tablet

Abstract

The objective is to provide stable tablets containing macitentan or a pharmaceutically acceptable salt thereof, which can maintain their properties over a long period of time without using hard and expensive PTP packaging materials that are impermeable to both oxygen and moisture. [Solution] A tablet containing macitentan or a pharmaceutically acceptable salt thereof and hydroxypropyl cellulose, wherein the tablet has a water vapor permeability of 0.5 g / m² according to JIS K 7129-2. 2 • Can be packaged with plastic film with a lifespan of 24 hours or more.

Description

[Technical Field]

[0001] This invention relates to tablets. [Background technology]

[0002] Macitentan or its pharmaceutically acceptable salts have traditionally been used to treat pulmonary arterial hypertension. Macitentan or its pharmaceutically acceptable salts are endothelin receptor antagonists, and typically, adults are given 10 mg of macitentan orally once daily (e.g., Non-Patent Document 1). Furthermore, macitentan has been proposed in Patent Document 1, etc., as a formulation containing at least one compound having prostacyclin receptor (IP) agonist properties. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Japanese Patent Publication No. 2015-187148 [Non-patent literature]

[0004] [Non-Patent Document 1] Package insert for Opsumit tablets [Overview of the project] [Problems that the invention aims to solve]

[0005] Tablets containing macitentan or its pharmaceutically acceptable salts are packaged in PTP (press-through pack) material that is impermeable to both oxygen and moisture. Such materials are hard, requiring force to push the tablets out of the PTP packaging. Furthermore, these materials are expensive. [Means for solving the problem]

[0006] The inventors of this invention were the first to discover that when tablets containing macitentan or a pharmaceutically acceptable salt thereof are packaged in a non-rigid material or removed from rigid PTP packaging and stored under high temperature and high humidity conditions, the dissolution rate decreases. This is done to facilitate the extrusion of tablets packaged in rigid PTP packaging for functional and physical ease of use. The inventors then diligently investigated methods to effectively prevent the decrease in dissolution rate without using rigid and expensive PTP packaging. As a result, they unexpectedly discovered that by using a specific additive for tablets containing macitentan or a pharmaceutically acceptable salt thereof, the dissolution stability of the tablets can be improved, and furthermore, the dissolution rate of the tablets can be adjusted, leading to the completion of the present invention. In other words, this application includes the following inventions. (1) Tablets containing macitentan or a pharmaceutically acceptable salt thereof and hydroxypropylcellulose. (2) The tablet described above, containing granules of macitentan or a pharmaceutically acceptable salt thereof and hydroxypropyl cellulose. (3) The tablet described above, comprising hydroxypropyl cellulose in a ratio of 7 parts by mass to 30 parts by mass per 100 parts by mass of macitentan or a pharmaceutically acceptable salt thereof. (4) The tablets described above, further coated with a film. (5) Moisture permeability of 0.5 g / m² according to JIS K 7129-2 2 The tablets described above, packaged in plastic film for 24 hours or longer. [Effects of the Invention]

[0007] According to the present invention, it is possible to provide tablets containing macitentan or a pharmaceutically acceptable salt thereof in which a decrease in dissolution stability is effectively prevented. [Brief explanation of the drawing]

[0008] [Figure 1]This graph shows the dissolution stability of tablets containing macitentan or a pharmaceutically acceptable salt thereof of the present invention after being held in a PE bag. [Figure 2] This graph shows the dissolution stability of tablets (film-coated) containing macitentan or a pharmaceutically acceptable salt thereof, as of the present invention, after being held in a PE bag. [Figure 3] This graph shows the dissolution stability of tablets (film-coated) containing macitentan or a pharmaceutically acceptable salt thereof of the present invention after being held in PTP (PVC) packaging. [Figure 4] As a comparative example, this graph shows the dissolution stability of the original product's macitentan-containing tablets (film-coated) after being held in a PE bag. [Figure 5] As a comparative example, this graph shows the dissolution stability of tablets containing povidone and macitentan or a pharmaceutically acceptable salt thereof after being held in a PE bag. [Modes for carrying out the invention]

