Tablet containing macitentan

Abstract

To provide a tablet containing macitentan, which exhibits superior disintegrability, and which prevents time-dependent formation of macitentan-derived impurities even during high-temperature storage.SOLUTION: A tablet comprises the following components (a), (b), and (c): (a) macitentan or a salt thereof or a solvate thereof, (b) polyvinyl alcohol, and (c) a disintegrant.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a tablet containing macitentan, more particularly to a tablet containing macitentan and a method for producing the same. [Background technology]

[0002] Macitentan (chemical name: N-[5-(4-bromophenyl)-6-[2-[(5-bromopyridin-2-yl)oxy]ethoxy}pyrimidin-4-yl]-N'-propylsulfuric acid diamide) is an endothelin receptor inhibitor represented by the following formula (1), and is effective in treating pulmonary hypertension. As a pharmaceutical containing macitentan as an active ingredient, a film-coated tablet made by film-coating a plain tablet consisting of macitentan, lactose monohydrate, crystalline cellulose, sodium starch glycolate, povidone, magnesium stearate, and polysorbate 80 is manufactured and sold (Non-Patent Documents 1-2).

[0003] [ka]

[0004] Furthermore, as preparations containing macitentan, tablets containing macitentan together with polyvinylpyrrolidone or the like as a disintegrant (Patent Document 1) and tablets containing macitentan together with hydroxypropylmethylcellulose as a binder (Patent Document 2) have been reported. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2007 / 031933 Brochure [Patent Document 2] International Publication No. 2022 / 045991 Brochure [Non-patent literature]

[0006] [Non-Patent Document 1] Opsumit Tablets Package Insert August 2022 Revision (6th Edition) [Non-Patent Document 2] Actelion Pharmaceuticals Japan Co., Ltd., "Documents regarding Opsumit Tablets 10mg", [online], [searched October 1, 2023], Internet<URL:https: / / www.pmda.go.jp / drugs / 2015 / P20150601007 / 100888000_22700AMX00649_B100_1.pdf> Summary of the Invention [Problem to be solved by the invention]

[0007] The present inventors have studied the above tablets described in Patent Documents 1 and 2, and found that there is a problem with storage stability in that impurities derived from macitentan are generated over time when stored under high-temperature conditions. On the other hand, in recent years, when a patient takes multiple medicines, efforts to improve medication adherence are often made by packaging the medicines in a single package when dispensing. For this reason, the period from when the medicine is taken out of the package or PTP sheet to when the patient takes it may be long, increasing the possibility that the medicine will actually be exposed to high-temperature conditions as described above. It was also found that there is still room for improvement in the disintegrability of the tablets described in Patent Documents 1 and 2. Tablets are required to have good disintegrability, and in recent years, there has been a demand for the development of tablets that disintegrate quickly in the oral cavity even without water (orally disintegrating tablets) when taken by patients with weak swallowing ability, such as the elderly and children.

[0008] The problem to be solved by the present invention is to provide a macitentan-containing tablet which has good disintegrability and is less likely to produce macitentan-derived impurities over time even when stored under high-temperature conditions. [Means for solving the problem]

[0009] The present inventors have conducted intensive research to solve the above-mentioned problems regarding macitentan-containing tablets, and have discovered that by forming tablets using polyvinyl alcohol in addition to macitentan or a salt thereof or a solvate of either of them and a disintegrant, the disintegration properties are improved and impurities derived from macitentan are less likely to be generated over time even when stored under high temperature conditions, thereby completing the present invention.

[0010] That is, the present invention provides the following: <1> ~ <11> This provides: <1> A tablet (hereinafter also referred to as "the tablet of the present invention") containing the following ingredients (a), (b) and (c). (a) Macitentan or a salt thereof, or a solvate thereof (b) Polyvinyl alcohol (c) Disintegrant

[0011] <2> The tablet comprises a plain tablet and contains component (b) in the plain tablet; <1> The tablet described in. <3> The tablet comprises a film coating layer or a sugar coating layer, and the plain tablet is coated with the film coating layer or the sugar coating layer. <2> The tablet described in. <4> The content of polyvinyl alcohol in the film coating layer or sugar coating layer is 0% by mass or more and 0.1% by mass or less based on the total mass of the tablet. <3> The tablet described in.

[0012] <5> The content of hydroxypropyl methylcellulose is 0% by mass or more and less than 1% by mass based on the total mass of the tablet, and the content of polyvinylpyrrolidone is 0% by mass or more and less than 1% by mass based on the total mass of the tablet. <1> ~ <4> A tablet according to any one of the preceding claims. <6> The content of component (b) is 2% by mass or more and 20% by mass or less based on the total mass of the tablet; <1> ~ <5> A tablet according to any one of the preceding claims. <7> Component (c) is at least one disintegrant selected from the group consisting of sodium starch glycolate and croscarmellose sodium; <1> ~ <6> A tablet according to any one of the preceding claims.

