Composition for sustained-release solid dosage forms, sustained-release tablets using the same, and method for producing the same.

Abstract

The present invention discloses a composition for a sustained-release solid preparation, said composition comprising: (A) a polyvinyl alcohol-based resin having an average degree of saponification of 78-96 mol% and an average degree of polymerization of 800 or more; and (B) a polyvalent phenolic compound, preferably tannic acid. A sustained-release tablet having a high hardness can be manufactured by a method that comprises a step for mixing a granulated composition comprising (A) a polyvinyl alcohol-based resin powder and a medicinal ingredient with a tannic acid powder followed by tableting.

Description

[Technical Field]

[0001] The present invention relates to a sustained-release composition for solid preparations, tablets using the same, and a method for producing the same. [Background Art]

[0002] Sustained-release preparations, which are controlled to elute a pharmaceutically active ingredient over a long period of time, can improve medication compliance associated with a reduction in the number of doses and prevent side effects by reducing the fluctuation range of blood concentration, and thus have been actively researched and developed in recent years.

[0003] Additives for solid preparations include excipients (substances added to adjust the preparation to an appropriately handleable volume and have no physiological activity), binders (substances added to bind raw material powder particles together and control the mechanical strength of tablets), disintegrants (substances added to disintegrate tablets by absorbing water in the body and swelling, etc. to facilitate the release of pharmaceutically active ingredients), lubricants (substances added to improve powder fluidity and facilitate compression molding), and the like.

[0004] Water-soluble and biodegradable polyvinyl alcohol (PVA) resins are excellent in adhesive force with various components, and thus are used as additives for pharmaceutical tablets (specifically, binders, tablet film coating agents, etc.). Among additives, binders and disintegrants are known to affect the strength of tablets and the dissolution rate of pharmaceutically active ingredients, and the use of polyvinyl alcohol-based resins in sustained-release preparations has been studied.

[0005] For example, Patent 6657949 (Patent Document 1) proposes a sustained-release pharmaceutical tablet in which adhesion is improved and sustained-release properties are imparted by using PVA microparticles with a predetermined proportion or more of gauche structure from the particle surface to the interior as a pharmaceutical binder. Here, it is shown that tablets made by adding PVA microparticles (crushed product: 50% particle size 96 μm) with a degree of saponification of 88% and an average degree of polymerization of 2400 to a wet granule mixture of a pharmacoactive ingredient and crystalline cellulose, mixing with crystalline cellulose, aerosil, and magnesium stearate, and then compression molding, exhibited sustained-release properties compared to PVA microparticles with a lower proportion of gauche structure (crushed product: 50% particle size 100 μm) (Figure 5).

[0006] Furthermore, Japanese Patent Publication No. 2020-152658 (Patent Document 2) proposes a sustained-release formulation using PVA with an average degree of polymerization of 2000 or more and a degree of saponification of 65 to 85 mol%. Specifically, it is shown that for tablets made by wet-granulating a mixture of PVA, a pharmacoactive ingredient, and crystalline cellulose, reducing the degree of saponification to 73.3 mol% and 80 mol% compared to using PVA with a degree of saponification of 88 mol%, the dissolution rate after 6 hours can be reduced to less than half, and sustained-release properties such as a dissolution rate of 50% or less after 24 hours can be achieved.

[0007] Furthermore, Japanese Patent Publication No. 2013-241341 (Patent Document 3) discloses a sustained-release formulation in which modified PVA powder, obtained by modifying polyvinyl alcohol (PVA with a degree of polymerization of 500 and 1700 and a degree of saponification of 88%) with acrylic acid and methyl methacrylate, is used as the matrix base material for tablets. This document shows that tablets obtained by direct compression using modified PVA powder as the matrix base material, mixed with crystalline cellulose and a pharmacoactive ingredient as excipients, can delay the time to reach a plateau compared to cases where only crystalline cellulose is used as the matrix base material. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] Patent No. 6657949 [Patent Document 2] Japanese Patent Publication No. 2020-152658 [Patent Document 3] Japanese Patent Publication No. 2013-241341 [Overview of the project] [Problems that the invention aims to solve]

[0009] Incidentally, in the case of solid dosage forms, especially tablets, there are formulation standards that specify physical properties such as hardness and abrasion resistance, and when used as a pharmaceutical additive, it is necessary to satisfy the range set by these standards. In this respect, the hardness of the tablets obtained in Patent Document 1 is insufficient, and further studies are needed to improve the hardness in order to commercialize them as sustained-release tablets.

[0010] Furthermore, the polyvinyl alcohol proposed in Patent Document 2 cannot satisfy the saponification degree of 85-89 mol%, which is required to meet the standards of the Japanese Pharmaceutical Excipients (JPE), the United States Pharmacopeia (USP), and the European Pharmacopeia (EP).

[0011] Patent Document 3 uses modified polyvinyl alcohol as a matrix, and in the examples, tablets with a hardness of 50N are obtained. However, the active ingredients used in the examples of Patent Document 3 are nifedipine (evaluation 1, evaluation 2) and sodium carbazochrome sulfonate (CCSS) (evaluation 3), both of which are poorly to slightly poorly water-soluble. Tablets using such poorly water-soluble drugs tend to have a long dissolution time (exhibiting sustained release) based on the water-soluble properties of the active ingredient itself. On the other hand, it has not been shown that sustained release can be achieved when applied to easily water-soluble drugs.

