Istradefylline-containing orally disintegrating tablets

Abstract

The present invention provides an orally disintegrating tablet containing istradefylline that possesses both sufficient tablet hardness and a rapid disintegration time. [Solution] An orally disintegrating tablet characterized by containing istradefylline and hydroxypropylcellulose.

Description

[Technical Field]

[0001] The present invention relates to an orally disintegrating tablet containing istradefylline. [Background technology]

[0002] Istradefylline exhibits adenosine A2 receptor antagonism and is useful in the treatment of Parkinson's disease and other conditions.

[0003] It is known that it is not easy to formulate solid dosage forms of diarylvinylene compounds such as istradefylline that have excellent formulation properties (e.g., hardness, disintegration, dissolution, stability, etc.). It has been reported that solid dosage forms with a general composition, such as those described in Japanese Patent Application Publication No. 6-211856 (Patent Document 1), have problems such as (a) insufficient hardness, (b) long disintegration time, (c) a tendency for delayed dissolution, and (d) poor stability (Patent Documents 2 and 3).

[0004] On the other hand, Parkinson's disease patients are predominantly elderly and often experience dysphagia (difficulty swallowing). To prevent aspiration of tablets due to dysphagia, methods such as mixing tablets with medication jelly or crushing tablets and mixing them with food are employed. Orally disintegrating tablets (OD tablets) are also useful for elderly patients with dysphagia.

[0005] However, orally disintegrating tablets have traditionally faced the challenge of balancing the conflicting properties of disintegration and hardness. To create an orally disintegrating tablet that is easy to take, it is necessary for it to disintegrate quickly in the mouth, or to have good disintegration properties. However, from the standpoint of maintaining quality, a certain degree of tablet hardness is also necessary. Generally, lowering the hardness of a tablet improves its disintegration properties, but this can lead to the tablet breaking or chipping due to mechanical impact from the automatic dispensing machine during unit-dose packaging. Considering these circumstances, there is a need for the development of istradefylline formulations that can improve medication adherence among Parkinson's disease patients and simplify prescribing for healthcare professionals. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] Japanese Patent Application Publication No. 6-211856 [Patent Document 2] Patent No. 4673745 [Patent Document 3] Patent No. 4413866 [Overview of the Initiative]

[0007] One of the objectives of the present invention is to provide an orally disintegrating tablet containing istradefylline having sufficient tablet hardness and a rapid disintegration time. Another objective of the present invention is to provide a method for producing the above-mentioned orally disintegrating tablet containing istradefylline. The inventors of the present invention investigated additives in order to provide orally disintegrating tablets containing istradefylline, and as a result found that by selecting hydroxypropylcellulose as a binder, it is possible to produce orally disintegrating tablets that have sufficient tablet hardness and a rapid disintegration time, thus completing the present invention.

[0008] In one aspect, the present invention provides an orally disintegrating tablet comprising istradefylline and hydroxypropylcellulose.

[0009] In one aspect, the present invention provides an orally disintegrating tablet containing istradefylline having an average particle size of more than 20 μm.

[0010] In one aspect, the present invention provides a method for producing orally disintegrating tablets containing istradefylline. [Modes for carrying out the invention]