[0009] The tablets of this application contain macitentan or a pharmaceutically acceptable salt thereof as the active ingredient. As described above, macitentan or a pharmaceutically acceptable salt thereof is an endothelin receptor antagonist and is an ingredient used in the treatment of pulmonary arterial hypertension, and is represented by the following structural formula. Macitentan or its pharmaceutically acceptable salts are usually prescribed in tablet form so that adults can take 10 mg of macitentan orally once daily. Therefore, each tablet can be formulated to contain between 1 mg and 30 mg of macitentan, preferably between 5 mg and 20 mg, and more preferably 10 mg. This tablet contains macitentan or a pharmaceutically acceptable salt thereof, and hydroxypropyl cellulose. Thus, in tablets containing macitentan or a pharmaceutically acceptable salt thereof, the inclusion of hydroxypropylcellulose can improve the dissolution stability of the tablets. Furthermore, the dissolution properties of the tablets can be adjusted. In addition, because the fluidity can be improved, it is possible to reduce raw material loss during tableting. In this specification, "dissolution stability" means that the change from the initial dissolution rate and dissolution behavior over time is small. Here, "small change" means, for example, a change of less than 9% from the initial dissolution rate, preferably a change of 8% or less, and more preferably a change of 5% or less. In the tablets, macitentan or a pharmaceutically acceptable salt thereof is contained in an amount of 5% by mass or more, more preferably 10% by mass or more, based on the mass of the tablet. In particular, it is preferable that it be contained in an amount of 12% by mass or more, based on the mass of the tablet. Furthermore, it is preferable that it be contained in an amount of 50% by mass or less, more preferably 40% by mass or less, and even more preferably 30% by mass or less. In particular, it is preferable that it be contained in an amount of 12% by mass or more and 30% by mass or less, based on the mass of the tablet, and even more preferably 12% by mass or more and 20% by mass or less.

[0010] In tablets, hydroxypropyl cellulose is present in amounts of 7 parts by mass or more, preferably 9 parts by mass or more, more preferably 12 parts by mass or more, even more preferably 15 parts by mass or more, and even more preferably 17 parts by mass or more, per 100 parts by mass of macitentan or a pharmaceutically acceptable salt thereof. Also, amounts of 30 parts by mass or less are present, preferably 28 parts by mass or less, more preferably 26 parts by mass or less, even more preferably 25 parts by mass or less, and even more preferably 23 parts by mass or less. In particular, it is preferable that hydroxypropyl cellulose is blended in a ratio of 7 parts by mass or more and 30 parts by mass or less per 100 parts by mass of macitentan or a pharmaceutically acceptable salt thereof. In tablets, hydroxypropyl cellulose is contained at 0.5% by mass or more, more preferably 1% by mass or more, based on the mass of the tablets. Further, it is contained at 12% by mass or less, more preferably 10% by mass or less, still more preferably 8% by mass or less. Among these, it is preferable to contain 1% by mass or more and 8% by mass or less based on the mass of the tablets.

[0011] Hydroxypropyl cellulose of a grade used as an additive for pharmaceuticals can be used. Among these, hydroxypropyl cellulose conforming to the eighteenth revised Japanese Pharmacopoeia can be used. For example, hydroxypropyl cellulose such as NISSO HPC-SL manufactured by Nippon Soda Co., Ltd. can be used. The molecular weight (GPC method) of hydroxypropyl cellulose is not particularly limited, and examples thereof include 10,000 or more and 3,000,000 or less. In addition, in tablets containing macitentan or a pharmaceutically acceptable salt thereof, when using hydroxypropyl cellulose, it is preferable not to use it in combination with povidone. Thereby, elution stability can be exhibited without inhibiting or reducing the function of hydroxypropyl cellulose in the tablets.

[0012] In the tablets of the present invention, in addition to macitentan or a pharmaceutically acceptable salt thereof and hydroxypropyl cellulose, various additives can be contained. Examples of the additives include all additives commonly used in the pharmaceutical formulation field. For example, binder, excipient, lubricant, disintegrant, fluidizing agent, stabilizer, coloring agent, coating agent, lubricant, wetting agent, surfactant, sweetening agent, flavoring agent, organic acid, flavoring agent, perfume, etc. These can be used alone or in combination of two or more. Any of these components can be of a grade used as an additive for pharmaceuticals. Among them, those conforming to the 18th revised Japanese Pharmacopoeia or Pharmaceutical Additive Standards 2018 can be used. These additives can exhibit multiple functions and can be used either as internal additives added to the inside of tablets, etc. or external additives added to the outside of tablets, etc., depending on the function to be obtained.

