Istradefylline formulation

Abstract

To provide novel formulations having the improved photostability of istradefylline or a pharmaceutically acceptable salt thereof.SOLUTION: Provided is a granule that contains a core part containing istradefylline or a pharmaceutically acceptable salt thereof, and a first coating layer located outside the core part, the core part containing iron oxide, and the first coating layer containing titanium oxide.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to granules containing istradefylline or a pharmaceutically acceptable salt thereof. The present invention also relates to an oral solid formulation containing the granules. Furthermore, the present invention relates to a method for producing the oral solid formulation and a method for stabilizing the oral solid formulation. [Background technology]

[0002] Istradefylline exhibits adenosine A2 receptor antagonistic activity and is therefore useful in the treatment of diseases caused by increased adenosine A2 receptor activity, such as Parkinson's disease, senile dementia, depression, asthma, osteoporosis, and the like.

[0003] Istradefylline has stability problems, particularly when exposed to light. It is known that the double bond (vinylene moiety) in its structure is prone to isomerization when exposed to light. Therefore, pharmaceutical preparations containing istradefylline must be handled with the utmost care during the formulation process, dispensing in hospitals and pharmacies, storage, etc.

[0004] To date, various formulations containing istradefylline have been developed.

[0005] For example, Patent Document 1 discloses a solid pharmaceutical preparation containing istradefylline microcrystals having an average particle size of 0.5 to 20 μm and a crystallinity of 40% or more.

[0006] Furthermore, Patent Document 2 discloses a solid preparation containing istradefylline or a pharmacologically acceptable salt thereof and crystalline cellulose. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Patent No. 4606326 [Patent Document 2] Patent No. 4673745 Summary of the Invention [Problem to be solved by the invention]

[0008] However, the formulations containing istradefylline as described in Patent Documents 1 and 2 have room for improvement in terms of photostability.

[0009] Therefore, one aspect of the present invention aims to provide a novel formulation containing istradefylline or a pharmaceutically acceptable salt thereof that has improved stability, particularly photostability, and a method for stabilizing an istradefylline formulation. [Means for solving the problem]

[0010] As a result of extensive research aimed at solving the above-mentioned problems, the present inventors discovered for the first time that the photostability of istradefylline can be improved by incorporating istradefylline and iron oxide into the core and incorporating titanium oxide into a coating layer located on the outside of the core, and thus completed the present invention. That is, one aspect of the present invention includes the following configuration. <1> A granule comprising a core containing istradefylline or a pharmaceutically acceptable salt thereof, and a first coating layer located on the outside of the core, the core contains iron oxide, Granules, characterized in that the first coating layer contains titanium oxide. <2> The first coating layer does not contain iron oxide. <1> The granules described in <3> The present invention is characterized in that the following coating layer (A) or (B) is further provided on the outside of the first coating layer: <1> or <2> Granules according to the invention: (A) a second coating layer comprising an aminoalkyl methacrylate copolymer; (B) a second coating layer comprising an aminoalkyl methacrylate copolymer, and a third coating layer comprising an excipient. <4> <1> ~ <3> 1. An oral solid formulation comprising the granules according to any one of the preceding claims. <5> Characterized in that it is a tablet, <4> 1. The oral solid formulation according to claim 1. <6> 1. A method for producing an oral solid formulation comprising istradefylline or a pharmaceutically acceptable salt thereof, comprising: obtaining granules comprising a core containing istradefylline or a pharmaceutically acceptable salt thereof and a first coating layer located on the outside of the core; The method, characterized in that in the step, the core portion contains iron oxide and the first coating layer contains titanium oxide. <7> A method for stabilizing an oral solid formulation containing istradefylline or a pharmaceutically acceptable salt thereof, comprising: The manufacturing process of the oral solid formulation includes a step of producing granules including a core containing istradefylline or a pharmaceutically acceptable salt thereof and a first coating layer located on the outside of the core, The method, characterized in that in the step, the core portion contains iron oxide and the first coating layer contains titanium oxide. [Effects of the Invention]

[0011] According to one aspect of the present invention, there is provided a novel formulation containing istradefylline or a pharmaceutically acceptable salt thereof, which has improved photostability, and a method for stabilizing a formulation containing istradefylline or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0012] Hereinafter, one embodiment of the present invention will be described in detail.

