JP2020186190A - Istradefylline preparation - Google Patents

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

The present invention relates to granules containing isstradefylline or a pharmaceutically acceptable salt thereof. The present invention also relates to an oral solid preparation containing the granules. Furthermore, the present invention relates to a method for producing the oral solid preparation and a method for improving the dissolution property of the oral solid preparation.

Istradefylline has an adenosine A ₂ receptor antagonism and is therefore in the treatment of diseases based on adenosine A ₂ receptor hyperactivity, such as Parkinson's disease, senile dementia, depression, asthma, osteoporosis and the like. It is useful.

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 in the gastrointestinal tract and their slow dissolution rate. Regarding istradefylline, improvement in solubility, dissolution rate, etc., improvement in bioavailability, etc. are desired.

Therefore, from the above viewpoint, various preparations containing istradefylline have been developed.

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

Further, Patent Document 2 discloses a solid preparation containing isstradefylline or a pharmacologically acceptable salt thereof and crystalline cellulose.

Japanese Patent No. 4606326 Japanese Patent No. 4673745

However, in the preparations containing istradefylline as described in Patent Documents 1 and 2, there is room for improvement in the elution of istradefylline from the preparations.

Therefore, one aspect of the present invention is to realize a novel preparation having improved elution of isstradefylline.

As a result of diligent studies to solve the above problems, the present inventors have added a specific amount of hydroxypropyl cellulose and / or sucrose fatty acid ester to the preparation containing istradefylline to obtain the above preparation. For the first time, it was found that the elution of isstradefylline was improved, and the present invention was completed. That is, one aspect of the present invention includes the following configurations.
<1> Granules containing istradefylline or a pharmaceutically acceptable salt thereof, and hydroxypropyl cellulose and / or sucrose fatty acid ester.
Granules comprising a total of 5.0% by mass or more of hydroxypropyl cellulose and / or sucrose fatty acid ester in the granules.
<2> An oral solid preparation comprising the granules according to <1>.
<3> The oral solid preparation according to <2>, which is a tablet.
<4> A method for producing an oral solid preparation containing isstradefylline or a pharmaceutically acceptable salt thereof.
At least hydroxypropyl cellulose and / or sucrose fatty acid ester is mixed with istradefylline or a pharmaceutically acceptable salt thereof, and the hydroxypropyl cellulose and / or sucrose fatty acid ester is contained in a total amount of 5.0% by mass or more. A method comprising the step of obtaining a mixture.
<5> A method for improving the elution of isstradefylline or a pharmaceutically acceptable salt thereof from an oral solid preparation containing istradefylline or a pharmaceutically acceptable salt thereof.
A method comprising containing hydroxypropyl cellulose and / or sucrose fatty acid ester in the oral solid preparation.
<6> An oral solid preparation containing istradefylline or a pharmaceutically acceptable salt thereof, hydroxypropyl cellulose, and sucrose fatty acid ester.

According to one aspect of the present invention, it is possible to provide a novel preparation having improved elution of isstradefylline or a pharmaceutically acceptable salt thereof. Also, according to one aspect of the present invention, it is possible to provide a method for improving the elution of isstradefylline or a pharmaceutically acceptable salt thereof.

It is a figure which shows the result of the dissolution test in the Example which concerns on one Embodiment of this invention. It is a figure which shows the result of the dissolution test in the Example which concerns on one Embodiment of this invention. It is a figure which shows the result of the dissolution test in the Example which concerns on one Embodiment of this invention. It is a figure which shows the result of the dissolution test in the comparative example. It is a figure which shows the result of the dissolution test in the Example and the comparative example which concerns on one Embodiment of this invention. It is a figure which shows the result of the dissolution test in the comparative example. It is a figure which shows the result of the dissolution test in the comparative example. It is a figure which shows the result of the dissolution test in the Example and the comparative example which concerns on one Embodiment of this invention.

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

Unless otherwise specified in the present specification, "A to B" representing a numerical range means "A or more and B or less".

