Istradefylline preparation

Abstract

To provide a novel preparation having improved leachability of istradefylline.SOLUTION: Granules contain istradefylline or a pharmaceutically acceptable salt thereof, and hydroxypropyl cellulose and / or sucrose fatty acid ester. In the granules, a total of 5.0 mass% or more of hydroxypropyl cellulose and / or sucrose fatty acid ester is contained.SELECTED DRAWING: Figure 3

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. The present invention further relates to a method for producing the oral solid formulation and a method for improving the dissolution property of the oral solid formulation. [Background technology]

[0002] Istradefylline has an adenosine A2 receptor antagonistic effect 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 is characterized by its low solubility in water. Drugs with low solubility in water are generally said to have low bioavailability due to their low solubility and slow dissolution rate in the gastrointestinal tract. Improvements in solubility, dissolution rate, and bioavailability are also desired for istradefylline.

[0004] Therefore, from the above viewpoint, various preparations 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, in the preparations containing istradefylline as described in Patent Documents 1 and 2, there is room for improvement in terms of the dissolution of istradefylline from the preparations.

[0009] Therefore, one aspect of the present invention aims to provide a novel formulation with improved dissolution properties of istradefylline. [Means for solving the problem]

[0010] As a result of extensive research aimed at solving the above problems, the present inventors discovered for the first time that the inclusion of a specific amount of hydroxypropyl cellulose and / or sucrose fatty acid ester in a formulation containing istradefylline improves the dissolution of istradefylline from the formulation, leading to the completion of the present invention. That is, one aspect of the present invention includes the following configuration. <1> Granules comprising istradefylline or a pharmaceutically acceptable salt thereof, and hydroxypropyl cellulose and / or a sucrose fatty acid ester, Granules characterized by containing a total of 5.0% by mass or more of hydroxypropyl cellulose and / or sucrose fatty acid ester. <2> <1> 1. A solid oral formulation comprising the granules according to claim 1. <3> Characterized in that it is a tablet, <2> 1. The oral solid formulation according to claim 1. <4> A method for producing an oral solid formulation comprising istradefylline or a pharmaceutically acceptable salt thereof, A method characterized by comprising a step of mixing istradefylline or a pharmaceutically acceptable salt thereof with at least hydroxypropyl cellulose and / or sucrose fatty acid ester to obtain a mixture containing a total of 5.0% by mass or more of the hydroxypropyl cellulose and / or sucrose fatty acid ester. <5> A method for improving the dissolution of istradefylline or a pharmaceutically acceptable salt thereof from an oral solid formulation containing istradefylline or a pharmaceutically acceptable salt thereof, comprising: A method characterized in that the oral solid formulation contains hydroxypropyl cellulose and / or sucrose fatty acid ester. <6> An oral solid formulation comprising istradefylline or a pharmaceutically acceptable salt thereof, hydroxypropyl cellulose, and a sucrose fatty acid ester. [Effects of the Invention]

[0011] According to one aspect of the present invention, there is provided a novel formulation having improved dissolution properties of istradefylline or a pharmaceutically acceptable salt thereof, and there is also provided a method for improving the dissolution properties of istradefylline or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 is a diagram showing the results of a dissolution test in an example according to one embodiment of the present invention. [Figure 2] FIG. 1 is a diagram showing the results of a dissolution test in an example according to one embodiment of the present invention. [Figure 3] FIG. 1 is a diagram showing the results of a dissolution test in an example according to one embodiment of the present invention. [Figure 4] FIG. 1 is a diagram showing the results of a dissolution test in a comparative example. [Figure 5] FIG. 1 is a diagram showing the results of dissolution tests in an example according to one embodiment of the present invention and a comparative example. [Figure 6] FIG. 1 is a diagram showing the results of a dissolution test in a comparative example. [Figure 7] FIG. 1 is a diagram showing the results of a dissolution test in a comparative example. [Figure 8] FIG. 1 is a diagram showing the results of dissolution tests in an example according to one embodiment of the present invention and a comparative example. DETAILED DESCRIPTION OF THE INVENTION

[0013] An embodiment of the present invention will be described in detail below.

[0014] Unless otherwise specified in this specification, "A to B" representing a numerical range means "A or more and B or less."

