Orally disintegrating tablet containing istradefylline

Abstract

To provide orally disintegrating tablets containing istradefylline, which suppress the decrease in dissolution rate after storage.SOLUTION: Provided is an orally disintegrating tablet characterized by containing istradefylline and crospovidone.SELECTED DRAWING: None

Description

Technical Field

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

Background Art

[0002] Istradefylline exhibits adenosine A2 receptor antagonistic activity and is useful for the treatment of Parkinson's disease and the like.

[0003] Regarding diarylvinylene compounds such as istradefylline, it is known that it is not easy to formulate a solid preparation having excellent pharmaceutical properties (for example, hardness, disintegrability, elution property, stability, etc.). In a solid preparation having a general composition as described in JP-A-6-211856 (Patent Document 1), there are reported problems such as (a) insufficient hardness, (b) long disintegration time, (c) tendency of delayed elution, and (d) poor stability (Patent Documents 2 and 3). Among these problems, regarding the elution property, in order to ensure the quality related to the elution property of pharmaceuticals, in the Japanese Pharmacopoeia, as the standard values are set from comparison with standard preparations, a preparation that suppresses the variation in elution property as much as possible is required.

[0004] On the other hand, Parkinson's disease patients have a high proportion of elderly people and often have swallowing disorders. In order to prevent accidental swallowing of tablets due to swallowing disorders, methods such as mixing tablets with a medicinal jelly for oral administration or crushing tablets and mixing them with food for administration are performed. In addition, orally disintegrating tablets (OD tablets) are useful for elderly people with swallowing disorders. In consideration of these circumstances, the development of an istradefylline preparation that can be safely handled by medical staff and is useful for improving the medication adherence of Parkinson's disease patients is desired.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

[0006] One of the problems of the present invention is to provide a pharmaceutical composition which is an orally disintegrating tablet containing istradefylline and in which a decrease in the dissolution rate after storage is suppressed. A preparation that maintains good dissolution properties and its effectiveness is expected even when exposed to harsh environments during distribution or after packaging. As a result of studying additives in order to provide an orally disintegrating tablet with stable dissolution of istradefylline, the present inventors have found that by selecting crospovidone as a disintegrant, an orally disintegrating tablet with little decrease in the dissolution rate after storage based on before storage can be manufactured, and completed the present invention.

[0007] In one aspect, the present invention provides an orally disintegrating tablet containing istradefylline and crospovidone.

[0008] In one aspect, the present invention provides an orally disintegrating tablet containing istradefylline having an average particle size exceeding 20 μm.

[0009] In one aspect, the present invention provides a method for manufacturing an orally disintegrating tablet containing istradefylline.

Mode for Carrying Out the Invention

[0010] The orally disintegrating tablet provided by the present invention contains istradefylline. Istradefylline has the following structure.

Chemical formula

[0011] The orally disintegrating tablets provided by the present invention contain crospovidone. In the field of pharmaceutical technology, it is known that crospovidone can function as a disintegrant, and it can be used without particular limitation as long as it is of a quality used as a pharmaceutical additive. The crospovidone contained in the orally disintegrating tablets of the present invention preferably has a swelling time of less than 40 seconds. Examples of crospovidone that can be obtained as a commercial product include, for example, Kollidon CL (swelling time 6.9 seconds), Kollidon CL-F (swelling time 13.1 seconds), Kollidon CL-SF (swelling time 32.9 seconds), and the like. The blending amount of crospovidone contained in the orally disintegrating tablet of the present invention is not particularly limited, but is preferably 5 to 100% by mass, more preferably 15 to 75% by mass, based on the mass of istradefylline. In one embodiment, it may be a granulated product containing istradefylline and crospovidone. Conventional additives may be included as necessary. The granulated product containing istradefylline and crospovidone may be included in the core tablet portion in the tablet. The weight ratio of istradefylline and crospovidone in the granulated product can be appropriately set by those skilled in the art. For example, the weight of crospovidone can be 0.1 to 1, preferably 0.1 to 0.5, of the weight of istradefylline. The preparation of the granulated product can be carried out by methods generally used in this field, for example, by wet granulation method, dry granulation method, etc.