[0012] Under the circumstances described above, the present invention aims to provide a sustained-release solid dosage form composition that satisfies the hardness and abrasion resistance requirements of a tablet, using polyvinyl alcohol that conforms to pharmacopoeia standards as a pharmaceutical additive, as well as a sustained-release tablet using the same, and a method for producing the same. [Means for solving the problem]

[0013] The inventors used a polyvinyl alcohol-based resin that could satisfy the standards of the Japanese Pharmaceutical Excipients (JPE), the United States Pharmacopeia (USP), and the European Pharmacopeia (EP), and investigated combinations of additives that would provide a tablet with satisfactory hardness, strength, and sustained release properties, thereby completing the present invention.

[0014] In other words, the sustained release of the present invention tablet The composition comprises (A) a polyvinyl alcohol-based resin with an average degree of saponification of 78 to 96 mol% and an average degree of polymerization of 800 or more; and (B) a polyhydric phenol compound. The polyhydric phenol compound (B) is preferably tannic acid.

[0015] The content of the polyvalent phenol compound (B) relative to 100 parts by weight of the polyvinyl alcohol resin (A) is preferably 0.1 to 35 parts by weight.

[0016] The degree of modification of the (A) polyvinyl alcohol-based resin is preferably less than 10 mol%. Furthermore, the (A) polyvinyl alcohol-based resin is preferably a powder with an average particle size of 40 to 200 μm. The (A) polyvinyl alcohol resin may be a mixture of a polyvinyl alcohol resin with an average degree of polymerization of 1500 or more to 3000 and a polyvinyl alcohol resin with an average degree of polymerization of 100 to less than 1500.

[0017] The present invention's sustained release tablet The composition may further contain (C) crystalline cellulose in amounts of 1 to 50 parts by weight per 100 parts by weight of the (A) polyvinyl alcohol-based resin.

[0018] The present invention also includes the method for producing the sustained-release tablets of the present invention described above. Such a production method is With an average degree of saponification of 78-96 mol%,The method comprises a step of mixing a granulated product of a composition containing a polyvinyl alcohol resin having an average degree of polymerization of 800 or more and a medicinal ingredient with tannic acid powder and compression-molding the mixture into tablets. The polyvinyl alcohol resin is preferably a powder having an average degree of polymerization of 1500 to 3000 and an average particle diameter of 40 to 200 µm, and the granulated product is preferably granulated by a fluidized bed granulation method.

[0019] Incidentally, the average degree of polymerization referred to in the present specification is an average degree of polymerization (number-average degree of polymerization) measured by a method in accordance with JIS K 6726 (1994). When two or more types of polyvinyl alcohol resins having different average degrees of polymerization are contained, the total is normally the number-average degree of polymerization multiplied by the respective content ratios.

[0020] By the way, as tablets using a composition containing a polyvinyl alcohol resin and tannic acid, for example, Japanese Unexamined Patent Application Publication No. 2014-224086 (Patent Document 4) discloses a rapidly disintegrating solid preparation in the oral cavity containing modified PVA obtained by modifying PVA with a polymerizable vinyl monomer ("POVACOAT type FM" used in the examples is a copolymer of polyvinyl alcohol:acrylic acid:methyl methacrylate = 32:1:7) and tannic acid, wherein the weight ratio of modified PVA to tannic acid is 1:0.1 to 10; WO2015 / 115453 (Patent Document 5) proposes a tablet obtained by stirring and mixing polyvinyl alcohol (PE-05JPS: average degree of polymerization 500) with excipients (D-mannitol, lactose hydrate), adding a tannic acid solution, granulating the mixture, and compression-molding into tablets. However, all of the tablets disclosed in these documents are rapidly disintegrating tablets. Furthermore, these documents even teach that when tannic acid is not contained, the disintegration time is prolonged, in other words, the addition of tannic acid can shorten the disintegration time. Furthermore, Patent Document 4 even teaches that higher hardness is obtained when tannic acid is not contained, in other words, the content of tannic acid reduces the hardness.

[0021] The sustained-release solid pharmaceutical preparation composition of the present invention secures the sustained-release property of a medicinal ingredient, while improving the hardness and moldability as a tablet. On the other hand, both Patent Documents 4 and 5 disclose a solid pharmaceutical preparation using a composition in which a polyvinyl alcohol-based resin and tannic acid are combined, but tannic acid is contained for the purpose of imparting quick disintegration property. Therefore, it is considered that the state of the polyvinyl alcohol-based resin and tannic acid in the formed tablet is different between the solid pharmaceutical preparation composition of the present invention and the sustained-release tablet prepared therefrom, and the quick-disintegrating tablet disclosed in Patent Documents 4 and 5. Effects of the Invention

[0022] In the sustained-release solid pharmaceutical preparation composition of the present invention, the polyvinyl alcohol-based resin and tannic acid can form hydrogel through hydrogen bonding, so sustained release can be achieved regardless of the water solubility property of the medicinal ingredient, and the composition has excellent compression properties and can provide a high-hardness sustained-release tablet. Mode for Carrying Out the Invention

[0023] [Composition for Sustained-Release Solid Pharmaceutical Preparation] (A) Polyvinyl alcohol-based resin for matrix base material The polyvinyl alcohol (PVA)-based resin used in the composition for solid pharmaceutical preparation according to the present invention is a resin mainly composed of vinyl alcohol structural units obtained by saponifying a polyvinyl ester-based resin obtained by polymerizing a vinyl ester-based monomer, and has vinyl alcohol structural units corresponding to the saponification degree and vinyl ester structural units in unsaponified portions.