[1. Overview〕
The granules according to one embodiment of the present invention (hereinafter, referred to as "granule of the present invention") may be referred to as isstradefylline or a pharmaceutically acceptable salt thereof (hereinafter, simply referred to as "istradefylline"). ) And / or hydroxypropyl cellulose and / or sucrose fatty acid ester, and the granules contain a total of 5.0% by mass or more of hydroxypropyl cellulose and / or sucrose fatty acid ester. And. In addition, the oral solid preparation according to the embodiment of the present invention (hereinafter, referred to as "the preparation of the present invention") is characterized by containing the above-mentioned granules.

The present inventors have succeeded in obtaining the following findings as a result of detailed studies on preparations containing istradefylline, in particular, components contained together with istradefylline from the viewpoint of dissolution.
The inclusion of hydroxypropyl cellulose and / or sucrose fatty acid ester with istradefylline improves the elution of istradefylline from granules and tablets containing istradefylline.

It has never been known that hydroxypropyl cellulose or sucrose fatty acid esters are associated with the elution of istradefylline. Therefore, the above findings obtained by the present inventors are extremely surprising.

Thus, since the granules (or formulations) of the present invention have an advantageous effect based on the above findings, it is intended to provide a formulation containing a useful novel isstradefylline or a pharmaceutically acceptable salt thereof. Can be done.

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

As used herein, the term "pharmaceutically acceptable salt" is medically free from excessive toxicity, irritation, allergic reactions, etc., and is suitable for use in contact with human or other mammalian tissues. Means salt.

Pharmaceutically acceptable salts of istradefylline are well known in the art and any can be used. Pharmaceutically acceptable salts of Istradefylin include, for example, hydrochlorides, hydrobromates, nitrates, sulfates, phosphates and other inorganic acid salts; acetates, oxalates, maleates, etc. Organic acid salts such as 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 Salts; ammonium salts, tetramethylammonium salts; additional salts such as morpholin, piperidine, lysine, glycine, phenylalanine, aspartic acid, glutamate and the like.

Further, as istradefylline, either crystalline or amorphous one can be used, and the particle size thereof is not particularly limited. For example, in one embodiment of the present invention, the particle size (D ₅₀ ) of istradefylline is preferably, for example, 21 to 100 μm, and more preferably 21 to 40 μm. Examples of the above-mentioned particle size (D ₅₀ ) measuring method include a laser diffraction type particle size distribution measuring method, and a specific example is a method using a laser diffraction scattering type particle size distribution measuring device (Mastersizer 3000, manufactured by Malvern). And so on.

The granules of the present invention contain hydroxypropyl cellulose and / or sucrose fatty acid ester. The inclusion of hydroxypropyl cellulose and / or sucrose fatty acid ester in the granules of the present invention has the effect of improving the elution of istradefylline from the oral solid preparation to which the granules are applied.

In addition, "hydroxypropyl cellulose" in this specification means general hydroxypropyl cellulose of molar substitution degree 3, and is clear as "low substitution degree hydroxypropyl cellulose" of molar substitution degree 0.2-0.4. Is distinguished by. That is, "hydroxypropyl cellulose" and low-substituted hydroxypropyl cellulose are different in the present specification.

The sucrose fatty acid ester contained in the granules of the present invention is not particularly limited as long as it is a grade that can be used in medicine. Examples of the sucrose fatty acid ester include sucrose behenic acid ester, sucrose stearic acid ester, sucrose palmitate ester, sucrose myristic acid ester, sucrose lauric acid ester, sucrose erucic acid ester, and sucrose oleic acid ester. And so on. Sucrose stearic acid ester, sucrose palmitic acid ester, sucrose myristic acid ester, and / or sucrose lauric acid ester are preferably used, and more preferably sucrose stearic acid ester is used.

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, 5.0% by mass or more in total, preferably 5.0% by mass or more, based on the mass of the granules. , A total of 7.0% by mass or more, more preferably a total of 11.0% by mass or more. When the amount of hydroxypropyl cellulose and / or sucrose fatty acid ester contained in the granules of the present invention is in the above range, there is an advantage of ensuring sufficient elution. 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, 50% by mass or less in total, preferably 40% by mass or less in total, and more preferably. The total is 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 elution is saturated.

In one embodiment of the 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. Yes, more preferably 5.5 to 15.0 mg.

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, based on the mass of the granules. Yes, more preferably 25-60% by mass.

In one embodiment of the invention, hydroxypropyl cellulose and sucrose fatty acid ester are added as binders and surfactants, respectively.