[0012] The orally disintegrating tablet provided by the present invention preferably has a disintegration time within 120 seconds (for example, 10 or more and 120 seconds or less), more preferably within 60 seconds (for example, 10 or more and 60 seconds or less), and even more preferably within 30 seconds (for example, 10 or more and 30 seconds or less). The method for measuring the disintegration time is not particularly limited, but for example, it can be measured using a disintegration tester according to the disintegration test method defined in the 17th revised Japanese Pharmacopoeia. The orally disintegrating tablet provided by the present invention can have a hardness of 20 N or more, for example, 20 N or more and 150 N or less, 20 N or more and 100 N or less, 20 N or more and 50 N or less, 25 N or more and 150 N or less, 25 N or more and 100 N or less, 25 N or more and 50 N or less, 50 N or more and 150 N or less, 50 N or more and 100 N or less, 60 N or more (for example, 60 to 100 N), 65 N or more (for example, 65 to 100 N), 70 N or more (for example, 70 to 100 N). The orally disintegrating tablet 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. Usually, the absolute hardness is 1.5 N / mm 2 or more, preferably 2.0 N / mm 2 or more, 2.5 N / mm 2 or more, more preferably 3.0 N / mm 2The above strength can be mentioned. The orally disintegrating tablet provided by the present invention can be used for the treatment of Parkinson's disease.

[0013] The orally disintegrating tablet 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 coloring agents. These additives can be commonly used in any of granules, pellets, and post-added powders.

[0014] Examples of excipients that can be used in the orally disintegrating tablet 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, pregelatinized starch), crystalline cellulose, magnesium aluminometasilicate, anhydrous calcium phosphate, calcium hydrogen phosphate anhydrous, precipitated calcium carbonate, calcium silicate, calcium lactate, and ethyl cellulose. Examples of preferred excipients used in the orally disintegrating tablet provided by the present invention include D-mannitol, calcium hydrogen phosphate anhydrous, and combinations thereof. The content of the excipient in the orally disintegrating tablet provided by the present invention may be 20 to 95% by weight, preferably 30 to 90% by weight, more preferably 30 to 85% by weight based on the pharmaceutical composition. In one embodiment, the excipient used in the orally disintegrating tablet provided by the present invention is D-mannitol, and those conforming to the pharmacopoeias of Japan, Europe, and the United States can be usually used. The crystal form, particle size, and specific surface area of D-mannitol are not particularly limited, but 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 24 m or more per g 2 2 m or less, more preferably 2 3.5 m or more per g 2 It may be or less per g. In addition, 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. Furthermore, the conductivity at 25 °C when 20 g is dissolved in 100 ml can be 20 μS·cm -1 It may 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 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, more preferably in the range of 10 to 70% by weight, and even more preferably in the range of 25 to 60% by weight, based on the pharmaceutical composition.

[0015] Examples of the binder that can be used in the orally disintegrating tablets provided by the present invention include hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, dextrin, methylcellulose, polyvinyl alcohol, sodium alginate, aminoalkyl methacrylate copolymer, polyethylene glycol, pregelatinized starch, agar, and gelatin. Examples of the preferred binder used in the orally disintegrating tablets provided by the present invention include hydroxypropyl cellulose. 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, more preferably 1 to 5% by weight, based on the pharmaceutical composition.

[0016] The orally disintegrating tablets of the present invention may also contain disintegrants commonly used in the pharmaceutical field other than crospovidone, as long as the effects of the present invention are not affected. 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, 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 1 to 15% by weight, and more preferably 3 to 10% by weight based on the pharmaceutical composition.

[0017] Examples of fluidizing agents that can be used in the orally disintegrating tablets provided by the present invention include light anhydrous silicic acid, magnesium aluminometasilicate, hydrous silicon dioxide, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium aluminum hydroxide, stearic acid, calcium stearate, magnesium stearate, and talc. Examples of preferred fluidizing agents used in the orally disintegrating tablets provided by the present invention include 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 based on the pharmaceutical composition.

[0018] Examples of sweeteners that can be used in the orally disintegrating tablets provided by the present invention include sodium saccharin, dipotassium glycyrrhizinate, aspartame (registered trademark), stevia, thaumatin, and sucralose. Examples of preferred sweeteners used in the orally disintegrating tablets provided by the present invention include aspartame (registered trademark), stevia, and sucralose. The content of the sweetener 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 based on the pharmaceutical composition.

