Tablets containing opicapon

Abstract

To provide a tablet comprising opicapone or a pharmaceutically acceptable salt thereof, having reduced tableting faults during manufacture.SOLUTION: The present invention relates to a tablet comprising opicapone or a pharmaceutically acceptable salt thereof, wherein the opicapone or pharmaceutically acceptable salt thereof is in the form of particles having the following particle size, and a manufacturing method thereof: (i) a maximum length D50 value of 45 μm or less and / or (ii) a maximum length D90 value of 110 μm or less.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Opicapone is given by the following formula (1): [ka]

[0003] The compound represented by is 2,5-dichloro-3-[5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazole-3-yl]-4,6-dimethylpyridine N-oxide. Note that 2,5-dichloro-3-[5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazole-3-yl]-4,6-dimethylpyridine N-oxide is sometimes named 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxypyridine-3-yl)-[1,2,4]oxadiazole-5-yl]-3-nitrobenzene-1,2-diol N-oxide.

[0004] Opicapone is a peripheral, long-acting catechol-O-methyltransferase (COMT) inhibitor that, when used in combination with levodopa and dopa decarboxylase inhibitors, suppresses the activity of COMT, a secondary pathway in levodopa metabolism, thereby extending the duration of levodopa's effect and improving diurnal or post-treatment fluctuations (wearing-off phenomenon) in Parkinson's disease.

[0005] Generally, tableting failures can occur during the manufacturing of tablets. The particle size of the active pharmaceutical ingredient (API) is an important factor in tableting failures; typically, smaller particle sizes are associated with a larger surface area, making tableting failures more likely. (Journal of Pharmaceutical Sciences, Vol. 107, pp. 2267-2282, 2018) [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] The inventors of this invention were the first to recognize that tableting problems occurred when manufacturing tablets containing opicapone. Therefore, the object of the present invention is to provide tablets in which tableting problems during manufacturing are reduced. [Means for solving the problem]

[0007] The inventors diligently conducted research to solve the aforementioned problems. As a result, they found that when manufacturing tablets containing opicapone or a salt thereof as an active ingredient, uncrushed active pharmaceutical ingredient (API) is more prone to tableting failure (sticking) than crushed API. This contradicts the general tendency that crushed API is more prone to tableting failure than uncrushed API because it has a larger specific surface area. Therefore, they explored the API profile used for tableting and found that the maximum length of the API particles affects tableting failure. In other words, they found that by keeping the maximum length of the API particles below a certain level, tableting failure during tablet manufacturing can be significantly reduced. Furthermore, the inventors found that by adding a lubricant to the tablet to a certain level or more, tableting failure can be further reduced.

[0008] The present invention encompasses the following embodiments. [1] A tablet containing opicapone or a pharmaceutically acceptable salt thereof, wherein the opicapone or pharmaceutically acceptable salt is a particle having the following particle size, (i) The D50 value of the maximum length is 45 μm or less, and / or (ii) The D90 value of the maximum length is 110 μm or less. [1-1] The tablet described in [1], wherein the maximum length of the particle is the maximum length when measured using iSPect DIA-10 (Shimadzu Corporation) and a 10% polysorbate 20 aqueous solution as the dispersion medium. [1-2] A tablet according to [1] or [1-1], wherein the indentation and roughness of the tablet surface are reduced (suppressed) compared to a tablet containing opicapone or a pharmaceutically acceptable salt of the same particle size as described above. [2] A tablet containing a lubricant, as described in any one of the following items: [1], [1-1], or [1-2]. [3] The tablet according to [2] contains a lubricant magnesium stearate, [4] Tablets containing magnesium stearate that are higher than 0.3% by mass, as described in [3], [5] The tablet according to any one of [1] to [4], wherein the particles are a pulverized (preferably jet-milled) product of opicapone or a pharmaceutically acceptable salt thereof. [6] A tablet according to any one of [1] to [5], comprising granules containing particles of opicapone or a pharmaceutically acceptable salt thereof (preferably granules obtained by a wet granulation method), [7] The tablet according to [6], wherein the granules contain particles of opicapone or a pharmaceutically acceptable salt thereof, further comprising at least one excipient (preferably lactose monohydrate), and / or at least one binder (preferably partially pregelatinized starch), and / or at least one disintegrant (preferably sodium starch glycolate). [8] The tablet obtained by compressing the granules is a tablet obtained by compressing a mixture of the granules, at least one excipient (preferably lactose monohydrate), at least one binder (preferably partially pregelatinized starch), and at least one lubricant (preferably magnesium stearate), as described in [6] or [7]. [9] A method for producing tablets containing opicapone or a pharmaceutically acceptable salt thereof, comprising the step of compressing particles of opicapone or a pharmaceutically acceptable salt thereof having the following particle size, (i) The D50 value of the maximum length is 45 μm or less, and / or (ii) The D90 value of the maximum length is 110 μm or less.

[10] The production method according to [9], wherein the particles are a pulverized product of opicapone or a pharmaceutically acceptable salt thereof (preferably, a jet mill pulverized product).

[11] The production method according to [9] or

[10] , comprising a step of pulverizing (preferably, jet mill pulverizing) opicapone or a pharmaceutically acceptable salt thereof to obtain particles of opicapone or a pharmaceutically acceptable salt thereof having the specific maximum length.

[12] The production method according to any one of [9] to

[11] , comprising a step of granulating (preferably, wet granulating) particles of opicapone or a pharmaceutically acceptable salt thereof to obtain a granulated product, a step of mixing the granulated product with a lubricant, and a step of tableting the mixture.

[13] A method for producing a tablet containing opicapone or a pharmaceutically acceptable salt thereof, (1) pulverizing opicapone or a pharmaceutically acceptable salt thereof so that its particle size (i) the D50 value of the maximum length is 45 μm or less, and / or (ii) the D90 value of the maximum length is 110 μm or less, to obtain particles of opicapone or a pharmaceutically acceptable salt thereof, (2) granulating the particles obtained in step (1) to obtain a granulated product, (3) if necessary, mixing the granulated product obtained in step (2) with a lubricant to obtain a mixture, and (4) tableting the granulated product obtained in step (2) or the mixture obtained in step (3) A method for producing a tablet, comprising

[14] The production method according to

[13] , wherein step (4) is a step of tableting the mixture obtained in step (3), and the lubricant contains magnesium stearate.