[0024] The polyvinyl alcohol (PVA) resin used in the solid formulation composition according to the present invention is not limited to an unmodified PVA resin consisting of vinyl alcohol units and vinyl ester units, but may also be a modified polyvinyl alcohol resin obtained by saponifying a polyvinyl ester resin obtained by polymerizing a vinyl ester monomer with a copolymerizable monomer (copolymerizable monomer), or a post-modified modified PVA resin. In the case of a modified PVA resin, the degree of modification (content of structural units other than vinyl alcohol units and vinyl ester structural units) is less than 10 mol%, preferably 5 mol% or less, and particularly preferably 1 mol% or less.

[0025] Examples of the vinyl ester monomers mentioned above 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 practically preferred.

[0026] Examples of copolymerizable monomers 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 their acylated derivatives; unsaturated acids such as acrylic acid, methacrylic acid, crotonic acid, maleic acid, maleic anhydride, itaconic acid, and undecylenic acid; their salts; monoesters or dialkyl esters; nitriles such as acrylonitrile and methacrylonitrile; and diacetone acrylamide. Examples include amides such as acrylamide and methacrylamide, olefin sulfonic acids such as ethylene sulfonic acid, allyl sulfonic acid, and methallyl sulfonic acid or their salts, alkyl vinyl ethers, dimethylallyl vinyl ketone, N-vinylpyrrolidone, vinyl chloride, vinylethylene carbonate, 2,2-dialkyl-4-vinyl-1,3-dioxolane, vinyl compounds such as 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, vinylene carbonate, and the like. Such copolymerizable monomers may be used individually or in combination of two or more. The copolymerizable monomers are less than 10 mol%, preferably 5 mol% or less, and particularly preferably 1 mol% or less, based on the total amount of polymer.

[0027] As modified PVA resins, copolymers with unsaturated acids, their salts, monoesters, or dialkyl esters are preferred, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymers are particularly recommended.

[0028] The polymerization of the above vinyl ester monomers (and copolymer monomers included as needed) can be carried out by conventionally known methods (such as bulk polymerization, solution polymerization, suspension polymerization, dispersion polymerization, or emulsion polymerization), and known polymerization catalysts and solvents can also be used during polymerization. Typically, polymerization is carried out by solution polymerization using methanol as the solvent. The saponification of the resulting vinyl ester polymer can also be carried out by conventionally known methods. Industrially, the polymer is dissolved in alcohol and saponified in the presence of an alkaline catalyst. As the alkaline catalyst, alkali metal hydroxides or alkoxides such as sodium hydroxide, potassium hydroxide, and sodium methylate are used.

[0029] The polyvinyl alcohol-based resin particles obtained by saponification are washed with a lower alcohol such as methanol, and then dried with hot air in a continuous or batch process to obtain PVA-based resin powder. The drying temperature is usually 50 to 150°C, particularly preferably 60 to 130°C, and especially preferably 70 to 110°C. If the drying temperature is too high, the PVA-based resin particles tend to degrade due to heat, and if the drying temperature is too low, drying tends to take a long time. The drying time is usually 1 to 48 hours, and especially preferably 2 to 36 hours. If the drying time is too long, the PVA-based resin particles tend to degrade due to heat, and if the drying time is too short, drying tends to be insufficient or high-temperature drying may be required. The solvent content in the PVA-based resin after drying is usually 10% by mass or less, particularly preferably 5% by mass or less, and especially preferably 1% by mass or less.

[0030] The average degree of saponification of the PVA resin used in this invention is 78-96 mol%, as defined in the Japanese Food Additives Standards (JPE) as partially saponified polyvinyl alcohol, and preferably 85-89 mol%, which satisfies all requirements of the European Pharmacopoeia (EP) and the United States Pharmacopoeia (USP). Within the above average degree of saponification range, the compound has high water solubility and, after oral administration, readily forms hydrogen bonds with the hydroxyl groups of polyhydric phenol compounds and crystalline cellulose, creating a gel for the sustained release of the active ingredient. On the other hand, if the degree of saponification is too low, the amount of hydroxyl groups contributing to gel formation decreases, resulting in a tendency for the gel-forming ability that contributes to sustained release to decline. Furthermore, a decrease in gel-forming ability leads to a decrease in the strength of the resin itself, resulting in a tendency for the tablet hardness to decrease. In this invention, the average degree of saponification refers to the degree of saponification measured according to the method compliant with JIS K 6726 (1994).

[0031] The average degree of polymerization of the PVA resin used in the present invention is preferably 800 or higher, more preferably 1500 to 3000, and even more preferably 2100 to 2600. If the average degree of polymerization is too low, the gel-forming ability will be insufficient, and the suppression of the elution of the active pharmaceutical ingredient will be insufficient. In other words, with polyvinyl alcohol resins with an average degree of polymerization of less than 800, which are commonly used as binders, after oral administration, the resin becomes more easily soluble in water than it forms a gel, so the elution of the active pharmaceutical 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 resin powder increases, which can reduce its compressibility and tablet-forming ability, so it is preferable to keep it at 3000 or lower. In this invention, the average degree of polymerization refers to the average degree of polymerization (number average degree of polymerization) measured by a method compliant with JIS K 6726 (1994).