[0011] The orally disintegrating tablet provided by the present invention contains istradefylline. Istradefylline has the following structure. [ka] The istradefylline content in the orally disintegrating tablets provided by the present invention may be 1 to 30% by weight, preferably 5 to 20% by weight, and more preferably 10 to 20% by weight, relative to the pharmaceutical composition. Each orally disintegrating tablet provided by the present invention may contain 20 mg of istradefylline. The particle size of istradefylline used in the orally disintegrating tablets provided by the present invention can be appropriately set by those skilled in the art. For example, istradefylline with an average particle size of 0.1 μm or more and less than 200 μm, 0.1 μm or more and less than 80 μm, preferably 0.5 μm or more and less than 35 μm, or 0.5 μm or more and less than 20 μm may be used in the orally disintegrating tablets provided by the present invention. More preferably, the average particle size of istradefylline that can be used in the orally disintegrating tablets provided by the present invention may be greater than 20 μm, and may be greater than 20 μm and less than or equal to 200 μm, greater than 20 μm and less than or equal to 100 μm, greater than 20 μm and less than or equal to 80 μm, greater than 20 μm and less than or equal to 60 μm, greater than 20 μm and less than or equal to 50 μm, greater than 20 μm and less than or equal to 40 μm, 25 μm to less than or equal to 200 μm, 25 μm to less than or equal to 100 μm, 25 μm to less than or equal to 80 μm, 25 μm to less than or equal to 40 μm, 50 μm to less than or equal to 200 μm, 50 μm to less than or equal to 100 μm, or 50 μm to less than or equal to 80 μm. The average particle size may be measured using, for example, a laser diffraction / scattering particle size distribution analyzer (e.g., SALD-2200; manufactured by Shimadzu Corporation, MASTERSIZER 2000 Ver.2.00J; manufactured by MALVERN Corporation, etc.) or an image analysis device (e.g., LUZEX registered trademark AP; manufactured by Nireco Corporation, etc.), and calculated as the average value obtained from the particle size distribution. The particle diameter and average particle size values ​​described in this application are values ​​measured using a laser diffraction / scattering particle size distribution analyzer.

[0012] The orally disintegrating tablets provided by this invention contain hydroxypropyl cellulose. While hydroxypropyl cellulose is known to function as a binder in the pharmaceutical technology field, it can be used without particular limitations as long as it is of a quality suitable for use as a pharmaceutical excipient. The hydroxypropylcellulose contained in the orally disintegrating tablets of the present invention preferably has a viscosity of less than 20 mPa·s in a 2% aqueous solution (20°C). Examples of commercially available hydroxypropylcellulose include Grade SSL (viscosity 2-2.9 mPa·s, molecular weight 40,000), Grade SL (viscosity 3-5.9 mPa·s, molecular weight 100,000), Grade L (viscosity 6-10 mPa·s, molecular weight 140,000), and Grade M (viscosity 150-400 mPa·s, molecular weight 620,000). The amount of hydroxypropylcellulose contained in the orally disintegrating tablets of the present invention is not particularly limited, but is preferably 5 to 50% by mass, more preferably 8 to 30% by mass, and even more preferably 10 to 20% by mass, relative to the mass of istradefylline. The amount of hydroxypropylcellulose contained in the orally disintegrating tablets of the present invention is preferably 0.1 to 8% by mass, more preferably 0.5 to 6% by mass, and even more preferably 1.0 to 4% by mass, based on the total mass of the tablets.

[0013] The orally disintegrating tablets provided by the present invention have a preferred disintegration time of 120 seconds or less (for example, 10 to 120 seconds), more preferably 60 seconds or less (for example, 10 to 60 seconds), and even more preferably 30 seconds or less (for example, 10 to 30 seconds). The method for measuring the disintegration time is not particularly limited, but for example, it can be measured using a disintegration tester in accordance with the disintegration test method specified in the 17th edition of the Japanese Pharmacopoeia. The orally disintegrating tablets provided by the present invention may have a hardness of 20N or more, for example, 20N to 150N, 20N to 100N, 20N to 50N, 25N to 150N, 25N to 100N, 25N to 50N, 50N to 150N, 50N to 100N, 60N or more (e.g., 60-100N), 65N or more (e.g., 65-100N), and 70N or more (e.g., 70-100N). The orally disintegrating tablets provided by the present invention can also be evaluated by absolute hardness. Absolute hardness is the value obtained by dividing the tablet hardness by the fracture cross-sectional area, and the fracture cross-sectional area can be calculated from the tablet shape and tablet thickness. The absolute hardness is usually 1.5 N / mm , or more, preferably 2.0 N / mm 2 or more, 2.5 N / mm 2 or more, more preferably 3.0 N / mm 2 or more of the strength can be mentioned. The orally disintegrating tablets provided by the present invention can be used for the treatment of Parkinson's disease.

[0014] The orally disintegrating tablets provided by the present invention may contain additives commonly used in the pharmaceutical technology field. Examples of such additives include excipients, binders, disintegrants, fluidizing agents, sweeteners, lubricants, pH adjusters, surfactants, flavors, and colorants. These additives can be commonly used for any of the granulated products, granules, and post-added powders.