[15] The production method according to

[14] , wherein the content of magnesium stearate in the tablet is higher than 0.3% by mass based on the total mass of the tablet.

[16] The amount of opicapone or a pharmaceutically acceptable salt thereof (active ingredient) adhered per 1 m [[ID=з0]]m 2 on the surface of the tableting machine punch in contact with the tablets after tableting 450 tablets is 1.0 μg / m m2 The manufacturing method according to any one of [9] to

[15] below,

[17] A method for reducing (suppressing) tableting failure in the production of tablets containing opicapone or a pharmaceutically acceptable salt thereof, characterized by using particles of the opicapone or a pharmaceutically acceptable salt thereof having the particle diameters shown below. (A) The D50 value of the maximum length is 45 μm or less, and / or (B) The D90 value of the maximum length is 110 μm or less.

[18] The method according to

[17] , wherein the tableting failure is a dent or roughness on the tablet surface. [Effect of the Invention]

[0009] According to the method for producing a tablet containing opicapone or a pharmaceutically acceptable salt thereof of the present invention, it is possible to suppress or reduce tableting failure, that is, dents or roughness on the tablet surface caused by the phenomenon (sticking) of the tableting powder or the raw drug adhering to the tableting machine pestle. Therefore, high-quality tablets can be produced. [Brief Description of the Drawings]

[0010] [Figure 1] Table 1 shows the state of the contact surface of the tableting powder of the tableting machine pestle and the amount of raw drug adhesion (μg) after tableting about 450 tablets using the unground or ground opicapone raw drug.

[0011] [Figure 2] Table 1 shows the amount of raw drug adhesion (μg / mm2) per 1 mm2 of the surface where the tablets contact the tableting machine pestle after tableting about 450 tablets using the unground or ground opicapone raw drug. [Modes for Carrying Out the Invention]

[0012] <Tablet> The tablet of the present invention (hereinafter simply referred to as "tablet") contains opicapone or a pharmaceutically acceptable salt thereof.

[0013] Opicapone is a compound represented by formula (1) above. Examples of its pharmaceutically acceptable salts include alkali metal salts or alkaline earth metal salts, preferably sodium salts, potassium salts, or salts of strongly basic organic compounds such as guanidine.

[0014] In this specification, all numerical ranges can be combined in any way. Furthermore, each numerical value may be rounded to its specified value. For example, if two significant figures are used, the third digit is rounded.

[0015] In this specification, "maximum length" refers to the maximum length between two points on the particle contour, which can be measured by dynamic image analysis. An example of equipment used for measurement is the iSpect DIA-10 dynamic particle image analysis system (Shimadzu Corporation). In the present invention, the maximum length of opicaponone or its pharmaceutically acceptable salt particles is less than 46 μm in D50 value, preferably 45 μm or less, more preferably 40 μm or less, even more preferably 35 μm or less, and particularly preferably 30 μm or less or 29 μm or less. In the present invention, the maximum length of opicaponone or its pharmaceutically acceptable salt particles is, for example, less than 111 μm in D90 value, preferably 110 μm or less, more preferably 100 μm or less, even more preferably 90 μm or less, and particularly preferably 80 μm or less.

[0016] Furthermore, in the present invention, the lower limit of the maximum length of opicapone or its pharmaceutically acceptable salt particles is not particularly limited, but is usually 5 μm or more, 10 μm or more, 15 μm or more, 20 μm or more, or 25 μm or more in terms of D50 value, preferably 10 μm or more, more preferably 15 μm or more, even more preferably 20 μm or more, and particularly preferably 25 μm or more. In the present invention, the lower limit of the maximum length of opicapone or its pharmaceutically acceptable salt particles is not particularly limited, but is usually 10 μm or more, 15 μm or more, 20 μm or more, 25 μm or more, 30 μm or more, 35 μm or more, 40 μm or more, 45 μm or more, 50 μm or more, 55 μm or more, or 60 μm or more in terms of D90 value, preferably 45 μm or more, more preferably 50 μm or more, even more preferably 55 μm or more, and particularly preferably 60 μm or more.

[0017] Furthermore, the D50 and D90 values ​​for the maximum particle length of opikapone or its pharmaceutically acceptable salt may be any combination of those described above. Examples of such combinations include (A) to (E) below. (A) D50 value: 45 μm or less (preferably 5 to 45 μm), D90 value: 110 μm or less (preferably 10 to 110 μm) (B) D50 value: 40 μm or less (preferably 5 to 40 μm), D90 value: 100 μm or less (preferably 10 to 100 μm) (C) D50 value: 35 μm or less (preferably 5 to 35 μm), D90 value: 90 μm or less (preferably 10 to 90 μm) (D) D50 value: 30 μm or less (preferably 5 to 30 μm), D90 value: 80 μm or less (preferably 10 to 80 μm) (E) D50 value: 29 μm or less (preferably 5 to 29 μm), D90 value: 80 μm or less (preferably 10 to 80 μm)

[0018] In this specification, "equivalent circle diameter" refers to the diameter of a circle with the same area as the projected area of ​​the particle image, and can be measured by dynamic image analysis. An example of equipment used for measurement is the dynamic particle image analysis system iSpect DIA-10 (Shimadzu Corporation).

[0019] In this specification, “ground opicapone or a pharmaceutically acceptable salt thereof” (hereinafter sometimes referred to as “ground material”) may be opicapone or a pharmaceutically acceptable salt thereof ground alone, or a mixture of opicapone or a pharmaceutically acceptable salt thereof and a lubricant and / or other pharmaceutically acceptable additive, ground together.