[0032] Furthermore, the viscosity of a 4% by mass aqueous solution of the PVA resin at 20°C is preferably 6.0 mPa·s or higher, 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 mass aqueous solution is too high, it means that the average degree of polymerization of the PVA resin is too high, which can increase the elasticity of the PVA resin powder, reduce the compressibility, and decrease the tablet moldability. On the other hand, if the viscosity of the 4% by mass aqueous solution is too low, it means that the average degree of polymerization of the PVA resin is too low, making it difficult to obtain sustained-release properties for the tablets. In this invention, the viscosity of the 4% by mass aqueous solution at 20°C is the viscosity measured by a method in accordance with JIS K 6726 (1994).

[0033] The polyvinyl alcohol-based resin (A) may be used in powder form, or it may be granulated using an aqueous solution in which it is dissolved in water, and then mixed with other components as a granular product. From the viewpoint of productivity, it is preferable to use it as a powder as a matrix base material.

[0034] When used as a powder, the average particle size of the PVA-based resin particles 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 becomes too large, the resulting tablet hardness tends to decrease. In this invention, the average particle size is the particle size measured by laser diffraction.

[0035] The polyvinyl alcohol-based resin (A) described above is used as a matrix base material for sustained-release solid dosage forms. When it comes into contact with water in the presence of compounds having many hydroxyl groups, such as the polyhydric phenol compounds described later, it can form a three-dimensional network structure by hydrogen bonding with these compounds and gel. This is thought to suppress the elution of the active ingredient dispersed in the matrix, resulting in sustained-release properties. It is thought that the higher the degree of polymerization of the PVA-based resin, the more complex the entanglement structure with tannic acid becomes, thus improving the sustained-release properties.

[0036] (B) Polyvalent phenolic compounds Examples of polyhydric phenolic compounds (B) used in the present invention include catechol, resorcinol, hydroquinone, pyrogallol, oxyhydroquinone, phloroglucin, and tannic acid. These can be used individually or in combination of two or more, but tannic acid is preferred among them.

[0037] Tannic acid can be extracted from various plant materials. For example, it can be extracted using water or ethanol from persimmon fruit, chestnut skin, gallnut, aralia powder, tamarind seed coat (a legume), or mimosa bark. Preferably, tannic acid extracted from gallnut or gall, as listed in the 17th edition of the Japanese Pharmacopoeia, can be used. Tannic acid may be unrefined or refined, but refined is more preferable.

[0038] Tannic acid is preferably present in an amount of 0.1 to 35 parts by weight (0.0001 to 0.35 parts by weight relative to the matrix PVA resin (A)) per 100 parts by weight, more preferably 1 to 25 parts by weight, and even more preferably 5 to 15 parts by weight. If the amount of tannic acid is too high, the tablets tend to become discolored.

[0039] Polyhydric phenolic 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 resin, contributing to the formation of a three-dimensional network structure. The formation of a gel with a three-dimensional network structure suppresses the dissolution of the active ingredient in the tablet, resulting in sustained release.

[0040] Furthermore, Patent Documents 4 and 5 disclose orally disintegrating tablets containing polyvinyl alcohol and tannic acid. These patent documents use PVA with a relatively low degree of polymerization and low gel-forming ability, and furthermore, granules of a solution containing tannic acid and PVA are compressed into tablets. In this case, not only can the PVA and tannic acid not form a sufficient three-dimensional network structure, but the tannic acid, which has a high affinity for water, is dispersed from the surface to the interior of the tablet. Therefore, it is thought that the tannic acid attracts water from the tablet surface and forms water channels to the interior of the tablet, resulting in rapid disintegration. Consequently, the action of tannic acid in tablets differs between the technology of Patent Documents 4 and 5 and the technology relating to the sustained-release solid dosage form composition of the present invention.

[0041] Since polyhydric phenols (B), such as tannic acid, are powders at room temperature, they can be used as powders, or a solution of polyhydric phenols can be sprayed and granulated by spray drying, and then used as granulated polyhydric phenol granules.

[0042] The particle size of tannic acid used as a powder is usually 5 to 100 μm, preferably 10 to 50 μm.

[0043] (C) Crystalline Cellulose Crystalline cellulose is included as an excipient. Because crystalline cellulose has excellent compressible properties, including it can increase the hardness of the tablets.

[0044] The crystalline cellulose used in this invention is not particularly limited, but preferably a powder with an average particle size of less than 150 μm, more preferably 100 to 140 μm.

[0045] The crystalline cellulose content is 100 / 1 to 100 / 50 in weight ratio of PVA resin to crystalline cellulose, preferably 100 / 5 to 100 / 35, and more preferably 100 / 10 to 100 / 30.

[0046] (D) Other additives The solid formulation composition of the present invention may contain various additives within a range that does not impair the effects of the present invention (20% by weight or less of the composition, preferably 10% by weight or less). Examples of other additives include excipients, binders, disintegrants, pH adjusters, fluidizers, surfactants, colorants, sweeteners, and coating agents.

[0047] (D-1) Binder These binders are added to provide interparticle bonding during dry or wet granulation, and during tablet manufacturing using direct compression and wet methods. Such binders are preferably used to control the disintegration properties of solid dosage forms (tablets).