[0013] Unless otherwise specified in this specification, "A to B" indicating a numerical range means "A or more and B or less."

[0014] [1. Overview] Granules according to one embodiment of the present invention (hereinafter referred to as "granules of the present invention") are granules comprising a core containing istradefylline or a pharmaceutically acceptable salt thereof (hereinafter sometimes simply referred to as "istradefylline") and a first coating layer located on the outside of the core, wherein the core contains iron oxide and the first coating layer contains titanium oxide. Furthermore, an oral solid formulation according to one embodiment of the present invention (hereinafter referred to as "formulation of the present invention") is characterized by comprising the above-mentioned granules.

[0015] The present inventors have conducted detailed studies on formulations containing istradefylline from the viewpoint of photostability, and as a result have succeeded in obtaining the following findings. By incorporating istradefylline and iron oxide into the core and titanium oxide into the first coating layer located on the outside of the core, the photostability of istradefylline is improved.

[0016] Furthermore, the present inventors have further investigated the above-mentioned formulations containing istradefylline and have succeeded in obtaining the following findings. The disintegration property of the oral solid formulation is improved by further providing, on the outside of the first coating layer, (A) a second coating layer containing an aminoalkyl methacrylate copolymer, or (B) a second coating layer containing an aminoalkyl methacrylate copolymer and a third coating layer containing an excipient.

[0017] Thus, the granules (or formulations) of the present invention exhibit advantageous effects based on the above findings, and can provide useful novel formulations containing istradefylline or a pharmaceutically acceptable salt thereof.

[0018] 2. Granules of the Present Invention The granules of the present invention contain istradefylline or a pharmaceutically acceptable salt thereof as an active ingredient. Istradefylline is a compound represented by the following formula (1), commonly known as (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione.

[0019] [ka]

[0020] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is medically suitable for use in contact with the tissues of humans or other mammals without causing excessive toxicity, irritation, allergic reactions, etc.

[0021] Pharmaceutically acceptable salts of istradefylline are well known in the art, and any can be used. Examples of pharmaceutically acceptable salts of istradefylline include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, and phosphate; organic acid salts such as acetate, oxalate, maleate, fumarate, citrate, benzoate, and methanesulfonate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; aluminum salt; zinc salt; ammonium salt, tetramethylammonium salt; and addition salts of morpholine, piperidine, lysine, glycine, phenylalanine, aspartic acid, glutamic acid, etc.

[0022] The pharmaceutically acceptable salt of istradefylline may be either crystalline or amorphous, and the particle size is not particularly limited. For example, in one embodiment of the present invention, the average particle size (D 50 ) is, for example, preferably 21 to 100 μm, and more preferably 21 to 40 μm.

[0023] The granules of the present invention contain iron oxide in the core and titanium oxide in the first coating layer, which has the effect of improving the photostability of istradefylline.

[0024] In this specification, iron oxide refers to an oxide of iron oxidized, and is not particularly limited as long as it is usable in medicines. In one embodiment of the present invention, the iron oxide may be yellow, red, black, or the like. Examples of iron oxide in one embodiment of the present invention include yellow iron oxides such as yellow iron sesquioxide and yellow iron oxide, red iron oxides such as iron sesquioxide, and black iron oxides such as black iron oxide. In one embodiment of the present invention, the iron oxide contained in the granules of the present invention is preferably yellow iron sesquioxide.

[0025] In this specification, titanium oxide is an oxide of oxidized titanium, and is not particularly limited as long as it can be used in medicine.

[0026] (core) The core of the granule of the present invention contains istradefylline or a pharmaceutically acceptable salt thereof and iron oxide.

[0027] In one embodiment of the present invention, the amount of iron oxide contained in the core is, for example, 0.1 to 50 mass %, preferably 0.5 to 30 mass %, and more preferably 1 to 20 mass %, based on the mass of the granule.

