Pharmaceutical composition and tablet

Abstract

Disclosed is a pharmaceutical composition which can provide a tablet capable of maintaining the shape of the tablet for a long period of time after administration while suppressing the content of polyvinyl alcohol. The pharmaceutical composition contains a polyvinyl alcohol-based resin (A), a polyphenol compound (B), and amorphous silica (C). The content of the amorphous silica (C) is 0.1-20 parts by mass with respect to 100 parts by mass of the polyvinyl alcohol-based resin. Further disclosed is a tablet which comprises a pharmaceutical composition as a matrix composition (I) and an active pharmaceutical ingredient (II) dispersed in the matrix composition (I), the active pharmaceutical ingredient (II) being contained in an amount of 30-90 mass% inclusive.

Description

Pharmaceutical compositions and tablets Technical Field

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

[0002] Sustained-release tablets prolong the drug's release time over a longer period by controlling the release rate of the active pharmaceutical ingredient. These tablets can reduce dosing frequency, thereby improving medication adherence; furthermore, they can reduce fluctuations in blood drug concentrations, thus decreasing side effects. Therefore, research and development of tablets has been very active in recent years.

[0003] There are various types of sustained-release tablets based on different drug release control mechanisms: membrane permeation control tablets with a sustained-release coating layer that can control the permeation of the active drug ingredient, matrix diffusion control tablets containing insoluble substances as the main excipients, matrix tablets using hydrophilic polymers as matrix materials, osmotic pressure control tablets, and so on.

[0004] Among these, matrix-type sustained-release tablets using hydrophilic polymers as the matrix material have advantages in manufacturing methods because they can be produced through direct compression. Therefore, formulations using this material have been actively researched recently.

[0005] When matrix-based sustained-release tablets are exposed to physiological media, the hydrophilic polymers that form the matrix expand to form a network gel matrix, thus preventing rapid drug release. The physiological media then gradually penetrate the tablet, causing the gel matrix to gradually disintegrate, eventually leading to the tablet losing its shape. This process is known as tablet disintegration.

[0006] Polyvinyl alcohol (PVA) is a biodegradable hydrophilic polymer and an effective candidate for matrix material in matrix-based sustained-release tablets.

[0007] In order to prolong the drug release time of matrix-type sustained-release tablets using polyvinyl alcohol as the matrix material, it is necessary to prolong the disintegration time of the formed gel matrix.

[0008] However, when the polyvinyl alcohol content in the matrix material is low, the resulting gel strength is insufficient, the sustained-release performance decreases, and the tablets are more prone to disintegration due to gastrointestinal motility. These factors can lead to excessive drug release.

[0009] Conversely, increasing the polyvinyl alcohol (PVA) content leads to the formation of a gel with a dense network structure, which can delay drug release. However, higher PVA content also increases tablet size. Since tablets must meet predetermined size requirements to achieve the correct dosage, the amount of PVA that can be added to a single tablet is limited.

[0010] In order to achieve the desired sustained-release effect by increasing the strength of the gel matrix, Patent Document 1 (WO2022 / 202138) proposes to incorporate polyphenolic compounds (tannic acid) into a matrix material using polyvinyl alcohol (PVA).

[0011] Patent document 1 also discloses that the combined use of tannic acid can increase tablet hardness and inhibit drug dissolution rate one hour and three hours after administration.

[0012] Furthermore, Patent Document 2 (WO2023 / 027056) discloses a method of increasing tablet hardness by using a combination of polyvinyl alcohol and crystalline cellulose as a matrix material, and adjusting the average particle size and blending ratio of this combination to fall within a specific range, thereby obtaining the desired sustained-release performance. Prior Art

[0013] Patent documents

[0014] [Patent Document 1] WO2022 / 202138

[0015] [Patent Document 2] WO2023 / 027056 Summary of the Invention

[0016] The technical problem that the invention aims to solve

[0017] Each sustained-release tablet disclosed in the embodiments of Patent Document 1 contains less than 50% by mass (approximately 47% by mass) of metformin hydrochloride as the active pharmaceutical ingredient. Furthermore, the embodiments also disclose that 100% by mass of the active pharmaceutical ingredient was released within 10 hours in a metformin hydrochloride dissolution test.

[0018] Currently, sustained-release tablets need to retain their active pharmaceutical ingredients for at least 10 hours after administration so that they can be taken only once daily. To meet this requirement, the content of polyvinyl alcohol, which serves as the base material for the matrix, needs to be adjusted within a predetermined range, while simultaneously extending the retention time of the matrix.

[0019] Patent Document 2 discloses a sustained-release tablet described in an embodiment containing less than 50% by mass (approximately 48% by mass) of the active pharmaceutical ingredient (metformin hydrochloride), with a dissolution rate of less than 100% even 10 hours after administration. However, nearly 50% of the drug is released early in the course of administration (one hour after administration), indicating that there is still room for improvement in obtaining sustained-release tablets that can maintain efficacy for a longer period of time.

[0020] In view of the above, the present invention is proposed, and its object is to provide a pharmaceutical composition capable of providing a sustained-release tablet using polyvinyl alcohol as a matrix material and containing more than 50% by mass of an active pharmaceutical ingredient per tablet, or providing a sustained-release tablet that retains a certain amount of active pharmaceutical ingredient after a dissolution test, as well as a tablet comprising the pharmaceutical composition.

[0021] Solution to the problem

[0022] To provide a tablet containing more than 50% by mass of an active pharmaceutical ingredient that exhibits excellent sustained-release efficacy and continues to release the active pharmaceutical ingredient even 10 hours after administration, the inventors conducted various studies on components that could increase gel strength while reducing the content of polyvinyl alcohol-based resins used as the matrix. Ultimately, it was discovered that incorporating a combination of silica particles and polyphenolic compounds into the matrix allows the tablet to maintain its expanded shape even 10 hours after administration, thus completing this invention.

[0023] According to one aspect of the present invention, the pharmaceutical composition comprises the following embodiments:

[0024] (1) A pharmaceutical composition comprising a polyvinyl alcohol resin (A), a polyphenolic compound (B) and amorphous silica (C), wherein the content of amorphous silica (C) is 0.1 to 20 parts by weight relative to 100 parts by weight of the polyvinyl alcohol resin (A).

[0025] (2) The pharmaceutical composition according to embodiment (1), wherein the pharmaceutical composition further comprises an active pharmaceutical ingredient (D) in a content of 30% by mass or more and 90% by mass or less.

[0026] (3) The pharmaceutical composition according to embodiment (1) or (2), wherein the content of polyvinyl alcohol resin (A) in the pharmaceutical composition is from 5% by mass to 35% by mass.

[0027] (4) The pharmaceutical composition according to any one of embodiments (1) to (3), wherein the content of polyphenol compound (B) is 0.05 to 32 parts by weight relative to 100 parts by weight of polyvinyl alcohol resin (A).

[0028] (5) The pharmaceutical composition according to any one of embodiments (1) to (4), wherein the amorphous silica (C) has a specific surface area of ​​50 to 1000 m² as measured by the BET method. 2 / g.