[0015] [1. Overview] Granules according to one embodiment of the present invention (hereinafter referred to as "granules of the present invention") are granules containing istradefylline or a pharmaceutically acceptable salt thereof (hereinafter sometimes simply referred to as "istradefylline") and hydroxypropyl cellulose and / or sucrose fatty acid ester, and are characterized in that the granules contain a total of 5.0% by mass or more of hydroxypropyl cellulose and / or sucrose fatty acid ester. Furthermore, an oral solid formulation according to one embodiment of the present invention (hereinafter referred to as "formulation of the present invention") is characterized in that it contains the above-mentioned granules.

[0016] The present inventors have conducted detailed studies on formulations containing istradefylline, particularly on components contained together with istradefylline from the viewpoint of dissolution properties, and as a result have succeeded in making the following discoveries. The inclusion of hydroxypropyl cellulose and / or sucrose fatty acid esters together with istradefylline improves the dissolution of istradefylline from granules and tablets containing istradefylline.

[0017] It was previously unknown that hydroxypropyl cellulose or sucrose fatty acid esters are involved in the dissolution of istradefylline, and therefore the above findings made by the present inventors are extremely surprising.

[0018] 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.

[0019] 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.

[0020] [ka]

[0021] 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.

[0022] 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.

[0023] In addition, either crystalline or amorphous istradefylline can be used, and the particle size is not particularly limited. For example, in one embodiment of the present invention, the particle size (D 50 The particle diameter (D ) is, for example, preferably 21 to 100 μm, and more preferably 21 to 40 μm. 50 ) can be measured by a laser diffraction particle size distribution measurement method, and a specific example is a method using a laser diffraction scattering particle size distribution measurement device (Mastersizer 3000, manufactured by Malvern Instruments).

[0024] The granules of the present invention contain hydroxypropyl cellulose and / or sucrose fatty acid ester, which has the effect of improving the dissolution of istradefylline from an oral solid formulation to which the granules are applied.

[0025] In this specification, "hydroxypropyl cellulose" refers to a general hydroxypropyl cellulose having a molar substitution of 3, and is clearly distinguished from "low-substituted hydroxypropyl cellulose" having a molar substitution of 0.2 to 0.4. In other words, in this specification, "hydroxypropyl cellulose" is different from low-substituted hydroxypropyl cellulose.

[0026] The sucrose fatty acid ester contained in the granules of the present invention is not particularly limited as long as it is of a grade suitable for pharmaceutical use. Examples of sucrose fatty acid esters include sucrose behenate, sucrose stearate, sucrose palmitate, sucrose myristate, sucrose laurate, sucrose erucate, and sucrose oleate. Preferably, sucrose stearate, sucrose palmitate, sucrose myristate, and / or sucrose laurate are used, and more preferably, sucrose stearate.

[0027] In one embodiment of the present invention, the amount of hydroxypropyl cellulose and / or sucrose fatty acid ester contained in the granules of the present invention is, for example, a total of 5.0% by mass or more, preferably a total of 7.0% by mass or more, and more preferably a total of 11.0% by mass or more, based on the mass of the granules. When the amount of hydroxypropyl cellulose and / or sucrose fatty acid ester contained in the granules of the present invention is within the above range, it has the advantage of ensuring sufficient dissolution. Furthermore, the upper limit of the amount of hydroxypropyl cellulose and / or sucrose fatty acid ester contained in the granules of the present invention is, for example, a total of 50% by mass or less, preferably a total of 40% by mass or less, and more preferably a total of 25% by mass or less. When the amount of hydroxypropyl cellulose and / or sucrose fatty acid ester contained in the granules of the present invention exceeds the above upper limit, the effect of improving dissolution becomes saturated.

[0028] In one embodiment of the present invention, the amount of hydroxypropyl cellulose and / or sucrose fatty acid ester contained in the granules of the present invention is, for example, 2.5 to 25 mg, preferably 3.5 to 17.5 mg, and more preferably 5.5 to 15.0 mg.

[0029] In one embodiment of the present invention, the amount of istradefylline contained in the granules of the present invention 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 granules.

[0030] In one embodiment of the present invention, hydroxypropyl cellulose and sucrose fatty acid ester are added as a binder and a surfactant, respectively.

[0031] The granules of the present invention may contain other ingredients besides those mentioned above, such as excipients, binders, disintegrants, and colorants.