The granules of the present invention may contain excipients, binders, disintegrants, colorants and the like as components other than the above.

The excipient is not particularly limited, and examples thereof include D-mannitol, lactose, sucrose, cornstarch (corn starch), calcium phosphate, sorbitol, crystalline cellulose and the like. Preferably, D-mannitol is used.

The binder is not particularly limited, and is, for example, hypromellose, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, a copolymer of N-vinylpyrrolidone and vinyl acetate, or a combination of these polymers, pregelatinized starch, and the like. Examples include gelatin, canten, and arabic rubber.

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

The colorant is not particularly limited, but is, for example, a yellow colorant (for example, yellow iron sesquioxide, iron yellow oxide, edible yellow No. 4 aluminum lake, red iron oxide, etc.), and a red colorant (for example, sesquioxide). Examples thereof include iron, edible red No. 2, edible red No. 3, edible red No. 102, etc.), colorants exhibiting black color (for example, black iron oxide, carbon black, medicated charcoal, etc.), caramel, and the like. Iron oxide and caramel are preferably used, and more preferably yellow iron sesquioxide is used.

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

In one embodiment of the present invention, the granules of the present invention may have a surface coated with a coating agent. The coating agent is not particularly limited, and examples thereof include those containing titanium oxide, talc, silicic acid, hydroxypropyl cellulose, hypromellose, ethyl cellulose, polyvinyl alcohol, a copolymer of polyvinyl alcohol, acrylic acid, and methyl methacrylate. Be done. Preferably, hydroxypropyl cellulose, titanium oxide or the like is used as a component of the coating agent.

In one embodiment of the invention, the granules of the invention are obtained by granulating istradefylline with hydroxypropyl cellulose and / or sucrose fatty acid ester and, if necessary, other additives. (Elementary granules) can be produced by coating with a coating agent, if necessary. The granulation method is not particularly limited, and conventionally known techniques can be applied. For example, a fluidized bed granulation method, a stirring granulation method, an extrusion granulation method and the like can be applied.

The water content (dry weight loss) in the granules of the present invention is not particularly limited, but is preferably 5% or less, and more preferably 1% or less.

[3. Formulation of the present invention]
In one embodiment of the present invention, [2. Provided is an oral solid preparation (hereinafter, referred to as “the preparation of the present invention”), which comprises the granules described in [Granule of the present invention].

The formulations of the present invention include granules containing hydroxypropyl cellulose and / or sucrose fatty acid ester, along with istradefylline. Therefore, it has the effect of improving the elution of isstradefylline from the above preparation.

In the present specification, the oral solid preparation is not particularly limited as long as it is a drug molded to be administered orally, and for example, tablets (including orally disintegrating tablets), capsules, granules, powders, and dry syrups. And so on. The preparation of the present invention is preferably a tablet.

In one embodiment of the present invention, the amount of hydroxypropyl cellulose and / or sucrose fatty acid ester contained in the preparation of the present invention is, for example, 1.8% by mass or more in total, preferably 1.8% by mass or more, based on the mass of the preparation. , 2.5% by mass or more in total, and more preferably 3.9% by mass or more in total. When the amount of hydroxypropyl cellulose and / or sucrose fatty acid ester contained in the preparation of the present invention is in the above range, there is an advantage of ensuring sufficient elution. The upper limit of the amount of hydroxypropyl cellulose and / or sucrose fatty acid ester contained in the preparation of the present invention is, for example, 18.0% by mass or less in total, preferably 12.5% by mass or less in total. More preferably, the total amount is 10.0% by mass or less. When the amount of hydroxypropyl cellulose and / or sucrose fatty acid ester contained in the preparation of the present invention exceeds the above upper limit, the effect of improving elution is saturated.

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

In one embodiment of the present invention, the amount of istradefylline contained in the preparation of the present invention is, for example, 1.0 to 50.0% by mass, preferably 5.0 to 5% based on the mass of the preparation. It is 30.0% by mass, more preferably 10.0 to 20.0% by mass.

In addition to the above granules, the preparation of the present invention may contain various components according to the type and form of the preparation. Examples of such components include excipients, binders, disintegrants, colorants, lubricants and the like.

Examples of excipients, binders, disintegrants and colorants include [2. The granules of the present invention] are used.