[0015] Examples of excipients that can be used in the orally disintegrating tablets provided by the present invention include saccharides such as lactose (e.g., lactose hydrate, anhydrous lactose), glucose, sucrose, fructose, maltose, sugar alcohols such as erythritol, sorbitol, maltitol, xylitol, D-mannitol, starches (e.g., corn starch, potato starch, rice starch, wheat starch, partially pregelatinized starch), crystalline cellulose, magnesium aluminometasilicate, anhydrous calcium phosphate, anhydrous calcium hydrogen phosphate, precipitated calcium carbonate, calcium silicate, calcium lactate, and ethyl cellulose. Examples of preferred excipients used in the orally disintegrating tablets provided by the present invention include D-mannitol, anhydrous calcium hydrogen phosphate, and combinations thereof. The content of the excipient in the orally disintegrating tablets provided by the present invention may be 20 to 95% by weight, preferably 30 to 90% by weight, and more preferably 30 to 85% by weight with respect to the pharmaceutical composition. In one embodiment, the excipient used in the orally disintegrating tablets provided by the present invention is D-mannitol, and those conforming to the pharmacopoeias of Japan, Europe, and the United States can be normally used. The crystal form, particle size, and specific surface area of D-mannitol are not particularly limited. The crystal form can be any of α-type, β-type, δ-type, and amorphous. The particle size is preferably 10 μm or more and 250 μm or less, more preferably 20 μm or more and 150 μm or less, and the specific surface area is 0.1 m 2 / g or more and 5 m 2 / g or less, more preferably 0.1 m 2 / g or more and 4 m 2 / g or less, and even more preferably 2 m 2 / g or more and 3.5 m 2 / g or less may also be acceptable. Moreover, the melting point of D-mannitol that can be used in the orally disintegrating tablets provided by the present invention is between 166 and 169 °C, and the loss on drying (105 °C, 4 hours) is 0.5% or less. Further, the conductivity at 25 °C when 20 g is dissolved in 100 ml can be 20 μS·cm -1 It can be. The crystal form, particle size, and specific surface area can be measured by well-known methods. For example, they can be measured by X-ray diffraction method, laser diffraction particle size measurement method, and BET specific surface area measurement method (multi-point method) respectively. Two or more types of D-mannitol with different properties such as particle size may be used in the orally disintegrating tablets provided by the present invention. Granulated or spray-dried D-mannitol may also be used in the orally disintegrating tablets provided by the present invention. D-mannitol is preferably contained in the range of 1 to 98% by weight with respect to the pharmaceutical composition, more preferably contained in the range of 10 to 70% by weight, and even more preferably may be contained in the range of 25 to 60% by weight. D-Mannitol may be mixed with istradefylline and contained in the orally disintegrating tablets provided by the present invention. In one embodiment, the mixture containing istradefylline and D-mannitol may be a granulated product. The mixture containing istradefylline and D-mannitol (e.g., granulated product) may be contained in the core tablet portion in the tablet. The weight ratio of istradefylline to D-mannitol in the mixture can be appropriately set by those skilled in the art. For example, the weight of D-mannitol can be 1 to 10, preferably 1 to 5 times the weight of istradefylline. The preparation of the granulated product can be carried out by methods generally used in this field, for example, it may be carried out by a wet granulation method, a dry granulation method, or the like.

[0016] In the orally disintegrating tablets of the present invention, binders commonly used in the pharmaceutical formulation field other than hydroxypropyl cellulose can also be added as long as they do not affect the effects of the present invention. Examples of binders that can be used in the orally disintegrating tablets provided by the present invention include hydroxypropyl methylcellulose, polyvinylpyrrolidone, dextrin, methylcellulose, polyvinyl alcohol, sodium alginate, aminoalkyl methacrylate copolymer, polyethylene glycol, pregelatinized starch, agar, and gelatin. The total content of the binder in the orally disintegrating tablets provided by the present invention may be 0.1 to 30% by weight, preferably 0.3 to 10% by weight, and more preferably 1 to 5% by weight based on the pharmaceutical composition.