[0013] <8> The content of component (c) is 0.5% by mass or more and 3.5% by mass or less based on the total mass of the tablet; <1> ~ <7> A tablet according to any one of the preceding claims. <9> The tablet comprises an uncoated tablet, the uncoated tablet comprising an additive layer and granules dispersed in the additive layer, the granules containing component (a), and the additive layer containing lactose hydrate. <1> ~ <8> A tablet according to any one of the preceding claims. <10> It is an orally disintegrating tablet. <1> ~ <9> A tablet according to any one of the preceding claims.

[0014] <11> A method for producing a tablet (hereinafter also referred to as "the production method of the present invention"), characterized by using macitentan or a salt thereof, or a solvate of the same, polyvinyl alcohol, and a disintegrant. Effect of the Invention

[0015] The tablet of the present invention has good disintegrability, is less likely to generate macitentan-derived impurities over time even when stored under high temperature conditions, and is less likely to change in dissolution property even when stored under high humidity conditions. Therefore, according to the manufacturing method of the present invention, it is possible to easily produce macitentan-containing tablets which have good disintegration properties, are less likely to produce macitentan-derived impurities over time even when stored under high-temperature conditions, and are less likely to change in dissolution properties even when stored under high-humidity conditions. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] 〔tablet〕 The tablet of the present invention contains (a) macitentan or a salt thereof, or a solvate thereof, (b) polyvinyl alcohol, and (c) a disintegrant, i.e., each tablet contains the components (a) to (c).

[0017] (Component (a)) Macitentan is a compound represented by the following formula (1). Examples of macitentan or a salt or solvate thereof include the free form of macitentan; inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrofluoride, and hydrobromide; organic acid salts such as acetate, tartrate, and lactate; and hydrates and alcohol solvates thereof, with the free form of macitentan being preferred.

[0018] [ka]

[0019] Macitentan may be amorphous or crystalline. In the case of crystals, the cumulative 90% particle size is not particularly limited, but from the viewpoints of solubility, bioavailability, etc., it is preferably 1 to 50 μm, more preferably 1 to 30 μm, and particularly preferably 1 to 15 μm.

[0020] The tablet of the present invention preferably includes a plain tablet and contains component (a) in the plain tablet. When the tablet of the present invention includes granules, the granules preferably contain component (a). In this specification, "granules" refers to granulated or sized products.

[0021] The content of component (a) is preferably 2 to 50% by mass, more preferably 5 to 30% by mass, even more preferably 5 to 25% by mass, and particularly preferably 10 to 20% by mass, based on the total mass of the tablet of the present invention, from the viewpoint of physical properties, etc. When the tablet of the present invention includes an uncoated tablet and contains component (a) in the uncoated tablet, the content of component (a) in the uncoated tablet is preferably 2 to 50% by mass, more preferably 5 to 30% by mass, even more preferably 5 to 25% by mass, and particularly preferably 10 to 20% by mass, based on the total mass of the uncoated tablet, from the viewpoint of physical properties, etc. When the tablet of the present invention contains granules and the granules contain component (a), the content of component (a) in the granules is preferably 5 to 60 mass%, more preferably 10 to 50 mass%, and even more preferably 15 to 35 mass%, relative to the total mass of the granules. The content (mg) of component (a) per tablet is not particularly limited, and can be appropriately selected from the doses used in clinical practice. Specifically, it is usually 2.5 to 20 mg, preferably 5 to 20 mg, more preferably 5 to 15 mg, calculated as the free form. When used as a therapeutic agent for pulmonary hypertension, it is particularly preferable that the tablet contains 10 mg calculated as the free form.

[0022] (ingredient (b)) The tablet of the present invention contains (b) polyvinyl alcohol. By containing polyvinyl alcohol, the tablet has good disintegrability, and impurities derived from macitentan are unlikely to be generated over time even when stored at high temperature conditions, and the dissolution property is unlikely to change even when stored at high humidity conditions. The cumulative 50% particle size of polyvinyl alcohol is preferably from 1 to 300 μm, more preferably from 10 to 200 μm, and particularly preferably from 20 to 100 μm.

[0023] From the viewpoints of disintegration, storage stability, and suppression of changes in dissolution, the tablet of the present invention preferably includes a plain tablet and contains component (b) in the plain tablet. Also, when the tablet of the present invention includes granules, from the viewpoints of disintegration, storage stability, and suppression of changes in dissolution, the granules preferably contain component (b). By incorporating component (b) in the uncoated tablet (particularly in the granules) in this manner, disintegration properties, storage stability, suppression of changes in dissolution properties, physical properties, and moldability are particularly improved.