[0048] As binders, dextrin, gum arabic, gelatin, hydroxypropyl starch, methylcellulose, hydroxypropylcellulose, hypromellose, pullulan, starch paste, and polyvinyl alcohol-based resins can be used. The amount of binder varies depending on the type of compound used, but is usually 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, per 100 parts by weight of the granulation composition.

[0049] Here, when a polyvinyl alcohol-based resin is used as a binder, the polyvinyl alcohol-based resin used as a binder is distinguishable from the polyvinyl alcohol-based resin contained as component (A) (matrix substrate) at least in terms of its average degree of polymerization. That is, the average degree of polymerization of the polyvinyl alcohol-based resin used as a binder is preferably 100 to less than 1500, and more preferably 200 to 1000. The average degree of saponification can be 70 to 99 mol%, but is usually 78 to 96 mol%, and preferably 85 to 89 mol%, similar to the PVA-based resin used as the matrix substrate.

[0050] As a polyvinyl alcohol-based resin that can be used as a binder, a copolymer saponified product (modified polyvinyl alcohol-based resin) with a copolymerizable monomer, as described for the polyvinyl alcohol-based resin used in the matrix substrate, can be used. When using polyvinyl alcohol-based resin as a binder, it is preferable to use it in an aqueous solution after dissolving it in water.

[0051] Furthermore, when a polyvinyl alcohol-based resin as described above is used as a binder, the tablet will contain two or more types of polyvinyl alcohol-based resins with different average degrees of polymerization. When two or more types of polyvinyl alcohol-based resins with different average degrees of polymerization are included, the average degree of polymerization of the polyvinyl alcohol-based resins contained in the entire solid dosage form composition will be the sum of the values ​​obtained by multiplying the average degree of polymerization of each polyvinyl alcohol-based resin by the proportion of each polyvinyl alcohol-based resin.

[0052] For example, when using two types of PVA resins, a matrix PVA resin and a binder PVA resin, the degree of saponification SDm and degree of polymerization Pm of the matrix PVA resin, the degree of saponification SDb and degree of polymerization Pb of the binder PVA resin, the proportion of matrix PVA resin in the total PVA resin M, and the proportion of binder PVA resin B can be calculated using the following formula. Note that M + B = 1.

[0053] Average degree of saponification = SDm × M + SDb × B Average degree of polymerization=Pm×M+Pb×B

[0054] Typically, the content of PVA resin for binders (B) is at most about 5% by weight of the total PVA resin (usually 3% by weight or less, preferably 2.5% by weight or less). Therefore, even if a PVA resin for binders with an average degree of polymerization of less than 800 is included, the average degree of polymerization measured for the PVA resin contained in the solid dosage form composition will be 800 or higher.

[0055] (D-2) Lubricant Lubricants are included to improve fluidity, providing lubrication during compression and tablet release within the mortar, and preventing tablets from sticking to the punch surface and mortar wall. Specifically, stearic acid, magnesium stearate, calcium stearate, talc, and anhydrous silicic acid can be used.

[0056] (D-3) Excipients As a bulking agent, excipients other than the crystalline cellulose mentioned above may be used alone or in combination with crystalline cellulose.

[0057] Examples of excipients that can be used include sugar alcohols (such as mannitol, erythritol, xylitol, sorbitol, and maltitol), sugars (such as glucose, fructose, lactose, sucrose, trehalose, maltose, and oligosaccharides), calcium phosphates, starches, sodium phosphates, and gelatin. Of these, sugar alcohols, particularly mannitol, are preferred.

[0058] (D-4) Others In addition to the above additives, disintegrants (carmellose calcium, carboxymethyl starch sodium, 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, carbonate 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 and lactic acid and its salts, etc.); fluidizers (light anhydrous silicic acid, hydrated silicon dioxide, titanium dioxide, stearic acid, corn gel and heavy anhydrous silicic acid, etc.); surfactants (phospholipids, glycerides, etc.) It may also contain ricerin 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, etc.; coloring agents (ferric oxide, yellow ferric oxide, Yellow No. 5, Yellow No. 4, aluminum chelate, titanium dioxide and talc, etc.); and sweeteners (saccharin, aspartame, acesulfame potassium, thaumatin and sucralose, etc.).

[0059] [Active pharmaceutical ingredient (API)] Examples of pharmacoactive ingredients applicable to the solid dosage forms according to the present invention include antipyretic, analgesic, and anti-inflammatory drugs, tonics and health supplements, psychotropic drugs, antidepressants, anxiolytics, hypnotics and sedatives, antispasmodics, central nervous system agents, cerebral metabolism improvers, cerebral circulation improvers, antiepileptic drugs, sympathomimetic agents, gastrointestinal drugs, antacids, anti-ulcer agents, antitussives and expectorants, antiemetics, respiratory stimulants, bronchodilators, anti-allergic drugs, antihistamines, dental and oral drugs, cardiac stimulants, antiarrhythmics, diuretics, antihypertensives, vasoconstrictors, coronary vasodilators, peripheral vasodilators, anticoagulants, antihyperlipidemia agents, choleretics, antibiotics, chemotherapeutic agents, antidiabetic agents, osteoporosis agents, antirheumatic drugs, skeletal muscle relaxants, antispasmodics, hormones, alkaloid narcotics, sulfonamides, gout treatments, and anticancer agents.