[0020] In the present invention, "lubricant" can be, for example, fatty acids or their salts (e.g., stearic acid, stearate (e.g., magnesium stearate (including light grade), calcium stearate, aluminum stearate), oleate (e.g., sodium oleate)), talc, carnauba wax, bleached beeswax, beeswax, sucrose fatty acid esters, or lauryl sulfate (e.g., sodium lauryl sulfate). In the present invention, stearate (e.g., magnesium stearate, calcium stearate, aluminum stearate) or stearic acid is preferred as the lubricant, stearate is more preferred, and magnesium stearate is most preferred. In the present invention, the lubricant may be included in the tablet powder together with other additives, or it may be added in the tableting process by an external lubrication method.

[0021] In the present invention, the content of the lubricant in the tablet (or uncoated tablet) is, for example, greater than 0.3% by mass, preferably 0.4% by mass or more, more preferably 0.5% by mass or more, and particularly preferably 1.0% by mass or more, based on the total mass of the tablet. The upper limit of the lubricant content is not particularly limited as long as it does not affect the dissolution properties or hardness of the formulation, but for example, it is less than 5.0% by mass, preferably 4.0% by mass or less, more preferably 3.0% by mass or less, and particularly preferably 2.0% by mass or less.

[0022] Furthermore, in the present invention, the preferred lubricant content is preferably more than 2.3 parts by mass, preferably 3.9 parts by mass or more, and more preferably 7.8 parts by mass or more, per 100 parts by mass of opicapone or a pharmaceutically acceptable salt thereof. The upper limit is, for example, 40 parts by mass or less, and preferably 25 parts by mass or less, per 100 parts by mass of opicapone or a pharmaceutically acceptable salt thereof.

[0023] The tablets of the present invention may contain other pharmaceutically acceptable additives, such as excipients, disintegrants, disintegration aids, binders, fluidizers, flavoring agents, odoring agents, surfactants, fragrances, colorants, antioxidants, and wetting agents. These may be used individually or in combination of two or more.

[0024] Examples of excipients include lactose monohydrate, anhydrous lactose, sucrose, refined sucrose, D-mannitol, D-sorbitol, glucose, trehalose, fructose, starch (e.g., wheat starch, rice starch, corn starch, potato starch), dextrin, macrogol 20000, light anhydrous silicic acid, calcium hydrogen phosphate hydrate, precipitated calcium carbonate, and kaolin.

[0025] Examples of disintegrants include starch (e.g., wheat starch, rice starch, corn starch, potato starch), agar powder, sodium starch glycolate, partially pregelatinized starch, and D-mannitol.

[0026] Examples of disintegration aids include lactose, macrogol 1500, and macrogol 4000.

[0027] Examples of binders include starch, partially pregelatinized starch, dextrin, pullulan, gum arabic, gelatin, tragacanth, sodium alginate, and polyvinylpyrrolidone.

[0028] Examples of fluidizing agents include light anhydrous silicic acid, talc, and hydrated silicon dioxide.

[0029] Examples of flavoring agents include sucrose, citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, sodium saccharin, dipotassium glycyrrhizin, monosodium glutamate, sodium 5-inosinate, and sodium 5-guanylate.

[0030] Examples of odor-masking agents include trehalose, malic acid, maltose, potassium gluconate, anise essential oil, vanilla essential oil, and cardamom essential oil.

[0031] Examples of surfactants include polysorbate (such as polysorbate 80), polyoxyethylene-polyoxypropylene copolymer, and sodium lauryl sulfate.

[0032] Examples of fragrances include lemon oil, orange oil, menthol, and peppermint oil.

[0033] Examples of coloring agents include iron oxide (ferric oxide, yellow iron oxide, black iron oxide, etc.) and titanium dioxide.

[0034] Examples of antioxidants include sodium ascorbate, L-cysteine, sodium sulfite, and vitamin E.

[0035] Examples of humectants include polysorbate 80, sodium lauryl sulfate, sucrose fatty acid esters, macrogol, and hydroxypropyl cellulose.

[0036] The content of excipients (e.g., lactose monohydrate) in the tablets may be, for example, 60% by mass or more, 65% by mass or more, 70% by mass or more, 75% by mass or more, or 77% by mass or more, based on the total mass of the tablets, and may also be 90% by mass or less, 85% by mass or less, or 83% by mass or less.

[0037] In one embodiment, the tablet contains granules, and the content of lactose monohydrate as an excipient in the granules is preferably 60-70% by mass, more preferably 60-65% by mass, 65-70% by mass, or 62-67% by mass, based on the total mass of the tablet. In another embodiment, the content of lactose monohydrate as an excipient in the granules is 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, or 70% by mass, based on the total mass of the tablet.

[0038] In one embodiment, the content of lactose monohydrate as an excipient in the tablet is preferably 70-85% by mass, more preferably 70-80% by mass, or 75-85% by mass, and even more preferably 77-82% by mass, based on the total mass of the tablet. In another embodiment, the content of lactose monohydrate as an excipient in the tablet is 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, or 85% by mass, based on the total mass of the tablet.

[0039] In one embodiment, with the tablet being 100% by mass, the content of extragranularly added lactose hydrate, which is added to the granules as an excipient in addition to the granules, is preferably 45 to 55% by mass, more preferably 45 to 50% by mass, or 50 to 55% by mass, and even more preferably 45 to 48% by mass. Also in another embodiment, with the tablet being 100% by mass, the content of extragranularly added lactose hydrate, which is added to the granules as an excipient in addition to the granules, is 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, or 55% by mass.

[0040] The content of the binder (e.g., partially pregelatinized starch) in the tablet may be, for example, 1% by mass or more, 2% by mass or more, 3% by mass or more, or 4% by mass or more, based on the total mass of the tablet, or it may be 20% by mass or less, or 15% by mass or less.

[0041] In one embodiment, the content of partially pregelatinized starch as a binder in the granules is preferably 1 to 10% by mass, more preferably 1 to 5% by mass, or 5 to 10% by mass, and even more preferably 5 to 10% by mass, based on the total mass of the tablets. In another embodiment, the content of partially pregelatinized starch as a binder in the granules is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% by mass, based on the total mass of the tablets.