[0013] Examples of the binder include, in addition to hydroxypropyl cellulose, those commonly used in the art, such as polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, hydroxypropyl methyl cellulose (hypromellose, HPMC), sodium carboxymethyl cellulose, polyvinyl alcohol, pregelatinized starch, agar, gelatin, sodium carboxymethyl cellulose, dextrin, ethyl cellulose, guar gum, and polyethylene oxide, etc. These can be used alone or in combination of two or more. The polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer is a polymer compound obtained by copolymerizing acrylic acid and methyl methacrylate with partially saponified polyvinyl alcohol. For example, those commercially available as POVACOAT (registered trademark) can be mentioned. Examples of the polyvinyl alcohol-polyethylene glycol graft copolymer include those commercially available as Colicoat (registered trademark) IR. The content of the binder is preferably 1% by mass or more and 20% by mass or less, more preferably 2% by mass or more and 15% by mass or less, based on the mass of the tablet.

[0014] Examples of excipients include sugars such as D-mannitol, anhydrous lactose, lactose monohydrate, refined sucrose, sucrose, fructose, fructooligosaccharides, glucose, maltose, reduced maltose, powdered sugar, powdered candy, and reduced lactose; sugar alcohols such as erythritol, sorbitol, maltitol, and xylitol; crystalline cellulose, microcrystalline cellulose, maltodextrin, kaolin, calcium hydrogen phosphate, discalcium phosphate dihydrate, calcium sulfate, calcium carbonate, pregelatinized starch, starch (e.g., natural starches such as potato starch, rice starch, wheat starch, and corn starch); light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate, and calcium silicate; and other silicic acids. These can be used individually or in combination of two or more. The excipient content is typically 10% to 80% by mass, preferably 15% to 80% by mass, and more preferably 20% to 80% by mass, based on the mass of the tablet.

[0015] Examples of disintegrants include crospovidone, low-substituted hydroxypropylcellulose (L-HPC), carmellose calcium, carmellose, croscarmellose sodium, crosslinked polyvinylpyrrolidone, polyvinylpyrrolidone, alginic acid, sodium alginate, sodium carboxymethyl starch, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium starch glycolate, talc, and pregelatinized starch. These can be used individually or in combination of two or more. In particular, tablets of this application that do not contain povidone are preferred. The disintegrant content is typically between 1% and 20% by mass, based on the mass of the tablet, with a preference of 1% to 15% by mass.

[0016] Examples of lubricants include magnesium stearate, calcium stearate, sodium lauryl sulfate, glyceryl monostearate, glyceryl palmitostearate, sodium stearyl fumarate, sucrose fatty acid esters, zinc stearate, talc, carnauba wax, L-leucine, and macrogol. These can be used individually or in combination of two or more. Among these, sodium stearyl fumarate is preferred. The lubricant content is typically between 0.01% and 5% by mass, and preferably between 0.25% and 5% by mass, based on the mass of the tablet. For example, tableting problems can be prevented by adding sodium stearyl fumarate after granulation, as described later.

[0017] The surfactants include sodium lauryl sulfate, polysorbate (commercially available as Tween®), polyethylene polyoxypropylene polymer (Pluronic F65), polyoxyethylene stearate (MYRJ), sodium dioctyl sulfosuccinate, polyoxyethylene sorbitan fatty acid ester (commercially available from Nikko Chemicals), and polyoxyethylene C 1~4 Examples include alkyl ethers, sucrose monoesters, lanolin esters, and ethers. Among these, polysorbates having an average degree of polymerization of 20 to 100 monomer units are preferred, and polysorbate 80 is more preferred, for example. These can be used individually or in combination of two or more. The surfactant content is typically between 0.01% by mass and 5% by mass, and preferably between 0.1% by mass and 4% by mass, based on the mass of the tablet.

[0018] Examples of fluidizing agents include talc, light anhydrous silicon, magnesium hydroxide, silicic acid, silicon dioxide, and magnesium aluminometasilicate. These can be used individually or in combination of two or more. The content of the fluidizing agent is preferably between 0% and 25% by mass, based on the mass of the tablet, and between 1% and 10% by mass.

[0019] Examples of stabilizers include macrogol (for example, with an average molecular weight of 200 to 20000, particularly preferably 6000 ± 1000), stearic acid, triethyl citrate, and carnauba wax. These can be used individually or in combination of two or more. The content of the stabilizer can be set as appropriate. Examples of colorants include titanium dioxide, caramel, iron oxide (yellow or black), ferric oxide, yellow ferric oxide, black ferric oxide, natural or synthetic organic pigments, or lake. These can be used individually or in combination of two or more. The content of the colorants can be set as appropriate.