[0019] 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. Examples of preferred lubricants used in the orally disintegrating tablets provided by the present invention include magnesium stearate. The content of the lubricant in the orally disintegrating tablets provided by the present invention can be 5% by weight or less based on the pharmaceutical composition, and for example, it may be 1% by weight or less, 0.01 - 5% by weight, 0.1 - 5% by weight, 0.1 - 3% by weight, 0.1 - 2% by weight, 0.3 - 5% by weight, 0.3 - 3% by weight, 0.3 - 2% by weight, 0.3 - 1% by weight, 0.5 - 5% by weight, 0.5 - 3% by weight, 0.5 - 2% by weight, or 0.5 - 1% by weight.

[0020] 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 content of the pH adjuster in the orally disintegrating tablets provided by the present invention may be 0.1 - 30% by weight, preferably 0.3 - 10% by weight, and more preferably 1 - 5% by weight based on the pharmaceutical composition.

[0021] 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 content of the surfactant in the orally disintegrating tablets provided by the present invention may be 0.01 - 3% by weight, preferably 0.03 - 1% by weight, and more preferably 0.03 - 0.5% by weight based on the pharmaceutical composition.

[0022] Examples of flavors that can be used in the orally disintegrating tablets provided by the present invention include citrus flavors such as lemon, orange, and grapefruit, and peppermint, spearmint, and menthol.

[0023] 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, Aluminum Lake of Food Yellow No. 4, Aluminum Lake of Food Yellow No. 5, 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 content of the colorant in the orally disintegrating tablets provided by the present invention is preferably contained in the range of 0.001 to 10.0% by weight, 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, based on the pharmaceutical composition. In one embodiment, a composition containing a colorant is included, and the colorant can be used as a photodegradation inhibitor of istradefirin.

[0024] In the orally disintegrating tablets provided by the present invention, the istradefirin drug substance, the granulated product containing istradefirin, and the core tablets may each be coated. The content of the coating layer can be appropriately set by those skilled in the art. For example, it may be 0.01 to 30% by weight, 0.01 to 10% by weight, based on the pharmaceutical composition. In addition to the coating base, the coating layer can appropriately contain a plasticizer, a colorant, a gloss agent, and the like. Examples of the coating base include hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, cellulose acetate phthalate, methacrylic acid copolymer, polyvinylpyrrolidone, polyvinyl alcohol-polyethylene glycol graft copolymer, and the like. Particularly, hydroxypropyl methylcellulose and polyvinyl alcohol-polyethylene glycol graft copolymer are 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, 0.3 to 3% by weight, based on the pharmaceutical composition. Examples of plasticizers that can be used for coating include triethyl citrate, medium-chain fatty acid triglycerides, triacetin, glycerin, propylene glycol, and polyethylene glycol (e.g., macrogol 6000), and polyethylene glycol is 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, based on the pharmaceutical composition. As the colorant that can be used for coating, the colorants that can be used for the orally disintegrating tablets provided by the present invention described above can be appropriately used. Examples of preferred colorants that can be used for coating include iron oxide, ferric oxide, and yellow ferric oxide. The content of the colorant used for coating may be 0.001 to 1% by weight, preferably 0.01 to 0.1% by weight, based on the pharmaceutical composition. Examples of the brightening agent that can be used for coating include carnauba wax. The content of the brightening agent used for coating may be 0.0001 to 0.1% by weight, preferably 0.001 to 0.01% by weight, based on the pharmaceutical composition.