[0060] Since the solid dosage form composition of the present invention can impart sustained release properties, it is preferable to use it in combination with pharmacoactive ingredients that require sustained release properties (especially oral pharmacoactive ingredients that require sustained release because the pharmacoactive ingredient itself is easily water-soluble) or pharmacoactive ingredients that are easily water-soluble. Here, readily water-soluble active ingredients refer to drugs that, in the solubility classification shown in the 18th revised Japanese Pharmacopoeia, are classified as very soluble, soluble, or slightly soluble in water, as well as drugs classified as Class 1 or 3 in the BCS classification.

[0061] Examples of easily water-soluble active ingredients include metformin hydrochloride, sodium salicylate, aminopyrine, benzydamine hydrochloride, benzydamine hydrochloride, tiaramide hydrochloride, doxycycline hydrochloride n hydrate, moxalactam sodium, bacampicillin hydrochloride, levamisole, dl-methylephedrine hydrochloride, noscapine, codeine phosphate hydrate, dihydrocodeine phosphate, cloperastine hydrochloride, dl-isoprenaline hydrochloride, L-ethylcysteine ​​hydrochloride, L-methylcysteine ​​hydrochloride, tolperisone hydrochloride, eperisone hydrochloride, tizanidine hydrochloride, roxatidine acetate hydrochloride, chlorpheniramine maleate, diphenhydramine hydrochloride, and imipla. Examples include methyl hydrochloride, clomipramine hydrochloride, diphenhydramine hydrochloride, chlorpheniramine maleate, cremisopropyl alcohol hydrochloride, methoxyphenamine hydrochloride, etilephrine hydrochloride, alprenolol hydrochloride, bufetrol hydrochloride, oxprenolol hydrochloride, procainamide hydrochloride, disopyramide phosphate, mexiletine hydrochloride, diltiazem hydrochloride, isosorbide mononitrate, diltiazem hydrochloride, dilzep hydrochloride hydrate, hexamethonium bromide, clonidine hydrochloride, diltiazem hydrochloride, buformin hydrochloride, isoniazid, ethambutol hydrochloride, thiamazole, vitamin C, B1, B2, loxoprofen sodium, and oxybutynin hydrochloride.

[0062] Furthermore, the solid dosage form composition of the present invention is particularly useful because it can improve moldability, hardness, and strength while ensuring sustained release. This makes it possible to provide sustained-release oral tablets with desired hardness and strength even when used in combination with pharmacoactive ingredients that are generally recognized as having poor compression moldability.

[0063] The above-mentioned active pharmaceutical ingredient (API) is used in a matrix PVA-based resin (A):API (weight ratio) of 0.5 / 100 to 1000 / 100, preferably 20:100 to 500:100, and more preferably 30:100 to 300:100.

[0064] Furthermore, the preferred ratio (by weight) of polyhydric phenol (B) to API is polyhydric phenol (B):API = 0.05:100 to 30:100, more preferably 0.1:100 to 20:100, and particularly preferably 1:100 to 10:100. When using a component with poor moldability as a pharmacoactive ingredient, if the content of polyhydric phenol (B), which can contribute to hardness improvement, becomes too low, sufficient hardness improvement cannot be achieved, and sustained release also tends to decrease.

[0065] <Sustained-release tablets and methods for manufacturing the same> The sustained-release tablet of the present invention is a tablet containing the sustained-release solid dosage form composition and the pharmacoactive ingredient of the present invention. As used herein, sustained-release tablets refer to tablets in which the release rate, release time, and release site of the active ingredient from the tablet have been adjusted in accordance with the 18th revised Japanese Pharmacopoeia, for purposes such as reducing the number of administrations or minimizing side effects. While there are no particular limitations on the active ingredients, those requiring sustained release and those that are easily water-soluble are preferably used.

[0066] Tablets are typically manufactured by compounding various ingredients and then compressing them, either directly or after granulation. The sustained-release tablets of the present invention are characterized in that the active ingredient is homogeneously dispersed in the matrix PVA resin (A) during the tableting process. By pre-dispersing the active ingredient homogeneously in the matrix PVA resin (A), it becomes possible to encapsulate the active ingredient in the hydrogel formed by the matrix PVA resin (A), thereby obtaining an effective sustained-release effect. Because the active ingredient can be encapsulated within a matrix gel (hydrogel) utilizing hydrogen bonds, it can exhibit sustained-release properties even for active ingredients classified as easily water-soluble.

[0067] Conventional tablet manufacturing methods can be applied as long as the active pharmaceutical ingredient is homogeneously dispersed in the PVA-based resin matrix during tablet formation. Specifically, this can be done by compression tableting methods such as direct powder compression (direct compression method), semi-dry granule compression method, and granule compression method; or by wet manufacturing methods. Direct powder compression is a method in which the drug and additive are directly mixed and compressed, without the addition of water. Dry granulation compression is a method in which granulation is performed in a dry manner (slugging) and then compressed into tablets. It has better homogeneity than direct powder compression. Semi-dry granulation compression or semi-direct compression is a method in which granules containing only the additive without the drug are granulated in a wet manner, and then the drug is added and compressed into tablets. By producing wet granules, the binding strength of the tablets is increased and surface powdering can be suppressed. Wet granulation compression is a method in which granules produced by granulating the drug and additive in a wet manner are compressed into tablets. The wet manufacturing method is a method in which a wet mixture is poured into a specific mold or punched out, and then dried to remove solvents such as water.