[0020] The tablets of the present invention preferably contain stearyl fumarate sodium in addition to macitentan or a pharmaceutically acceptable salt thereof and hydroxypropyl cellulose, and more preferably do not contain povidone. In this case, per 100 parts by weight of macitentan or a pharmaceutically acceptable salt thereof, the amount of hydroxypropyl cellulose is preferably 7 to 35 parts by weight and the amount of stearyl fumarate sodium is preferably 5 to 25 parts by weight, and more preferably the amount of hydroxypropyl cellulose is preferably 10 to 30 parts by weight and the amount of stearyl fumarate sodium is preferably 8 to 20 parts by weight.

[0021] The tablets of the present invention may be uncoated, or they may be coated with a film coating for purposes such as improving appearance, moisture resistance, oxygen resistance, adjusting the drug dissolution rate (e.g., sustained release, enteric coating), and masking the odor or bitterness of the drug. In particular, it is preferable that the tablets are coated with a film coating to mask the taste, color, and / or odor of the active ingredient. The coating agent is not particularly limited as long as it can film-coat the tablets, and examples include water-soluble polymers, water-insoluble polymers, gastric-soluble polymers, enteric-coated polymers, etc. Examples of water-soluble polymers include natural polymers such as gum arabic powder, gelatin pullulan, dextrin, sodium carboxymethyl starch, and sodium alginate; polysaccharides; cellulose derivatives such as carmellose, sodium carmellose, calcium carmellose, hydroxypropyl cellulose, hypromellose, hydroxyethyl cellulose, hydroxymethyl cellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, and cellulose acetate; and water-soluble vinyl derivatives such as polyvinylpyrrolidone and polyvinyl alcohol. Examples of water-insoluble polymers include ethylcellulose, vinyl acetate polymer, aminoalkyl methacrylate copolymer, and ethyl acrylate / methyl methacrylate copolymer dispersion. Examples of gastric-soluble polymers include aminoacetal compounds such as polyvinyl acetal diethylaminoacetate. Examples of enteric-coated polymers include enteric-coated cellulose esters such as cellulose acetate propionate, hydroxypropyl methylcellulose acetate succinate, hypromellose phthalate, hydroxymethyl ethylcellulose phthalate, carboxymethyl ethylcellulose, and cellulose acetate phthalate. In addition to the above, titanium dioxide, polyethylene glycol, talc, carnauba wax, macrogol 1000 to 10000, such as macrogol 6000, can also be used as coating agents. These coating agents can be used individually or in combination of two or more types. In other words, the coating may consist of only one layer or two or more layers. Among the coating agents, those containing sodium carboxymethylcellulose, cellulose acetate, methylcellulose, polyethylene glycol, hypromellose, etc., are preferred. The coating agent content is typically 0.1% to 12% by mass, based on the mass of the tablet, with a preference of 3% to 7% by mass.

[0022] [Method for producing tablets containing macitentan or its pharmaceutically acceptable salts] The tablets of the present invention are manufactured by a step of incorporating hydroxypropyl cellulose into macitentan or a pharmaceutically acceptable salt thereof. Such a step may involve preparing macitentan or a pharmaceutically acceptable salt thereof, mixing it with hydroxypropyl cellulose, and granulating it. In other words, the tablets of the present invention contain granules of macitentan or a pharmaceutically acceptable salt thereof and hydroxypropyl cellulose. Alternatively, macitentan or a pharmaceutically acceptable salt thereof may be granulated by mixing it with other additives such as excipients, binders, disintegrants, and / or surfactants, and the tablets may contain granules of macitentan or a pharmaceutically acceptable salt together with other additives such as excipients, binders, disintegrants, and / or surfactants. Next, it is preferable to dry the granules, optionally sizing them, then add other additives and mix them, and finally compress them into tablets. Alternatively, the resulting tablets may be optionally film-coated. Thus, by adding hydroxypropyl cellulose to macitentan or a pharmaceutically acceptable salt thereof and granulating it, the dissolution stability of the resulting tablets can be improved, and the dissolution properties of the tablets can also be adjusted, making it possible to easily and inexpensively provide high-quality tablets.

[0023] (Preparation of macitentan or its pharmaceutically acceptable salts and various additives) Prepare macitentan or a pharmaceutically acceptable salt thereof. Commercially available macitentan or a pharmaceutically acceptable salt thereof may be used. If necessary, macitentan or a pharmaceutically acceptable salt thereof may be ground by applying mechanical forces such as compression, impact, shear, and friction, primarily in combination. Methods known in the art may be used for grinding, such as hammer mills, atomizers, ball mills, stamp mills, jet mills, Wiley mills, rotary ball mills, vibratory ball mills, vibratory mills, colloid mills, etc. Grinding may be carried out wet or cyclic.