[0024] The content of component (b) is preferably 0.1 to 20% by mass, more preferably 0.2 to 10% by mass, even more preferably 0.5 to 5% by mass, and particularly preferably 2 to 5% by mass, based on the total mass of the tablet of the present invention, from the viewpoints of disintegration, storage stability, suppression of dissolution change, and moldability. When the tablet of the present invention includes an uncoated tablet and contains component (b) in the uncoated tablet, the content of component (b) in the uncoated tablet is preferably 0.1 to 20% by mass, more preferably 0.2 to 10% by mass, even more preferably 0.5 to 5% by mass, and particularly preferably 2 to 5% by mass, based on the total mass of the uncoated tablet, from the viewpoints of disintegration, storage stability, suppression of dissolution change, and moldability. When the above content and content ratio of component (b) is 2% by mass or more, the storage stability and the effect of suppressing changes in dissolution property are particularly improved.

[0025] When the tablet of the present invention contains granules and these granules contain component (b), the content of component (b) in the granules is preferably 0.5 to 20 mass%, more preferably 1 to 15 mass%, and even more preferably 4 to 10 mass%, relative to the total mass of the granules, from the viewpoints of disintegrability, storage stability, inhibition of dissolution change, and moldability.

[0026] The mass ratio of the component (b) to the component (a) [(b) / (a)] is preferably from 0.005 to 2, more preferably from 0.01 to 1, and particularly preferably from 0.1 to 0.5, from the viewpoints of disintegrability, storage stability, suppression of dissolution changes, and moldability. When the content mass ratio [(b) / (a)] is 0.1 or more, the storage stability and the effect of suppressing changes in dissolution property are particularly improved.

[0027] (component (c)) Examples of the disintegrant (c) used in the tablet of the present invention include croscarmellose sodium, sodium starch glycolate, crospovidone, carmellose, carmellose calcium, corn starch, sodium carboxymethyl starch, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, etc. One type of disintegrant may be used alone, or two or more types may be used in combination. Among these, croscarmellose sodium and sodium starch glycolate are preferred from the viewpoints of disintegration property, storage stability, and suppression of change in dissolution property. In order to further improve disintegration property, croscarmellose sodium is particularly preferred, and in order to further improve storage stability, sodium starch glycolate is particularly preferred.

[0028] From the viewpoints of disintegration property, storage stability, and suppression of changes in dissolution property, the tablet of the present invention preferably includes a plain tablet and contains component (c) in the plain tablet. In addition, when the tablet of the present invention contains granules, the component (c) may be contained either in the granules or outside the granules, or the component (c) may be contained both in the granules and outside the granules. For example, when the tablet of the present invention contains an additive layer and granules dispersed in the additive layer, the component (c) may be contained either in the additive layer or in the granules, or the component (c) may be contained both in the additive layer and in the granules, but it is preferable that the component (c) is contained both in the additive layer and in the granules.

[0029] The content of component (c) (preferably at least one disintegrant selected from the group consisting of sodium starch glycolate and croscarmellose sodium) is preferably 0.5 to 20% by mass, more preferably 1 to 10% by mass, even more preferably 1 to 7% by mass, and particularly preferably 1 to 3.5% by mass, based on the total mass of the tablet of the present invention, from the viewpoints of disintegration, storage stability, suppression of dissolution change, and moldability. When the tablet of the present invention includes an uncoated tablet and contains component (c) in the uncoated tablet, the content of component (c) in the uncoated tablet is preferably 0.5 to 20% by mass, more preferably 1 to 10% by mass, even more preferably 1 to 7% by mass, and particularly preferably 1 to 3.5% by mass, based on the total mass of the uncoated tablet, from the viewpoints of disintegration, storage stability, suppression of dissolution change, and moldability. When the above content and content ratio of component (c) is 3.5% by mass or less, the disintegration property, storage stability and effect of inhibiting change in dissolution property are particularly improved.

[0030] When the tablet of the present invention contains granules and the granules contain component (c), the content of component (c) in the granules is preferably 0.1 to 10 mass%, more preferably 0.5 to 7.5 mass%, and even more preferably 1 to 5 mass%, relative to the total mass of the granules, from the viewpoints of disintegrability, storage stability, inhibition of dissolution change, and moldability. When the tablet of the present invention comprises an additive layer and this additive layer contains component (c), the content of component (c) in the additive layer is preferably 0.1 to 17.5 mass%, more preferably 0.5 to 15 mass%, and even more preferably 1 to 10 mass%, based on the total mass of the additive layer, from the viewpoints of disintegrability, storage stability, suppression of dissolution change, and moldability.

[0031] The content mass ratio of component (a) to component (c) [(a) / (c)] is preferably from 0.5 to 12.5, more preferably from 1 to 10, and particularly preferably from 2.5 to 7.5.