The lubricant is not particularly limited, and is, for example, carnauba wax, hydrous silicon dioxide, hydrous amorphous silicon oxide, dry aluminum hydroxide gel, magnesium silicate, light anhydrous silicic acid, synthetic aluminum silicate, magnesium oxide, and heavy. Silicic anhydride, 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, silicate hydrate, Examples thereof include magnesium aluminometasilicate. Preferably, magnesium stearate is used.

The content of the additive is not particularly limited and may be appropriately set based on a conventionally known technique.

In one embodiment of the present invention, when the preparation of the present invention is a tablet, granule, etc., a film coating may be further provided on the outside of the tablet, granule, etc. The coating agent used for film coating is not particularly limited, and examples thereof include talc, silicic acid, hydroxypropyl cellulose, hypromellose, ethyl cellulose, polyvinyl alcohol, a copolymer of polyvinyl alcohol, acrylic acid, and methyl methacrylate. .. Preferably, polyvinyl alcohol, hydroxypropyl cellulose, hypromellose, talc and the like are used.

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

The molding of the preparation of the present invention is not particularly limited, and any shape can be adopted. When the preparation of the present invention is a tablet, it may have, for example, a circular shape, an oval shape, a spherical shape, a rod shape, a donut shape, or the like. When the preparation of the present invention is a tablet, it may be a single layer tablet, a laminated tablet, a nucleated tablet or the like.

The water content (dry weight loss) in the preparation of the present invention is not particularly limited, but is preferably 10% or less, and preferably 3% or less.

When the preparation of the present invention is 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. Others]
In one embodiment of the present invention, a method for producing an oral solid preparation containing istradefylline or a pharmaceutically acceptable salt thereof, wherein at least hydroxypropyl cellulose and a pharmaceutically acceptable salt thereof are added to istradefylline or a pharmaceutically acceptable salt thereof. A method comprising the step of mixing / or sucrose fatty acid ester to obtain a mixture containing the hydroxypropyl cellulose and / or sucrose fatty acid ester in a total amount of 5.0% by mass or more (hereinafter, "the present invention". It is referred to as "manufacturing method").

In the production 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, granules obtained by granulating the composition, and the like. If necessary, other additives may be mixed in the "mixture".

The production method of the present invention may include, for example, a production step of a granulated product and a mixed tableting step. For example, by the method described in Examples, an istradefylline-containing granule (A grain) and another isstradefylline-free granule (B grain) are produced. Then, the obtained preparation (tablet) of the present invention can be obtained by mixing the obtained A granules and B granules, adding a lubricant, and tableting. In addition, the production method of the present invention also includes directly tableting a composition (mixture) in which istradefylline and hydroxypropyl cellulose and / or sucrose fatty acid ester are mixed to obtain a tablet.

Description of each component (eg, "istradefylline or a pharmaceutically acceptable salt thereof", "oral solid preparation", "hydroxypropyl cellulose and / or sucrose fatty acid ester", etc.) in the production method of the present invention. Is [2. Granules of the present invention] and [3. The formulation of the present invention] is incorporated.

Further, in one embodiment of the present invention, it is a method for improving the elution of isstradefylline or a pharmaceutically acceptable salt thereof from an oral solid preparation containing istradefylline or a pharmaceutically acceptable salt thereof. The present invention provides a method characterized by containing hydroxypropyl cellulose and / or sucrose fatty acid ester in the oral solid preparation (hereinafter, referred to as “method for improving elution of the present invention”).

In the stabilizing method of the present invention, for each component (eg, "istradefylline or a pharmaceutically acceptable salt thereof", "oral solid preparation", "hydroxypropyl cellulose and / or sucrose fatty acid ester", etc.) The explanation is [2. Granules of the present invention] and [3. The formulation of the present invention] is incorporated.

The present invention is not limited to the above-described embodiments, and various modifications can be made within the scope of the claims, and the embodiments obtained by appropriately combining the technical means disclosed in the different embodiments. Is also included in the technical scope of the present invention.

An embodiment of the present invention will be described below.

[Measurement and evaluation method]
Evaluation in Examples and Comparative Examples was carried out by the following method.

(Dissolution test)
According to the 17th revised Japanese Pharmacopoeia dissolution test method (paddle method / immediate release preparation), the dissolution test was carried out using 900 mL of pH 6.8 (polysorbate 1%) as a test solution. The details are as follows.