[0017] Examples of disintegrants that can be used in the orally disintegrating tablets provided by the present invention include sodium alginate, sodium starch glycolate, croscarmellose sodium, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, and carmellose. Examples of preferred disintegrants used in the orally disintegrating tablets provided by the present invention include crospovidone and carmellose. The content of the disintegrant in the orally disintegrating tablets provided by the present invention may be 0.3 to 20% by weight, preferably 0.5 to 15% by weight, 1 to 10% by weight, and more preferably 3 to 5% by weight, relative to the pharmaceutical composition.

[0018] Examples of fluidizers that can be used in the orally disintegrating tablets provided by the present invention include light anhydrous silicic acid, magnesium aluminometasilicate, hydrated silicon dioxide, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, magnesium stearate, and talc. A preferred example of a fluidizer used in the orally disintegrating tablets provided by the present invention is magnesium aluminometasilicate. The content of the fluidizing agent in the orally disintegrating tablets provided by the present invention may be 0.03 to 3% by weight, preferably 0.1 to 3% by weight, and more preferably 0.3 to 3% by weight, relative to the pharmaceutical composition.

[0019] Examples of sweeteners that can be used in the orally disintegrating tablets provided by the present invention include sodium saccharin, dipotassium glycyrrhizinate, aspartame®, stevia, thaumatin, and sucralose. Examples of preferred sweeteners used in the orally disintegrating tablets provided by the present invention include aspartame®, stevia, and sucralose. The sweetener content in the orally disintegrating tablets provided by the present invention may be 0.03 to 3% by weight, preferably 0.1 to 3% by weight, and more preferably 0.3 to 3% by weight, relative to the pharmaceutical composition.

[0020] Examples of lubricants that can be used in the orally disintegrating tablets provided by the present invention include magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, hydrogenated oil, sucrose fatty acid ester, and sodium stearyl fumarate. A preferred example of a lubricant used in the orally disintegrating tablets provided by the present invention is magnesium stearate. The lubricant content in the orally disintegrating tablets provided by the present invention may be 5% by weight or less relative to the pharmaceutical composition, for example, 1% by weight or less, 0.01 to 5% by weight, 0.1 to 5% by weight, 0.1 to 3% by weight, 0.1 to 2% by weight, 0.3 to 5% by weight, 0.3 to 3% by weight, 0.3 to 2% by weight, 0.3 to 1% by weight, 0.5 to 5% by weight, 0.5 to 3% by weight, 0.5 to 2% by weight, or 0.5 to 1% by weight.

[0021] Examples of pH adjusters that can be used in the orally disintegrating tablets provided by the present invention include citrates, phosphates, carbonates, tartrates, fumarates, acetates, and amino acid salts. The pH adjusting agent content in the orally disintegrating tablets provided by the present invention may be 0.1 to 30% by weight, preferably 0.3 to 10% by weight, and more preferably 1 to 5% by weight, relative to the pharmaceutical composition.

[0022] Examples of surfactants that can be used in the orally disintegrating tablets provided by the present invention include sodium lauryl sulfate, polysorbate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, and poloxamer. The surfactant content in the orally disintegrating tablets provided by the present invention may be 0.01 to 3% by weight, preferably 0.03 to 1% by weight, and more preferably 0.03 to 0.5% by weight, relative to the pharmaceutical composition.

[0023] Examples of flavorings that can be used in the orally disintegrating tablets provided by the present invention include citrus flavorings such as lemon, orange, and grapefruit, as well as peppermint, spearmint, and menthol.

[0024] Examples of colorants that can be used in the orally disintegrating tablets provided by the present invention include iron oxide, yellow iron oxide, yellow ferric oxide, brown iron oxide, ferric oxide, Food Yellow No. 4, Food Yellow No. 5, Food Yellow No. 4 aluminum lake, Food Yellow No. 5 aluminum lake, Food Red No. 2, Food Red No. 3, Food Red No. 102, red iron oxide, black iron oxide, carmine-P, riboflavin, carbon black, medicinal charcoal, and the like. The coloring agent content in the orally disintegrating tablets provided by the present invention is preferably in the range of 0.001 to 10.0% by weight relative to the pharmaceutical composition, more preferably in the range of 0.005 to 5.0% by weight, and even more preferably in the range of 0.01 to 5.0% by weight. In one embodiment, a composition containing a coloring agent can be used as an inhibitor of istradefylline photodegradation.