[0042] In one embodiment, the content of partially pregelatinized starch as a binder in the tablet is preferably 1 to 10% by mass, more preferably 1 to 5% by mass, 5 to 10% by mass, or 2 to 6% by mass, based on the total mass of the tablet. In another embodiment, the content of partially pregelatinized starch as a binder in the tablet is 1% by mass, 2% by mass, 3% by mass, 4% by mass, 5% by mass, 6% by mass, 7% by mass, 8% by mass, 9% by mass, or 10% by mass, based on the total mass of the tablet.

[0043] The content of the disintegrant (e.g., sodium starch glycolate) in the tablet may be, for example, 1% by mass or more, 2% by mass or more, 3% by mass or more, or 20% by mass or less, or 15% by mass or less, based on the total mass of the tablet.

[0044] In one embodiment, the content of sodium starch glycolate as a disintegrant in the granules is preferably 1 to 10% by mass, more preferably 1 to 5% by mass, and even more preferably 1 to 2% by mass, 2 to 3% by mass, 3 to 4% by mass, or 4 to 5% by mass, based on the total mass of the tablets. In another embodiment, the content of sodium starch glycolate as a disintegrant in the granules is 1% by mass, 2% by mass, 3% by mass, 4% by mass, or 5% by mass, based on the total mass of the tablets.

[0045] In one embodiment, the content of sodium starch glycolate as a disintegrant in the tablet is preferably 1 to 10% by mass, more preferably 1 to 5% by mass, and even more preferably 1 to 2% by mass, 2 to 3% by mass, 3 to 4% by mass, or 4 to 5% by mass. In another embodiment, the content of sodium starch glycolate in the tablet is 1% by mass, 2% by mass, 3% by mass, 4% by mass, or 5% by mass, based on the total mass of the tablet.

[0046] In one embodiment, with the tablet being 100% by mass, the tablet contains granules, and the content of extragranular sodium starch glycolate added to the granules as a disintegrant is preferably 0.5 to 5% by mass, and more preferably 0.5 to 2% by mass. In another embodiment, with the tablet being 100% by mass, the content of extragranular sodium starch glycolate added to the granules as a disintegrant is 0.5%, 1.0%, 1.5%, or 2.0% by mass.

[0047] One embodiment of the granules in the present invention is a granule containing lactose monohydrate as an excipient, partially pregelatinized starch as a binder, and sodium starch glycolate as a disintegrant.

[0048] One embodiment of the granules in the present invention is a granule containing, based on the total mass of the granules, 60 to 65% by mass of lactose monohydrate (a) as an excipient, 1 to 10% by mass of partially pregelatinized starch (d) as a binder, and 1 to 2% by mass of sodium starch glycolate (e) as a disintegrant.

[0049] One embodiment of the granules in the present invention is a granule containing, based on the total mass of the granules, 60-65% by mass of lactose monohydrate (a) as an excipient, 5-10% by mass of partially pregelatinized starch (d) as a binder, and 2-3% by mass of sodium starch glycolate (e) as a disintegrant.

[0050] One embodiment of the granules in the present invention is a granule containing, based on the total mass of the granules, 65 to 70% by mass of lactose monohydrate (a) as an excipient, 1 to 10% by mass of partially pregelatinized starch (d) as a binder, and 1 to 2% by mass of sodium starch glycolate (e) as a disintegrant.

[0051] One embodiment of the granules in the present invention is a granule containing, based on the total mass of the granules, 65-70% by mass of lactose monohydrate (a) as an excipient, 5-10% by mass of partially pregelatinized starch (d) as a binder, and 2-3% by mass of sodium starch glycolate (e) as a disintegrant.

[0052] One embodiment of the granules in the present invention is a granule containing, based on the total mass of the granules, 62 to 67% by mass of lactose monohydrate (a) as an excipient, 1 to 10% by mass of partially pregelatinized starch (d) as a binder, and 1 to 2% by mass of sodium starch glycolate (e) as a disintegrant.

[0053] One embodiment of the granules in the present invention is a granule containing, based on the total mass of the granules, 62 to 77% by mass of lactose monohydrate (a) as an excipient, 5 to 10% by mass of partially pregelatinized starch (d) as a binder, and 2 to 3% by mass of sodium starch glycolate (e) as a disintegrant.

[0054] One embodiment of the granules in the present invention is a granule containing, based on the total mass of the granules, 62% by mass of lactose monohydrate (a) as an excipient, 10% by mass of partially pregelatinized starch (d) as a binder, and 3% by mass of sodium starch glycolate (e) as a disintegrant.

[0055] One embodiment of the granules in the present invention is a granule containing, based on the total mass of the granules, 63% by mass of lactose monohydrate (a) as an excipient, 9-10% by mass of partially pregelatinized starch (d) as a binder, and 2-3% by mass of sodium starch glycolate (e) as a disintegrant (the sum of (d) and (e) is 12% by mass).

[0056] One embodiment of the granules in the present invention is a granule containing, based on the total mass of the granules, 64% by mass of lactose monohydrate (a) as an excipient, 8-10% by mass of partially pregelatinized starch (d) as a binder, and 1-3% by mass of sodium starch glycolate (e) as a disintegrant (the sum of (d) and (e) is 11% by mass).

[0057] One embodiment of the granules in the present invention is a granule containing, based on the total mass of the granules, 65% by mass of lactose monohydrate (a) as an excipient, 7-9% by mass of partially pregelatinized starch (d) as a binder, and 1-3% by mass of sodium starch glycolate (e) as a disintegrant (the sum of (d) and (e) is 10% by mass).

[0058] One embodiment of the granules in the present invention is a granule containing, based on the total mass of the granules, 66% by mass of lactose monohydrate (a) as an excipient, 6-8% by mass of partially pregelatinized starch (d) as a binder, and 1-3% by mass of sodium starch glycolate (e) as a disintegrant (the sum of (d) and (e) is 9% by mass).

[0059] One embodiment of the granules in the present invention is a granule containing, based on the total mass of the granules, 67% by mass of lactose monohydrate (a) as an excipient, 5-7% by mass of partially pregelatinized starch (d) as a binder, and 1-3% by mass of sodium starch glycolate (e) as a disintegrant (the sum of (d) and (e) is 8% by mass).