[0032] The tablet of the present invention may further contain additives other than the components (b) and (c). Such additives may be any medicamentously acceptable, and examples thereof include excipients, lubricants, surfactants, flow agents, binders, film coating agents, plasticizers, colorants, preservatives, sweeteners, flavoring agents, flavoring agents, flavoring agents, stabilizers, etc. Among these, one kind may be used alone, or two or more kinds may be used in combination. The tablet of the present invention preferably contains one or more selected from the group consisting of excipients, lubricants and surfactants in addition to the components (a) to (c), more preferably contains an excipient in addition to the components (a) to (c), and particularly preferably contains an excipient, lubricant and surfactant in addition to the components (a) to (c). When the tablet of the present invention is a film-coated tablet, the film coating may be performed using a film coating agent and, if necessary, one or more selected from a plasticizer and a colorant.

[0033] (Excipients) Examples of the excipient include sugar alcohol excipients such as mannitol, erythritol, sorbitol, maltitol, lactitol, xylitol, etc.; lactose excipients such as lactose, lactose hydrate, anhydrous lactose, etc.; cellulose excipients such as crystalline cellulose, powdered cellulose, etc.; starch excipients such as corn starch, potato starch, pregelatinized starch, partially pregelatinized starch, etc.; calcium hydrogen phosphate hydrate, anhydrous calcium hydrogen phosphate, calcium silicate, fructose, sucrose, glucose, etc. Among these, one type may be used alone, or two or more types may be used in combination. Among these excipients, from the viewpoints of disintegration property, storage stability, and suppression of changes in dissolution property, sugar alcohol-based excipients, lactose-based excipients, and cellulose-based excipients are preferred, lactose-based excipients and cellulose-based excipients are more preferred, and a combination of lactose-based excipients and cellulose-based excipients is particularly preferred.

[0034] The tablet of the present invention preferably includes a plain tablet and contains an excipient in the plain tablet. In addition, when the tablet of the present invention contains granules, it is preferable to contain the excipient at least in the granules, and it is more preferable to contain the excipient both in and outside the granules. For example, when the tablet of the present invention contains an additive layer and granules dispersed in the additive layer, it is preferable to contain the excipient at least in the granules, and it is more preferable to contain the excipient both in the additive layer and the granules. Moreover, the granules preferably contain at least one excipient selected from the group consisting of lactose-based excipients and cellulose-based excipients, and more preferably contain a combination of a lactose-based excipient and a cellulose-based excipient. The additive layer preferably contains at least one excipient selected from the group consisting of lactose-based excipients and cellulose-based excipients, more preferably contains a lactose-based excipient (preferably lactose hydrate), and particularly preferably contains a combination of a lactose-based excipient and a cellulose-based excipient (preferably a combination of lactose hydrate and crystalline cellulose). When a lactose-based excipient (preferably lactose hydrate) is contained in the additive layer as described above, the disintegration property, storage stability and effect of inhibiting changes in dissolution property are particularly improved.

[0035] The content of the excipient is preferably 5 to 95% by mass, more preferably 30 to 90% by mass, and particularly preferably 60 to 85% by mass, based on the total mass of the tablet of the present invention. When the tablet of the present invention includes a plain tablet and contains an excipient in the plain tablet, the content of the excipient in the plain tablet is preferably 5 to 95% by mass, more preferably 30 to 90% by mass, and particularly preferably 60 to 85% by mass, based on the total mass of the plain tablet, from the viewpoints of disintegration, storage stability, suppression of dissolution change, and moldability.

[0036] When the tablet of the present invention contains granules and the granules contain an excipient, the content of the excipient in the granules is preferably 10 to 95% by mass, more preferably 30 to 90% by mass, and even more preferably 50 to 80% by mass, relative to the total mass of the granules. When the tablet of the present invention includes an additive layer and this additive layer contains an excipient, the content of the excipient in the additive layer is preferably 40 to 99 mass%, more preferably 60 to 99 mass%, and even more preferably 80 to 99 mass%, based on the total mass of the additive layer.

[0037] When the tablet of the present invention contains a cellulose-based excipient (preferably crystalline cellulose), the mass ratio of the cellulose-based excipient (preferably crystalline cellulose) to component (a) [(total of cellulose-based excipients) / (a)] is preferably 0.1 to 10, more preferably 1 to 5, even more preferably 2 to 4, and particularly preferably 2.5 to 3, from the viewpoints of disintegration property, storage stability, and suppression of changes in dissolution property. When the content mass ratio [(cellulose-based excipient) / (a)] is set to 2 or more, 2.5 or more, or 3 or less, the disintegration property, storage stability, and effect of suppressing change in dissolution property are particularly improved.

[0038] Furthermore, when the tablet of the present invention contains granules, and the granules contain a cellulose-based excipient (preferably crystalline cellulose), the mass ratio of the cellulose-based excipient (preferably crystalline cellulose) in the granules to component (a) [(cellulose-based excipient in granules) / (a)] is preferably 0.05 to 10, more preferably 0.1 to 5, even more preferably 1 to 4, and particularly preferably 1.2 to 3, from the viewpoints of disintegration property, storage stability, and suppression of changes in dissolution property. When the content mass ratio [(cellulose-based excipient in granule) / (a)] is 1 or more or 1.2 or more, the disintegration property, storage stability and effect of inhibiting change in dissolution property are particularly improved.