[0028] In one embodiment of the present invention, the amount of iron oxide contained in the core is, for example, 0.01 to 20 mg, preferably 0.05 to 15 mg, and more preferably 0.1 to 10 mg.

[0029] In one embodiment of the present invention, the amount of istradefylline contained in the core is, for example, 1.0 to 80% by mass, preferably 10 to 70% by mass, and more preferably 25 to 60% by mass, based on the mass of the granule.

[0030] In one embodiment of the present invention, iron oxide is added as a colorant.

[0031] The core of the granule of the present invention may contain other ingredients besides those mentioned above, such as an excipient, a binder, a disintegrant, a colorant, etc.

[0032] The excipient is not particularly limited, but examples thereof include D-mannitol, lactose, sucrose, cornstarch, calcium phosphate, sorbitol, crystalline cellulose, etc. Preferably, D-mannitol is used.

[0033] The binder is not particularly limited, but examples thereof include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, a copolymer of N-vinylpyrrolidone and vinyl acetate, or a combination of these polymers, pregelatinized starch, gelatin, agar, gum arabic, and the like.

[0034] The disintegrant is not particularly limited, but examples thereof include crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, croscarmellose sodium, potato starch, etc. Preferably, low-substituted hydroxypropyl cellulose is used.

[0035] The coloring agent is not particularly limited, and examples thereof include, in addition to the iron oxides described above, yellow coloring agents (e.g., Food Yellow No. 4 Aluminum Lake, red iron oxide, etc.), red coloring agents (e.g., Food Red No. 2, Food Red No. 3, Food Red No. 102, etc.), black coloring agents (e.g., carbon black, medicinal charcoal, etc.), white coloring agents (e.g., titanium oxide, etc.), caramel, etc. Titanium oxide is preferably used.

[0036] The content of each of the additives is not particularly limited and can be appropriately set based on conventionally known techniques.

[0037] (coating layer) <First coating layer> The first coating layer in the granules of the present invention contains titanium oxide.

[0038] The granules of the present invention can more effectively exhibit photostability effects by containing titanium oxide in the first coating layer in addition to containing iron oxide in the core.

[0039] In one embodiment of the present invention, the amount of titanium oxide contained in the first coating layer is, for example, 0.01 to 50 mass%, preferably 0.05 to 40 mass%, and more preferably 0.1 to 30 mass%, based on the mass of the granules.

[0040] In one embodiment of the present invention, the amount of titanium oxide contained in the first coating layer is, for example, 0.1 to 50 mg, preferably 0.5 to 30 mg, and more preferably 1 to 15 mg.

[0041] In one embodiment of the present invention, titanium dioxide is added as a colorant.

[0042] The colorant contained in the first coating layer is sometimes called a "coating agent" from the viewpoint of its function in the manufacturing process.

[0043] In one embodiment of the present invention, the first coating layer of the granules of the present invention does not contain iron oxide. That is, in one embodiment of the present invention, the granules of the present invention are granules comprising a core containing istradefylline or a pharmaceutically acceptable salt thereof and a first coating layer located on the outside of the core, wherein the core contains iron oxide and the first coating layer contains titanium oxide but does not contain iron oxide.

[0044] The effect of improving the photostability of istradefylline in the granules of the present invention is exerted by the core containing iron oxide and the first coating layer containing titanium oxide.

[0045] The first coating layer of the granules of the present invention may further contain other colorants in addition to titanium oxide. Examples of such colorants include, but are not limited to, yellow colorants (e.g., Food Yellow No. 4 Aluminum Lake, red iron oxide, etc.), red colorants (e.g., Food Red No. 2, Food Red No. 3, Food Red No. 102, etc.), black colorants (e.g., carbon black, medicinal charcoal, etc.), caramel, etc.

[0046] The first coating layer of the granules of the present invention may also contain components other than those mentioned above.