After setting the container containing the above test solution in the dissolution test device, the sample is charged and the device is operated at a rotation speed of 50 rpm for a specified time (5 minutes, 15 minutes, 30 minutes, 60 minutes, 120 minutes). The test solution was collected every minute).

The amount of istradefylline in the collected test solution was measured by the ultraviolet-visible absorptiometry (UV), and the percentage with respect to the indicated amount (the amount of istradefylline shown in Tables 1, 3 and 4) was the elution rate (%). Asked as.

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

(Collapse test)
According to the 17th revised Japanese Pharmacopoeia disintegration test method (immediate disintegration preparation), a disintegration test was carried out without an auxiliary plate, and the disintegration time when the tablet disintegrated was measured.

[Example 1]
(Manufacturing of A grain)
Istradefylin, D-mannitol, hydroxypropyl cellulose ("HPC-L" manufactured by Nippon Soda Co., Ltd.), low-substituted hydroxypropyl cellulose, sucrose fatty acid ester ("Surf Hope (registered trademark) manufactured by Mitsubishi Chemical Foods Co., Ltd." ) J1816 "/ sucrose stearic acid ester) and yellow iron sesquioxide were mixed with purified water to granulate. The obtained granulated product was crushed, dried, and then sized to obtain A granules.

(Manufacturing of B grains)
D-mannitol, ethyl cellulose, corn starch, crospovidone, light silicic acid anhydride, and yellow iron sesquioxide were mixed with purified water to granulate, dried, and then sized to obtain B granules.

(Mixing / locking)
The A granules, the B granules, aspartame and light anhydrous silicic acid were mixed. Magnesium stearate was added to the obtained mixture and mixed to obtain a tableting powder. The tableted powder was tableted using a circular punch having a diameter of 7.0 mm to obtain a tablet (orally disintegrating tablet).

See Table 1 for the amount of each component.

[Example 2]
By the same method 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. Obtained tablets.

[Example 3]
By the same method 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 Corporation) was changed to 3.5 mg. Obtained tablets.

[Example 4]
The tablets were prepared by the same method 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.). Obtained.

[Example 5]
By the same method 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 Corporation) was changed to 3.5 mg. Obtained tablets.

[Example 6]
Tablets were prepared by the same method 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 Corporation) was changed to 5 mg. Obtained.

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

See Table 1 for details of the amounts of each component of Examples 2 to 7.

The tablet thickness, hardness and disintegration time of the tablets produced in Examples 1 to 7 were as shown in Table 2, respectively.

[Comparative Example 1]
(Manufacturing of B grains)
D-mannitol, ethyl cellulose, corn starch, crospovidone, light silicic acid anhydride, and yellow iron sesquioxide were mixed with purified water to granulate, dried, and then sized to obtain B granules.

(Mixing / locking)
Istradefylline and the above B granules were mixed, and magnesium stearate was further mixed with the obtained mixture to prepare a tablet powder. This tableting powder was tableted to obtain a tablet.

See Table 3 for the amount of each component.

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

See Table 4 for the amount of each component.

[Example 8]
Kneaded product by the same method 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. Samples were prepared.

[Example 9]
Kneaded product by the same method 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. Samples were prepared.

[Example 10]
A sample of the kneaded product was prepared by the same method 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.

[Example 11]
A sample of the kneaded product was prepared by the same method 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.

[Comparative Example 3]
A kneaded sample was prepared by the same method 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.

[Comparative Example 4]
A kneaded sample was prepared by the same method 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.

[Comparative Example 5]
A sample of the kneaded product was prepared by the same method 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.

[Comparative Example 6]
A sample of the kneaded product was prepared by the same method 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.

See Table 4 for details of the amounts of each component of Examples 8 to 11 and Comparative Examples 3 to 6.

〔result〕
FIG. 1 shows the results of an elution test of istradefylline on the tablets produced in Examples 1 to 7 and Comparative Example 1 and the samples of the kneaded products prepared in Examples 8 to 11 and Comparative Examples 2 to 6. It is shown in ~ 8.

The following results were obtained from the experimental examples using tablets. That is, according to Comparative Example 1, it was found that the tablet containing neither hydroxypropyl cellulose nor sucrose fatty acid ester had a low elution rate (FIG. 4).