[0029] (6) The pharmaceutical composition according to any one of embodiments (1) to (5), wherein the amorphous silica (C) is a chain aggregate of silica nanoparticles.

[0030] (7) The pharmaceutical composition according to any one of embodiments (1) to (6), wherein the polyvinyl alcohol resin (A) has an average degree of polymerization of 500 to 3000 and a degree of saponification of 78 to 96 mol.

[0031] (8) The pharmaceutical composition according to any one of embodiments (1) to (7), wherein the mass ratio (B / C) of the content of the polyphenolic compound (B) to the content of amorphous silica (C) is 30 / 70 to 95 / 5.

[0032] According to another aspect of the invention, the present invention relates to a tablet.

[0033] (9) A tablet comprising the pharmaceutical composition of any one of embodiments (1) to (8) above. The tablets of the present invention include the following embodiments:

[0034] (10) A tablet comprising a matrix composition (I) and an active pharmaceutical ingredient (II) dispersed in the matrix composition (I), wherein the matrix composition (I) comprises a polyvinyl alcohol resin (A), a polyphenolic compound (B), and amorphous silica (C); and the remaining portion of the tablet has a loss tangent of 10° or less after a dissolution test according to the Japanese Pharmacopoeia. The loss tangent (tan δ) is defined as the ratio of the loss modulus (E″) to the storage modulus (E′) determined by dynamic viscoelasticity measurement.

[0035] (11) The tablet according to embodiment (10), wherein the content of the active pharmaceutical ingredient (II) is 30% by mass or more and 90% by mass or less.

[0036] (12) The tablet according to embodiment (10) or (11), wherein the content of the polyvinyl alcohol resin (A) is from 5% by mass to 35% by mass.

[0037] (13) A tablet according to any one of embodiments (10) to (12), wherein the amorphous silica (C) has a specific surface area of ​​50 to 1000 m² as measured by the BET method. 2 / g.

[0038] (14) A tablet according to any one of embodiments (10) to (13), wherein the amorphous silica (C) is a chain aggregate of silica nanoparticles.

[0039] (15) A tablet according to any one of embodiments (10) to (14), wherein the polyvinyl alcohol resin (A) has an average degree of polymerization of 500 to 3000 and a degree of saponification of 78 to 96 mol.

[0040] (16) The tablet according to any one of embodiments (10) to (15), wherein the mass ratio (B / C) of the content of the polyphenolic compound (B) to the content of amorphous silica (C) is 30 / 70 to 95 / 5.

[0041] Effects of the present invention

[0042] Tablets containing the pharmaceutical composition of the present invention have high gel strength, such that the loss tangent (tan δ) of the gel remaining as a tablet after a tablet dissolution test is less than 10. The loss tangent is determined by viscoelasticity measured using a dynamic viscoelasticity analyzer. Therefore, this pharmaceutical composition can be used as a matrix material for tablets (especially sustained-release tablets). Tablets using this pharmaceutical composition as a matrix material can accommodate a high content of the active pharmaceutical ingredient within a limited size, thereby ensuring easy administration while maintaining sustained release of the active pharmaceutical ingredient over an extended period. Attached Figure Description

[0043] Figure 1 is a schematic diagram illustrating the dissolution behavior of sustained-release tablets.

[0044] Figure 2 is a schematic diagram illustrating the tablet shape used to determine the shape retention percentage evaluated in the embodiments. Detailed Implementation

[0045] [Composition for use in pharmaceutical tablets]

[0046] The pharmaceutical composition of the present invention comprises a polyvinyl alcohol resin (A), a polyphenolic compound (B), and amorphous silica (C), wherein the content of amorphous silica (C) is 0.1 to 20 parts by weight relative to 100 parts by weight of the polyvinyl alcohol resin (A). Furthermore, the pharmaceutical composition may also comprise an active pharmaceutical ingredient (D) in an amount of 30% by weight or more and 90% by weight or less. Each component will be described below.

[0047] Polyvinyl alcohol (PVA) based resins (A)

[0048] Polyvinyl alcohol (PVA) based resins (A) are resins obtained by saponifying polyvinyl ester based resins (polymers of vinyl ester based monomers). PVA based resins are resins mainly composed of vinyl alcohol structural units, which are produced by the saponification of vinyl ester based monomers. PVA based resins contain: vinyl alcohol structural units in a content corresponding to their degree of saponification, and vinyl ester structural units as the unsaponified portion.

[0049] Polyvinyl alcohol (PVA) based resins (A) are not limited to unmodified PVA based resins composed of ethylene alcohol units and ethylene ester units. Modified PVA based resins, which are saponified copolymers of ethylene ester monomers and monomers that can copolymerize with ethylene ester monomers, can also be used. In addition, post-modified PVA based resins can also be used. However, unmodified PVA based resins are preferred. For modified PVA based resins, the degree of modification (corresponding to the content of structural units other than ethylene alcohol units and ethylene ester structural units) is less than 10 mol%, preferably 5 mol% or less, more preferably 1 mol% or less.

[0050] Examples of vinyl ester monomers include vinyl formate, vinyl acetate, vinyl propionate, vinyl valerate, vinyl butyrate, vinyl isobutyrate, vinyl neovalerate, vinyl decanoate, vinyl laurate, vinyl stearate, vinyl benzoate, vinyl tert-carbonate, etc. Among these vinyl esters, vinyl acetate is preferred for practical reasons.

[0051] Examples of copolymerizable monomers include: olefins, such as ethylene, propylene, isobutylene, α-octene, α-dodecene, and α-octadecene; hydroxyl-containing α-olefins, such as 3-buten-1-ol, 4-penten-1-ol, 5-hexen-1-ol, 3,4-dihydroxy-1-butene, and their derivatives, such as acylated products; unsaturated acids, such as acrylic acid, methacrylic acid, crotonic acid, maleic acid, maleic anhydride, itaconic acid, undecenoic acid, and their salts, monoesters, or dialkyl esters; nitriles, such as acrylonitrile and methacrylonitrile; and amides, such as diacetone acrylamide, acetone acetamide, and acetone acetamide. Acrylamides and methacrylamides; olefin sulfonic acids, such as vinyl sulfonic acid, allyl sulfonic acid, methyl allyl sulfonic acid, or their salts; alkyl vinyl ethers; vinyl compounds, such as dimethyl allyl vinyl ketone, N-vinylpyrrolidone, vinyl chloride, vinylene carbonate, 2,2-dialkyl-4-vinyl-1,3-dioxolane, and glycerol monoallyl ether; substituted vinyl acetates, such as isopropylene acetate and 1-methoxyvinyl acetate; vinylidene chloride, 1,4-diacetoxy-2-butene, 1,4-dihydroxy-2-butene, vinylene carbonate, etc. These copolymerizable monomers can be used alone or in combination of two or more. Based on the total amount of the polymer, the content of the copolymerizable monomer is less than 10 mol%, preferably less than 5 mol%, and particularly preferably less than 1 mol%.

[0052] A preferred modified PVA-based resin is a copolymer in which an unsaturated acid or its salt, a monoester or a dialkyl ester is copolymerized as a copolymerizable monomer. Polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer is a particularly preferred modified PVA-based resin.