[0047] Examples of such ingredients include talc, silicic acid, hydroxypropyl cellulose, hypromellose, ethyl cellulose, polyvinyl alcohol, copolymers of polyvinyl alcohol, acrylic acid, and methyl methacrylate, etc. Hydroxypropyl cellulose is preferably used.

[0048] In one embodiment of the present invention, the granules of the present invention can be produced by granulating istradefylline together with iron oxide and, if necessary, other additives, and coating the resulting granules (elementary granules) with a coating agent containing titanium oxide. The granulation method is not particularly limited, and any conventionally known technique can be applied, such as fluidized bed granulation, agitation granulation, or extrusion granulation.

[0049] The content of the additives is not particularly limited and can be appropriately set based on conventionally known techniques.

[0050] <Second coating layer> In one embodiment of the present invention, the granules of the present invention further comprise a second coating layer on the outside of the first coating layer. The second coating layer of the granules of the present invention comprises an aminoalkyl methacrylate copolymer. By providing the granules of the present invention with a second coating layer on the outside of the first coating layer that comprises an aminoalkyl methacrylate copolymer, the disintegration property of an oral solid preparation containing the granules is improved.

[0051] The disintegration property of the oral solid preparation is measured by the method described in the Examples. In this specification, "improved disintegration property" means that the disintegration time is less than 17 seconds when measured by the method described in the Examples. Generally, a tablet having a disintegration time of 60 seconds or less can be used as an orally disintegrating tablet.

[0052] The aminoalkyl methacrylate copolymer contained in the second coating layer is not particularly limited as long as it is of a grade suitable for use in pharmaceuticals, but aminoalkyl methacrylate copolymer E (Eudragit (registered trademark) E100 manufactured by Evonik Japan Co., Ltd.) is preferred.

[0053] In one embodiment of the present invention, the amount of aminoalkyl methacrylate copolymer contained in the second coating layer is, for example, 0.01 to 30.0 mass%, preferably 0.5 to 15.0 mass%, and more preferably 1.0 to 10.0 mass%, based on the mass of the granules.

[0054] In one embodiment of the present invention, the second coating layer of the granules of the present invention may contain components other than the aminoalkyl methacrylate copolymer. Such components include, but are not limited to, titanium oxide, talc, silicic acid, hydroxypropyl cellulose, hypromellose, ethyl cellulose, polyvinyl alcohol, and copolymers of polyvinyl alcohol, acrylic acid, and methyl methacrylate. Talc is preferably used.

[0055] The content of the above-mentioned components in the second coating layer is not particularly limited and can be appropriately set based on conventionally known techniques.

[0056] <Third coating layer> In one embodiment of the present invention, the granules of the present invention further comprise a second coating layer and a third coating layer on the outside of the first coating layer, in this embodiment, the third coating layer is disposed on the outside of the second coating layer.

[0057] The third coating layer of the granules of the present invention contains an excipient. The granules of the present invention have a third coating layer containing an excipient on the outside of the first coating layer in addition to the second coating layer, which has the effect of further improving disintegration properties.

[0058] The excipient contained in the third coating layer may be, for example, one of those described above in the section (Core).

[0059] In one embodiment of the present invention, the amount of excipient contained in the third coating layer is, for example, 0.1 to 100% by mass, preferably 0.3 to 80% by mass, and more preferably 0.5 to 50% by mass, based on the mass of the granules.

[0060] In one embodiment of the present invention, the third coating layer of the granules of the present invention may contain ingredients other than the excipients, such as, but not limited to, erythritol, maltitol, reduced maltose syrup, xylitol, etc.

[0061] The content of the above components in the third coating layer is not particularly limited and can be appropriately set based on conventionally known techniques.

[0062] 3. Preparations of the Present Invention In one embodiment of the present invention, there is provided an oral solid formulation (hereinafter referred to as "the formulation of the present invention") comprising the granules described in [2. Granules of the present invention].