[0025] The orally disintegrating tablets provided by the present invention can be manufactured by methods known in the pharmaceutical field. For example, it may include a mixing step of mixing istradefylline and crospovidone, and further optionally other additives, a granulation step, a tableting step, and / or a coating step. The mixing step can be carried out by methods known in the pharmaceutical field. For example, it can be carried out using a V-type mixer, a W-type mixer, a container mixer, a tumbler mixer, a stirring mixer, etc. The granulation step can be carried out by granulation methods known in the pharmaceutical field. For example, a granulation liquid in which a binder is dispersed or dissolved in a solvent (such as purified water) is sprayed for granulation. Examples of granulation methods include a wet granulation method and a fluidized bed granulation method. After preparing a granulated product containing istradefylline, additives (such as 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 and mixed with the granulated product before tableting. In one embodiment, the mixture obtained in the mixing step or the granulated product obtained in the granulation step can be made into a mixture or granulated product having a desired particle size by appropriately pulverizing and / or sieving. Pulverization can be carried out, for example, using a pulverizer known in the pharmaceutical field such as a ball mill, a jet mill, or a hammer mill. Sieving can be carried out using a 16-mesh sieve (aperture 1000 μm) to a 32-mesh sieve (aperture 500 μm) or the like. The tableting step can be carried out by a tableting method known in the pharmaceutical field. Examples of tableting methods include direct tableting, dry tableting, wet tableting, and external lubrication tableting. For example, a mixture or granulated product obtained in the above steps can be tableted using a tableting machine known in the pharmaceutical field such as a single-shot tableting machine or a rotary tableting machine. When using a single-shot tableting machine, a rotary tableting machine, etc., a tableting pressure of 1 kN to 30 kN, preferably 1 to 10 kN, more preferably 1 to 5 kN can be adopted. In one embodiment, when tableting a mixture (for example, granules) containing istradefirin and crospovidone to produce tablets (for example, tablets with a diameter of about 7 mm), the upper limit of the tableting pressure is preferably 30 kN, and the lower limit of the tableting pressure is preferably the tableting pressure at which a tablet hardness of 20 N can be achieved. For example, a mixture (for example, granules) containing istradefirin and crospovidone can be tableted 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 step can be carried out by a method known in the pharmaceutical field. For example, it can be carried out by spray-coating a coating solution appropriately containing a coating base, a plasticizer, a coloring agent, a gloss agent, etc. on the outside of the istradefirin drug substance, the granulated product, or the plain tablet.

[0026] The orally disintegrating tablets provided by the present invention can improve the dissolution of istradefylline from the orally disintegrating tablets by preparing a granulated product containing istradefylline by a wet granulation method. Therefore, the method for manufacturing the orally disintegrating tablets provided by the present invention may include a step of preparing a granulated product containing istradefylline by a wet granulation method.

[0027] In one embodiment, the istradefylline contained in the orally disintegrating tablets provided by the present invention has an average particle size exceeding 20 μm (for example, exceeding 20 μm and 70 μm or less, exceeding 20 μm and less than 50 μm, 25 μm or more and 40 μm or less). In one embodiment, the orally disintegrating tablets provided by the present invention have a hardness of 20 N or more, more preferably 30 N or more (for example, 50 N or more, 65 N or more, 70 N or more, 20 N or more and 60 N or less, 20 N or more and 100 N or less, 30 N or more and 100 N or less, 70 N or more and 100 N or less, 70 N or more and 150 N or less), and disintegrate within 60 seconds (for example, 10 seconds or more and 60 seconds or less) in the oral cavity. In one embodiment, the orally disintegrating tablets provided by the present invention have no bitterness or astringency and exhibit a good taste. In one embodiment, the orally disintegrating tablets provided by the present invention contain D-mannitol, lactose hydrate or anhydrous calcium hydrogen phosphate. In one embodiment, the orally disintegrating tablets provided by the present invention contain magnesium stearate, calcium stearate or sodium stearyl fumarate. In one embodiment, the orally disintegrating tablets provided by the present invention contain D-mannitol and a lubricant, and the lubricant is magnesium stearate, calcium stearate or sodium stearyl fumarate. In one embodiment, the orally disintegrating tablets provided by the present invention contain D-mannitol and a lubricant, 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).

[0028] Examples of other embodiments provided by the present invention include the following (1) to (12). (1) An orally disintegrating tablet containing istradefylline and crospovidone; (2) The orally disintegrating tablet according to (1), further containing D-mannitol as an excipient; (3) The orally disintegrating tablet according to (1) or (2), having a coating layer; (4) The orally disintegrating tablet according to any one of (1) to (3), wherein istradefylline is istradefylline having an average particle size exceeding 20 μm and not exceeding 200 μm (for example, exceeding 20 μm and not exceeding 70 μm, or 50 μm or more and 100 μm or less); (5) The orally disintegrating tablet according to any one of (1) to (4), wherein the orally disintegrating tablet disintegrates within 60 seconds by the disintegration test of the 17th revised Japanese Pharmacopoeia; (6) The orally disintegrating tablet according to any one of (1) to (5), having a hardness of 20 N or more (for example, 60 N or more); (7) The orally disintegrating tablet according to any one of (1) to (6), containing a granulated product containing istradefylline and crospovidone; (8) The orally disintegrating tablet according to any one of (1) to (7), not containing crystalline cellulose; (9) A method for producing an orally disintegrating tablet according to any one of (1) to (8), including a step of preparing a mixture containing istradefylline and crospovidone. (10) The method for producing an orally disintegrating tablet according to (9), wherein the step of preparing the mixture includes a step of preparing a granulated product; (11) The method for producing an orally disintegrating tablet according to (10), wherein the step of preparing the granulated product is performed by a wet granulation method; (12) The method for producing an orally disintegrating tablet according to any one of (9) to (11), further including a step of tableting a mixture containing istradefylline and crospovidone, and having a tableting pressure of 30 kN or less (preferably 10 kN or less).