[0053] Vinyl ester monomers (optionally including copolymerizable monomers) can be polymerized using known conventional methods, such as bulk polymerization, solution polymerization, suspension polymerization, dispersion polymerization, emulsion polymerization, etc. The polymerization catalysts and solvents used in the polymerization process can also be those conventionally known. Solution polymerization using methanol as a solvent is commonly employed.

[0054] The saponification of the resulting ethylene ester polymers can also be carried out using known conventional methods. Industrially, the ethylene ester polymers are dissolved in alcohols and saponified in the presence of a base catalyst. Common base catalysts include alkali metal hydroxides or alkoxides, such as sodium hydroxide, potassium hydroxide, and sodium methoxide.

[0055] The polyvinyl alcohol (PVA) resin particles obtained by saponification are washed with a lower alcohol (e.g., methanol) and then dried continuously or intermittently with hot air or the like. Suitable drying temperatures are typically 50°C to 150°C, preferably 60°C to 130°C, and more preferably 70°C to 110°C. Excessively high drying temperatures can cause thermal degradation of the PVA resin particles. Insufficient drying temperatures will prolong the drying time. Suitable drying times are typically 1 to 48 hours, preferably 2 to 36 hours. If the drying time of the PVA resin particles is too long, thermal degradation may occur. Conversely, if the drying time is insufficient, the PVA resin particles may not be fully dried, or a higher drying temperature may be required. The PVA resin is dried such that the remaining solvent content in the dried PVA resin is typically 10% by mass or less, preferably 5% by mass or less, and particularly preferably 1% by mass or less.

[0056] The average saponification degree of the PVA-based resin (A) is 78 to 96 mol%, which meets the requirements for partially saponified polyvinyl alcohol in the Japanese Food Additives Standard (JPE). Preferably, the average saponification degree of the PVA-based resin (A) is 85 to 89 mol%, which meets the requirements of the European Pharmacopoeia (EP) and the United States Pharmacopeia (USP).

[0057] PVA-based resins with an average saponification degree within the specified range can exhibit high water solubility. Therefore, PVA-based resins contained in orally administered tablets can form hydrogen bonds with the hydroxyl groups in polyphenolic compounds and silica particles, creating a hydrogel that facilitates the sustained release of the active pharmaceutical ingredient from the tablet. Conversely, PVA-based resins with excessively low saponification degrees have reduced gel-forming ability due to a decreased number of hydroxyl groups, resulting in unsatisfactory sustained-release performance. Here, the average saponification degree refers to the value measured according to the method of JIS K6726 (1994).

[0058] The average degree of polymerization of the PVA-based resin (A) is 500 or higher, preferably 800 or higher, 1000 or higher, 1500 or higher, or 2100 or higher. The upper limit is preferably 3000 or lower, more preferably 2600 or lower. When the average degree of polymerization is too low, the resin's gel-forming ability is insufficient, resulting in insufficient inhibition of drug release. In particular, polyvinyl alcohol-based resins with an average degree of polymerization below 800 (commonly used as binders, as described below) tend to dissolve in water rather than form a gel after oral administration. Therefore, they cannot adequately inhibit the release of the active pharmaceutical ingredient, making it difficult to achieve the desired sustained-release performance. On the other hand, if the average degree of polymerization is too high, the elasticity of the PVA-based resin particles increases, which can lead to decreased compressibility and tablet formability. The average degree of polymerization referred to herein is the number-average degree of polymerization measured according to the method of JIS K 6726 (1994).

[0059] The viscosity of a 4% by mass aqueous solution of PVA-based resin (A) at 20 °C is preferably 6.0 mPa·s or higher, more preferably 15.0 mPa·s to 70.0 mPa·s, and most preferably 20.0 mPa·s to 60.0 mPa·s. Excessively high viscosity of the aqueous solution (4% by mass) is usually caused by PVA-based resins with excessively high average polymerization. Therefore, PVA-based resins with excessively high measured aqueous solution viscosity tend to have decreased formability during compression or tableting due to increased elasticity. Conversely, if the viscosity of the aqueous solution (4% by mass) is too low, it indicates insufficient average polymerization of the PVA-based resin, and the strength and density of the hydrogel formed after contact with physiological media tend to decrease, resulting in insufficient sustained-release performance of the tablets. Hereinafter, the viscosity of the aqueous solution (4% by mass) at 20 °C is the viscosity measured according to the method of JIS K 6726 (1994).

[0060] In tablet manufacturing, polyvinyl alcohol (PVA) resin in powder form, consisting of numerous fine particles, can be blended with other components. Alternatively, PVA resin (PVA) resin (PVA) resin (A) can be dissolved in water for granulation, and the granulated product can be blended. From the perspective of tablet manufacturing methods and production efficiency, the use of PVA resin in powder form is preferred.

[0061] The average particle size of the PVA-based resin particles constituting the powder is from 40 μm to 200 μm, preferably from 45 μm to 100 μm, more preferably from 45 μm to 80 μm, and most preferably from 45 μm to 70 μm. If the average particle size is too large, the compacted powder may contain more voids, which can lead to a decrease in tablet hardness. The average particle size refers to the median diameter determined by the particle size distribution (volume basis) measured using laser diffraction.

[0062] The content of polyvinyl alcohol resin (A) in the pharmaceutical composition is preferably from 5% to 35% by mass. Tablets made from the compositions of the present invention contain 30% or more by mass, preferably 40% or more by mass, and more preferably 50% or more of the active pharmaceutical ingredient. This limits the content of the polyvinyl alcohol resin to the above range.

[0063] Polyphenolic compounds (B)

[0064] Examples of polyphenolic compounds (B) include catechol, resorcinol, hydroquinone, pyrogallol, hydroquinone, phloroglucinol, tannic acid, etc. These compounds can be used alone or in combination of two or more. Among these polyphenols, tannic acid is preferred.

[0065] Tannic acid can be extracted from a variety of plant materials. For example, tannic acid can be extracted from persimmon fruit, chestnut peel, gallnut, gallnut, cod meal, tamarind seed coat (from the legume family), or mimosa stem bark using water or ethanol. Preferred tannic acid is that extracted from gallnut or gallnut, which is listed in the 18th edition of the Japanese Pharmacopoeia. Both unrefined and refined tannic acid can be used, but refined tannic acid is preferred.

[0066] Polyphenolic compounds (such as tannic acid) have a high affinity for water and, in the presence of PVA-based resins, can form hydrogen bonds with the hydroxyl groups of the PVA-based resins and the silanol groups (Si-OH) on the surface of the silica particles described below. These hydrogen bonds can promote the formation of a three-dimensional network structure in the tablet. When tablets containing the composition are prepared, the gel with the three-dimensional network structure can inhibit the release of the active pharmaceutical ingredient contained in the tablet, thereby achieving the desired sustained-release effect.