[0025] In the orally disintegrating tablets provided by the present invention, istradefylline, istradefylline-containing granules, and uncoated tablets may each be coated. The content of the coating layer can be appropriately determined by those skilled in the art, but for example, it may be 0.01 to 30% by weight or 0.01 to 10% by weight relative to the pharmaceutical composition. In addition to the coating base, the coating layer may appropriately contain plasticizers, colorants, glossing agents, etc. Examples of coating bases include hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, cellulose phthalate acetate, methacrylic acid copolymer, polyvinylpyrrolidone, and polyvinyl alcohol-polyethylene glycol graft copolymer, with hydroxypropylmethylcellulose and polyvinyl alcohol-polyethylene glycol graft copolymer being particularly preferred. The content of the coating base in the orally disintegrating tablets provided by the present invention may be 0.01 to 30% by weight, 0.01 to 10% by weight, preferably 0.3 to 5% by weight, or 0.3 to 3% by weight, relative to the pharmaceutical composition. Examples of plasticizers that can be used for coating include triethyl citrate, medium-chain triglyceride, triacetin, glycerin, propylene glycol, and polyethylene glycol (e.g., macrogol 6000), with polyethylene glycol being particularly preferred. The content of the plasticizer used for coating may be 0.01 to 3% by weight, preferably 0.03 to 1% by weight, relative to the pharmaceutical composition. As a coloring agent that can be used for coating, any coloring agent that can be used for the orally disintegrating tablets provided by the present invention as described above can be used as appropriate. Examples of preferred coloring agents that can be used for coating include iron oxide, ferric oxide, and yellow ferric oxide. The content of the coloring agent used for coating may be 0.001 to 1% by weight, preferably 0.01 to 0.1% by weight, relative to the pharmaceutical composition. Examples of glossing agents that can be used in coatings include carnauba wax. The content of the glossing agent used in the coating may be 0.0001 to 0.1% by weight, preferably 0.001 to 0.01% by weight, relative to the pharmaceutical composition.

[0026] The orally disintegrating tablets provided by the present invention can be manufactured by methods known in the pharmaceutical field. For example, this may include a mixing step of mixing istradefylline and hydroxypropylcellulose, and optionally other additives, a granulation step, a tableting step, and / or a coating step. The mixing process can be carried out using methods known in the pharmaceutical field, such as using a V-type mixer, a W-type mixer, a container mixer, a tumbler mixer, or a stirring mixer. The granulation process can be carried out by granulation methods known in the pharmaceutical field. For example, a granulation solution in which a binder is dispersed or dissolved in a solvent (such as purified water) is sprayed and granulated. Examples of granulation methods include dry granulation, wet granulation, and fluidized bed granulation. After preparing granules containing istradefylline, additives (for example, excipients such as D-mannitol, disintegrants such as crospovidone, fluidizing agents such as magnesium aluminometasilicate, and / or lubricants such as magnesium stearate) may be added to the granules and mixed before tableting. In one embodiment, the mixture obtained in the mixing step or the granules obtained in the granulation step can be appropriately ground and / or sieved to obtain a mixture or granules having a desired particle size. Grinding can be performed using grinders known in the pharmaceutical field, such as ball mills, jet mills, and hammer mills. Sieving can be performed using sieves ranging from 16-mesh (mesh opening 1000 μm) to 32-mesh (mesh opening 500 μm), etc. The tableting process can be carried out using tableting methods known in the pharmaceutical field. Examples of tableting methods include direct tableting, dry tableting, wet tableting, and external lubrication tableting. For example, the mixture or granules obtained in the above process can be tableted using tablet presses known in the pharmaceutical field, such as single-pull tablet presses or rotary tablet presses. When using single-pull tablet presses, rotary tablet presses, etc., a tableting pressure of 1kN to 30kN, preferably 1 to 10kN, and more preferably 1 to 5kN can be used. In one embodiment, when a mixture containing istradefylline and hydroxypropylcellulose (e.g., granules) is compressed to produce tablets (e.g., tablets with a diameter of approximately 7 mm), the upper limit of the compression pressure is preferably 30 kN, and the lower limit of the compression pressure is preferably a compression pressure that can achieve a tablet hardness of 20 N. For example, a mixture containing istradefylline and hydroxypropylcellulose (e.g., granules) may be compressed at 1 kN to 30 kN, 1 kN to 25 kN, 1 kN to 20 kN, 1 kN to 10 kN, 1 kN to 5 kN, 5 kN to 30 kN, 5 kN to 25 kN, 5 kN to 20 kN, 10 kN to 30 kN, 10 kN to 25 kN, or 10 kN to 20 kN. The coating process can be carried out by methods known in the pharmaceutical field. For example, it can be carried out by spray coating the outside of the istradefylline active pharmaceutical ingredient, granules, or uncoated tablets with a coating solution containing a coating base and appropriate amounts of plasticizers, colorants, and glossing agents.