[0060] One embodiment of the tablet in the present invention is a tablet containing lactose monohydrate as an excipient, partially pregelatinized starch as a binder, and sodium starch glycolate as a disintegrant.

[0061] One embodiment of the tablet in the present invention is a tablet containing, based on the total mass of the tablet, 75-80% by mass of lactose monohydrate (c) as an excipient, 2-6% by mass of partially pregelatinized starch (d) as a binder, and 2-3% by mass of sodium starch glycolate (g) as a disintegrant.

[0062] One embodiment of the tablet in the present invention is a tablet containing, based on the total mass of the tablet, 77-82% by mass of lactose monohydrate (c) as an excipient, 2-6% by mass of partially pregelatinized starch (d) as a binder, and 2-3% by mass of sodium starch glycolate (g) as a disintegrant.

[0063] One embodiment of the tablet in the present invention is a tablet containing, based on the total mass of the tablet, 80-85% by mass of lactose monohydrate (c) as an excipient, 2-6% by mass of partially pregelatinized starch (d) as a binder, and 2-3% by mass of sodium starch glycolate (g) as a disintegrant.

[0064] One embodiment of the tablet in the present invention is a tablet containing, based on the total mass of the tablet, 77% by mass of lactose monohydrate (c) as an excipient, 6% by mass of partially pregelatinized starch (d) as a binder, and 3% by mass of sodium starch glycolate (g) as a disintegrant.

[0065] One embodiment of the tablet in the present invention is a tablet containing, based on the total mass of the tablet, 78% by mass of lactose monohydrate (c) as an excipient, 5-6% by mass of partially pregelatinized starch (d) as a binder, and 2-3% by mass of sodium starch glycolate (g) as a disintegrant (the sum of (d) and (g) is 8% by mass).

[0066] One embodiment of the tablet in the present invention is a tablet containing, based on the total mass of the tablet, 79% by mass of lactose monohydrate (c) as an excipient, 4-5% by mass of partially pregelatinized starch (d) as a binder, and 2-3% by mass of sodium starch glycolate (g) as a disintegrant (the sum of (d) and (g) is 7% by mass).

[0067] One embodiment of the tablet in the present invention is a tablet containing, based on the total mass of the tablet, 80% by mass of lactose monohydrate (c) as an excipient, 3-4% by mass of partially pregelatinized starch (d) as a binder, and 2-3% by mass of sodium starch glycolate (g) as a disintegrant (the sum of (d) and (g) is 6% by mass).

[0068] One embodiment of the tablet in the present invention is a tablet containing, based on the total mass of the tablet, 81% by mass of lactose monohydrate (c) as an excipient, 3% by mass of partially pregelatinized starch (d) as a binder, and 2% by mass of sodium starch glycolate (g) as a disintegrant.

[0069] One embodiment of the tablet in the present invention is a tablet containing, based on the total mass of the tablet, 82% by mass of lactose monohydrate (c) as an excipient, 2% by mass of partially pregelatinized starch (d) as a binder, and 2% by mass of sodium starch glycolate (g) as a disintegrant.

[0070] One embodiment of the tablet in the present invention is a tablet in which the tablet, with 100% by mass, contains granules, with 50.8% by mass of granules, and further contains 40-48.7% by mass (preferably 45-48% by mass) of lactose monohydrate (b) added outside the granules as an excipient, and 0.5-3% by mass (preferably 0.5-2% by mass) of sodium starch glycolate (f) added outside the granules as a disintegrant.

[0071] One embodiment of the tablet in the present invention is a tablet in which the tablet is 100% by mass, and the tablet contains granules, with 50.8% by mass of granules, and further contains 45% by mass of lactose monohydrate (b) added outside the granules as an excipient, and 3% by mass of sodium starch glycolate (f) added outside the granules as a disintegrant.

[0072] One embodiment of the tablet in the present invention is a tablet in which the tablet is 100% by mass, and the tablet contains granules, with 50.8% by mass of granules, and further contains 46% by mass of lactose monohydrate (b) added outside the granules as an excipient, and 2% by mass of sodium starch glycolate (f) added outside the granules as a disintegrant.

[0073] One embodiment of the tablet in the present invention is a tablet in which the tablet is 100% by mass, and the tablet contains granules, with 50.8% by mass of granules, and further contains 47% by mass of lactose monohydrate (b) added outside the granules as an excipient, and 1% by mass of sodium starch glycolate (f) added outside the granules as a disintegrant.

[0074] One embodiment of the tablet in the present invention is a tablet in which the tablet is 100% by mass, and the tablet contains granules, with 50.8% by mass of granules, and further contains 48% by mass of lactose monohydrate (b) added outside the granules as an excipient, and 1% by mass of sodium starch glycolate (f) added outside the granules as a disintegrant.

[0075] One embodiment of the tablet in the present invention is a tablet in which the tablet is 100% by mass, and the tablet contains granules, with 50.8% by mass of granules, and further containing 48% by mass of lactose monohydrate (b) added outside the granules as an excipient, and 0.5% by mass of sodium starch glycolate (f) added outside the granules as a disintegrant.

[0076] Preferred examples of the tablets of the present invention include the following tablets C1 to C4. Tablet C1, wherein the magnesium stearate content is 0.5% by mass or more (especially 1.0-2.0% by mass) when the total weight of the tablet is 100% by mass. (C2) Tablet C2 further contains lactose monohydrate in addition to tablet C1. (C3) Tablet C3 further comprising partially pregelatinized starch in tablet C1 or C2. (C4) Tablet C4, further comprising sodium starch glycolate in tablet C1, C2, or C3.

[0077] In the present invention, opicapone or a pharmaceutically acceptable salt thereof contained in the tablet may be pulverized. The pulverization method is not particularly limited and includes air-jet milling (such as jet milling), rotary impact milling (such as pin milling and hammer milling), tumbler milling (such as ball milling), and wet milling (such as bead milling), of which jet milling is preferred.