[0067] The content of the polyphenolic compound (tannic acid) having the above-mentioned effects is preferably 0.05 to 32 parts by weight, more preferably 0.1 to 30 parts by weight, 1 to 25 parts by weight, or 5 to 15 parts by weight, relative to 100 parts by weight of PVA-based resin (A). When the composition is used as a matrix material for tablets, the polyphenolic compound can help to densify the network structure of the gel matrix. On the other hand, it is effective to increase the content of the polyphenolic compound while reducing the content of the polyvinyl alcohol-based resin, but if the amount of added tannic acid is too high, the tablets are prone to becoming discolored.

[0068] Since polyphenols (B) (such as tannic acid) are in powder form at room temperature, they can be used directly. However, granules prepared from polyphenol solutions by spraying and drying can also be used.

[0069] The particle size of tannic acid powder is typically 5 to 100 μm, preferably 10 to 50 μm. The particle size of tannic acid is determined by laser diffraction.

[0070] Amorphous silica (C)

[0071] Amorphous silica (C) is amorphous silica particles with silanol groups on their surface.

[0072] There are no particular limitations on the type and manufacturing method of amorphous silica used in this invention. Wet silica (e.g., precipitated silica or sol-gel derived silica) and dry silica (e.g., silica produced by combustion or electric arc methods) can be used.

[0073] Dry-process silica is an amorphous silica (silicon dioxide) produced by reacting silicon tetrachloride with oxygen in a high-temperature flame; a typical example is fumed silica. Commercially available products (including the Aerosil (trademark) series) can be used as dry-process silica.

[0074] Wet-process silica is generally classified into precipitated silica and sol-gel derived silica. Precipitated silica can be obtained by neutralizing an alkaline aqueous solution of sodium silicate or a similar compound, then recovering the amorphous silica by filtration, washing with water, and drying. Sol-gel derived silica is prepared by reacting sodium silicate with sulfuric acid in an acidic pH range, thereby causing aggregation and inhibiting the growth of primary particles.

[0075] Commercially available precipitated silica products include, for example, Nipsil, Ultrasil, Carplex, Mizukasil, and Tokusil. Commercially available sol-gel derived silica (including silica gel) products include, for example, Silysia, Syloid, and Nipgel.

[0076] Wet silica and dry silica exist as aggregates (secondary particles) composed of primary particles (silica nanoparticles) with a particle size of a few nanometers to hundreds of nanometers, or as aggregates formed by further aggregation of secondary particles.

[0077] Preferably, the specific surface area of ​​the silica particles is 50 to 1000 m². 2 / g, more preferably 75 to 800 m 2 / g, and more preferably 100 to 500 m 2 / g, particularly preferably 120 to 450 m 2 / g, and more preferably 150 to 400 m 2 / g. Specific surface area was determined by the BET method.

[0078] The shape, aggregation state (i.e., pore volume, pore diameter, etc.), and agglomeration force of primary particles in amorphous silica (C) aggregates vary depending on the type of silica, manufacturing method, and manufacturing conditions. Typically, dry-process silica aggregates are structures where spherical primary silica particles are linked together in chain, bead, or irregular shapes. In dry-process silica aggregates, the primary silica particles are held together by a weaker cohesive force than in wet-process silica. Due to the relatively strong cohesive force between primary silica particles, wet-process silica aggregates tend to form spherical aggregates. Therefore, wet-process silica aggregates typically exist in the form of porous particles with pores that constitute the internal surface area, similar to silica gel. Preferred silica aggregates are chain-like aggregates composed of silica nanoparticles because this type of structure exhibits excellent shape retention.

[0079] Typically, the specific surface area of ​​chain-like aggregates is smaller than that of spherical aggregates composed of porous particles (such as silica gel). Therefore, dry-process silica, when considered as aggregates, often exhibits greater porosity and specific surface area compared to wet-process silica.

[0080] The silica particles described herein have silanol groups (Si-OH) on their surface. These silanol groups form hydrogen bonds with hydroxyl groups present in PVA-based resins and polyphenolic compounds (e.g., tannic acid) under physiological conditions, thereby contributing to increased density and mechanical strength of the resulting gel matrix. Therefore, in the pharmaceutical compositions of the present invention, the release duration of the active pharmaceutical ingredient is prolonged due to the extended maintenance of tablet structural integrity. Consequently, the pharmaceutical tablets made from the pharmaceutical compositions exhibit improved sustained-release properties.

[0081] From the perspective of forming hydrogels with a three-dimensional network structure through hydrogen bonding with the OH groups of PVA molecules, the functions and reactions between silica and polyphenolic compounds appear similar. However, gels obtained by combining PVA with tannic acid and silica can exhibit a higher crosslinking density compared to gels obtained by combining PVA alone with polyphenolic compounds or by combining PVA alone with silica. This is likely because the combination of polyphenolic compounds and silica leads to a higher density of hydrogen bonds, thereby enhancing the durability of the network structure of the matrix formed by PVA-based resins. On the other hand, if the pore size of silica particles (aggregates) is too small, it may hinder the formation of hydrogen bonds with PVA-based resins due to the relatively large molecules of PVA-based resins. In other words, silica can readily form hydrogen bonds with other components (such as polyphenolic compounds and PVA-based resins), and the weak cohesion of the primary particles in its chain aggregates can contribute to increasing the degree of crosslinking and stabilizing the hydrogel.

[0082] Silica particles can also act as fluidizing agents. The presence of silica particles helps reduce the porosity and pore size of tablets manufactured by dry tableting processes. Silica particles can enhance the compressibility of the composition, thereby enabling the production of high-hardness tablets.

[0083] Amorphous silica (C) is typically supplied in powder form (primary silica particles or aggregates of primary particles) in pharmaceutical processes. The particle size (median diameter D) of these powders is... 50 The particle size is 0.1 μm or larger, 0.5 μm or larger, 1 μm or larger, or 5 μm or larger, and is less than 500 μm, less than 200 μm, less than 100 μm, or less than 50 μm. The median diameter refers to the particle size at which the cumulative value in the particle size distribution is 50%. Silica powder having the above particle sizes is blended with other components and compressed into tablets using a compression molding process. In the presence of silica as aggregates or agglomerates formed by weak cohesion, these aggregates or agglomerates may decompose and disperse in the mixture during the mixing operation. Therefore, a mixed powder as a pharmaceutical composition is obtained, wherein amorphous silica (C) is dispersed in other components including a PVA-based resin (A) and a polyphenolic compound (B).

[0084] Median particle size D 50 The particle size is determined as the cumulative value of 50% in the particle size distribution (volume standard) measured using a laser diffraction particle size distribution analyzer.

[0085] In addition, hydrophobic silica particles with hydrophobic surfaces can be obtained by chemically fixing compounds (e.g., organosilicon compounds or silicone oils) onto the surface of fumed silica particles through the reaction of silanol groups (Si-OH) present on the particle surface.

[0086] According to the present invention, both hydrophobic and hydrophilic silica can be used as amorphous silica (C), provided that the material meets the above-mentioned specific surface area and particle size range. However, hydrophilic silica is preferred because it has more hydroxyl groups (OH) on its surface, which can form hydrogen bonds with the hydroxyl groups of polyvinyl alcohol molecules and polyphenolic compounds, contributing to the formation of a dense hydrogel.