[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 hypromellose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, 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 colorant is not particularly limited, but examples thereof include yellow colorants (e.g., yellow ferric oxide, yellow iron oxide, Food Yellow No. 4 aluminum lake, red iron oxide, etc.), red colorants (e.g., iron sesquioxide, Food Red No. 2, Food Red No. 3, Food Red No. 102, etc.), black colorants (e.g., black iron oxide, carbon black, medicinal charcoal, etc.), caramel, etc. Preferably, iron oxide and caramel are used, and more preferably, yellow ferric oxide is used.

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

[0037] In one embodiment of the present invention, the surface of the granules of the present invention may be coated with a coating agent. The coating agent is not particularly limited, but examples thereof include titanium oxide, talc, silicic acid, hydroxypropyl cellulose, hypromellose, ethyl cellulose, polyvinyl alcohol, and copolymers of polyvinyl alcohol, acrylic acid, and methyl methacrylate. Preferably, hydroxypropyl cellulose, titanium oxide, or the like is used as a component of the coating agent.

[0038] In one embodiment of the present invention, the granules of the present invention can be produced by granulating istradefylline with hydroxypropyl cellulose and / or a sucrose fatty acid ester, and, if necessary, other additives, and coating the resulting granules (elementary granules) with a coating agent, if necessary. 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.

[0039] The moisture content (loss on drying) of the granules of the present invention is not particularly limited, but is preferably 5% or less, more preferably 1% or less.

[0040] 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].

[0041] The formulation of the present invention contains granules containing istradefylline as well as hydroxypropyl cellulose and / or sucrose fatty acid esters, thereby improving the dissolution of istradefylline from the formulation.

[0042] 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.

[0043] In one embodiment of the present invention, the amount of hydroxypropyl cellulose and / or sucrose fatty acid ester contained in the formulation of the present invention is, for example, a total of 1.8% by mass or more, preferably a total of 2.5% by mass or more, and more preferably a total of 3.9% by mass or more, based on the mass of the formulation. When the amount of hydroxypropyl cellulose and / or sucrose fatty acid ester contained in the formulation of the present invention is within the above range, it has the advantage of ensuring sufficient dissolution. Furthermore, the upper limit of the amount of hydroxypropyl cellulose and / or sucrose fatty acid ester contained in the formulation of the present invention is, for example, a total of 18.0% by mass or less, preferably a total of 12.5% by mass or less, and more preferably a total of 10.0% by mass or less. When the amount of hydroxypropyl cellulose and / or sucrose fatty acid ester contained in the formulation of the present invention exceeds the above upper limit, the effect of improving dissolution becomes saturated.

[0044] In one embodiment of the present invention, the amount of hydroxypropyl cellulose and / or sucrose fatty acid ester contained in the formulation of the present invention is, for example, 2.5 to 25 mg, preferably 3.5 to 17.5 mg, and more preferably 5.5 to 12.5 mg.

[0045] 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.

[0046] 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.

[0047] As the excipient, binder, disintegrant and colorant, for example, those described in [2. Granules of the present invention] can be used.

[0048] 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.

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

[0050] In one embodiment of the present invention, when the formulation of the present invention is in the form of tablets, granules, etc., a film coating may be further provided on the outside of the tablets, granules, etc. Coating agents used for film coating are not particularly limited, but examples include talc, silicic acid, hydroxypropyl cellulose, hypromellose, ethyl cellulose, polyvinyl alcohol, copolymers of polyvinyl alcohol, acrylic acid, and methyl methacrylate, etc. Preferably, polyvinyl alcohol, hydroxypropyl cellulose, hypromellose, talc, etc. are used.

[0051] In one embodiment of the present invention, the formulation of the present invention is an oral solid formulation comprising istradefylline or a pharmaceutically acceptable salt thereof, hydroxypropyl cellulose, and a sucrose fatty acid ester.

[0052] 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.

[0053] The water content (loss on drying) of the preparation of the present invention is not particularly limited, but is preferably 10% or less, and more preferably 3% or less.