[0027] The orally disintegrating tablets provided by the present invention can have improved istradefylline dissolution from the orally disintegrating tablets by preparing granules containing istradefylline using a wet granulation method. Therefore, the method for producing the orally disintegrating tablets provided by the present invention may include a step of preparing granules containing istradefylline using a wet granulation method.

[0028] When the orally disintegrating tablets provided by the present invention contain a mixture of istradefylline and hydroxypropylcellulose in the tablet core, they have sufficient hardness while possessing appropriate disintegration properties. This offers the advantage of preventing breakage or chipping during the manufacturing process, transportation, and dispensing, such as unit-dose packaging in automatic dispensing machines at pharmacies.

[0029] In one embodiment, the istradefylline contained in the orally disintegrating tablet provided by the present invention has an average particle size greater than 20 μm (for example, greater than 20 μm and less than or equal to 70 μm, greater than 20 μm and less than 50 μm, or 25 μm and greater than or equal to 40 μm). In one embodiment, the orally disintegrating tablet provided by the present invention has a hardness of 20N or more, more preferably 30N or more (for example, 50N or more, 65N or more, 70N or more, 20N to 60N, 20N to 100N, 30N to 100N, 70N to 100N, 70N to 150N) and disintegrates in the oral cavity within 60 seconds (for example, within 10 to 60 seconds). In one embodiment, the orally disintegrating tablets provided by the present invention have no bitterness or astringency and exhibit a pleasant taste. In one embodiment, the orally disintegrating tablet provided by the present invention comprises D-mannitol, lactose monohydrate, or anhydrous calcium hydrogen phosphate. In one embodiment, the orally disintegrating tablet provided by the present invention contains magnesium stearate, calcium stearate, or sodium stearyl fumarate. In one embodiment, the orally disintegrating tablet provided by the present invention comprises D-mannitol and a lubricant, wherein the lubricant is magnesium stearate, calcium stearate, or sodium stearyl fumarate. In one embodiment, the orally disintegrating tablet provided by the present invention comprises D-mannitol and a lubricant, wherein the lubricant is magnesium stearate, calcium stearate, or sodium stearyl fumarate, and the content of the lubricant is 5% by weight or less (for example, 2% by weight or less, 0.1 to 1% by weight).

[0030] Examples of other embodiments provided by the present invention include (1) to (11) below. (1) Orally disintegrating tablets containing istradefylline and hydroxypropylcellulose; (2) Orally disintegrating tablets as described in (1), further comprising D-mannitol as an excipient; (3) Orally disintegrating tablets according to (1) or (2), further comprising crospovidone and / or carmellose as disintegrants; (4) An orally disintegrating tablet according to any of (1) to (3), wherein the istradefylline has an average particle size of more than 20 μm and less than or equal to 200 μm (for example, more than 20 μm and less than or equal to 70 μm, or 50 μm and less than or equal to 100 μm); (5) Orally disintegrating tablets as described in any of (1) to (4), which disintegrate within 60 seconds according to the disintegration test of the 17th edition of the Japanese Pharmacopoeia; (6) Orally disintegrating tablets as described in any of (1) to (5), having a hardness of 20N or higher (for example, 60N or higher); (7) An orally disintegrating tablet according to any of (1) to (6), having a coating layer; (8) A method for producing an orally disintegrating tablet according to any one of (1) to (7), comprising the step of preparing a mixture containing istradefylline and hydroxypropylcellulose. (9) A method for producing an orally disintegrating tablet according to any of (8), wherein the step of preparing a mixture includes a step of preparing granules; (10) A method for producing an orally disintegrating tablet according to (9), wherein the step of preparing the granules is carried out by a wet granulation method; (11) A method for producing an orally disintegrating tablet according to any one of (8) to (10), further comprising the step of compressing a mixture containing istradefylline and hydroxypropylcellulose into tablets, wherein the compression pressure is 30 kN or less (preferably 10 kN or less).