[0087] The mass ratio (B) / (C) of the polyphenol compound (B) to the amorphous silica (C) is 30 / 70 to 95 / 5, preferably 40 / 60 to 92 / 8, and more preferably 50 / 50 to 90 / 10.

[0088] The matrix substrate containing PVA-based resin as the main component needs to be easily swollen and undergo appropriate decomposition through dissolution. Therefore, an excessively high silica particle content should be avoided. Based on this, the silica (C) content relative to 100 parts by weight of polyvinyl alcohol-based resin (A) is 0.1 parts by weight or more, preferably 1 part by weight or more, more preferably 1.5 parts by weight or more, even more preferably 2 parts by weight or more, and is 20 parts by weight or less, preferably 10 parts by weight or less, more preferably 8 parts by weight or less.

[0089] Active pharmaceutical ingredient (API) (D)

[0090] The pharmaceutical compositions of the present invention may further comprise an active pharmaceutical ingredient (D).

[0091] Examples of active pharmaceutical ingredients (D) include: antipyretics, analgesics, and anti-inflammatory drugs; nutritional and tonic supplements; psychotropic drugs; antidepressants; anxiolytics; sedatives and hypnotics; anticonvulsants; CNS-acting drugs; brain metabolism improvers; brain circulation improvers; antiepileptics; sympathomimetic drugs; gastrointestinal drugs; acid suppressants; antiulcer drugs; antitussives; antiemetics; respiratory stimulants; bronchodilators; antihistamines; dental or oral medications; cardiotonics; antiarrhythmics; diuretics; antihypertensives; vasoconstrictors; coronary artery vasodilators; peripheral vasodilators; coagulation inhibitors; lipid-lowering drugs; choleretics; antibiotics; chemotherapy drugs; diabetes medications; osteoporosis medications; antirheumatic drugs; skeletal muscle relaxants; antispasmodics; hormones; alkaloids; sulfonamides; antiarthritis drugs; and antitumor drugs.

[0092] The active pharmaceutical ingredients applicable to this invention include those requiring sustained-release administration, particularly those readily soluble in water for oral administration. Active pharmaceutical ingredients known to have poor compressibility are also suitable for this invention. A particularly suitable active pharmaceutical ingredient is metformin hydrochloride.

[0093] The content of the active pharmaceutical 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.

[0094] Tablets containing the pharmaceutical compositions of the present invention can maintain their tablet shape for a long time, and therefore can contain active pharmaceutical ingredients at high concentrations within the range described above.

[0095] Furthermore, the content of the active pharmaceutical ingredient in the tablets made from the composition of the present invention is preferably 30% by mass or more, more preferably 40% by mass or more, and even more preferably 50% by mass or more.

[0096] Other components (E)

[0097] The pharmaceutical composition of the present invention may contain various additives within a certain range (less than 20% by mass of the composition, preferably less than 10% by mass) that do not affect the efficacy of the present invention.

[0098] Adhesive (E1)

[0099] During the granulation process (whether dry or wet), a binder is added to promote adhesion between particles and ensure sufficient adhesive force during tableting (direct compression or wet tableting).

[0100] Examples of suitable adhesives include dextrin, gum arabic, gelatin, hydroxypropyl starch, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pullulan, starch paste, and polyvinyl alcohol resins.

[0101] The amount of binder is selected according to the type of compound used; the amount of binder is typically 0.1 to 10 parts by weight, preferably 0.2 to 5 parts by weight, and more preferably 0.5 to 3 parts by weight, relative to 100 parts by weight of the composition used for granulation.

[0102] The polyvinyl alcohol-based resin used as an adhesive (referred to as "PVA-based resin for adhesives") differs from the polyvinyl alcohol-based resin (A) used as a matrix, at least in terms of average degree of polymerization. The number-average degree of polymerization of the polyvinyl alcohol resin used as an adhesive is typically from 100 to less than 800, preferably from 200 to less than 500.

[0103] The average saponification degree of the PVA-based resin used for adhesives can be 70 to 99 mol%, typically 78 to 96 mol%, preferably 85 to 89 mol%, which is similar to that of the PVA-based resin (A) used for matrix materials.

[0104] The PVA-based resin used as an adhesive may be a modified polyvinyl alcohol resin disclosed for polyvinyl alcohol resin (A), which is a saponifiable copolymer containing copolymerizable monomers.

[0105] When using PVA-based resins as adhesives, it is preferable to use an aqueous solution obtained by dissolving the resin in water.

[0106] When a tablet contains PVA-based resins as a matrix material and binder, the tablet contains two or more polyvinyl alcohol-based resins with different average degrees of polymerization. In this case, the total average degree of polymerization of the polyvinyl alcohol-based resins contained in the solid dosage form is calculated as the sum of the average degrees of polymerization of each polyvinyl alcohol-based resin, and the average degree of polymerization of each polyvinyl alcohol-based resin is determined independently based on its content.

[0107] In the case of two PVA-based resins (e.g., matrix PVA-based resin (A) and binder PVA-based resin), the average degree of saponification and the average degree of polymerization can be calculated using the following formulas, where SDm and Pm represent the degree of saponification and degree of polymerization of the matrix PVA-based resin, respectively, and SDb and Pb represent the degree of saponification and degree of polymerization of the binder PVA-based resin, respectively. Furthermore, M and B represent the proportions of the matrix PVA-based resin and the binder PVA-based resin to the total amount of PVA-based resin, respectively, where M+B=1.

[0108] Average degree of saponification = SDm × M + SDb × B

[0109] Average degree of polymerization = Pm × M + Pb × B

[0110] Based on the total mass of PVA-based resins, the content of PVA-based resins used as adhesives is typically at most about 5% by mass, usually less than 3% by mass, and preferably less than 2.5% by mass. Therefore, even if the adhesive PVA-based resin contains an average degree of polymerization of less than 800, the measured average degree of polymerization of the PVA-based resin contained in the composition for use in solid dosage forms can be 500 or more.

[0111] Lubricant (E2)

[0112] Lubricants can be added to improve flowability, provide lubrication during compression and tablet ejection in the die, and prevent adhesion to the punch surface or die walls. In particular, when tableting by direct compression, this helps reduce friction between the powder and the punch and die during compression.

[0113] Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, talc, etc.

[0114] Other (E3)

[0115] In addition to the additives mentioned above, the following may also be used as needed: other excipients (crystalline cellulose, sugar alcohols (e.g., mannitol, erythritol, xylitol, sorbitol, maltitol), sugars (e.g., glucose, fructose, lactose, sucrose, trehalose, maltose, oligosaccharides), calcium phosphate, starch, sodium phosphate, and gelatin, etc.); disintegrants (calcium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, cellulose or its derivatives, and 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... Salts of succinic acid and its salts, lactic acid and its salts, etc.; gliding agents (titanium dioxide, stearic acid, corn gum, heavy anhydrous silica, etc.); surfactants (phospholipids, glycerol 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, polysorbate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.); colorants (ferric oxide, yellow iron oxide, Edible Yellow No. 5, Edible Yellow No. 4, aluminum chelates, titanium dioxide, talc, etc.); and sweeteners (saccharin, aspartame, acesulfame potassium, sematriol, sucralose, etc.).