Further, by comparing Examples 1 to 6 with Comparative Example 1, the tablets containing hydroxypropyl cellulose and sucrose fatty acid ester had a higher elution rate than the tablets containing neither hydroxypropyl cellulose nor sucrose fatty acid ester. It turned out to be high (Figs. 1, 2 and 4).

Furthermore, by comparison between Example 7 and Comparative Example 1, tablets containing only hydroxypropyl cellulose (without sucrose fatty acid ester) were compared with tablets containing neither hydroxypropyl cellulose nor sucrose fatty acid ester. It was found that the dissolution rate was high (Figs. 3 and 4).

In addition, the following results were obtained from an experimental example using a sample of a kneaded product. That is, by comparing Examples 8 to 11 with Comparative Example 2, the sample of the kneaded product containing either hydroxypropyl cellulose or sucrose fatty acid ester is a kneaded product containing neither hydroxypropyl cellulose nor sucrose fatty acid ester. It was found that the elution rate was higher than that of the mixed sample (FIGS. 5 and 8).

Further, by comparing Examples 10 to 11 with Comparative Examples 3 to 6, it was found that the elution rate was high when the sucrose fatty acid ester was used among the surfactants (FIGS. 6 to 8).

From the above results, by including hydroxypropyl cellulose and / or sucrose fatty acid ester in the granules or the kneaded product (mixture) together with istradefylline, the istradefylline from the granules or the kneaded product (mixture) can be obtained. It was shown that the dissolution rate was increased (dissolution was improved). In addition, it was shown that the elution rate of istradefylline from the tablet is increased (the elution property is improved) by using the tablet containing the granules.

[Prescription example 1]
Titanium oxide and hydroxypropyl cellulose were added in the manufacturing process of A grains, D-mannitol was not added in the mixed tableting step, the amount of each component was changed to the amount shown in Table 5, and (A grains A tablet is obtained by the same method as in Example 1 except that (manufacturing) is changed to the method described below.

(Manufacturing of A grain)
Istradefylin, D-mannitol, hydroxypropyl cellulose ("HPC-SSL" manufactured by Nippon Soda Co., Ltd.), low-substituted hydroxypropyl cellulose, sucrose fatty acid ester ("Surf Hope (registered trademark) manufactured by Mitsubishi Chemical Foods Co., Ltd." ) J1816 "/ sucrose stearic acid ester) and yellow iron sesquioxide are mixed with purified water to granulate. The obtained granulated product is crushed, dried, and then sized to obtain A granules. A solution prepared by dissolving titanium oxide and hydroxypropyl cellulose (“HPC-SSL” manufactured by Nippon Soda Corporation) in purified water is sprayed onto A granules for coating.

The tablets of the present invention have improved elution of isstradefylline or a pharmaceutically acceptable salt thereof, and therefore, as a novel preparation of istradefylline (for example, Parkinson's disease, senile dementia, depression, asthma). , In the treatment of osteoporosis, etc.), can be suitably used.

Claims (6)

Granules comprising istradefylline or a pharmaceutically acceptable salt thereof and hydroxypropyl cellulose and / or sucrose fatty acid ester.
Granules comprising a total of 5.0% by mass or more of hydroxypropyl cellulose and / or sucrose fatty acid ester in the granules. An oral solid preparation comprising the granules according to claim 1. The oral solid preparation according to claim 2, characterized in that it is a tablet. A method for producing an oral solid preparation containing isstradefylline or a pharmaceutically acceptable salt thereof.
At least hydroxypropyl cellulose and / or sucrose fatty acid ester is mixed with istradefylline or a pharmaceutically acceptable salt thereof, and the hydroxypropyl cellulose and / or sucrose fatty acid ester is contained in a total amount of 5.0% by mass or more. A method comprising the step of obtaining a mixture. A method of improving the elution of istradefylline or a pharmaceutically acceptable salt thereof from an oral solid preparation containing istradefylline or a pharmaceutically acceptable salt thereof.
A method comprising containing hydroxypropyl cellulose and / or sucrose fatty acid ester in the oral solid preparation. An oral solid preparation comprising istradefylline or a pharmaceutically acceptable salt thereof, hydroxypropyl cellulose, and sucrose fatty acid ester.

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