[0024] (granulation) Next, granulation is carried out using macitentan or a pharmaceutically acceptable salt thereof, hydroxypropyl cellulose, and optionally other additives. The granulation method is not particularly limited, but examples include fluidized bed granulation and wet granulation. These granulation methods are known in the art, and granulated products can be manufactured in accordance with these methods. Fluidized bed granulation is a method of granulating macitentan or a pharmaceutically acceptable salt thereof while spraying or stirring a solvent or a mixture of a solvent and a binder. For this purpose, equipment used in the art (such as a fluidized bed granulator) can be used. In the present invention, the fluidized bed granulation treatment may be a rolling fluidized bed granulation treatment. Specifically, in the fluidized bed granulation method, one method involves spraying a solution of hydroxypropyl cellulose and purified water onto macitentan or a pharmaceutically acceptable salt thereof. Wet granulation is a process in which raw material powders are mixed with a solvent and then granulated. If necessary, methods and apparatus used for general tablet manufacturing can be used. In the present invention, among wet granulation methods, agitation granulation is preferred. The stirring granulation method can be carried out, for example, by introducing a mixture of macitentan or a pharmaceutically acceptable salt thereof, hydroxypropyl cellulose, and a solvent into a stirring granulator and stirring it. Granulation is preferably carried out at a product temperature of 20°C to less than 40°C, and more preferably at 24°C to 39°C. The solvents used in these fluidized bed granulation and wet granulation methods are not particularly limited, but for example, alcohols such as ethanol and isopropanol, water such as purified water, or mixtures thereof, which are commonly used in the manufacture of tablets, can be used. The particle size of the granulated material can be increased or decreased by increasing or decreasing various conditions during granulation, such as the amount of granulation liquid and the blade rotation speed. Furthermore, the dissolution rate of the resulting tablets can be increased or decreased by adjusting the particle size. For example, increasing the particle size of the granulated material reduces the dissolution rate, while decreasing the particle size increases it. The particle size of the granulated material can be arbitrarily set according to the purpose. Therefore, it is preferable to appropriately adjust various conditions during granulation, such as the amount of granulation liquid and the blade rotation speed, so that the final tablets exhibit an appropriate dissolution rate.

[0025] (Drying) After granulation, the granules are dried. The drying method is not particularly limited; as long as the drying temperature is below 80°C, known drying methods used in tablet manufacturing, such as fluidized bed dryers and shelf dryers, can be used. Furthermore, after drying the granulated material, it is preferable to perform sieving using a co-mill, screen mill, jet mill, hammer mill, pin mill, etc., or using a vibrating sieve, in order to sizing the particles. The particle size of the sizing particles can be arbitrarily set according to the purpose.

[0026] (Addition and mixing of additives) The obtained granules are mixed with any additives, such as lubricants. Mixing can be carried out using methods known in the art. For example, the granules and additives may be mixed using a mixer known in the art, such as a V-type mixer, W-type mixer, container mixer, tumbler mixer, or agitator mixer. The mixing here may be done using a solvent, but it is preferable to mix without using a solvent. Furthermore, it is preferable to include sodium stearyl fumarate as a lubricant added to the granules. This prevents tableting failures from occurring in the tableting process described later.

[0027] (Tablet compression) The mixture containing the obtained granules is compressed into tablets. Tablets can be manufactured using tablet presses known in the art. For example, a method of compressing or press-molding a mixture can be used. Compression or press-molding can be carried out using methods and apparatus commonly used for tablet formation, such as rotary tablet presses and single-stroke tablet presses. The compression pressure or press-molding pressure is not particularly limited, but for example, it can be between 1kN and 50kN, preferably 3kN or more, and preferably 5kN or more. It is also preferably 20kN or less, and more preferably 15kN or less. In particular, a press-molding pressure within the range of 5kN to 10kN is preferred. This ensures appropriate hardness and dissolution of the active ingredient. The hardness of the resulting tablets is preferably 20N or more, and more preferably 30N or more, and more preferably 35N or more. The "hardness" of the tablets can be measured using a tablet hardness tester (for example, the MultiTest 50 manufactured by Dr. Schleuniger Pharmatron). The tablets of the present invention may have score lines, identification marks, etc. The tablets may be in any shape, such as round tablets, round R tablets, round corner tablets, round two-tiered R tablets, or various irregularly shaped tablets, and may also be split tablets. Tablets of macitentan or its pharmaceutically acceptable salt may, for example, have a diameter of about 2 mm to 10 mm, preferably about 3 mm to 9 mm, and more preferably about 4 mm to 8 mm. They may also have a thickness of about 1 mm to 8 mm, preferably about 1 mm to 5 mm, and more preferably about 1 mm to 4 mm.