[0063] In one embodiment of the present invention, the formulation of the present invention includes granules having a core containing istradefylline and iron oxide and a first coating layer surrounding the core containing titanium oxide, thereby improving the photostability of istradefylline. In another embodiment of the present invention, the formulation of the present invention includes granules further comprising, outside the first coating layer, a second coating layer containing an aminoalkyl methacrylate copolymer, or a second coating layer containing a methacrylate copolymer and a third coating layer containing an excipient, thereby improving the disintegration properties of the formulation.

[0064] In this specification, the oral solid preparation is not particularly limited as long as it is a drug formed for oral administration, and examples thereof include tablets (including orally disintegrating tablets), capsules, granules, powders, dry syrups, etc. The preparation of the present invention is preferably a tablet.

[0065] In one embodiment of the present invention, the amount of iron oxide contained in the formulation of the present invention is, for example, 0.01 to 20 mass%, preferably 0.05 to 15 mass%, and more preferably 0.1 to 10 mass%, based on the mass of the formulation.

[0066] In one embodiment of the present invention, the amount of iron oxide contained in the formulation of the present invention is, for example, 0.01 to 20 mg, preferably 0.05 to 15 mg, and more preferably 0.1 to 10 mg.

[0067] In one embodiment of the present invention, the amount of titanium oxide contained in the preparation of the present invention is, for example, 0.01 to 30 mass%, preferably 0.05 to 25 mass%, and more preferably 0.1 to 20 mass%, based on the mass of the preparation.

[0068] In one embodiment of the present invention, the amount of titanium oxide contained in the formulation of the present invention is, for example, 0.01 to 50 mg, preferably 0.05 to 30 mg, and more preferably 0.1 to 20 mg.

[0069] In one embodiment of the present invention, the amount of aminoalkyl methacrylate copolymer contained in the formulation of the present invention is, for example, 0.01 to 30 mass%, preferably 0.1 to 25 mass%, and more preferably 0.5 to 20 mass%, based on the mass of the formulation.

[0070] In one embodiment of the present invention, the amount of titanium oxide contained in the preparation of the present invention is, for example, 0.1 to 50 mg, preferably 0.5 to 30 mg, and more preferably 1 to 15 mg.

[0071] In one embodiment of the present invention, the amount of istradefylline contained in the formulation of the present invention is, for example, 1.0 to 50.0% by mass, preferably 5.0 to 30.0% by mass, and more preferably 10.0 to 20.0% by mass, based on the mass of the formulation.

[0072] In addition to the granules, the formulation of the present invention may contain various ingredients depending on the type and form of the formulation, such as excipients, binders, disintegrants, colorants, lubricants, etc.

[0073] As the excipient, binder, disintegrant and colorant, for example, those described in [2. Granules of the present invention] can be used.

[0074] The lubricant is not particularly limited, but examples thereof include carnauba wax, hydrous silicon dioxide, hydrous amorphous silicon oxide, dried aluminum hydroxide gel, magnesium silicate, light anhydrous silicic acid, synthetic aluminum silicate, magnesium oxide, heavy anhydrous silicic acid, sucrose fatty acid ester, aluminum hydroxide gel, stearyl alcohol, stearic acid, calcium stearate, magnesium stearate, cetanol, magnesium carbonate, precipitated calcium carbonate, sodium stearyl fumarate, talc, anhydrous silicic acid hydrate, magnesium aluminometasilicate, etc. Magnesium stearate is preferably used.

[0075] The content of the additives is not particularly limited and can be appropriately set based on conventionally known techniques.

[0076] The formulation of the present invention is not particularly limited, and any shape can be adopted. When the formulation of the present invention is a tablet, it may be, for example, circular, oval, spherical, rod-shaped, donut-shaped, etc. Furthermore, when the formulation of the present invention is a tablet, it may be a single-layer tablet, a layered tablet, a dry-coated tablet, etc.

[0077] The water content contained in the formulation of the present invention is, for example, preferably 5% or less, more preferably 2% or less.

[0078] When the formulation of the present invention is a tablet, its hardness is preferably 20 to 100 N. When the formulation of the present invention is a tablet, its thickness (tablet thickness) is, for example, 2.5 to 4.5 mm, preferably 3.0 to 4.0 mm, and more preferably 3.2 to 3.6 mm.