[0054] Furthermore, when the preparation of the present invention is in the form of a tablet, its hardness is not particularly limited, but is preferably, for example, about 20 to 150 N, and more preferably about 40 to 100 N. [4. Other] In one embodiment of the present invention, there is provided a method for producing an oral solid formulation containing istradefylline or a pharmaceutically acceptable salt thereof, characterized in that the method comprises a step of mixing istradefylline or a pharmaceutically acceptable salt thereof with at least hydroxypropyl cellulose and / or sucrose fatty acid ester to obtain a mixture containing a total of 5.0% by mass or more of the hydroxypropyl cellulose and / or sucrose fatty acid ester (hereinafter referred to as the "production method of the present invention").

[0055] In the manufacturing method of the present invention, the "mixture" is not particularly limited as long as it is a mixture of istradefylline and hydroxypropyl cellulose and / or sucrose fatty acid ester. Examples of the mixture include a composition in which istradefylline is mixed with hydroxypropyl cellulose and / or sucrose fatty acid ester, and granules obtained by granulating the composition. If necessary, other additives may be mixed into the "mixture."

[0056] 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. The resulting granules A and B are then mixed, a lubricant is added, and the mixture is compressed into tablets to obtain the formulation (tablets) of the present invention. Additionally, the manufacturing method of the present invention also includes directly compressing a composition (mixture) in which istradefylline is mixed with hydroxypropyl cellulose and / or a sucrose fatty acid ester to obtain tablets.

[0057] 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," "hydroxypropyl cellulose and / or sucrose fatty acid ester," etc.) are incorporated by reference from those described in [2. Granules of the present invention] and [3. Preparations of the present invention].

[0058] In addition, in one embodiment of the present invention, there is provided a method for improving the dissolution of istradefylline or a pharmaceutically acceptable salt thereof from an oral solid formulation containing istradefylline or a pharmaceutically acceptable salt thereof, characterized in that the oral solid formulation contains hydroxypropyl cellulose and / or a sucrose fatty acid ester (hereinafter referred to as the "dissolution improvement method of the present invention").

[0059] In the stabilization method of the present invention, the descriptions of each component (e.g., "istradefylline or a pharmaceutically acceptable salt thereof," "oral solid formulation," "hydroxypropyl cellulose and / or sucrose fatty acid ester," etc.) are incorporated by reference from those described in [2. Granules of the present invention] and [3. Preparations of the present invention].

[0060] 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]

[0061] An embodiment of the present invention will now be described.

[0062] [Measurement and evaluation methods] The evaluations in the examples and comparative examples were carried out by the following methods.

[0063] (Dissolution test) Dissolution tests were conducted in accordance with the dissolution test method (paddle method / immediate-release preparations) of the 17th edition of the Japanese Pharmacopoeia using 900 mL of test solution at pH 6.8 (polysorbate 1%). The details are as follows:

[0064] After placing the container containing the test solution in the dissolution tester, the sample was added and the device was operated at a rotation speed of 50 rpm, and the test solution was sampled at specified intervals (5 minutes, 15 minutes, 30 minutes, 60 minutes, and 120 minutes).

[0065] The amount of istradefylline in the collected test solution was measured by ultraviolet-visible spectrophotometry (UV), and the percentage of the labeled amount (the amount of istradefylline listed in Tables 1, 3, and 4) was calculated as the dissolution rate (%).

[0066] As the sample, one tablet was used in Examples 1 to 7 and Comparative Example 1, and 50 mg of a kneaded product was used in Examples 8 to 11 and Comparative Examples 2 to 6.

[0067] (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.

[0068] Example 1 (Production of grain A) Istradefylline, D-mannitol, hydroxypropyl cellulose (HPC-L manufactured by Nippon Soda Co., Ltd.), low-substituted hydroxypropyl cellulose, sucrose fatty acid ester (Surfhope (registered trademark) J1816 manufactured by Mitsubishi Chemical Foods Corporation / sucrose stearate ester), and yellow ferric oxide were mixed with purified water and granulated. The resulting granules were crushed, dried, and then sized to produce Granule A.

[0069] (Production of B grains) D-mannitol, ethyl cellulose, corn starch, crospovidone, light anhydrous silicic acid, and yellow ferric oxide were mixed with purified water and granulated, dried, and then sized to give Granule B.

[0070] (mixing / tableting) The above-mentioned granules A, the above-mentioned granules B, aspartame, and light anhydrous silicic acid were mixed. Magnesium stearate was added to the obtained mixture and mixed to obtain a tablet powder. The tablet powder was compressed using a circular punch with a diameter of 7.0 mm to obtain tablets (orally disintegrating tablets).