[0028] (Film coating) Optionally, the resulting uncoated tablets may be film-coated. The film coating method is not particularly limited, and methods commonly used in the field can be used. For example, film coating can be performed by wet spray coating of a suspension of coating agent and solvent onto the uncoated tablet using a coating machine. As the solvent, for example, alcohols such as ethanol and isopropanol, water, or mixtures thereof can be used. After film coating, the resulting tablets can be dried to obtain tablets of macitentan or a pharmaceutically acceptable salt thereof according to the present invention. Drying can be performed at a drying temperature of 70°C or lower, preferably 65°C or lower, and known drying methods for coating agents in the art can be used. Furthermore, a glossing agent may be sprayed onto dried macitentan or its pharmaceutically acceptable salt tablets using conventional methods.

[0029] (packaging) Tablets of macitentan or its pharmaceutically acceptable salt obtained as described above can usually be contained in a container or bag. The container or bag can be one that is commonly used for tablets, for example, packaging using plastic film. Specifically, PTP packaging is one example. The plastic film used for PTP packaging is not particularly limited and any material may be used. For example, various materials such as polyvinylidene chloride, polyvinyl chloride, polypropylene, polyethylene, and polychlorotrifluoroethylene can be used. Furthermore, these materials may consist of a single-layer structure or a laminated structure made of one material, or a laminated structure made of multiple materials. Also, from another point of view, for example, a moisture permeability of 0.5 g / m² according to JIS K 7129-2 may be used. 2 • Plastic film less than 24 hours old, 0.5 g / m² 2 Examples include plastic films with a moisture permeability of 24 hours or more. In particular, those with a moisture permeability of 0.5 g / m². 2 A plastic film with a moisture permeability of 24 hours or more is preferred, and with a moisture permeability of 3.0 g / m². 2· Plastic film for more than 24 hours (specifically, manufactured by Sumitomo Bakelite Co., Ltd., product name: Sumilite VSS-F110 (moisture permeability: 3.2 g / m 2 · 24 hours, Sumilite (registered trademark) VSS series (rigid vinyl chloride single-layer sheet)), moisture permeability is 5 g / m 2 · Plastic film for more than 24 hours (specifically, product name: Unipack, moisture permeability: 8 g / m 2 · 24 hours (by Wintex Co., Ltd., etc.). By using such a plastic film, since it is inexpensive by itself, it is possible to reduce the manufacturing cost. Regardless of whether the plastic film has a single-layer or laminated structure, the total thickness for coating the tablets is, for example, 20 μm or more and 1000 μm or less, and preferably 20 μm or more and 500 μm or less. That is, the tablets of masitinib or its pharmaceutically acceptable salts of the present invention are not only plastic films with low moisture permeability settings, but also those with a moisture permeability limit of 0.5 g / m 2Even when using a plastic film with a moderate humidity level of 24 hours or more, the tablet itself, as described above, contains hydroxypropyl cellulose, allowing it to exhibit dissolution stability without being affected by humidity. In other words, in the prior art, tablets containing macitentan or its pharmaceutically acceptable salts were packaged in PTP materials that were impermeable to both oxygen and moisture (for example, single-layer or laminated materials such as polyvinylidene chloride or polychlorotrifluoroethylene). On the other hand, the tablets of the present invention can provide tablets that exhibit dissolution stability even when using single-layer or laminated materials such as polyvinyl chloride, polyethylene, and polypropylene, without using hard and expensive materials with such specific properties. In addition, it is possible to improve the dissolution properties themselves, and consequently, to adjust the dissolution properties. Furthermore, in PTP-packaged tablets, there is no need to use hard materials, and the tablets can be easily pushed out of the PTP packaging. Moreover, the tablets of the present invention can exhibit dissolution stability even in their uncoated state without a film coating that takes into account moisture permeability, etc. [Examples]