[0068] In the above manufacturing method, it is preferable to first produce granules containing a matrix PVA-based resin (A) and a pharmaceutically active ingredient, mix these granules with a polyhydric phenol (B), and then compress them into tablets.

[0069] In the granulation process, a mixture (granulation composition) may be prepared by adding and mixing a matrix PVA-based resin (A) and the active ingredient, as well as an excipient ((C) crystalline cellulose). Furthermore, it is preferable to include a binder in the granulation composition. In addition, other additives may be added and mixed.

[0070] Granulation methods include: a wet method in which a binder solution is added to the powder and granulated as is, or a wet mass is 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 mixed with a large amount of water to form a slurry, which is then spray-dried and granulated. The solvent used in the binder solution is appropriately selected depending on the type of compound used as the binder. When PVA is used as the binder, water can be used as the solvent.

[0071] As granulators, dry granulators (applying strong pressure to the powder to form a clump while keeping it dry, then crushing it to obtain granules with an appropriate particle size), basket-type extrusion granulators, agitator granulators (mixing the raw material powder with agitator blades for several minutes, then adding a binder solution and performing agitation granulation), centrifugal tumbling granulators, fluidized bed granulators (fluidizing and mixing the powder raw material with air, then spraying a binder solution from a nozzle in convection or countercurrent to agglomerate the powder raw material with spray droplets, and further drying to promote particle growth), and spray dryers (spray drying granulators) can be used. Among these, the granulation method using a fluidized bed granulator is preferred because it is easy to obtain granules with excellent compression moldability and is compatible with productivity.

[0072] A wet granulation process involves, for example, mixing each component with a solvent and then granulating the mixture. Examples of this process include crushing granulation, extrusion granulation, agitation granulation, and rolling granulation. In this process, alcohols such as ethanol and isopropanol, or water, are used as solvents.

[0073] Next, the granules are compressed into tablets. It is preferable to mix the polyhydric phenol (B) with the granules during tableting, and it is preferable to add and mix in a lubricant to improve the compressibility.

[0074] For tablet formation, any of the manufacturing methods for solid dosage forms using rotary tablet presses, single-shot tablet presses, etc., which are commonly used in the pharmaceutical field, can be employed. For example, tablets can be manufactured using a direct powder compression method, in which various components are uniformly mixed before tableting, or by a wet granule compression method or dry granule compression method, in which various components are wet or dry granulated, and the resulting granules are then compressed into tablets. In particular, from the viewpoint of improving fluidity and mixing uniformity, it is preferable to manufacture it by the wet granule compression method.

[0075] The compression pressure (tablet pressure) in compression molding is preferably about 1 kN or more, more preferably about 2 kN or more, and even more preferably about 4 kN or more. Furthermore, it is preferably about 60 kN or less, more preferably about 50 kN or less, and even more preferably about 30 kN or less. Within this range, the burden on the die and punch during tableting is reduced, and it is also easy to maintain a constant tablet pressure during tableting.

[0076] The shape of the pharmaceutical tablet can be any shape, such as ellipsoid, cylindrical, donut-shaped, or spherical. Furthermore, the resulting tablet may be further coated with a film if necessary.

[0077] The sustained-release tablets manufactured in the manner described above generally have a hardness of 50-200N, 80-150N for a diameter of 11mm, preferably 90-130N, depending on the tablet's shape and size, and thus satisfy the required properties as tablets. Furthermore, although it depends on the type of composition, particularly the average degree of polymerization and average degree of saponification of the polyvinyl alcohol resin, the type of polyhydric phenol compound, the content ratio of the polyvinyl alcohol resin to the polyhydric phenol compound, and the type and content ratio of the active ingredient, sustained release is possible regardless of the water solubility of the active ingredient.

[0078] In the release behavior of the sustained-release tablets of the present invention, when a dissolution test was conducted based on DISSOLUTION Test 1 of USP41 "Metformin Hydrochloride extended-Release Tablets", using a dissolution tester NTR-6400ACT (manufactured by Toyama Sangyo Co., Ltd.), a 500 mg tablet manufactured by the above method was subjected to a dissolution test in 900 mL of distilled water at 37°C. With the dissolution rate at 10 hours from the start of measurement (when the dissolution rate nearly plateaus) set at 100%, the release amounts of the active ingredient at 1 hour and 3 hours can satisfy the following ranges. Release amount of the active ingredient one hour after the start of measurement: 10-45%, preferably 20-43%, more preferably 30-42%. Release rate of the active ingredient 3 hours after the start of measurement: 45-75%, preferably 50-73%, more preferably 55-70%. [Examples]

[0079] The present invention will be further described below with reference to examples and comparative examples, but the present invention is not limited to the following examples.

[0080] [Measurement and evaluation method] (1) Tablet hardness (N) The hardness of the tablets after compression was measured using a hardness tester PC-30 (manufactured by Okada Seikou).

[0081] (2) Elution rate Based on Dissolution Test 1 of USP41 "Metformin Hydrochloride Extended-Release Tablets," a dissolution test was conducted on tablets containing metformin, a readily water-soluble pharmacoactive ingredient. Dissolution tests were performed on 500 mg tablets in 900 mL of distilled water at 37°C using an NTR-6400ACT dissolution tester (manufactured by Toyama Sangyo Co., Ltd.). The amount of the active ingredient (metformin) dissolved was measured after 1 hour, 3 hours, and 10 hours. The dissolution rate (%) after 1 hour and 3 hours was calculated, with the amount dissolved after 10 hours set as 100%.