[0039] Furthermore, when the tablet of the present invention comprises an additive layer, and this additive layer contains a lactose-based excipient (preferably lactose hydrate), the content mass ratio of the lactose-based excipient (preferably lactose hydrate) in the additive layer to component (a) [(lactose-based excipient in additive layer) / (a)] is preferably 0.05 to 10, more preferably 0.1 to 5, even more preferably 1 to 3, and particularly preferably 1.2 to 1.7, from the viewpoints of disintegration property, storage stability, and suppression of changes in dissolution property. When the content mass ratio [(lactose-based excipient in the additive layer) / (a)] is 0.1 or more, 1 or more, or 1.2 or more, or 1.7 or less, the disintegration property, storage stability, and effect of inhibiting change in dissolution property are particularly improved.

[0040] (lubricant) Examples of lubricants include hardened oil, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, etc. Among these, one type may be used alone, or two or more types may be used in combination.

[0041] The tablet of the present invention preferably includes a plain tablet and contains a lubricant in the plain tablet. When the tablet of the present invention includes an additive layer, the additive layer preferably contains a lubricant. The content of the lubricant is preferably 0.1 to 5% by mass, more preferably 0.3 to 2% by mass, based on the total mass of the tablet of the present invention, from the viewpoints of disintegration, dissolution, hardness, etc. When the tablet of the present invention includes an uncoated tablet and contains a lubricant in the uncoated tablet, the content of the lubricant in the uncoated tablet is preferably 0.1 to 5% by mass, more preferably 0.3 to 2% by mass, based on the total mass of the uncoated tablet, from the viewpoints of disintegration, dissolution, hardness, etc.

[0042] (Surfactant) Examples of surfactants include sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80, sorbitan monostearate, etc. Among these, one type may be used alone, or two or more types may be used in combination.

[0043] The tablet of the present invention preferably includes a plain tablet and contains a surfactant in the plain tablet. When the tablet of the present invention includes granules, the granules preferably contain a surfactant. The content of the surfactant is preferably 0.01 to 5% by mass, more preferably 0.1 to 2% by mass, based on the total mass of the tablet of the present invention, from the viewpoints of disintegrability, dissolution property, hardness, etc. When the tablet of the present invention includes an uncoated tablet and contains a surfactant in the uncoated tablet, the content of the surfactant in the uncoated tablet is preferably 0.01 to 5% by mass, more preferably 0.1 to 2% by mass, based on the total mass of the uncoated tablet, from the viewpoints of disintegrability, dissolution property, hardness, etc.

[0044] (Superplasticizer) Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, corn starch, magnesium aluminometasilicate, synthetic aluminum silicate, etc. Among these, one type may be used alone, or two or more types may be used in combination. The content of the fluidizing agent is preferably 0 to 5 mass %, more preferably 0 to 2 mass %, based on the total mass of the tablet of the present invention, from the viewpoints of disintegration, dissolution property, hardness, and the like.

[0045] (Binding Agent) Examples of the binder include hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, etc. Among these, one type may be used alone, or two or more types may be used in combination. The content of the binder is preferably 0.1 to 7.5% by mass, more preferably 0.1 to 5% by mass, based on the total mass of the tablet of the present invention. The content of hydroxypropyl methylcellulose (preferably the content of hydroxypropyl methylcellulose in the uncoated tablet) is preferably 0% by mass or more and less than 1% by mass, more preferably 0 to 0.1% by mass, even more preferably 0 to 0.01% by mass, and particularly preferably 0% by mass, relative to the total mass of the tablet. Furthermore, the content of polyvinylpyrrolidone (preferably the content of polyvinylpyrrolidone in the uncoated tablet) is preferably 0% by mass or more and less than 1% by mass, more preferably 0 to 0.1% by mass, even more preferably 0 to 0.01% by mass, and particularly preferably 0% by mass, relative to the total mass of the tablet. Even when the tablet of the present invention contains hydroxypropyl methylcellulose or polyvinylpyrrolidone (preferably hydroxypropyl methylcellulose or polyvinylpyrrolidone in the uncoated tablet) in such amounts, the tablet has excellent disintegrability, storage stability, and suppression effect on changes in dissolution property.

[0046] (Film coating agent) Examples of film coating agents include hydroxypropylmethylcellulose, hypromellose acetate succinate, hypromellose phthalate, ethyl acrylate-methyl methacrylate copolymer, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, ammonioalkyl methacrylate copolymer, carboxyvinyl polymer, methacrylic acid copolymer S, methacrylic acid copolymer L, methacrylic acid copolymer LD, carnauba wax, etc. Among these, one type may be used alone, or two or more types may be used in combination.