[0079] In this embodiment, the explanations of each component (e.g., "istradefylline or a pharmaceutically acceptable salt thereof," "core," "coating layer," etc.) are those described in [2. Granules of the present invention].

[0080] [4. Other] One embodiment of the present invention provides a method for producing an oral solid formulation containing istradefylline or a pharmaceutically acceptable salt thereof, the method comprising the step of obtaining granules comprising a core containing istradefylline or a pharmaceutically acceptable salt thereof and a first coating layer surrounding the core, wherein the core is impregnated with iron oxide and the first coating layer is impregnated with titanium oxide. Another embodiment of the present invention provides a method for producing an oral solid formulation containing istradefylline or a pharmaceutically acceptable salt thereof, the method comprising the step of obtaining granules comprising a core containing istradefylline or a pharmaceutically acceptable salt thereof and a first and second coating layer, or a first, second and third coating layer, surrounding the core, wherein the core is impregnated with iron oxide, the first coating layer is impregnated with titanium oxide, the second coating layer is impregnated with an aminoalkyl methacrylate copolymer, and the third coating layer is impregnated with an excipient. The above manufacturing methods are hereinafter collectively referred to as the "manufacturing method of the present invention."

[0081] The manufacturing method of the present invention may include, for example, a granulation manufacturing step and a mixing and tableting step. For example, a granulation containing istradefylline (granules A) and another granulation not containing istradefylline (granules B) are manufactured by the method described in the Examples. Next, granules A are coated, and the coated granules A and B are mixed, and a lubricant is added and tableted to obtain the formulation (tablet) of the present invention. In this example, the tableting pressure during tableting is preferably 4 to 12.

[0082] In the manufacturing method of the present invention, the descriptions of each component (e.g., "istradefylline or a pharmaceutically acceptable salt thereof," "oral solid formulation," "core," "coating layer," "titanium oxide," "iron oxide," "aminoalkyl methacrylate copolymer," "excipient," etc.) are incorporated by reference from those described in [2. Granules of the present invention] and [3. Preparations of the present invention].

[0083] In addition, in one embodiment of the present invention, there is provided a method for stabilizing an oral solid formulation containing istradefylline or a pharmaceutically acceptable salt thereof, which comprises, in the manufacturing process of the oral solid formulation, a step of producing granules comprising a core containing istradefylline or a pharmaceutically acceptable salt thereof and a first coating layer located on the outside of the core, and which is characterized in that, in this step, the core is impregnated with iron oxide and the first coating layer is impregnated with titanium oxide (hereinafter referred to as the "stabilization method of the present invention").

[0084] Furthermore, in one embodiment of the present invention, there is provided a method for improving the stabilization and disintegration properties of an oral solid formulation containing istradefylline or a pharmaceutically acceptable salt thereof, wherein the manufacturing process of the oral solid formulation includes a step of producing granules comprising a core containing istradefylline or a pharmaceutically acceptable salt thereof and a first coating layer and a second coating layer, or a first coating layer, a second coating layer and a third coating layer, located on the outside of the core, wherein the core is impregnated with iron oxide, the first coating layer is impregnated with titanium oxide, the second coating layer is impregnated with an aminoalkyl methacrylate copolymer, and the third coating layer is impregnated with an excipient (hereinafter referred to as the "method for improving stabilization and disintegration properties of the present invention").

[0085] In the stabilization method of the present invention and the stabilization and disintegration improvement method of the present invention, the descriptions of each component (e.g., "istradefylline or a pharmaceutically acceptable salt thereof," "oral solid formulation," "core," "coating layer," "titanium oxide," "iron oxide," "aminoalkyl methacrylate copolymer," "excipient," etc.) are incorporated by reference in [2. Granules of the present invention] and [3. Preparations of the present invention].

[0086] The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope of the claims. Embodiments obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention. [Example]

[0087] An embodiment of the present invention will be described below.