[0029] Hereinafter, the present invention will be further described by way of examples, but the present invention is not limited thereto.

Examples

[0030] Tablets were prepared as follows. Example 1 100 g of estradiol valerate, 237.5 g of D-mannitol (Mannitol C, manufactured by Mitsubishi Corporation Life Sciences, Ltd.), and 25 g of crospovidone (Kollidon CL-SF, manufactured by BASF Japan Ltd.) were placed in a fluidized bed granulator dryer (SFC-MINI). A granulating solution (12.5 g of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) was added to 225 g of purified water and stirred until dissolved.) was sprayed for granulation, followed by drying and sizing with a sizing machine (QC-197S). The obtained granules were put into a plastic bag, and 44.0000% of D-mannitol (Granutol F, manufactured by Freund Industry Co., Ltd.) and 6.6667% of crospovidone (Kollidon CL-SF, manufactured by BASF Japan Ltd.) were added as the final product and mixed. Next, 2.6667% of sodium stearyl fumarate (PRUV, manufactured by JRS Pharma Co., Ltd.) was added as the final product and mixed. The obtained mixture was tabletted using a rotary tableting machine (VELA-5) to obtain tablets with a tablet weight of 115 mg and a tablet thickness of 3.2 mm. 200 g of the obtained tablets were placed in a coating machine (HCT-MINI), and a coating solution (12 g of polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR, manufactured by BASF Japan Ltd.) and 0.5 g of Yellow No. 4 (Yellow No. 4, manufactured by Kisuika Kasei Co., Ltd.) were added to 50 g of purified water and stirred until dispersed. Separately, 3 g of titanium oxide (Titanium Oxide, manufactured by Fujifilm Wako Pure Chemical Corporation) was added to 40 g of purified water and ultrasonically dispersed. After mixing and stirring these solutions, they were filtered.) was used to coat the tablets so that the tablet weight became 118 mg. Furthermore, carnauba wax (Polishing Wax 105, manufactured by Freund Industry Co., Ltd.) was added at 0.0061% of the tablet weight for glossing.

[0031] Comparative Example 1 100 g of istradefylline, 225 g of D-mannitol (mannitol C, manufactured by Mitsubishi Corporation Life Sciences, Ltd.), and 37.5 g of carmellose (NS-300, manufactured by Gode Chemical Co., Ltd.) were placed in a fluidized bed granulator dryer (SFC-MINI). A granulating solution (12.5 g of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) was added to 175 g of purified water and stirred until dissolved.) was sprayed for granulation, followed by drying and sizing with a sizing machine (QC-197S). The obtained granules were placed in a plastic bag, and 44.0000% of D-mannitol (PEARLITOL 160C, manufactured by Rocket Japan Co., Ltd.), 6.6667% of crospovidone (Kollidon CL-F, manufactured by BASF Japan Ltd.), and 6.6667% of carmellose (NS-300, manufactured by Gode Chemical Co., Ltd.) were added and mixed. Subsequently, 2.6667% of sodium stearyl fumarate (PRUV, manufactured by JRS Pharma GmbH) was added and mixed. The obtained mixture was tabletted using a rotary tablet press (VELA-5) to a tablet weight of 120 mg and a tablet thickness of 3.2 mm. 200 g of the obtained tablets were placed in a coating machine (HCT-MINI), and a coating solution (12 g of polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR, manufactured by BASF Japan Ltd.) and 0.5 g of Yellow No. 4 (Yellow No. 4, manufactured by Kisuika Kasei Co., Ltd.) were added to 50 g of purified water and stirred until dispersed. Separately, 3 g of titanium oxide (titanium oxide, manufactured by Fujifilm Wako Pure Chemical Corporation) was added to 40 g of purified water and ultrasonically dispersed. After mixing and stirring these solutions, they were filtered.) was used to coat the tablets to a tablet weight of 123 mg. Furthermore, carnauba wax (Polishing Wax 105, manufactured by Freund Industry Co., Ltd.) was added at 0.0058% of the tablet mass for glossing.