[0047] When the tablet of the present invention is a film-coated tablet, the content of the film coating agent in the film coating layer is preferably 0.1 to 10 mass %, more preferably 0.3 to 8 mass %, based on the total mass of the tablet of the present invention.

[0048] (Plasticizer) Examples of plasticizers include diethyl sebacate, dibutyl sebacate, triethyl citrate, stearic acid, polyethylene glycol (e.g., macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000), triacetin, etc. Among these, one type may be used alone, or two or more types may be used in combination.

[0049] When the tablet of the present invention is a film-coated tablet, the content of the plasticizer in the film coating layer is preferably 0.1 to 5 mass %, more preferably 0.3 to 3 mass %, based on the total mass of the tablet of the present invention.

[0050] (Coloring agent) Examples of colorants include Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, food lake color, yellow ferric oxide, ferric oxide, titanium oxide, β-carotene, riboflavin, etc. Among these, one kind may be used alone, or two or more kinds may be used in combination.

[0051] When the tablet of the present invention is a film-coated tablet, the content of the colorant in the film coating layer is preferably 0.1 to 5 mass %, more preferably 0.3 to 3 mass %, based on the total mass of the tablet of the present invention.

[0052] The tablet of the present invention preferably includes a plain tablet, more preferably includes a plain tablet and a film-coating layer or a sugar-coating layer, and the plain tablet is coated with a film-coating layer or a sugar-coating layer (film-coated tablet or sugar-coated tablet), and particularly preferably is a film-coated tablet. The tablet of the present invention includes such plain tablets, film-coated tablets, sugar-coated tablets, as well as multi-layer tablets and dry-coated tablets. When the tablet of the present invention includes a film coating layer or a sugar coating layer, the content of polyvinyl alcohol in the film coating layer or the sugar coating layer is preferably 0 to 0.1% by mass, more preferably 0 to 0.01% by mass, and particularly preferably 0% by mass, based on the total mass of the tablet of the present invention. Even when the polyvinyl alcohol content in the film coating layer or the sugar coating layer is in this range, the tablet of the present invention is excellent in disintegration property, storage stability, and effect of suppressing change in dissolution property.

[0053] In addition, the plain tablet preferably contains an additive layer and granules dispersed in the additive layer. It is sufficient that at least a part of the granules is dispersed in the additive layer, and a plurality of granules in the additive layer may be in contact with each other as long as at least a part of the granules is dispersed in the additive layer. The additive layer is preferably a solid additive layer.

[0054] The granules preferably contain component (a), more preferably contain components (a) to (c) and, if necessary, additives other than components (b) and (c). The additive layer preferably contains at least one selected from the group consisting of component (c) and additives other than components (b) and (c), more preferably contains additives other than components (b) and (c), and from the viewpoints of disintegration, storage stability, and dissolution change suppression effect, more preferably contains a lactose-based excipient (preferably lactose hydrate), even more preferably contains component (c) and a lactose-based excipient (preferably lactose hydrate), and particularly preferably contains component (c), a lactose-based excipient (preferably lactose hydrate), and a cellulose-based excipient (preferably crystalline cellulose).

[0055] The total content of the granules and the additive layer is preferably 80 to 100% by mass, and more preferably 90 to 100% by mass, based on the total mass of the tablet.

[0056] In addition, the tablet of the present invention is preferably for oral administration. Specific dosage forms of the tablet of the present invention include, for example, normal tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, enteric tablets, sustained-release tablets, etc. Among these, normal tablets and orally disintegrating tablets are preferred, and orally disintegrating tablets are more preferred. In this specification, "orally disintegrating tablets" refers to tablets that disintegrate quickly in the oral cavity. Specifically, it refers to tablets that disintegrate preferably within 60 seconds, more preferably within 45 seconds, and can be taken by disintegrating in the oral cavity without ingesting water. The disintegration time can be measured, for example, using an orally disintegrating tablet measuring device (Tricope Tester, manufactured by Okada Seiko Co., Ltd.).

[0057] [Tablet manufacturing method] Next, the method for producing the tablet of the present invention will be described. The manufacturing method of the present invention is characterized by using macitentan or a salt thereof, or a solvate thereof, polyvinyl alcohol, and a disintegrant. For example, the pharmaceutical composition can be manufactured by a method including a tableting step of mixing granules containing (a) macitentan or a salt thereof, or a solvate thereof, and other components ((b) polyvinyl alcohol, (c) a disintegrant, and one or more additives other than components (b) and (c)) with additives, and tableting the mixture.

[0058] The above granules can be obtained by a granulation step of granulating a composition containing component (a) and, if necessary, component (b) and / or component (c) (hereinafter also referred to as a composition for granulation) in accordance with a known granulation method described in the General Provisions for Preparations of the Japanese Pharmacopoeia, Seventeenth Edition, etc. The granulation composition can be prepared, for example, by mixing component (a) and, if necessary, other components, or by kneading component (a) and, if necessary, other components with a solvent such as water or water-containing alcohol. Prior to preparing the granulation composition, component (a) to be used for granulation may be pulverized.