[0031] The present invention will be further described below with reference to examples, but the present invention is not limited thereto. [Examples]

[0032] The tablets were prepared as follows: Example 1 Using a mortar and pestle, istradefylline (2 g; average particle size 41.0 μm (measured using Shimadzu Corporation SALD-2200)), D-manthol (4.35 g, mannitol C, manufactured by Mitsubishi Corporation Life Sciences, Ltd.), crospovidone (0.75 g, coridone CL-F, manufactured by BASF Japan Ltd.), talc (0.1 g, crown talc, manufactured by Matsumura Sangyo Co., Ltd.), and hydroxypropylcellulose (0.3 g, HPC-L, manufactured by Nippon Soda Co., Ltd.) were mixed, and 1.5 g of purified water was added to the mixture to granulate it. After granulation, it was dried in a dryer at 50°C. After drying, it was passed through a No. 30 sieve to obtain uniform granules. The obtained whole granules were placed in a plastic bag, and for every 100 parts by weight of whole granules, 46.7 parts by weight of D-mannitol (Granitol F, Freund Industrial Co., Ltd.) and 4.0 parts by weight of crospovitone (Coridon CL-F, manufactured by BASF Japan Ltd.) were added and mixed. To this, 2.6 parts by weight of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed to obtain granules for tableting. Using a simple tablet forming machine (HANDTAB-200, Ichihashi Seiki Co., Ltd.), the obtained granules for tableting were made into tablets at 4kN to obtain uncoated tablets (tablet mass: 115mg, tablet shape: round tablet (φ7.0mm)). Comparative Example 1 In Example 1, a tablet was obtained in the same manner as in Example 1, except that hydroxypropyl cellulose was replaced with PVA-PEG graft copolymer (Coricoat IR, manufactured by BASF Japan Ltd). Comparative Example 2 In Example 1, a tablet was obtained in the same manner as in Example 1, except that hydroxypropyl cellulose was replaced with hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.). Comparative Example 3 In Example 1, a tablet was obtained in the same manner as in Example 1, except that hydroxypropyl cellulose was replaced with methyl cellulose (Metholose SM-4, manufactured by Shin-Etsu Chemical Co., Ltd.). Comparative Example 4 In Example 1, a tablet was obtained in the same manner as in Example 1, except that hydroxypropyl cellulose was replaced with povidone (Plasdone K29 / 32, manufactured by ISP Japan Co., Ltd.).

[0033] The prepared tablets were tested as follows: Test Example 1: Tablet Physical Property Test (Hardness and Tablet Thickness) (method) Hardness was measured using a load cell type tablet hardness tester PC-30 (manufactured by Okada Seikou Co., Ltd.). Hardness was measured on three tablets, and the average value was taken as the hardness (N). The lock thickness was measured using a thickness gauge IDC-1012B (manufactured by Mitutoyo Corporation). The lock thickness was measured on three locks, and the average value was taken as the lock thickness (mm).

[0034] Test Example 2: Collapse Test (method) Based on the disintegration test method of the 17th revised Japanese Pharmacopoeia, a disintegration tester NT-6H (manufactured by Toyama Sangyo Co., Ltd.) was used, and water was used as the test solution to measure the disintegration time of each tablet. Disintegration time was measured for three tablets, and the average value was defined as disintegration time (seconds).

[0035] (result) Table 1 shows the tablet characteristics of the uncoated tablets obtained in Example 1 and Comparative Examples 1-4.

[0036] [Table 1]

[0037] The uncoated tablets obtained in Example 1 were confirmed to have sufficient hardness and a short disintegration time of less than 30 seconds, making them orally disintegrating tablets. On the other hand, the uncoated tablets obtained in Comparative Examples 1-4 had high hardness and disintegration times exceeding 30 seconds, indicating that they had poor disintegration properties as orally disintegrating tablets.

