / C) of the content of the polyhydric phenol compound (B) to the content of the amorphous silica (C) is 30 / 70 to 95 / 5.

9. A tablet comprising the pharmaceutical composition according to any one of claims 1 to 8.

10. A tablet having a medicinal ingredient (II) dispersed in a matrix composition (I), said matrix composition (I) comprising a polyvinyl alcohol resin (A), a polyhydric phenol compound (B), and amorphous silica (C), and having a loss tangent tan δ [loss modulus E" / storage modulus E'] of 10 or less, calculated by dynamic viscoelasticity measurement of the remaining portion of said tablet after a dissolution test based on Japanese Pharmacopoeia 6.

10.

11. The tablet according to claim 10, wherein the content of the active ingredient (II) is 30% by mass or more and 90% by mass or less.

12. A tablet according to claim 10 or 11, wherein the content of the polyvinyl alcohol resin (A) is 5 to 35 mass%.

13. The specific surface area of ​​the amorphous silica (C) measured by the BET method is 50 to 1000 m ２ The tablet according to any one of claims 10 to 12, wherein the tablet weight is 100g.

14. A tablet according to any one of claims 10 to 13, wherein the amorphous silica (C) is a chain-like aggregate of silica nanoparticles.

15. A tablet according to any one of claims 10 to 14, wherein the polyvinyl alcohol resin (A) has an average degree of polymerization of 500 to 3,000 and a degree of saponification of 78 to 96 mol %.

16. A tablet described in any one of claims 10 to 15, wherein the mass ratio (B / C) of the content of the polyhydric phenol compound (B) to the content of the amorphous silica (C) is 30 / 70 to 95 / 5.

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