[0088] [Measurement and evaluation methods] (Photostability test) Several tablets manufactured in the Examples and Comparative Examples were placed in a Petri dish and irradiated with xenon at 1.2 million Lx. Also, several tablets manufactured in the Formulation Examples were placed in a Petri dish and irradiated with D65 at 1.2 million Lx.

[0089] (Disintegration test) A disintegration test was carried out without an auxiliary disc in accordance with the disintegration test method (rapidly disintegrating preparations) of the 17th edition of the Japanese Pharmacopoeia, and the disintegration time when the tablet disintegrated was measured.

[0090] Example 1 (Production of grain A) Istradefylline, D-mannitol, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, sucrose fatty acid ester, and yellow ferric oxide (Kishi Co., Ltd.) were mixed with purified water and granulated. The resulting granules were crushed, dried, and sized to give Granule A.

[0091] (coating) The above-mentioned granules A, hydroxypropyl cellulose, and titanium oxide were mixed with purified water and coated, dried, and then sized to give a coated powder.

[0092] (Production of B grains) D-mannitol, ethyl cellulose, corn starch, crospovidone, light anhydrous silicic acid, and yellow ferric oxide (Kishi Co., Ltd.) were mixed with purified water and granulated, dried, and then sized to give Granule B.

[0093] (mixing / tableting) The coated particles A (coated powder), the particles B, aspartame, and light anhydrous silicic acid were mixed together. Magnesium stearate was added to the resulting mixture and mixed to form a tableting powder. The tableting powder was compressed using a circular punch with a diameter of 7.0 mm at a tableting pressure of 6 kN to obtain tablets (orally disintegrating tablets) with a hardness of 53 N and a thickness of 3.4 mm.

[0094] For the amount of each component, see Table 1 (the same applies to the following Examples). In Table 1, the amount of each component is expressed in mg. In Table 1, the amount of each component other than those in the coating II and coating III steps indicates the amount of each component in the manufactured tablets. The amount of each component in the coating II and coating III steps indicates the amount charged.

[0095] Example 2 Tablets with a hardness of 57 N and a thickness of 3.4 mm were obtained in the same manner as in Example 1, except that the amounts of each component were changed as shown in Table 1.

[0096] Example 3 (Production of grain A) Istradefylline, D-mannitol, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, sucrose fatty acid ester, yellow ferric oxide (Kishi Co., Ltd.), and light anhydrous silicic acid were mixed with purified water and granulated. The resulting granules were crushed, dried, and sized to give Granule A.

[0097] (coating) The above-mentioned granules A, hydroxypropyl cellulose, and titanium oxide were mixed with purified water and coated, dried, and then sized to obtain sized product (I). Next, the above-mentioned sized product (I), aminoalkyl methacrylate copolymer E, and talc were mixed with a mixture of ethanol and purified water and coated, dried, and then sized to obtain a coated powder.

[0098] (Production of B grains) D-mannitol, ethyl cellulose, corn starch, crospovidone, light anhydrous silicic acid, and yellow ferric oxide (Kishi Co., Ltd.) were mixed with purified water and granulated, dried, and then sized to give Granule B.

[0099] (mixing / tableting) The coated A particles (coated powder), the B particles, aspartame, and light anhydrous silicic acid were mixed together. Magnesium stearate was added to the resulting mixture and mixed to prepare a tableting powder. The tableting powder was compressed using a 7.0 mm diameter circular punch at a tableting pressure of 6 kN to obtain tablets (orally disintegrating tablets) with a hardness of 69 N and a thickness of 3.4 mm.

[0100] For the amounts of each ingredient, please refer to Table 1.

[0101] Example 4 The above steps (coating) were carried out in the same manner as in Example 3. The "coated powder" obtained in (coating) of Example 3 was designated as "sized product (II)", and the sized product (II) and D-mannitol were mixed with purified water and coated, dried, and then sized to obtain the coated powder.

[0102] Using the above-obtained coated powder, tablets with a hardness of 67N and a thickness of 3.4mm were obtained using the same methods as (Production of Granule B) and (Mixing and Tableting) in Example 3, except that the amount of each component was changed as shown in Table 1.