[0078] When pulverizing opicapone or a pharmaceutically acceptable salt thereof, the pulverization step can be performed before the tablet manufacturing process (particularly before the granulation process) or during the tablet manufacturing process (particularly during the process of mixing opicapone or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive). For example, opicapone or a pharmaceutically acceptable salt thereof itself can be pulverized to obtain particles (pulverized material) having the aforementioned particle size, and then this pulverized material can be subjected to a granulation process together with a pharmaceutically acceptable additive. Alternatively, a mixture containing opicapone or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive can be pulverized to obtain a mixture containing opicapone or a pharmaceutically acceptable salt particles (pulverized material) having the aforementioned particle size, and then subjected to a granulation process.

[0079] In the present invention, the manufacturing process for tablets is not particularly limited and may include a granulation process, and may further include a sizing process (including wet or dry sizing) and a mixing process. The granulation process may be either wet granulation or dry granulation, but wet granulation is preferred. Examples of wet granulation methods include agitation granulation, spray granulation, fluidized bed granulation, rolling granulation, and extrusion granulation, but agitation granulation is preferred.

[0080] Specifically, particles of opicapone or a pharmaceutically acceptable salt thereof can be granulated together with the aforementioned pharmaceutically acceptable additives as needed to form granules. The components and their content in the granules can be arbitrarily selected from the embodiments described above.

[0081] Next, the obtained granules can be mixed with the aforementioned pharmaceutically acceptable additives, lubricants, etc., as needed, and compressed to produce tablets. The components and their content in the tablets can be arbitrarily selected from the embodiments described above. Tablets can be obtained by compressing them using a tablet press (e.g., a rotary tablet press, a single-stroke tablet press, etc.). The compression pressure is usually 1 to 35 kN / cm². 2 Preferably 2-30 kN / cm 2 , more preferably 3 to 25 kN / cm 2 More preferably 4-20 kN / cm 2 Particularly preferred is 5-20 kN / cm² 2 or 10-20 kN / cm 2 That is the case.

[0082] In this specification, "tableting defect" means the phenomenon of tablet powder or active pharmaceutical ingredient adhering to the punch die of a tablet press (sticking), or indentations or roughness on the tablet surface resulting from this phenomenon.

[0083] The tablets may be, for example, uncoated tablets or coated tablets (e.g., sugar-coated tablets, film-coated tablets). Of these, coated tablets are preferred, and film-coated tablets are more preferred.

[0084] As used herein, "reducing tableting failure" means, for example, preventing adhesion of tablet powder or active ingredient to the tableting pestle and mortar of a tableting machine, or making the adhesion in a mild (cloudy) state, or reducing the amount of active ingredient adhering to the contact surface between the upper and lower pestles and the tablets after tableting 450 tablets to m m 2 less than 0.60 μg / m m 2 the following state. Further, by reducing tableting failure, compared with tablets containing particles of opicapone or a pharmaceutically acceptable salt thereof that do not have the above particle size, the dents and roughness on the tablet surface are reduced (suppressed) (the tablet surface is smooth).

[0085] Regarding the dents and roughness on the tablet surface, in addition to visual confirmation, it can be evaluated from the determination result of the roughness state of the tablet surface using, for example, a surface roughness measuring machine (Japanese Patent Laid-Open No. 8-20537). Examples of the equipment used for evaluation include Surfcom 575A (Tokyo Seimitsu), Surfcom C5 (Tokyo Seimitsu), Surfcom 1400G (Tokyo Seimitsu), Surfcom TOUCH35 (Tokyo Seimitsu), Surfcom TOUCH40 (Tokyo Seimitsu), Surfcom TOUCH45 (Tokyo Seimitsu), Surfcom TOUCH50 (Tokyo Seimitsu), and Surfcom TOUCH550 (Tokyo Seimitsu).

[0086] Film-coated tablets are tablets in which the core tablets are coated with a film coating. The film coating usually contains a base.

[0087] The base is usually a water-soluble base, and specific examples include methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylcellulose, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, polyvinylpyrrolidone, dextrin, pullulan, aminoalkyl methacrylate copolymer, (meth)acrylic acid copolymer, carboxyvinyl polymer, sucrose, mannitol, and gelatin. The base can be used alone or in combination of two or more. As the base, at least one selected from the group consisting of polyvinyl alcohol, hydroxypropylcellulose, and hydroxypropylmethylcellulose is preferred.

[0088] The film coating may contain pharmaceutically acceptable additives in addition to the base, such as lubricants, plasticizers, and colorants. These can be used individually or in combination of two or more.

[0089] Examples of lubricants include talc.

[0090] Examples of plasticizers include polyethylene glycol, triacetin, medium-chain triglyceride, acetylglycerol fatty acid ester, triethyl citrate, and combinations of two or more of these.

[0091] Examples of coloring agents include iron oxides (ferric oxide, yellow iron oxide, black iron oxide, etc.), titanium dioxide, and combinations of two or more of these.

[0092] The mass ratio of the film coating is, for example, 1 to 15 parts by mass, preferably 2 to 10 parts by mass, per 100 parts by mass of the uncoated tablet.

[0093] The tablets are useful for the treatment or prevention of Parkinson's disease, and more preferably for improving diurnal variation or discontinuation of symptoms (wearing-off phenomenon) in Parkinson's disease when used in combination with levodopa-containing preparations.

[0094] The frequency of tablet administration is not particularly limited and may be, for example, once, twice, or three times a day, or once every two days, but preferably once a day. The timing of tablet administration may be in the morning, at noon, in the evening, before bedtime, or at least one hour before or after administration of other medications or meals, but preferably at least one hour before or after administration of other medications or meals.

[0095] In the present invention, the content of opicapone or a pharmaceutically acceptable salt in the tablet is, for example, 20 to 100 mg, preferably 25 mg or 50 mg, and more preferably 25 mg.