[0030] Examples of the present invention will be described in detail below. In the following examples, the detailed parameters of the various test methods are as follows. Dissolution test The dissolution test was performed in accordance with the dissolution test method (paddle method) of the Japanese Pharmacopoeia. Testing equipment: Constant temperature water bath type dissolution tester NTR-6600AS (Toyama Sangyo Co., Ltd.) or equivalent. Temperature: 37.0±0.5℃ Speed: 50rpm Volume: 900ml Solvent: Dissolution test solution 2 (pH=6.8) with 1.0% polysorbate 80 added. Sampling volume: 10 ml Sampling times: 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes HPLC Equipment: Prominence (Shimadzu Corporation) or equivalent Mobile phase: Acetonitrile / water / formic acid (1→10) mixture (700:300:1) Flow rate: 1ml / min Column: L-column ODS 4.6×150mm 5μm Column temperature: 30℃ Injection volume: 20μl Detector: UV absorbance spectrophotometer (measurement wavelength 260 nm) Measurement time: 5 minutes Hausner ratio 50 ml of powder was placed in a 50 ml graduated cylinder, and its bulk density was measured. Then, it was tapped for 3 minutes (approximately 900 times). The volume after tapping was read from the graduated cylinder's scale to measure the tap density, and the Hausner ratio was calculated from the tap density / bulk density. The powder used here is the powder after granulation, wet sizing, drying, and sizing processes; specifically, it is dried granulated material that has been passed through a screen to remove coarse particles.

[0031] Example 1 Each of the following components was weighed according to the formulation proportions shown in Table 1, and tablets were prepared using the following method. [Table 1] In Table 1, the following components were used for each component. Lactose monohydrate is manufactured by DFE Pharma Co., Ltd. under the registered trademark Pharmatose® 200M. Crystalline cellulose is manufactured by Shin-Etsu Chemical Co., Ltd., Ceolus® PH-101. Hydroxypropyl cellulose is manufactured by Nippon Soda Co., Ltd., NISSO HPC-SL. Sodium starch glycolate is manufactured by DFE Pharma Co., Ltd. under the brand name Primojel®. Polysorbate 80 is made by Genuine Chemical, Polysorbate 80 Stearyl narolium fumarate is manufactured by Pharmatrans Sanaq AG, LubriSanaq®.

[0032] First, we prepared Masitentane and the various additives mentioned above. Next, macitentan, lactose monohydrate, crystalline cellulose, hydroxypropyl cellulose, and sodium starch glycolate were mixed using a high-speed stirring granulator. Next, the mixture was granulated using polysorbate 80 and water in a high-speed agitator granulator, dried in a fluidized bed granulator at 65°C or higher for 30 minutes or more, and then dry-sized using a co-mill. Sodium stearyl fumarate was weighed and mixed into the resulting granules. The resulting mixture was compressed into tablets using a small rotary tablet press at a pressure of 8kN to obtain tablets A with a diameter of 5.5 mm and a thickness of 2.65 mm. During the mixing and tableting of the granules, the fluidity of the resulting granules and mixture was good, with a Hausner ratio of 1.16. The obtained tablets A were placed in polyethylene bags (product name: Unipack) and stored for one or two months under conditions of 40°C and 75% relative humidity. Dissolution tests were then performed to investigate dissolution stability. The results, along with the results before storage under 40°C and 75% relative humidity, are shown in Figure 1. The results in Figure 1 confirm that tablet A, which is an uncoated tablet and not in PTP packaging, exhibits high dissolution stability, with almost no reduction in dissolution rate even after extended storage periods. Furthermore, it was confirmed that the dissolution rate was improved compared to the original product in Comparative Example 1 (tablets removed from PTP packaging and stored for 1 month and 3 months under conditions of 40°C and 75% relative humidity), which will be described later. Furthermore, it has been confirmed that when tablet A is stored in PTP packaging (manufactured by Sumitomo Bakelite Co., Ltd., product name: Sumilight VSS-F110), it exhibits the same dissolution rate as the tablet in Example 3 (which was film-coated and stored in PTP packaging).