[0038] To confirm the effect of tablet hardness on disintegration, a plain tablet was obtained in the same manner as in Example 1, except that the granules for tableting were manufactured at 5 kN instead of 4 kN. The obtained plain tablet had a hardness of 52 N and a disintegration time of 27 seconds. When the manufacturing pressure was changed to 6 kN, the obtained plain tablet had a hardness of 60 N and a disintegration time of 29 seconds.

[0039] Based on the above, it was demonstrated that hydroxypropylcellulose is the optimal binder compared to other binders when providing orally disintegrating tablets containing istradefylline.

[0040] Example 2 100 g of istradefylline, 225 g of D-mannitol, and 37.5 g of carmellose were placed in a fluid bed granulator (SFC-MINI), and granulation was performed by spraying with a granulation solution (175 g of purified water with 12.5 g of hydroxypropyl cellulose added and stirred until dissolved). After granulation, the mixture was dried and sized using a granulator (QC-197S). The resulting granules were placed in a polybag, and 44.0000% of the total weight of D-mannitol, 6.6667% of carmellose, and 6.6667% of crospovidone were added and mixed. Next, 2.6667% of stearyl sodium fumarate was added and mixed. The resulting mixture was compressed into tablets with a weight of 120 mg and a thickness of 3.2 mm using a rotary tablet press (VELA-5). 200g of the obtained tablets were placed in a coating machine (HCT-MINI) and coated with a coating solution (50g of purified water, 12g of polyvinyl alcohol polyethylene glycol graft copolymer, and 0.5g of Yellow No. 4 were added and stirred until dispersed. Separately, 40g of purified water was set aside, 3g of titanium dioxide was added and ultrasonically dispersed. After mixing and stirring these solutions, they were sieved) to coat the tablets to a mass of 123mg. Furthermore, carnauba wax was added at a concentration of 0.0057% of the tablet mass to give it a glossy finish. [Industrial applicability]

[0041] The present invention provides an orally disintegrating tablet useful for the treatment of Parkinson's disease.

Claims

1. An orally disintegrating tablet comprising granules containing istradefylline and a post-addition powder, wherein the orally disintegrating tablet contains istradefylline and hydroxypropylcellulose (except in the case of low-substituted hydroxypropylcellulose).

2. The orally disintegrating tablet according to claim 1, wherein the hydroxypropyl cellulose is contained in the granules containing istradefylline.

3. The orally disintegrating tablet according to claim 1 or 2, wherein the content of hydroxypropyl cellulose is 0.1 to 8% by mass relative to the total mass of the orally disintegrating tablet.

4. An orally disintegrating tablet according to any one of claims 1 to 3, further comprising D-mannitol as an excipient.

5. An orally disintegrating tablet according to any one of claims 1 to 4, further comprising crospovidone and / or carmellose as a disintegrant.

6. An orally disintegrating tablet according to any one of claims 1 to 5, wherein the istradefylline is istradefylline having an average particle size greater than 20 μm and less than or equal to 200 μm.

7. A method for producing an orally disintegrating tablet according to any one of claims 1 to 6, comprising the step of preparing granules containing istradefylline and hydroxypropylcellulose (except in the case of low-substituted hydroxypropylcellulose).

8. A method for improving the disintegration properties of an orally disintegrating tablet containing istradefylline and a binder, The orally disintegrating tablet is characterized by containing 0.1 to 8% by mass of hydroxypropylcellulose relative to its total mass. A method wherein the viscosity of a 2% aqueous solution (20°C) of the hydroxypropyl cellulose is 3 mPa·s or more and less than 20 mPa·s.

9. A method for improving the disintegration properties of an orally disintegrating tablet containing istradefylline and a binder, The orally disintegrating tablet is characterized by containing 0.1 to 8% by mass of hydroxypropylcellulose relative to its total mass. A method wherein the molecular weight of the hydroxypropyl cellulose is 100,000 to 140,000.

10. A method for improving the disintegration properties of an orally disintegrating tablet containing istradefylline and a binder, By incorporating 0.1 to 8% by mass of hydroxypropylcellulose relative to the total mass of the orally disintegrating tablets, A method for shortening the disintegration time of the orally disintegrating tablet to within 30 seconds.

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