[0071] For the amounts of each ingredient, please refer to Table 1.

[0072] Example 2 Tablets were obtained in the same manner as in Example 1, except that the amount of D-mannitol was changed to 17.74 mg and the amount of hydroxypropyl cellulose ("HPC-L" manufactured by Nippon Soda Co., Ltd.) was changed to 2.5 mg.

[0073] Example 3 Tablets were obtained in the same manner as in Example 1, except that the amount of D-mannitol was changed to 16.74 mg and the amount of hydroxypropyl cellulose ("HPC-L" manufactured by Nippon Soda Co., Ltd.) was changed to 3.5 mg.

[0074] Example 4 Tablets were obtained in the same manner as in Example 1, except that hydroxypropyl cellulose ("HPC-L" manufactured by Nippon Soda Co., Ltd.) was changed to hydroxypropyl cellulose ("HPC-SSL" manufactured by Nippon Soda Co., Ltd.).

[0075] Example 5 Tablets were obtained in the same manner as in Example 4, except that the amount of D-mannitol was changed to 16.74 mg and the amount of hydroxypropyl cellulose ("HPC-SSL" manufactured by Nippon Soda Co., Ltd.) was changed to 3.5 mg.

[0076] Example 6 Tablets were obtained in the same manner as in Example 4, except that the amount of D-mannitol was changed to 15.24 mg and the amount of hydroxypropyl cellulose ("HPC-SSL" manufactured by Nippon Soda Co., Ltd.) was changed to 5 mg.

[0077] Example 7 Tablets were obtained in the same manner as in Example 2, except that the amount of D-mannitol was changed to 19.74 mg and the sucrose fatty acid ester was omitted.

[0078] For details of the amounts of each component in Examples 2 to 7, see Table 1.

[0079] [Table 1]

[0080] The tablet thickness, hardness and disintegration time of the tablets produced in Examples 1 to 7 are shown in Table 2.

[0081] [Table 2]

[0082] Comparative Example 1 (Production of B grains) D-mannitol, ethyl cellulose, corn starch, crospovidone, light anhydrous silicic acid, and yellow ferric oxide were mixed with purified water and granulated, dried, and then sized to give Granule B.

[0083] (mixing / tableting) Istradefylline and the above-mentioned granules B were mixed, and magnesium stearate was further mixed with the resulting mixture to prepare a tableting powder. This tableting powder was compressed to obtain tablets.

[0084] For the amounts of each ingredient, please refer to Table 3.

[0085] [Table 3]

[0086] Comparative Example 2 Istradefylline and D-mannitol were placed in a mortar, and an appropriate amount of water was added thereto and kneaded. The resulting kneaded product was vacuum dried and sieved through a 30M sieve to prepare a sample of the kneaded product.

[0087] For the amounts of each ingredient, see Table 4.

[0088] Example 8 A kneaded sample was prepared in the same manner as in Comparative Example 2, except that the amount of D-mannitol was changed to 27.5 mg and 2.5 mg of hydroxypropyl cellulose ("HPC-L" manufactured by Nippon Soda Co., Ltd.) was added.

[0089] Example 9 A kneaded sample was prepared in the same manner as in Comparative Example 2, except that the amount of D-mannitol was changed to 27.5 mg and 2.5 mg of hydroxypropyl cellulose ("HPC-SSL" manufactured by Nippon Soda Co., Ltd.) was added.

[0090] Example 10 A kneaded product sample was prepared in the same manner as in Comparative Example 2, except that the amount of D-mannitol was changed to 29 mg and 1 mg of sucrose fatty acid ester was added.

[0091] Example 11 A kneaded product sample was prepared in the same manner as in Comparative Example 2, except that the amount of D-mannitol was changed to 28 mg and 2 mg of sucrose fatty acid ester was added.

[0092] Comparative Example 3 A kneaded product sample was prepared in the same manner as in Comparative Example 2, except that the amount of D-mannitol was changed to 29 mg and 1 mg of sodium lauryl sulfate was added.

[0093] Comparative Example 4 A kneaded product sample was prepared in the same manner as in Comparative Example 2, except that the amount of D-mannitol was changed to 28 mg and 2 mg of sodium lauryl sulfate was added.