[0096] The tablets may be combined with other drugs, such as drugs to enhance the effect, drugs to reduce side effects, or drugs to prevent or treat other diseases (such as lifestyle-related diseases). Other drugs to be combined with the tablets of the present invention include, for example, levodopa, dopa decarboxylase inhibitors (carbidopa, benseraside), dopamine agonists (bromocriptine, pergolide, talipexole, etc.), monoamine oxidase B inhibitors (selegiline, rasagiline), amantadine, anticholinergics, droxidopa, zonisamide, or istradefylline, preferably levodopa or a dopa decarboxylase inhibitor. These drugs may be administered in the form of a combination preparation containing both components in a single formulation, or in the form of separate formulations. When administered in separate formulations, this includes simultaneous administration and administration with a time difference. Furthermore, in the case of delayed administration, the compound of the present invention may be administered first, followed by the other drug, or the other drug may be administered first, followed by the compound of the present invention. The respective administration methods may be the same or different.

[0097] As used herein, "contains," "contains," or "has" includes, but is not limited to, the meanings of "essentially consisting of" and "consisting of." [Examples]

[0098] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. In the examples, "%" means "mass%" unless otherwise specified.

[0099] Example 1: Grinding of opicapone active ingredient The opicapone active ingredient was ground under the following conditions to obtain pulverized materials A1 to A4. <Grinding conditions for pulverized materials A1 and A2> Grinding equipment: MC Jetmill MC200 (Dietrich Engineering Consultants sa) Supply rate: 200-400g per 30 seconds Pulverization pressure: 3.0~7.0bar (300~700kPa) <Grinding conditions for pulverized materials A3 and A4> Grinding equipment: MC Jetmill MC200 (Dietrich Engineering Consultants sa) Supply speed: 100-400g per 30 seconds Pulverization pressure: 3.0~4.0bar (300~400kPa)

[0100] Example 2: Evaluation of particle size The particle size of the unground opicapone active pharmaceutical ingredient and the ground materials A1 to A4 prepared in Example 1 were measured under the following conditions. <Measurement conditions> Measurement equipment: Dynamic particle image analysis system iSpect DIA-10 (Shimadzu Corporation) Evaluation items: Equivalent diameter of a circle, maximum length Dispersion medium: 10% polysorbate 20 aqueous solution Sample: Approximately 10 mg of the sample was placed in 1 mL of dispersion medium and suspended, then diluted 100-fold.

[0101] <Results / Discussion> The table below shows the particle size measurement results for the unground material and ground materials A1-A4. While no significant difference was observed in the equivalent circle diameter between the unground material and ground materials A1-A4, the maximum length of the unground material was significantly larger than that of the ground materials A1-A4. Furthermore, it was found that the difference in particle size between the unground and ground materials was more clearly apparent in the maximum lengths of D50 and D90 than in the equivalent circle diameter.

[0102] [Table 1]

[0103] Example 3: Preparation of the test formulation The formulations and preparation quantities for formulation examples B1 to B6 are shown in the table below. For each formulation example, the unground or ground active pharmaceutical ingredient shown in the table was used. The numbers in Table 2 indicate the amount of active pharmaceutical ingredient or excipient added (mass%) relative to the total weight of the uncoated tablet, while the numbers in Tables 2, 3, and 4 indicate the amount of raw material or excipient added (g). Formulation examples B5 to B6 use the same granules, but the amount of lactose monohydrate (b) added as an extragranule addition to the granules is increased by 0.5g in B6 compared to B5.

[0104] [Table 2]

[0105] [Table 3]

[0106] [Table 4]

[0107] The manufacturing methods for formulation examples B1 to B6 are as follows. Opicapone (unground material, ground materials A1-A4), lactose monohydrate, partially pregelatinized starch, and sodium starch glycolate were placed in a high-speed stirring granulator FM-VG-25 or FM-VG-01 (manufactured by Powrec Co., Ltd.), purified water was added, and granulation was carried out for 7 minutes to obtain granules.

[0108] Furthermore, lactose monohydrate, sodium starch glycolate, and magnesium stearate were mixed with the obtained granules to obtain tablet powder. Tablets were obtained by compressing the tablet powder using a rotary tablet press VEL2 (manufactured by Kikusui Seisakusho Co., Ltd.) at a pressure of approximately 10kN to obtain tablets weighing 195mg (oval shape, major diameter 11.5mm, minor diameter 5mm). The surface area of ​​each punch used in the tablet press was 50.883 m m 2 Therefore, the surface area of ​​the upper and lower pestles is 101.766 m m 2 That is the case.

[0109] Example 4: Evaluation of tablet compression failure <Evaluation Method> After preparing 450 tablets each of formulation examples B1 to B6, photographs were taken of the contact surface of the tablet powder on the punch and die of the tableting machine used in the tableting process. In addition, the condition of the active ingredient adhering to the mortar and pestle was visually inspected. If the active ingredient was determined to be firmly attached, it was marked as "×", if it was judged to be cloudy (a state where the active ingredient is only slightly attached), it was marked as "△", and if it was determined that the active ingredient was not attached, it was marked as "〇". Furthermore, the contact surfaces of the upper and lower punches with the tableting residue were wiped after tableting, and the amount of active pharmaceutical ingredient (API) was quantified to calculate the total amount of API adhering to the upper and lower punches (API adhering amount (μg)). From the calculated API adhering amount, the tableting punch 1 m m 2 Amount of active ingredient attached per unit (μg / m m 2 The following was calculated: Specifically, one swab (sterilized by K-Pine, manufactured by Kawamoto Sangyo Co., Ltd.) soaked in 2 mL of a 0.5 w / v% citric acid aqueous solution / pharmacopoeia anhydrous ethanol mixture (1:1) was used to wipe the tablet powder surface evenly more than 20 times, ensuring that the solvent-containing portion was in contact with the tablet powder surface. Next, another swab soaked in 1 mL of pharmacopoeia-grade anhydrous ethanol was used, and the swab was wiped thoroughly at least 20 times, ensuring that the solvent-containing portion was in contact with the area to be wiped. 17 mL of the sample solvent (water / acetonitrile mixture = 1 / 1) was precisely added to the container containing the two used swabs and shaken. Opicapone was extracted by pressing the swab against the inner wall of the container to extract the solvent. The extract was appropriately diluted, and the opicapone content in the extract was measured by liquid chromatography. The measurement conditions were as follows. The opicapone standard solution was prepared by weighing the opicapone standard substance and adjusting the sample solvent to achieve an opicapone concentration of 0.5 μg / mL. In addition, adjustments were made.