[0032] The prepared tablets were tested as follows. Test Example 1: Sensory Test of Oral Disintegration Time For the tablets of Example 1 and Comparative Example 1, one subject was used. Each tablet was administered orally, sandwiched between the tongue and the palate, and the tongue was moved back and forth to measure the time until complete disintegration. The measurement results were calculated as the average of two tests. As a result, the disintegration time was 32 seconds for the tablets of Example 1 and 33 seconds for the tablets of Comparative Example 1.

[0033] Test Example 2: Dissolution Test (Method) According to the second method (paddle method) described in the dissolution test method of the 17th revised Japanese Pharmacopoeia, dissolution tests were performed on the tablets obtained in Example 1 and Comparative Example 1 before storage, after storage at 40°C ± 2°C / 75% RH ± 5% RH for 2 weeks, and after storage at 25°C ± 2°C / 75% RH ± 5% RH for 2 weeks, respectively. 900 mL of an aqueous solution of 2.0 wt% polysorbate 80 (manufactured by Junsei Chemical Co., Ltd.) was used as the test solution, and the test was carried out with the paddle rotating at 50 revolutions per minute. After starting the dissolution test, the test solution was sampled over time, and the dissolution amount of istradefirin from each tablet was determined by high performance liquid chromatography (HPLC) analysis. The HPLC analysis conditions are as follows. <HPLC Analysis Conditions> Detector: Ultraviolet absorptiometer Mobile phase: Acetonitrile / diluted phosphoric acid (1→1000) mixed solution (3:2) Equipment, etc.: High performance liquid chromatograph (Hitachi High-Tech Science), ultraviolet absorptiometer (Hitachi High-Tech Science)

[0034] (Results) The dissolution characteristics of the tablets obtained in Example 1 and Comparative Example 1 are shown in Tables 1 to 4.

[0035] [Table 1]

[0036] [Table 2]

[0037] [Table 3]

[0038] [Table 4]

[0039] The tablets obtained in Example 1 and the tablets obtained in Comparative Example 1 had high dissolution rates of about 90% at 45 minutes before storage. However, the dissolution rates after 2 weeks were about 88% and about 81% respectively when stored at 25°C ± 2°C / 75% RH ± 5% RH, and about 84% and about 81% respectively when stored at 40°C ± 2°C / 75% RH ± 5% RH. Therefore, it was revealed that the tablets obtained in Example 1 had less reduction in dissolution compared to the tablets obtained in Comparative Example 1.

[0040] Referring to the description in the Draft of the Eighteenth Revision of the Japanese Pharmacopoeia, when setting the dissolution standard with the tablets before storage as the standard preparations respectively, the individual dissolution rates at 45 minutes are 75% or more. When stored at 25°C ± 2°C / 75% RH ± 5% RH, the tablets obtained in Comparative Example 1 had an average dissolution rate of about 81% at 45 minutes, with only a 6% margin over 75%. Considering the variation of individual tablets and test errors, there is a possibility of falling below the standard value. On the other hand, the tablets obtained in Example 1 maintained a high average dissolution rate of about 88% at 45 minutes, and it is considered that the possibility of falling below the standard value is low. Also, even when stored at 40°C ± 2°C / 75% RH ± 5% RH, which is a more severe condition, the tablets obtained in Example 1 had an average dissolution rate of about 84% at 45 minutes, with a margin of nearly 10% over 75%, and it is considered that the possibility of falling below the standard value is low. From this, it is considered that the preparation of the present invention is likely to maintain its effectiveness even when exposed to a severe environment during distribution or after packaging.

[0041] From the above, in the provision of orally disintegrating tablets containing istradefirin, it was shown that crospovidone is the most suitable disintegrant compared to other disintegrants.

Industrial Applicability

[0042] The present invention provides an orally disintegrating tablet useful for the treatment of Parkinson's disease.

Claims

[Claim 1] An orally disintegrating tablet containing istradefylline and crospovidone.

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