[0094] Comparative Example 5 A kneaded sample was prepared in the same manner as in Comparative Example 2, except that the amount of D-mannitol was changed to 29 mg and 1 mg of polyoxyethylene (160) polyoxypropylene (30) glycol was added.

[0095] Comparative Example 6 A kneaded sample was prepared in the same manner as in Comparative Example 2, except that the amount of D-mannitol was changed to 28 mg and 2 mg of polyoxyethylene (160) polyoxypropylene (30) glycol was added.

[0096] For details of the amounts of each component in Examples 8 to 11 and Comparative Examples 3 to 6, see Table 4.

[0097] [Table 4]

[0098] 〔result〕 The tablets produced in Examples 1 to 7 and Comparative Example 1, and the kneaded product samples prepared in Examples 8 to 11 and Comparative Examples 2 to 6 were subjected to a dissolution test of istradefylline, and the results are shown in FIGS.

[0099] The following results were obtained from the experimental examples using tablets: That is, Comparative Example 1 revealed that tablets containing neither hydroxypropyl cellulose nor sucrose fatty acid ester had a low dissolution rate (FIG. 4).

[0100] Furthermore, a comparison of Examples 1 to 6 with Comparative Example 1 revealed that tablets containing hydroxypropyl cellulose and sucrose fatty acid esters had a higher dissolution rate than tablets containing neither hydroxypropyl cellulose nor sucrose fatty acid esters (Figures 1, 2 and 4).

[0101] Furthermore, a comparison between Example 7 and Comparative Example 1 revealed that tablets containing only hydroxypropyl cellulose (without sucrose fatty acid ester) had a higher dissolution rate than tablets containing neither hydroxypropyl cellulose nor sucrose fatty acid ester (Figures 3 and 4).

[0102] Furthermore, the following results were obtained from experimental examples using kneaded samples: That is, by comparing Examples 8 to 11 with Comparative Example 2, it was found that kneaded samples containing either hydroxypropyl cellulose or sucrose fatty acid ester had a higher dissolution rate than kneaded samples containing neither hydroxypropyl cellulose nor sucrose fatty acid ester (FIGS. 5 and 8).

[0103] Furthermore, by comparing Examples 10 to 11 with Comparative Examples 3 to 6, it was found that the dissolution rate was high when sucrose fatty acid esters were used among surfactants (FIGS. 6 to 8).

[0104] The above results demonstrate that the inclusion of hydroxypropyl cellulose and / or sucrose fatty acid ester together with istradefylline in granules or kneaded products (mixtures) increases the dissolution rate of istradefylline from the granules or kneaded products (mixtures) (improved dissolution properties). Furthermore, the inclusion of the granules in tablets increases the dissolution rate of istradefylline from the tablets (improved dissolution properties).

[0105] [Prescription example 1] Tablets are obtained in the same manner as in Example 1, except that titanium oxide and hydroxypropyl cellulose are added in the manufacturing process of Granule A, D-mannitol is not added in the mixing and tableting process, the amounts of each component are changed to those listed in Table 5, and (Manufacturing of Granule A) is changed to the method described below.

[0106] (Production of grain A) Istradefylline, D-mannitol, hydroxypropyl cellulose ("HPC-SSL" manufactured by Nippon Soda Co., Ltd.), low-substituted hydroxypropyl cellulose, sucrose fatty acid ester ("Surfhope® J1816" / sucrose stearate ester manufactured by Mitsubishi Chemical Foods Corporation), and yellow ferric oxide are mixed with purified water and granulated. The resulting granules are crushed, dried, and then sized to form granules A. A solution of titanium oxide and hydroxypropyl cellulose ("HPC-SSL" manufactured by Nippon Soda Co., Ltd.) dissolved in purified water is sprayed onto granules A to coat them.

[0107] [Table 5] [Industrial Applicability]

[0108] The tablet of the present invention has improved dissolution properties 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 Parkinson's disease, senile dementia, depression, asthma, osteoporosis, etc.).

Claims

[Claim 1] Granules comprising istradefylline or a pharmaceutically acceptable salt thereof, and hydroxypropyl cellulose and / or a sucrose fatty acid ester, Granules characterized by containing a total of 5.0% by mass or more of hydroxypropyl cellulose and / or sucrose fatty acid ester.

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