[0082] [Tablet manufacturing] PVA resin for the matrix base material, metformin hydrochloride as the active ingredient, and crystalline cellulose (Asahi Kasei Chemicals "PH102") were mixed in the proportions shown in Table 1. This mixture was fluidized in a granulator (Pawrec "MP-01"), and a PVA aqueous solution (6%, viscosity of 5.0 mPa·s in a 4% aqueous solution) prepared by dissolving 1.0 part of PVA resin (average degree of polymerization 600, degree of saponification 88 mol%) in water was added as a binder to obtain granules. The granulation conditions were an air supply temperature of 70°C and an air supply airflow rate of 0.9 m³. 3 The atomizing air pressure was 0.5 MPa and the atomizing air volume was 30 NL / min. Tannic acid and magnesium stearate were added to the obtained granules in the amounts shown in Table 1 to produce a composition. This composition was then compressed into tablets (11 mm in diameter, 500 mg in weight) using a rotary tablet press (HT-EX12SS-U, manufactured by Hata Iron Works Co., Ltd.) at a compression pressure of 25 N.

[0083] [Table 1]

[0084] The following two types of PVA were used as the PVA-based resin for the matrix. PVA1: Average degree of polymerization 2500, degree of saponification 88 mol%, alkali metal salt content 0.03 wt%, average particle size 48 μm, 78 μm, or 97 μm PVA2: Average degree of polymerization 600, degree of saponification 88 mol%, alkali metal salt content 0.03 wt%, average particle size 320 μm

[0085] Tablets No. 1 to No. 7 were manufactured using the PVA-based matrix resins shown in Table 2, with different mixing ratios of tannic acid. The hardness and dissolution rate of the obtained tablets were measured and the results are also shown in Table 2. The average degree of polymerization of the PVA resin contained in tablets No. 1 to 6 is 2454, calculated using the following formula. On the other hand, the average degree of polymerization of the PVA resin contained in tablet No. 7 is 600. Average degree of polymerization=2500×39.9 / 40.9+600×1 / 40.9=2454

[0086] [Table 2]

[0087] A comparison between No. 1 and No. 6 reveals that the presence of tannic acid contributes to sustained release. Numbers 1, 4, and 5 differ only in their tannic acid content. It can be seen that hardness increases as the tannic acid content increases. On the other hand, a comparison between No. 1 and No. 7 reveals that sustained release properties cannot be ensured when the average degree of polymerization of the polyvinyl alcohol-based resin contained in the composition is low enough to be used as a binder. [Industrial applicability]

[0088] Solid dosage forms (tablets) produced using the solid dosage form composition of the present invention have sustained-release properties and sufficient hardness. Therefore, the solid dosage form composition of the present invention is useful because it can be combined with various pharmacoactive ingredients for which sustained-release tablets are desired to provide desired sustained-release tablets.

Claims

1. (A) Polyvinyl alcohol-based resins with an average degree of saponification of 78 to 96 mol% and an average degree of polymerization of 800 or more; and (B) Polyhydric phenolic compounds A composition for sustained-release tablets containing the following:

2. The sustained-release tablet composition according to claim 1, wherein the average degree of saponification of the polyvinyl alcohol-based resin (A) is 85 to 96 mol%.

3. The sustained-release tablet composition according to claim 1 or 2, wherein the (B) polyhydric phenol compound is tannic acid.

4. The sustained-release tablet composition according to any one of claims 1 to 3, wherein the content of the polyhydric phenol compound (B) per 100 parts by weight of the polyvinyl alcohol resin (A) is 0.1 to 35 parts by weight.

5. The sustained-release tablet composition according to any one of claims 1 to 4, wherein the degree of modification of the (A) polyvinyl alcohol-based resin is less than 10 mol%.

6. The sustained-release tablet composition according to any one of claims 1 to 5, wherein the (A) polyvinyl alcohol-based resin is a powder with an average particle size of 40 to 200 μm.

7. The sustained-release tablet composition according to any one of claims 1 to 6, wherein the (A) polyvinyl alcohol resin is a mixture of a polyvinyl alcohol resin having an average degree of polymerization of 1500 or more to 3000 and a polyvinyl alcohol resin having an average degree of polymerization of 100 to less than 1500.

8. Furthermore, the sustained-release tablet composition according to any one of claims 1 to 7, wherein (C) crystalline cellulose is contained in an amount of 1 to 50 parts by weight per 100 parts by weight of the (A) polyvinyl alcohol-based resin.

9. A sustained-release tablet comprising the sustained-release tablet composition according to any one of claims 1 to 8.

10. A method for producing sustained-release tablets, comprising mixing granules of a composition containing a polyvinyl alcohol-based resin having an average degree of saponification of 78 to 96 mol% and an average degree of polymerization of 800 or more, and a pharmaceutically active ingredient, with tannic acid powder and compressing the mixture into tablets.

11. The method for producing sustained-release tablets according to claim 10, wherein the polyvinyl alcohol-based resin is a powder with an average degree of polymerization of 1500 to 3000 and an average particle size of 40 to 200 μm.

12. The method for producing sustained-release tablets according to claim 10 or 11, wherein the granules are granulated by a fluidized bed granulation method.

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