[0116] <Tablets and their manufacturing methods>

[0117] The tablets of the present invention are tablets containing the pharmaceutical compositions disclosed herein.

[0118] The tablets of the present invention are tablets in which an active pharmaceutical ingredient (II) is distributed in a matrix composition (I), said matrix composition (I) comprising a polyvinyl alcohol resin (A), a polyphenolic compound (B), and amorphous silica (C).

[0119] Tablets are typically manufactured by blending various ingredients and then directly molding them or molding them after granulation. Molding can be performed by tablet compression or wet tableting. In tablet compression, the mixture is directly compressed into tablets. Wet tableting is performed by drying or cooling the wet material. Tablet manufacturing processes are not limited to a specific method, but compression molding is preferred because it allows for dry processes. Furthermore, hard tablets with fewer pores can be easily obtained through compression molding.

[0120] In the case of compression molding, the matrix composition (I) is a homogeneous powder mixture obtained by uniformly mixing powders of PVA-based resin (A), polyphenolic compound (B), and amorphous silica (C). In this case, the average particle size (referred to as median diameter D) of the amorphous silica (C) powder used is... 50The particle size is 0.1 μm or larger, 0.5 μm or larger, 1 μm or larger, or 5 μm or larger, and is less than 500 μm, less than 200 μm, less than 100 μm, or less than 50 μm. Silica powder has a fluidizing effect, thereby reducing the voids between particles in the matrix composition.

[0121] Examples of compression processes include direct powder compression (direct compression), semi-dry particle compression, particle compression, or appropriate combinations thereof, and any of the above processes may be used.

[0122] The preferred tableting process ensures that the active pharmaceutical ingredient (II) is uniformly distributed within the PVA-based resin (A) in the final tablet. A preferred manufacturing method includes: first preparing granules containing the active pharmaceutical ingredient (II), then blending these granules with a powder of the matrix composition (I), and then compressing the mixture into tablets.

[0123] A mixture of matrix composition (I) and active pharmaceutical ingredient (II) can be used as a granulation composition, followed by granulation. If necessary, other additives can be added to and mixed into the granulation composition, or the granulation composition can be blended with other additives before tableting.

[0124] Examples of granulation processes include wet granulation, dry granulation, and spray-drying granulation. In wet granulation, a binder solution is added to the powder composition, and then granulation is performed. Another method is to first knead the mixed composition into a wet mass, and then granulate it. In dry granulation, the powder composition is pressed in a dry state, and then the pressed composition mass is broken up and granulated. In spray-drying granulation, a slurry made from the composition and a large amount of water is spray-dried to form granules.

[0125] The solvent used as an adhesive is selected appropriately based on the type of adhesive compound. If a PVA-based resin adhesive is used, water can be used as the solvent.

[0126] Granulators can include dry granulators, basket extruders, stirred granulators, centrifugal rounding granulators, fluidized bed granulators, and spray dryers. A dry granulator is a device that applies high pressure to a powder blend to form agglomerates, then breaks up the agglomerates to obtain powder with a suitable particle size. A stirred granulator is a device that mixes powder components for several minutes using stirring blades, and adds a binder solution dropwise while stirring to granulate. A fluidized bed granulator is a granulation device that involves mixing powder components using air to form a powder blend, then spraying a binder solution through nozzles in a convection or counter-current manner, causing the powder blend to agglomerate through the sprayed droplets, and then drying to increase the size of the agglomerates. A spray dryer is a device that granulates by spray drying. Among these, considering both the ease of obtaining granules with excellent compressibility and production efficiency, fluidized bed granulators are preferred for granulation processes.

[0127] For tablet manufacturing, rotary tablet presses and single-punch tablet presses commonly used in the pharmaceutical industry can be used.

[0128] In compression molding, the compression pressure (tablet forming pressure) is preferably about 1 kN or more, more preferably about 2 kN or more, and tableting can be performed at a pressure of 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. The pharmaceutical composition of the present invention can be in powder form, exhibiting excellent compressibility and providing a mixture of raw material powders with fewer voids. Therefore, even when the composition powder is tableted at a compression pressure as high as described above, crumb-free tablets can be obtained.

[0129] Drug tablets can be oval, cylindrical, spherical, ring-shaped, or any other shape. Furthermore, tablets can be coated with a film as needed.

[0130] The tablets of the present invention are tablets comprising the matrix composition (I), active pharmaceutical ingredient (II), and other ingredients (III) as described above, and can be manufactured by, for example, the methods described above, preferably by tableting. Other components (E) listed in the pharmaceutical composition of the present invention may be used as other ingredients (III).

[0131] From the perspective of convenient oral administration, the preferred tablet volume is 1000 mm. 3 Hereinafter, 800 mm is preferred. 3 Below, or even more preferably 750 mm 3 the following.

[0132] The tablets manufactured as described above typically have a hardness of 50 to 200 N, depending on the tablet's shape and size. These high-hardness tablets are generally difficult to chew and swell upon contact with physiological mediators after ingestion, forming a gel matrix with a dense cross-linked structure, making them suitable as sustained-release tablets.

[0133] In the dissolution test of the tablets, the tablets were immersed in a solution corresponding to a physiological medium (Fig. 1(a)). The tablets absorbed the medium and swelled to form a gel (Fig. 1(b)). The formed gel matrix dissolved and gradually disintegrated (Fig. 1(c)). In this way, the tablets retained some of their shape while disintegrating.

[0134] When the matrix composition (I) comes into contact with physiological media (e.g., intestinal fluid), the polyvinyl alcohol (PVA) resin (A) forms a gel by forming hydrogen bonds with compounds having multiple hydroxyl groups (including polyphenolic compounds and silica particles) to construct a three-dimensional network structure. The hydrogel formed by hydrogen bonds between the polyphenolic compounds and silica exhibits higher strength and longer durability than hydrogels formed from PVA resins alone, although the reason for this is not yet clear. Therefore, the formed hydrogel can prolong the release time of the active pharmaceutical ingredient encapsulated in the matrix, thereby achieving excellent sustained-release performance. Higher degrees of polymerization of the PVA resin can lead to more complex entanglement structures with tannins and silica particles, resulting in improved sustained-release performance. According to the present invention, tablets containing the disclosed pharmaceutical composition can form a gel with a long-lasting effect after administration, releasing the active pharmaceutical ingredient over a prolonged period. This indicates that the tablets possess excellent sustained-release properties.

[0135] Specifically, after a dissolution test conducted according to Japanese Pharmacopoeia 18th Edition 6.10, the loss tangent (tan δ) value of the remaining portion of the tablet 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. The tan δ value is defined as the ratio of loss modulus (E") to storage modulus (E'), and is determined by a dynamic viscoelasticity analyzer.