[0033] Example 2 Tablet B was obtained by applying a film coating to tablet A, which was obtained in Example 1. The composition of the coating agent for the film coating is shown below. [Table 2] In Table 2, the following components were used for each component. HPMC is manufactured by Shin-Etsu Chemical Co., Ltd., TC-5R Triacetin is manufactured by Tokyo Chemical Industry Co., Ltd. Titanium dioxide is manufactured by Freund Industrial Co., Ltd., Titanium Dioxide FG The talc is manufactured by Matsumura Sangyo Co., Ltd., and is Crown Talc. The obtained tablets B were placed in polyethylene bags (product name: Unipack) and stored for one or two months under conditions of 40°C and 75% relative humidity. Dissolution tests were then performed using the same method as in Example 1 to examine dissolution stability. The results before storage under 40°C and 75% relative humidity, as well as the results before storage of the uncoated tablets under 40°C and 75% relative humidity, are shown in Figure 2. The results in Figure 2 confirm that tablet B, which is a film-coated tablet but not in PTP packaging, maintains dissolution stability, with almost no reduction in dissolution rate even after extended storage periods. Furthermore, it was confirmed that it exhibits a comparable dissolution rate to uncoated tablets without film coating, which correspond to tablet A in Example 1.

[0034] Example 3 Tablet B obtained in Example 2 was packaged in PTP packaging (Sumitomo Bakelite Co., Ltd., product name: Sumilight VSS-F110), and dissolved for one or two months under conditions of 40°C and 75% relative humidity. Dissolution tests were then performed to investigate the dissolution stability. The results, along with the results before storage under the conditions of 40°C and 75% relative humidity, are shown in Figure 3. The results shown in Figure 3 confirm that tablet B, which is a film-coated tablet with PTP packaging, maintains its dissolution stability, with almost no reduction in dissolution rate even after extended storage periods. Furthermore, these results confirm that it exhibits a good dissolution rate comparable to tablets without PTP packaging.

[0035] Comparative Example 1 After preparing Opsumit 10 mg tablets (film-coated tablets, PTP packaging containing polyvinylidene chloride, hereinafter sometimes referred to as "tablet C") manufactured by Janssen Pharma K.K., which are marketed as the original product, tablets C were extruded from the PTP packaging and stored for 1 month and 3 months under conditions of 40°C and 75% relative humidity. Dissolution tests were performed at 1 month and 3 months after storage using the same method as in Example 1. The results, along with the results before storage under conditions of 40°C and 75% relative humidity, are shown in Figure 4. The results in Figure 4 confirm that for tablet C, which is not packaged in PTP blister packs, the dissolution rate decreases and dissolution stability decreases as the storage period lengthens.

[0036] Comparative Example 2 In the formulation shown in Table 1, hydroxypropylcellulose was replaced with povidone, and tablets (hereinafter sometimes referred to as "Tablet D") were prepared in the same manner as in Example 1. The povidone used here was Kollidon® 30, manufactured by BASF Japan Ltd., with a K value of 28-32 (Japanese Pharmacopoeia XVIII). The Hausner ratio of the powder after granulation, wet sizing, drying, and sizing was 1.35, which was slightly unsatisfactory. Dissolution tests were performed on the obtained tablets D at 1 month and 2 months after storage using the same method as in Example 1. The results, along with the results before storage under conditions of 40°C and 75% relative humidity, are shown in Figure 5. The results in Figure 5 confirm that, for tablet D containing povidone, the dissolution rate decreases and dissolution stability decreases as the storage period lengthens.

[0037] As described above, the tablets of the present invention have been confirmed to exhibit good dissolution stability. Furthermore, it has been confirmed that the tablets of the present invention exhibit dissolution stability even in their uncoated state without a film coating that takes into account moisture permeability, etc. In addition, it is possible to improve the dissolution properties themselves, and thus adjust the dissolution properties. Moreover, since fluidity can be improved in the manufacturing of tablets compared to when povidone is used, material loss during manufacturing can be reduced, and manufacturing costs can be reduced. In addition, with PTP-packaged tablets, there is no need to use hard materials, the tablets can be easily pushed out of the PTP packaging, and inexpensive PTP packaging materials can be used, thus reducing manufacturing costs.

Claims

1. A tablet containing macitentan or a pharmaceutically acceptable salt thereof and hydroxypropylcellulose.

2. A tablet according to claim 1, comprising granules of macitentan or a pharmaceutically acceptable salt thereof and hydroxypropylcellulose.

3. A tablet according to claim 1 or 2, wherein hydroxypropyl cellulose is blended in a ratio of 7 parts by mass to 30 parts by mass per 100 parts by mass of macitentan or a pharmaceutically acceptable salt thereof.

4. The tablet according to claim 1 or 2, further comprising a film coating.

5. The moisture permeability according to JIS K 7129-2 is 0.5 g / m². ２ - The tablet according to claim 1 or 2, which is packaged with a plastic film with a lifespan of 24 hours or more.

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