[0059] The granulation in the granulation step may be performed by a wet granulation method or a dry granulation method. Specifically, examples of the method include extrusion granulation, rolling granulation, stirring granulation, fluidized bed granulation, spray drying granulation, and crushing granulation. The granules obtained in the granulation step may be dried before being used in the tableting step.

[0060] The additive to be mixed with the granules is preferably in a solid state, more preferably in a powder state. By this mixing, an additive layer is formed.

[0061] The tableting in the tableting step may be carried out according to a conventional method using a rotary tableting machine, a single punch tableting machine, etc. By the tableting step, uncoated tablets (plain tablets) are obtained.

[0062] Furthermore, the uncoated tablets obtained in the tableting step may be film-coated with a film-coating agent and, if necessary, one or more selected from a plasticizer and a colorant.

[0063] The tablet of the present invention obtained as described above has good disintegration properties, and is less likely to generate macitentan-derived impurities over time even when stored under high temperature conditions. In addition, the dissolution properties are less likely to change even when stored under high humidity conditions. EXAMPLES

[0064] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0065] In the present examples, unless otherwise specified, the following were used: lactose hydrate, D-mannitol, crystalline cellulose, sodium starch glycolate, croscarmellose sodium, polyvinyl alcohol, povidone, copolyvidone, hydroxypropyl cellulose, hypromellose, polysorbate 80, and magnesium stearate. Lactose hydrate: SuperTab11SD (DFE Pharma) D-mannitol: Granutol S (Freund Corporation) Crystalline cellulose: Ceolas UF-711 (manufactured by Asahi Kasei Corporation) Sodium starch glycolate: VIVASTAR P (manufactured by JRS Pharma) Croscarmellose sodium: Ac-Di-Sol (Dupont) Polyvinyl alcohol: EG-05PW (Mitsubishi Chemical) Povidone: Kolidon K30 (BASF) Copolyvidone: Kolidon VA64 (manufactured by BASF) Hydroxypropyl cellulose: HPC-SL (manufactured by Nippon Soda Co., Ltd.) Hypromellose: TC-5E (manufactured by Shin-Etsu Chemical Co., Ltd.) Polysorbate 80: NIKKOL TO-10MV (Nikko Chemicals) Magnesium stearate: Magnesium stearate, vegetable-based (manufactured by Taihei Chemical Industry Co., Ltd.)

[0066] (Example 1 Plain Tablet) Tablets (weight 70 mg, hardness 40 N, diameter 5.5 mm, thickness 2.75 mm) each containing 10 mg of macitentan were obtained by the following process. (1) 0.3 g of macitentan, 1.166 g of lactose hydrate, 0.105 g of crystalline cellulose, 0.042 g of sodium starch glycolate, and 0.063 g of polyvinyl alcohol were mixed in a mortar. 0.4 g of polysorbate 80 was added to 33 mL of purified water and dissolved, and 0.33 mL of this liquid was weighed out. This liquid was added to the above macitentan-containing mixture and granulated (mixing and granulation process). (2) Next, the granulated product obtained in the above mixing and granulation process was dried (drying process), and then sized using a JIS test sieve (sizing process). (3) Next, 0.368 g of crystalline cellulose, 0.042 g of sodium starch glycolate, and 0.011 g of magnesium stearate were added to the sized product obtained in the above sizing process and mixed (mixing and granulation process), and then compressed into tablets (tabletting process) to obtain the tablets of Example 1.

[0067] (Examples 2 to 11 and Comparative Examples 1 to 4: Plain tablets) Uncoated tablets containing 10 mg of macitentan per tablet were produced in the same manner as in Example 1, except that the ingredients, amounts (% by mass) and final formulation weights were as shown in Tables 1 to 3.

[0068] [Table 1]

[0069] [Table 2]

[0070] [Table 3]

[0071] <Test Example 1: Disintegration test> The tablets of Examples 1 to 11 and Comparative Examples 1 to 4 were evaluated for disintegration property. That is, using an oral disintegrating tablet measuring device (Tricoop Tester, manufactured by Okada Seiko Co., Ltd.), the disintegration time was measured by dropping a fixed amount of artificial saliva onto a tablet sandwiched between meshes with a load of 40 g at a dropping rate of 6 mL / min and a dropping height of 80 mm. The disintegration properties of the tablets were evaluated according to the following criteria. The results are shown in Table 4.