[0136] The dissolution medium and dissolution time used in dissolution tests are specified by the pharmacopoeia according to the type of drug being evaluated. The tablets disclosed herein are characterized in that, regardless of the dissolution medium and dissolution time specified for the specific drug contained therein, the matrix composition ensures that the loss tangent (tan δ) of the tablet falls within the aforementioned range. The loss tangent (tan δ) refers to the ratio of the loss modulus E" to the storage modulus E', calculated from the results of dynamic viscoelastic measurements performed on the remaining portion of the tablet after the aforementioned dissolution test.

[0137] The tablets of the present invention can adjust the release rate, release time and release site of the active pharmaceutical ingredient from the tablet according to the 18th revision of the Japanese Pharmacopoeia, so as to reduce the frequency of administration or reduce side effects.

[0138] The time a tablet remains in the stomach is typically about 2 to 3 hours. Therefore, in order to maintain the drug concentration in the blood within the required range, it is preferable that the drug has a low dissolution level within one hour after administration and is released in a controlled manner over 3 to 10 hours.

[0139] For the tablets of the present invention, even if they contain a high content of active pharmaceutical ingredient of 50% or more by mass, the dissolution rate can be suppressed to about 20% to 40% in the initial stage of administration (i.e., one hour after the start of the dissolution test). Thereafter, about 10 hours after administration (i.e., ten hours after the start of the dissolution test), about 85% or more of the active pharmaceutical ingredient dissolves.

[0140] The desired release characteristics can vary depending on the type of drug. When the drug is metformin hydrochloride, the tablets of this invention meet the Grade A or Grade B criteria specified in USP41 "Metformin Hydrochloride Extended-Release Tablets," indicating that the tablets have the desired extended-release characteristics. The grades specified in USP41 are shown below.

[0141] Grade A:

[0142] One hour after the start of the test, the dissolution rate of the active pharmaceutical ingredient was 20% to 40%.

[0143] Three hours after the start of the test, the dissolution rate of the active pharmaceutical ingredient was 45% to 65%.

[0144] Ten hours after the start of the experiment, the dissolution rate of the active pharmaceutical ingredient was over 85%.

[0145] Grade B:

[0146] One hour after the start of the test, the dissolution rate of the active pharmaceutical ingredient was 20% to 42%.

[0147] Three hours after the start of the experiment, the dissolution rate of the active pharmaceutical ingredient was 45% to 69%.

[0148] Ten hours after the start of the experiment, the dissolution rate of the active pharmaceutical ingredient was over 85%.

[0149] Grade C:

[0150] The dissolution rate of the active pharmaceutical ingredient exceeds 42% within 1 hour after the start of the test, or exceeds 69% within 3 hours after the start of the test.

[0151] Example

[0152] The present invention will be further described below with reference to embodiments and comparative examples, but the present invention is not limited to the following embodiments.

[0153] [Measurement and Evaluation Methods]

[0154] (1) Tablet hardness (N)

[0155] The hardness of the compressed tablets was measured using a PC-30 hardness tester (manufactured by Okada Seiko Co., Ltd.).

[0156] (2) Dissolution test

[0157] Dissolution tests were performed in accordance with Japanese Pharmacopoeia 18th Revision 6.10.

[0158] Dissolution test solution 2 (Fujifilm and Koko Pure Chemical Industries, Ltd.) conforming to the Japanese Pharmacopoeia was degassed at 45°C for 2 hours. One liter of the degassed medium was measured using a graduated cylinder and transferred to a constant-temperature water bath dissolution apparatus (model: NTR-6600, Toyama Sangyo Co., Ltd.). After confirming that the test medium reached 37°C, a dissolution test was started using a single tablet. The dissolution rate was measured at 1 hour, 3 hours, and 10 hours after the start of the dissolution test.

[0159] Dissolution rate was determined according to the method described in the United States Pharmacopeia (USP) "Metformin Hydrochloride Extended-Release Tablets". In this method, UV detection is used to quantify the amount of metformin hydrochloride present in the eluent obtained from the dissolution test. Specifically, the metformin hydrochloride content is calculated based on the ratio of the peak area attributable to metformin hydrochloride in the standard solution to the peak area attributable to metformin hydrochloride in the dissolution test solution. Assuming a single tablet contains 500 mg of metformin hydrochloride, the dissolution rate (%) can be obtained by calculating the proportion of metformin hydrochloride detected in the dissolution test solution relative to the nominal content. When the calculated amount of metformin hydrochloride in the dissolution test solution is 500 mg, the dissolution rate is defined as 100%.

[0160] (3) Dynamic viscoelasticity measurement

[0161] Ten hours after the start of the dissolution test (2), the remaining tablets (i.e. the remaining portion of the tablets) were removed and measured using a dynamic viscoelasticity analyzer (model: Rheogel-E4000, UBM Corporation) under the following test conditions to determine the loss tangent (tan δ) value (loss modulus E″ / storage modulus E′).

[0162] (Test conditions)

[0163] Measurement frequency: 0.05 Hz

[0164] Strain measurement: 5%

[0165] Fixture spacing: Adjusted according to sample size

[0166] Deformation measurement mode: Compression

[0167] Temperature measured: 22℃

[0168] (4) Shape retention of tablet structure

[0169] Shape retention was calculated as the ratio of the thickness of the gel remaining in the tablet (i.e., the portion of the tablet remaining ten hours after the start of the dissolution test (2)) to the thickness of the molded tablet shown in Figure 2(a). Shape retention was evaluated as the percentage of tablet structure retained after the dissolution test. Gel thickness was measured as the distance between the clamps holding the gel (as shown in Figure 2(b)), which was part of the dynamic viscoelasticity analyzer (Rheogel-E4000, UBM Corporation) used in the measurement.

[0170] Shape retention rate (%) = gel thickness / tablet thickness × 100.

[0171] ○: Shape retention rate ≥ 60%

[0172] △: 40% ≤ shape retention rate < 60%

[0173] ×: Shape retention rate <40%.

[0174] (5) Particle size of raw material powder

[0175] The particle size distribution (volume basis) was measured using a laser diffraction particle size analyzer (Mastersizer 3000, Malvern Panaco), thereby determining the median diameter (D) of the powder. 50 ).

[0176] <Compounds used in tablet manufacturing>

[0177] Matrix composition (I)

[0178] PVA (A) used as a matrix material

[0179] The PVA (A) used as the matrix material is unmodified polyvinyl alcohol manufactured by Mitsubishi Chemical Corporation, with an average degree of saponification of 88 mol% and an average degree of polymerization of 2500.

[0180] Polyphenolic compound (B)

[0181] The polyphenol compound (B) is tannic acid (a product purified with alcohol) manufactured by Kishida Chemical Co., Ltd., with a median diameter of 33.8 μm.

[0182] Amorphous silica (C)

[0183] - Silica 1: "AEROSIL 200" manufactured by AEROSIL Corporation of Japan, is a silica powder with a median diameter of 14.2 μm. The individual particles of the powder are chain-like aggregates of spherical silica particles (hydrophilic), with a specific surface area of ​​200 m². 2 / g.

[0184] - Silica 2: "AEROSIL 300" manufactured by AEROSIL Corporation of Japan, is a silica powder with a median diameter of 12.8 μm. The individual particles of the powder are chain-like aggregates of spherical silica particles, with a specific surface area of ​​300 m². 2 / g.