[0110] Test conditions Detector: UV absorbance spectrophotometer (measurement wavelength: 275 nm) Column: XTerra RP18 (Length 10cm, Inner diameter 4.6mm, Particle size 3.5μm, Waters) Column temperature: Constant temperature around 30°C Mobile phase: 10 mmol / L potassium dihydrogen phosphate solution (pH 2.2) / acetonitrile (11:9) Flow rate: 1.0 mL per minute Sample cooler temperature: 10℃ Analysis time: 12 minutes

[0111] Calculation method Amount of active pharmaceutical ingredient attached (μg) = M S ×P×(A T / A S ) × (1 / 2R) × k M S : Amount of opicapone standard substance weighed (mg) P: Purity correction factor for opicapone standard material A T : Peak area of ​​opikapon A S : Average peak area of ​​opikapon R: Recovery rate calculated by validation (%) k: Dilution ratio

[0112] <Results / Discussion> After compressing approximately 450 tablets of formulations manufactured using unpulverized and pulverized active pharmaceutical ingredients (Formulation Examples B1-B5) and formulations containing 1.0-0.5% lubricant (Formulation Examples B5 and B6), the adhesion of the drug to the tablet press punch was visually inspected and the amount of drug adhering to the tablet press punch's contact surface was quantitatively evaluated. Photographs of the tablet press punch's contact surface and the measurement results of the amount of drug adhering to the punch are shown in Figure 1, and the measurement results of the amount of drug adhering per unit surface area of ​​the punch are shown in Figure 2. The results of the study on the effects of using unpulverized and pulverized active pharmaceutical ingredients (formulation examples B1-B5) showed that in formulation example B1, which used unpulverized active pharmaceutical ingredients, there was strong adhesion of the drug to the contact surface of the tableting punch after tableting. m m 2 The amount of active pharmaceutical ingredient attached per unit is approximately 1.0 μg / m m 2 It was to that extent. On the other hand, in formulation examples B2 to B5 using crushed active pharmaceutical ingredients, no adhesion was observed to the tablet powder contact surface of the tablet press punch, and the tablet press punch 1 m m 2 The amount of active pharmaceutical ingredient attached per unit is approximately 0.1 μg / m m 2 It showed a low value, below the normal level. The results of the study on the effect of the amount of lubricant included showed that in the formulation with a lubricant content of 0.5% (Formulation Example B6), the adhesion of the tablet powder to the contact surface of the tablet press punch after tableting was only slight, such as clouding, and the tablet press punch 1 m m 2 The amount of active pharmaceutical ingredient attached per unit is approximately 0.5 μg / m m 2 It was to that extent. [Industrial applicability]

[0113] The present invention provides high-quality tablets containing opicapone or a pharmaceutically acceptable salt thereof, as it reduces tableting defects during manufacturing.

Claims

1. A tablet containing opicapone or a pharmaceutically acceptable salt thereof, wherein the opicapone or pharmaceutically acceptable salt thereof is a particle having the following particle size, and the tablet comprises granules containing particles of opicapone or a pharmaceutically acceptable salt thereof. (i) The D50 value of the maximum length is 25 μm or more and 45 μm or less, and / or (ii) The D90 value of the maximum length is 60 μm or more and 110 μm or less.

2. The tablet according to claim 1, further containing a lubricant within the tablet.

3. The tablet according to claim 2, wherein the lubricant contains magnesium stearate.

4. The tablet according to claim 3, wherein the magnesium stearate content in the tablet is higher than 0.3% by mass, based on the total mass of the tablet.

5. The tablet according to any one of claims 1 to 4, wherein the particles of opikapone or a pharmaceutically acceptable salt thereof are a pulverized product of opikapone or a pharmaceutically acceptable salt thereof.

6. The tablet according to any one of claims 1 to 5, wherein the granules contain particles of opicapone or a pharmaceutically acceptable salt thereof, at least one excipient, at least one binder, and at least one disintegrant.

7. The tablet according to any one of claims 1 to 6, wherein the tablet is obtained by compressing a mixture of granules, at least one excipient, at least one binder, and at least one lubricant.

8. The tablet according to any one of claims 1 to 7, wherein the opicapone or a pharmaceutically acceptable salt thereof is a particle having particle sizes (i) and (ii).

9. A tablet according to any one of claims 1 to 8, wherein opicapone or a pharmaceutically acceptable salt thereof is opicapone.

10. The tablet according to claim 1, wherein the granules contain particles of opicapone or a pharmaceutically acceptable salt thereof, at least one excipient, at least one binder, and at least one disintegrant, and the tablet is obtained by compressing a mixture of the granules, at least one excipient, at least one binder, and at least one lubricant, the lubricant containing magnesium stearate, and the content of said magnesium stearate is higher than 0.3% by mass based on the total mass of the tablet.

11. A tablet containing particles of opicapone or a pharmaceutically acceptable salt thereof: (a) The particles have a particle diameter such that (i) the D50 value of the maximum length is 25 μm or more and 45 μm or less, and / or (ii) the D90 value of the maximum length is 60 μm or more and 110 μm or less. (b) A granule comprising the particles of (a), at least one excipient, at least one binder, and at least one disintegrant, (c) The tablet is obtained by compressing a mixture of the granules of (b), at least one excipient, at least one binder, and at least one lubricant, and (d) The lubricant contains magnesium stearate, and the content of magnesium stearate is higher than 0.3% by mass based on the total mass of the tablet. tablet.

12. A tablet according to any one of claims 1 to 11, wherein tableting disorders are reduced.

13. The tablet according to claim 12, wherein the tableting defect is an indentation or roughness on the tablet surface.

14. The tablet according to any one of claims 1 to 13, wherein the amount of opicapone or a pharmaceutically acceptable salt thereof adhering per 1 mm² of the surface of the tablet press punch that comes into contact with the tablets after compressing 450 tablets is 1.0 μg / mm² or less.

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