[0072] (Evaluation criteria for disintegration) AA: Disintegration time is 20 seconds or less A: Disintegration time is more than 20 seconds and less than 40 seconds B: Disintegration time is more than 40 seconds and less than 60 seconds C: Disintegration time is over 60 seconds

[0073] <Test Example 2: Dissolution test> The tablets of Examples 1 to 11 and Comparative Examples 1 to 4 were evaluated for changes in dissolution properties under high humidity conditions. One tablet was added to 900 mL of dissolution test fluid 2 containing 0.5% polysorbate 80, and a dissolution test was performed at 50 revolutions per minute using the paddle method. Test fluid was collected at each collection time point (15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240 minutes, and 360 minutes) and the dissolution rate of macitentan was measured by liquid chromatography (HPLC). The dissolution rate of macitentan was also measured in the same manner as above for those stored under conditions of 25°C, 93% RH for 2 weeks, and the change in dissolution rate was calculated using the following formula. (Change in dissolution rate) = (% dissolution rate of tablet after storage) - (% dissolution rate of tablet before storage) Among the changes in dissolution rate at each sampling time point, the sampling time point (time from the start of the dissolution test) at which the change in dissolution rate between before and after storage was the largest within the test time, as well as the dissolution rate before storage and the change in dissolution rate at that time, were recorded and shown in Table 4. In addition, the change in dissolution rate of the tablets under high humidity conditions was evaluated according to the following criteria. The results are shown in Table 4.

[0074] (Evaluation criteria for change in dissolution rate) A: The change in dissolution rate is within ±3% B: The change in dissolution rate is greater than ±3% and less than ±5%. C: The change in dissolution rate is more than ±5%

[0075] <Test Example 3 Storage Stability Test> The storage stability of the tablets of Examples 1 to 11 and Comparative Examples 1 to 4 under high temperature and high humidity conditions was evaluated. That is, for each tablet before and after storage, the amount of impurities derived from macitentan was calculated from the peak area ratio to that of the standard macitentan solution using HPLC. The storage conditions were 60°C, 75% RH, and 2 weeks. The increase in impurities after storage at 60°C and 75% RH for two weeks was calculated using the following formula. (Increase in impurities%) = (Amount of impurities in tablets after storage%) - (Amount of impurities in tablets before storage%) The storage stability of the tablets under high temperature and high humidity conditions was evaluated according to the following criteria. The results are shown in Table 4.

[0076] (Evaluation criteria for storage stability) A: Impurity increase is 0.45% or less B: Impurity increase is more than 0.45% and less than 0.55% C: Impurity increase is more than 0.55%

[0077] [Table 4]

[0078] As shown in Table 4, the tablets of Examples 1 to 11 containing polyvinyl alcohol exhibited good results in terms of both disintegration property and storage stability. In addition, there was little change in dissolution rate during storage. Moreover, the tablets of Examples 2, 8 and 11 were particularly good in both disintegration property and storage stability, and the change in dissolution rate during storage was small.

[0079] (Formulation Examples 1-11: Film-coated tablets) Hypromellose, macrogol 6000, and titanium oxide are dissolved or dispersed in purified water in a mass ratio of 8:1:1 to obtain a liquid composition. 100 parts by mass of the plain tablets obtained in Examples 1 to 11 are coated with 5 parts by mass of the above liquid composition using HC-FZ-LABO (manufactured by Freund) (film coating step) to obtain film-coated tablets of Formulation Examples 1 to 11. The film-coated tablets of Formulation Examples 1 to 11 have good disintegration properties and storage stability, and the change in dissolution rate during storage is small.

Claims

1. A tablet comprising the following ingredients (a), (b) and (c): (a) Macitentan or a salt thereof, or a solvate thereof (b) Polyvinyl alcohol (c) Disintegrant

2. The tablet of claim 1, comprising a plain tablet and containing component (b) in the plain tablet.

3. The tablet according to claim 2, comprising a film coating layer or a sugar coating layer, the uncoated tablet being coated with the film coating layer or the sugar coating layer.

4. The tablet according to claim 3, wherein the content of polyvinyl alcohol in the film coating layer or sugar coating layer is from 0% by mass to 0.1% by mass based on the total mass of the tablet.

5. The tablet according to claim 1 or 2, wherein the content of hydroxypropyl methylcellulose is 0% by mass or more and less than 1% by mass with respect to the total mass of the tablet, and the content of polyvinylpyrrolidone is 0% by mass or more and less than 1% by mass with respect to the total mass of the tablet.

6. The tablet according to claim 1 or 2, wherein the content of component (b) is 2% by mass or more and 20% by mass or less relative to the total mass of the tablet.

7. 3. The tablet according to claim 1 or 2, wherein component (c) is at least one disintegrant selected from the group consisting of sodium starch glycolate and croscarmellose sodium.

8. The tablet according to claim 1 or 2, wherein the content of component (c) is 0.5% by mass or more and 3.5% by mass or less relative to the total mass of the tablet.

9. 3. The tablet of claim 1 or 2, comprising an uncoated tablet, the uncoated tablet comprising an additive layer and granules dispersed in the additive layer, the granules containing component (a), and the additive layer containing lactose hydrate.

10. 3. The tablet according to claim 1 or 2, which is an orally disintegrating tablet.

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