[0185] - Silica 3: "AEROSIL 50" manufactured by AEROSIL Corporation of Japan, is a silica powder with a median diameter of 11.4 μm. The individual particles of the powder are chain-like aggregates of spherical silica particles, with a specific surface area of ​​50 m². 2 / g.

[0186] - Silica 4: "SYLOSPHOBIC 200" manufactured by Fuji Silicon Chemicals Co., Ltd., is a silica powder with a median diameter of 2.9 μm. The individual particles of the powder are sol-gel derived silica particles with a hydrophobic surface treatment and a specific surface area of ​​220 m². 2 / g.

[0187] Active pharmaceutical ingredient (II)

[0188] The active pharmaceutical ingredient (II) uses metformin hydrochloride.

[0189] Other (III)

[0190] - PVA used as an adhesive: Polyvinyl alcohol manufactured by Mitsubishi Chemical Corporation, with an average degree of saponification of 88 mol% and an average degree of polymerization of 300.

[0191] - Crystalline cellulose: "PH102" manufactured by Asahi Kasei Chemicals Co., Ltd.

[0192] - Magnesium stearate: Magnesium stearate manufactured by NOF Co., Ltd. that meets the standards of the Japanese Pharmacopoeia.

[0193] [Tablet Manufacturing]

[0194] Tablets 1 to 7:

[0195] 3.8 g of PVA used as an adhesive was dissolved in 15.1 g of purified water to prepare an aqueous PVA-based resin solution. This PVA solution and 296 g of metformin hydrochloride were added to a vertical mixing granulator (FM-VG-01, Powrex) and wet granulated for 1 minute. The resulting granules were dried using a rolling fluidized bed granulator (FD-MP-01, Powrex) to obtain granules containing metformin hydrochloride with a median diameter of 170 μm and a water content of 0.4%.

[0196] 63.3 g of metformin hydrochloride granules, 34.1 g of PVA for the matrix material, 3.4 g of tannic acid, and silica powder (as shown in Table 1) were placed in a plastic bag and vigorously shaken to mix for 5 minutes. Then, 1.0 g of magnesium stearate was added and gently mixed. The resulting mixture was compressed using a rotary tablet press (HT-EX12SS-U model manufactured by Hata Tetsuko Co., Ltd.) at 35 kN to produce round tablets as shown in Figure 2(a). The tablets had a diameter of 14.2 mm, a thickness of 5.9 mm, and a metformin hydrochloride content of 500 mg.

[0197] Tablet No. 8:

[0198] The tablets are prepared in the same manner as tablet #1, except that they do not contain silica powder.

[0199] The results of the above measurement and evaluation methods for sustained-release tablets are shown in Table 1.

[0200] Tablet No. 9:

[0201] The tablets were prepared in the same manner as tablet No. 1, but with crystalline cellulose instead of silica particles. The results of the above-described measurements and evaluations for the resulting sustained-release tablets are shown in Table 1.

[0202] [Table 1]

[0203]

[0204] Compared to silica-free tablets 8 and 9, silica-containing tablets 1 through 7 exhibit higher tablet hardness and shape retention. Furthermore, tablets 1 through 7 show inhibited drug release in the initial stages of administration (one hour and three hours after administration) and meet the sustained-release performance ratings of Grade A and Grade B, while tablets 8 and 9 are rated as Grade C.

[0205] When using the same type of silica, shape retention improves with increasing silica content. For example, when silica 1 is present, shape retention improves in the order of silica 1, silica 2, and silica 3; when silica 2 is present, shape retention improves in the order of silica 4 and silica 5.

[0206] Increasing the silica content decreases the tan δ value, which may indicate that silica enhances the crosslinking density of the hydrogel and helps maintain the solid state of the tablet.

[0207] Tablets No. 1, 4, and 6 have the same silica content and the same mixing ratio with tannic acid. Comparisons show that a larger specific surface area tends to result in a smaller tan δ value. The results indicate that a larger specific surface area of ​​chain-like silica leads to more hydrogen bonds formed with other components (including the matrix PVA and tannic acid), thereby increasing the crosslinking density of the formed gel.

[0208] A comparison of tablets No. 2, No. 5, and No. 7 revealed that tablet No. 7 had lower hardness, larger volume, and poorer shape retention. Furthermore, although tablets No. 2 and No. 7 had similar silica content and specific surface area, tablet No. 7 exhibited significantly worse shape retention. Tablet No. 7 used silica particles with a hydrophobic surface treatment. This hydrophobic surface treatment may interfere with the formation of hydrogen bonds with other components, potentially reducing the crosslinking density of the resulting gel.

[0209] Industrial applicability

[0210] Tablets containing the pharmaceutical composition of the present invention have sufficient hardness to resist chewing and maintain their tablet shape for a prolonged period after administration, thereby achieving sustained release of the active pharmaceutical ingredient over a longer period. Therefore, the pharmaceutical composition of the present invention can be used as a raw material for the production of tablets with high patient compliance and is suitable for use as a sustained-release dosage form.

Claims

1. A pharmaceutical composition comprising a polyvinyl alcohol resin (A), a polyphenolic compound (B), and amorphous silica (C), wherein, The content of amorphous silica (C) is 0.1 to 20 parts by weight relative to 100 parts by weight of polyvinyl alcohol resin (A).

2. The pharmaceutical composition according to claim 1, wherein, The pharmaceutical composition further comprises an active pharmaceutical ingredient (D), wherein the content of the active pharmaceutical ingredient (D) in the pharmaceutical composition is 30% by mass or more and 90% by mass or less.

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

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein, The content of the polyphenol compound (B) is from 0.05 to 32 parts by weight relative to 100 parts by weight of polyvinyl alcohol resin (A).

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein, The specific surface area of ​​the amorphous silica (C) measured by the BET method is 50 to 1000 m². 2 / g.

6. The 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 3000 and a degree of saponification of 78 to 96 mol.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein, The mass ratio (B / C) of the content of the polyphenolic compound (B) to the content of the amorphous silica (C) is from 30 / 70 to 95 / 5.

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

10. A tablet comprising a matrix composition (I) and an active pharmaceutical ingredient (II) dispersed in the matrix composition (I), wherein, The matrix composition (I) comprises a polyvinyl alcohol resin (A), a polyphenolic compound (B), and amorphous silica (C). After dissolution testing according to Japanese Pharmacopoeia 6.10, the loss tangent (tan δ) of the remaining portion of the tablet is 10 or less, where the loss tangent is the ratio of the loss modulus E" to the storage modulus E' measured by dynamic viscoelasticity.

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

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

13. The tablet according to any one of claims 10 to 12, wherein, The specific surface area of ​​the amorphous silica (C) measured by the BET method is 50 to 1000 m². 2 / g.

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

15. The 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 3000 and a degree of saponification of 78 to 96 mol.

16. The tablet according to any one of claims 10 to 15, wherein, The mass ratio (B / C) of the content of the polyphenolic compound (B) to the content of the amorphous silica (C) is from 30 / 70 to 95 / 5.

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