[0103] [Table 1]

[0104] Comparative Example 1 Tablets were obtained in the same manner as in Example 1, except that the amount of each component was changed as shown in Table 2 and the coating step was omitted. In Table 2, the amount of each component is expressed in mg. In Table 2, the amount of each component indicates the amount of each component in the produced tablets.

[0105] Comparative Example 2 Tablets were obtained in the same manner as in Comparative Example 1, except that in the manufacturing process for granules A, 5 mg of titanium oxide was added and the amount of D-mannitol was changed to 16.74 mg.

[0106] Comparative Example 3 Tablets were obtained in the same manner as in Comparative Example 1, except that in the manufacturing process for granules A, the amount of D-mannitol was changed to 9.24 mg and the amount of titanium oxide was changed to 7.5 mg.

[0107] Comparative Example 4 Tablets were obtained in the same manner as in Comparative Example 1, except that in the manufacturing process of granule B, 1.896 mg of titanium oxide was added and the amount of D-mannitol was changed to 58.626 mg.

[0108] [Table 2]

[0109] 〔result〕 (1. Photostability test) The results of a photostability test of istradefylline for the tablets produced in Examples 1 and 2 and Comparative Examples 1 to 4 are shown in Table 3. In Table 3, "Z-Istra" and "Dimer-2" represent related substances. The units for "Z-Istra," "Dimer-2," and "total related substances" are "%."

[0110] [Table 3]

[0111] In Table 3, the photostability of istradefylline was evaluated using the proportions of Z-istra (a geometric isomer of istradefylline), Dimer-2 (a dimer of istradefylline), and total analogs (decomposition products of istradefylline) as indicators. The proportions of Z-istra, Dimer-2, and total analogs increase as istradefylline becomes destabilized. In Examples 1 and 2 above, the increase in Z-istra, Dimer-2, and total analogs (i.e., the value shown as "1.2 million lx (xenon)" - "INITIAL" in Table 3) was lower than in Comparative Examples 1 to 4.

[0112] Therefore, it was shown that in a formulation containing istradefylline, the photostability of istradefylline can be improved by incorporating iron oxide into the core and titanium oxide into the first coating layer located on the outside of the core.

[0113] (2. Disintegration Test) The tablets produced in Examples 1 to 4 were subjected to a disintegration test, and the results are shown in Table 4.

[0114] [Table 4]

[0115] As can be seen from Table 4, when a second coating layer containing an aminoalkyl methacrylate copolymer was provided, the disintegration property was improved (Example 3). Furthermore, when a third coating layer containing D-mannitol (excipient) was provided in addition to the second coating layer, the disintegration property was further improved (Example 4).

[0116] Therefore, it was shown that the disintegration property of the above formulation was improved by providing a second coating layer containing an aminoalkyl methacrylate copolymer, or by providing a third coating layer containing D-mannitol (excipient) in addition to the second coating layer.

[0117] [Prescription example 1] Tablets with a hardness of 50 N and a thickness of 3.4 mm were obtained in the same manner as in Example 4, except that the type and amount of each component was changed as shown in Table 5. In Table 5, the amount of each component is expressed in mg.

[0118] [Table 5]

[0119] The results of a photostability test and a disintegration test of istradefylline for the tablets produced in Formulation Example 1 above are shown in Tables 6 and 7, respectively. In Table 6, "Z-Istra" and "Dimer-2" represent related substances. The units for "Z-Istra," "Dimer-2," and "total related substances" are "%."

[0120] [Table 6]

[0121] [Table 7] [Industrial Applicability]

[0122] The formulation of the present invention has improved photostability, or photostability and disintegrability, of istradefylline or a pharmaceutically acceptable salt thereof, and can therefore be suitably used as a novel formulation of istradefylline (e.g., in the treatment of various diseases based on adenosine A2 receptor activation, such as Parkinson's disease).

Claims

[Claim 1] Any granule or formulation described herein.

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